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.

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.

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.

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.

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: 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: 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.

Background: Saccadic eye velocity (SEV) has been shown to be a reliable neurophysiological tool for the assessment of gamma-aminobutyric acid GABA(A) receptor sensitivity. Administration of benzodiazepines targeting the GABA(A) receptor decreases SEV in healthy volunteers. Tiagabine is a new antiepileptic drug which acts via selective blockade of GABA reuptake. Therefore, we examined the effects of tiagabine on saccade parameters. Methods: SEV was analyzed in 8 healthy volunteers before and after 7 days of tiagabine treatment. Subjects received tiagabine in a daily dose of 15 mg. Saccades were measured using a noninvasive infrared oculographic device. Amplitude, latency, and SEV were analyzed as a function of treatment and target eccentricity. Results: SEV and saccade latency increased with target amplitude. Treatment with tiagabine had no significant effect on SEV and saccade amplitude. A trend was found for increased latencies after tiagabine. Conclusion: In contrast to findings with benzodiazepines, tiagabine treatment had no impact on SEV in healthy volunteers. The subchronic tolerance effects or the different site of action on the GABA(A)/BZD receptor complex may account for this deviating profile. Copyright (C) 2005 S. Karger AG, Basel.

Objectives: We have previously reported reduced serum levels of soluble intercellular adhesion molecule-1 (sICAM-1) in schizophrenic patients. A single-nucleotide polymorphism ( SNP) of the ICAM-1 gene was described at position 241. The G --> A SNP results in a nonsynonymous amino acid exchange of the ICAM-1 protein, and the A allele was shown to be also associated with several immunological disorders like rheumatoid arthritis. Methods: We investigated 70 schizophrenic patients and 128 unrelated healthy control persons regarding the relationship between the serum levels of sICAM-1 and the ICAM-1 G214A polymorphism. Results: We were able to replicate our previous finding of reduced sICAM-1 levels in schizophrenia. Healthy control persons carrying the polymorphic A allele showed markedly lower sICAM-1 serum levels than carriers of the homozygous GG wild type ( p < 0.004). In contrast, no significant difference in the sICAM-1 serum levels were seen regarding the G241A genotype distribution in schizophrenic patients. Conclusion: We hypothesize that the biochemical effect of the G241A SNP is masked in schizophrenic patients, indicating a disease-related mechanism leading to reduced levels of sICAM-1 in schizophrenia. Copyright (C) 2005 S. Karger AG, Basel.

Gonadal steroids are known to influence hypothalamic functions through both genomic and non-genomic pathways. Sex hormone-binding globulin ( SHBG) may act by a non-genomic mechanism independent of classical steroid receptors. Here we describe the immunocytochemical mapping of SHBG-containing neurons and nerve fibers in the human hypothalamus and infundibulum. Mass spectrometry and Western blot analysis were also used to characterize the biochemical characteristics of SHBG in the hypothalamus and cerebrospinal fluid (CSF) of humans. SHBG-immunoreactive neurons were observed in the supraoptic nucleus, the suprachiasmatic nucleus, the bed nucleus of the stria terminalis, paraventricular nucleus, arcuate nucleus, the perifornical region and the medial preoptic area in human brains. There were SHBG-immunoreactive axons in the median eminence and the infundibulum. A partial colocalization with oxytocin could be observed in the posterior pituitary lobe in consecutive semithin sections. We also found strong immunoreactivity for SHBG in epithelial cells of the choroid plexus and in a portion of the ependymal cells lining the third ventricle. Mass spectrometry showed that affinity-purified SHBG from the hypothalamus and choroid plexus is structurally similar to the SHBG identified in the CSF. The multiple localizations of SHBG suggest neurohypophyseal and neuroendocrine functions. The biochemical data suggest that CSF SHBG is of brain rather than blood origin. Copyright (c) 2005 S. Karger AG, Basel