Adjuvant low-dose interferon {alpha}2a with or without dacarbazine compared with surgery alone: a prospective-randomized phase III DeCOG trial in melanoma patients with regional lymph node metastasis.

BACKGROUND: More than half of patients with melanoma that has spread to regional lymph nodes develop recurrent disease within the first 3 years after surgery. The aim of the study was to improve disease-free survival (DFS) and overall survival (OS) with interferon (IFN) alpha2a with or without dacarbazine (DTIC) compared with observation alone. PATIENTS AND METHODS: A total of 444 patients from 42 centers of the German Dermatologic Cooperative Oncology Group who had received a complete lymph node dissection for pathologically proven regional node involvement were randomized to receive either 3 MU s.c. of IFNalpha2a three times a week for 2 years (Arm A) or combined treatment with same doses of IFNalpha2a plus DTIC 850 mg/m(2) every 4-8 weeks for 2 years (Arm B) or to observation alone (Arm C). Treatment was discontinued at first sign of relapse. RESULTS: A total of 441 patients were eligible for intention-to-treat analysis. Kaplan-Meier 4-year OS rate of those who had received IFNalpha2a was 59%. For those with surgery alone, survival was 42% (A versus C, P = 0.0045). No improvement of survival was found for the combined treatment Arm B with 45% survival rate (B versus C, P = 0.76). Similarly, DFS rates showed significant benefit for Arm A, and not for Arm B. Multivariate Cox model confirmed that Arm A has an impact on OS (P = 0.005) but not Arm B (P = 0.34). CONCLUSIONS: 3 MU interferon alpha2a given s.c. three times a week for 2 years significantly improved OS and DFS in patients with melanoma that had spread to the regional lymph nodes. Interestingly, the addition of DTIC reversed the beneficial effect of adjuvant interferon alpha2a therapy.

Dose-intensified bi-weekly temozolomide in patients with asymptomatic brain metastases from malignant melanoma: a phase II DeCOG/ADO study.

BACKGROUND: Temozolomide has shown some efficacy in metastatic melanoma and recently received extended approval to treat brain tumours. The purpose of this study was to test a dose-intensified regimen of temozolomide in melanoma patients with brain metastases in a prospective, open-label, multicentre phase II trial. PATIENTS AND METHODS: Forty-five patients with asymptomatic brain metastases from melanoma were stratified into arm A (no prior chemotherapy; n = 21) and arm B (previous chemotherapy; n = 24). Patients received oral temozolomide either 150 mg/m(2)/day (arm A) or 125 mg/m(2)/day (arm B), days 1-7 and 15-21, every 28 days. The primary study end point was objective response, and secondary end points were overall survival and safety. RESULTS: Two patients (4.4%) achieved a partial response (PR) in brain metastases (one in each arm), one of them (2.2%) also showing a PR in extracerebral disease. An additional five patients (11.1%; two in arm A, three in arm B) showed disease stabilisation (SD) in brain and other sites. However, 82% revealed progressive disease (PD) already evident 8 weeks after therapy initiation. Median survival time from therapy onset was 3.5 months (range 0.7-8.3; arm B) and 4.3 months (range 1.6-11.8; arm A), P = 0.43. Dose modifications and prolongations of therapy cycles due to toxicity were required in 20% of patients. Grade 3/4 toxicity was observed in one patient only (2.2%). CONCLUSIONS: Oral administration of temozolomide given bi-weekly is well-tolerated in melanoma patients with cerebral involvement. However, the efficacy is limited, with lower than 5% objective responses observed in brain and extracerebral metastases.

[The question of surgical therapy for necrolytic migratory erythema, a cutaneous disease]. / Erythema necrolyticum migrans: Chirurgische Therapie einer Hauterkrankung?

Necrolytic migratory erythema (NME) is a rare paraneoplastic dermatologic condition. Its underlying cause is usually a pancreatic islet cell tumour with marked glucagon secretion. The glucagonoma syndrome is characterised by pancreatic neuroendocrine neoplasm, NME, and diabetes mellitus. We present a case of glucagonoma syndrome in a 58-year-old woman with a history of recurrent cutaneous manifestations who was referred for surgical resection of a pancreatic neoplasm after the NME was finally diagnosed. We discuss diagnostic methods, differential diagnosis, and therapeutic management of this disease.

The borderline syndrome in psychosomatic dermatology. Overview and case report.

The borderline syndrome is one of the most severe disturbances of psychosomatic dermatology. Patients with borderline syndrome are situated 'on the border' of psychosis, neurosis and personality disorders. The skin as a borderline organ carries a symbolic role. The clinical picture includes artefactual skin diseases due to self-mutilation by conscious or unconscious cutting, and rubbing, scratching or para-artefactual manipulations of pre-existing dermatoses. Leading symptoms of the borderline syndrome are poor impulse control, emotional instability and poor ego strength with low frustration tolerance and unstable personal relationships. We present the case of a 38-year-old female patient with borderline syndrome suffering from para-artefactual skin diseases of the face and a massive hyperhidrosis of the hands and feet. Within 9 months she was treated in four acute psychiatric hospitals and by 12 psychiatrists and psychotherapists. Early and accurate diagnosis and high-quality, sophisticated long-term therapy are necessary.

[Prevalence of psychosomatic disorders in dermatologic patients. Experiences in 2 dermatology clinics with a liaison therapy model]. / Prävalenz psychosomatischer Charakteristika in der Dermatologie Erfahrungen mit Liaisonmodellen an 2 Hautkliniken.

INTRODUCTION: The prevalences and differences of biopsychosocial disorders were investigated in the dermatologic clinics of Erfurt and Giessen, where a liaison-therapy model has been established. Different dermatological diseases were compared by a variety of psychological tests, and patients with the same diagnosis were compared between the two clinics. PATIENTS AND METHODS: We examined 406 patients for psychosomatic problems with diagnostic interviews and psychometric tests. The coping of skin disease questionnaire (CSD) and the Symptom Checklist (SCL-90R) served as diagnostic measures. Between 1995-2000, 71 patients were seen in Erfurt and 335 in Giessen. The distribution of skin diseases and the psychosomatic disorders are shown by ICD-10 diagnoses. RESULTS: The comparison of an East and a West German city showed no significant differences in the whole group or the parallel groups using the CSD and SCL-90R. There was only a tendency to a greater reduction of quality of life in Erfurt. Patients with glossodynia evaluated themselves in all psychometric tests as very "normal". By contrast, patients suffering from alopecia and acne felt very helpless and seemed to have a need of greater psychosocial care. CONCLUSIONS: The biopsychosocial characteristics of the patients treated in the dermato-psychosomatic units in Erfurt and Giessen show no significant differences. Patients with diseases such as alopecia and acne are underestimated in regard to the need for additional psychosocial care. The liaison therapy model is an effective approach to diagnose psychosomatic-dermatological disorders and decide if further psychosomatic treatment is indicated.

[Dermatological stigmata in Rubinstein-Taybi syndrome]. / Dermatologische Stigmata beim Rubinstein-Taybi-Syndrom.

The clinical features of the Rubinstein-Taybi syndrome include mental deficiency and broad thumbs and toes. Typical dermatological findings are capillary hemangioma of the forehead and hypertrichosis. Rubinstein-Taybi syndrome patients also seem to be prone to develop keloids. We present a case of a one year old girl with Rubinstein-Taybi syndrome and the typical dermatological features.

Botulinophilia: contraindication for therapy with botulinum toxin.

Botulinum toxin inhibits neuromuscular transmission and is one of the most potent toxins. It has proven to be effective in the treatment of hyperhidrosis and is being more frequently demanded for therapy. Patients with body dysmorphic disorder also seek costly treatment with botulinum toxin. This botulinophilia is a new venenophilia. Body dysmorphic disorder is defined as a preoccupation with an imagined defect in appearance. If a slight physical anomaly is present, the person's concern is markedly exessive. The patient's preoccupation causes clinically significant distress or impairment in socially, occupational, or other important areas of functioning. The sweat test according to Minor is negative. Patients with botulinophilia are among the most difficult patients managed by the dermatologist. They are demanding and time-consuming. In our clinic, 23.1% of a series of patients seeking treatment with botulinum toxin screened positive for body dysmorphic disorder. Botulinophilia is a contraindication for therapy with botulinum toxin but is an indication for psychotherapy.

Body dysmorphic disorder and life-style drugs. Overview and case report with finasteride.

The body dysmorphic disorder is the repeated preoccupation with a minimal or non-evident defect and includes a wide spectrum of imagined defects in appearance. These patients present themselves in every clinical practice and are extraordinarily difficult to treat. The focus of the preoccupation concerns head, face, chest and the genital area. Following the introduction of the new "life-style" drug, finasteride, we observed a dramatic increase in the number of patients suffering from body dysmorphic disorder attending our clinic for skin diseases in Erfurt. These patients frequently contact their doctor demanding specifically for prescription of a particular life-style drug. However, there is no indication for using life-style drugs for the treatment of a body dysmorphic disorder. The appropriate treatment includes psychotherapy and psychopharmacological treatment.

[Botulinophilia. The new life style venenophilia]. / Botulinophilie. Die neue Lifestyle-Venenophilie.

BACKGROUND AND OBJECTIVE: Botulinum toxin is effective in the treatment of hyperhidrosis and the demand for therapy is increasing. Simultaneously we have observed an increase in patients with body dysmorphic disorders who also want botulinum toxin therapy. This botulinophilie is a new variant of venenophilie. We investigated the prevalence of this new diagnosis in our patient population. PATIENTS/METHODS: In the first quarter of 2000 we studied the biopsychosocial features of 13 patients with hyperhidrosis. RESULTS: In 23.1% of our cases we were able to confirm a botulinophilie with body dysmorphic disorder and a normal Minor sweat test. CONCLUSIONS: Botulinophilie is not an indication for botulinum toxin therapy but for psychotherapy.

Dacarbazine and interferon alpha with or without interleukin 2 in metastatic melanoma: a randomized phase III multicentre trial of the Dermatologic Cooperative Oncology Group (DeCOG).

In several phase II-trials encouraging tumour responses rates in advanced metastatic melanoma (stage IV; AJCC-classification) have been reported for the application of biochemotherapy containing interleukin 2. This study was designed to compare the efficacy of therapy with dacarbazine (DTIC) and interferon alpha (IFN-alpha) only to that of therapy with DTIC and IFN-alpha with the addition of interleukin 2 (IL-2) in terms of the overall survival time and rate of objective remissions and to provide an elaborated toxicity profile for both types of therapy. 290 patients were randomized to receive either DTIC (850 mg/m(2)every 28 days) plus IFN-alpha2a/b (3 MIU/m(2), twice on day 1, once daily from days 2 to 5; 5 MIU/m(2)3 times a week from week 2 to 4) with or without IL-2 (4.5 MIU/m(2)for 3 hours i.v. on day 3; 9.0 MIU/m(2) i.v. day 3/4; 4.5 MIU/m(2) s.c. days 4 to 7). The treatment plan required at least 2 treatment cycles (8 weeks of therapy) for every patient. Of 290 randomized patients 281 were eligible for an intention-to-treat analysis. There was no difference in terms of survival time from treatment onset between the two arms (median 11.0 months each). In 273 patients treated according to protocol tumour response was assessable. The response rates did not differ between both arms (P = 0.87) with 18.0% objective responses (9.7% PR; 8.3% CR) for DTIC plus IFN-alpha as compared to 16.1% (8.8% PR; 7.3% CR) for DTIC, IFN-alpha and IL-2. Treatment cessation due to adverse reactions was significantly more common in patients receiving IL-2 (13.9%) than in patients receiving DTIC/IFN-alpha only (5.6%). In conclusion, there was neither a difference in survival time nor in tumour response rates when IL-2, applied according to the combined intravenous and subcutaneous schedule used for this study, was added to DTIC and IFN-alpha. However, toxicity was increased in melanoma patients treated with IL-2. Further phase III trials with continuous infusion and higher dosages must be performed before any final conclusions can be drawn on the potential usefulness of IL-2 in biochemotherapy of advanced melanoma.

Dermatological symptoms and sexual abuse: a review and case reports.

Dermatological symptoms in cases of sexual abuse can be very diverse. To establish a causal relationship between skin diseases and sexual abuse is particularly difficult. In dermatology, three main areas of presentation can be identified. ACUTE CONSEQUENCES: Direct injuries found on the genitalia and body. Behaviour and psychological changes seen. Sexually transmitted diseases (STD) may be identified, after an appropriate incubation period. LONG-TERM CONSEQUENCES: In the long term, even decades later, patients may manifest with a wide spectrum of psychosomatic manifestations of skin diseases, particularly factitious disorders. IMITATIONS: A group whose skin manifestations may mimic and be mistaken for sexual abuse. The initial suspicion of sexual abuse and the need for specific questioning and investigations can lead to a disturbance in the doctor-patient relationship.

[Tubero-pustular demodicosis]. / Tuberös-pustulöse Demodikose.

A 38-year-old female patient suddenly developed an unusual tuberous, pustular tumor on her chin. On the basis of clinical pattern, histological and microbiological investigations the diagnosis of demodicosis was established. Histological investigation revealed follicular cysts and a chronic granulomatous perifolliculitis with many of Demodex folliculorum. A large number of mites could be also identified by microscopy of smears from pustules. No cellular or humoral immunological defects, tumours nor systemic disorders were found. After oral therapy with steroids and metronidazole, the lesions improved rapidly.

[Keratosis follicularis spinulosa decalvans associated with patent ductus arteriosus and hypospadia in an Asiatic patient]. / Keratosis follicularis spinulosa decalvans mit persistierendem Ductus arteriosus Botalli und Hypospadie bei einem asiatischen Patienten.

Keratosis follicularis spinulosa decalvans (KFSD) appeared sporadically in an Asian boy, who also presented with naevus teleangiectaticus lateralis, patent ductus arteriosus (Botalli) and hypospadia. The association of these findings raises the question of a new syndrome. In addition, this is the first report of KFSD in a patient of Asian origin.

Adhesion molecules in atopic dermatitis: upregulation of alpha6 integrin expression in spontaneous lesional skin as well as in atopen, antigen and irritative induced patch test reactions.

Atopic dermatitis is a lymphocyte-mediated skin disease. We studied the expression of the adhesion molecule alpha6 integrin by immunohistochemistry in spontaneous atopic inflammation as well as during the eliciting phase of atopen (Dermatophagoides pteronyssinus), antigen (nickel sulfate) and irritative (anthralin) induced patch test reactions in atopic skin. Results were compared with nickel sulfate patch test reactions in normal skin. A role of the alpha6 integrin, expressed at the luminal side of blood vessels, for T cell migration in lesional atopic skin was supposed. In normal human skin the alpha6 integrin was weakly expressed by blood vessels and by basal epithelial cells of the epidermis. In acute and chronic lesional skin of patients with atopic dermatitis dramatic upregulation of alpha6 integrin expression was observed on endothelial cells and in the epidermis. The similar pattern of upregulated suprabasal alpha6 integrin expression was established in the patch test reactions 48 h after atopen and antigen application or irritation of the skin without differences in dependence on the eliciting substance. No difference of alpha6 integrin expression was seen between atopic and normal skin. Tumor necrosis factor alpha, interleukin-1, interleukin-4 and interferon gamma play a role in atopic inflammation. Tumor growth factor beta and interleukin-6 are mitogenic/growth factors for keratinocytes. For this reason the effect of these cytokines and of phorbol-12-myristate-13-acetate on the expression level of alpha6 integrin was tested in short-term skin organ culture of normal and atopic skin as well as in keratinocyte cultures. In these assays no cytokines had an effect on alpha6 integrin expression suggesting another mechanism which regulates this integrin. However, the increased expression of alpha6 integrin in the suprabasal epidermis is associated with a T cell influx into the epidermis. We speculate that the alpha6 integrin expression may lead to an epidermotropism of T cells during inflammation.

The sweat of patients with atopic dermatitis contains specific IgE antibodies to inhalant allergens.

We have investigated levels of total and specific IgE against inhalant allergens in the sweat of 15 patients with atopic dermatitis, 10 patients with allergic rhinitis and high levels of specific IgE in the serum, and five patients with psoriasis without atopy as controls, by means of various commercial methods such as fluorescence immunoassay, nephelometry, chemiluminescence assay, enzyme immunoassay and the radioallergosorbent test. Total IgE and specific IgE antibodies were detectable in the sweat of patients with atopic dermatitis as well as of patients with allergic rhinitis alone. These levels of total IgE in the sweat correlated with the severity of the skin disease (P < 0.05). By means of the Ciba Corning assay (P < 0.001), the fluorescence immunoassay (P < 0.05) and the nephelometry assay (P < 0.05), positive correlations were then established between the levels of total IgE in the serum and the sweat. Moreover, specific IgE antibodies to birch pollen and Dermatophagoides pteronyssinus were detectable in the sweat and correlated positively with these specific IgE levels in the serum (P < 0.05). Further, the specific IgE levels against these allergens in the sweat also correlated with the severity of dermatitis (P < 0.05). It is suggested that these specific IgE antibodies against certain inhalant allergens in the sweat of patients with atopic dermatitis may play a role in allergen trapping in the skin.

Autosomal recessive cutis laxa syndrome. A case report.

Congenital cutis laxa (CCL) is a rare, genetically heterogeneous connective tissue disorder, manifested by loose, hanging skin, giving the appearance of premature aging. We report a 6-year-old female child with autosomal recessive CCL type III, to assess possible correlations between clinical, ultrastructural, cellular and biochemical features. Morphological aberrations of the elastic and collagen tissue, increased collagen I mRNA expression associated with increased protein synthesis and increased collagenase gene expression of the cutis laxa fibroblasts could be established. Our results suggest that CCL is not only a disease of the elastic fibers of the connective tissue but also of the collagen fibers, with a central role of the fibroblast.

[Hailey-Hailey disease. Early detection of heterozygotes by an ultraviolet provocation tests--clinical relevance of the method]. / Morbus Hailey-Hailey. Früherfassung von Merkmalsträgern durch einen UV-Provokationstest--klinische Relevanz der Methode.

An UV provocative test to identify genotypical carriers of Hailey-Hailey disease was developed, and performed on 30 non-affected family members of 8 families. The test revealed that 10 individuals were genotypical carriers without clinical signs. We checked the reliability of the UV provocative test during a 3-year follow-up period (family register method). In 50% of the carriers identified by the UV provocative test the first clinical manifestations of Hailey-Hailey disease developed in this period. All individuals with negative UV provocative test results remained clinically healthy. Up to now our results with the UV provocative test have been verified by the clinical development in 80% of cases. The UV provocative test is a practicable and reliable method of determining genotypical carriers of Hailey-Hailey disease.

[Histology of UV-induced epidermis reactions. 1. A contribution to the differentiation of sunburn cells]. / Zur Histologie UV-induzierter Epidermisreaktionen. 1. Mitteilung: Ein Beitrag zur Differenzierung von sunburn-Zellen.

The UV-induced reaction of the epidermis is marked be extra- and intracellular edema and intraepidermal vesicles. Characteristical is the appearance of sunburn cells. In semithin section they can be differentiated in two cell types: "fried egg cells" prevail as early type in the exsudative phase (type I), "dark cells" as late type in the degenerative phase (type II) of the UV-reaction.

[Genetics of Hailey-Hailey familial chronic benign pemphigus]. / Zur Genetik des Pemphigus benignus chronicus familiaris Hailey-Hailey.

Starting from 12 index patients with familial benign chronic pemphigus from 11 kindreds, systematic kindred examinations were carried out with 182 relatives. 11 pedigrees were established. In this process 6 patients out of 3 kindreds were identified additionally. 10 genotypic carriers of the disease were found of 30 examined relatives by a newly developed UV-provocation test. An autosomal-dominant hereditary pattern was proven for sure and with high probability, respectively, in 10 out of 11 kindreds by formal genetic genealogy-examinations. There was an incomplete penetrance in 3 kindreds. A sex-determined heredity of disease can be excluded. There was no association between familial benign chronic pemphigus and HLA-A, B, C-system.