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.

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.

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.

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.

[Demonstration of clonal heterogeneity in adenocarcinomas on Barrett's esophagus by flow cytometric study of cellular DNA content]. / Mise en évidence d'une hétérogénéité clonale au niveau des adénocarcinomes sur endobrachyoesophage par l'étude cytofluorométrique du contenu cellulaire en ADN.

Flow cytometry was used to examine the spatial distribution of nuclear DNA content in Barrett's mucosa, in one patient with high grade dysplasia and in 6 patients with Barrett's adenocarcinoma. All tumors were aneuploid. Each adenocarcinoma but the most advanced seemed to arise from a single clone of aneuploid or near-tetraploid cells which was found in all biopsy specimens taken from the tumor. Multiple aneuploid populations of cells were seen in the larger tumors. Eight clones were individualized in the most advanced case of cancer. In all patients with carcinoma, the mucosa surrounding the tumor was aneuploid. Some areas were characterized by the same DNA index as in the tumor, others contained distinct aneuploid cell populations. The spatial distributions of aneuploid clones and dysplastic areas were not perfectly superimposed. These data suggest that neoplastic progression in Barrett's esophagus is associated with genomic instability preceding the development of malignancy. Clonal heterogeneity in Barrett's adenocarcinoma is more marked when compared to other tumors and suggests a majoration of genomic instability during tumor progression.

[Mucus-secreting tumors of the appendix: a preoperative diagnosis is possible. Apropos of 2 cases]. / Tumeurs muco-sécrétantes de l'appendice: un diagnostic pré-opératoire est possible. A propos de deux observations.

The authors present two cases of pseudo tumoral type Mucus Secreting Tumours (MST) of the appendix. In this type (32% of the cases), the clinical presentation, barium enema, ultrasonography and most importantly CT scan generally confirm the preoperative diagnosis. We found three advantages this preoperative diagnosis. 1) Primarily it allows selection of a large surgical approach that permits full exploration of the abdominal cavity especially the ovaries (2-18% associated lesions); 2) also it allows a histopathological examination (frozen section) of the appendix to be performed during the operation; 3) and finally the surgical treatment will depend on the operative findings and the result of the histopathological examination: in the benign forms simple appendicectomy will be sufficient but the malignant forms (12% of the cases) should be treated by right hemicolectomy.

[Primary colonic intussusception protruding from the anus in adults. Two cases]. / Invagination colique primitive de l'adulte, procidente à l'anus. Deux observations.

The authors report two cases of colonic intussusception in the adult protruding from the anus--or colo-anal intussusception--, not due to a tumor. The first case was a chronic ileo-caeco-colique intussusception, the second case was an acute colo-rectal intussusception. Colo-anal intussusceptions are very rare: less than twenty cases have been described since 1925 in adults. The absence of a tumor origin in our cases represents a special feature, as only three other similar cases have been described. The surgical treatment in both cases was primary colonic resection without colostomy. The surgical treatment of the first case was subtotal colectomy with ileo-rectal anastomosis. The second case was primarily reduced by barium enema which allowed optimal secondary surgical resection of a prepared colon.

[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.

[Isolated portal vein thrombosis: a rare complication of chronic pancreatitis]. / Thrombose isolée de la veine porte: une complication rare de la pancréatite chronique.

In chronic pancreatitis (CP) portal vein thrombosis (PT) is a less well known complication than splenic vein thrombosis (ST). In the literature up until 1990, 26 cases with PT, have been reported and only 10 cases presented a isolated PT, without ST. We report a new case of isolated PT without ST in a non alcoholic man, who presented with gastroesophageal CP and a cavernomatous transformation of the portal vein. No varices ere detected by endoscopy; because the risk of bleeding was very small, a prophylactic treatment was unnecessary. The pancreas was resected preserving the spleen and cavernomatous transformation or the periportal veins and the patient was cured from his pains. The surgical tactic is an original treatment, particularly when curable pancreatic cancer is suspected.

[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.

[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.

[Adenocarcinoma of the duodenum. Apropos of 2 cases: review of the literature]. / Les adénocarcinomes du duodénum. A propos de deux observations: étude de la littérature.

The authors report two cases of duodenal adenocarcinoma. Review of literature has permitted them to conclude the rarity of the lesion which among malignant tumours of the small intestine, is the gommenest. Localization of the tumour in the periampullary area in 47% of cases rendered it difficult to differentiate from ampullary and pancreatic tumours especially with the unknown etiological factors (with exception to villous tumours which has a 35% rate of malignant transformation), and also with unspecific symptoms. Diagnosis by x-ray and endoscopy has an accuracy rate of more then 85%. Prognosis is bad and depend mainly on histological differentiation and lymph node spread. 5 years survival rate of 40-50% can be achieved by curative surgery namely cephalic duodeno-pancreatectomy in cases with no lymph node involvement.

[Annular pancreas. Apropos of 4 cases]. / Le pancréas annulaire. A propos de 4 observations.

Annular pancreas is a rare congenital anomaly cause of duodenal obstruction. Associated ulcus is frequent. Chronic pancreatitis complicating annular pancreas can lead to resection. Among 4 observations, evolution and treatment are presented. Treatment requires derivation or resection of the stenosis.

[Experimental model for metastasis of cecal origin]. / Modèle expérimental de métastases à point de départ caecal.

The pre-selected tumor cells injection in the cecal wall of rat, seems to be a intermediate model between spontaneous evolution of a colon tumor and intrasplenic or direct intraportal injections. From rhabdomyosarcoma cells (RMS S4-MH-) which present the advantage to prudce up lymphatic, pulmonary and hepatic metastases after subcutaneously injection, first subcutaneously (S.C.), intrasplenic (I.S.) and intracecal sites were compared: In the I.C. model, tumor was obtained in 80% of case and the survival was nearly similar to S.C. model's one. The lymphatic metastases were more and more distal as the evolution and the liver metastases were rarely observed. The I.S. model increased quickly and there were always liver metastases; In the two cases, pulmonary metastases were rarely observed (0 and 2/5). With adenocarcinoma colonic cells (Pro b) I.C. injection in the rat, tumor were obtained in 48% of cases without peritoneal dissemination; lymphatic nodes metastases were observed in 80% of cases; liver metastases was obtained in one animal from metastasis pulmonary selection cell lines. The I.C. model allows to estimate the liver and lymphatic nodes part; improved, it would be used to test adjuvant therapies and immunoscintigraphy.

[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)

[Postoperative obstructions]. / Occulsions postopératoires.

The intestinal obstructions after a laparotomy in adult may be caused by an inflammatory or a mechanic pathology; the incidence of the bowel obstruction in the early postoperative period is about 0.5 to 2% of all surgical procedures; these obstructions are often related to the degree of contamination or infection; contrary to postoperative paralytic ileus, they result in a reoperation, so as a peritonitis may be associated. In the later postoperative period intestinal obstructions may be caused by adhesions, internal strangulation or fibrosis bridles; these obstructions are frequent and they affect especially the small intestine (5% of laparotomies will be complicated by small bowel obstruction). The intestine volvulus due to bridles or adhesions is observed in approximately 10% of cases and the diagnosis must be conjured up in principle because it necessities an operation immediately; it's the same for the strangulation by incarceration. The absence of classic indicators of gangrene permits a non-operative treatment using a naso-gastric tube decompression during 24 to 48 hours: generally the causes of obstruction are small bowel adhesions, nevertheless it's important to eliminate a colonic obstruction. The management of chronic postoperative adherences is a difficult problem because the iterative operations increase the risk of intestinal obstructions; the video-laparoscopic surgery seems to be a promising technique to prevent and to treat (laparoscopic adhesiolysis) the post-operative adherences; its results are not evaluated.

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.