iDermatoPath - a novel software tool for mitosis detection in H&E-stained tissue sections of malignant melanoma.

BACKGROUND: Malignant Melanoma (MM) is characterized by a growing incidence and a high malignant potential. Besides well-defined prognostic factors such as tumour thickness and ulceration, the Mitotic Rate (MR) was included in the AJCC recommendations for diagnosis and treatment of MM. In daily routine, the identification of a single mitosis can be difficult on haematoxylin and eosin slides alone. Several studies showed a big inter- and intra-individual variability in detecting the MR in MM even by very experienced investigators, thus raising the question for a computer-assisted method. OBJECTIVE: The objective was to develop a software system for mitosis detection in MM on H&E slides based on machine learning for diagnostic support. METHODS: We developed a computer-aided staging support system based on image analysis and machine learning on the basis of 59 MM specimens. Our approach automatically detects tumour regions, identifies mitotic nuclei and classifies them with respect to their diagnostic relevance. A convenient user interface enables the investigator to browse through the proposed mitoses for fast and efficient diagnosing. RESULTS: A quantitative evaluation on manually labelled ground truth data revealed that the tumour region detection yields a medium spatial overlap index (dice coefficient) of 0.72. For the mitosis detection, we obtained high accuracies of above 83%. CONCLUSION: On the technical side, the developed iDermatoPath software tool provides a novel approach for mitosis detection in MM, which can be further improved using more training data such as dermatopathologist annotations. On the practical side, a first evaluation of the clinical utility was positive, albeit this approach provides most benefit for difficult cases in a research setting. Assuming all slides to be digitally processed and reported in the near future, this method could become a helpful additional tool for the pathologist.

Efficacy and safety of oral alitretinoin in severe oral lichen planus--results of a prospective pilot study.

BACKGROUND: Patients with severe oral lichen planus refractory to standard topical treatment currently have limited options of therapy suitable for long-term use. Oral alitretinoin (9-cis retinoic acid) was never systematically investigated in clinical trials, although case reports suggest its possible efficacy. OBJECTIVES: To assess the efficacy and safety of oral alitretinoin taken at 30 mg once daily for up to 24 weeks in the treatment of severe oral lichen planus refractory to standard topical therapy. METHODS: We conducted a prospective open-label single arm pilot study to test the efficacy and safety of 30 mg oral alitretinoin once daily for up to 24 weeks in severe oral lichen planus. Ten patients were included in the study. Primary end point was reduction in signs and symptoms measured by the Escudier severity score. Secondary parameters included pain and quality of life scores. Safety parameters were assessed during a follow-up period of 5 weeks. RESULTS: A substantial response at the end of treatment, i.e. >50% reduction in disease severity measured by the Escudier severity score, was apparent in 40% of patients. Therapy was well tolerated. Adverse events were mild and included headache, mucocutaneous dryness, musculoskeletal pain, increased thyroid-stimulating hormone and dyslipidaemia. CONCLUSIONS: Alitretinoin given at 30 mg daily reduced disease severity of severe oral lichen planus in a substantial proportion of patients refractory to standard treatment, was well tolerated and may thus represent one therapeutic option for this special group of patients.

Transferring innovative freehand SPECT to the operating room: first experiences with sentinel lymph node biopsy in malignant melanoma.

PURPOSE: The purpose of this study was to report on the first experiences with freehand single-photon emission-computed tomography (freehand SPECT) in sentinel lymph node biopsy (SLNB) in patients with malignant melanoma. Freehand SPECT is a novel imaging modality combining gamma probes, surgical navigation systems, and emission tomography algorithms, designed to overcome some of the limitations of conventional gamma probes. METHODS: In this study 20 patients with malignant melanoma underwent conventional planar scintigraphy prior to surgery. In the operating room, the number and location of separable SLNs were detected first by a pre-incisional scan with freehand SPECT to render a 3D-image of the target site and afterwards by a scan with a conventional gamma probe. After SLNB another scan was performed to document the removal of all targeted SLNs. RESULTS: Planar scintigraphy identified 40 SLNs in 26 nodal basins. Pre-incisional freehand SPECT mapped 38 of these nodes as well as one additional node in one patient (95.0% node based sensitivity). The results of freehand SPECT were identical to those of planar scintigraphy in 25 basins, while it missed one basin (96.2% basin based sensitivity). In comparison, the gamma probe failed to detect 7 nodes in 4 basins (82.5% node based sensitivity and 84.6% basin based sensitivity). After resection freehand SPECT detected 9 remaining radioactive spots, two of whichwere resected as they matched the position of SLNs detected on preoperative planar scintigraphy. CONCLUSIONS: Freehand SPECT provides a real-time, intraoperative 3D-image of the radioactive labelled SLNs, facilitating their detection and resection.

First Experiences with Navigated Radio-Guided Surgery Using Freehand SPECT.

BACKGROUND: Sentinel lymph node biopsy (SLNB) in melanoma using one-dimensional gamma probes is a standard of care worldwide. Reports on the performance are claimed by most groups to successfully detect the SLNs during the surgical procedure in almost 100% of the patients. In clinical practice, however, several issues remain which are usually not addressed: the difficulty of intraoperative detection of deeply located nodes, SLN detection in obese patients or in the groin and the impossibility to make a scan of the entire wound after SLN resection to avoid false negative testing for eventually remaining SLNs. MATERIALS AND METHODS: The concept behind freehand SPECT is to combine a gamma probe as used for conventional radio-guided surgery with a tracking system as used in neurosurgical navigation. From this combination and a proper algorithm framework the 3D reconstruction of radioactivity distributions and displaying these intraoperatively is possible. CONCLUSION: In summary, the feasibility of freehand SPECT could be shown and provides an image-guided SLNB and a truly minimally invasive and optimized surgical procedure.

In melanoma, beta-catenin is a suppressor of invasion.

Cell-type-specific signalling determines cell fate under physiological conditions, but it is increasingly apparent that also in cancer development the impact of any given oncogenic pathway on the individual cancer pathology is dependent on cell-lineage-specific molecular traits. For instance in colon and liver cancer canonical Wnt signalling produces increased cytoplasmic and nuclear localised beta-catenin, which correlates with invasion and poor prognosis. In contrast, in melanoma increased cytoplasmic and nuclear beta-catenin is currently emerging as a marker for good prognosis, and thus seems to have a different function compared with other cancer types; however, this function is unknown. We discovered that in contrast to its function in other cancers, in melanoma, beta-catenin blocks invasion. We demonstrate that this opposing role of nuclear beta-catenin in melanoma is mediated through MITF, a melanoma-specific protein that defines the lineage background of this cancer type. Downstream of beta-catenin MITF not only suppresses the Rho-GTPase-regulated cell morphology of invading melanoma cells, but also interferes with beta-catenin-induced expression of the essential collagenase MT1-MMP, thus affecting all aspects of an invasive phenotype. Importantly, overexpression of MITF in invasive colon cancer cells modifies beta-catenin-directed signalling and induces a 'melanoma phenotype'. In summary, the cell-type-specific presence of MITF in melanoma affects beta-catenin's pro-invasive properties otherwise active in colon or liver cancer. Thus our study reveals the general importance of considering cell-type-specific signalling for the accurate interpretation of tumour markers and ultimately for the design of rational therapies.

Effects of topical treatment with the raft modulator miltefosine and clobetasol in cutaneous mastocytosis: a randomized, double-blind, placebo-controlled trial.

Background Mastocytosis is characterized by the accumulation and activation of mast cells in different organs, most commonly the skin. Miltefosine, a raft modulator, has recently been shown to inhibit the activation of mast cells and to reduce mast cell-driven skin inflammatory responses. Objectives To study the safety and efficacy of topical miltefosine treatment of skin lesions in patients with mastocytosis. Methods Thirty-nine adult patients with mastocytosis with skin involvement were treated in a double-blind, placebo-controlled, parallel trial with topical miltefosine and clobetasol for 2 weeks. Treatment areas were analysed for changes in skin lesions and symptoms following mechanical irritation using novel volumetric imaging techniques and quantitative histomorphometry. Results Miltefosine and clobetasol failed to reduce significantly weals and flare-type skin responses following mechanical provocation. Miltefosine showed a trend towards reducing the volume of weals. Clobetasol significantly decreased the volume of weals and the number of mast cells in the upper dermis. Treatment with miltefosine, but not with clobetasol, was often associated with eczematous skin irritation, which may, at least in part, be related to the formulation of miltefosine containing the potentially irritating alkanol propanediol as the vehicle. Conclusions Raft modulators such as miltefosine are promising candidates for novel therapeutic strategies in patients with cutaneous mastocytosis. Future studies should be performed with improved formulations using nonirritant vehicles.

Looking Ahead in Dermatology: Skin and Allergy / Mirando Hacia el Futuro e Dermatología: Piel y Alergia

The prevalence of allergic diseases has increased tremendously over the last decades. Clinically they comprise a spectrum of many different conditions caused by specific immunological hypersensitivity in response to a mostly a pathogenic substance. Environmental factors such as lack of immune-stimulating contacts (infection, vaccination) and exposure to allergy-enhancing anthropogenic pollutants from tobacco smoke or traffic exhaust particles are suspected to be involved in the increase of allergies. Recently it has been shown that pollens are not only allergen carriers but also secrete highly active proinflammatory lipid mediators, pollen-associated lipid mediators(PALMs), which have proinflammatory and immuno-modulatory capacity that facilitates allergic sensitization of the skin and mucous membranes. The skin is one of the most important organs where allergic reactions manifest. Many different morphological and physiopathological entities can be observed in the skin that represent all kinds of pathogenetic immune reactions from immediate-type allergy, urticaria, angioedema, anaphylaxis, cytotoxic and immune complex reactions such asthrombocytopenic purpura or allergic leukocytoclastic vasculitis, exanthematous drug eruptions, granulomatous skin reactions to tattoos or fillers as well as a wide spectrum of dermatitis and eczema with allergic contact dermatitis being one of the most common occupational diseases in many countries. Recent progress in pathophysiology has revealed a role of epidermal barrier function as well as immunodeviation in atopic eczema giving rise to new diagnostic and therapeutic strategies. The interdisciplinary character of allergy implies a close cooperation between different disciplines where dermatology plays a major role in the management of allergic diseases, covering diagnostic, therapeutic and preventive aspects (AU)

La prevalencia de las enfermedades alérgicas ha aumentado tremendamente en las últimas décadas. Clínicamente abarcan un espectro de diferentes entidades que están causadas por una hipersensibilidad inmunológica específica como respuesta a una sustancia, en general, no patógena. Se sospecha que el aumento de las alergias se debe a factores ambientales como la falta de contactos que estimulen el sistema inmunitario (infección, vacunas) y la exposición a contaminantes antropogénicos que intensifican las alergias como el humo del tabaco o las partículas de combustión. Recientemente se ha demostrado que los pólenes no son solo portadores de alérgenos, sino que también segregan mediadores lipídicos altamente proinflamatorios, mediadores lipídicos asociados al pólen (siglas en inglés PALM), que facilitan la sensibilización alérgica de la piel y las membrabas mucosas por su capacidad proinflamatoriae inmunomoduladora. La piel es uno de los órganos más importantes donde se manifiestan las reacciones alérgicas. En la piel se pueden observar diferentes entidades morfológicas y fisiopatológicas que representan todos los tipos de reacciones inmunitarias patogénicas desde alergia inmediata, urticaria, angioedema, anafilaxia, reacciones citotóxicas y mediadas por inmunocomplejos como la púrpura trombocitopénica o la vasculitis leucocitoclástica, toxicodermias exantemáticas, reacciones cutáneas granulomatosas por tatuajes o rellenos así como un amplio espectro de dermatitis y eccema, siendo la dermatitis alérgica de contacto una de las enfermedades profesionales más frecuentes en muchos países. Los recientes avances en la fisiopatología han revelado un rol de la función de la barrera epidérmica así como una desviación inmunitaria en el eccema atópico, lo que da lugar a nuevas estrategias diagnósticas y terapéuticas. El carácter interdisciplinar de la alergia implica una estrecha colaboración entre diferentes disciplinas donde la dermatología tiene un papel principal tanto en el diagnóstico, el tratamiento como en la prevención de las enfermedades alérgicas (AU)

Allergenicity of wine containing processing aids: a double-blind, placebo-controlled food challenge.

BACKGROUND: The European Union requires allergenic food ingredients to appear on labels in order to protect allergic consumers. OBJECTIVE: To determine whether traces of egg-, milk-, and fish-derived processing aids used in winemaking might elicit clinical reactions in food-allergic patients. METHODS: Five German wines were fined with a high dose of egg albumin, lysozyme, milk casein, fish gelatin, or isinglass, and filtered. Fourteen adults with allergy to egg (n = 5), milk (n = 5), or fish (n = 4) were included. Skin prick tests were performed with fining agents, and fined and unfined wines. All patients underwent double-blind placebo-controlled food challenges with fined and unfined wines. RESULTS: Skin prick tests were positive to hen's egg (n = 5), ovalbumin (n = 5), lysozyme (n = 4), cow's milk (n = 5), casein (n = 4), and cod (n = 3), but not to isinglass or fish gelatin (n = 0). Positive skin prick test results were observed for wines fined with albumin (n = 3), lysozyme (n = 2), casein (n = 1), gelatin (n = 0), and isinglass (n = 3), and for unfined wines (n = 1-2 in each patient group), with no significant differences between groups. Seventy-five percent of skin test-positive patients had specific immunoglobulin E to other allergens present in wine (eg, carbohydrates). The provocation test revealed no reactions to fined or unfined wines. CONCLUSIONS: Although concentrated fining agents containing ovalbumin, lysozyme, and casein were allergenic in the skin prick test, no patient reacted adversely in the provocation test to fined wine. Wines treated with fining agents at commercial concentrations appear not to present a risk to allergic individuals when filtered,

Looking ahead in dermatology: skin and allergy.

The prevalence of allergic diseases has increased tremendously over the last decades. Clinically they comprise a spectrum of many different conditions caused by specific immunological hypersensitivity in response to a mostly apathogenic substance. Environmental factors such as lack of immune-stimulating contacts (infection, vaccination) and exposure to allergy-enhancing anthropogenic pollutants from tobacco smoke or traffic exhaust particles are suspected to be involved in the increase of allergies. Recently it has been shown that pollens are not only allergen carriers but also secrete highly active proinflammatory lipid mediators, pollen-associated lipid mediators (PALMs), which have proinflammatory and immuno-modulatory capacity that facilitates allergic sensitization of the skin and mucous membranes. The skin is one of the most important organs where allergic reactions manifest. Many different morphological and physiopathological entities can be observed in the skin that represent all kinds of pathogenetic immune reactions from immediate-type allergy, urticaria, angioedema, anaphylaxis, cytotoxic and immune complex reactions such as thrombocytopenic purpura or allergic leukocytoclastic vasculitis, exanthematous drug eruptions, granulomatous skin reactions to tattoos or fillers as well as a wide spectrum of dermatitis and eczema with allergic contact dermatitis being one of the most common occupational diseases in many countries. Recent progress in pathophysiology has revealed a role of epidermal barrier function as well as immunodeviation in atopic eczema giving rise to new diagnostic and therapeutic strategies. The interdisciplinary character of allergy implies a close cooperation between different disciplines where dermatology plays a major role in the management of allergic diseases, covering diagnostic, therapeutic and preventive aspects.

[Reticular erythematous plaques]. / Netzförmig angeordnete erythematöse Plaques.

Reticular erythematous mucinosis (REM) syndrome primarily affects young women; the skin lesions usually appear on the chest and upper back. REM is diagnosed on the basis of the clinical picture and histological findings. REM syndrome is often associated with lupus erythematosus tumidus. Both diseases respond well to treatment with chloroquin. Topical tacrolimus and the use of a pulsed dye laser have fewer side effects and have also proved to be effective.