Preoperative versus postoperative docetaxel-cisplatin-fluorouracil (TCF) chemotherapy in locally advanced resectable gastric carcinoma: 10-year follow-up of the SAKK 43/99 phase III trial.

BACKGROUND: Fluorouracil-based adjuvant chemotherapy in gastric cancer has been reported to be effective by several meta-analyses. Perioperative chemotherapy in locally advanced resectable gastric cancer (RGC) has been reported improving survival by two large randomized trials and recent meta-analyses but the role of neoadjuvant chemotherapy and optimal regimen remains to be determined. We compared a neoadjuvant with adjuvant docetaxel-based regimen in a prospective randomized phase III trial, of which we present the 10-year follow-up data. PATIENTS AND METHODS: Patients with cT3-4 anyN M0 or anyT cN1-3 M0 gastric carcinoma, staged with endoscopic ultrasound, computed tomography, bone scan, and laparoscopy, were assigned to receive four 21-day/cycles of docetaxel 75 mg/m(2) day 1, cisplatin 75 mg/m(2) day 1, and fluorouracil 300 mg/m(2)/day over days 1-14, either before (arm A) or after (arm B) gastrectomy. Event-free survival was the primary end point, whereas secondary end points included overall survival, toxicity, down-staging, pathological response, quality of life, and feasibility of adjuvant chemotherapy. RESULTS: This trial was activated in November 1999 and closed in November 2005 due to insufficient accrual. Of the 70 enrolled patients, 69 were randomized, 34 to arm A and 35 to arm B. No difference in EFS (2.5 years in both arms) or OS (4.3 versus 3.7 years, in arms A and B, respectively) was found. A higher dose intensity of chemotherapy was observed in arm A and more frequent chemotherapy-related serious adverse events occurred in arm B. Surgery was safe after preoperative chemotherapy. A 12% pathological complete response was observed in arm A. CONCLUSION: Docetaxel/cisplatin/fluorouracil chemotherapy is promising in preoperative setting of locally advanced RGC. The early stopping could mask the real effectiveness of neoadjuvant treatment. However, the complete pathological tumour responses, feasibility, and safe surgery warrant further investigation of a taxane-based regimen in the preoperative setting.

Does perioperative nutrition and oral carbohydrate load sustainably preserve muscle mass after bariatric surgery? A randomized control trial.

BACKGROUND: Perioperative nutrition and preoperative oral carbohydrate loading (CHL) have a beneficial impact on the outcomes of gastrointestinal oncological surgery. However no data exists on their effect on morbidly obese patients. OBJECTIVES: Our aim was to establish the short-term and long-term impact of these modalities, notably on metabolically active lean body mass (LBM) - an important factor in maintaining long-term weight loss. METHODS: Patients undergoing laparoscopic Roux-en-Y gastric bypass were randomized to standard management or intervention: CHL drinks consumed 12 and 2 hours presurgery, and immediate postoperative peripheral parenteral nutrition. The primary outcome measured was LBM, measured by Bioelectrical Impedance Analysis (BIA), one and 12 months postsurgery. Secondary outcomes included excess weight loss (EBWL), 30-day complication rate, and length of stay. RESULTS: Of the 203 randomized patients, 198 were included in the analysis. All 101 patients in the control group completed the one-year follow up and 76 completed the BIA. In the intervention group, 93 of 97 patients completed the one-year follow-up and 71 completed the BIA. At one and 12 months follow-up, body composition, LBM, or EBWL were comparable. There was no difference in operative outcomes, complications rates, or length of stay. There was no adverse effect in the intervention group. CONCLUSIONS: In a highly homogeneous group of morbidly obese patients with one-year follow-up, CHL and short-term parenteral nutrition did not lead to significant or sustained LBM preservation or modification in EBWL. There was no significant decrease in complications or length of stay. Our study confirms the safety of these interventions, even in previously unstudied Type 2 diabetic patients.

Plastic surgery after gastric bypass improves long-term quality of life.

BACKGROUND: Excess skin after massive weight loss impairs patient's health-related quality of life (HRQoL). Therefore, body-contouring surgeries can be proposed. However, few data exist concerning the effect of body contouring after bariatric surgery on HRQoL, including control group with a long-term follow-up. METHODS: In a prospective study, 98 consecutive patients who had body contouring after gastric bypass for obesity (BMI > 40) were included (group A). A matched control-group containing 102 patients who had only gastric bypass was selected (group B). HRQoL was measured by Moorehead-Ardelt questionnaire before (group A1) and after (A2) body contouring, and at different time points for group B until 8 years post-gastric bypass. To evaluate the effect of body contouring by two parallel methods, HRQoL was compared between groups A1 and A2, and between A2 and B. RESULTS: We found that body contouring procedures improved significantly patients' HRQoL, in comparison to those who had only gastric bypass. Of the patients who had body contouring (group A2), 57 % evaluated their HRQoL "much better" in comparison to only 22 % of patients before body contouring (group A1) or those who never had body contouring (group B) (p < 0.001). The improvement was significant in all sub-domains of HRQoL: self-esteem, social life, work ability, sexual activity and physical activity (p < 0.001), and remained stable over time. CONCLUSIONS: Our study confirms the important role of plastic surgery in treatment of patients after massive weight loss. We demonstrated that body contouring, despite important scars, significantly improves satisfaction and HRQoL of patients after gastric bypass. Therefore, the treatment of morbid obesity should not be deemed achieved unless plastic surgery has been considered.

DSC3 expression is regulated by p53, and methylation of DSC3 DNA is a prognostic marker in human colorectal cancer.

BACKGROUND: Desmocollin 3 (DSC3), a member of the cadherin superfamily and integral component of desmosomes, is involved in carcinogenesis. However, the role of DSC3 in colorectal cancer (CRC) has not yet been established. METHODS: Desmocollin 3 expression in CRC cell lines was analysed by RT-PCR and western blotting. Methylation status of DSC3 was examined by demethylation tests, methylation-specific PCR, and bisulphite sequencing (BS). The regulatory role of p53 was investigated by transfection. RESULTS: Desmocollin 3 was downregulated in CRC cells at mRNA and protein levels. Desmocollin 3 expression was restored in five out of seven cell lines after 5-aza-2'-deoxycytidine (DAC) treatment. A heterogeneous methylation pattern was detected by BS in promoter region and exon 1 of DSC3. Methylation of DSC3 genomic sequences was found in 41% (41 out of 99) of primary CRC, being associated with poor prognosis (P=0.002). Transfection of p53 alone or in combination of DAC increased the DSC3 expression. Similarly, treatment with p53 inducer adriamycin alone or in combination with DAC enhanced DSC3 expression. CONCLUSIONS: DNA methylation contributes to downregulation of DSC3 in CRC cell lines. Methylation status of DSC3 DNA is a prognostic marker for CRC. P53 appears to have an important role in regulating DSC3 expression.

[Oesophageal cancer: multidisciplinary approach]. / Cancer de l'oesophage: traitement multidisciplinaire.

Despite recent progresses, the prognosis of oesophageal cancer is still bad, mostly because of frequent late diagnosis. In early cases, radical surgery alone is able to cure 60-70% of the patients. In locally-advanced cases, on the other hand, surgical results are considerably worse and combined therapies are contemplated. In these cases, neoadjuvant therapy (induction chemotherapy followed by radiotherapy and surgical resection) is often proposed, but without formal proof of superiority. These combined therapies are heavy for the patient and complex for the team. They can only be decided and managed in the frame of intensive multidisciplinary collaboration. Future progresses will come at the same time from larger studies and from the efforts of the medical community towards earlier diagnosis of this disease.

Surgical management of gastrointestinal stromal tumours.

BACKGROUND: Over the past decade, gastrointestinal stromal tumours (GISTs) have served as a model for the application of tyrosine kinase inhibitors in the treatment of solid neoplasms. Operative and medical management of GISTs is rapidly evolving, but current guidelines appear restricted to basic non-organ-specific recommendations. METHODS: A PubMed search was made of the English literature from 1998 to 2008 for references containing the terms 'gastrointestinal stromal tumours' and 'surgery'. This paper reviews the various operative strategies so far reported for GISTs within the digestive tract. RESULTS: Many original procedures tailored to the specific characteristics of these rare sarcomas have been reported. GISTs exhibit distinct features, in particular an absence of metastases within locoregional lymph nodes. Operations requiring extended lymph node dissection, typically designed for adenocarcinomas, such as gastrectomy with extended lymph node dissection, Whipple's procedure and total mesorectum excision, are inappropriate for treating GISTs originating from the stomach, duodenum and rectum respectively. CONCLUSION: GISTs allow the possibility of performing oncologically adequate but limited (wedge; segmental) resections. Such surgery can be carried out in a variety of ways, such as open, laparoscopic, trans-sacral or endoscopic.

Persistent correlation of ghrelin plasma levels with body mass index both in stable weight conditions and during gastric-bypass-induced weight loss.

BACKGROUND: Studies done on serial changes in plasma ghrelin levels after gastric bypass (GBP) have yielded contrasting results since decreased, unchanged, or increased levels have been reported in the literature. This study investigates whether or not GBP has an inhibitory effect on fasting ghrelin levels independently of weight loss. METHODS: Fasting ghrelin levels were measured in 115 stable body weight females, classified as normal body weight (NW; body mass index (BMI)<25 kg/m2), overweight (OW; BMI 25-30 kg/m2), and obese subjects, divided in three subgroups with increasing BMI (BMI 30-40 kg/m2; BMI 40-50 kg/m2; BMI>50 kg/m2). RESULTS: Each obese subgroup showed significantly lower ghrelin levels as compared to both NW (p<0.0001) and OW subjects (p<0.05 or 0.005); however, no significant differences were observed within the three obese subgroups. Forty-nine obese patients underwent a GBP. Plasma ghrelin, measured at 3, 6, and 12 months after GBP, significantly increased from the sixth month on (p<0.0001). When patients were classified, at each postoperative time point, according to their actual BMI, ghrelin was significantly (p=0.0002) related to postoperative BMI and not significantly different from ghrelin measured in stable body weight conditions. CONCLUSIONS: Fasting ghrelin displays an inversely significant correlation with BMI in both stable body weight conditions and after GBP. No evidence was found that GBP had an effect on fasting ghrelin levels, independent of weight loss.

Trans-sacral (Kraske) approach for gastrointestinal stromal tumour of the lower rectum: old procedure for a new disease.

Gastrointestinal stromal tumours (GISTs) of the lower rectum are rare cancers from mesenchymatous origin, which are characterized by; 1) the absence of metastases in loco-regional lymph nodes; and 2) a tendency to grow opposite to the intestinal lumen. Thus, the two preferred surgical approaches for rectal adenocarcinomas (i.e. abdominal and transanal) are inappropriate for GISTs, due to: 1) the uselessness of total mesorectal excision; and 2) to the difficulty to locate the tumour with a transanal approach. We report here a case of a large GIST of the lower rectum which was successfully treated with a posterior trans-sacral approach. Lower rectum GISTs are good indications for the Kraske procedure, and this relatively new disease entity may contribute to the reintroduction of an old procedure into the armamentarium of 21(st) century colorectal surgeons.

Preoperative work-up in asymptomatic patients undergoing Roux-en-Y gastric bypass: is endoscopy mandatory?

BACKGROUND: We aimed to determine before Roux-en-Y gastric bypass (RYGBP) in asymptomatic morbidly obese patients: 1) the prevalence of abnormal findings at upper gastrointestinal (UGI) endoscopy; 2) Helicobacter pylori (HP) status; 3) clinical consequences of these findings; and 4) associated costs. METHODS: We retrospectively reviewed 468 consecutive patients, excluded those with UGI symptoms, drug intake or previous UGI endoscopy/surgery, and analyzed findings in the 319 remaining patients (68%). RESULTS: There were abnormal findings in 147 patients (46%), including 54 hiatal hernias and 146 parietal (i.e. mucosal or submucosal) lesions. The most significant were 7 ulcers and 2 gastric polyposis. HP was detected (using CLO-test) in 124 patients (39%). Histopathological examination of biopsies was abnormal in 109/161 patients (68%), and disclosed mainly chronic gastritis (n=98). Abnormal findings were more frequent in HP-positive compared to HP-negative patients (94 vs 51%, P<0.001). Findings had clinical implications in only 4% of patients: delayed surgery (7 ulcers), prophylactic gastrectomy (2 gastric polyposis), unnecessary work-up (3 irrelevant/false-positive diagnoses), and inclusion in a screening program (1 Barrett's esophagus). Mean cost of complete UGI work-up was 389 euro/patient. CONCLUSION: Asymptomatic morbidly obese patients frequently harbour UGI lesions warranting UGI work-up before RYGBP. However, routine endoscopy presents drawbacks. We propose a less invasive strategy which reduces costs and limits false-positive results and the subsequent investigations that they require. In our series, it would have missed two gastric polyposis only, for which no formal recommendation has yet been issued. This strategy could be a valuable alternative to routine UGI endoscopy before RYGBP in asymptomatic patients.

The effect of insulin on cardiac autonomic balance predicts weight reduction after gastric bypass.

AIMS/HYPOTHESIS: The aim of this study was to assess the predictive role of autonomic reactivity in body weight loss induced by gastric bypass. METHODS: A group of 22 morbidly obese subjects, who were due to undergo a gastric bypass, were submitted, before surgery, to a euglycaemic-hyperinsulinaemic clamp, during which a continuous recording of the ECG was performed. The effect of insulin on cardiac autonomic balance was evaluated by performing power spectral analysis of heart rate variability. The low-to-high frequency ratio was calculated before and during the clamp and its modifications were expressed as % delta low-to-high frequency ratio (%Delta L: H). RESULTS: Preoperative %Delta L: H showed a significant (p=0.0009, r2=0.43), positive relationship to the reduction of body weight, measured 1 year after surgery and expressed as % excess weight loss (% EWL). Preoperative BMI was also significantly (p=0.0009, r2=0.43) negatively related to the 12-month % EWL. In a multiple regression analysis, %Delta L: H remained a significant (p=0.003), independent predictor of body weight loss, even when preoperative BMI or age, % fat mass, insulinaemia and glucose disposal were taken into account. CONCLUSIONS/INTERPRETATION: The best correction of excess body weight was achieved by those obese subjects who had a preserved capacity to shift their cardiac autonomic balance towards a sympathetic prevalence in response to an euglycaemic-hyperinsulinaemic clamp. Further studies are needed to elucidate the mechanisms through which the autonomic nervous system influences weight reduction.

A second protein kinase CK1-mediated step negatively regulates Wnt signalling by disrupting the lymphocyte enhancer factor-1/beta-catenin complex.

Deregulated activation of the canonical Wnt signalling pathway leads to stabilization of beta-catenin and is critically involved in carcinogenesis by an inappropriate induction of lymphocyte enhancer factor (LEF-1)/beta-catenin-dependent transcription of Wnt target genes. Phosphorylation of the pathway components beta-catenin, Dishevelled, Axin and APC (adenomatous polyposis coli) by glycogen synthase kinase-3beta, CK1 and CK2 is of central importance in the regulation of the beta-catenin destruction complex. Here, we identify CK1 and CK2 as major kinases that directly bind to and phosphorylate LEF-1 inducing distinct, kinase-specific changes in the LEF-1/DNA complex. Moreover, CK1-dependent phosphorylation in contrast to CK2 disrupts the association of beta-catenin and LEF-1 but does not impair DNA binding of LEF-1. Sequential phosphorylation assays revealed that for efficient disruption of the LEF-1/beta-catenin complex, beta-catenin also has to be phosphorylated. Consistent with these observations, CK1-dependent phosphorylation inhibits, whereas CK2 activates LEF-1/beta-catenin transcriptional activity in reporter gene assays. These data are in line with a negative regulatory function of CK1 in the Wnt signalling pathway, where CK1 in addition to the beta-catenin destruction complex at a second level acts as a negative regulator of the LEF-1/beta-catenin transcription complex, thereby protecting cells from development of cancer.

Treatment of hepatocellular carcinoma at the dawn of the third millennium: liver transplantation and its alternatives.

Hepatocellular carcinoma is one of the most frequent tumors worldwide, and its frequency is increasing. The management of hepatocellular carcinoma has changed in recent years, this because screening allows to discover tumors at an earlier stage, and because of effective treatments are available, such as liver transplantation, liver resection, percutaneous ablation and transarterial chemoembolization. Each one of these treatments has its own advantages and drawbacks, and range of application according to the stage of the tumor and of the underlying liver disease. This review summarizes the recent progress in the management of HCC and the practice in our unit.

Relationship between sympathetic reactivity and body weight loss in morbidly obese subjects.

OBJECTIVE: To investigate the possible role of peripheral sympathetic activity in gastric bypass-induced body weight loss. SUBJECTS AND METHODS: In 42 morbidly obese patients (sex: 36 f/6 m; BMI: 46.0+/-0.7 kg/m(2)) undergoing a gastric bypass, the skin vasoconstrictor reflex in answer to a deep inspiration was measured by laser Doppler fluximetry. The extent of vasoconstriction, measured at the second finger of the left hand, was expressed as percent reduction of the basal blood flux (% vasoconstriction). Insulin sensitivity was assessed before surgery in a subset of patients (n=11), by the method of euglycemic, hyperinsulinemic clamp. Body weight and composition were evaluated before, and 3, 6 and 12 months after surgery. At the same time points, energy intake (kJ/day) was evaluated by means of both food record diary and alimentary anamnesis. RESULTS: The % vasoconstriction, which was significantly (P=0.01) greater in normoglycemic subjects than in diabetic ones, was also significantly (P=0.03) related to the extent of insulin sensitivity measured during the euglycemic clamp. The % vasoconstriction showed a significant (P>0.0001), positive correlation with weight reduction obtained between the 6th and 12th months following surgery; as a consequence, % vasoconstriction was significantly (P=0.0004) related to the overall body weight loss achieved during the year following the operation. These correlations remained significant in multiple regression analysis with adjustment for age, initial body weight, plasma glucose and insulin (P=0.0007 and 0.006, respectively). The % vasoconstriction was also significantly (P=0.0006), negatively related to energy intake measured 12 months after surgery. CONCLUSIONS: In conditions of stable body weight, the sympathetic nervous system (SNS) reactivity is influenced by the degree of insulin resistance. A high capacity to activate the SNS, measured before surgery, is associated with both a larger gastric bypass-induced weight loss and a lower energy intake, at the phase of weight stabilization.

Adult-to-adult living-donor liver transplantation. A summary of current status and an outline of the program in Geneva.

Living donor liver transplantation is a relatively new procedure in which the right side of the liver is harvested in a healthy donor and transplanted into a recipient. After the first case in 1994, over 3000 cases have been done worldwide. This review summarizes the reasons why the procedure is needed, describes its main technical aspects, highlights the boundaries in which it can be done safely, summarizes the current experience worldwide and describes the main points of the program in our unit. We argue that living-donor transplantation is a viable alternative to a long time on the waiting list for several patients, and it can be performed safely and successfully provided that all precautions are undertaken to minimize the risks in the donor and to increase the chances of a good outcome in the recipients. If these prerequisites are met, and within the framework of a structured multidisciplinary program, we believe that living-donor liver transplantation should be funded by health insurances as a recognized therapeutic option.

Neoadjuvant radiochemotherapy for locally advanced gastric cancer: a phase I-II study.

BACKGROUND: To study in a phase I-II trial the maximum tolerated dose, the toxicity, and the tolerance of adding radiotherapy to systemic chemotherapy administered preoperatively in patients with locoregionally advanced gastric adenocarcinoma. PATIENTS AND METHODS: Patients with adenocarcinoma of the stomach (T(3)(-)(4)N(any) or T(any)N+), performance status

Cleavage and shedding of E-cadherin after induction of apoptosis.

Apoptotic cell death induces dramatic molecular changes in cells, becoming apparent on the structural level as membrane blebbing, condensation of the cytoplasm and nucleus, and loss of cell-cell contacts. The activation of caspases is one of the fundamental steps during programmed cell death. Here we report a detailed analysis of the fate of the Ca(2+)-dependent cell adhesion molecule E-cadherin in apoptotic epithelial cells and show that during apoptosis fragments of E-cadherin with apparent molecular masses of 24, 29, and 84 kDa are generated by two distinct proteolytic activities. In addition to a caspase-3-mediated cleavage releasing the cytoplasmic domain of E-cadherin, a metalloproteinase sheds the extracellular domain from the cell surface during apoptosis. Immunofluorescence analysis confirmed that concomitant with the disappearance of E-cadherin staining at the cell surface, the E-cadherin cytoplasmic domain accumulates in the cytosol. In the presence of inhibitors of caspase-3 and/or metalloproteinases, cleavage of E-cadherin was almost completely blocked. The simultaneous cleavage of the intracellular and extracellular domains of E-cadherin may provide a highly efficient mechanism to disrupt cadherin-mediated cell-cell contacts in apoptotic cells, a prerequisite for cell rounding and exit from the epithelium.

Combined midline-transverse surgical approach for severe blunt injuries to the right liver.

BACKGROUND: Although nonoperative treatment has been a major advance in the management of liver trauma, emergency surgery is still required for unstable patients. Severe hepatic lesions located in the right lobe, notably juxtahepatic venous injuries, are difficult to access and still carry a high mortality. METHODS: We describe a surgical approach for severe blunt injury to the right liver by a combined midline-transverse incision. This techniques allows simple, easy, and rapid mobilization and compression of the liver to control bleeding. RESULTS: This technique was used in 10 patients with blunt liver trauma, with grade III (n = 2), IV (n = 5), and V (n = 3) injuries. Mean intraoperative blood transfusion required was 21 units. Six patients underwent mandatory anatomic resection, three patients were treated by hepatic suture, and one patient was treated by packing. This patient developed brain death after surgery and was the only mortality. CONCLUSION: This technique is efficient and less cumbersome than shunting approaches.

Energy economy hampers body weight loss after gastric bypass.

The impact of energy economy on body weight loss was investigated in 20 obese women, submitted to Roux-en-Y gastric bypass. Resting energy expenditure (REE), substrate oxidation rates, plasma glucose, free fatty acid, and insulin and leptin levels were measured before and 3, 6, and 12 months after surgery. Predicted REE was obtained from linear regression analysis of REE and fat free mass, in a group of 85 women, whose body mass index ranged between 20 and 60 kg/m(2). The deviation from predicted REE, calculated as area under the curve (AUC) over the 12-month period for each patient, was considered as the expression of energy economy. Energy economy AUC was significantly (P: < 0.005) negatively related to the weight lost during 12 months after surgery. Energy intake, calculated from self-reported food consumption, was also expressed as AUC. Energy intake AUC showed a significant (P: < 0.002) positive correlation with weight loss. Lipid oxidation rate, also calculated as AUC, significantly correlated, negatively, with energy economy (P: < 0. 001) and, positively, with energy intake (P: < 0.002). Preoperative leptin values were significantly (P: < 0.01) linked to individual energy economy capacity. In conclusion, after Roux-en-Y gastric bypass, energy economy hampers the weight loss process, probably through a low fat oxidation rate.

Functional characterization of multiple transactivating elements in beta-catenin, some of which interact with the TATA-binding protein in vitro.

beta-Catenin, a member of the family of Armadillo repeat proteins, plays a dual role in cadherin-mediated cell adhesion and in signaling by Wnt growth factors. Upon Wnt stimulation beta-catenin undergoes nuclear translocation and serves as transcriptional coactivator of T cell factor DNA-binding proteins. Previously the transactivation potential of different portions of beta-catenin has been demonstrated, but the precise location of transactivating elements has not been established. Also, the mechanism of transactivation by beta-catenin and the molecular basis for functional differences between beta-catenin and the closely related proteins Armadillo and Plakoglobin are poorly understood. Here we have used a yeast system for the detailed characterization of the transactivation properties of beta-catenin. We show that its transactivation domains possess a modular structure, consist of multiple subelements that cover broad regions at its N and C termini, and extend considerably into the Armadillo repeat region. Compared with beta-catenin the N termini of Plakoglobin and Armadillo have different transactivation capacities that may explain their distinct signaling properties. Furthermore, transactivating elements of beta-catenin interact specifically and directly with the TATA-binding protein in vitro providing further evidence that a major function of beta-catenin during Wnt signaling is to recruit the basal transcription machinery to promoter regions of Wnt target genes.