Medizin - Open Access LMU - Teil 13/22 Archiv

Background: Docetaxel is one of the most effective antitumor agents currently available for the treatment of metastatic breast cancer (MBC). This phase II multicenter study prospectively analyzed the efficacy and toxicity of docetaxel given on a weekly schedule as first-line treatment of metastatic breast cancer. Patients and Methods: All patients received docetaxel, 35 mg/m(2) weekly for 6 weeks, followed by 2 weeks of rest. Subsequent cycles ( 3 weeks of treatment, 2 weeks of rest) were given until a maximum of 5 cycles or disease progression. Premedication consisted of 8 mg dexamethasone intravenously 30 min prior to the infusion of docetaxel. Results: Fifty-four patients at a median age of 58 years with previously untreated MBC were included in the study. A median of 10 doses ( median cumulative dose 339 mg/m(2)) was administered ( range: 2 - 18). The overall response rate was 48.1% ( 95% CI: 34 - 61%, intent-to-treat). Median survival was 15.8 months and median time to progression was 5.9 months ( intent-to-treat). Hematological toxicity was mild with absence of neutropenia-related complications. Grade 3 neutropenia was observed in 3.7% of patients and grade 3 and 4 anemia was observed in 5.6 and 1.9% of patients, respectively. Conclusion: The weekly administration of docetaxel is highly efficient and safe as first-line treatment for MBC and may serve as an important treatment option specifically in elderly patients and patients with a reduced performance status. Copyright (C) 2005 S. Karger AG, Basel.

Objective: To determine the expression of endogenous adhesion/growth-regulatory lectins and their binding sites using labeled tissue lectins as well as the binding profile of hyaluronic acid as an approach to define new prognostic markers. Methods: Sections of paraffin-embedded histological material of 481 lungs from lung tumor patients following radical lung excision processed by a routine immunohistochemical method (avidin-biotin labeling, DAB chromogen). Specific antibodies against galectins-1 and - 3 and the heparin-binding lectin were tested. Staining by labeled galectins and hyaluronic acid was similarly visualized by a routine protocol. After semiquantitative assessment of staining, the results were compared with the pT and pN stages and the histological type. Survival was calculated by univariate and multivariate methods. Results: Binding of galectin-1 and its expression tended to increase, whereas the parameters for galectin-3 decreased in advanced pT and pN stages at a statistically significant level. The number of positive cases was considerably smaller among the cases with small cell lung cancer than in the group with non-small-cell lung cancer, among which adenocarcinomas figured prominently with the exception of galectin-1 expression. Kaplan-Meier computations revealed that the survival rate of patients with galectin-3-binding or galectin-1-expressing tumors was significantly poorer than that of the negative cases. In the multivariate calculations of survival lymph node metastases ( p < 0.0001), histological type ( p = 0.003), galectin-3-binding capacity ( p = 0.01), galectin-3 expression ( p = 0.03) and pT status ( p = 0.003) proved to be independent prognostic factors, not correlated with the pN stage. Conclusion: The expression and the capacity to bind the adhesion/growth regulatory galectin-3 is defined as an unfavorable prognostic factor not correlated with the pTN stage. Copyright (C) 2005 S. Karger AG, Basel.

Background: The aim of this retrospective analysis was to evaluate the impact of trastuzumab-based regimens on the survival of patients with HER2-overexpressing metastatic breast cancer (MBC). The study specifically focussed on the influence of the continuation of trastuzumab-based treatment despite tumor progression on survival. Patients and Methods: Patients with HER2 overexpressing MBC were included in this retrospective analysis. HER2 overexpression was determined by the immunohistochemical staining score (DAKO Hercep Test (TM)). Trastuzumab was applied at a loading dose of 4 mg/kg and a maintenance dose of 2 mg/kg. Results: Among 136 HER2 overexpressing patients (DAKO score 3+), 66 patients received first-line trastuzumab, 47 patients received trastuzumab as second-line therapy and 23 patients received trastuzumab beyond disease progression. There was no significant difference regarding the duration of trastuzumab-based treatment (first-line: 29.5 weeks vs. second-line: 25 weeks). Moreover, there was no difference in the response rate (first-line: 37.9% vs. second-line: 35.7%) or the median survival (p = 0.47 log rank). Patients who received >= 2 trastuzumab-based regimens for MBC survived significantly longer compared to those who had received only 1 regimen (>= 2 regimens: 62.4 months vs. 1 regimen: 38.5 months; p = 0.01 log rank). Conclusions: Trastuzumab is highly effective in the treatment of HER2 overexpressing MBC. Compared to historical controls, overall survival appears to be markedly prolonged, particularly in patients who received sequential trastuzumab-based treatment beyond disease progression.

Objective: The purpose of this pilot study was to evaluate the feasibility and toxicity of concurrent chemotherapy with vinorelbine and mitomycin C in combination with accelerated radiotherapy (RT) in patients with locally advanced cancer of the head and neck. Patients and Methods: Between January 2003 and March 2004, 15 patients with T4/N2-3 squamous cell carcinoma (12/15) and with N3 cervical lymph node metastases of carcinoma of unknown primary (3/15) were treated with chemotherapy and simultaneous accelerated RT. Results: 11 patients completed therapy without interruption or dose reduction. Grade 3 - 4 acute mucosal toxicity was observed in 9/15 patients, grade 4 hematologic toxicity in 6/15 patients. At a median follow-up of 7.5 months, 2 patients have died of intercurrent disease, 2 patients have experienced local relapse; 5 patients are alive with no evidence of disease at the primary tumor site. Discussion: The described regimen is highly effective, but led to remarkable side effects.

Vascular endothelial growth factors ( VEGF)- A, - C and - D are members of the proangiogenic VEGF family of glycoproteins. VEGF-A is known to be the most important angiogenic factor under physiological and pathological conditions, while VEGF-C and VEGF-D are implicated in the development and sprouting of lymphatic vessels, so called lymphangiogenesis. Local tumor progression, lymph node metastases and hematogenous tumor spread are important prognostic factors for esophageal carcinoma ( EC), one of the most lethal malignancies throughout the world. We found solid evidence in the literature that VEGF expression contributes to tumor angiogenesis, tumor progression and lymph node metastasis in esophageal squamous cell carcinoma ( SCC), and many authors could show a prognostic value for VEGF-assessment. In adenocarcinoma (AC) of the esophagus angiogenic properties are acquired in early stages, particularly in precancerous lesions like Barrett's dysplasia. However, VEGF expression fails to give prognostic information in AC of the esophagus. VEGF-C and VEGF-D were detected in SCC and dysplastic lesions, but not in normal mucosa of the esophagus. VEGF-C expression might be associated with lymphatic tumor invasion, lymph node metastases and advanced disease in esophageal SCC and AC. Therapeutic interference with VEGF signaling may prove to be a promising way of anti-angiogenic co-treatment in esophageal carcinoma. However, concrete clinical data are still pending.

Background: HER2 is overexpressed in 20 - 30% of breast cancers. Compared to chemotherapy alone, chemotherapy with trastuzumab improves clinical outcome in patients with HER2- positive metastatic breast cancer ( MBC). In general, HER2 status in a primary lesion predicts the status of metastases, so that biopsy of metastatic lesions appears unnecessary. Case Report: A 39- year old woman was diagnosed with primary breast cancer in November 2000. Using the method and scoring system of the DAKO Hercep Test, the tumor has shown low HER2 expression ( DAKO score 1+). After failure of several chemotherapy regimens for metastatic disease ( liver, skeletal), the patient underwent CT- guided needle biopsy of the liver which showed HER2 positive adenocarcinoma ( DAKO score 3+). In consequence, the patient was treated with vinorelbine ( 30 mg/ m(2) d1,8,15 q4w) and trastuzumab ( 4 mg/ kg loading dose, 2 mg/ kg weekly). During a treatment period of 4 months imaging results as well as tumor marker kinetics indicated an excellent response with sustained decrease of tumor markers. A retrospective analysis of the HER2 shed antigen in metastatic stage revealed excessively increased serum levels and supports HER2 overexpression observed in liver metastasis. The kinetics of the HER2 shed antigen during therapy for metastatic disease were found to be in phase with the kinetics of CEA and CA15- 3. Conclusion: This case report demonstrates that re- evaluation of the HER2 status may be helpful in single patients not sufficiently responding to treatment of metastatic disease. Determination of HER2 overexpression may be facilitated by a determination of the HER2 shed antigen level in peripheral blood.

Purpose: To investigate retinal thickness and optic disc parameters by the Retinal Thickness Analyzer (RTA) glaucoma program in older normal subjects and to determine any age effect. Methods: Subjects over 40 years of age without any prior history of eye diseases were recruited. Only subjects completely normal on clinical ophthalmologic examination and on visual field testing by Humphrey Field Analyzer (HFA) using the SITA 24-2 program were included. A total of 74 eyes from 74 subjects with even age distribution over the decades were enrolled and underwent topographic measurements of the posterior pole and of the optic disc by RTA. The `glaucoma full' program in software version 4.11B was applied. Results: Mean patient age was 59.9 +/- 10.3 years with a range from 40 to 80 years. The only parameter intraocular pressure (IOP) correlated with was retinal posterior pole asymmetry (r=0.27, p=0.02). IOP itself increased significantly with age (r=0.341, p=0.003). Mean defect and pattern standard deviation of the HFA did not correlate with any of the retinal or optic disc measurements. Increasing age correlated significantly with some of the morphologic measurements of the RTA: decreasing perifoveal minimum thickness (r=-0.258, p=0.026), increased cup-to-disc area ratio (r=0.302, p=0.016) and increased cup area (r=0.338 p=0.007). Conclusions: An age effect exists for some of the retina and optic disc measurements obtained by the RTA. Copyright (C) 2005 S. Karger AG, Basel.

Introduction: Facial lipoatrophy is a crucial problem of HIV-infected patients undergoing highly active antiretroviral therapy (HAART). Poly-L-lactic acid (PLA), provided as New-Fill(R)/Sculptra(TM), is known as one possible treatment option. In 2004 PLA was approved by the FDA as Sculptra(TM) for the treatment of lipoatrophy of the face in HIV-infected patients. While the first trials demonstrated relevant efficacy, this was to some extent linked to unwanted effects. As the depth of injection was considered relevant in this context, the application modalities of the preparation were changed. The preparation was to be injected more deeply into subcutaneous tissue, after increased dilution. Material and Methods: To test this approach we performed a pilot study following the new recommendations in 14 patients. Results: While the efficacy turned out to be about the same, tolerability was markedly improved. The increase in facial dermal thickness was particularly obvious in those patients who had suffered from lipoatrophy for a comparatively small period of time. Conclusion: With the new recommendations to dilute PLA powder and to inject it into the deeper subcutaneous tissue nodule formation is a minor problem. However, good treatment results can only be achieved if lipoatrophy is not too intense; treatment intervals should be about 2 - 3 weeks. Copyright (C) 2005 S. Karger AG, Basel.

Topical glucocorticoids have always been considered first-line drugs for inflammatory diseases of the skin and bronchial system. Applied systemically, glucocorticoids are used for severe inflammatory and immunological diseases and the inhibition of transplant rejection. Owing to the progress in molecular pharmacology, the knowledge of the mechanism of action has increased during the last years. Besides distinct genomic targets, which are due to the activation of specific cytoplasmatic receptors resulting in the (trans-) activation or (trans-) repression of target genes, there are non-genomic effects on the basis of the interference with membrane-associated receptors as well as with membrane lipids. In fact, various glucocorticoids appear to differ with respect to the relative influence on these targets. Thus, the extended knowledge of glucocorticoid-induced cellular signalling should allow the design and development of even more specifically acting drugs-as it has been obtained with other steroids, e.g. estrogens for osteoporosis prevention. Copyright (C) 2005 S. Karger AG, Basel.

Fluticasone propionate - the first carbothioate corticosteroid - has been classified as a potent anti-inflammatory drug for dermatological use. It is available as 0.05% cream and 0.005% ointment formulations for the acute and maintenance treatment of patients with dermatological disorders such as atopic dermatitis, psoriasis and vitiligo. This glucocorticoid is characterized by high lipophilicity, high glucocorticoid receptor binding and activation, and a rapid metabolic turnover in skin. Although skin blanching following fluticasone propionate exceeds that of corticosteroids of medium strength, several clinical trials demonstrate a low potential for cutaneous and systemic side-effects, even in difficult-to-treat areas like the face, the eyelids and intertriginous areas. Even among paediatric patients with atopic dermatitis, fluticasone propionate proved to be safe and effective. These pharmacological and clinical properties are reflected by the high therapeutic index of this glucocorticoid.

Recommendations are presented for the routine clinical use of serum and tissue-based markers in the diagnosis and management of patients with breast cancer. Their low sensitivity and specificity preclude the use of serum markers such as the MUC-1 mucin glycoproteins ( CA 15.3, BR 27.29) and carcinoembryonic antigen in the diagnosis of early breast cancer. However, serial measurement of these markers can result in the early detection of recurrent disease as well as indicate the efficacy of therapy. Of the tissue-based markers, measurement of estrogen and progesterone receptors is mandatory in the selection of patients for treatment with hormone therapy, while HER-2 is essential in selecting patients with advanced breast cancer for treatment with Herceptin ( trastuzumab). Urokinase plasminogen activator and plasminogen activator inhibitor 1 are recently validated prognostic markers for lymph node-negative breast cancer patients and thus may be of value in selecting node-negative patients that do not require adjuvant chemotherapy. Copyright (C) 2005 S. Karger AG, Basel.

The number of people aged 14 and older that use the Internet in Germany has doubled to 35.7 millions (55.3%) since the year 2000. The Internet also more and more expands into the domain of psychiatry and psychotherapy, and is used by psychiatric patients for information, communication and therapeutic purposes. Nevertheless, the infinite possibilities of the World Wide Web are linked with several advantages and disadvantages. Easily accessible information, numerous opportunities for exchange among like-minded people and therapeutic support from online therapies are juxtaposed with such risks as frequently lacking quality and transparency of the available information, possible enhancement of social withdrawal and certain Websites concerning suicide. If the mentioned risks of the Internet rather provoke new problems and trigger suicidality or if the chance of an easily accessible online discussion rather results in mental relief cannot be answered generally.

According to official statistics every year 11,000 persons in Germany die from suicide. 20 years ago nearly 19,000 suicides were registered. What are the causes for this decrease? Do suicide preventive measures contribute to the reduction of suicide rates? Different universal prevention strategies ( e. g. restriction of access to means) and selective approaches ( programs for special high-risk groups; e. g. patients after attempted suicide) are presented and discussed regarding their preventive value. In most cases it is hardly possible to scientifically prove the efficacy of suicide prevention strategies. Neither the role of psychosocial interventions nor the impact of psychotropic agents can be sufficiently quantified. Due to various methodological reasons ( e. g. small sample sizes and the lack of randomization), interpretation of the data is difficult. In terms of a comprehensive approach of suicide prevention a combination of different activities should be most adequate in the long run.

Even if the freedom to suicide is part of our human existence, about 90% of all suicides occur in the context of psychiatric disorders and thus in states of limited power of judgment. Depressive disorders represent the most frequent cause for suicides. Thus, optimization of medical care for depressive patients is one of the most promising strategies to prevent suicides. In the context of the `Nuremberg Alliance Against Depression' it came to an obvious reduction of suicidal acts compared to a baseline year and compared to the control region of Wurzburg. The reduction could be reached by a cooperation with GPs, multipliers such as teachers, priests, geriatric caregivers and the media, through intensive public relations work and through support of self help activities. This approach is carried forward within the Germany-wide `Alliance Against Depression' and within the `European Alliance Against Depression' ( EAAD) which is funded by the European Commission. In the last part of the article the suicide- preventive, but also the possible suicide-inducing effect of antidepressants is discussed.