European Guidelines (S1) on the use of high-dose intravenous immunoglobulin in dermatology.

BACKGROUND: The treatment of severe dermatological autoimmune diseases and toxic epidermal necrolysis (TEN) with high-dose intravenous immunoglobulin (IVIg) is a well-established procedure in dermatology. As treatment with IVIg is usually considered for rare clinical entities or severe clinical cases, the use of immunoglobulin is not generally based on data from randomized controlled trials that are usually required for the practice of evidence-based medicine. Owing to the rarity of the indications for the use of IVIg, it is also unlikely that such studies will be available in the foreseeable future. Because the high costs of IVIg treatment also limit its first-line use, the first clinical guidelines on its use in dermatological conditions were established in 2008 and renewed in 2011. MATERIALS AND METHODS: The European guidelines presented here were prepared by a panel of experts nominated by the EDF and the EADV. The guidelines were developed to update the indications for treatment currently considered as effective and to summarize the evidence base for the use of IVIg in dermatological autoimmune diseases and TEN. RESULTS AND CONCLUSION: The current guidelines represent consensual expert opinions and definitions on the use of IVIg reflecting current published evidence and are intended to serve as a decision-making tool for the use of IVIg in dermatological diseases.

Systemic corticosteroids for subcutaneous panniculitis-like T-cell lymphoma.

BACKGROUND: Primary cutaneous γ/δ T-cell lymphoma (PCGD-TCL) is aggressive and has a poor prognosis. In contrast, subcutaneous panniculitis-like T-cell lymphoma (SPTCL) of the α/ß T-cell receptor phenotype is known to follow an indolent course and have a more favourable prognosis. In the past, PCGD-TCL and SPTCL were often considered to be a manifestation of the same disease, and aggressive systemic polychemotherapy has commonly been the first-line therapy for both. Given the understanding that SPTCL is a separate and less aggressive entity, clinical data exclusively evaluating the efficacy of conservative treatment in SPTCL are needed. OBJECTIVES: To assess the overall clinical response to systemic corticosteroids in the treatment of SPTCL. METHODS: This was a retrospective cross-sectional study based on a patient data repository from two tertiary care university hospitals in Zürich (Switzerland) and Tübingen (Germany). The repository spanned 13 years. RESULTS: In four of the five patients (80%) with SPTCL, treatment with systemic corticosteroids induced a complete remission. CONCLUSIONS: Systemic corticosteroids may be an excellent first-line single-agent therapy for SPTCL.

Quality of life in men with involuntary childlessness: long-term follow-up.

We conducted a longitudinal cohort study on the quality of life of infertile male patients measured at baseline and after 5 years with a specific quality of life instrument for male patients who are involuntarily childless. It was distributed to patients who were seen at the andrology and gynaecology clinics for infertility diagnoses and treatment. At baseline (T1), 275 patients took part in the study. A subset of these patients (N = 133) had released two semen samples, and the results of the semen analysis had been communicated to them before they received the questionnaire. Semen quality of this subset was assessed according to WHO recommendations. After 5 years (T2), the questionnaires were mailed again and were sent back by N = 101 patients. No significant quality of life difference was found between the semen quality groups. After 5 years, an improvement was found for the dimensions 'desire for a child' [mean score 1.92 (T1) versus 1.72 (T2)] and 'gender identity' [mean score 1.56 (T1) versus 1.42 (T2)] while no change was found for 'partnership' and 'psychological well-being'. We did not find significant differences between patients who had fathered a child in the meantime and patients who did not become fathers.

[Behçet's disease]. / Morbus Behçet.

Behçet's disease is a systemic disorder with the histopathological correlate of leukocytoclastic vasculitis. Pathogenetically, besides a strong genetic component participation of the innate immune system and an autoinflammatory component are discussed. The disease is most common in countries along the former silk route but in Germany the disease is rare (prevalence approximately 0.6/100,000). Oral aphthous ulcers are the main symptom, followed by skin manifestations, genital ulcers and oligoarthritis of large joints. Severe manifestations, threatening quality of life and even life itself, are the gastrointestinal manifestations which often perforate, arterial, mainly pulmonary arterial aneurysms which cause life-threatening bleeding, CNS manifestations and ocular disease, which with occlusive retinal vasculitis often leads to blindness. For milder manifestations low-dose steroids and colchicine are used, for moderate manifestations such as arthritis or ocular disease not immediately threatening visual acuity, azathioprin or cyclosporin A are combined with steroids. For severe manifestations, interferon-alpha, TNF-antagonists or cytotoxic drugs are recommended. Interleukin 1 (IL-1) antagonists are currently being examined in clinical studies.

[Sexually transmitted infections relevant in andrologic diagnostics]. / Für die andrologische Diagnostik relevante sexuell übertragbare Infektionen.

Affects on male fertility are associated with many sexually transmitted diseases. Genital tract infections play a major role in this context. The evidence for an impact on fertility differs for the pathogens; however early treatment may be very important. This requires fast and precise clinical diagnostics. Further, sexually transmitted infections may have major relevance in andrologic diagnostics because of the risk of transmission to the mother or fetus. Particularly for the increasingly relevant HIV and hepatitis infections, current guidelines are available for use in diagnostics and assisted reproduction techniques.

The registry of the German Network for Systemic Scleroderma: frequency of disease subsets and patterns of organ involvement.

OBJECTIVE: Systemic sclerosis (SSc) is a rare, heterogeneous disease, which affects different organs and therefore requires interdisciplinary diagnostic and therapeutic management. To improve the detection and follow-up of patients presenting with different disease manifestations, an interdisciplinary registry was founded with contributions from different subspecialties involved in the care of patients with SSc. METHODS: A questionnaire was developed to collect a core set of clinical data to determine the current disease status. Patients were grouped into five descriptive disease subsets, i.e. lcSSc, dcSSc, SSc sine scleroderma, overlap-syndrome and UCTD with scleroderma features. RESULTS: Of the 1483 patients, 45.5% of patients had lcSSc and 32.7% dcSSc. Overlap syndrome was diagnosed in 10.9% of patients, while 8.8% had an undifferentiated form. SSc sine scleroderma was present in 1.5% of patients. Organ involvement was markedly different between subsets; pulmonary fibrosis for instance was significantly more frequent in dcSSc (56.1%) than in overlap syndrome (30.6%) or lcSSc (20.8%). Pulmonary hypertension was more common in dcSSc (18.5%) compared with lcSSc (14.9%), overlap syndrome (8.2%) and undifferentiated disease (4.1%). Musculoskeletal involvement was typical for overlap syndromes (67.6%). A family history of rheumatic disease was reported in 17.2% of patients and was associated with early disease onset (P < 0.005). CONCLUSION: In this nationwide register, a descriptive classification of patients with disease manifestations characteristic of SSc in five groups allows to include a broader spectrum of patients with features of SSc.

Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma.

PURPOSE: To compare, in 305 patients with advanced metastatic melanoma, temozolomide and dacarbazine (DTIC) in terms of overall survival, progression-free survival (PFS), objective response, and safety, and to assess health-related quality of life (QOL) and pharmacokinetics of both drugs and their metabolite, 5-(3-methyltriazen-1-yl)imidazole-4-carboximide (MTIC). PATIENTS AND METHODS: Patients were randomized to receive either oral temozolomide at a starting dosage of 200 mg/m(2)/d for 5 days every 28 days or intravenous (IV) DTIC at a starting dosage of 250 mg/m(2)/d for 5 days every 21 days. RESULTS: In the intent-to-treat population, median survival time was 7.7 months for patients treated with temozolomide and 6.4 months for those treated with DTIC (hazards ratio, 1.18; 95% confidence interval [CI], 0.92 to 1.52). Median PFS time was significantly longer in the temozolomide-treated group (1.9 months) than in the DTIC-treated group (1.5 months) (P =.012; hazards ratio, 1.37; 95% CI, 1.07 to 1.75). No major difference in drug safety was observed. Temozolomide was well tolerated and produced a noncumulative, transient myelosuppression late in the 28-day cycle. The most common nonhematologic toxicities were mild to moderate nausea and vomiting, which were easily managed. Temozolomide therapy improved health-related QOL; more patients showed improvement or maintenance of physical functioning at week 12. Systemic exposure (area under the curve) to the parent drug and the active metabolite, MTIC, was higher after treatment with oral temozolomide than after IV administration of DTIC. CONCLUSION: Temozolomide demonstrates efficacy equal to that of DTIC and is an oral alternative for patients with advanced metastatic melanoma.

Tumor-associated cysteine proteinase activities in human melanoma cells and fibroblasts of different origin.

Specific catalytic activities of cysteine proteinases including cathepsins B (EC 3.4.22.1) and L (EC 3.4.22.15) in human melanoma cell lines SK-MEL-28, SK-MEL-30, MEL-HO and in fibroblasts of different origin are reported. Cell line-specific pH profiles of these cysteine proteinases were determined fluorometrically with benzyloxycarbonyl-phenylalanyl-arginine-amidomethylcoumarine (Z-Phe-Arg-AMC) under saturated conditions. Single activities of cathepsins B and L were inactivated by urea and by benzyloxycarbonyl-phenylalanyl-phenylalanine-diazomethylketone (Z-Phe-Phe-CHN2) in order to describe the activities of these enzymes separately. The melanoma cell line MEL-HO, which originated from a primary lesion, showed highest activity of an unknown cysteine proteinase. This enzyme is not inactivated by urea and Z-Phe-Phe-CHN2 and has a Michaelis constant (K(M) value) of approximately 1 mM. The specific characteristics suggest that it is a tumor-associated cathepsin B. In addition, high invasive subpopulations of SK-MEL-28 and SK-MEL-30 cell lines isolated by an invasion assay showed higher proteinase activities than the low invasive subpopulations. Furthermore, in fibroblasts originating from melanoma tissue cysteine proteinase activities were increased compared to normal skin fibroblasts. In conclusion, these results indicate that these cysteine proteinases shown here are tumor-associated proteinases, possibly facilitating invasion and dissemination of melanoma cells.

Treatment of psoriasis and psoriatic arthritis with interferon gamma.

In a placebo-controlled double-blind randomized study, 24 patients with psoriatic arthritis were given 28 d of treatment, and in an open study, 56 patients were treated for 9 months. We treated patients with 100 micrograms IFN gamma per subcutaneous injections, which were given daily for the first 2 weeks and then 3 times per week. The principal criterion for evaluation of therapeutic success on arthritis was improvement of the Ritchie joint pain index by at least 25% in the double-blind and 30% in the long-term study. In the double-blind study, the interferon arm was superior to the placebo arm with a statistically significant, one-side error probability of less than 5% in the chi-square test. In the long-term study, IFN gamma caused an improvement in a portion of patients in the first 3 months of therapy. No further improvement was observed after the third month, and patients classified as responders in the first months showed a deterioration of the disease by continuing treatment. The humoral inflammatory parameters did not normalize during therapy. Regression of the skin manifestations could not be observed. IFN gamma is evidently capable of inducing a psoriasis on the injection site. Investigations of IFN gamma serum levels, IFN antibodies, 2'-5' A synthetase levels in serum, and mononuclear blood cells and NK cell activity under long-term therapy showed no explanation for the loss of efficacy after 3 months treatment.

Butcher's wart virus (HPV 7) infections in non-butchers.

The analysis of a total of 654 benign and malignant lesions of the skin, genitalia, lungs and bronchi, intestine, kidneys, bladder, mammae, and of the head and neck region, resulted in the identification of human papilloma virus 7 (HPV 7) infections in 3 individuals. One of these was an ordinary "butcher's wart," whereas the other 2 patients have never been involved in meat-handling or farming. One of the latter revealed extensive verrucosis of hands, feet, axilla, neck, and face, persisting for about 27 years, with new lesions arising in the neck region. Particularly the new lesions showed filiform morphology. The second patient has, for a period of more than 2 years, been showing filiform papillomas in the face which recurred after surgical removal. These 2 patients appear to represent the first cases of HPV 7 infections in non-butchers or non-meathandlers.

Pharmacodynamics of recombinant IFN-beta during long-term treatment of malignant melanoma.

The pharmacodynamics and biologic activities of recombinant human interferon-beta (rHuIFN-beta) derived from chinese hamster ovary (CHO) cells were examined during long-term therapy in 7 melanoma patients. The CHO-derived rHuIFN-beta was given s.c. in a dose of 3 x 10(6) U three times per week for 24 weeks. Serum levels of IFN could not be detected before and 48 h after the s.c. injections. 2'-5'-Oligoadenylate synthetase (2-5 OAS), beta 2-microglobulin, and neopterin levels increased significantly 48 h after application, with a maximum after 96 h. Subsequently, the values decreased and remained only slightly elevated during the long-term therapy. Natural killer (NK) cell activity increased in the first 96 h significantly and fell below pretreatment values after 4 weeks. The decrease of biologic response could not be attributed to the occurrence of anti-IFN-beta antibodies because only 2 of the 7 patients developed neutralizing antibodies after 16 and 24 weeks of treatment, respectively. This trial confirms the biologic potency of CHO-derived rHuIFN-beta. However, the selected parameters demonstrate that immunostimulation is only possible over a short treatment period.

Lysis of neuroblastoma cells by the ADCC-reaction: granulocytes of patients with chronic granulomatous disease are more effective than those of healthy donors.

Granulocytes from healthy donors lyse human neuroblastoma cells in the ADCC-reaction using antibody MAb 14.18 directed to ganglioside GD2 present on the surface of most neuroblastoma cells. Addition of catalase, superoxide dismutase and azide do not impair this process. Granulocytes from patients with chronic granulomatous disease (CGD) kill neuroblastoma cells even better than those collected from healthy donors. These results indicate that reactive oxygen intermediates (ROI) are not involved in killing of neuroblastoma cells using MAb 14.18, and that granulocytes from patients with CGD may compensate for defects in generation of reactive oxygen intermediates by more effective oxygen-independent killing mechanisms. One patient with CGD was treated with interferon-gamma. During and after treatment, generation of ROI could not be detected and neuroblastoma cell killing was not significantly altered.

Chemotactic activity of substances derived from antibody-loaded tumor cells on granulocytes.

Chemotactic activity of granulocytes attracted by tumor cells loaded either with anti-ganglioside monoclonal antibodies (mAb) or with antibody-glucose oxidase conjugates (mAb-GO) was investigated. The melanoma cell line SK-Mel-28 which expresses the ganglioside GD3 at high density as well as the neuroectodermal cell line SK-N-LO which expresses GD2 were used for the experiments. In the presence of 50% human AB-serum, antibody-loaded tumor cells induced chemotactic activity on granulocytes, probably due to the generation of C3a/C5a which could be detected in serum incubated with anti-GD3 loaded SK-Mel-28 cells. Both compounds could also be detected in vivo in the plasma of patients suffering from neuroblastoma during therapy with anti-GD2 antibodies. In another set of experiments mAb-GO conjugates generating high amounts of H2O2 in the presence of glucose were bound to these tumor cells. A significant lipid peroxidation could be observed in the simultaneous presence of iron and ascorbate. The lipid peroxidation products were measured as thiobarbituric acid-reactive substances (TBARS) and were also shown to induce chemotactic effects on granulocytes.

Anaphylactic reaction to bovine serum albumin after embryo transfer.

OBJECTIVE: To increase the awareness of bovine serum albumin (BSA) sensitivity as a potentially lethal complication during ET. DESIGN: Case report. SETTING: Routine ET in university hospital. PATIENT(S): A 26-year-old woman who was undergoing her first ET. INTERVENTION(S): ET with BSA containing standard fluid medium. MAIN OUTCOME MEASURE(S): Specific immunoglobulin (Ig) E antibodies and skin tests. RESULT(S): The patient demonstrated increased levels of specific IgE antibodies to BSA and a clearly positive scratch test for BSA. CONCLUSION(S): Anaphylactic reactions to BSA can occur during ET. The risk can be reduced substantially if a detailed medical history is obtained.

Psoriasis induced at the injection site of recombinant interferon gamma. Results of immunohistologic investigations.

Recombinant human interferon gamma used for treatment of psoriatic arthritis was found to induce expression of HLA-DR, but not HLA-DP or HLA-DQ, on keratinocytes at the site of injection. Some patients showed an improvement of their joint symptoms, but the cutaneous manifestations remained unaffected. In 10 of 42 patients, punctiform psoriatic foci could be induced at the site of injection of interferon gamma. For this presentation, we selected a female patient with psoriatic arthropathy and type II diabetes mellitus in whom psoriasis was induced at the site of application of interferon gamma, but not after subcutaneous injection of insulin or placebo. We conclude that interferon gamma is an important lymphokine in the development of psoriasis.

Positron emission tomography and ultrasonography. A comparative retrospective study assessing the diagnostic validity in lymph node metastases of malignant melanoma.

BACKGROUND AND DESIGN: A retrospective study involving 20 patients with melanoma with clinically suspicious lymph nodes was conducted to compare the diagnostic validity of fludeoxyglucose F 18 positron emission tomography (PET) and real-time ultrasonography in lymph node metastases of malignant melanoma. RESULTS: A total of 83 lymph nodes were assessed with ultrasonography and PET. Imaging results were confirmed by histologic studies or close follow-up ultrasonographic examinations. Positron emission tomography revealed a sensitivity of 74% and a specificity of 93%. Both investigative methods show comparative sensitivity and specificity. CONCLUSIONS: Ultrasonography is much easier to perform, less time-consuming, and less expensive than PET and it is nonhazardous; therefore, it is ideal for follow-up procedures. Since in routine staging procedures, only sites of expected lymph node involvement are examined, there is a risk of metastases being missed in cases of atypical drainage patterns. Fludeoxyglucose F 18 PET can image proliferating tumors in multiple organ systems and lymph node sites in one session, making it suitable for screening in primary staging procedures and for monitoring response to therapy. Since it is based on metabolic changes, there is good differentiation between scar and tumor tissue. Major disadvantages are restricted access to investigation centers, high imaging costs, and limited anatomical location of metastatic lesions. We conclude that PET does not offer significant advantages in the diagnosis of lymph node metastases compared with ultrasonography.

Systemic scleroderma. Multicenter trial of 1 year of treatment with recombinant interferon gamma.

OBJECTIVE: To confirm significant improvement of the skin score in systemic sclerosis by treatment with interferon gamma in a larger group of patients and to investigate on a molecular level the influence of interferon gamma on collagen type I messenger RNA expression. DESIGN: Open, noncontrolled multicenter study. SETTING: Five outpatient clinics specializing in the care of systemic scleroderma. PATIENTS: Thirty-two patients suffering from the diffuse or limited form of systemic sclerosis and progressive disease were recruited; 20 patients finished the study. INTERVENTION: Each patient received interferon gamma, 50 micrograms subcutaneously 3 times a week for 1 year. MAIN OUTCOME MEASURE: Skin score, collagen type I messenger RNA in skin biopsy specimens. RESULTS: The patients who completed the study showed an unchanged median skin score after 1 year of therapy. In addition, similar collagen type I messenger RNA levels were detected in skin biopsy specimens taken from involved skin before and after therapy in these patients. CONCLUSIONS: Treatment of systemic scleroderma with interferon gamma is associated with stabilization of the skin score and lack of worsening of visceral involvement.

Morphologically intact melanoma cells may be detected in peripheral blood of melanoma patients.

The detection of circulating melanoma cells has been the subject of numerous investigations in recent years. We developed a cellular approach to identifying circulating melanoma cells in peripheral blood using immunomagnetic cell sorting. The examination covered 205 blood samples from 155 melanoma patients and 30 samples from healthy persons and nonmelanoma patients. After density gradient centrifugation, the interphase was incubated with the 9.2.27 antibody. Positive cells were labeled with magnetic microbeads and enriched by immunomagnetic cell sorting. Cells were stained using an alkaline phosphatase-anti-alkaline phosphatase assay and examined by light microscopy. In spiking experiments, melanoma cells seeded at a concentration of one melanoma cell per milliliter of whole blood could be detected reliably. Circulating melanoma cells were not found in 30 controls, nor were 9.2.27-positive cells found in 41 patients with primary malignant melanoma. In patients with regional lymph node metastases and disseminated disease, circulating 9.2.27-positive cells could be detected in 3 of 29 patients (10%) and 13 of 85 patients (15%) examined, respectively. We conclude that immunomagnetic cell sorting is a promising method with high sensitivity and specificity. The method is not suitable for early detection of metastases but is a valuable tool for further investigating the biological characteristics of circulating melanoma cells.

Successful palliation of stenosing anorectal melanoma by intratumoral injections with natural interferon-beta.

Anorectal malignant melanoma is an uncommon tumour. Unlike for cutaneous melanoma, there are few guidelines for its optimal management. In particular, very few palliative treatment strategies have been described for patients with advanced disease. We report on an 80 year old patient with locally advanced anorectal melanoma nearly completely blocking the anal orifice and disseminated metastases. Complete regression of the primary tumour and partial remission of the metastases was achieved with intratumoral injections of natural interferon-beta and systemic administration of dacarbazine. The quality of life in this patient was improved markedly by providing relief from severe rectal pain and bleeding. We propose that conservative treatment strategies such as intratumoral injections with interferon-beta should be considered as a palliative treatment option for stenosing anorectal melanoma before an abdominoperineal resection is recommended.