Hepatic lesions in an elderly woman - cancer isn't always the answer.

Multiple hepatic lesions in an elderly woman usually suggest metastatic malignant disease, in most situations already beyond cure. However, we present the case of an 81-year-old female in whom histopathology verified granulomas and PCR proved hepatic tuberculosis. Tuberculostatic quadruple therapy resulted in complete remission. Isolated hepatic tuberculosis is rare, especially in HIV-negative subjects living in areas of low tuberculosis prevalence. This case highlights the need to histopathologically confirm malignancy as withholding therapy would have been deleterious in this curable patient.

Acetylsalicylic acid enhances antiproliferative effects of the EGFR inhibitor gefitinib in the absence of activating mutations in gastric cancer.

The epidermal growth factor receptor (EGFR) is highly expressed in gastric cancer indicating its suitability as a target for receptor tyrosine kinase (RTK) inhibitors. In the current study we explored the role of EGFR and its potential use as a therapeutic target in gastric cancer. First we analyzed 66 gastric cancer samples of Asian and Caucasian patients for the presence of EGFR mutations. No activating EGFR mutations were found and gefitinib alone was only weakly effective in gastric cancer cell lines. However, acetylsalicylic acid (ASA) significantly enhanced the inhibitory effects of gefitinib indicating synergistic action. Whole genome expression profiling indicated significant regulation of 120 genes in the case of co-administration of gefitinib and ASA (32 induced, 88 repressed) in gastric adenocarcinoma cells. Further analyses indicated that several important signalling pathways were effectively inhibited by simultaneous exposure to gefitinib and ASA. Our findings indicate that although gastric cancer does not seem to harbour mutations which render the cancer cells constitutively susceptible to gefitinib, the co-administration of ASA can strengthen RTK inhibitor activity in adenocarcinoma cells by EGFR activation. This is the first report of effective modulation of EGFR-inhibition activity in cancer.

Role of receptor tyrosine kinases in gastric cancer: new targets for a selective therapy.

Receptor tyrosine kinases (RTKs) such as the epidermal growth factor receptor family participate in several steps of tumor formation including proliferation and metastatic spread. Several known RTKs are upregulated in gastric cancer being prime targets of a tailored therapy. Only preliminary data exist, however, on the use of the currently clinically available drugs such as trastuzumab, cetuximab, bevacizumab, gefitinib, erlotinib, and imatinib in the setting of gastric cancer. Preclinical data suggest a potential benefit of their use, especially in combination with "conventional" cytostatic therapy. This review summarizes the current knowledge about their use in cancer therapy as well as new approaches and drugs to optimize treatment success.

[Suicide attempt by means of phenobarbital overdose. Effective treatment with continuous veno-venous hemodialysis]. / Phenobarbitalintoxikation in suizidaler Absicht. Kontinuierliche venovenöse Hämodialyse als effektive Therapie.

A 68-year-old woman tried to commit suicide using phenobarbital, which was initially prescribed for her dog that suffered from seizures. At admission she was unconscious and ventilated. Five days of intensive care therapy did not improve her state of consciousness. Subsequent continuous veno-venous hemodialysis accelerated the elimination of phenobarbital compared to endogenous elimination by a factor of five. The patient survived without sequelae. Detailed history taking and well-timed indication for dialysis were crucial.

Gastric electrical stimulation results in improved metabolic control in diabetic patients suffering from gastroparesis.

AIMS/HYPOTHESIS: Symptoms of gastroparesis possess a heavy impact on the quality of life; delayed gastric emptying may result in poor metabolic control in diabetics. Gastric electrical stimulation (GES) has recently been introduced as a treatment option in patients with drug refractory gastroparesis to increase the quality of life by alleviating nausea and vomiting frequencies. However, the effect of GES on metabolic control has not been assessed yet. METHODS: We performed a prospective single center study on the long-term effect (12 months) of continuous high-frequency/low-energy GES on symptoms, gastric emptying (measured scintigraphically), and metabolic control (HbA1c) in insulin-dependent diabetic subjects suffering from drug-refractory gastroparesis for more than one year. RESULTS: Seventeen (12 female, 5 male) patients entered the study; all were available for analysis at all time points. No therapy-associated adverse events occurred. Weekly vomiting and nausea frequencies decreased significantly at 6 and 12 months. Gastric retention rates improved significantly from 83 % (2 h) and 38 % (4 h) to 35 % (2 h)/14 % (4 h) and 25 % (2 h)/17 % (4 h) at 6 and 12 months, respectively. HbA1c values were lowered in all 17 subjects; initially, all HbA1c values were above 7.5 %; at 6 and 12 months, mean values had significantly decreased from 8.6 % to 6.2 % and 6.5 %, respectively. CONCLUSIONS/INTERPRETATION: Gastric electrical stimulation offers symptom control in diabetics with drug-refractory gastroparesis and decreases gastric retention. This study, for the first time, documents a positive effect of this therapy on metabolic control as indicated by HbA1c, a surrogate marker of the risk of diabetic complications.

Effect of basic fibroblast growth factor on gastric ulcer healing and its own mRNA expression.

BACKGROUND: The application of an acid-stable mutein of basic fibroblast growth factor (bFGF) called CS23 results in acceleration of ulcer healing. The modes by which this cytokine exerts these effects are not yet completely understood. AIM: To describe the pattern of bFGF-mRNA expression during ulcer healing and to examine the effects of exogenously applied CS23 on gastric ulcer healing in an animal model. METHODS: The speed of healing of gastric ulcers, expression of extracellular matrix gene mRNAs such as pro alpha(I) collagen (by non-radioactive in situ hybridization), cellular proliferation evidenced by the display of PCNA (by immunohistochemistry), angiogenesis, and the feedback of this growth factor on its own mRNA expression pattern were used to evaluate the effects of CS23 on rat gastric ulcer healing in an animal model. RESULTS: CS23 accelerates gastric ulcer healing at 7, 14 and 21 days after ulcer induction. We found an increase in connective tissue beneath the ulcer bed in treated animals in comparison to controls. The expression of PCNA as well as pro alpha(I) collagen mRNA was markedly increased in ulcers, yet there was no distinct difference between treatment arms. In contrast, the density of microvessels was significantly increased in the submucosa of ulcers by CS23 application. bFGF-mRNA expression is up-regulated in the submucosa during early ulcer healing; this increase diminishes within days but can be restituted by the exogenous application of CS23. CONCLUSIONS: CS23 speeds gastric ulcer healing and significantly increases the density of microvessels in the ulcerated tissue without affecting the numbers of proliferating cells or the transcription of collagen mRNA. In addition, it augments the expression of bFGF-mRNA during the later stages of healing, suggesting a positive feedback loop.

Eradication of Helicobacter pylori with lansoprazole, roxithromycin and metronidazole--an open pilot study.

BACKGROUND: The most extensively studied Helicobacter pylori eradication regimen comprises omeprazole, clarithromycin and metronidazole. Macrolide antibiotics other than clarithromycin should achieve similar efficacy, but they have not yet been thoroughly tested. AIM: To determine the efficacy and safety of a triple therapy regimen using lansoprazole, roxithromycin, and metronidazole on the basis of multicentre outpatient care in an open pilot study. METHODS: 163 patients with duodenal ulcer and proven H. pylori infection received lansoprazole 30 mg b.d., roxithromycin 300 mg b.d. and metronidazole 500 mg b.d. for 7 days followed by another 7 days of lansoprazole 30 mg once daily. H. pylori status was determined by urease quick test, histology, microbiology and 13C-urea breath test before starting and at least 4 weeks after completing treatment. RESULTS: 150 patients were available for evaluation; H. pylori was successfully eradicated in 84.7% (127/ 150) as determined by urease quick test, 78.0% (117/150) by histology, 81.3% (109/134) by 13C-urea breath test; and in 75.3% (113/150), at least two tests were negative. Side-effects were reported in 34 patients (most commonly diarrhoea and changes in liver function tests), in two cases the study medication was interrupted. Prior to treatment, 23% of the H. pylori isolates were resistant against metronidazole and 3.4% against roxithromycin. After unsuccessful treatment, 84% of the isolates were resistant against metronidazole and 21% against roxithromycin. Primary resistance to metronidazole increased the chance of treatment failure approximately sevenfold (7% vs. 53%). CONCLUSIONS: For H. pylori eradication, the combination of lansoprazole, roxithromycin and metronidazole proved to be as safe as other current triple therapy regimens, while a comparison of efficacy rates yet remains to be assessed in prospective controlled trials. The metronidazole-resistant H. pylori is not rare in Germany and, in the present study, has strongly influenced treatment success.

Role of reactive oxygen metabolites in aspirin-induced gastric damage in humans: gastroprotection by vitamin C.

BACKGROUND: The roles of active oxygen metabolites and anti-oxidative defenses in aspirin (ASA)-induced gastric damage have been little studied. AIM: We determined the effects of aspirin (400 mg b.d.) with or without vitamin C (480 mg b.d.) for 3 days on gastric mucosa in human volunteers. METHODS: Gastric injury was assessed endoscopically; gastric blood flow, reactive oxygen release (quantified by chemiluminescence), lipid peroxidation, myeloperoxidase, superoxide dismutase and glutathione peroxidase activity and intragastric vitamin C content were measured. Expression of superoxide dismutase and glutathione peroxidase mRNAs was assayed semi-quantitatively. RESULTS: ASA produced erosions, a marked increase in chemiluminescence, lipid peroxidation, and myeloperoxidase activity. It also resulted in a suppression of gastric blood flow, intragastric vitamin C levels, superoxide dismutase and glutathione peroxidase activities. The addition of vitamin C significantly attenuated gastric damage and reversed the effects of ASA on these parameters. Superoxide dismutase and glutathione peroxidase mRNAs were decreased in ASA-treated subjects; the addition of vitamin C restored their regular levels. CONCLUSIONS: (i) free radical-induced lipid peroxidation and suppression of antioxidizing enzymes play an important role in gastric damage induced by aspirin; (ii) increased myeloperoxidase activity suggests activated neutrophils to be the major source of these radicals; (iii) vitamin C protects against ASA-induced damage due to its anti-oxidizing activity.

Remodeling of extracellular matrix in gastric ulceration.

The quality of ulcer repair remains crucial for the stability of the injured tissue and for preventing recurrence. Therefore, we studied the temporo-spatial expression of the fibrillar and basement membrane collagens (types I, III, and IV), the collagenase MMP-2 as well as its inhibitor TIMP-1 before and after oral administration of basic fibroblast growth factor (b-FGF) over 30 days in acetic acid-induced rat gastric ulcers. The alterations and the exact location of the mRNA transcripts and their precipitated proteins were visualized by means of radioactive in situ hybridization and immunohistochemistry. Our data show that hybridization signals of procollagen I could first be identified 2 hours after ulcer induction. After 12 hours the ulcer was established and the mRNA was enhanced at the ulcer margin. After 24-48 hours the other procollagen transcripts were detected and all were further upregulated over the mesenchymal cells of all gastric layers up to 21 days, then declined at 30 days. In contrast, MMP-2 became prominent after 48 hours and up to 21 days. TIMP-1 was enhanced at 72 hours. After oral administration of b-FGF the transcriptional activity of the procollagens and MMP-2 was not significantly altered, while ulcer diameter was significantly reduced. We conclude that the early onset and long duration of collagens' expression points to their central structural and functional role in gastric ulcer healing. MMP-2 seems to be involved in both active ulceration and ECM remodeling. The timing of TIMP/MMP expression may be critical for proper restoration of gastric wall integrity.

Aspirin effects on gastric epithelial cell proliferation and cytokine expression.

Aspirin is known to cause gastric injury and to delay ulcer healing. The effects of aspirin on gastric epithelial cell function are heterogeneous; in contrast to injuring the mucosa, aspirin may also act beneficially by inducing adaptation; a mechanism that is poorly understood. We aimed to document the effects of different doses of aspirin on gastric epithelial cell function defined as proliferation, and secretion as well as mRNA expression of cytokines. Furthermore, we studied the effects of aspirin pretreatment on cytokine secretion as a potential element of gastric adaptation. The proliferative activity of three different gastric epithelial cell lines (AGS, KATO III, RGM-1) was assessed by (3)H-thymidine incorporation; secretion of growth factors PDGF-AB and VEGF into culture supernatant was documented by ELISA. mRNA transcripts of both cytokines were quantified by real time RT-PCR. Low doses of aspirin did not alter the proliferative dynamics in two of the three studied cell lines; high doses abolished proliferation. Secretion of PDGF-AB and VEGF increased during the first days of low dose aspirin exposition; higher concentrations led to a depletion of cytokines after an initial liberation in the case of VEGF, mRNA of which was also dose-dependently increased by aspirin. Seven-day pretreatment with low amounts of aspirin did not alter the secretory response of the epithelia caused by higher doses of this drug. The secretion of cytokines and proliferation of gastric epithelial cells are adversely effected by aspirin in a similarly dose-dependent fashion as the intended effects of this drug on platelet function and pain relief.

Concepts and methods in chronic thalamic stimulation for treatment of tremor: technique and application.

OBJECTIVE: To rationalize the technique and reduce the costs associated with chronic deep brain stimulation of the thalamus for treatment of refractory tremor. METHODS: The efficacy and safety of a modification in surgical techniques was prospectively assessed in 94 patients with tremor. Bilateral electrodes were implanted in 29 patients, and 65 patients received unilateral implants. Forty-five patients had Parkinson's disease tremor, 42 patients had essential tremor, and 7 patients had kinetic tremors of different causes. In all instances, intraoperative stimulations to analyze the thresholds of intrinsic and extrinsic responses were performed directly with the implanted leads. The electrodes were repositioned until satisfactory results were achieved. The pulse generators were implanted directly after the first step in the same operative session. Patients were not subjected to interoperative test stimulation trials. RESULTS: Postoperative improvement of tremor at a mean follow-up of 11.9 months was rated as excellent in 47 patients (50%), marked in 37 patients (39%), moderate in 8 patients (9%), and minor in 2 patients (2%). There was no persistent morbidity related to surgery. In patients with Parkinson's disease, the symptomatic improvement of tremor was rated as excellent in 51% of patients, marked in 36%, moderate in 11%, and minor in 2%. In patients with essential tremor, symptomatic outcome was classified as excellent in 57% of patients, marked in 36%, moderate in 5%, and minor in 2%. Six of the seven patients with kinetic tremor achieved marked symptomatic improvement, and one patient experienced moderate improvement. Forty patients experienced stimulation-related side effects. Side effects were mild in general, and they were reversible with a change in electrical parameters. They occurred more frequently in patients who had bilateral stimulation. CONCLUSION: Excellent to marked improvement of tremor is achieved in the majority of patients with physiological target determination via implanted leads in thalamic deep brain stimulation. Interoperative test stimulation trials are unnecessary. Modifications in technique may help to reduce the costs of the related hospital stay.

Movement disorders following nonfunctional neurosurgery.

OBJECT: Knowledge is scarce about movement disorders that follow neurosurgical operations other than functional stereotactic surgery. The cases of 14 patients who suffered from movement disorders secondary to craniocerebral or spinal surgery are analyzed. None of these patients was initially treated by any of the authors. METHODS: Twelve patients underwent surgery for cerebral diseases. Nine of these patients harbored tumors and three patients had neurovascular disorders. Two patients underwent spinal surgery for cervicothoracic ependymoma or for multiple cervical disc herniations. Twelve of the 14 patients had immediate postoperative side effects such as hemiparesis, ataxia, and somnolence. In all but two patients, movement disorders became manifest only after a delay. Dystonic movement disorders developed in eight patients, unilateral tremors in three patients, unilateral facial myokymia in one patient, and hemichorea-hemiballism in two patients. The mean delay of onset for tremor was 5 weeks and that for dystonic movement disorders was 5.5 months. Movement disorders were transient in three patients; however, they were persistent in 11 patients at a mean follow-up period of 5 years. These movement disorders caused marked persistent disability in four patients. Lesions of the contralateral striatum were identified in patients with dystonic syndromes and lesions of the dentatothalamic outflow in patients with tremors. In three patients who had postoperative basal ganglia lesions after partial removal of astrocytomas, tumor regrowth was later documented. Medical treatment in patients with persistent movement disorders rendered only limited benefit. Two patients improved with botulin injections. In one patient postoperative hemidystonia was alleviated by contralateral thalamotomy. CONCLUSIONS: Dystonic syndromes and tremors are the most common movement disorders that occur after craniocerebral and spinal surgery. Postoperative movement disorders can lead to various degrees of functional disability. The pathoanatomical correlations are similar to those described in other patients with secondary movement disorders.

Collagen mRNA and fibronectin are increased in healing gastric ulcers in man.

The fibrillar collagens, types I and III, have been demonstrated in healthy human gastric mucosa as well as in the submucosa of gastric ulcer edges, where they were found to be remarkably increased. In order to verify the occurrence and activity of de novo collagen synthesis, we examined gastric biopsy specimens from six patients with antral ulcers and six normal controls. By means of in situ hybridization, using a 35-S-labelled RNA probe, we could identify the specific procollagen mRNA for type I collagen. Fibronectin was stained immunohistochemically employing specific polyclonal antibodies. In normal gastric mucosa, procollagen type I mRNA was expressed by only a very limited number of cells while at the ulcer edges the specific signal could be demonstrated in a large number of submucosal cells. Fibronectin as marker of newly built connective tissue was found to be markedly increased in the submucosa of healing gastric ulcers as compared to normal controls. These results suggest a substantial role of fibroneogenesis in the process of gastric ulcer healing.

Localization of elastase and tumor necrosis factor alpha mRNA by non-radioactive in situ hybridization in cultures of alveolar macrophages.

Digoxigenin is a new tool for labeling probes which can be detected with the help of specific antibodies in the cell by indirect or direct immunostaining. In contrast to the biotin-reaction, the advantage of digoxigenin is that it does not appear in animal or human cells in nature. In comparison to radioactive labeling methods it is favorable in terms of short exposure time and precise localization of signals in the cell. In this paper we describe the localization of elastase and tumor necrosis factor alpha (TNF alpha) mRNA by non-radioactive in situ hybridization of rat alveolar macrophages in cell culture after stimulation with welder steam dusts. Using digoxigenin labeled probes the determination of specific mRNA's expression and their precise localization in the cytoplasm of the cell could be achieved within one day.

Deactivation of thalamocortical activity is responsible for suppression of parkinsonian tremor by thalamic stimulation: a 99mTc-ECD SPECT study.

Four patients with Parkinson's disease (PD) achieved excellent improvement of their unilateral tremor by chronic deep brain stimulation (DBS) of the contralateral ventral intermediate (Vim) nucleus of the thalamus. Repeated measurements of cerebral blood flow were obtained 14 days apart off and on stimulation using 99mTc-ECD SPECT. Subjects were scanned at rest and the data were compared with those of normal healthy volunteers. During stimulation, there were highly significant deactivations in the motor area and supplementary motor area on the electrode side and in the prefrontal area and the anterior cingulum bilaterally. No cerebellar deactivation was detected. We conclude that the mechanism responsible for suppression of parkinsonian tremor by thalamic stimulation is deactivation of thalamocortical activity.

Influence of stepwise uncoupling and temporary anoxia on pancreatic enzyme secretion by isolated rat acini.

For special studies on pancreatic diseases a parameter is needed to record alterations of the cellular energy metabolism. In the in vitro model of isolated pancreatic acini, we investigated whether or not at standardized cholecystokinin stimulation the energy-consuming process of enzyme secretion can be used to monitor changes of the energy-supplying capacity. Rat pancreatic acini were isolated via collagenase digestion and characterized by basal and stimulated release of amylase and trypsin, oxygen uptake under resting and maximally uncoupled conditions and by their ability to accumulate actively rhodamine-6G, as a measure of the mitochondrial membrane potential. The stimulation of enzyme release did not find a measurable reflection in rhodamine-6G accumulation and in the respiratory rat. Stepwise uncoupling of oxidative phosphorylation by 2,4-dinitrophenol (DNP) and temporary anoxia were used to simulate disturbances of the pancreatic energy metabolism in vitro. With increasing DNP concentration the enzyme release was significantly reduced. While after 30 min anoxia the enzyme release still exceeded that of unstimulated control, after 60 min anoxia there was no further response to hormonal stimulation. At standardized stimulation and after suitable calibration the enzyme release by acini may be used to monitor alterations of the pancreatic energy metabolism in vitro.

[Medicinal prevention of gastrointestinal tumors: aspirin, Helicobacter and more?]. / Medikamentöse Prävention gastrointestinaler Tumoren: Aspirin, Helicobacter und mehr?

Despite the huge number of drugs on the market and recent advances in pharmacotherapy, only a few substances are available for the prevention of gastrointestinal tumors--most of which are not approved for this indication or not validated in appropriately designed randomized trials. General recommendations include lifestyle modifications such as avoidance of smoking, only moderate consumption of alcohol, regular physical exercise and a nutrition rich in fresh fruits and vegetables with limited meat. A global eradication therapy for Helicobacter pylori would be desirable to prevent gastric carcinoma, but this does not seem feasible from the socio-economic point of view. Therefore, at least patients at high risk should be screened and this pathogen eradicated, preferentially in their youth. Hepatitis B vaccination of newborns to prevent the development of hepatocellular carcinoma has already been established in Germany; a specific antiviral therapy should be offered to all patients with hepatitis B or C infections, taking into consideration the risks associated with this treatment. The use of non-steroidal anti-inflammatory drugs (NSAIDs) to prevent gastrointestinal malignancies cannot generally be recommended and should be restricted to patients at high risk and to clinical studies. However, the appropriate substance, dose and duration of NSAID therapy are still being debated.