Long-term weekly treatment of colorectal metastatic cancer with fluorouracil and leucovorin: results of a multicentric prospective trial of fluorouracil dosage optimization by pharmacokinetic monitoring in 152 patients.

PURPOSE: A relationship between fluorouracil (5-FU) dose and response has been previously shown in advanced colorectal cancer. In a previous study with 5-FU stepwise dose escalation in a weekly regimen, and pharmacokinetic monitoring, we defined a therapeutic range for 5-FU plasma levels: 2,000 to 3,000 microg/L (area under the concentration-time curve at 0 to 8 hours [AUC0-8], 16 to 24 mg x h/L). The current study investigated 5-FU therapeutic intensification with individual dose adjustment in a multicentric phase II prospective trial. PATIENTS AND METHODS: Weekly high-dose 5-FU was administered by 8-hour infusion with 400 mg/m2 leucovorin. The initial dose of 5-FU (1,300 mg/m2) was adapted weekly according to 5-FU plasma levels, to reach the therapeutic range previously determined. RESULTS: A total of 152 patients entered the study from December 1991 to December 1994: 117 patients with measurable metastatic disease and 35 with assessable disease. Toxicity was mainly diarrhea (39%, with 5% grade 3) and hand-foot syndrome (30%, with 2% grade 3). Among 117 patients with measurable disease, 18 had a complete response (CR), 48 a partial response (PR), 35 a minor response (MR) and stable disease (SD), and 16 progressive disease (PD). Median overall survival time was 19 months. The 5-FU therapeutic plasma range was rapidly reached with a variable 5-FU dose in the patient population: mean, 1,803 +/- 386 mg/m2/wk (range, 950 to 3,396). Thirteen patients were immediately in the toxic zone, whereas 51 required a > or = 50% dose increase. CONCLUSION: Individual 5-FU dose adjustment with pharmacokinetic monitoring provided a high survival rate and percentage of responses, with good tolerance.

[Cirrhosis induced by vitamin A]. / Cirrhose induite par la vitamine A.

The case of a 75-year-old woman who had been treated for 12 years by vitamin A (250,000 UI/day) for psoriasis is presented. During the hospitalisation, hepatic cirrhosis was detected and attributed to hypervitaminosis A based on disease history, clinical hypervitaminosis A features, increased vitamin A blood values and histological patterns, i. e. perisinusoidal fibrosis and spontaneous fluorescence of lipid vacuoles within fat-storing cells. Thus, although rare, vitamin A intoxication can be responsible for cirrhosis.

[Antro-pyloro-bulbar contractibility in diabetics studied by cineradiography. Effect of erythromycin]. / Etude de la contractilité antro-pyloro-bulbaire chez le diabétique par analyse de cinéradiographies. Effet de l'érythromycine.

We studied antropyloroduodenal contractility in diabetics and the effect of erythromycin IV (100-500 mg) using the non invasive Boiron cineradiographic method analysis. Fourteen diabetics and 22 controls were examined. Four hours after a standard liquid-solid meal, patients drank 250 mL baryum solution. Fluorographic plates (10 x 10 cm) were taken every 2 s during 30 s. Semi-automatic data processing analysis allowed to measure motility parameters including antral (CA) and bulbar (CB) contractility indexes; pyloric opening index (OP), gastric (FG) and bulbar (FB) frequencies. Three types of pylorus behaviour patterns were define: A and B related to antropyloric and antropyloroduodenal coordination respectively and N without coordination. In diabetics, CA, OP and FG were decreased vs controls (P < 0.01) (CA: 65.5 +/- 6.8 vs 83.1 +/- 2.4%; OP: 60.9 +/- 8.7 vs 84.8 +/- 1.9%; FG: 2.42 +/- 0.14 vs 3.08 +/- 0.04 c/min) and antropylorbulbar coordination altered (N was predominant; no bulbar cycles at 3/min). Antral hypocontractility was correlated with autonomic neuropathy. After erythromycin, radiological parameters returned to normal values (CA = 83.0 +/- 2.4%; OP = 86.0 +/- 4.7%; FG = 3.0 +/- 0.16 c/min) and coordination improved type N disappeared and FB = 3 c/min (58%). Cineradiographic analysis is simple, able to show antropylorobulbar contractile abnormalities, to study pharmacological effects, and in diabetics is capable of studying improvement of motility parameters with erythromycin.

[Simplified measurement of colonic transit time by one radiography of the abdomen and a single type of marker. Normal values in 82 volunteers related to the sexes]. / Mesure simplifiée du temps de transit colique par une seule radiographie de l'abdomen et un seul type de marqueur. Normes chez 82 témoins en fonction du sexe.

Assessment of total and segmental colonic transit times (CTT) in man using a single type of radiopaque marker and one abdominal X-ray has been validated but not extensively studied. The aims of our prospective study were to establish normal values of this method as a function of age, gender and fiber intake in healthy subjects. Eighty-two healthy volunteers (51 men, 31 women, mean age 38 yr, range 21-61) with normal stool frequency (between 3/day and 3/week) and no history of gastrointestinal disease or medication were enrolled and ingested 10 small (3 mm edge) radiopaque markers every morning for 6 consecutive days. On the 7th day, an abdominal X-ray was performed to calculate total and segmental (right, left, rectosigmoid) CTT according to Arhan's method (CCT = 2.4 N; N = number of markers in the considered zone). During the study the number of stools was recorded and fiber intake estimated on a questionnaire. Stool frequency, total and segmental CTT were evaluated for differences due to age, gender and/or fiber intake. In volunteers, total, left and rectosigmoid CTT were closely related to stool frequency (P = 0.0001) being longer in women than in men (P < 0.02). In contrast, right CTT was independent of gender or stool frequency. Finally, in this group CTT were independent of age and fiber intake. This study confirms the influence of gender on CTT and demonstrate the ability of this simple and non-invasive method (0.08 mrad surface exposure) to assess CTT. Its use as a diagnostic tool in self-defined constipated patients would be of interest in clinical practice.

[Profile and evolution of irritable bowel syndrome. Prospective national epidemiological study of 1301 patients followed-up for 9 months in Gastroenterology. Groupe d'Etude Nationale sur le Syndrome de l'Intestin Irritable (SII)]. / Profil et évolution du syndrome de l'intestin irritable. Etude épidémiologique nationale prospective chez 1,301 consultants en Gastroentérologie suivis 9 mois. Groupe d'Etude Nationale sur le Syndrome de l'Intestin Irritable (SII).

From March to October 1989, 237 French gastroenterologists included 1,301 patients referred for irritable bowel syndrome in a 9-month epidemiological survey based on questionnaires and monthly auto-evaluation. In the patient population, the high preponderance of women (sex ratio: 2.33), the high prevalence of cholecystectomy (9%), appendectomy (53%) and an association with at least one symptom of non-ulcer dyspepsia (70%) were observed. Fifty per cent of the patients completed the 9-month follow-up period; among them, 60% declared an improvement in their symptoms, but only 30% in their quality of life and independently of the clinical course. This study suggests that symptoms and quality of life in patients consulting for irritable bowel syndrome should be taken into account separately, both in daily practice and in therapeutic evaluation.

[Abdominal emergencies in type IV ehlers-Danlos syndrome]. / Urgences abdominales du syndrome d'Ehlers-Danlos de type IV.

Ehlers-Danlos syndrome denotes a group of inherited connective tissue diseases comprising nine types. Type IV Ehlers-Danlos syndrome is the most life-threatening form. It is characterized by a type III collagen deficiency resulting in arterial fragility and death from vascular rupture or bowel perforation. This disease involves a col 3A1 gene mutation. We report the case of a 44 year-old woman with type IV Ehlers-Danlos syndrome. The medical history of our patient included bowel necrosis and two vascular ruptures. We indicate data required to establish Ehlers-Danlos syndrome diagnosis and guidelines for patient management.

[Gastric granulocytic sarcoma revealed by a massive digestive hemorrhage]. / Sarcome granulocytaire gastrique révélé par une hémorragie digestive massive.

We report the case of a 37-year-old-man having a chronic myelogenous leukemia, who presented, one month after a splenic acutization, massive gastrointestinal bleeding from ulcerated nodules of the gastric fundus. The histologic examination of one of these nodules showed granulocytic sarcoma. In spite of an endoscopic treatment by sclerotherapy with adrenalined serum, the death occurred during a hemorrhagic recurrence. This observation, which is the third case reported of gastric granulocytic sarcoma during the acutization of a myelogenous chronic leukemia, and the first revealed by fatal gastrointestinal bleeding, shows the particular gravity of gastrointestinal bleeding complicating granulocytic sarcoma.

Alterations in gastric mucus secretion in rhesus monkeys after exposure to ionizing radiation.

The aim of the present study was to evaluate the effect of gamma-irradiation on soluble gastric mucus. Six conscious chair-adapted rhesus monkeys were studied once before and twice after exposure to ionizing irradiation (800 rads). Using a marker (99mTc-DTPA) dilution technique, acidic glycoprotein (AG), neutral glycoprotein (NG), ion, and fluid output were determined during a basal period and after the administration of an 80-ml water load. Irradiation significantly increased the outputs of both AG and NG during the basal period. After the water load, NG output remained elevated but irradiation abolished postload AG output thus inhibiting the normal rise in AG output stimulated by the load. Two days after irradiation NG output had returned to control levels whereas AG output was still suppressed. Sodium and potassium ion outputs were unaltered by irradiation. Chloride and fluid outputs were significantly inhibited on the day of irradiation but had returned to control levels within 3 days. These results indicate that irradiation produces significant changes in both the quantity and nature of the soluble mucus glycoproteins secreted into the gastric juice. It is suggested that these changes may compromise the protective ability of gastric mucus.

The role of endogenous prostaglandins in the regulation of gastric secretion in rhesus monkeys.

Prostaglandins (PG) are known to alter a variety of gastrointestinal functions, but the physiological role of endogenous PG remains unclear. This experiment was designed to evaluate changes in gastric secretion following both acute and chronic inhibition of PG synthesis with indomethacin (5 mg/kg s.c.). Gastric juice was collected by continuous aspiration in 8 conscious chair-adapted male rhesus monkeys following treatment with saline or indomethacin for one or four days. The gastric juice was analyzed for H+, Na+, K+, and Cl- concentrations. The amount of soluble mucus in the gastric juice was estimated using Alcian Blue dye binding of acidic glycoproteins and Periodic Acid Schiff reaction with neutral glycoproteins. PG levels were measured in the plasma and in biopsy samples of fundus, antrum and duodenum. Both one and four days of indomethacin significantly (p less than 0.05) decreased tissue PG levels in the fundus, antrum and duodenum. Plasma levels of PGF2 alpha were significantly (p less than 0.05) decreased after both one and four days of indomethacin, while PGE2 and 6-keto PGF1 alpha were significantly inhibited only after four days of indomethacin. Both acute and chronic inhibition of PG synthesis was accompanied by a decrease in the concentration of sodium and mucus in the gastric juice but by an increase in the output and concentration of hydrogen ion. These changes suggest a possible mechanism by which endogenous PG play a role in the regulation of gastric secretion and in the protection against gastrointestinal damage.