Low-dose 5-fluorouracil in combination with salicylic acid for the treatment of actinic keratoses on the hands and/or forearms - results of a non-interventional study.

BACKGROUND: As an in situ carcinoma, actinic keratoses should be treated early. Previous studies on the efficacy of a low-dose 0.5% 5-fluorouracil solution in combination with 10% salicylic acid (low-dose 5-FU/SA) are mostly related to lesions appearing on the head and face. In contrast, actinic keratoses (AK) lesions of the upper extremities are considered to be difficult to treat. OBJECTIVE: The efficacy of low-dose 5-FU/SA in the treatment of actinic keratoses on the hands and/or forearms was studied for the first time in this non-interventional study (NIS) under practical conditions in a large patient population. In addition to the clinical course during therapy and a follow-up period, the length of application and adherence were documented. METHODS: As part of this NIS, 649 patients with AK were treated at 207 centres with low-dose 5-FU/SA. The data of the study were recorded at baseline, optionally during an intermediate examination, at the end of therapy and during a final assessment. RESULTS: The average number of AK lesions decreased during the entire observation period by 92%. Side-effects were documented only rarely in the form of local skin reactions (2%). The attending physicians assessed the efficacy, tolerability and safety of the therapy as being predominantly very good or good (in each case ≥90%). CONCLUSION: AK lesions on the hands and/or forearms were effectively treated with low-dose 5-FU/SA under routine conditions in dermatological practice and the treatment was well tolerated.

Drug-resistant MS spasticity treatment with Sativex(®) add-on and driving ability.

OBJECTIVE: The aim of the present observational study was to determine the effects of a delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) oromucosal spray (Sativex(®) spray), brand name Sativex(®), indicated for drug-resistant MS spasticity, on the driving ability of treated MS patients. METHODS: The study was conducted over a period of 4-6 weeks. Thirty-three MS patients with moderate to severe treatment-resistant spasticity and planned to begin add-on treatment with Sativex(®) were enrolled at three specialized MS centres in Germany. A set of five driving test procedures from a validated computerized test battery was used to evaluate the driving ability of eligible patients. Tests were performed by patients at baseline and repeated after 4-6 weeks of treatment with Sativex(®) oromucosal spray. According to German normative data, the test thresholds achieved by the general population served as a reference to allow for a fitness/unfitness to drive classification. RESULTS: Patients showed comparable driving test results at baseline and at final visits. Only two patients changed classification shifting from 'unfit' to drive to 'fit' and vice versa. The mean severity of spasticity, as self-reported by the patients, improved with statistical significance. Sativex(®) was generally well tolerated. CONCLUSIONS: Treatment of MS patients with Sativex(®) does not negatively impact on driving ability and may improve moderate to severe treatment-resistant MS spasticity.

Randomized adjuvant chemotherapy trial in high-risk, lymph node-negative breast cancer patients identified by urokinase-type plasminogen activator and plasminogen activator inhibitor type 1.

BACKGROUND: Most patients with lymph node-negative breast cancer are cured by locoregional treatment; however, about 30% relapse. Because traditional histomorphologic and clinical factors fail to identify the high-risk patients who may benefit from adjuvant chemotherapy, other prognostic factors are needed. In a unicenter study, we have found that levels of urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor type 1 (PAI-1) in the primary tumor are predictive of disease recurrence. Thus, we designed the Chemo N(0) prospective randomized multicenter therapy trial to investigate further whether uPA and PAI-1 are such prognostic factors and whether high-risk patients identified by these factors benefit from adjuvant chemotherapy. After 4.5 years, we present results of the first interim analysis. METHODS: We studied 556 patients with lymph node-negative breast cancer. The median follow-up was 32 months. All patients with low tumor levels of uPA (< or = 3 ng/mg of protein) and of PAI-1 (< or = 14 ng/mg of protein) were observed. Patients with high tumor levels of uPA (> 3 ng/mg of protein) and/or of PAI-1 (> 14 ng/mg of protein) were randomly assigned to combination chemotherapy or subjected to observation only. All statistical tests were two-sided. RESULTS: A total of 241 patients had low levels of uPA and PAI-1, and 315 had elevated levels of uPA and/or PAI-1. The estimated 3-year recurrence rate for patients with low tumor levels of uPA and PAI-1 (low-risk group) was 6.7% (95% confidence interval [CI] = 2.5% to 10.8%). This rate for patients with high tumor levels of uPA and/or PAI-1 (high-risk group) was 14.7% (95% CI = 8.5% to 20.9%) (P = 0.006). First interim analysis suggests that high-risk patients in the chemotherapy group benefit, with a 43.8% lower estimated probability of disease recurrence at 3 years than high-risk patients in the observation group (intention-to-treat analysis: relative risk = 0.56; 95% CI = 0.25 to 1.28), but further follow-up is needed for confirmation. CONCLUSIONS: Using uPA and PAI-1, we have been able to classify about half of the patients with lymph node-negative breast cancer as low risk, for whom adjuvant chemotherapy may be avoided, and half as high risk, who appear to benefit from adjuvant chemotherapy.

Tumor-biological factors uPA and PAI-1 as stratification criteria of a multicenter adjuvant chemotherapy trial in node-negative breast cancer.

In axillary node-negative primary breast cancer, 70% of the patients will be cured by locoregional treatment alone. Therefore, adjuvant systemic therapy is only needed for those 30% of node-negative patients who will relapse after primary therapy and eventually die of metastases. Traditional histomorphological and clinical factors do not provide sufficient information to allow accurate risk group assessment in order to identify node-negative patients who might benefit from adjuvant systemic therapy. In the last decade various groups have reported a strong and statistically independent prognostic impact of the serine protease uPA (urokinase-type plasminogen activator) and its inhibitor PAI-1 (plasminogen activator inhibitor type 1) in node-negative breast cancer patients. Based on these data, a prospective multicenter therapy trial in node-negative breast cancer patients was started in Germany in June 1993, supported by the German Research Association (DFG). Axillary node-negative breast cancer patients with high levels of either or both proteolytic factors in the tumor tissue were randomized to adjuvant CMF chemotherapy versus observation only. Recruitment was continued until the end of 1998, by which time 684 patients had been enrolled. Since then, patients have been followed up in order to assess the value of uPA and PAI-1 determination as an adequate selection criterion for adjuvant chemotherapy in node-negative breast cancer patients. This paper reports on the rationale and design of this prospective multicenter clinical trial, which may have an impact on future policies in prognosis-oriented treatment strategies.

[Blood transfusion in surgical gynecology. Strategies for preventing homologous blood transfusion]. / Blutbedarf in der operativen Gynäkologie. Strategien zur Vermeidung von Fremdblut.

A statistical evaluation of homologous blood transfusions is imperative in any gynecological surgical department, to be able to define the transfusion-associated risk of the individual interventions. On the basis of our own statistical data and reports in the literature, strategies for limiting the use of homologous blood are discussed. So far, experience with autologous blood transfusion in surgical gynecology is limited, and clinical studies are needed to better define its role. In special cases, the use of erythropoietin and gonadotropin-releasing hormone (GnRH) analogues extends the possibilities for reducing homologous blood transfusion.

Both the cytosols and detergent extracts of breast cancer tissues are suited to evaluate the prognostic impact of the urokinase-type plasminogen activator and its inhibitor, plasminogen activator inhibitor type 1.

The serine protease urokinase-type plasminogen activator (uPA) plays a key role in tumor-associated proteolysis in malignant solid tumors. Proteolytic activity of uPA is controlled by its naturally occurring plasminogen activator inhibitor type 1. As an initial observation, a correlation of enzymatic uPA activity in breast cancer cytosols with prognosis was described in 1988 (Duffy et al., Cancer (Phila.), 62: 531-533, 1988). A pronounced prognostic impact of uPA, independent of classical risk parameters, was then first demonstrated in detergent-extracted (Triton X-100) breast cancer tissues by applying enzyme-linked immunosorbent assay techniques (Jänicke et al., Lancet, 2: 1049, 1989; Fibrinolysis, 4:69-78, 1990; Duffy et al., Cancer Res., 50: 6827-6829, 1990). In addition, not only uPA but also plasminogen activator inhibitor type 1 were shown to be of prognostic value in breast cancer (Jänicke et al., Semin. Thromb. Hemostasis, 17: 303-312, 1991; Breast Cancer Res. Treat., 24: 195-208, 1993). Subsequently, the prognostic value of uPA and plasminogen activator inhibitor type 1 was also confirmed in studies using archived "cytosol fractions" of breast cancer tissues (Foekens et al., Cancer Res., 52: 6101-6105, 1992; Spyratos et al., J. Natl. Cancer Inst., 84: 1266-1272, 1992; Grondahl-Hansen et al., Cancer Res., 53: 2513-2521, 1993; Sumiyoshi et al., Int. J. Cancer, 50: 345-348, 1992). A direct comparison of both methods with regard to prognosis, however, was lacking. We therefore prepared both the detergent-treated tissue extracts and the cytosol fractions from the same breast cancer specimens to allow a direct comparison of both methods. In 247 breast cancer patients investigated, the Triton X-100-extracted tissues revealed about twice as much uPA antigen (uPATx: median, 2.32 ng/mg protein) than the cytosol fractions (uPAcyt: median, 1.07 ng/mg protein). In contrast, the presence of Triton X-100 did not result in an increase of PAI-1 (PAI-1Tx: median, 6.34 ng PAI-1/mg protein) compared to the cytosol fractions (PAI-1cyt: median, 7.15 ng PAI-1/mg protein). Good correlations between uPATx and uPAcyt (R = 0.72) and between PAI-1Tx and PAI-1cyt (R = 0.88) were observed. Furthermore, PAI-1 and uPA are moderately correlated with each other (uPATx versus PAI-1Tx: R = 0.40; uPAcyt versus PAI-1cyt: R = 0.39). The prognostic power of uPA showed its best advantage in Triton X-100-extracted tissues (RR = 3.22), most pronounced in the subgroups of node-negative and premenopausal patients, respectively.(ABSTRACT TRUNCATED AT 400 WORDS)

Bipolar cells of the chick retina containing alpha-bungarotoxin-sensitive nicotinic acetylcholine receptors.

Two cDNA clones for nicotinic acetylcholine receptor (nAChR) subunits sensitive to alpha-bungarotoxin (alpha-Bgt) have been isolated, the so-called alpha-Bgt binding proteins alpha 1 (or alpha 7 nAChR subunit) and alpha 2 (or alpha 8 nAChR subunit). Immunohistochemical experiments have shown that both alpha 7 and alpha 8 subunits, as well as subunits insensitive to alpha-Bgt (beta 2 and alpha 3), are present in amacrine and ganglion cells of the chick retina. However, only the alpha 8 subunit was observed in presumptive bipolar cells. The present study investigated in detail the pattern of distribution of the bipolar cells containing the alpha 8 nAChR subunit and its relation to the pattern of distribution of bipolar cells immunoreactive to protein kinase C (PKC). Presumptive alpha 8- and PKC-like immunoreactive (alpha 8-LI and PKC-LI) bipolar cells were observed sending their dendrites to the outer plexiform layers and their axons to the inner plexiform layer. Whereas alpha 8-LI bipolar cells corresponded to 40-53% of the whole population of bipolar cells, PKC-LI bipolar cells represented only 6-8% of the same population. The soma sizes of the alpha 8-LI bipolar cells were slightly smaller (mean +/- S.D.; 4.9 +/- 0.8 microns) than the soma sizes of the PKC-LI bipolar cells (5.4 +/- 0.9 microns). Double-labeling experiments indicated that probably all PKC-LI bipolar cells also contain alpha 8-LI. This indicates that two distinct groups of cholinoceptive bipolar cells exist in the chick retina, one that contains PKC-LI, and another one that does not.

Three subtypes of alpha-bungarotoxin-sensitive nicotinic acetylcholine receptors are expressed in chick retina.

A recent report described the isolation of cDNA clones encoding alpha 7 and alpha 8 subunits of alpha-bungarotoxin-sensitive nicotinic ACh receptors (alpha BgtAChRs) from chick brain and demonstrated that they were related to, but distinct from, the alpha subunits of nicotinic ACh receptors (nAChRs) from muscles and neurons. Monoclonal antibodies against the two alpha BgtAChR subunits were used to demonstrate that at least two subtypes are present in embryonic day 18 chicken brain. The predominant brain subtype contains alpha 7 subunits, while a minor subtype contains both alpha 7 and alpha 8 subunits. Both subtypes may also contain other subunits. Here we report the results of immune precipitation studies and immunohistochemical studies of alpha BgtAChRs in the chick retina. In addition to the two subtypes found in brain, a new alpha BgtAChR subtype that contains alpha 8 subunits, but not alpha 7 subunits, was identified and was found to be the major subtype in chick retina. This subtype has a lower affinity for alpha-bungarotoxin (alpha Bgt) than does the subtype containing only alpha 7 subunits. Small amounts of this alpha 8 subtype were also detected in brain by labeling with higher concentrations of 125I-alpha Bgt than had been used previously. The subtype containing only alpha 7 subunits comprised 14% of the alpha BgtAChRs in hatchling chick retina. The subtype containing alpha 8 subunits (but no alpha 7 subunits) accounted for 69%, and the alpha 7 alpha 8 subtype accounted for 17%. Amacrine, bipolar, and ganglion cells displayed alpha 8 subunit immunoreactivity, and a complex pattern of labeling was evident in both the inner and outer plexiform layers. In contrast, only amacrine and ganglion cells exhibited alpha 7 subunit immunoreactivity, and the pattern of alpha 7 subunit labeling in the inner plexiform layer differed from that of alpha 8 subunit labeling. These disparities suggest that the alpha BgtAChR subunits are differentially expressed by different populations of retinal neurons. In addition, the distribution of alpha BgtAChR subunit immunoreactivity was found to differ from that of alpha-Bgt-insensitive nAChR subunits.

GABA-like immunoreactive cells containing nicotinic acetylcholine receptors in the chick retina.

The possibility that GABA-like immunoreactive cells of the chick retina also contain neuronal nicotinic acetylcholine receptors was investigated by means of immunohistochemical techniques. Double-labeled cell bodies containing GABA-like immunoreactivity and nicotinic receptor-like immunoreactivity were seen in the inner third of the inner nuclear layer and were presumably amacrine cells. Approximately 29-36% of the GABA-positive cells in the inner nuclear layer contained nicotinic receptor immunoreactivity. Their soma sizes ranged from 5-12 microns. Some double-labeled cells ranging from 7-21 microns were observed in the ganglion cell layer as well. Between 9-37% of the GABA-positive cells in this layer contained nicotinic receptor-like immunoreactivity. Following injection of a retrograde tracer into the optic tectum, some of the retrogradely labeled cells were also double labeled with antibodies against GABA and nicotinic receptors. This indicates that at least some of the GABA-positive cells containing nicotinic acetylcholine receptors in the ganglion cell layer are indeed ganglion cells. The present data appear to represent the first demonstration of the presence of acetylcholine receptors in GABA-containing cells in the retina, thus providing a basis for a possible influence of acetylcholine upon those presumptive GABAergic cells.