Conservative surgical management of Boerhaave's syndrome: experience of two tertiary referral centers.

BACKGROUND: Surgery is generally proposed for Boerhaave's syndrome, spontaneous rupture of the esophagus. But diagnosis can be difficult, delaying appropriate management. The purpose of the present study was to evaluate outcome of conservative surgery for primary or T-tube repair performed in two tertiary referral centers. METHODS: From June 1985 to November 2010, among 53 patients presenting with Boerhaave's syndrome treated surgically, 39 underwent a conservative procedure. These patients were retrospectively divided into two groups by type of repair: primary suture (group 1, n = 25) or suture on a T-tube (group 2, n = 14). Patients in group 1 were further stratified into two subgroups depending on whether the primary suture was made with reinforcement (subgroup rS) or not (subgroup S). RESULTS: Length of stays in hospital and intensive care were shorter in patients in group 1 (p = 0.037), but after a shorter delay before therapeutic management (p = 0.003) compared with group 2. For the other variables studied, outcome was more favorable in group 1, but the differences were not significant. Comparing subgroups rS and S showed that the rate of persistent leakage was significantly lower after reinforced suture (p = 0.021). CONCLUSIONS: These findings from the largest reported cohort of Boerhaave's syndrome patients undergoing conservative surgery showed that primary and T-tube repair provide at least equivalent results. Reinforced sutures appear to provide better outcomes by reducing postoperative leakage.

Use of positron emission tomography in surgery follow-up of esophageal cancer.

INTRODUCTION: Although the prognosis of patients with esophageal cancer has been improved by extended dissection, the incidence of recurrence still remains high. In esophageal cancer, positron emission tomography (PET) using (18)F-fluorodeoxyglucose (FDG) already demonstrated to be useful for initial staging and monitoring response to therapy. This prospective study compared the ability of FDG-PET and conventional imaging to detect early recurrence of esophageal cancer after initial surgery in asymptomatic patients. MATERIALS AND METHODS: Between October 2003 and September 2006, 41 patients with esophageal cancer were included in a prospective study after initial radical esophagectomy. FDG-PET, thoracoabdominal computed tomography (CT), abdominal ultrasonography, and endoscopy were performed every 6 months after initial treatment. RESULTS AND DISCUSSION: Twenty-three patients had recurrent disease (56%), mostly within the first 6 months after surgery (70%). Despite two false-positive scans due to postoperative changes, FDG-PET was more accurate than CT (91% vs. 81%, p = 0.02) for the detection of recurrence with a sensitivity of 100% (vs. 65%), a specificity of 85% (vs. 91%), and a negative predictive value of 100% on a patient-by-patient-based analysis. For the detection of locoregional recurrence, FDG-PET was more accurate than CT (96.2% vs. 88.9%). FDG-PET was also more accurate than CT for the detection of distant metastases (92.5% vs. 84.9%), especially when involving either bones (100%) or liver (98.1%). A lower sensitivity of FDG-PET (57%) for the early detection of small lung metastases did not affect patient management (accuracy = 92.5%). CONCLUSION: FDG-PET appears to be very useful for the systematic follow-up of asymptomatic patients after esophagectomy with an initial scan performed 6 months after surgery.

Cytochrome P450 hydroxylation of carbon atoms of the alkyl chain of symmetrical N-nitrosodialkylamines by human liver microsomes.

A panel of 14 human liver microsomal preparations metabolized at variable rates three symmetrical nitrosodialkylamines (N-nitroso-dipropyl, dibutyl and diamyl-amines, NDPA, NDBA, NDAA) into aldehydes and hydroxynitrosamines. Formation of linear aldehydes, convenient probes for alpha-hydroxylation of alkyl chain, and production of hydroxy metabolites of NDPA, NDBA and NDAA were simultaneously monitored by two specific HPLC detection methods. The longer the alkyl chain, the smaller the metabolic rate of the alpha-hydroxylation of the alkyl chain and the greater was the metabolic rate of the corresponding (omega-1)-hydroxy metabolite formation. Thus, the (omega-1)-hydroxylation of the alkyl chain was the major metabolic pathway of NDBA and NDAA in so far as it represented 3.3- and 86-fold of the alpha-hydroxylation. The balance between beta- to omega-hydroxylations and alpha-hydroxylation of carbon atoms of the alkyl chain depends upon its length and also upon the specific P450 isoform(s) involved. The hydroxylation site of the alkyl chain by P450 2E1 depends upon its length. For short alkyl chains, the main pathway was alpha-hydroxylation while for long alkyl chains, such as pentyl, (omega-1)-hydroxylation became the major pathway. The rate of alpha-hydroxylation was shown to be correlated with mutagenesis of 5 dialkylnitrosamines, as inferred from literature data, while the (omega-1)-hydroxylation was inversely correlated. Furthermore, other P450s than P450 2E1, such as P450 3A4 and 2C were shown to be involved in the metabolism of nitrosodialkylamines bearing long alkyl chains.

Involvement of cytochrome P450 3A4 in N-dealkylation of buprenorphine in human liver microsomes.

Buprenorphine is a long acting analgesic of the opiate family. Recently, it has been proposed for the opioid dependency treatment at a large scale. The drug is extensively metabolized by the hepatic cytochrome P450 in man, yielding a N-dealkylated metabolite, norbuprenorphine. The specific forms of P450 involved in this oxidative N-demethylation were examined in a panel of 18 human liver microsomal preparations previously characterized with respect to their P450 contents. Buprenorphine was N-dealkylated with an apparent Km of 89 +/- 45 microM (n = 3). The metabolic rates were 3.46 +/- 0.43 nmol/(min x mg of protein). This metabolic pathway was strongly correlated with 6 catalytic activities specific to P450 3A4 and with the immunodetectable P450 3A content of liver microsomal samples (r = 0.87). Buprenorphine metabolism was 62-71% inhibited by three mechanism-based inhibitors (TAO, erythralosamine, gestodene), by nifedipine as competitive inhibitor (Ki = 129 microM) and by ketoconazole 0.6 microM (25% residual activity), all these inhibitors specific to P450 3A. Among 10 heterologously expressed P450s tested, only P450 3A4 was able to dealkylate buprenorphine with a turnover number of 9.6 min(-1). Morever, this catalytic activity was inhibited up to 80% (vs control) by anti-rat P450 3A antibody. Taken together, all these data demonstrate that P450 3A4 is the major enzyme involved in hepatic buprenorphine N-dealkylation.

Involvement of cytochrome P450 3A4 enzyme in the N-demethylation of methadone in human liver microsomes.

Methadone has become one of the most widely used drugs for opiate dependency treatment. This drug is extensively metabolized by the cytochrome P450 hepatic enzyme family in man, yielding an N-demethylated metabolite that cyclizes spontaneously into 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine. The specific forms of cytochrome P450 involved in this oxidative N-demethylation were examined in a panel of 20 human liver microsomal preparations previously characterized with respect to their P450 enzyme contents. Methadone was demethylated with an apparent Km of 545 +/- 258 microM (n = 3). The metabolic rates were 745 +/- 574 pmol/(min.mg of protein). This metabolic pathway was strongly correlated with estradiol 2-hydroxylation, testosterone 6 beta-hydroxylation, nifedipine oxidation, erythromycin N-demethylation, and toremifene N-demethylation, all of these monooxygenase activities being supported by P450 3A4. Furthermore, the total P450 3A content of liver microsomal samples, determined by immuno-quantification using a monoclonal anti-human P450 3A4 antibody, was correlated with methadone demethylation (r = 0.72; p < 0.003). Methadone metabolism was 60-72% inhibited either by three mechanism-based inhibitors of P450 3A4 (gestodene, TAO, and erythralosamine) or by four reversible inhibitors of P450 3A (ketoconazole, dihydroergotamine, quercetin, and diazepam with an apparent Ki of 50 microM) and by two nonspecific inhibitors (metyrapone and SKF-525A). Conversely, quinidine (inhibitor of P450 2D6), 7,8-benzoflavone (inhibitor of P450 1A), or sulfaphenazole (inhibitor of P450 2C) did not significantly inhibit, and may even have activated, methadone metabolism. Four heterologously expressed P450 proteins were able to catalyze the N-demethylation of methadone, namely, P450 2C8, P450 2C18, P450 2D6, and P450 3A4. However, referring to their relative liver content, it can be asserted that P450 3A4 is the major enzyme involved in the N-demethylation of methadone on average. Accordingly, caution should be advised in the clinical use of methadone when other drugs are also administered that induce or inhibit P450 3A4, such as rifampicin or diazepam, respectively.

[Complications of colostomies. Follow-up study of 500 colostomized patients]. / Les complications des colostomies. Suivi de 500 patients colostomisés.

The complications of colostomies may constitute a handicap for patients: their prevalence severity and methods of treatment remain poorly known. 500 colostomy patients, with a mean age of 66 +/- 14 years, were retrospectively reviewed. The mean follow-up of the study was 6 +/- 5 years. Colorectal cancers represented 65% of the initial diseases. 59.5% of colostomies were terminal. They were performed for resection of the colon and or rectum in 56.5% of cases. 30.5% of patients (n = 152) presented complications (n = 235). The early complications (n = 147) observed in 29.5% of patients were mostly benign (20 required emergency operations). The late complications (n = 88), observed in 22.5% of 391 patients with a follow-up of more than one year required another operation in 1/3 of cases (11 cases of stenosis, 9 incisional hernias and 8 prolapses). Complications of colostomies remain frequent (one out of every 4 stomies ends in a complication) and the reoperation rate is situated between 13 and 33%. The therapeutic success rate of late reoperation is between 63 and 74%. When a reoperation is necessary, it should be ideally radical via a midline incision. The transposition technique gives better results than the repositioning technique via a local approach.

Molecular analysis of the TP53 gene in Barrett's adenocarcinoma.

The TP53 gene is the most frequently mutated gene in human cancers. Barrett's esophagus provides an excellent model by which to understand the genetic events that lead from dysplasia to cancer. We screened for mutations in the TP53 gene by a combination of denaturing gradient gel electrophoresis and DNA sequencing in ten cases of adenocarcinoma arising in Barrett's mucosa. We have identified missense mutations in five of the ten samples, three transitions (R282W, G245S, R248W) and two transversions (E286Q and C176F). In one case we have analyzed biopsy specimens taken from the same site, one year before the patient developed an intra mucosal carcinoma. The mutation that was identified in this high grade dysplastic area was identical to that detected in the cancer. This would suggest TP53 mutations occur as an early genetic event in the development of Barrett's adenocarcinoma.

Validation of the (omega-1)-hydroxylation of lauric acid as an in vitro substrate probe for human liver CYP2E1.

The (omega-1)-hydroxylation of lauric acid (11-OH-LA), a model substrate of fatty acids, was previously shown to be due to CYP2E1 in rat liver microsomes. The present study examined changes in hepatic CYP2E1 content and 11-OH-LA in a panel of 29 human liver microsomes. The 11-OH-LA activity was strongly correlated with the CYP2E1 content, quantitated by immunoblot (r = 0.75) and with four monooxygenase activities known to be mediated by CYP2E1: chlorzoxazone-6-hydroxylation (r = 0.73), 4-nitrophenol hydroxylation (r = 0.84), N-nitrosodimethylamine demethylation (r = 0.79) and n-butanol oxidation (r = 0.73). The (omega-1)-hydroxylation of lauric acid was inhibited by ethanol (Ki = 3.5 mM), acetone (IC50 = 10 mM) dimethylsulfoxide, chlorzoxazone (competitive inhibitors of CYP2E1), diethyldithiocarbamate, and diallylsulfide (both selective mechanism-based inactivators of CYP2E1). The weak value of ethanol Ki on the (omega-1)-hydroxylation of lauric acid suggested that low levels of alcohol could modify fatty acid metabolism in the liver. Furafylline and gestodene, suicide substrates of CYP1A and CYP3A4, respectively, did not modify the 11-hydroxylation of lauric acid. Polyclonal antibody directed against rat CYP2E1 inhibited the formation of 11-OH-LA without affecting 12-OH-LA activity. Taken together, these results suggest that CYP2E1 is involved in the (omega-1)-hydroxylation of lauric acid in human liver microsomes, and omega-hydroxylation is mediated by another enzyme. Finally, the use of yeasts and mammalian cells genetically engineered for expression of 9 human P450s demonstrated that CYP2E1 was the one enzyme involved in the (omega-1)-hydroxylation of lauric acid.

[Value of colonic irrigation. Long-term followed-up in 432 colostomized patients]. / Intérêt de l'irrigation colique. Suivi à distance de 432 malades colostomisés.

OBJECTIVES: Irrigating colostomies allows patients to achieve nearly complete fecal continence using a simple technique. We assessed long-term results in our series of 432 patients. METHODS: From 1979 to 1992, we followed 432 patients who had undergone definitive colostomy surgery (mean follow-up = 8.4 years). RESULTS: Colonic irrigation was impossible in 281 cases mainly due to retarded patient information (42%) or patient incapacity (31%). It was possible in 151 patients (globally 31%). In patients with abdominoperineal amputations the rate was 63%, for Hartmann procedures 17% and for derivations 6%. Most of the derivations were supraombilical colostomies (n = 51) including 6 who used colonic irrigation. No complications related to the technique were observed and minor incidents (usually problems with the cannula and/or pain) occurred in 61 patients. Thirteen patients (9%) abandoned the technique including 5 who complained of incontinence. CONCLUSIONS: Based on these observations, we conclude that colonic irrigation is not used enough. The key to success is a quality stomy and early patient information and training. This technique is particularly adapted for active patients. It is performed every 48 hours and lasts about 35 minutes.

[Fistulas after Lewis-Santy's operations. Diagnosis, treatment, prevention]. / Les fistules après interventions de Lewis-Santy. Diagnostic, traitement, prévention.

Fistulas of the anastomosis is the most severe complication after the Lewis-Santy operation. Over the last 10 years, we have performed 227 such operations for cancer of the oesophagus and have observed 16 fistulizations (7%). The aim of this study was to analyze the clinical manifestations and laboratory findings in these cases of fistulization as a function of the site of the plasty, the treatment and the results. We attempted to determine factors which could lead to means of preventing this complication. The fistula occurred at the oeso-gastric anastomosis in 11 cases (4.8%), at the apex of the gastric tube in 2 and on the line of gastric tubulization in 3. A comparison between patients with fistulas (group 1) and those without (group 2) showed that 19% of the patients in group 1 were over 70 years of age versus 9% in group 2 (NS). Three of the 16 patients (19%) with fistula had cirrhosis due to ethylism versus 2 of the 211 patients in group 2 (p < 0.001). Six patients among the 58 with palliative with a fistula (6%) (NS). Thoracic drainage was sufficient in 11 patients and surgical treatment was not required. In 5 reoperation (thoracotomy 4, cervicotomy 1) was necessary due to an intrapleural abscess. After 227 Lewis-Santy operations, 11 patients died during hospitalization (4.8%, 4 of which were complicated with fistula (1.7% of the operated patients and 25% of the patients with fistulas). The frequency of fistulizations after Lewis-Santy operation has decreasing (8%) and the gravity has improved (3 out of 4 were cured).(ABSTRACT TRUNCATED AT 250 WORDS)

[Cavernous hemangioma of the spleen: values and limitations of ultrasonic and computed tomographic diagnosis]. / Hémangiome caverneux de la rate: intérêts et limites d'un diagnostic écho-tomodensitométrique.

A case of a cavernous haemangioma associated with an hepatic haemangioma is reported. It presented in the form of a hyperechogenic mass on ultrasound imaging. On the Computed Tomography scan with contrast, the splenic tumour became progressively hyperdense: this last characteristic is observed in 6 out of 9 cases reported in the literature. MR imaging seems to allow an accurate preoperative diagnosis; nevertheless, splenectomy is often indicated because of the risk of rupture, in which case histological examination removes any doubt concerning an exceptional malignant form.

Experimental model of liver metastases: adhesion and growth of cells on contact with endothelial or hepatocyte cell monolayer cultures.

In a rat colon carcinoma model (DHD/K 12-PROb), two varieties of cells were selected after in vivo passaging: PROb h2, representing a liver-specific variant and PROb Mp1, representing a lung metastatic variant and producing liver and lung metastases after intracecal injection (one out of four). The study of the adhesion and the growth of cells in vitro for contact hepatocytes and/or endothelial cells gave the following results: (1) except for PROb Mp1, tumor cell growth was independent of the cell support; (2) adhesion of PROb Mp1 to endothelial cells was lower between 30 and 120 min, whereas adhesion of PROb h2 to hepatocytes was greater and durable after 60 min (P < or = 0.05). These results suggest that the formation of liver metastases in a dynamic process and that tumor cells have a great ability to adhere to hepatocytes. Improved by serial passaging in vivo, our intracecal model might be useful for studying many aspects of the pathogenesis of colon cancer metastasis, while concurrent in vitro studies of the adhesion and growth ability of cells might be a useful indicator for assessing the in vivo behavior.

TP53 gene mutation profile in esophageal squamous cell carcinomas.

Esophageal squamous cell carcinoma is a form of cancer occurring most commonly in males, particularly those living in some areas of Asia, Africa, and western Europe. In some of these tumors, a sequence alteration has been identified in the coding region of the TP53 gene which is known to inactivate the tumor suppressor function of its product. Using a GC clamp (i.e., a GC rich domain) denaturing gradient gel electrophoresis assay we have been able to identify sequence modifications in 27 of the 32 tumor samples analyzed (84%). Most of the mutations occur in exon 6, a region of the gene which has not previously been reported as being a hot spot for the mutations of other cancers. Twelve of the mutations reported here have not been described in other types of tumors and these consist mostly of frameshift or splice mutations. The distribution of mutations [transitions (45%), transversions (34%), and frameshift (21%)] suggests that the etiological contribution of genotoxic factors might be complex and might associate different exogenous and endogenous mutagen exposures.

Thoracoscopic dissection of the esophagus in human cadavers.

A technique for thoracoscopic dissection of the esophagus is described which gives a large and magnified view of the pleural cavity, the mediastinum, and the esophagus. This technique was developed on human cadavers which gives excellent technical resources for learning and practicing endoscopic surgical anatomy of the esophagus. It avoids the need to change the position of the patient to perform a total thoracoabdominal esophagectomy via a triple surgical approach.