Ultrasound-guided laser interstitial thermo therapy for treatment of non-resectable primary and secondary liver tumours--a feasibility study.

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.

Ultrasound imaging of Nd:YAG laser-induced tissue coagulation in porcine livers.

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.

Immunoreactive leptin and leptin mRNA expression are increased in rat hypo- but not hyperthyroidism.

In this study, plasma leptin concentrations were measured in rats artificially rendered hyper- or hypothyroid by administration of thyroxine or TRH, by administration of methimazole, or by thyroidectomy. Compared with those in untreated controls, leptin immunoreactivity was not affected in the hyperthyroid state, but was significantly increased in hypothyroid animals. Methimazole administration for longer time periods caused a stepwise increase in plasma leptin immunoreactivity. Greatest leptin concentrations were seen after 28 days of methimazole. Seven days after withdrawal of the methimazole, leptin concentrations no longer differed from those observed in control animals. In hypothyroid animals, expression of leptin mRNA was increased in both retroperitoneal and epididymal adipose tissue, whereas no difference was seen for subcutaneous or mesenteric fat. Incubation of rat leptin with plasma of eu- or hypothyroid rats and subsequent HPLC analysis of leptin plasma peaks gave no indication of an altered hormone stability. We conclude that, in hypothyroid rats, leptin concentrations may be increased as a result of stimulated leptin synthesis in retroperitoneal and epididymal adipose tissue.

Circulating human hepatic lipase mRNA in patients with hepatocellular carcinoma and healthy controls.

OBJECTIVE: 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). DESIGN: Prospective study SETTING: University hospital, Germany. SUBJECTS: 15 patients with hepatocellular carcinoma and 8 healthy volunteers. INTERVENTIONS: 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. MAIN OUTCOME MEASURES: Detection of hepatic-lipase-specific RT-PCR products in peripheral blood. RESULTS: Circulating hepatic lipase-specific PCR products were detected in all patients with HCC and in all healthy controls. CONCLUSION: Detection of circulating human hepatic lipase-mRNA by RT-PCR does not indicate metastasising HCC.

A synthetic glucagon-like peptide-1 analog with improved plasma stability.

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.

Serum leptin levels in hypo- and hyperthyroidism.

Leptin, the product of the ob gene, is an important circulating signal for the regulation of body weight. In the present study the role of immunoreactive leptin (leptin-IR) was investigated in functional thyroid disease. Serum leptin-IR levels of 23 hypothyroid and 19 hyperthyroid patients were compared with 21 controls. Leptin-IR was quantified by a specific RIA. In hyperthyroid patients, leptin-IR was not different from controls. Serum leptin-IR levels were significantly increased in hypothyroid patients (21.0 +/- 2.7 micrograms/l vs controls 10.8 +/- 2.1 micrograms/l, P = 0.0044). When serum leptin of hypothyroid patients was compared with euthyroid controls of the same body mass index the difference was still significant (P = 0.0333 by paired Student's t-test). This might indicate that elevation of the serum leptin level does not merely reflect changes in body weight secondary to hypothyroidism, but might be increased to overcome the gain of body weight caused by hypothyroidism.

Release of glucagon-like peptide-1 (GLP-1) by carbohydrates in the perfused rat ileum.

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.

Detection of circulating albumin-mRNA by RT-PCR does not indicate metastasizing hepatocellular carcinoma.

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 PCR 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.

Effect of a platelet-activating factor antagonist on pancreas perfusion after 24 h of ischemia.

Platelet-activating factor (PAF) is a strong mediator of inflammation that is present in many mammalian tissues and cell types. In the pancreas, PAF can be synthesized in acinar cells after stimulation with secretagogues. The present study uses a perfused porcine pancreas model to investigate the role of PAF in pancreatic ischemia and the effect of the PAF antagonist bepafant on pancreas preservation. Pancreata were preserved with or without bepafant, stored for 24 h at 4 degrees C, and then reperfused at 37 degrees C in a perfusion chamber. Reperfusions were significantly improved by the addition of bepafant. This was indicated by a significantly increased arteriovenous volume flow (16.54 +/- 1.88 ml/min versus controls 8.54 +/- 1.31 ml/min; p = 0.0068; bepafant, n = 7; controls, n = 12) and a reduced vascular resistance (p = 0.0068; bepafant, 1.95 +/- 0.22 mm Hg * min/ml versus controls 4.08 +/- 0.56 mm Hg * min/ml). Radioimmunological quantification of PAF in pancreatic tissue revealed that PAF levels remain unchanged during storage in a cold protective solution at 4 degrees C but increase significantly during surgical pancreas preparation under general anesthesia (from 142.1 +/- 21.2 to 368.8 +/- 52.5 pg/g; n = 15; p = 0.0007). The present study shows that bepafant improves pancreas preservation after cold ischemia. The beneficial effect might be explained by antagonizing inflammatory and vasoconstrictory responses to PAF synthesized during surgical pancreas preparation.

Treatment of metastasized midgut carcinoids with dacarbazine.

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.