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Although evidence suggests an inverse relationship between microsatellite instability and p53 alterations in colorectal cancer, no study has thoroughly examined the use of p53 immunohistochemistry in phenotyping colorectal cancers. We investigated the value of p53 immunohistochemistry in microsatellite instability-positive colorectal cancers prescreening and attempted to clarify the relationship between DNA mismatch repair system and p53 pathway. In a series of 104 consecutive colorectal cancers, we performed p53 immunohistochemistry, TP53 mutational analysis, DNA mismatch repair system efficiency evaluation (DNA mismatch repair system immunohistochemistry, microsatellite instability status, MLH1/MSH2 germ line, and BRAF, murine double minute 2, and p21 immunohistochemistry. Microsatellite instability high was observed in 25 of 104 colorectal cancers, with DNA mismatch repair system protein loss (24/25) and germ line (8/25) or BRAF mutations (8/25). p53 immunohistochemistry revealed 3 distinct patterns of expression: complete negative immunostaining associated with truncating TP53 mutations (P < .0001), diffuse overexpression associated with missense TP53 mutations (P < .0001), and restricted overexpression characterized by a limited number of homogenously scattered strongly positive tumor cells in 36.5% of colorectal cancers. This latest pattern was associated with wild-type TP53 and microsatellite instability high colorectal cancers (P < .0001) including all Lynch tumors (8/8), but its presence among 22% of DNA mismatch repair system-competent colorectal cancers decreased its positive predictive value (55.2% [95% confidence interval, 45%-65%]). It was also correlated with murine double minute 2 overexpression (P < .0001) and inversely with p21 loss (P = .0002), independently of microsatellite instability status. In conclusion, a restricted pattern of p53 overexpression is preferentially associated with microsatellite instability high phenotype and could, therefore

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Context: In obesity, adipocyte hypertrophy and macrophage infiltration lead to overproduction of proinflammatory adipokines, which play a crucial role in the metabolic syndrome. The molecular mechanisms underlying this overproduction are still unsettled. The role of TNF-alpha also remains controversial in human obesity. Objective: We revisited the contribution of TNF-alpha to adipokine dysregulation in central obesity. We more particularly assessed the involvement of TNF-alpha vs. other stromal-vascular cell (SVC)-secreted factors and searched for potential differential responses to TNF-alpha between adipocytes of lean and obese individuals. Design and participants: Primary cultures of omental adipocytes from obese and non-obese age- and sex-matched subjects were used. For some experiments, we generated media previously conditioned by SVC, which mimic adipocyte microenvironment. Results: Adipocytes of obese subjects mainly overexpressed adipokines, in comparison to those of lean ones, when cultured SVC-conditioned media. This was abrogated by immunoneutralization of TNF-alpha, indicating that among the numerous factors secreted by SVC, TNF-alpha is a crucial contributor to adipokine dysregulation. Accordingly, adipocytes of obese subjects overproduced adipokines in response to direct exposure of TNF-alpha. This hyper-responsiveness was mediated by TNF-alpha-receptor-1 and hyper-activation of the NF-kappaB pathway. Correspondingly, NF-kappaB activity was increased in adipocytes of obese subjects and correlated with adipocyte size, adipokine expression and in vivo insulin resistance. Eventually, adipokine overexpression in adipocytes of obese subjects was prevented by NF-kappaB inhibitors. Conclusions: In obesity, TNF-alpha that is, over other SVC-secreted factors, a crucial determinant of adipokine dysregulation acts on enlarged adipocytes, which are hyper-responsive to this triggering signal. This ultimately exacerbates adipokine production, inflammation and the met

Melanoma accounts for one third of tumors metastasizing to the gastro-intestinal tract. The preferential site for metastases is the small bowel. Primary melanoma is also described in the digestive tract. Abdominal symptoms or anaemia in a patient with a history of melanoma should be considered as a potential abdominal metastasis whatever the time passed since the primary lesion diagnosis. Although the role of surgery in the treatment of gastrointestinal metastases was primarily reserved for symptomatic patients or for palliation, it is now recognised that complete surgical resection is associated with better long-term survival. Selection of patients for resection of abdominal melanoma metastases is difficult because prognostic factors are not clearly identified. In the absence of these prognosis factors, the decision to perform radical surgery can only be taken within the framework of a multidisciplinary meeting.

In obesity, adipocyte hypertrophy and macrophage infiltration lead to overproduction of proinflammatory adipokines, which play a crucial role in the metabolic syndrome. The molecular mechanisms underlying this overproduction are still unsettled. The role of TNF-alpha also remains controversial in human obesity. We revisited the contribution of TNF-alpha to adipokine dysregulation in central obesity. We more particularly assessed the involvement of TNF-alpha vs. other stromal-vascular cell (SVC)-secreted factors and searched for potential differential responses to TNF-alpha between adipocytes of lean and obese individuals. Primary cultures of omental adipocytes from obese and nonobese age- and sex-matched subjects were used. For some experiments, we generated media previously conditioned by SVCs, which mimic adipocyte microenvironment. Adipocytes of obese subjects mainly overexpressed adipokines, in comparison with those of lean ones, when cultured in SVC-conditioned media. This was abrogated by immunoneutralization of TNF-alpha, indicating that among the numerous factors secreted by SVCs, TNF-alpha is a crucial contributor to adipokine dysregulation. Accordingly, adipocytes of obese subjects overproduced adipokines in response to direct exposure of TNF-alpha. This hyperresponsiveness was mediated by TNF-alpha receptor 1 and hyperactivation of the nuclear factor-kappaB (NF-kappaB) pathway. Correspondingly, NF-kappaB activity was increased in adipocytes of obese subjects and correlated with adipocyte size, adipokine expression, and in vivo insulin resistance. Eventually adipokine overexpression in adipocytes of obese subjects was prevented by NF-kappaB inhibitors. In obesity, TNF-alpha that is [corrected] over other SVC-secreted factors, a crucial determinant of adipokine dysregulation acts on enlarged adipocytes, which are hyperresponsive to this triggering signal [corrected]

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Central-omental obesity plays a causative role in the pathogenesis of the metabolic syndrome. Adipokines are involved in the pathogenesis of this syndrome. However, adipokines secreted by omental adipose tissue (OAT) are still poorly characterized in human obesity. Therefore, we searched for novel adipokines abnormally secreted by OAT in obesity and examined their relationships with some features of metabolic syndrome and the respective contribution of adipocytes vs. stromal-vascular cells. OAT from obese and nonobese men was fractionated into adipocytes and SV cells, which were then cultured. Medium was screened by medium-scale protein arrays and ELISAs. Adipokine mRNA levels were measured by real-time RT-qPCR. We detected 16 cytokines secreted by each cellular fraction of lean and obese subjects. Of the 16 cytokines, six adipokines were newly identified as secretory products of OAT, which were dysregulated in obesity: three chemokines (growth-related oncogen factor, RANTES, macrophage inflammatory protein-1beta), one interleukin (IL-7), one tissue inhibitor of metalloproteinases (TIMP-1), and one growth factor (thrombopoietin). Their secretion and expression were enhanced in obesity, with a relatively similar contribution of the two fractions. The higher proportion of macrophages and endothelial cells in obesity may contribute to this enhanced production as well as changes in intrinsic properties of hypertrophied adipocytes. Accordingly, mRNA concentrations of most of these adipokines increased during adipocyte differentiation. Eventually, expression of the investigated adipokines did correlate with several features of the metabolic syndrome. In conclusion, six adipokines were newly identified as oversecreted by OAT in obesity. These adipokines may link obesity to its cardiovascular or metabolic comorbidities.

Background. The role of duodenogastric reflux in the genesis of gastric polyps in familial adenomatous polyposis (FAP), although suggested by scintigraphy scanning studies, remains unclear. Methods. Twenty-four hour intragastric bilirubin monitoring with the Bilitec (R) optoelectronic device was carried out in 25 FAP patients, of whom 19 had gastric polyps (fundic gland in 13, adenomatous in 2, and both histologic types in 4) on endoscopic examination. Gastric exposure to bilirubin was expressed as the Percentage of total recording time that absorbance exceeded the threshold of 0.25 and was calculated in reference to values obtained from 25 healthy volunteers. Helicobacter pylori status of the stomach was checked as well. Results. Gastric exposure to bilirubin was pathologic in 14 (56%) patients. Gastric exposure to bilirubin was of longer duration in FAP patients than in healthy volunteers (mean +/- SEM: 19% 4% vs 6% +/- 2 %) (P < .005). It increased from healthy volunteers (6 % 2 %) to FAP patients without gastric polyps (10 % +/- 3 %), and to EAP patients with gastric polyps (22 % 5 %) (P <.604). Bilirubin exposure times were similar in FAP patients with fundic gland polyps only and in those having either adenomalous polyps only or both types of polyps (24 % +/- 7 % vs 17 % +/- 4 %). No patient with pathologic gastric exposure to bilirubin as well as none having gastric polyps, had H. pylori in the antrum. Conclusions. This study shows that gastric exposure to bilirubin is of longer duration in FAP patients than in healthy volunteers, and in FAP patients with gastric polyps than in those without polyps. This study supports the existence of a direct correlation between pathologic duodenogastric reflux (DGR), the absence of H. pylori in the antrum, and the presence of gastric polyps in FAP patients.

Background and Aims: Obesity, and more particularly central obesity, is strongly associated with chronic disorders such as type 2 diabetes, cardiovascular disease and cancer. Adipokines are involved in the pathogenesis of these obesity-linked disorders. However, adipokines secreted by visceral adipose tissue (AT), unlike those secreted by other fat depots, are still poorly characterised. In this study, we searched for novel adipokines secreted by visceral AT, compared their production in lean versus obese subjects and examined the relative contribution of the different cell types to this production [...]

The authors compare their experience in the surgical treatment of Crohn's disease with the results from several large series in the literature, Over 25 years 533 intestinal operations in adults were performed, including a first operation in 348 patients (177 women, 171 men, median age: 33 years, range: 15-80 years), with no mortality. The main indications for intestinal resection limited to macroscopic disease were symptomatic strictures (45.7%) and fistulas (37 %). As observed in other series reported, recurrences assessed as reoperations have been frequent, with a cumulative resection rate of 11% after 5 years, 29% after 10 years, 41% after 15 years and 70% after 20 years. However, 10-year cumulative reoperation rate was nil after coloproctectomy + ileostomy. In 18 patients, including 8 with previous surgery, 68 stricturoplasties were performed, associated with ileocolic and/or segmental jejuno-ileal resections in 15. After stricturoplasty, the reoperation rate was 33% over a median followup of 33.5 months (8-144). The confirmation of the high risk of recurrence after conservative surgery for Crohn's disease, which can only be reduced by cessation of smoking, urges the need to pursue randomized trials about post-surgical chemoprevention. If effective and safe, chemoprevention could allow even more conservative surgery, such as ileal-pouch anastomosis in patients with satisfactory anal sphincter function.

SCOPUS: ar.j, info:eu-repo/semantics/published

Whole-body fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) has proved effective in the diagnosis and staging of recurrent colorectal cancer. In this study, we analysed how PET affects the management of patients with recurrent colorectal cancer by permitting more accurate selection of candidates for curative resection. The data of 79 patients with known or suspected recurrent colorectal cancer were analysed. Conventional imaging modalities (CIM) and PET results were compared with regard to their accuracy in determining the extent and the resectability of tumour recurrence. Recurrence was demonstrated in 68 of the 79 patients. The data indicate that PET was superior to CIM for detection of recurrence at all sites except the liver. Based on the CIM+PET staging, surgery with curative intent was proposed in 39 patients and was indeed achieved in 31 of them (80%). PET was more accurate than CIM alone in predicting the resectability or non-resectability of the recurrence (82% vs 68%, P=0.02). It is concluded that whole-body FDG-PET is highly sensitive for both the diagnosis and the staging of patients with recurrent colorectal cancer. Its use in conjunction with conventional imaging procedures results in a more accurate selection of patients for surgical treatment with curative intent.

Adiponectin (ApN) is thought to play a major role in the pathogenesis of the Metabolic Syndrome. Production of ApN and regulation of its related gene (apM1) have not yet been studied in human visceral adipose tissue. ApN was mainly associated with adipocyte membranes and abundantly secreted in medium from isolated adipocytes. apM1 gene expression, restricted to the adipocyte fraction of adipose tissue, decreased spontaneously when adipose explants were cultured in basal medium for 24 h while the expression of other adipose genes barely changed (PPARgamma, GAPDH) or increased (PAI-1). Unexpectedly, the fall of apM1 mRNA was prevented by the addition of actinomycin D, an inhibitor of transcription, or cycloheximide, an inhibitor of protein synthesis, and by reducing the amount of adipose tissue cultured per dish, thereby suggesting that a newly synthesized factor released by adipose tissue destabilizes apM1 mRNA. apM1 gene expression was also negatively regulated by glucocorticoids and positively by insulin and IGF-1. This regulation could contribute to the decreased apM1/ApN levels in insulin-resistant patients with obesity and the Metabolic Syndrome.

Cancer colo-rectal: utilité du suivi après chirurgie

Plasma levels of type 1 plasminogen activator inhibitor (PAI-1), a risk factor for cardiovascular disease, are elevated in obese subjects, especially those with omental fat accumulation. We investigated the hormonal control of PAI-1 gene expression and secretion in cultured human adipose tissue. We more particularly focused on the effects of glucocorticoids, insulin, cAMP, and catecholamines in explants from the omental region. The addition of dexamethasone to the culture medium increased PAI-1 secretion in a time-dependent manner for up to 24 h. The stimulation by the glucocorticoid was preceded by a 2-fold rise in PAI-1 messenger ribonucleic acid levels between 4-8 h of culture. The effectiveness of the glucocorticoid was concentration dependent, with a half-maximal effect within a physiological range. This stimulation was also observed in sc fat, but dexamethasone-stimulated as well as basal PAI-1 secretion rates were always higher in omental fat. Unlike dexamethasone, 24-h insulin did not modify PAI-1 secretion while accelerating glucose consumption. In contrast, 24-h cAMP inhibited PAI-1 gene expression and protein production under basal conditions and in the presence of dexamethasone. This inhibition was already detectable after 1 h and was maximal after 4 h at the level of gene expression. It occurred in both omental and sc adipose tissues. Importantly, epinephrine dose dependently inhibited PAI-1 parameters, an effect that was reproduced by isoproterenol. Dexamethasone- and cAMP-induced changes in PAI-1 messenger ribonucleic acid abundance were similar in explants and isolated fat cells. In isolated stromal-vascular cells, only dexamethasone was effective. In conclusion, we provide evidence for a reciprocal regulation of PAI-1 by dexamethasone (positive effector) and cAMP/catecholamines (negative effectors) in cultured human adipose tissue. The stimulation by glucocorticoids could contribute to enhanced production of PAI-1 by adipose tissue and high plasma l

This study was undertaken to assess the reliability of the endoscopic biopsies in the evaluation of colorectal villous tumors (CRVT). In 163 consecutive patients referred for surgical treatment of CRVT, preoperative evaluation had been routinely done by colonoscopy and multiple biopsies. Tumors were classified in 3 groups: low grade tumors, high grade tumors and adenocarcinomas. Infiltration in depth was staged on the postoperative specimens according to the Dukes-Aster-Coller's classification. All the tumors were completely resected by surgery and definitive pathological diagnosis was established. An exact correlation between the pre- and postoperative staging was observed in 48% of the cases. Accuracy averaged 54% in the group-by-group comparison, with an overstaging rate of 6.7%, and an understaging rate of 39%. The incidence of adenocarcinomas was 22% in the group with clearly benign preoperative biopsies and 50% in the other cases. There were significantly more B2 and C tumors among the patients referred after 3 or more endoscopic attempts (33%) than after one or two sessions (10%) (p < 0.0003). We confirm that in spite of multiple endoscopic biopsies, only a complete resection permits an exact staging and an appropriate therapeutic choice.

Thirty three patients were placed under early oral feeding after elective colorectal surgery. There were 15 male and 18 female patients, mean age: 52 years. Nasogastric tube was removed as soon as they were widely awake, or on the morning following the afternoon operations. Oral feeding was resumed 4 hours later, and the first meal consisted in a slight solid meal. There was no postoperative mortality or significant morbidity. Liquid and solid oral intakes were resumed 18 and 24 hours respectively after the operation. Tolerance was perfect in 22 patients (66%), good (slight complaints) in 16%, and was considered as fair or bad in the last six cases. Intestinal transit was observed after a median period of 2 days. Tube insertion rate was 12%. No adverse effect on the anastomoses was noted. Data from the literature confirm that early feeding is tolerable and safe after open colorectal surgery. More patients should be included in this protocol to take benefit of the physiological effects of early oral feeding.

The direct role of hormones on leptin synthesis has not yet been studied in cultured adipose cells or tissue from lean and obese subjects. Moreover, this hormonal regulation has never been addressed in human visceral fat, although this site plays a determinant role in obesity-linked disorders. In this study, we investigated the hormonal control of ob expression and leptin production in cultured visceral adipose tissue from lean and obese subjects. We more particularly focused on the interactions between glucocorticoids and insulin. We also briefly tackled the role of cAMP, which is still unknown in man. Visceral (and subcutaneous) adipose tissues from eight obese (body mass index, 41 +/- 2 kg/m2) and nine nonobese (24 +/- 1 kg/m2) subjects were sampled during elective abdominal surgery, and explants were cultured for up to 48 h in MEM. The addition of dexamethasone to the medium increased ob gene expression and leptin secretion in a time-dependent manner. Forty-eight hours after dexamethasone (50 nmol/L) addition, the cumulative integrated ob messenger ribonucleic acid (mRNA) and leptin responses were, respectively, approximately 5- and 4-fold higher in obese than in lean subjects. These responses closely correlated with the body mass index. The stimulatory effect of the glucocorticoid was also concentration dependent (EC50 = approximately 10 nmol/L). Although the maximal response was higher in obese than in lean subjects, the EC50 values were roughly similar in both groups. Unlike dexamethasone, insulin had no direct stimulatory effect on ob gene expression and leptin secretion. Singularly, insulin even inhibited the dexamethasone-induced rise in ob mRNA and leptin release. This inhibition was observed in both lean and obese subjects, whereas the expected stimulation of insulin on glucose metabolism and the accumulation of mRNA species for the insulin-sensitive transporter GLUT4 and glyceraldehyde-3-phosphate dehydrogenase occurred in lean patients only. This inhib