A phase II study of escalated-dose docetaxel with granulocyte colony-stimulating factor support in patients with advanced breast cancer.

PURPOSE: Docetaxel is highly active in the treatment of patients with breast cancer. The principal dose-limiting toxicities of the 3-weekly regimen are neutropenia and febrile neutropenia. In a previous phase I dose-escalation study with granulocyte colony-stimulating factor (G-CSF) support, the recommended dose was determined to be docetaxel 160 mg/m(2) 3-weekly. The objectives of this phase II study were to determine the response rate and toxicity of this dose and schedule, given as first-line in patients with advanced breast cancer. Mobilisation of peripheral blood stem cells (PBSCs) was also investigated. PATIENTS AND METHODS: Eligible women had metastatic breast cancer and were aged 18-75 years with ECOG performance status < or =2. Strict criteria for liver function were followed, and adjuvant chemotherapy must have been completed at least 6 months previously. Treatment was docetaxel 160 mg/m(2) over 60-90 min every 21 days with G-CSF 5 micro g/kg/day until neutrophil recovery, for up to six cycles. A 3-day corticosteroid prophylaxis was given. Bloods samples to determine PBSC levels [CD34+, granulocyte-macrophage colony-forming cells (GM-CFC) and burst-forming units-erythroid (BFU-E)] were taken on days 6, 8, 9 and 11 following docetaxel. RESULTS: Twenty-five women with median age 50 years (range 35-66) were included. Seventeen (68%) had previously received adjuvant chemotherapy. In total, 112 cycles were delivered (median four per patient), with dose reductions required in 12.5% of cycles. G-CSF was given for a median of 6 days. The median neutrophil nadir was 0.5 x 10(9)/l and occurred a median 5 days after treatment. The median duration of grade 3 or 4 neutropenia was 2 days (range 1-7). Grade 4 neutropenia occurred in 44% of patients, but there was only one episode of febrile neutropenia. Five patients were taken off study due to toxicities that included oedema, neurosensory toxicity and asthenia. Confirmed partial response was seen in nine patients (37.5%; 95% confidence interval 19% to 59%). CD34+ cells, GM-CFC and BFU-E levels peaked at day 8 following docetaxel administration. The median CD34+ cell peak was 6.5 x 10(4)/ml, with only 20% of patients <2 x 10(4)/ml, a level below which leukapheresis is not usually attempted. CONCLUSIONS: Docetaxel 160 mg/m(2) was delivered with G-CSF support with a very low rate of febrile neutropenia. Non-haematological toxicity was significant, causing five patients to go off study. Effective mobilisation of PBSCs was seen. The response rate of 37.5% was less than that obtained in first-line studies using standard-dose docetaxel 100 mg/m(2), suggesting that there is no additional benefit in dose escalation of this cytotoxic agent in breast cancer patients using this schedule.

A phase I dose-escalation study of docetaxel with granulocyte colony-stimulating factor support in patients with solid tumours.

BACKGROUND: Docetaxel is a widely active cytotoxic agent. The principal dose-limiting toxicities (DLTs) of the 3-weekly regimen are neutropenia and febrile neutropenia. Use of prophylactic granulocyte colony-stimulating factor (G-CSF) may allow higher doses of docetaxel to be administered with potentially greater anticancer efficacy. The objectives of this study were to determine the maximum tolerated dose (MTD) and toxicity profile of docetaxel given with G-CSF support. PATIENTS AND METHODS: Eligible patients had solid tumours and were aged 18-75 years with a WHO performance status of up to 2. Strict criteria for liver function were followed. Patients may have received one previous regimen of chemotherapy in addition to adjuvant chemotherapy. Cohorts of three to six patients received docetaxel over 60-90 min every 3 weeks, commencing at 110 mg/m(2) and escalating at 10 mg/m(2) increments. Patients also received G-CSF 5 micro g/kg/day until neutrophil recovery. A 3-day corticosteroid prophylaxis was given. RESULTS: Twenty-nine patients with median age 55 years (range 29-75) were included. Fourteen (48%) had previously received chemotherapy. At the 170 mg/m(2) dose level (the MTD), two of three patients had DLTs and 160 mg/m(2) was determined to be the recommended dose. The principal DLTs were skin and neurosensory toxicity. Asthenia was frequent, especially at dose levels >/=140 mg/m(2). Grade 4 neutropenia occurred in only 10 patients (35%) and was not dose related, with febrile neutropenia in three patients (10%). CONCLUSIONS: Docetaxel may be escalated considerably above standard doses when administered with G-CSF support. The recommended dose for phase II studies is 160 mg/m(2). With escalated-dose docetaxel, DLTs were non-haematological and qualitatively similar to the toxicity profile at standard doses.

[Symptomatic and surgical results after integrated CT-MR study of a central giant cell tumor of the maxilla]. / Risultati semeiologici e chirurgici conseguenti allo studio integrato TC-RM del tumore gigantocellulare centrale del massiccio facciale.

The AA. examine the possibilities of the present imaging to the diagnostic definition of the extensive and destructive forms of the Central Giant cells Tumor of the maxilla. The CT and MR studies are compared with conventional x-Ray. The analysis performed evinces, besides the well-known semeiological CT superiority for the evidence of the osseous erosions, the ability to follow by MR imaging the evolution of the tumor, in the its relationships with the fascial, muscular, adipose and fibromucous soft tissues, when it exceeds the osseous barrier of the maxillofacial skeleton, enclosed therein the palatal plane.

[Role of NMR in staging and treatment of extensive myxoma of the upper jaw]. / Ruolo della RM ai fini della stadiazione e del trattamento del mixoma esteso del mascellare superiore.

The diagnostical possibilities of the RM in the study of the odontogenic myxoma at extensive diffusion in the upper maxilla are examined. Owing to its complexity and to close connections with the surrounding soft tissues, the midfacial region makes the conventional means of imaging difficult and inadequate. Really the tumor have very high local aggressivity. Where it is much bulky, invades diffusely the cavitary components, damages their walls with laminar structure, insinuates itself among the soft tissues of the jugal, pterygo-maxillary and infraorbital regions, taking up gorges where it slips the classical clinical an also the conventional instrumental diagnostics. The AA. have verified the utility of the MR imaging to the definition of the limits of the tumor, which makes the surgery more adequate to the necessities of an oncological treatment tending both to the radicality and to conservation of structures with high morphological and functional complexity.

Physiological enteric stimulation elicits cardiovascular reflexes in the rat.

By use of anesthetized rats, parameters for the activation of cardiovascular reflexes by stimulation of gastric or hepatic receptors have been established. For reflex activation, the mean minimum intragastric volume was 4 ml, and the mean minimum rate of hepatic portal vein infusion was 0.3 ml/min. Subdiaphragmatic vagotomy affected the response to gastric distension but did not appear to affect the response to hepatic portal vein infusion, indicating that vagal afferents are involved in mediating gastric-cardiovascular but not hepatic-cardiovascular reflexes. Experiments designed to emphasize the vagal component of the response to gastric distension confirmed this finding. Antagonist effects indicated that the tachycardia was mediated by beta-adrenoreceptor stimulation and that the pressor response was mainly mediated by alpha-adrenoreceptors. The data show that stimuli used in experiments to assess central processing of sensory information from the gastrointestinal tract can activate cardiovascular reflexes. Caution in the design of such experiments and in the interpretation of the data generated is indicated.

Central and peripheral inhibition of exocrine pancreatic secretion by alpha-2 adrenergic agonists in the rat.

The effect of ST91, a clonidine derivative crossing poorly the blood-brain barrier, was compared to that of clonidine on exocrine pancreatic secretion in rats. The experiments were performed in anaesthetized rats after stimulation by a maximal dose of 2-deoxy-D-glucose, and in conscious rats under basal interdigestive conditions. In anaesthetized rats, the 2-deoxy-D-glucose-induced stimulation of pancreatic secretion was suppressed by clonidine but not by ST91, both injected subcutaneously. This effect of clonidine was not antagonized by prazosin, but was decreased by 70-100% (according to the variables measured) by yohimbine. The alpha-2 antagonists rauwolscine and corynanthine were less efficient than yohimbine, while idazoxan suppressed totally the effect of clonidine. In conscious rats, the basal interdigestive secretion was inhibited by ST91 and by clonidine. After sc injections, the potency of ST91 was about ten times smaller than that of clonidine, whereas after injections in the cerebral ventricles, ST91 was as potent as clonidine to inhibit pancreatic secretion. Most (70-90%) of the inhibition induced by sc ST91 and clonidine in conscious rats was suppressed by yohimbine or by prazosin. It is concluded that both ST91 and clonidine inhibit pancreatic secretion in rats, and that this effect has probably both central and peripheral components. The central effect involves alpha-2 receptors, while the peripheral effect may involve alpha-1 and alpha-2 receptors.

Effect of modafinil on pancreatic exocrine secretion in rats. A comparison with adrafinil and related drugs.

The effects of modafinil and adrafinil, 2 drugs that induce locomotor hyperactivity, and those of the parent compounds CRL 40467 and CRL 40385, were studied on the external pancreatic secretion of anaesthetized and conscious rats. In anaesthetized rats modafinil, adrafinil, and CRL 40385 antagonized the central vagal stimulation of protein output induced by 2-deoxy-D-glucose in the pancreatic juice. In conscious rats, modafinil and adrafinil inhibited the output of protein in the basal interdigestive pancreatic secretion. Modafinil was more active than adrafinil as an inhibitor of pancreatic secretion. The effects of modafinil and adrafinil were different from those of sympathetic amines and dopamine: they did not stimulate the output of bicarbonate in anaesthetized rats, and pancreatic inhibition observed in conscious rats was not inhibited by either yohimbine or prazosin.

Acetorphan, an enkephalinase inhibitor, decreases gastric secretion in cats.

Acetorphan is an inhibitor of "enkephalinase" (EC 3.4.24.11) which has been shown to reduce in vivo and in vitro the degradation of enkephalins and other peptides. The effects of acetorphan on gastric secretion were studied in cats fitted with gastric fistulae and Heidenhain pouches. Acetorphan inhibited by 40-60% the acid secretion from the gastric fistulae after stimulation by submaximal doses of pentagastrin, histamine and 2 deoxy-D-glucose. These inhibitions were reduced or suppressed by naloxone. The meal-stimulated secretion from the fistulae was not changed after acetorphan. Acetorphan slightly and progressively reduced the pentagastrin-stimulated acid output from the Heidenhain pouches, and this effect was naloxone resistant. No change was found in the secretion from Heidenhain pouches under histamine stimulation, while meal-induced secretion of the pouches was increased by acetorphan, and this increase was not prevented by naloxone. Endogenous opioids probably exert an inhibitory regulatory control upon the gastric secretion of cats. In addition, non-opioid factors may be involved in the effect of acetorphan on meal-stimulated secretion.

Convergence of sensory information from abdominal viscera in the rat brain stem.

This study was carried out to establish whether there was convergence of sensory information in the rat brain stem stimulated by physiological activation of gastric mechanoreceptors and hepatic glucoreceptors. Extracellular recordings were made from single neurons in the region of the dorsal vagal nucleus and nucleus of the solitary tract in the medulla. The responses of these neurons to gastric distension, hepatic portal vein perfusion of isotonic D-glucose, and hepatic portal vein infusion of isotonic saline were studied. Fifty-six neurons were studied; it was found that there was no significant difference in the proportion of neurons responding to gastric distension compared with the number responding to either form of hepatic stimulation. In 20 neurons (all 3 types of stimulation were tested on the same neuron), both excitation and inhibition were observed with both forms of visceral stimulation. Of the seven of these neurons that responded to hepatic portal vein infusion, four of them also had an input from gastric mechanoreceptors. Only three of the neurons that responded to hepatic stimulation showed a specific response to hepatic glucose perfusion; in the remainder a component of the response was due to the infusion of the volume itself. The results from these experiments have demonstrated an apparently weak functional synaptic projection carried by hepatic vagal afferents, particularly those responding to changes in portal glucose concentration, which may indicate a rather diffuse and nonspecific sensory system in the liver. These results have also demonstrated the convergence onto neurons in the brain stem of information from gastric and hepatic enteroceptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Etorphine inhibition of pancreatic exocrine secretion in rats: comparison with methadone.

The effects of etorphine, a potent opiate agonist without preferential affinity for mu, delta or kappa receptors, on exocrine pancreatic secretion were studied in rats fitted with chronic or acute pancreatic fistulas and compared to those of methadone, a well-documented mu agonist. In conscious rats etorphine (3 micrograms/kg s.c.) inhibited basal pancreatic secretion by about 50% for volume and bicarbonate output and by 70% for protein output. Pancreatic secretion returned to its basal level within 2 h. Methadone (5 mg/kg s.c.) was about equipotent but the inhibition lasted longer. The effects of both etorphine and methadone were completely antagonized by naloxone (1 mg/kg s.c.) and to a lesser extent by diprenorphine (10 microgram/kg s.c.). Yohimbine did not suppress the inhibitory effect of etorphine on protein output but showed some antagonism against the effects of etorphine on water and bicarbonate output. In anaesthetized rats etorphine (3 micrograms/kg) inhibited the pancreatic secretion stimulated by 2-deoxy glucose, a centrally acting vagal stimulatory agent, by 50-60% for volume and bicarbonate output and totally for protein output. The same dose of etorphine did not inhibit the pancreatic secretion evoked by vagal electrical stimulation, a peripheral stimulus. Methadone (5 mg/kg) inhibited the pancreatic secretion stimulated by 2-deoxy glucose to the same extent, but for a longer time than etorphine, and at the same dose did not suppress the pancreatic pancreatic response to vagal electrical stimulation. The inhibitory effects of etorphine and methadone in anaesthetized rats were completely suppressed by naloxone (1 mg/kg s.c.) and only reduced by diprenorphine (10 micrograms/kg s.c.).(ABSTRACT TRUNCATED AT 250 WORDS)

[Effect of 5-thioglucose on external pancreatic secretion in rats. Comparison with 2-deoxyglucose]. / Action du 5-thio-glucose sur la sécrétion pancréatique externe chez le rat. Comparaison avec le 2-désoxy-glucose.

The aim of this study was to compare the stimulation of the external pancreatic secretion induced in rats by two glucose analogs: 5-thio-glucose (5-TG) and 2-deoxy-glucose (2-DG). In rats with an acute pancreatic fistula, 5-TG and 2-DG induced a dose-related increase in outputs of sodium (reflecting the volume), bicarbonate and total protein of the pancreatic juice. The efficacy of both drugs was not significantly different. Maximal responses were obtained with 75 mg/kg 5-TG and 225 mg/kg 2-DG and were approximately 3.5 x (sodium), 5 x (bicarbonate) and 8.5 x (protein) the basal level. Dose-response curves to 5-TG were shifted to the left with respect to 2-DG. The DE50 was approximately 25 mg/kg for 5-TG and 60 mg/kg for 2-DG. The molar potency ratio was 2.5 x, 3.1 x and 3.3 x in favor of 5-TG, for sodium, bicarbonate and protein respectively. The potency, but not the efficacy, of 5-TG is thus greater than that of 2-DG in stimulating external pancreatic secretion.

Loperamide-induced inhibition of pancreatic secretion in rats.

The effects of loperamide on exocrine pancreatic secretion were studied in rats fitted with chronic or acute fistulas. Intraduodenal injection of loperamide in conscious rats resulted in a dose-dependent inhibition of basal pancreatic secretion involving volume and bicarbonate and protein output with an ED50 of about 0.5 mg/kg. The maximal inhibition observed was about 60% for volume and bicarbonate output and 90% for protein output. Loperamide induced an inhibition of pancreatic secretion in conscious rats that was naloxone-sensitive and persisted in cimetidine-treated rats. Thus, it did not depend on modifications of gastric secretion. In anaesthetized rats, loperamide did not inhibit the pancreatic secretion evoked by agents acting directly on the pancreatic cells (acetylcholine, secretin, CCK) but it inhibited by 100% the pancreatic secretion induced by vagal electrical stimulation (VES) and by 80-100% that induced by 5 thio-glucose, a centrally acting vagal stimulatory agent. Loperamide inhibition of VES-induced pancreatic secretion was different from that obtained with morphine or methadone since these opiate drugs could only inhibit by 50-60% maximally the VES-stimulated pancreatic secretion. The loperamide inhibition of VES-induced secretion was naloxone-insensitive, while loperamide inhibition of 5 thio-glucose-induced secretion was in part naloxone-sensitive. These results suggest that loperamide exerts a potent inhibition of pancreatic secretion by acting on the nerve supply to the pancreas through both opiate and non-opiate mechanisms.

Clonidine inhibition of pancreatic secretion in rats: a possible central site of action.

The effects of clonidine on pancreatic secretion were studied in rats fitted with chronic or acute fistulas. Subcutaneous and intracerebroventricular injections of clonidine in conscious rats induced a dose-dependent inhibition of basal pancreatic secretion involving volume, bicarbonate output and protein output with an ED50 of about 10 micrograms/kg. Clonidine inhibition of pancreatic secretion was not dependent on the associated inhibition of gastric acid output. In conscious rats, the pancreatic inhibitory effect of clonidine was completely antagonized by yohimbine and slightly by piperoxane and prazosin. Propranolol, mianserin, naloxone and cimetidine did not antagonize the clonidine effect. Clonidine decreased the basal pancreatic secretion in anaesthetized rats and this action was completely reversed by yohimbine. Clonidine inhibited the pancreatic secretion stimulated by 2-deoxyglucose. This effect was reversed by yohimbine, while prazosin had no effect. Clonidine did not inhibit the pancreatic secretion induced by electrical stimulation of the vagus nerves. These results suggest that clonidine inhibition of pancreatic secretion is mediated through alpha 2-adrenergic receptors, and at least in part by a central nervous system mechanism. Yohimbine alone increased basal pancreatic secretion in conscious rats. This suggests that alpha 2-adrenergic receptors might be involved in the physiological nerve tone to the pancreas.