[Semi-automatic measurements of hepatic lobes. Application to study of liver volumes. Analysis of 50 computed tomography of normal liver]. / Mesure semi-automatique des différents lobes hépatiques. Application à la recherche d'une corrélation entre volumes des lobes du foie. Une étude sur 50 angioscanners de foies sains.

OBJECTIVE: Healthy and pathological hepatic volumetry can be of great interest in Liver pathology and treatment. We studied the hepatic segmentation in order to verify if it is possible to estimate the volume of one lobe, when the volume of the other lobe or the total liver is known. PATIENTS AND METHODS: We studied 50 normal hepatic angiotomographies. For each exam and using the Couinaud classification, we measured the total hepatic volume, the right lobe, the left lobe and the caudate lobe volumes. We used a software called "Hepato" developed in order to quantify automatically CTScan images of the liver. We performed a linear regression analysis (least squares method) and calculated the determination coefficient to study the correlation between the different volumes. RESULTS: The mean total hepatic volume was 1497 cm3. We obtained for the right lobe 1231 cm3, 226 cm3 for left lobe, and 39 cm3 for the caudate lobe. Moreover there was a weak correlation between these volumes. CONCLUSION: Exact volume estimation of an hepatic lobe in one patient can not be obtained from the total hepatic volume. However, theses volumes can only be measured from three-dimensional images. Since classical image editing tools are time request, it becomes impossible to utilize them in a clinical routine to get the different volumes of the Liver. Thus, a software dedicated for liver parenchyma recognition is necessary.

Lipid-mediated transfection of normal adult human hepatocytes in primary culture.

The aim of this work was to develop a procedure for the lipid-mediated transfection of DNA into normal adult human hepatocytes in culture. Cells were plated in a serum-free culture medium at various cell densities, on plastic or collagen-coated dishes, both in the absence and in the presence of epidermal growth factor (EGF). The cells were incubated for various periods of time with mixtures of DNA-lipofectin or DNA-3 beta[N-(N',N'-dimethylaminoethane)-carbamoyl] cholesterol (DC-chol) liposomes, and the efficiency of transfection was assessed by measuring the activity of reporter genes, beta-galactosidase or chloramphenicol acetyl-transferase (CAT). For comparison, similar experiments were carried out with human cell lines including HepG2, Caco-2, and WRL68. The efficiency of transfection (in percentage of cells) was not significantly different after transfection with lipofectin or DC-chol and comprised between 0.04 and 1.7% (extreme values) for different cultures. The efficiency of transfection decreased as the age or density of the culture increased and increased in cultures treated with EGF. Direct measurement of the rate of DNA synthesis suggested that the efficiency of transfection was related to the number of cells entering the S phase. Under the same conditions, the efficiency of transfection was one to two orders of magnitude greater in the three cell lines. A plasmid harboring 660 bp of the 5'-flanking region of CYP1A1 (containing two xenobiotic enhancer elements) fused upstream of the promoter of thymidine kinase and the CAT reporter gene was constructed. When this plasmid was transfected in human hepatocytes, CAT activity was induced as expected. We conclude that normal adult human hepatocytes can be transfected with exogenous DNA and that the transfected construct is regulated in the manner expected from in vivo studies.

[Application of three-dimensional computer graphics in oncology]. / Application de l'infographie tridimensionnelle en cancérologie.

Accurate 3D tumoral volume evaluation is now possible through the combined use and progress of computer graphics technics (3D reconstruction and visualization) and medical imagery (helicoidal TDM scanner). Specific organ and pathology oriented softwares can help answer rapidly to problems posed by oncologic praticians. A new decision support for diagnosis, therapy and follow-up is emerging. First results in liver tumors and hepatic regeneration macroscopic biometrics are presented. Tumoral or organ volumic index will be usable in the follow-up. TNM staging, external conformal radiotherapy for prostatic or brain tumors, drugs cytolytic effects evaluation will take great advantage of these technologies. 3D visualization and matching CT and MRI imagery can help computed assisted surgery.

[Total and prolonged parenteral nutrition at the hospital and at the patient's home: its socio-economic importance]. / La nutrition parentérale totale et prolongée à l'hôpital et au domicile du malade: son intérêt socio-économique.

Total parenteral nutrition with "All in one" nutritive mixtures is used in France from 1970. These advances ensure a more simple treatment for intensive care units. Nutritive mixtures provide the caloric and nitrogen daily requirements added with micronutrients (electrolytes, trace elements and vitamins) and this technique allows home parenteral nutrition. "All in one" nutritive mixtures have reduced the infectious complications and the industrial quality control during parenteral solutes admixing has decreased again this infectious risk. So, nutritive mixtures result in sparing of nurse time, material for preparation and antibiotic costs. Moreover, although the costs of home parenteral nutrition are considerable, this technique still reduces annual costs by 50% to 70%, avoids prolonged hospitalization and allows the patients to resume a more normal existence at home. Development of new technologies and nutritive mixtures for specific malnutrition are now required to improve treatment of these patients with insufficiency digestive tract.

Oxidative metabolism of lansoprazole by human liver cytochromes P450.

The aim of this work was to identify the form(s) of human cytochrome P450 (P450) involved in the hepatic biotransformation of lansoprazole to its two main metabolites, i.e., the sulfone and the hydroxy derivative. In liver microsomes, the production of the sulfone of lansoprazole correlated with the level of P450 3A4, cyclosporin oxidase, and the production of the hydroxy derivative, as well as of omeprazole sulfone. The production of hydroxylansoprazole moderately correlated with the level of P450 3A4, cyclosporin oxidase, and (S)-mephenytoin 4'-hydroxylase. The production of the sulfone and of the hydroxy derivative of lansoprazole was significantly inhibited by anti-P450 3A4 antibodies, by cyclosporin and ketoconazole, and by tolbutamide. Anti-P450 2C8 and 2C3 antibodies moderately inhibited the biotransformation of lansoprazole, whereas they completely inhibited (S)-mephenytoin 4'-hydroxylase activity under the same conditions. In primary cultures of human hepatocytes, the biotransformation of lansoprazole and the oxidation of cyclosporin were strongly increased by rifampicin and phenobarbital, whereas (S)-mephenytoin 4'-hydroxylation was not. beta-Naphthoflavone did not induce the formation of the sulfones but stimulated the production of hydroxylansoprazole. Among several forms of cDNA-expressed human P450s, 3A4 generated significant amounts of the sulfones of lansoprazole and omeprazole and 2C18 was active for the production of hydroxylansoprazole but inactive in the 4'-hydroxylation of (S)-mephenytoin. We conclude that P450 3A4 is the major enzyme involved in the production of the sulfone of lansoprazole and that this P450, as well as P450 2C18 and/or another 2C-related form, could contribute to the production of hydroxylansoprazole.

Mediation by an androgen receptor of the stimulatory effect of testosterone on the growth of a fibrosarcoma in the rat.

We studied the effect of testosterone on the growth of a 20- methylcholanthrene-induced transplanted fibrosarcoma and assayed androgen receptors in this tumor. The effect of an antiandrogen in male rats and the comparative tumor growth in females confirmed the androgen sensitivity. A synthetic androgen that strongly binds to the androgen receptor was used to characterize the binding activity in nuclear extracts of tumor. Scatchard analysis showed that the dissociation constant of the hormone receptor complexes (Kd) was 26 +/- 2 nmol/l and the number of binding sites was about 95 +/- 12 fmol/mg of protein. The hormone-receptor complexes sedimented in the region of 3.7 S.

Repeated hepatic resections for liver metastases from colon carcinoma. Montpellier Cancer Institute experience.

The main cause of death after hepatic resection for colorectal liver metastases is tumor recurrence. An improvement in survival may be achieved by resection of recurrent hepatic metastases as previously reported. In this paper we report our experience with 13 repeated liver resections in 11 patients. The post-operative mortality was 8% and the morbidity was 23% with two biliary tract fistulas and one recurrent pleural effusion. The median survival time from the first hepatic resection was 23 months, but differed according to the length of the disease-free interval (more than 1 year and less than 1 year: 49 and 17 months, respectively (P < 0.05). Our results suggest that repeated hepatic resection is technically a safe procedure and may be beneficial to selected patients. All candidates should be carefully evaluated pre-operatively for extrahepatic disease.

Omeprazole and lansoprazole are mixed inducers of CYP1A and CYP3A in human hepatocytes in primary culture.

The ability of several gastric antiulcer drugs including lansoprazole, cimetidine and ranitidine to affect the expression of human liver microsomal cytochromes P450 comparatively to omeprazole, reported previously to be a CYP1A inducer, was evaluated in primary cultures of human hepatocytes. Poly (A)+ RNA and microsomes extracted from the cells were analyzed in Northern and Western blots with specific cDNA probes and antibodies, and assayed for form-specific monoxygenase activities. Lansoprazole induced both CYP1A1 and CYP1A2 as omeprazole and did not apparently bind to the aryl hydrocarbon receptor with high affinity. Omeprazole sulfone was not an inducer of CYP1A. Omeprazole, omeprazole sulfone and lansoprazole induced CYP3A in approximately 50% of tested cultures, whereas 100% of tested cultures responded to omeprazole and to rifampicin in terms of CYP1A and CYP3A induction, respectively. Finally, cimetidine and ranitidine were not inducers. We conclude that omeprazole and lansoprazole constitute a new class of mixed inducers of CYP1A and CYP3A in human hepatocytes in primary culture and that the induction of CYP3A in response to these molecules could be polymorphic in humans.

[Short bowel syndromes in adults. Prognostic factors. Evaluation and treatment. Retrospective study. Apropos of 80 cases]. / Les syndromes de l'intestin grêle court de l'adulte. Facteurs pronostics. Evaluation et traitement. Etude rétrospective. A propos de 80 cas.

Since 1981, a consensus is appeared in order to define and to precise the natural evolution of short bowel with a maximal remaining small bowel of 150 cm. The phenomenon of intestinal adaptation which are better known in animals than in humans, are on the dependence of luminal, hormonal and humoral factors (epidermal growth factor, polyamines). The knowledge of prognostical factors and the anatomical and functional evaluation of remaining small bowel allow to "measure" the improvement of digestive absorption and to decide the duration of nutritional support. An experience in 80 cases of short bowel syndrome is reported. A significant correlation exists between the duration of parenteral nutrition support and the length of the remaining gut (p < 0.001) and multifactorial analysis differentiates 3 groups of short bowel characterized by their length and parenteral support duration.

[Serum marker of the functional hepatic mass after extensive hepatectomy. The branched/aromatic amino acid ratio. Experimental and clinical studies]. / Un marqueur sérique de la masse hépatique fonctionelle après hépatectomie élargie. Le rapport des acides aminés ramifiés (AAR) sur les aromatiques (AAA). Etudes expérimentales et cliniques.

During severe hepatic insufficiency, serum amino acid profile is modified with an increase of aromatic amino acids (AAA) (Tyrosine and Phenylalanine) and methionine concentrations and a decreased value of 3 branched chain amino acids (BCAA) (leucine, isoleucine and valine). These observations have been confirmed after hepatic surgery in experimental and clinical studies. In experimental models, after 10, 32, 68, 77 or 90% hepatectomy in Wistar rats, the BCAA/AAA ratio (R) is correlated with the extent of hepatectomy: r = 0.74, p < 0.001; with the post-operative interval time (8, 24, 32, 48, 168 or 240 hours): r = 0.60, p < 0.001 and with the liver weight when animals are sacrificed: r = 0.64, p < 0.001. In clinical studies, 26 patients have undergone 60 to 80% hepatectomy for primary or secondary tumors of the liver and R is determined on the immediate post-operative day and every day during the first post-operative week. Liver regeneration is followed by single photon emission computerized tomoscintigraphy on days 0, 7 and 30 with assessment of hepatic growth index (HGI) estimated by the ratio: liver mass on day 7 or 30/remnant liver mass on day 0. On post-operative day 7, R is 1.61 +/- 0.3 (normal: 3.5 +/- 0.51). Mean liver volume is 60 +/- 11% and HGI is 1.9 +/- 0.3. On this day, a correlation is found between R and HGI (r = 0.76). On post-operative day 30, HGI is 2.34 +/- 0.50, mean liver volume is 89.6 +/- 0.9% and R is 2.02 +/- 0.65.(ABSTRACT TRUNCATED AT 250 WORDS)

[Liver tumors around the vena cava. Strategy for surgical approach of segments I and IX]. / Les tumeurs du foie autour de la veine cave. Stratégie d'abord chirurgical des segments I et IX.

The technical problems raised by the delicate surgery of tumours of the liver developing around the vena cava, with and without invasion of segments I and IX was studied on the basis of 7 cases reports. The intra- or extra-hepatic pedicule route, the denudation of the entire retrohepatic vena cava, and the clamping needed for exsanguinous surgery are presented together with future perspectives including 3-D liver imaging, stimulation of liver regeneration potential and ex-vivo techniques are discussed with the aim of more and more carcinological liver surgery.

[Therapeutic strategy in 46 cases of radiation injury of the intestine]. / Stratégie thérapeutique dans 46 cas d'intestin radique.

Our expérience in the treatment of 46 cases with radiation enteritis (RE) permitted to summarize 5 key points in the Surgical Strategy: laparotomy incision, enterolysis technique, small bowel and colon preservation, anastomosis technic and parenteral nutritional support. Surgery is imposed most of the time in digestive and nutritional Insufficiencies due to radiation enteritis. 46 patients aged to 33-81 years (mean age = 59) were included for possible surgery. The first clinical digestive symptoms were occlusion (n = 39) and/or digestive fistula (n = 7) and/or perforation (n = 3). These abnormalities were often associated with severe malnutrition (weight loss > or = 20% of usual weight) inducing surgery preparation with pre-operative parenteral nutrition (8 to 350 days). 3 patients were not operated because of general problems and lived 1 to 7 months after the beginning of parenteral nutrition. For operated patients (n = 43), 12 underwent 2 operations (resection and/or enteral liberation) and one patient underwent 4 surgical interventions because of digestive fistula. In 35 cases, small bowel resection was performed leaving 135.4 +/- 62.6 cm of intestine (0 to 225 cm of jejunum and/or ileum) and in 13 cases, complete enterolysis was achieved. All the patients received a post-operative parenteral nutrition during 1 to 23 months (median = 6.2 +/- 5.3 months). 31 patients received home parenteral nutrition during the pre and/or post-operative phase for a median duration of 6.3 +/- 3.2 months (range: 1-23 months). 4 patients died during the immediate post-operative phase and among them, 3 died after the second surgery. 12 deaths were observed due to the primary cancer and 6 due to the evolution of radiation lesions. Median survival of patients without cancer evolution reach 180 months with a 5-year survival rate of 94% (Kaplan-Meier method). In patients with radiation enteritis, the pre and post-operative nutritional support associated with radical surgery allows to obtain prolonged survival in non cancer patients.

[Therapeutic strategy for large cervical, mediastinal metastatic mature teratomas and large retro- and intraperitoneal lesions]. / Stratégie thérapeutique devant de volumineuses métastases tératomateuses matures cervicales, médiastinales et d'énormes lésions rétro et intra-péritonéales.

A 27 years old man was treated after surgery and classic chemotherapy for a right testicular teratoma (stage IV). Two months after the end of chemotherapy the patient developed "a Growing Teratoma Syndrome" with left subclavian and mediastinal nodes enlargement and bulky abdominal cystic masses with vena cava compression, collateral circulation and oedema of inferior members. Four debulking surgical approaches: cervical, thoracic and abdominal were performed and permitted complete functional recovery.

Conservative treatment for low rectal carcinoma by local excision with or without radiotherapy.

Thirty-seven patients with low rectal carcinoma were treated by transanal resection between January 1979 and December 1988. Adjuvant radiotherapy was used in eight patients before operation, in 13 after operation and six patients had both preoperative and postoperative radiotherapy. The selection criteria for transanal resection were low, superficial tumours treated conservatively with curative intent (group 1, 18 patients) or patients medically unfit for (12) or refusing (seven) abdominoperineal resection (APR) (group 2, 19 patients). In group 1, the local recurrence rate was 11 per cent with an overall 5-year survival rate of 100 per cent. In group 2, the local recurrence rate was 53 per cent with an overall 5-year survival rate of 35 per cent. There was no postoperative mortality and minimal morbidity. Salvage of local failure was by APR in six patients. The survival rate after local recurrence was 70 per cent at 1 year and 30 per cent at 5 years. Transanal resection can be proposed as a curative procedure for selected low, small, minimally infiltrating and well differentiated adenocarcinomas. Local control might be improved by postoperative radiotherapy for Astler-Coller stage B1 tumours or those above 3 cm in diameter. Further trials should examine the results of high-dose (60 Gy) preoperative radiotherapy so that transanal resection might be employed for favourable post-irradiation stage (0 or A) lesions. This new strategy will benefit from a better evaluation of tumour response after primary radiotherapy and an improved assessment of histological excision margins.

Importance of the paracellular pathway for the transport of a new bisphosphonate using the human CACO-2 monolayers model.

The transport of a new bisphosphonate, Tiludronate, was investigated on the human adenocarcinoma cell line, CACO-2. Experiments were performed 7-16 days after cells achieved confluence, conditions under which they form well-differentiated monolayers joined by tight junctions. Tiludronate transport rate across CACO-2 monolayers was independent of the temperature (4 degrees versus 37 degrees), of the polarity of the cell membrane (apical-to-basolateral versus basolateral-to-apical), and of the presence of metabolic poisons (sodium azide). Its transport was enhanced by either the presence of EGTA in the incubation buffer, i.e. when extracellular Ca2+ concentration was reduced, or by the pretreatment of monolayers with EGTA, i.e. when the intercellular spaces and the tight junctions were widened. Based on these different observations, we could suggest that Tiludronate mainly used the paracellular pathway to cross the intestinal epithelium. An increase in the Tiludronate permeability coefficient was also observed following treatment of cells with high Tiludronate concentrations, as a consequence of the direct effect of this compound on the extracellular Ca2+ ions. Hence, for high drug concentrations, i.e. 20 mM, we observed a decrease in free extracellular Ca2+ concentration, an increase in the transepithelial electrical resistance and an increase in the transport of [14C]polyethyleneglycol ([14C]PEG400), a probe for the paracellular pathway. The results indicate that Tiludronate is transported across CACO-2 monolayers by the paracellular route. Moreover, it can affect its own transport by its concentration-dependent effect on tight junction widening.

Evidence for CYP3A-mediated N-deethylation of amiodarone in human liver microsomal fractions.

Metabolism of amiodarone to its N-deethylated derivative was investigated on a bank of human hepatic microsomal fractions, two of them lacking the CYP2D6 isozyme. Michaelis-Menten constants for amiodarone N-deethylation were 0.33 +/- 0.11 microM and 2.38 +/- 0.74 nmol/min/mg for KM and Vmax. The specific involvement of CYP3A gene subfamily in amiodarone N-deethylation was provided by the following observations: 1) metabolism of amiodarone is inhibited in a concentration-dependent manner by ketoconazole, a specific CYP3A inhibitor, and by nifedipine, a specific substrate for CYP3A gene subfamily, with IC50 of 0.3 and 25 microM, respectively; 2) nifedipine competitively inhibits amiodarone metabolism with a Ki of 38 microM; 3) amiodarone N-deethylation is increased following incubation with hepatic microsomal fractions prepared from CYP3A-inducers such as rifampycin and triacetyloleandomycin, but also following the in vitro disruption of the "cytochrome P-450-Fe-(II)-triacetyloleandomycin nitroso derivative" complex; 4) antibodies raised against either rabbit or baboon monkey CYP3A gene subfamily inhibit amiodarone N-deethylation; and 5) microsomal fractions that specifically express CYP3A4 biotransform amiodarone to its N-deethylated derivative. These studies indicate that CYP3A isozyme(s) mainly metabolize amiodarone to its N-deethylated derivative in human hepatic microsomal fractions.

Treatment of fistulas of the gastrointestinal tract with total parenteral nutrition and octreotide in patients with carcinoma.

The development of a fistula is a serious postoperative complication. Conservative medical treatment with total parenteral nutrition, skin care and intensive infection control usually succeeds in closing fistulas (60 to 75 percent), but the treatment is of long duration (two to three months), high cost and high morbidity related to prolonged hospitalization. We have used octreotide, a long half-life stomatostatin analog, in 40 patients from two European university centers with postoperative enterocutaneous fistulas. Twenty-two patients had low fistula output and 28 patients had high fistula output. Spontaneous closure was achieved in 77.5 percent of the patients after a mean of 13.6 days. One patient died. Glucose intolerance, which has been reported with stomatostatin treatment of fistulas, was not observed. Previous chemotherapy or radiotherapy or low albumin level (23 grams per deciliter) negatively influenced fistula closure. As an adjunct treatment to primary care (total parenteral nutrition, skin care and infection control), octreotide is efficient in reducing fistula output and accelerating spontaneous fistulas closure.

Comparison of two methods of autologous intrasplenic hepatocellular transplantation in partially hepatectomized dogs.

Autologous hepatocellular transplantation using reflux into the spleen via the venous tributaries was compared in 65% hepatectomized dogs to direct injection into the splenic pulp. Transplantation into the spleen via the inferior terminal polar splenic vein led to a better survival rate (50 vs. 0%). Hepatocytes embolization to the intrahepatic portal vein system was observed. Although hepatocyte transplantation into the spleen can be accomplished either by direct punction of the spleen or by retrograde injection into a splenic vein, the second method decreases the frequency of cell embolization.