Peritonectomy and hyperthermic antiblastic perfusion in the treatment of peritoneal carcinomatosis.

AIMS: Some low-grade malignant tumours arising in the abdomen tend to remain loco-regionally confined to peritoneal surfaces, without systemic dissemination. In these cases complete surgical tumour cytoreduction followed by intra- or post-operative regional chemotherapy has curative potential. The aim of this study was to evaluate the outcome for patients treated in this way. METHODS: Peritonectomy was performed, involving the complete removal of all the visceral and parietal peritoneum involved by disease. After peritonectomy, hyperthermic antiblastic perfusion was carried out throughout the abdominopelvic cavity for 90 min, at a temperature of 41.5-42.5 degrees C, with mitomycin C (3.3 mg/m2/l) and cisplatin (25 mg/m2/l) (for appendicular or colorectal primaries), or cisplatin alone (for ovarian primaries). Alternatively, the immediate post-operative regional chemotherapy was performed with 5-fluorouracil (13.5 mg/kg) and Lederfolin (125 mg/m2) (for colonic or appendicular tumours) or cisplatin (25 mg/m2) (for ovarian tumours), each day for 5 days. RESULTS: Thirty-five patients affected by extensive peritoneal carcinomatosis were submitted to peritonectomy, with no residual macroscopic disease in all cases except three. Twenty-six patients were able to undergo the combined treatment involving loco-regional chemotherapy. Complications were observed in 54% of the patients and led to death in four of them. At a mean follow-up of 17 months overall 2-year survival was 55.2%, with a median survival of 26 months. CONCLUSIONS: After a learning curve of 18 months the feasibility of the integrated treatment increased to more than 90%, while mortality decreased dramatically. The curative potential of the combined therapeutic approach seems high in selected patients with peritoneal carcinomatosis not responding to systemic chemotherapy. Careful selection of patients can minimize the surgical risk, but the treatment should currently be reserved for clinical trials.

Gene expression and in vitro release of galanin in rat hypothalamus during development.

The expression and distribution of the mRNA coding for galanin precursor, preprogalanin (ppGAL), were analysed in several rat hypothalamic nuclei (periventricular, paraventricular, supraoptic, dorsomedial and arcuate nuclei and the lateral hypothalamic area) during development by an in situ hybridization technique and computer-assisted grain counting over individual cells. ppGAL mRNA (expressed as number of grains/100 microns2) was detectable from postnatal day (PD) 1 in all the nuclei considered, and the amount of transcript per cell was 6-11 times less than in the adult. ppGAL mRNA progressively increased from PD8 to 14 to 21. The level of ppGAL mRNA in all the nuclei at PD21 was about half that in adulthood, except in the dorsomedial nucleus, where the difference was no more than 20%. As an index of the activity of galanin-containing neurons, we measured the basal and K(+)-evoked in vitro release of galanin-like immunoreactivity from hypothalamic slices of PD14, 21 and 90 rats by radioimmunoassay. Basal release of galanin-like immunoreactivity remained at the same level from PD14 to PD90, but the response to KCl (50 mM) stimulation was lower at PD14 (approximately 90%) and PD21 (> 200%) than at PD90 (350%). Basal and K(+)-evoked release was sensitive to tetrodotoxin, indicating a neuronal origin. This study provides the first evidence that the increase in ppGAL mRNA during the ontogeny of hypothalamic nuclei is associated with an increase in galaninergic neuronal function.

Expression of GAL mRNA in rat hypothalamus: effect of frontal deafferentation and colchicine treatment.

The expression of galanin (GAL) mRNA was determined by in situ hybridization after frontal deafferentation and colchicine treatment in the rat hypothalamus. Frontal deafferentation significantly increased the signal in the paraventricular nucleus (PVN), the supraoptic nucleus (SON), and dorsomedial nucleus (DMN). Colchicine treatment induced a diffuse enhancement of GAL mRNA in hypothalamic nuclei. When the two treatments were combined there was an additivity of GAL mRNA expression in the previous hypothalamic nuclei and also in the arcuate nucleus (AN), where the single treatments did not modify the signal. These results suggest the regulation of GAL mRNA expression mediated by a multineuronal pathway, separate from the colchicine-induced GAL mRNA increase.

Effect of tianeptine on the central cholinergic system: involvement of serotonin.

The effect of tianeptine on in vivo acetylcholine (ACh) release from brain hemispheric regions of freely moving rats was investigated using the microdialysis technique coupled with a sensitive radioenzymatic method. Tianeptine, at the dose of 30 mg/kg i.p., reduced ACh release from dorsal hippocampi by 40% in 40 min, and induced a 30% decrease of ACh output from frontal cortices while at the doses of 10 and 20 mg/kg it had no effect. In striata the drug did not significantly affect ACh release although it showed a tendency to increase it. The ACh content in the three areas considered was not affected by tianeptine at above doses. The drug did not alter choline-o-acetyltransferase and acetylcholinesterase activities suggesting that it did not influence the cholinergic system through direct action on the ACh metabolism; furthermore, it did not influence the sodium-dependent high-affinity uptake of choline in striatum, cortex and hippocampus. Impairment of serotonergic (5-HT) neurotransmission by chemical lesion of the median raphe nucleus or by metergoline, a blocker of 5-HT receptors, antagonized the cholinergic effect of tianeptine. The involvement of the serotonergic system is specific because lesions of the noradrenergic dorsal bundle failed to prevent the inhibitory action of tianeptine. The present data suggest that 5-HT may mediate the effect of tianeptine on the cholinergic system in dorsal hippocampi.

Activity of centrally administered galanin fragments on stimulation of feeding behavior and on galanin receptor binding in the rat hypothalamus.

Synthetic fragments of galanin 1-29 were administered intraventricularly or into the paraventricular nucleus of the hypothalamus for analysis of the critical amino acid sequence necessary to stimulate feeding behavior in rats. Galanin 1-29 and galanin fragment 1-16 significantly increased feeding at doses of 6 nmol microinjected into the lateral ventricles and 1 nmol microinjected into the hypothalamus. There was no significant effect of D-TRP2 galanin 1-16 microinjected into the hypothalamus, and no significant effect of galanin fragments 1-9, 10-20, 12-29, 17-29, or 21-29 microinjected intraventricularly, on food consumption. Synthetic fragments of galanin 1-29 were assayed for displacement of 125I-galanin 1-29 binding to rat hypothalamic membranes. The efficacies of the galanin fragments in the feeding paradigm were consistent with the relative affinities of these fragments for the hypothalamic galanin receptor in equilibrium binding experiments. The first 16 N-terminal amino acids appear to contain galanin agonist activity on increasing food consumption and to bind to the galanin receptor in the rat hypothalamus.