TNF promotes metastasis by impairing natural killer cell activity.

Inflammatory mediators such as tumor necrosis factor (TNF) and interleukin-1 enhance tumor colony formation in different models of experimental and spontaneous metastasis. The involvement of the natural killer (NK) cell system in this process was investigated. Tumor necrosis factor does not appear to act directly on tumor cells by reducing their susceptibility to the cytotoxic action of NK cells but rather impairs NK activity in tumor-bearing mice. Such impairment of the natural killer system might be one means by which TNF supports tumor colony formation. Even though the metastasis- enhancing effect of TNF remained detectable in mice which have a greatly reduced NK cell cytotoxic activity due to a defect in the bg locus, normal mice which were depleted of NK cells by antibody treatment did not show enhanced metastasis after TNF injection. Therefore, the TNF-enhanced metastasis can only be seen as long as some NK cell function is operating in the animals.

[Endoscopic management of benign strictures of the common bile duct]. / A ductus hepaticus communis benignus szükületeinek endoscopos kezelése.

UNLABELLED: 3 females with benign hepatic duct strictures were treated endoscopically. The treatment consisted of placement of one or two endoprostheses in all cases and endoscopic balloon dilatation in two cases. The stent was removed from the first patient--who had hepatic duct stones as well--after a 15 months stenting period and mechanical lithotripsy and balloon dilatation were performed with good results. The second and third patient-after stent insertion--was operated with suspicion of malignancy. Tumor was not proved. In the second patient the endoscopically placed stent was changed by a large diameter teflon stent surgically. The third patient's stents were left in place. These stents were removed after 3 months and balloon dilatation was performed. Patients' jaundice subsided and cholangitis improved following the stent insertion. COMPLICATIONS: Stent occlusion developed and common bile duct stones occurred once. There was not observed any other complication. Benign hepatic duct strictures can be treated by combination of prolonged endoscopic biliary stenting and balloon dilatation successfully.

[Palliative endoscopic treatment of proximal malignant biliary stenosis]. / Májkapui malignus epeúti stenosisok endoscopos palliatív kezelése.

24 patients (median age 71.5 years) with inoperable proximal malignant biliary obstruction were treated by insertion of endoscopic endoprostheses from January 1991 to August 1994. 10 patients had gallbladder cancer, 6 cancer of body or tail of pancreas, 5 cholangiocarcinoma and 3 other metastatic malignancy, respectively. 13 patients had type I, 10 had type II and 1 had type III proximal biliary stenosis (Bismuth classification). Stent occlusion or dislocation required a secondary stent insertion in 9 patients. In all cases there was adequate biliary drainage after stent insertion. Complications were: early cholangitis developed in 2 patients, late cholangitis in 5, stent dislocation in 3. One patient underwent an operation because of necrotising cholecystitis and subhepatic abscess. There was no bleeding, retroperitoneal perforation or pancreatitis. 18 patients died (median survival time 28 weeks) and 6 have been alive at the time of review for 15 weeks in average. Endoscopic stent insertion can be applied effectively also in the palliative treatment of proximal malignant biliary obstruction.

Promotion of experimental liver metastasis by tumor necrosis factor.

Models for experimental metastasis were established to investigate the influence of rmTNF on tumor-colony formation in the liver. Highly metastatic lymphoma tumor cells were either injected i.v. or inoculated s.c. to form spontaneous metastases. In both systems, administration of rmTNF to the animals led to significant enhancement of the number of liver metastases in comparison with control groups. The number of metastatic tumor-cell colonies at an early stage of metastasis was increased, as well as the number of surface metastases in a late stage. Consequently, TNF-treated animals revealed a higher mortality. The optimal time for TNF to exert this metastasis-enhancing effect was found to be 7 days after tumor inoculation. In vitro adhesion of the lymphoma tumor cells to a mouse endothelioma cell line was strongly inhibited by monoclonal antibodies interfering with the interaction of VCAM-1 with VLA-4. These results support and extend earlier results with a fibrosarcoma lung colonization model. In addition, they show that stimulation of the immune system in tumor-bearing hosts activates tumor-promoting pathways, in addition to having possible beneficial effects.

Role of adhesion molecules and platelets in TNF-induced adhesion of tumor cells to endothelial cells: implications for experimental metastasis.

Mechanisms for TNF-enhanced adhesion of tumor cells to endothelial cells were investigated for their in vivo relevance in a model of experimental metastasis. Mouse fibrosarcoma and thymoma cells were used to analyze TNF-modified adherence to three different mouse endothelioma cell lines and the results were compared to the in vivo colonization behavior of the tumor cells. TNF enhanced tumor cell adhesion in vitro and extravasation in vivo with similar characteristics. The role of different adhesion molecules in these experimental systems was tested. Blocking of ICAM-1, LFA-1, VCAM-1, E-selectin, and P-selectin did not reduce TNF-enhanced metastasis even though tumor cell adhesion in vitro was reduced. However, the correlation between inhibition of integrin binding and inhibition of metastasis achieved with competing peptides indicated an important role for extracellular matrix components in tumor cell attachment. Platelets play a dual role: although in vitro platelets prevented tumor cell adhesion to endothelial cells, in vivo platelet-depletion of mice reduced metastasis.

[One year results after extracorporeal shock wave lithotripsy of gallbladder stones]. / Extracorporalis lökéshullám-kezelés egy éves eredményei epehólyag-kövességben.

512 patients with gallbladder stones (393 females, mean age 52.7 years; 119 males, mean age 46.9 years) were treated by extracorporeal shock wave lithotripsy with an electrohydraulic Dornier MPL 9000 lithotripter. The Munich criteria were used for patients selection. Midazolam (15 mg im) and piritramid (mean 7.5 mg iv) were administered as analgetics. Stone fragmentation was achieved after an average of 1.92 treatment sessions. In 12 cases (2.3%) there was no fragmentation. Ursodeoxycholic acid (10 mg/kg/day) was administered as adjuvant litholytic therapy until 3 months after total fragment clearance. During a period of a year the patients returned for follow-up investigations in decreasing number. The total fragment clearance rate was 43.3%, for the I. group (single stone of 5 to 20 mm) was 58%, for the II. group (single stone of 21 to 30 mm) was 28.6%, for the III. group (2 or 3 stones of 30 mm maximum diameter) was 21.4%. In 12 cases (1.2%) vasovagal reactions, in 31 cases (3.1%) atrial and ventricular extrasystoles, in 27 cases (2.7%) transient gross hematuria were observed. During a period of a year 18 cholecystitis (3.5%), 8 pancreatitis (1.56%) and 5 obstructive jaundice (0.97%) developed. 28 cholecystectomies (5.4%), 1 necrectomy because of necrotic pancreatitis (0.19%) and 5 endoscopic sphincterotomies (0.97%) were required.

Mechanisms involved in metastasis enhanced by inflammatory mediators.

The enhancement of tumor metastasis by concurrent inflammatory processes is mainly due to the cytokines TNF and IL-1. In the case of TNF this effect is not restricted to metastasis models as measured by in vivo colony formation but also found in experimental model systems of spontaneous metastasis. Direct effects on the tumor cells or interference with the host NK cell system did not seem to account for the observed TNF effect. Experimental evidence from different test systems rather points to TNF- or IL-1-induced enhanced adhesion of tumor cells to the endothelial cell layer as the underlying mechanism. Blocking of integrin-matrix interactions with monoclonal antibodies or competing peptides inhibited tumor cell adhesion to endothelioma cells in vitro and lung colony formation of tumor cells in vivo.

[Thr role pf extracorporeal shock wave therapy in the removal of common bile duct stones]. / Az extracorporalis lökéshullám-kezelés szerepe nagyméretü choledochus kövek eltávolításában.

Extracorporeal shock wave lithotripsy was performed on 4 high risk patients with large common bile duct stones by a Dornier MPL 9000 lithotripter and X-ray positioning. Every patient was treated twice using 2000 shock wave discharges and 21 kV average generator voltage in a single session. Average treatment time was 51 minutes. Desintegration of 3 patients stone was successful and fragments were removed by Dormia basket extraction and by biliary lavage. One out of the four patients stone failed to be desintegrated this patient underwent an operation. Apart from mild fleabite-like petechiae and some atrial and ventricular extrasystoles no other side effects were observed.

[Surgical treatment of gallbladder diseases in patients over 70 years of age]. / A 70 éven felüliek epebetegségének sebészeti kezelése.

The authors give a retrospective analysis of the results of 162 biliary operations performed in a five-year period on patients over 70 years of age. The mortality rate of 87 elective operations was 3.45%, of 75 acute operations 6.17%. During the same period 321 ERCPs and 120 ESTs were carried out in patients over 70, out of whom 2 were operated on and lost (mortality: 1.67%) because of bleeding after EST. The total mortality rate was 7.41% (n = 12). The circumstances of negative and positive choledochotomies were analysed together with the relationship between the operating time and the course of the disease. Out of the negative choledochotomised patients (n = 10) 3, out of the positive ones (n = 40) 5 patients died. For each patient over 70, to shorten the operative time and to prevent perioperative complications, the authors recommend the consideration of ERCP prior to biliary operation, and in certain cases, instead of elective biliary surgery, for bile duct stone, EST and stone extraction is advisable, leaving the calculous gallbladder "in situ". Further investigations are necessary, in the authors opinion, to decide whether prior to emergency operation on patients over 70 urgent ERCP and, when bile duct stone is diagnosed, EST with stone extraction is justified, too.

Enhancement of experimental metastasis by tumor necrosis factor.

The influence of endogenous and exogenous tumor necrosis factor (TNF) on metastasis was investigated in an experimental fibrosarcoma metastasis model. A single intraperitoneal injection of recombinant human (rh) TNF or recombinant mouse (rm) TNF into mice 5 h before intravenous inoculation of methylcholanthrene-induced fibrosarcoma cells (CFS1) induced a significant enhancement of the number of metastases in the lung. Dose responses of rmTNF and rhTNF demonstrated a stronger metastasis-augmenting effect by rmTNF compared with rhTNF. This effect was time dependent, as administration of rmTNF 5 h before or 1 h but not 24 h after tumor cell inoculation caused an increase of tumor cell colony formation on the lung surface, suggesting an influence of TNF on the vascular adhesion and diapedesis of tumor cells. Since tumor-bearing mice showed an enhanced ability to produce TNF after endotoxin injection compared to control mice, tumor-bearing mice were treated with anti-mTNF antibodies. Neutralization of endogenous tumor-induced TNF led to a significant decrease of the number of pulmonary metastases. Histological analysis of micrometastases in the lung on day 5 by silver staining of proteins associated with nucleolar organizer regions revealed more metastatic foci and augmented proliferative activity of the tumor cells after rmTNF pretreatment of mice. However, no direct effect of rmTNF on the proliferation rate of tumor cells was seen in vitro. These findings suggest that low doses of endogenous TNF or administered TNF during cytokine therapy might enhance the metastatic potential of circulating tumor cells.