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BACKGROUND: Basal cell carcinomas are the most common periocular malignant tumor. In advanced periocular basal cell carcinoma, vismodegib is a new treatment option which might potentially avoid surgical eye removal. CASE REPORT: We treated a 76-year-old patient unwilling to consent to surgery with vismodegib for advanced periocular basal cell carcinoma on the left forehead that had already undergone several previous treatments. After initial partial remission, the tumor regrew under ongoing therapy, so that radical surgical excision including orbital exenteration was performed. Unfortunately, the patient died thereafter due to septic multi-organ failure. CONCLUSION: Basal cell carcinoma and its new treatment options are gaining importance for ophthalmology due to rising incidence and prevalence rates. Vismodegib is a new encouraging option. However, for advanced tumors, it must be resolved whether complete histological remission may be achieved to avoid surgical intervention, or whether the area of resection can be significantly reduced. Current multicenter studies investigate these aspects further (ClinicalTrails.gov identifier: NCT03035188).

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Cutaneous dipththeria is an infectious bacterial disease endemic in tropical regions, but rarely diagnosed in Germany. Following travel in Sri Lanka, a 60-year-old German presented to our dermatological clinic with a skin ulcer and extensive erythematous erosive edema of his left foot. Corynebacterium diphtheriae was isolated from a swab of the lesion. There were no clinical signs of toxic diphtheria. The patient was treated with penicillin G and erythromycin, followed by a slow healing of the lesion. The isolated strain could be identified as toxigenic C. diphtheriae mitis. Due to increased travel activity, dermatologists should have uncommon infections like cutaneous diphtheria in mind.

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BACKGROUND: Asthma is a disease affecting many locations throughout the airway. Most studies have used spirometry as the primary assessment of airway obstruction, a method that may be less sensitive in regard to peripheral airway obstruction. The aim of this study was to elucidate the associations between asthma phenotypes based on age of onset and duration of symptoms, and (i) spirometry and (ii) small airway involvement measured by impulse oscillometry (IOS) in adolescence. METHODS: Children and adolescents taking part in BAMSE, a prospective birth cohort study, performed spirometry at 8 and 16 years and IOS at 16 years of age. Based on data collected in questionnaires, children were categorized into the following groups: 'never asthma', 'early transient asthma', 'early persistent asthma', and 'late onset asthma'. RESULTS: Compared with the never asthma group, all asthma groups were associated with lower FEV1 at 16 years of age (early transient-119 ml, 95% confidence interval -204 to -34; early persistent-410 ml, 95%CI -533; -287; and late onset-148 ml, 95%CI -237; -58). Between 8 and 16 years, significantly less increase in FEV1 was observed in the early persistent and late onset groups. The small airway index 'R5-20 ' was significantly associated with active asthma at 16 years, but not transient asthma. CONCLUSIONS: All asthma phenotypes studied were negatively associated with FEV1 in adolescence. IOS measurements indicated that active asthma could be associated with small airway impairments. These results provide new insights into the physiology underlying wheezing phenotypes based on age of onset and duration of disease.

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Malignant melanoma is a highly aggressive although immunogenic tumor which can be recognized and destroyed by the immune system. Therefore, immunotherapy has been represented an essential part of the therapeutic arsenal for decades. Besides non-specific immunotherapeutic approaches (whole tumor cell vaccine, cytokine therapy, toll-like receptor agonists), targeted immunotherapy has been made possible by the identification of tumor-associated antigens. Despite undisputable successes, the ultimate breakthrough has not yet been achieved. This overview deals with the fundamental aspects of antigen-specific immunotherapy and highlights future strategies to improve its clinical efficacy.

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BACKGROUND: The aim of the study was the characterization of patients with metastatic cutaneous squamous cell carcinoma involving the parotid gland. PATIENTS AND METHODS: The clinical, radiological and pathological tumor data of 16 patients with parotid metastasis of a previously treated squamous cell carcinoma of the skin were analyzed retrospectively. RESULTS: Patients over 70 years of age with a primary skin cancer of at least 1.5 centimeter in diameter were defined as the high risk group for development of regional metastasis involving the parotid gland. The time interval between therapy of the skin cancer and detection of the metastatic involvement of the parotid gland was 9.8 (2-24) months on average. The average maximal diameter of the parotid metastasis was 3.2 (1.5-4.9) centimeter at diagnosis. Metastatic infiltration of cervical lymph nodes could be shown in 9 patients and in 2 patients pulmonary metastases were detected. The average survival after parotid metastasis was 11.7 (3-31) months. CONCLUSION: The early diagnosis and therapy of locoregional metastasis from cutaneous squamous cell carcinoma of the scalp have a high prognostic value. High-risk patients with cutaneous squamous cell carcinoma should be followed up sonographically in narrow intervals for detection of parotid and cervical lymph node metastasis.

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In Germany, 6100 women and 5300 men contract a malignant melanoma of the skin every year. The chances of being cured are good in the early stages of the disease, but the average survival following distant metastasis is only 6 to 9 months. Therefore, early diagnosis is crucial, particularly as the skin is, by nature, a readily accessible organ. The introduction of epiluminescence microscopy has increased diagnostic accuracy significantly. In cases of doubt, complete excision of the suspect pigmented lesion is always advisable. A light skin type, presence of numerous naevi, genetic predisposition (familial history) and increased UV exposure are considered as risk factors. As a rule, adjuvant imunotherapy with interferon-alphais recommended in high-risk patients. A multidisciplinary approach consisting of surgery, radiotherapy, chemotherapy and immunotherapy has proved beneficial in advanced stages of metastasis.

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Dendritic cell (DC)-based vaccinations represent a promising approach for the immunotherapy of cancer and infectious diseases as DCs play an essential role in initiating cellular immune responses. A number of clinical trials using ex vivo-generated DCs have been performed so far and only minor toxicity has been reported. Both the induction of antigen-specific T cells and clinical responses have been observed in vaccinated cancer patients. Nevertheless, DC-based immunotherapy is still in its infancy and there are many issues to be addressed such as antigen loading procedures, DC source and maturational state, migration properties, route, frequency, and dosage of DC vaccination. The increasing knowledge of DC biology should be used to improve the efficacy of this new therapy.

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Antigens encoded by MAGE genes are of particular interest for cancer immunotherapy because of their tumoral specificity and because they are shared by many tumors. Antigenic peptide MEVDPIGHLY, which is encoded by MAGE-3 and is known to be presented by human leukocyte antigen (HLA)-B44, is currently being used in therapeutic vaccination trials. We report here that a cytolytic T lymphocyte (CTL) clone, which is restricted by HLA-B*1801, recognizes the same peptide and, importantly, lyzes HLA-B18 tumor cells expressing MAGE-3. These results imply that the use of peptide MEVDPIGHLY can now be extended to HLA-B18 patients. We also provide evidence that, under limiting amounts of protein MAGE-3, HLA B*1801 and B*4403 compete for binding to the peptide.

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Antigens encoded by MAGE genes and recognized by T cells are of interest for cancer immunotherapy because of their strict tumoral specificity and because they are shared by many tumors. Several MAGE-1 peptide that are recognized by CD8(+) cytolytic T lymphocytes have been used in therapeutic vaccination trials. To obtain anti-tumor immune response, vaccines combining peptides recognized by CD8(+) and peptides recognized by CD4(+) T cells might be optimal. We focused therefore on the identification of MAGE peptides recognized by CD4(+) T cells. We report here the identification of MAGE-1 epitope EYVIKVSARVRF, which is presented to CD4(+) T lymphocytes by HLA-DR15. This HLA allele is present in 29 % of Asians and 17 % of Caucasians.

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Antigens encoded by MAGE genes are of particular interest for cancer immunotherapy because of their strict tumoral specificity and because they are shared by many tumors. Antigenic peptide EVDPIGHLY encoded by MAGE-3 and known to be presented by HLA-A*0101 is currently being used in therapeutic vaccination trials. We report here that a cytolytic T-lymphocyte (CTL) clone, which is restricted by HLA-B*3501, recognizes the same peptide and, importantly, lyses HLA-B*3501 tumor cells expressing MAGE-3. These results infer that the current clinical use of peptide EVDPIGHLY can now be extended to HLA-B*3501 patients.

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Antigens encoded by MAGE-A3 and recognized by T cells are interesting targets for tumor immunotherapy because they are strictly tumor specific and shared by many tumors of various histological types. A number of MAGE-A3 antigenic peptides presented by HLA class I molecules have been used in clinical trials, and regressions of melanoma metastasis have been observed. We report here the identification of a MAGE-A3 epitope, TQHFVQENYLEY, presented to CD4+ T lymphocytes by HLA-DP4 molecules, which are expressed in approximately 76% of Caucasians. This new epitope may be useful both for therapeutic vaccination and for the evaluation of the immune response in cancer patients. Interest ingly, the CD4+ T cells lysed HLA-DP4 tumor cells expressing MAGE-A3, indicating that this epitope, in contrast to other class-II MAGE-A3 epitopes, is presented at the surface of tumor cells. The study of this disparity in the presentation of two epitopes from the same protein may lead to a better understanding of the endogenous class II presentation pathway.

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A 23-year-old patient suffered from episodic angioedema of the face and neck, accompanied by diarrhea and abdominal pain. Additionally, the patient had bronchial asthma, recurrent nasal polyps and allergic rhinoconjunctivitis. Blood examination revealed leucocytosis with eosinophilia. Histological studies showed eosinophilic infiltrates in the skin and the gastrointestinal mucosa. Allergic food reactions and parasites were ruled out. With systemic corticosteroid treatment, the clinical symptoms and the eosinophilia disappeared. This case shows some parallels to previously described syndromes (eosinophilic gastroenteritis, Samter's syndrome, episodic angioedema with eosinophilia), but to the best of our knowledge this combination of symptoms has not yet been reported.

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To assess the clinical and prognostic relevance of serum S-100 beta in malignant melanoma serum levels of S-100 beta protein were measured in 84 patients with malignant melanoma. Using a cut-off value of 0.3 microgram/L the sensitivity was 0% (none of 36) in patients with stage II, 31% (four of 13) in patients with stage III and 69% (24 of 35) in patients with stage IV. In the reference group serum S-100 beta was below 0.3 microgram/L in all cases (specificity = 100%). A significant correlation existed between serum S-100 beta values and clinical staging as well as survival. In patients with distant metastases the serum concentration of S-100 beta protein correlated well with the number of affected organs. Serial measurement in these patients revealed that tumour progression was accompanied by rising S-100 beta values whereas declining values could only be revealed in one patient with a dramatic clinical response to therapy. Our results suggest that serum S-100 beta determination is a useful marker for the evaluation of prognosis in patients with metastatic malignant melanoma and should be included in the clinical staging.

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Fournier's gangrene represents an acute severe necrotizing inflammatory process affecting the scrotum and penis. It has an associated mortality of 30-50%. In most cases, aetiological factors can be identified, such as diabetes mellitus, chronic alcoholism and perianal, perirectal or periurethral infection. The disease is characterized by a polybacterial infection, and the classic treatment includes surgical removal of the necrotic tissue and the use of broad-spectrum antibiotics. We report a case of Fournier's gangrene, histologically characterized by a necrotizing vasculitis, in which surgical resection of the necrotic tissue and antibiotic treatment failed to halt progression of the disease, whereas complete remission was achieved by high-dose corticosteroid therapy. This suggests that Fournier's gangrene is related to some form of localized vasculitis, and represents a local Shwartzman phenomenon.

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To obtain information about useful combinations of various cytokines in melanoma therapy, we studied the influence of interleukin-2 (IL-2) in combination with interferon-alpha (IFN-alpha), IFN-gamma and tumour necrosis factor-alpha (TNF-alpha) on the lytic activity of IL-2-stimulated cells in vitro. Peripheral mononuclear cells (PMC) were incubated for 4 days with various combinations of cytokines and used as effector cells. Two different melanoma cell lines (M19 and M26) were used as target cells. The lytic activity of stimulated PMC was determined using a modified hexosaminidase assay. IL-2 was mainly responsible for the lytic activity of the effector cells in a dose-dependent manner. IFN-alpha, IFN-gamma and TNF-alpha did not enhance lytic activity with an optimal IL-2 dose (50 IU/ml IL-2). Using a suboptimal IL-2 dose (5 IU/ml), they increased cytotoxicity. The specific lysis of M19 cells was significantly increased by pretreatment of the cells with 5 IU/ml IFN-alpha together with 50 IU/ml TNF-alpha (t-test, P < or = 0.001), while the specific lysis of M26 cells was increased by pretreatment with 5 IU/ml IFN-gamma. We conclude that the lysis of melanoma cells by cytotoxic cells in vitro can be enhanced by various cytokines. The optimal cytokine combination differed for the two melanoma cell lines tested.

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