Search PubMed⌕ Search

Biomedical subjects

E B Bröcker

Publications and source records attributed to E B Bröcker.

At least 19 recordsLinked to original sources
PubMed2007

Rituximab in autoimmune bullous diseases: mixed responses and adverse effects.

BACKGROUND: Intolerably high doses of systemic corticosteroids and additional immunosuppressants may be required to control disease activity in autoimmune bullous skin diseases. New therapeutic options are needed for such patients. OBJECTIVES: To determine the efficacy and adverse effects of adjuvant rituximab. METHODS: Seven patients with refractory autoimmune blistering diseases (pemphigus vulgaris, PV, n = 4; bullous pemphigoid, BP, n = 2; mucous membrane pemphigoid, MMP, n = 1) were treated four times with rituximab at an individual dose of 375 mg m(-2) at weekly intervals. RESULTS: All lesions cleared in three patients (two PV, one BP), while they were reduced by more than 50% in three others (two PV, one BP). The concomitant immunosuppressive medication was reduced in five patients (four PV, one BP). The patient with MMP developed bilateral blindness while nasopharyngeal lesions resolved. Three patients (two BP, one PV) experienced severe adverse events including fatal pneumonia. CONCLUSIONS: Adjuvant B-cell depletion by rituximab is effective in otherwise therapy-resistant bullous autoimmune disorders but may be associated with substantial adverse effects including fatal outcomes.

Adolescent↗
PubMed2006

Gain of 11q/cyclin D1 overexpression is an essential early step in skin cancer development and causes abnormal tissue organization and differentiation.

Non-melanoma skin cancers, in particular keratoacanthomas (KAs) and squamous cell carcinomas (SCCs), have become highly frequent tumor types especially in immune-suppressed transplant patients. Nevertheless, little is known about essential genetic changes. As a paradigm of 'early' changes, that is, changes still compatible with tumor regression, we studied KAs by comparative genomic hybridization and show that gain of chromosome 11q is not only one of the most frequent aberration (8/18), but in four tumors also the only aberration. Furthermore, 11q gain correlated with amplification of the cyclin D1 locus (10/14), as determined by fluorescence in situ hybridization, and overexpression of cyclin D1 protein (25/31), as detected by immunohistochemistry. For unraveling the functional consequence, we overexpressed cyclin D1 in HaCaT skin keratinocytes. These cells only gained little growth advantage in conventional and in organotypic co-cultures. However, although the control vector-transfected cells formed a well-stratified and orderly differentiated epidermis-like epithelium, they showed deregulation of tissue architecture with an altered localization of proliferation and impaired differentiation. The most severe phenotype was seen in a clone that additionally upregulated cdk4 and p21. These cells lacked terminal differentiation, exhibited a more autonomous growth in vitro and in vivo and even formed tumors in two injection sites with a growth pattern resembling that of human KAs. Thus, our results identify 11q13 gain/cyclin D1 overexpression as an important step in KA formation and point to a function that exceeds its known role in proliferation by disrupting tissue organization and thereby allowing abnormal growth.

Aneuploidy↗
PubMed2005

Successful adjuvant treatment of severe bullous pemphigoid by tryptophan immunoadsorption.

Bullous pemphigoid (BP) is an autoimmune blistering skin disease associated with circulating autoantibodies to the hemidesmosomal antigens BP180 and BP230. We report two cases of therapy-refractory BP adjuvantly treated by tryptophan immunoadsorption. In both patients, this treatment was associated with rapid clinical improvement and reduction in the required corticosteroid dosage. In addition, levels of circulating anti-BP180 autoantibodies decreased markedly. Antibodies that were eluted from the tryptophan matrix bound to BP180 and induced dermal-epidermal separation in cryosections of human skin. Our observations suggest that immunoadsorption may be a helpful adjuvant treatment in severe BP.

Adrenal Cortex Hormones↗
PubMed2004

Clinical evaluation of in vitro chemosensitivity testing: the example of uveal melanoma.

PURPOSE: Results from in vitro chemosensitivity testing recommend treosulfan/gemcitabine chemotherapy for the treatment of stage IV uveal melanoma. METHODS: Twenty patients received treosulfan 3,500 mg/m2 followed by gemcitabine 1,000 mg/m2 on day 1 and day 8 repeated on day 29. In cases of prior chemotherapy only 75% of these dosages were used. RESULTS: Without any patient achieving an objective response, 25% of patients (95% confidence interval, 8.6-49.1%) had stabilisation of disease. This stabilisation was associated with a prolonged median overall survival of 17 months compared with 7 months for the patients with progressive disease. First-line treatment was not associated with better response or survival although prognostic parameters did not significantly differ from that of other patients. CONCLUSIONS: The results are disappointing and question the value of individualized chemotherapy based on in vitro assays.

Adult↗
PubMed2004

Final results of the EORTC 18871/DKG 80-1 randomised phase III trial. rIFN-alpha2b versus rIFN-gamma versus ISCADOR M versus observation after surgery in melanoma patients with either high-risk primary (thickness >3 mm) or regional lymph node metastasis.

Between 1988 and 1996, the European Organisation for Research and Treatment of Cancer Melanoma Group (EORTC-MG) performed a prospective, randomised phase III adjuvant trial to evaluate the efficacy and toxicity of low dose recombinant interferon-alpha 2 b (rIFN-alpha2b) (1 MU) or recombinant interferon gamma (rIFN-gamma), (0.2 mg) both given subcutaneously (s.c.), every other day (qod), for 12 months in comparison with an untreated control group. The German Cancer Society (DKG) added a fourth arm with Iscador M, a popular mistletoe extract. High-risk stage II patients (thickness >3 mm) and stage III patients (positive lymph nodes) without distant metastasis were randomised and followed until their first progression or death. An intention-to-treat analysis was performed. From 1988 to 1996, a total of 830 patients were randomised: 423 in the three-arm EORTC 18871 trial and 407 patients in the four-arm DKG 80-1 trial. The median follow-up was 8.2 years and a total of 537 relapses and 475 deaths were reported. At 8 years, the disease-free interval (DFI) rate was 32.4% and the overall survival (OS) rate was 40.0%. In terms of the DFI, the hazard ratio estimates (95% Confidence Intervals (CI)) were: 1.04 (0.84, 1.30) for the comparison of rIFN-alpha2b versus control, 0.96 (0.77, 1.20) for rIFN-gamma versus control, and 1.32 (0.93, 1.87) for Iscador M versus control. In terms of OS, the corresponding estimates (95% CI) for the 3 treatment comparisons were: for IFN-alpha2b 0.96 (0.76, 1.21), for rIFN-gamma 0.87 (0.69, 1.10) and for Iscador M 1.21 (0.84, 1.75), respectively. The results show no clinical benefit for adjuvant treatment with low dose rIFN-alpha2b or rIFN-gamma or with Iscador M in high-risk melanoma patients.

Adolescent↗
PubMed2003

Anorectal melanoma: surgical management guidelines according to tumour thickness.

Management of patients with anorectal melanoma is still controversial. To reach a rationale therapeutic approach, we reviewed our experience obtained over the past decade. In all, 19 consecutive patients with the diagnosis of anorectal melanoma were included in this retrospective survey. Details of the patients' presentation, symptoms, tumour size and histology and tumour state were recorded, and the primary therapeutic procedures were evaluated in detail. The size of the tumours ranged between 0.5 and 7 cm in diameter. The median tumour thickness was 10 mm (range 0.6-40 mm). At diagnosis, six of 19 patients already presented with either regional or distant metastases. The remaining 13 patients were treated with curative intend, either by abdomino-perineal resection (APR) or wide local excision (WLE). The form of operative therapy, however, had no impact on overall survival. Nevertheless, the incidence of local recurrences was lower after APR even for patients with less favourable tumours. In conclusion, WLE alone is not sufficient for local tumour control of thick anorectal melanoma.

Anus Neoplasms↗
PubMed2002

Combination chemotherapy with or without s.c. IL-2 and IFN-alpha: results of a prospectively randomized trial of the Cooperative Advanced Malignant Melanoma Chemoimmunotherapy Group (ACIMM).

The purpose of this randomized trial was to evaluate the efficacy of combination chemoimmunotherapy compared with chemotherapy alone. A total of 124 patients were randomized to receive intravenous cisplatin (35 mg m(-2), days 1-3), carmustine (150 mg m(-2), day 1, cycles 1 and 3 only), dacarbacine (220 mg m(-2), days 1-3) and oral tamoxifen (20 mg m(-2), daily) in combination with (n=64) or without (n=60) sequential subcutaneous IL-2 and IFN-alpha. In those patients who received sequential immunotherapy, each cycle of chemotherapy was followed by outpatient s.c. IL-2 (10 x 10(6) IU m(-2), days 3-5, week 4; 5 x 10(6) IU m(-2), days 1, 3, 5, week 5) and s.c. IFN-alpha (5 x 10(6) IU m(-2), day 1, week 4; days 1, 3, 5, week 5). The overall response rate of patients treated with the combination of chemotherapy and IL-2/IFN-alpha was 34.3% with seven complete responses (10.9%) and 15 partial responses (23.4%). In patients treated with chemotherapy, only, the overall response rate was 29.9% with eight complete responses (13.3%) and 10 partial responses (16.6%). There was no significant difference in median progression free survival (0 months vs 4 months) and in median overall survival (12 months vs 13 months) for combined chemoimmunotherapy and for chemotherapy, respectively.

Administration, Oral↗
PubMed2002

[Role of matrix-degrading enzymes in melanoma progression].

Cutaneous melanoma is an invasive and early metastazising tumor. Melanoma cells detach from the primary tumor, penetrate the basement membrane, invade lymphatics and blood vessels, and form metastases. These processes all depend on coordinated expression and/or activation of proteolytic enzymes. In addition to aspartyl- and cysteineproteinases, serine proteinases including the plasminogen activator system (uPA, uPAR, tPA, PAI-1 and PAI-2) and matrix metalloproteinases (MMPs) with their tissue inhibitors (TIMPs) play an essential role in these processes. In addition, melanoma cells require specific adhesion molecules such as integrins and CD44 for interaction with other cells and components of the extracellular matrix (ECM); these are also involved in binding activated MMPs on the cell surface. In this review we discuss these functional aspects of melanoma progression.

Animals↗
PubMed2002

[Eosinophilic ulcer of the mouth mucosa. Differential mouth ulcer diagnosis].

Eosinophilic ulcers of the oral mucosa represent a rare, self-limiting disease of unknown origin. Single lesions occur typically in the oral cavity or on the lower lip. Characteristically, they have a short history and resolve spontaneously. Diagnosis is verified by the histologic feature of a deep polymorphic inflammatory infiltrate with numerous eosinophils. The clinical aspect shows a usually nontender ulcer with a white or yellowish base and elevated indurated borders or a tumor with central ulceration. Lymphadenopathy is not found. Differential diagnoses include malignant tumors and the primary stage of syphilis. We present three cases recently diagnosed in our department to show the characteristics and the different appearances of the disease. A 74-year-old woman presented with an ulcer at the base of the tongue, a 59-year-old man had one on the lower lip, and in a 48-year-old man the lesion was atypically located at the edge of the mouth. Here we demonstrate the importance of knowledge of the disease, its course, and the characteristic histology to avoid troublesome diagnostic and therapeutic procedures.

Aged↗
PubMed2002

[Skin manifestations of Fanconi anemia].

Fanconi's anemia is a rare autosomal recessive disorder associated with variable clinical manifestations. So far, eight complementation groups have been identified, and the genes of four of them have been cloned. Early-onset progressive bone marrow failure and a predisposition to malignancies, particularly acute myelogenous leukemia, liver tumors, and mucocutaneous squamous cell carcinomas, result in a poor prognosis. Additionally, almost all organs can be affected by this defect. Widespread areas of hyper- and hypopigmentation of the skin in a characteristic pattern and café-au-lait spots preceding the manifestation of panmyelopathy can aid early diagnosis. Here we report an 11-year-old boy with Fanconi's anemia presenting with typical cutaneous manifestations. We emphasize the important role of skin abnormalities of Fanconi's anemia as signs enabling early diagnosis. Moreover, we summarize clinical features, course, therapy, and new aspects of the molecular basis of Fanconi's anemia.

Adolescent↗
PubMed2002

Increased incidence of pemphigus vulgaris in southern Europeans living in Germany compared with native Germans.

BACKGROUND: The two major subtypes of pemphigus include: pemphigus vulgaris (PV) and pemphigus foliaceus. Only limited data are available on the epidemiology of these diseases. OBJECTIVE: The aim of the present study was to estimate the gender- and age-specific incidences of PV in two well-defined regions of Germany and to compare the incidences among native Germans with those in citizens from other countries living in Germany. METHODS: We performed a retrospective review of records from all patients that were diagnosed with PV at the Departments of Dermatology in Würzburg and Mannheim between 1989 and 1997. RESULTS: During the observation period, 14 patients were diagnosed with PV coming from an area with 1.46 million residents. With regard to the patients' age, the highest incidence for women was found in the 51-65-year-old-age group with 2.34 [95% confidence interval (CI): 0.36; 7.76] new cases per 1 million inhabitants per year. The highest incidence for men was observed in the over 65-year-old age group with 3.72 (95% CI: 0.95; 9.8) cases/million peryear. In the 51-65-year-old age group,we found a 25-foldhigher incidence of PV in foreigners living in Germany compared with native Germans. The age-adjusted incidence of PV was ninefold higher in foreigners compared with native Germans. Interestingly, all non-German patients came from two southern European countries (Turkey and Italy). CONCLUSIONS: The age-adjusted incidence of PV differs between native Germans and foreigners living in Germany. Further studies are necessary to address the risk factors (genetic and/or environmental) that contribute to this difference.

Aged↗
PubMed2001

Induction of systemic CTL responses in melanoma patients by dendritic cell vaccination: cessation of CTL responses is associated with disease progression.

Two HLA-A2-positive patients with advanced stage IV melanoma were treated with monocyte-derived dendritic cells (DC) pulsed with either tumor peptide antigens from gp100, MART-1 and MAGE-3 alone or in combination with autologous oncolysates. Clinically, the rapid progression of disease was substantially stalled and both patients were alive for more than 15 months after initiation of therapy. Specific CTL reactivity against several tumor antigens was detectable in peripheral blood, which declined just before reactivation of disease progression. Furthermore, CD3 zeta-chain expression detected by Western lotting was decreased in PBL at this time. In summary, our data confirm that DC-based vaccinations induce peptide-specific T cells in the peripheral blood of advanced-stage melanoma patients. Although successful induction of systemic tumor antigen-specific CTL may not lead to objective clinical tumor regression, their presence are indicative of a prolonged survival.

Aged↗
PubMed2001

CD19+ B lymphocytes are the major source of human antibody-secreting hybridomas generated by electrofusion.

Human monoclonal antibodies may be generated by electrofusion of human B lymphocytes with a human/mouse heteromyeloma line. In addition to a fusion protocol optimised for the fusion partners, the activation of B lymphocytes is crucial for fusion and hybrid efficiency. In this study, we initially treated peripheral blood mononuclear cells (PBMC) from normal blood donors with a large panel of known stimulants and determined the yield of human antibody-secreting hybridomas after electrofusion with the heteromyeloma cell line H73C11; 3- to 5-day incubation with phytohaemagglutinin L (PHA-L) resulted in the highest number of secreting hybrids. In a second set of experiments, PBMC were depleted from various cell populations, including CD14+ monocytes, CD8+ T lymphocytes, and CD2+ T cells, respectively. Undepleted PBMC stimulated with PHA-L were shown to give rise to the highest number of secreting hybridomas when subjected to electrofusion, whereas depletion of CD2+ T lymphocytes greatly reduced the yield. In a final set of experiments, CD19+ B lymphocytes were identified as the major source of secreting hybridomas. For optimal fusion efficiency, CD19+ B cells were shown to require direct physical contact with other cell populations, most probably T lymphocytes, during the stimulation process. Our data highlight the importance of an adequate stimulation prior to electrofusion and may be helpful to further facilitate the development of human monoclonal antibodies.

Animals↗