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Biomedical subjects

R Kaufmann

Publications and source records attributed to R Kaufmann.

At least 37 records · Page 2Linked to original sources
PubMed2003

Topical methyl aminolaevulinate photodynamic therapy in patients with basal cell carcinoma prone to complications and poor cosmetic outcome with conventional treatment.

BACKGROUND: Conventional treatment of basal cell carcinoma (BCC) causes morbidity and/or disfigurement in some patients because of the location (e.g. mid-face) and size of the lesion. OBJECTIVES: Following reports that such difficult-to-treat BCC lesions have been treated successfully with topical methyl aminolaevulinate (MAL) photodynamic therapy (PDT), a multicentre study was performed to determine the response of such BCC to MAL-PDT. METHODS: An open, uncontrolled, prospective, multicentre study was conducted comprising patients with superficial and/or nodular BCC who were at risk of complications, poor cosmetic outcome, disfigurement and/or recurrence using conventional therapy. Patients were given one or two cycles within 3 months of topical MAL-PDT, each consisting of two treatments 1 week apart. Tumour response was assessed clinically at 3 months after the last PDT, with histological confirmation of all lesions in clinical remission. The cosmetic outcome was rated. Patients with a BCC in remission will be followed up for 5 years for recurrence, of which the 24-month follow-up is reported here. Ninety-four patients with 123 lesions were enrolled and treated with MAL-PDT at nine European primary care and referral university hospitals. An independent blinded study review board (SRB) retrospectively excluded nine patients and a total of 15 lesions from the efficacy analysis, for not having a difficult-to-treat BCC according to the protocol. RESULTS: The lesion remission rate at 3 months was 92% (45 of 49) for superficial BCC, 87% (45 of 52) for nodular BCC, and 57% (four of seven) for mixed BCC, as assessed by clinical examination, and 85% (40 of 47), 75% (38 of 51), and 43% (three of seven), respectively, as assessed by histological examination and verified by the SRB. At 24 months after treatment, the overall lesion recurrence rate was 18% (12 of 66). The cosmetic outcome was graded as excellent or good by the investigators in 76% of the cases after 3 months follow-up, rising to 85% at 12 months follow-up, and 94% at 24 months follow-up. CONCLUSIONS: Topical MAL-PDT is effective in treating BCC at risk of complications and poor cosmetic outcome using conventional therapy. MAL-PDT preserves the skin and shows favourable cosmetic results.

Administration, Topical↗
PubMed2003

Paraneoplastic syndromes: detection of malignant tumors using [(18)F]FDG-PET.

AIM: Paraneoplastic syndromes (PS) comprise a variety of clinical symptoms and diseases associated with underlying malignancy. Differentiation towards benign autoimmune diseases is necessary due to different therapeutic options. This diagnostic challenge includes cost- and time-consuming methods and is not successful in many cases. The aim of this study was the evaluation of [(18)F]fluorodeoxyglucose positron emission tomography ([(18)F]FDG-PET) for detecting or ruling out malignancy in these patients. METHODS: In this retrospective work-up a total of 30 patients with suspected PS (m:f = 17:13, mean age 55, range 22-76 years) were examined with [(18)F]FDG-PET between 1996 and 2001. Diagnoses were erythrodermia, cerebellar degeneration, dermatomyositis, polyneuropathia and others. PET scans were compared to histopathological (n=14), radiological and follow up data (mean follow up 3.6 years, range 1-6 years). RESULTS: In 7 out of 30 patients (23%) an underlying malignancy was detected. Six out of 7 malignant neoplasms showed a distinctly increased glucose consumption. One benign neoplasm caused increased tracer uptake, another PET positive patient refused biopsy and showed no growth of a malignant tumour during clinical follow up of 28 months. The remaining 21 patients without suspicious glucose consumption did not demonstrate a malignancy in other diagnostic modalities or during subsequent clinical follow-up. CONCLUSION: [(18)F]FDG-PET seems to be a useful tool in the diagnostic work-up of patients with suspected paraneoplastic syndrome.

Adult↗
PubMed2002

Morbidity risk in HFE associated hereditary hemochromatosis C282Y heterozygotes.

Hereditary hemochromatosis (HHC) is a late-onset, autosomal recessive disorder leading to a chronic iron overload syndrome, finally causing diabetes, cardiomyopathy and liver disease. HHC is the most common single gene disorder in northern Europeans that occurs with a frequency of approximately 0.5%, and most of these patients carry the C282Y and H63D mutation in the HFE gene on chromosome 6p21.3. The vast majority of HHC patients are homozygous for the C282Y mutation, but HHC phenotypes are observed in other genotypes. Expression of the disease, in those homozygous for the C282Y mutation, is highly variable depending on the various features of the population studied. C282Y heterozygotes have slightly increased iron stores and in absence of other genetic and/or environmental factors do usually not develop the HHC phenotype. It is currently a matter of debate whether C282Y heterozygotes may have an increased risk for morbidity. Different studies investigating the association of C282Y heterozygocity with morbidity have given conflicting results, as is exemplified by extrahepatic cancers, cardiovascular diseases, alcoholic liver disease, and diabetes. However, there are examples of clear and unambiguous disease associations, such as with sporadic pophyria cutanea tarda. It remains to be seen whether a strong correlation between the C282Y heterozygous state and distinct pathological conditions will exist and large-scale genotyping studies will help to identify such potential risk groups in the future.

Australia↗
PubMed2002

The serine proteinase thrombin promotes migration of human renal carcinoma cells by a PKA-dependent mechanism.

In this study, we demonstrated that thrombin activates protein kinase C (PKC), mitogen activated protein kinases (MAP kinases), transcription factor nuclear factor-kappa B (NF-kappa B), and cAMP-dependent protein kinase (PKA) in the human renal carcinoma cell line A-498. In addition, it enhanced the migratory capacity, but had no effect on the proliferation of A-498 cells. The effect of thrombin on migration could be blocked by the PKA inhibitor H-89 but was not influenced by inhibition of PKC, MAP kinases or NF-kappa B. We concluded, that thrombin acts as a regulator on human A-498 renal carcinoma cell migration including PKA.

Cell Division↗
PubMed2002

Minimization of protein adsorption on poly(vinylidene fluoride).

Surfaces covered with polyethylene glycol (PEG) have been shown to be biocompatible because PEG yields nonimmunogenicity, nonantigenicity and protein rejection. To produce a biocompatible surface coating, we have developed a method for grafting PEG onto modified poly(vinylidene fluoride) (PVDF) films. The first step was to create carboxy groups on the PVDF surface following covalente coupling of polyethylenimine (PEI) to achieve high density of amino groups. These surface amines were reacted with formyl-terminated PEG's with various molecular weight. The modified PVDF surface was characterized by means of static contact angle measurements, infrared (IR) spectroscopy and X-ray photoelectron spectroscopy (XPS). The influence of the chain length on lysozyme repellence was investigated by means of surface-MALDI-Tof mass spectrometry (Surface-MALDI-Tof-MS). Lysozyme adsorption was significantly suppressed on the PEG 5000 modified PVDF surface.

Adsorption↗
PubMed2002

Positive patch test reactions to celecoxib may be due to irritation and do not correlate with the results of oral provocation.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among those therapeutics most frequently causing pseudoallergic and sometimes allergic cutaneous adverse reactions. Coxibs preferentially inhibiting cyclooxygenase-2 are increasingly propagated as alternatives in NSAID-sensitive patients. We evaluated the tolerability of celecoxib in NSAID-sensitive patients. In 14 consecutive patients (6 males, 8 females, age 18-72 years), scratch and patch tests with homogenized Celebrex were performed, followed by single-blind, placebo-controlled oral provocation (maximal single dose: 200 mg; cumulative dose: 350 mg). 8 of the first 10 patients showed erythematous reactions to celecoxib on patch testing after 2 days with decrescendo kinetics between then and day 3. 9 patients with no history of NSAID intolerance showed similar reactions. When the patch tests were repeated with homogenized Celebrex at final concentrations of 5% and 10% in petrolatum, no reaction was observed in any patient. Subsequent oral provocation was tolerated without adverse effects by all individuals. We conclude that patch tests with high concentrations of celecoxib cause irritant reactions and do not correlate with the outcome of oral provocation tests. Therefore, these tests should be performed with lower concentrations of celecoxib (Celebrex). Celecoxib itself seems to be a valuable alternative drug in NSAID-sensitive patients.

Administration, Oral↗
PubMed2002

Topical calcipotriol plus oral fumaric acid is more effective and faster acting than oral fumaric acid monotherapy in the treatment of severe chronic plaque psoriasis vulgaris.

BACKGROUND: Calcipotriol is an established topical therapy for psoriasis vulgaris. OBJECTIVE: This study aimed to investigate whether the addition of calcipotriol to fumaric acid ester (FAE) monotherapy had an additive efficacy and an FAE-sparing effect in patients with severe plaque psoriasis. METHODS: This multicentre, randomised, double-blind, vehicle-controlled study included 143 patients for up to 13 weeks treatment. Group A received FAE tablets (Fumaderm) with an increasing daily dosage from 105 to 1,075 mg + ointment vehicle. Group B received FAE tablets + calcipotriol ointment (50 microg/g). Ointments were applied twice daily. Clinical response was assessed using percentage changes in the Psoriasis Area and Severity Index (PASI), from baseline to treatment end. RESULTS: The mean percentage change in the PASI was -76.1% in group B and -51.9% in group A, the difference between treatments was -24.2% (95% CI from -34.2 to -14.2%; p < 0.001). Group B responded more rapidly to treatment. Investigators' and patients' overall efficacy assessments were significantly more favourable for group B (p < or = 0.001). Group B was prescribed less FAE than group A. This difference was greatest at the last visit (mean daily dose 529 and 685 mg, respectively; p = 0.006). Overall adverse events in the two groups were similar. CONCLUSION: This study shows that the combination of calcipotriol and FAEs is significantly more effective and faster acting than FAE monotherapy in the treatment of severe plaque psoriasis. The combination has a slight FEA-sparing effect and therefore a superior benefit/risk ratio.

Administration, Oral↗
PubMed2002

Body-weight-independent dosing of cyclosporine micro-emulsion and three times weekly maintenance regimen in severe psoriasis. A randomised study.

BACKGROUND: Body-weight-dependent (BWD) treatment of psoriasis with cyclosporine A (CsA is well established. It has recently been reported that this is not necessary for the treatment of atopic dermatitis. OBJECTIVES: (1) To investigate the efficacy and safety of a CsA micro-emulsion administered in a new body-weight-independent (BWI) protocol and to compare it to a BWD dosage regimen in the treatment of severe psoriasis. (2) To investigate the duration of disease remission after intermittent treatment of psoriasis with CsA. PATIENTS AND METHODS: 122 adult patients with severe plaque-type psoriasis (PASI > or = 12) were included in this study which consisted of two treatment periods: period I was a randomised parallel-group comparison of daily CsA doses of 100-300 mg (BWI) or 1.25-5.0 mg/kg (BWD) for 12 weeks; period II was a randomised double-blind placebo-controlled extension treatment of patients, who had responded (>75% PASI recovery) to the treatment in period I and continued the treatment on their last effective dose or placebo 3 times weekly for a further 12 weeks. RESULTS: In period I, the increase in creatinine in the BWI group (2.7 micromol/l) was proven to be non-inferior to that of the BWD group (3.5 micromol/l) at a non-inferiority limit of 5 micromol/l (p < 0.05). The PASI decreased with BWI dosing from 22.0 to 3.0 and with the BWD scheme from 19.5 to 2.5 (p = 0.98). In period II, the relapse rates were 40.5% (17/42) with intermittent CsA and 56.9% (29/51) with placebo (p = 0.15). CONCLUSIONS: BWI dosing is as effective and safe as conventional BWD dosing for the short-term treatment of severe psoriasis. There was a tendency toward a prolongation of remission with intermittent CsA treatment.

Administration, Topical↗
PubMed2002

A new calcipotriol/betamethasone dipropionate formulation (Daivobet) is an effective once-daily treatment for psoriasis vulgaris.

BACKGROUND: Topical corticosteroids and calcipotriol have been used separately for many years to treat psoriasis. A new combination ointment has been formulated, which contains both calcipotriol and the corticosteroid betamethasone dipropionate. OBJECTIVE: To compare the combination ointment with betamethasone dipropionate ointment, calcipotriol ointment and ointment vehicle in patients with psoriasis vulgaris. METHODS: 1,603 patients were randomised to one of the 4 double-blind treatments used once daily for 4 weeks. RESULTS: The mean percentage change in the PASI at the end of treatment was -71.3 (combination), -57.2 (betamethasone), -46.1 (calcipotriol) and -22.7 (vehicle). The mean difference of combination minus betamethasone was -14.2 (95% CI: -17.6 to -10.8, p < 0.001), of combination minus calcipotriol -25.3 (95% CI: -28.7 to -21.9, p < 0.001) and of combination minus vehicle -48.3 (95% CI: -53.2 to -43.4, p < 0.001). 6.0% of patients (combination) reported local adverse reactions compared to 4.9% (betamethasone), 11.4% (calcipotriol) and 13.6% (vehicle). CONCLUSION: Calcipotriol/betamethasone dipropionate combination ointment used once daily is well tolerated and more effective than either active constituent used alone.

Administration, Topical↗
PubMed2002

PAR-1- and PAR-3-type thrombin receptor expression in primary cultures of human renal cell carcinoma cells.

In this study, we report coexpression of proteinase-activated receptor (PAR)-1- and PAR-3-type thrombin receptors in primary cultures obtained from surgically resected specimens of renal cell carcinomas (RCCs). Receptor expression on RNA level was evaluated by using the RT-PCR technique. Results demonstrated the presence of mRNA encoding PAR-1 and PAR-3, but mRNA encoding PAR-4 could not be found in human RCC cells. The expression of PAR-1 and PAR-3 on protein level was investigated with confocal laser fluorescence and freeze-fracture electron microscopy. Both thrombin receptor types were localized on the cell membrane but were also found on intracellular compartments of RCC cells. On the outer cell membrane, clustering of PAR-1 and PAR-3 molecules was partly observed. This is the first study demonstrating presence of both PAR-1 and PAR-3 in human carcinoma cells.

Calcium↗
PubMed2001

Evidence for a novel thrombopoietin signalling event: activation of protein kinase A in human megakaryoblastic CMK cells.

Thrombopoietin (TPO) plays a crucial role in megakaryocyte development. TPO signalling, which is mediated by its receptor Mpl, includes Janus kinase, (JAK) signal transducer and activator of transcription (STAT) and Shc/Ras/mitogen-activated protein kinase (MAPK) pathways. The precise nature of these signalling routes has not been clarified in detail up until now. We investigated the effect of TPO on activation of cAMP-dependent protein kinase (PKA) and its involvement in MAPK signalling in human megakaryoblastic leukaemia CMK cells. For estimation of PKA activity, phosphorylation of a PKA-specific peptide substrate was assayed in CMK cell lysates. Since activation of PKA is associated with translocation of its catalytic subunit alpha (C-PKA) into the cell nucleus, Western blot analysis of nuclear fractions with an anti-C-PKA antibody was additionally performed. The activation of TPO-induced MAPK activation and the effect of the PKA inhibitor H-89 was measured using immunoblotting with a monoclonal anti-pERK antibody. TPO enhanced cAMP and induced activation of PKA in CMK cells. In addition, H-89 partly blocked TPO-induced MAPK activation in CMK cells. Our results indicate a novel TPO-triggered signalling event, activation of the cAMP/PKA pathway in human megakaryoblastic CMK cells. This signal transduction route seems to be involved in TPO-induced MAPK signaling.

Cell Nucleus↗
PubMed2001

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.

Adolescent↗
PubMed2001

A novel PAR-1-type thrombin receptor signaling pathway: cyclic AMP-independent activation of PKA in SNB-19 glioblastoma cells.

Cellular effects of thrombin are mediated by members of a new subfamily of G protein-coupled receptors designated proteinase-activated receptors (PARs) with the prototype PAR-1. Investigation of PAR-1-induced signaling has been shown to be very important in clarifying thrombin's role in cell metabolism, differentiation, and growth. We evaluated connection of PAR-1 with the cAMP/PKA pathway in SNB-19 glioblastoma cells. Alpha-thrombin and the synthetic PAR-1 agonist SFLLRN stimulated PKA as shown by increased PKA activity and translocation of the catalytic PKA alpha subunits (PKA(cat)alpha) into the nucleus. However, no effect on cAMP could be observed. PKA(cat)alpha was found to be associated with nuclear factor-kappa B (NF-kappaB) p65 and its inhibitor protein IkappaB in SNB-19 cells. After PAR-1 stimulation, this association was markedly diminished. We conclude that PAR-1 mediates PKA activation without altering cAMP levels but includes NF-kappaB-associated PKA(cat)alpha in SNB-19 glioblastoma cells. This is the first evidence for a cAMP-independent PKA signaling by a G protein-coupled receptor.

Active Transport, Cell Nucleus↗