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Aim Therapeutic options for primary and secondary liver tumours not suitable for resection or transplantation are limited. In this palliative situation, the scope of ablative therapeutic procedures has improved. Laser interstitial thermotherapy is a minimal invasive procedure for local tumour destruction within solid organs. This pilot study reports initial clinical experience using ultrasound-guided percutaneous laser interstitial thermotherapy. Methods Sixty patients between the ages of 34 and 78 years with non-resectable primary and secondary liver tumours were treated palliatively with Nd:YAG laser interstitial thermotherapy. High resolution abdominal ultrasound with power duplex was used to control the placement and coagulation procedure. Results In all cases, sonographic imaging allowed exact placement of the laser probe and verification of thermocoagulation by a resulting hyperechogenic signal enhancement. The maximum diameter of laser-induced destruction measured 5 cm. Ultrasound with power duplex and echo enhancer, CT or MRI scans indicated necrosis of treated tumour lesions. No serious adverse event occurred and 30-day-mortality was zero. Conclusions Ultrasound-guided laser interstitial thermotherapy is safe and reliably ablates primary and secondary liver tumours. The combination of high resolution ultrasound and laser therapy facilitates a minimally invasive but elaborate treatment. Besides chemotherapy, this procedure could be a useful palliative treatment to control the mass of liver tumours unsuitable for resection or transplantation.

Primary biliary cirrhosis (PBC) is an autoimmune disease of the liver with inflammation of small and middle-sized bile ducts. Serum lipids are frequently elevated, but the use of a lipid lowering drug therapy in PBC is still a matter of debate. Application of an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase in hypercholesterolemic PBC patients was therefore the subject of the present study.Six female patients (aged 46.5 (32-61) years; median (range)) were treated with the HMG-CoA reductase inhibitor simvastatin (5 or 20 mg/day). Levels of serum total cholesterol, low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol were determined prior to and after 2 months of treatment. Concentrations of serum markers of cholestasis, antimitochondrial antibodies (AMA), and immunoglobulins A, G and M were also assessed.Simvastatin significantly (P0.05) reduced serum levels of total cholesterol, LDL cholesterol, alkaline phosphatase, -glutamyltransferase, and immunoglobulin M (by 19, 26, 12, 37 and 14%, respectively).The lipid lowering potency of the HMG-CoA reductase inhibitor simvastatin was confirmed in hypercholesterolemic patients with PBC. The drug might also prove useful as modulator of cholestasis and of immune response in this disease.

Fallbericht: Eine 83-jahrige Patientin wurde mit gastrointestinalen Symptomen, zunehmender Verwirrtheit und verwaschener Sprache notfallmasig stationar aufgenommen. In der Vorgeschichte waren ein Diabetes mellitus Typ 2, weshalb die Patientin Metformin einnahm, und eine grenzwertig eingeschrankte Nierenfunktion bekannt. Bei Aufnahme fanden wir eine soporose Patientin mit Kussmaul'scher Atmung, die mit einer Korpertemperatur von 32.1°C deutlich unterkuhlt war. Die Kreislaufverhaltnisse waren bei einem Blutdruck von 80/30 mm Hg und einer Herzfrequenz von 86/min instabil. Laborchemisch fiel bei Aufnahme eine Lactatazidose mit einem pH-Wert von 6,71, einem Base Excess von −30, einem Standardbicarbonat von 4,0 mmol/l und einem Lactatwert von 24,4 mmol/l auf. Zudem bestand ein akutes Nierenversagen mit einem Serumkreatinin von 10,6 mg/dl und einem Harnstoff-N von 134 mg/dl. Die Elektrolyte lagen im Normbereich, die Blutglucose war mit 147 mg/dl erhoht. Aufgrund von Anamnese, klinischer Symptomatik und typischer Laborkonstellation konnte sofort die Verdachtsdiagnose Metformin-assoziierte Lactatazidose mit akutem Nierenversagen gestellt werden. Ein bei Aufnahme deutlich erhohter Metforminwert im Serum bestatigte spater diese Diagnose. Es wurde schnellstmoglich eine Bicarbonathamodialyse eingeleitet. Nach insgesamt 8-stundiger Hamodialyse war der Saure-Basen-Haushalt nahezu normwertig. Der Vigilanzzustand der Patientin normalisierte sich unter dieser Therapie rasch. Im Folgenden waren keine weiteren Hamodialysen mehr notwendig, die Nierenfunktion normalisierte sich unter ausreichender Flussigkeitszufuhr fast vollstandig. Die Patientin wurde auf eine Insulintherapie umgestellt. Schlussfolgerungen: Die Metformin-assoziierte Lactatazidose ist keine seltene Nebenwirkung bei Patienten mit zunehmender Niereninsuffizienz. Um eine fruhzeitige Diagnose stellen zu konnen, sollten Arzten und Patienten die klinischen Symptome einer Metforminintoxikation gut bekannt sein. Zur Normalisierung des Saure-Basen-Haushalts ist die Bicarbonathamodialyse Therapie der Wahl, da hierdurch auch Metformin effektiv eliminiert werden kann. Natriumbicarbonatinfusionen erscheinen dagegen wenig erfolgversprechend. Um dieser Nebenwirkung von Metformin vorzubeugen, sollten die Nierenfunktion regelmasig uberwacht und bei Verschlechterung Metformin abgesetzt werden.

To evaluate circulating human hepatic lipase mRNA as an indicator of circulating hepatoma cells by reverse transcriptase-polymerase chain reaction (RT-PCR) in patients with hepatocellular carcinoma (HCC).Prospective studyUniversity hospital, Germany.15 patients with hepatocellular carcinoma and 8 healthy volunteers.Peripheral venous blood was obtained and total RNA was extracted from the lymphocytic layer by caesium chloride gradient centrifugation. The mRNA was reverse transcripted, and hepatic lipase cDNA was amplified by hepatic lipase specific primers with PCR. The integrity of isolated RNA was confirmed by RT-PCR with beta-actin specific primers. Amplificates were visualised by agarose gel electrophoresis and ethidium bromide staining.Detection of hepatic-lipase-specific RT-PCR products in peripheral blood.Circulating hepatic lipase-specific PCR products were detected in all patients with HCC and in all healthy controls.Detection of circulating human hepatic lipase-mRNA by RT-PCR does not indicate metastasising HCC.

Glucagon-like peptide-1 (GLP-1) is the most potent endogenous insulin-stimulating hormone. In the present study the plasma stability and biological activity of a GLP-1 analog, [Ser]GLP-1(7-36)amide, in which the second N-terminal amino acid alanine was replaced by serine, was evaluated in vitro and in vivo. Incubation of GLP-1 with human or rat plasma resulted in degradation of native GLP-1(7-36)amide to GLP-1(9-36)amide, while [Ser]GLP-1(7-36)amide was not significantly degraded by plasma enzymes. Using glucose-responsive HIT-T15 cells, [Ser]GLP-1(7-36)amide showed strong insulinotropic activity, which was inhibited by the specific GLP-1 receptor antagonist exendin-4(9-39)amide. Simultaneous i.v. injection of [Ser]GLP-1(7-36)amide and glucose in rats induced a twofold higher increase in plasma insulin levels than unmodified GLP-1(7-36)amide with glucose and a fivefold higher increase than glucose alone. [Ser]GLP-1(7-36)amide induced a 1.5-fold higher increase in plasma insulin than GLP-1(7-36)amide when given 1 h before i.v. application of glucose. The insulinotropic effect of [Ser]GLP-1(7-36)amide was suppressed by i.v. application of exendin-4(9-39)amide. The present data demonstrate that replacement of the second N-terminal amino acid alanine by serine improves the plasma stability of GLP-1(7-36)amide. The insulinotropic action in vitro and in vivo was not impaired significantly by this modification.

The effect of various carbohydrates on glucagon-like peptide-1 (GLP-1) release was studied in the in vivo perfused rat ileum. GLP-1 concentrations in the mesenteric venous effluent increased significantly after luminal perfusion with substrates of a sodium/glucose co-transporter (D-glucose, D-galactose, methyl-alpha D-glucoside, and 3-O-methyl-D-glucose). D-Fructose induced a sodium-independent release of GLP-1. Carbohydrates like 2-deoxy-D-glucose and N-acetyl-D-glucosamine, which are not substrates of a luminal sodium/glucose or fructose transporter, did not affect GLP-1 release. Since methyl-alpha D-glucoside is not a substrate of the basolateral glucose transport mechanism and 3-O-methyl-D-glucose is not metabolized within intestinal cells, it is concluded that intracellular metabolism of carbohydrates and intracellular removal are not essential to induce GLP-1 secretion in rats.

BACKGROUND Data on the blood glucose response of diabetic patients to mixed meals containing food both rich in fiber and with a low glycemic index, such as dried peas, is scarce. Thus, the extent to which type 2 diabetic patients should take into account low-glycemic, high-fiber foods for their daily carbohydrate intake is uncertain. OBJECTIVE We compared the glycemic and insulinemic responses to 3 different meals based on dried peas, potatoes, or both in patients with type 2 diabetes undergoing dietary treatment. DESIGN The meals, prepared according to local recipes and consumed at weekly intervals in random order at lunchtime, contained comparable amounts of carbohydrate, fat, protein, and water. The carbohydrate source of the meals differed and was supplied from either dried peas (meal 1), potatoes (meal 3), or a combination thereof (meal 2). Peripheral and venous blood was sampled over 180 min. RESULTS The increases in postprandial plasma glucose and insulin concentrations were delayed and significantly smaller after the pea meal than after the potato meal. The areas under the glucose curve were 164 +/- 40, 257 +/- 57, and 381 +/- 40 mmol x 180 min/L for meals 1, 2, and 3, respectively (P < 0.01). The areas under the insulin curve were 13.8 +/- 4.3, 15.4 +/- 3.9, and 31.2 +/- 6.9 nmol x 180 min/L, respectively (P = 0.0514). CONCLUSION These findings suggest that carbohydrates in dried peas may be largely disregarded in carbohydrate counting and that type 2 diabetic patients should probably increase their consumption of low-glycemic, high-fiber foods at the expense of high-glycemic, low-fiber foods.

AIMS: Absorption of laser light energy induces denaturation of proteins and thermocoagulation of irradiated tissue. Recently, MRI-guided laser coagulation in combination with MR thermometry was reported as a treatment of liver tumours. In the present study ultrasonographic imaging was evaluated for its suitability in laser induced tissue thermocoagulation. METHODS: Fresh porcine livers were used for ex vivo examinations. Placement of the laser catheter and tissue coagulation during laser light emission were online monitored by ultrasonography. Nd:YAG laser-induced tissue damage was evaluated by macroscopical and microscopical examinations of histological sections. RESULTS: During laser light emission a marked hyperdense signal enhancement was observed by ultrasonography which strongly correlated with the extent of macroscopic tissue damage. The size of laser-induced coagulation zone depended on both the power setting and total energy delivered. Carbonization of the tissue surrounding the laser tip is a limiting factor because of laser light absorption. However our data indicate that using appropriate laser energy and exposure time prevent carbonization although carbonization can not be visualized by ultrasonography. CONCLUSIONS: It is concluded from the present ex vivo studies that laser coagulation can be effectively performed under ultrasonographic guidance.

Increased c-fos mRNA or fos immunoreactivity within the central nervous system has been used as a marker of neuronal activation. Acute stress and acute immune challenge result in an increase in c-fos mRNA in corticotrophin-releasing factor (CRF)-containing neurons in the paraventricular nucleus (PVN). It has often been implied that an increase in fos in the PVN can be equated to an increase in the activity of CRF itself, although there is some evidence to suggest these events are not linked. In the present study we have used the rat model of adjuvant-induced arthritis (AA), in which, despite the activation of the pituitary-adrenal system associated with inflammation, there is a paradoxical decrease in CRF mRNA and CRF peptide release. AA rats are unable to mount a hypothalamo-pituitary-adrenal (HPA) axis response to acute stress. They are, however, able to mount a response to acute immune stimulation, e.g. lipopolysaccharide injection. Despite the lack of HPA axis response to stress, there is an increase in c-fos mRNA to these challenges in AA. This suggests that the increase in c-fos mRNA in response to acute stress is not related to a subsequent increase in CRF mRNA in this model. We can conclude that under these conditions, c-fos mRNA is not a good marker of HPA axis activation and independent estimation of the involvement of CRF in the stimulation of the HPA axis should always be obtained. The AA model may prove useful for the comparison of the relationship between immediate early genes and heteronuclear RNAs in response to acute stress and immune stimuli with which to tease apart the molecular mechanisms underlying the control of releasing factor activation at the level of the PVN.

Hepatocellular carcinomas (HCC) frequently recur after partial liver resection or orthotopic liver transplantation, possibly because of the presence of a small number of hepatoma cells in the peripheral blood. Detection of circulating HCC cells might improve therapeutic options and could predict disease recurrence resulting from a metastasizing disease. In the present study, human albumin-mRNA was detected by RT-PCR in the peripheral blood of patients with hepatocellular carcinoma. Circulating albumin-specific PRC products were detected in each patient with HCC, but also in healthy volunteers. It is concluded that albumin-mRNA is not specific to circulating hepatoma cells and therefore does not indicate metastasizing disease.

Seven patients with metastasized midgut carcinoids were treated with intravenous infusion of dacarbazine [dimethyltriazenoimidazole carboxamide (DTIC)] (650 mg/m2) every 4 wk. After 2 wk, white blood cell counts decreased transiently in three patients. No other DTIC-associated side effects occurred. Biochemical markers of disease activity decreased significantly in four patients for 4-20 months (mean duration, 12 months). Size of hepatic metastases was reduced or remained unchanged in six patients for 6-20 months (mean duration, 10 months). Clinical symptoms such as cutaneous flush, diarrhea, abdominal pain, constipation, night sweat, or weight loss improved in six of seven patients. We conclude that DTIC represents a useful therapeutic option in the treatment of advanced and metastasized carcinoid tumors.

Background: In patients with unresectable hepatic metastases or primary liver tumors therapeutic options are limited. Laser-induced thermotherapy could be a minimal invasive option for palliative treatment of hepatic metastasized tumors. Thereby, absorption of laser light energy induces denaturation of proteins and thermocoagulation of tumor cells. Methods: Laser coagulation was performed by using a neodymium-yttrium alum/n/urn garnet (Nd:YAG) laser (Dornier MediLas fibertom 4100) with a scattering-dome light emitter and a water-cooled application catheter (Somatex). On the basis of ex vivo experiments 36 patients with unresectable hepatic tumors (15 colorectal carcinomas, 7 pancreatic adenocarcinomas, 4 gastric carcinomas, 4 metastasized midgut carcinoids, 5 hepatocellular carcinomas, 1 cholangiocellular carcinoma) were treated with LII3. After local anesthesia and intravenous sedation with midazolam laser probes were placed percutaneously under ultrasonographic guidance. Up to 5 metastases were treated per session. Results: During laser light emission uitrasonographic imaging showed a marked signal enhancement that allowed estimation of the coagulation zone. Percutaneous LITT was performed without any side effects such as bleeding, infection or liver injury. The 30 day mortality was zero. Patients left the hospital within 3 days after LITT. A significant tumor reduction was demonstrated by abdominal CT or MRT. Conclusions: It can be concluded that percutaneous LITT can be safely performed under ultrasonngraphic guidance in patients with malignant liver tumors. LITI induces significant destruction of tumor mass as verified by abdominal CT or MRT.

INTRODUCTION: Explorative laparoscopy combined with guided liver biopsy offers many advantages in the diagnosis and staging of liver diseases. Its use might be limited by the invasivity of the technique and the development of non-invasive diagnostic imaging techniques, respectively. In the present publication we report about a minilaparoscopic technique that uses miniaturized scopes to reduce the risc of trauma. PATIENTS AND METHODS: Between April 1999 and Novembre 1999 30 patients (6 females and 24 males) underwent diagnostic assessment for chronic liver disease by minilaparoscopy. The mean age was 56 years in the female patients (range:27 to 73 years) and 43 years in the male patients (range: 20 to 72 years). Minilaparoscopy was performed in local anesthesia and weak sedation using a 1.9 mm optical instrument, which was inserted through the same 2.75 mm trocar as the Veress needle used for inflating the pneumoperitoneum. The minilaparoscop was connected to a video converting system that enabled monitoring on a video scope. Liver specimens were obtained under laparoscopical sight through an additional 2.3 mm trocar. RESULTS: Minilaparoscopy could be performed in all 30 patients without any severe complications. In one of the initial cases liver biopsy was not performed because of technical difficulties. In all other patients it was performed without any limitations. Macroscopic evaluation of the liver revealed a steatosis in 4 cases (histological diagnosis idem), acute hepatitis in 2 cases (histological diagnosis idem), cirrhosis in 7 cases (agreement with histological diagnosis in 6 cases), and no sighns of cirrhosis in 16 cases (histological diagnosis idem). In one patient a disseminated peritoneal carcinosis was found that appeared histologically as a low differenciated adenocarcinoma. CONCLUSIONS: The minilaparoscopical technique allows macroscopic and histological diagnosis of liver diseases with a minimum of invasiveness. It is tolerated excellent by the patients and is a safe technique. It is concluded that explorative minilaparoscopy is a useful technique in the diagnosis of liver diseases and peritoneal carcinosis.