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The picture shows the marine macrolide mandelalide A together with the starting materials and advanced intermediates that have enabled a highly convergent total synthesis of the macrolactone core of this complex natural product. Like other bioactive macrocycles, mandelalide A is of polyketide origin and it has been described to exhibit antiproliferative activity against some human cancer cell lines, but not others. Here, mandelalide A was found to reduce the proliferation of two lung cancer cell lines with nM potency, but it did not kill all cells even at much higher concentrations. More information can be found in the Full Paper by K.‐H. Altmann et al. on page 1292 ff. [ABSTRACT FROM AUTHOR]

Duodenal diverticula (DD) are frequently encountered and are usually asymptomatic, with an incidence at autopsy of 22%. Perforation of DD is a rare complication (around 160 cases reported) with potentially dramatic consequences. However, little evidence regarding its treatment is available in the literature. The aim of this study was to review our experience of perforated DD, with a focus on surgical management. Between January 2001 and June 2011, all perforated DD were retrospectively reviewed at a single centre. Seven cases (5 women and 2 men; median age: 72.4 years old, rang: 48-91 years) were found. The median American Society of Anesthesiologists' score in this population was 3 (range: 3-4). The perforation was located in the second portion of duodenum (D2) in six patients and in the third portion (D3) in one patient. Six of these patients were treated surgically: five patients underwent DD resection with direct closure and one was treated by surgical drainage and laparostomy. One patient was treated conservatively. One patient died and one patient presented a leak that was successfully treated conservatively. The median hospital stay was 21.1 d (range: 15-30 d). Perforated DD is an uncommon presentation of a common pathology. Diverticular excision with direct closure seems to offer the best chance of survival and was associated with a low morbidity, even in fragile patients.

Questions Under Study/principles: In most centers, Upper Gastrointestinal series (UGI) following Roux-en-Y Gastric Bypass (RYGB) is performed to rule out GJ anastomotic leak. According to the introduction of robotic technology associated with a hypothetical decrease of anastomotic complications, we aim to assess the validity and cost effectiveness of early routine UGI following robot-assisted RYGB., Methods: Between July 2006 and December 2010, 167 robot-assisted RYGB were performed at a single institution. All data were collected prospectively in a computerised database and reviewed retrospectively. Patients underwent a gastrografin UGI at postoperative day 2 to exclude anastomotic leak or stenosis., Results: None of the 167 patients who underwent an early UGI experienced leak radiologically and clinically. The only radiological abnormalities were two GJ edema (1.2%) and one jejunojenunostomy stenosis (0.6%), all treated conservatively with success. The total cost for the 167 UGI was CHF 93,520 (= USD 96,886)., Conclusions: In most centres, the risk of anastomotic leak has been the rationale for obtaining an UGI following RYGB. However, provided low leak rates as for our experience with robotic RYGB, the authors show this exam to be expensive and of limited value. A decisional algorithm for on demand UGI has been developed according to patient's characteristics and is now under validation.

Aim: To evaluate the results of segmental duodenectomy (SD) and pancreaticoduodenectomy (PD) for duodenal gastrointestinal stromal tumor (GIST) and help clinicians with surgical management., Methods: All patients who underwent surgery for non-metastatic GIST of the duodenum in a single institution since 2000 were prospectively followed up. Seven patients (median age 51 years, range: 41-73 years) were enrolled: five underwent SD and two underwent PD., Results: All the patients had a complete resection (R0), with no postoperative morbidity and mortality. Among the SD group, GIST was classified as low risk in two patients, intermediate risk in two, and high risk in one, according to the Fletcher scale, (vs two high risk patients in the PD group). With a median follow-up of 41 (18-85) mo, disease-free survival (DFS) rates were 100% after SD and 0% after PD (P < 0.05). The median DFS was 13 mo in the PD group., Conclusion: Whenever associated with clear surgical margins, SD is a reliable and curative option for most duodenal GISTs, and is compatible with long-term DFS.

Background: Laparoscopic gastrojejunostomy allows effective palliation and rapid recovery for the patient with limited survival due to advanced pancreatic cancer presenting with gastric outlet obstruction. Transumbilical single-incision laparoscopic surgery (SILS) offers excellent cosmetic results and may be associated with decreased postoperative pain, reduced need for analgesia, and thus accelerated recovery. The authors report the first transumbilical single-incision laparoscopic intracorporeal anastomosis for gastrojejunostomy., Methods: Preliminary experience with transumbilical single-incision, intracorporeal anastomosis for gastrojejunostomy for a patient with gastric outlet obstruction caused by advanced pancreatic cancer is reported., Results: Transumbilical single-incision laparoscopic intracorporeal anastomosis for gastrojejunostomy was performed with a linear endoscopic stapler using an omega loop. The operative time was 117 min. No intra- or postoperative complications were recorded., Conclusion: Transumbilical single-incision laparoscopic intracorporeal anastomoses are feasible using the endoscopic linear stapler. Transumbilical single-incision gastrojejunostomy for gastric outlet obstruction may improve cosmetic results and allow accelerated recovery for patients with limited survival. This anastomosis technique of single-incision laparoscopic surgery for other digestive tract procedures needs further evaluation.

Background: Single port access (SPA) surgery is a rapidly evolving field due to the complexity of NOTES (natural orifice translumenal endoscopic surgery). SPA combines the cosmetic advantage of NOTES and possibility to perform surgical procedure with standard laparoscopic instruments. We report a technique of umbilical SPA cholecystectomy using standard laparoscopic instruments and complying with conventional surgical principle and technique of minimally invasive cholecystectomy., Methods: Preliminary, prospective experience of SPA cholecystectomy in 11 patients (median age, 46 (range, 27-63) years) scheduled for cholecystectomy was evaluated. Diagnoses for cholecystectomy were: symptomatic gallbladder lithiasis (n = 7), previous acute cholecystitis (n = 3), and biliary pancreatitis (n = 1)., Results: SPA cholecystectomy was feasible in all patients (median body mass index, 24 (range, 20-34) kg/m(2)) who were scheduled for preliminary experience using conventional laparoscopic instruments. Median operative time was 52 (range, 40-77) minutes. Intraoperative cholangiography was performed in all patients, except one, and was considered normal. No peroperative or postoperative complications were recorded. Median hospital stay was less than 24 h., Conclusions: SPA cholecystectomy is feasible and seems to be safe when performed by experienced laparoscopic surgeons using standard laparoscopic instrumentation. SPA cholecystectomy may be safer than the NOTES approach at this time. It has to be determined whether this approach would benefit patients, other than cosmesis, compared with standard laparoscopic cholecystectomy.

Background: Single port access (SPA) surgery is a rapidly evolving field as it combines some of the cosmetic advantage of the Natural Orifice Translumenal Endoscopic Surgery (NOTES) and allows performing surgical procedure with standard surgical instruments. We report in this paper a new technique of umbilical SPA right hemicolectomy with conventional surgical oncologic principle and technique of minimally invasive colectomy., Methods: Preliminary experience with umbilical SPA right hemicolectomy in a patient with degenerated ascending colon polyp., Results: Umbilical SPA right hemicolectomy was feasible with conventional laparoscopic instruments. Carcinologic surgical principle can be respected using this technique as pathological specimen had sufficient surgical margins (>10 cm) and lymph nodes (33). Operative time was 158 min. No peroperative or postoperative complications were recorded., Conclusion: SPA right hemicolectomy is feasible and safe when performed by experienced laparoscopic surgeons. SPA right hemicolectomy may have the advantage over NOTES approach to offer the safety of laparoscopic colectomy especially for haemostasis and anastomosis. It has to be determined whether or not this approach would offer benefit to patients, except in cosmesis, compared to standard laparoscopic right hemicolectomy.

Background: A number of surgical techniques for colorectal anastomosis have been described for laparoscopic left-sided colectomies. Due to the complexity of these procedures, open preparation of the proximal bowel for circular stapler anastomosis through a Pfannenstiel incision has become the gold standard. We report a new laparoscopic technique for totally intracorporeal colorectal circular anastomosis (TLCCA) using a circular stapler., Methods: Preliminary experience using TLCCA in three patients scheduled for laparoscopic left colectomies (two) and sigmoidectomy (one)., Results: Side-to-end colorectal anastomosis through TLCCA was feasible in all patients scheduled for preliminary experience. Median time from anvil insertion into abdominal cavity to anastomosis was 14 (11-17) minutes. No postoperative complications were recorded., Conclusion: Side-to-end anastomosis can be easily and safely performed using conventional circular stapler through TLCCA. TLCCA is performed using four laparoscopic ports without additional skin incision (except trocars incision) and allows the retrieval of surgical pieces through a specimen bag.

Background: Anastomotic dehiscence is the most severe surgical complication after large bowel resection. This study was designed to assess the incidence, to observe the consequences, and to identify the risk factors associated with anastomotic leakage after colorectal surgery., Materials and Methods: All procedures involving anastomoses of the colon or the rectum, which were performed between November 2002 and February 2006 in a single institution, were prospectively entered into a computerized database., Results: One thousand eighteen colorectal resections and 811 anastomoses were performed over this 40-month period. The most frequent procedures were sigmoid (276) and right colectomies (217). The overall anastomotic leak rate was 3.8%. The mortality rate associated with anastomotic leak was 12.9%. In univariate analysis, the following parameters were associated with an increased risk for anastomotic dehiscence: (1) ASA score >or= 3 (p = 0.004), (2) prolonged (>3 h) operative time (p = 0.02), (3) rectal location of the disease (p < 0.001), (4) and a body mass index > 25 (p = 0.04). In multivariate analysis, ASA score >or= 3 (OR = 2.5; 95% CI 1.5-4.3, p < 0.001), operative time > 3 h [OR = 3.0; 95% CI 1.1-8.0, p = 0.02), and rectal location of the disease (OR = 3.75; 95% CI 1.5-9.0 (vs left colon), p = 0.003; OR = 7.69; 95% CI 2.2-27.3 (vs right colon), p = 0.001] were factors significantly associated with a higher risk of anastomotic dehiscence., Conclusions: Three risk factors for anastomotic leak have been identified, one is patient-related (ASA score), one is disease-related (rectal location), the third being surgery-related (prolonged operative time). These factors should be considered in perioperative decision-making regarding defunctioning stoma formation.

Objective: Abdominoperineal resection (APR) is a disfiguring procedure, frequently associated with significant urogenital dysfunction. The aim of this prospective study was to repeatedly assess quality of life (QoL) 1, 6, and 12 months after APR., Methods: Twenty patients who underwent APR between June 2002 and September 2005 were considered for analysis. QoL was assessed using two self-rating validated questionnaires developed by the European Organization for Research and Treatment of Cancer (EORTC)., Results: All patients were free of recurrence at time of last interview. At 1-year follow-up patients reported significant improvement in global QoL [scores: 53 +/- 23 (1 month) vs. 70 +/- 15 (1 year), P = 0.01], and physical function (74 +/- 16 vs. 91 +/- 12, P = 0.001). Patients also reported significant improvement in symptoms such as fatigue (39 +/- 30 vs. 15 +/- 19, P = 0.01); and pain (33 +/- 31 vs. 10 +/- 14, P = 0.01). By contrast, there was no improvement at 1 year for the following items: body image (75 +/- 33 vs. 75 +/- 30, P = 0.99), sexual dysfunction (10 +/- 21 vs. 21 +/- 27, P = 0.40); and stoma-related problems (19 +/- 14 vs. 11 +/- 28, P = 0.34)., Conclusion: One year after APR, patients demonstrated significant improvement in global QoL and tumor-related symptoms, while body image remained significantly altered. Similarly, treatment-related side effects did not improve over the time period considered., ((c) 2007 Wiley-Liss, Inc.)

Background: Conservative treatment of perforated gastroduodenal ulcer has been shown to be associated with good results in patients whose general condition is good. However, its use in patients not eligible for surgical repair has not been supported. The aim of this study is to evaluate the results of conservative treatment in these patients in the era of proton pump inhibitor., Material and Methods: In the period 1978-2004, 533 patients were admitted for perforated gastroduodenal ulcer. 503 patients underwent surgery, while 30 (median age 79 [42-98] years) were allocated to conservative treatment due to poor general condition. Conservative treatment consisted of nasogastric aspiration, antibiotics and antisecretory therapy (H2-blockers from 1978-1995, 11 patients, and proton pump inhibitors (PPI) from 1996, 19 patients). Endpoints were: hospital morbidity and mortality and hospital stay., Results: Overall morbidity and mortality were 33% and 30%. Median hospital stay was 11 days (range 0-32). General complications developed in 73% versus 16% of patients (p = 0.023) and mortality was 64% versus 11% (p = 0.008) for the H2-blocker and PPI groups respectively. On multivariate analysis mortality correlated with presence of shock at admission and type of antisecretory therapy., Conclusion: In the era of PPI conservative treatment for perforated ulcer is possible with acceptable morbidity and mortality in patients not eligible for surgical repair. However, presence of shock at admission was associated with high mortality and, even in these patients, militates in favour of a surgical approach.

Background/aims: Vater's ampulla neoplasms account for 30% of resected bilio-pancreatic confluent tumors. Study aim was to review long-term results of surgical treatment for ampullary neoplasms., Methodology: A retrospective review from 1993 to 2002 identified 55 patients admitted for Vater's ampulla neoplasm in our institution. Follow-up was complete for all cases with a median follow-up of 24 (range 2-180) months., Results: Among the ampullary neoplasms, 10 were adenomas (median age 71) and 45 adenocarcinomas (median age 69). Of the adenomas 60% were treated surgically with excellent long-term results. The resectability rate of ampullary carcinomas was 84%. 34 patients had pancreaticoduodenectomy and 4 ampullectomy. Importantly, the rate of false-negative preoperative biopsies was 45%. Seven patients were treated by stenting or derivation due to poor condition. Actuarial five-year survival rate after pancreatoduodenectomy was 68% (median follow-up 24 months), compared to 0% for other approaches (p < 0.01). After pancreatoduodenectomy, the lymph node status influenced survival, while disease-free survival at 5 years was 85% for NO and 27% for N1 (p < 0.001). Among the pancreatoduodenectomies, 55% consisted of pylorus-preserving procedure which did not influence prognosis compared to absence of pylorus preservation., Conclusions: Pancreatoduodenectomy remains the gold standard for Vater's ampulla neoplasms resection due to the low sensitivity of diagnostic biopsies for carcinoma detection. Vater's ampulla neoplasms resection by pancreatoduodenectomy is associated with good long-term results; however survival after curative resection is influenced by lymph node status.

Aim: Postoperative ileus is an important factor of complications following gastrointestinal procedures. Its pathophysiology and the parameters, which may impact on its duration, remain unclear. The aim of this study was to measure the role of various clinical determinants on restoration of intestinal function after elective colorectal surgery., Methods: From July 2002 to September 2003, all patients who underwent laparotomy for colectomy (laparoscopic resections excluded) with either an ileotransverse, colocolic, or high colorectal anastomosis were entered in this prospective study. The intervals in hours between the end of the surgical procedure and passing of flatus (PG) and passing of stool (PS) were recorded by an independent investigator. PG and PS were eventually correlated with the following parameters: type of colectomy, early removal of nasogastric tube (NGT), mechanical bowel preparation (MBP), type of underlying disease, systemic administration of opiates, and surgical training (colorectal fellowship or other)., Results: One hundred twenty-four patients were entered in this study. Four patients (3.2%) developed septic complications (3 anastomotic leaks and 1 intraabdominal abscess) and were excluded from the analysis. Median age in this population was 68 (range 30-95) years. Mean duration of postoperative ileus was 70+/-28 h (PG) and 99+/-34 h (PS). The type of colectomy, underlying disease, MBP, and early NGT removal failed, in univariate analysis, to correlate with the duration of postoperative ileus. By contrast, time intervals PG and PS were statistically shorter in the group of patients treated by a colorectal surgeon [56+/-23 vs 74+/-28 h (PG); 82+/-26 vs 103+/-35 h (PS), p=0.004], as well as in patients who received systemic opiates for less than 2 days [64+/-27 vs 75+/-28 h (PG), p=0.04; 88+/-32 vs 108+/-33 h (PS), p=001]., Conclusion: Restoration of normal intestinal function after elective open colectomy takes 3 (PG) to 4 (PS) days. In our series, specialized training in colorectal surgery has a positive impact on the duration of postoperative ileus. Surgical specialization should be considered an important parameter in future clinical trials aiming to minimize postoperative ileus.

Introduction: The aim of this study was to assess the outcome of surgery for rectal cancer in patients 80 years of age or more., Methods: A retrospective study of 29 patients older than 80 years, who presented in our institution between 1997 and 2001 with the diagnosis of rectal adenocarcinoma, was undertaken., Results: Median follow-up was 54 (range 27-78) months, and the median age of patients was 85 (range 80-94) years. Twenty-four out of 29 patients (83%) underwent surgery, 23 being operated electively. Twenty out of 24 patients (83%) underwent resection with curative intent, while four patients (17%) had a palliative procedure. Median hospital stay was 13 (range 10-35) days. Postoperative morbidity and mortality were 46% and 12.5%, respectively. However, when considering only elective procedures with curative intent, operative mortality was 5%. At the time of last follow-up, 13 patients were alive, five of them with no evidence of recurrent disease at 5 years, for an overall 2- and 5-year survival rate of 80% and 67%, respectively. Four out of the 7 deaths, which occurred after surgery, were due to medical causes unrelated to cancer., Conclusion: In our institution, two thirds of patients older than 80 years who presented with rectal cancer underwent surgery with curative intent. In this selected population, good results in terms of short-term survival can be achieved, at the price of an elevated postoperative morbidity. Whenever possible, treatment with curative intent should be considered in patients with rectal cancer, irrespective of the age.

Purpose: The feasibility and safety of left-sided colorectal procedures with avoidance of mechanical bowel preparation has recently been demonstrated. Moreover, mechanical preparation has been associated with an increased risk for abdominal septic complications, including anastomotic leakage. This study was designed to determine whether mechanical bowel preparation is associated with histologic alterations in the colon., Methods: Fifty patients (mean age, 61 (range, 45-78) years) scheduled to undergo elective colorectal surgery were prospectively randomized to receive mechanical preparation (polyethylene glycol; Group 1) or no preparation (Group 2) preoperatively. A macroscopically healthy segment of the bowel was excised at the proximal margin of the colectomy piece. A pathologist, blinded to the patient's group allocation, assessed various morphologic parameters., Results: Indications for colectomy (cancer and complicated diverticulosis) did not differ between groups. Bowel wall alterations were more frequent in patients who received a preparation. The most striking alterations associated with mechanical preparation were loss of superficial mucus (moderate-to-severe in 96 and 52 percent in Groups 1 and 2, respectively; P < 0.001) and epithelial cells (moderate-to-severe in 88 and 40 percent in Groups 1 and 2, respectively; P < 0.01). In addition, inflammatory changes, i.e., lymphocytes (severe in 48 and 12 percent in Groups 1 and 2, respectively; P < 0.02) and polymorphonuclear cells infiltration (severe in 52 and 8 percent in Groups 1 and 2, respectively; P < 0.02), were more prevalent after mechanical preparation., Conclusions: Mechanical bowel preparation is associated with structural alteration and inflammatory changes in the large bowel wall. Although bowel wall inflammation is a known risk factor for anastomotic leak, it remains to be elucidated whether these changes have a direct relation to the deleterious effect of mechanical bowel preparation in terms of abdominal morbidity.

Adenocarcinoid of the appendix is an infrequent tumor with histologic features of both adenocarcinoma and carcinoid tumor. Although its malignant potential remains unclear, adenocarcinoids seem to be biologically more aggressive than conventional carcinoids. The aim of this study was to analyze long-term results of surgical treatment for appendiceal adenocarcinoid. A retrospective review (1991-2003) identified seven patients (median age 72, range 27-81 years) treated for appendiceal adenocarcinoid. The clinical data of these patients were reviewed. Follow-up was complete for all patients (median 60 months, range 24-108 months). Most cases presented with associated acute appendicitis (71%). First intention surgery consisted of appendectomy (m = 6) and right hemicolectomy (m = 1). In three patients, additional surgical procedures were performed (right colectomy). Indications for colectomy were tumor size (three cases) associated with appendectomy margin invasion in one case. One patient with lymph node and peritoneal involvement experienced recurrence 9 months after hemicolectomy and died of the disease at 2 years. One patient subsequently died of colon carcinoma 6 years after adenocarcinoid treatment. Five patients were alive without disease at the time of the last follow-up. Synchronous or metachronous colon carcinomas developed in three patients (43%). Our results suggest that appendectomy alone could be used for appendiceal adenocarcinoid provided that the tumor (1) is less than 1 cm; (2) does not extend beyond the appendix adventitia; (3) has less than 2 mitoses/10 high power fields; and (4) has surgical margins that are tumor free. Otherwise, carcinologic right colectomy seems to be indicated. The risk for developing colorectal adenocarcinoma seems to be extremely high in patients treated for appendiceal adenocarcinoid and warrants close follow-up with colonoscopic screening.

The immunosuppressive (IS) regimen based on sirolimus/low-dose tacrolimus is considered a major determinant of success of the Edmonton protocol. This regimen is generally considered safe or even protective for the kidney. Herein, we analyzed the impact of the sirolimus/low-dose tacrolimus combination on kidney function. The medical charts of islet transplant recipients with at least 6 months follow up were reviewed. There were five islet-after-kidney and five islet transplantation alone patients. Serum creatinin, albuminuria, metabolic control markers and graft function were analyzed. Impairment of kidney function was observed in six of 10 patients. Neither metabolic markers nor IS drugs levels were significantly associated with the decrease of kidney function. Although a specific etiology was not identified, some subsets of patients presented a higher risk for decline of kidney function. Low creatinin clearance, albuminuria and long-established kidney graft were associated with poorer outcome.

Currently, the number of patients awaiting transplantation is continuously increasing, and shortage of available deceased organ donors is the major limitation for organ and cell allotransplantation. Research to develop alternative sources of tissues is ongoing and xenogeneic organs or cells represent an attractive solution. This review focuses on recent progress achieved in this field, including the development of newly genetically modified animal donors and new immunosuppressive approaches. As xenotransplantation is moving closer to clinical application, future perspectives must establish guidelines to ensure that future clinical trials are carried out ethically and safely.

The aim of the study was to investigate microbiological contamination rate during human pancreatic islet isolation. Between 1996 and 2002, pancreas preservation media and post-purification islet preparations were screened for microbiological contamination. After arrival in the laboratory, pancreata were washed prior to enzyme perfusion with either Hank's balanced salt solution (Group I, n = 170, 1996 to 2001) or decontaminated with polyvidonum-iodine, cefazoline, and amphotericine B (Group II, n = 45, 2001 to 2002). Microbiological contamination of preservation media was observed in 56% and 84% for Groups I and II, respectively. Analysis of contaminants revealed 74% Gram-positive, 21% Gram-negative bacteria and 5% fungi. Duration of transport had an influence on the rate of contamination (P < 0.05). After islet isolation, Group I presented microbial contamination of 16 islet preparations (9.4%) [i.e. Gram-positive bacteria (n = 10), Gram-negative bacteria (n = 4), and fungi (n = 2)]. In Group II, only 2 islet preparations (4.4%) presented microbial contamination. Microbial contamination during pancreas procurement occurs frequently. Most microorganisms are eliminated during islet isolation, and de novo contaminations during islet isolation are rare. Pancreas decontamination reduces the risk of infection of the final islet preparation.

The aim of the study was to evaluate the role of recipient CD40 and CD154 in the rejection process of concordant and discordant islets xenotransplantation (Tx). Diabetic C57BL/6 mice, CD40- or CD154-knockout (KO) and complement C3-deficient (C3-/-) mice were transplanted with either rat or human islets. Group 1, C57BL/6 Tx without therapy; Group 2, C57BL/6 Tx with anti-CD154 monoclonal antibody (mAb) (MR1) therapy; Group 3, CD40-KO; and Group 4, CD154-KO Tx without therapy; Group 5, C3-/- Tx without therapy and Group 6, C3-/-Tx with MR1 therapy. Mixed lymphocyte reactions (MLR) were performed. Compared to Group 1, MR1 induced long-term survival of xenografts in Group 2, but not in Group 6, survival of islets was not prolonged significantly in Groups 3 and 4. MLR responses in Group 2 were reduced approximately 50% compared to Group 1. In Groups 3, 4 and 6, MLR responses were not modified by the absence of CD40 or CD154 molecules, or MR1 and were similar to Group 1. Improved graft survival and reduced MLR responses in Group 2, but not in Group 6, could be explained by specific targeting of activated T cells with inactivation by complement- or cellular-mediated mechanisms. Rejection of xenografts and strong MLR responses in Groups 3 and 4 are possible through efficient activation of alternate pathways of costimulation.

Purpose: This study was undertaken to assess the incidence of 1) metachronous colorectal cancer and 2) subsequent extracolonic cancers, in relation to the location (proximal or distal to the splenic flexure) of the first primary colorectal tumor., Methods: In this population-based study, a cancer registry database was used to identify patients diagnosed with colorectal adenocarcinoma between 1970 and 1999. Patients with familial adenomatous polyposis and those with hereditary nonpolyposis colorectal cancer syndrome were excluded from the study, as were patients with nonepithelial tumors. Location of the first tumor was established according to International Classification of Diseases-Oncology-02 classification. The registry covers a population of 500,000 residents., Results: A total of 5,006 patients had sporadic adenocarcinoma of the colon or rectum during this period of time, with 1,703 first primary tumors (34 percent) being located proximal to the splenic flexure. One hundred twenty occurrences of second primary colorectal cancer were observed in this population (2.39 percent). The risk for developing a second incidence of primary colorectal cancer was higher in patients whose initial tumor was located in the proximal colon (3.4 percent vs. 1.8 percent; odds ratio, 1.92; 95 percent confidence interval, 1.33-2.77; P < 0.001). The risk for each segment of the large bowel was as follows: cecum, 3.4 percent; right colon, 3 percent; transverse colon, 3.8 percent; left colon, 2.8 percent; sigmoid colon, 1.7 percent; and rectum, 1.8 percent. By contrast, the risk for developing a second, extracolonic tumor did not differ between patients with proximal and distal tumors (13.7 percent vs. 13.4 percent, P = 0.73)., Conclusion: Patients with a first tumor located within the proximal colon are at twice the risk for developing metachronous colorectal cancer. From an epidemiologic standpoint, these data are in accordance with 1) the increasing incidence and 2) the better prognosis of proximal colon cancer in various populations. Our results confirm that proximal colon cancer is a distinct entity, which justifies the reporting of cases of colon cancer according to their location proximal or distal to the splenic flexure.

Embryological and physiological data suggest that proximal (in relation to the splenic flexure) and distal parts of the colon represent distinct anatomical and functional entities. Since 1990, molecular biologists have identified two distinct pathways, microsatellite instability (MSI) and chromosomal instability (CIN), which are involved in the pathogenesis of colon cancer (CC). Thus, a new paradigm has emerged with the discovery that CC is a heterogeneous disease; furthermore recent data have demonstrated that these two distinct pathways in colorectal carcinogenesis are characterized by a different clinical outcome. The implications for the clinicians are twofold; (1) tumors originating from the proximal colon have a better prognosis due to a high percentage of MSI-positive lesions; and (2) location of the neoplasm in reference to the splenic flexure should be documented before group stratification in ongoing trials of adjuvant chemotherapy for CC. In the future, clinical decision-making regarding adjuvant chemotherapy might be stratified according to the MSI status of cancers located proximally to the splenic flexure.

Hypothesis: There is little scientific evidence to support the routine practice of mechanical bowel preparation (MBP) before elective colorectal surgery in order to minimize the risk of postoperative septic complications., Data Sources: Trials were retrieved using a MEDLINE search followed by a manual search of the bibliographic information in select articles. Languages were restricted to English, French, Spanish, Italian, and German. There was no date restriction., Study Selection: Only prospective randomized clinical trials (RCTs) evaluating MBP vs no MBP before elective colorectal surgery were included., Data Extraction: Outcomes evaluated were anastomotic leakage, intra-abdominal infection, wound infection, reoperation, and general and extra-abdominal morbidity and mortality rates. Data were extracted by 2 independent observers., Data Synthesis: Seven RCTs were retrieved. The total number of patients in these RCTs was 1297 (642 who had received MBP and 655 who had not). Among all the RCTs reviewed, anastomotic leak was significantly more frequent in the MBP group, 5.6% (36/642), compared with the no-MBP group, 2.8% (18/655) (odds ratio, 1.84; P = .03). Intra-abdominal infection (3.7% for the MBP group vs 2.0% for the no-MBP group), wound infection (7.5% for the MBP group vs 5.5% for the no-MBP group), and reoperation (5.2% for the MBP group vs 2.2% for the no-MBP group) rates were nonstatistically significantly higher in the MBP group. General morbidity and mortality rates were slightly higher in the MBP group., Conclusions: There is no evidence to support the use of MBP in patients undergoing elective colorectal surgery. Available data tend to suggest that MBP could be harmful with respect to the incidence of anastomotic leak and does not reduce the incidence of septic complications.

Background: Stromal tumors of the digestive tract, or gastrointestinal stromal tumors (GIST), originate from an intestinal mesenchymal precursor cell. Criteria that predict the outcome of small intestinal stromal tumors (SIST) after surgical resection are not clearly established. The aim of the study was to define prognostic criteria for SIST., Methods: All c-kit positive SIST treated in our center over a 10-year period were reviewed., Results: Eighteen patients with SIST treated by surgical resection were included. Overall actuarial 5-year survival was 74% (median follow-up of 69 months). We developed a panel of five criteria (tumor size, mitotic rate, proliferation index, presence of necrosis, and invasion of mucosa or adjacent structures) that permitted distinction between low and high malignant potential SIST. Presence of any four of these five criteria defined a high malignant potential SIST, and was associated with disease recurrence and poor prognosis after surgical resection (P <0.01). Patients with low malignant potential SIST had a 5-year survival of 92%, compared with 0% for high malignant potential SIST (P <0.01)., Conclusions: This study demonstrates that a panel of morphologic factors can reliably distinguish between low and high malignant potential SIST. Although patients with low malignant potential SIST have an excellent prognosis after surgical resection, the role of adjuvant treatment for high malignant potential SIST remains to be defined.

An up-to-date synthesis of pancreatic islet allotransplantation is included in this summary, with emphasis on new developments and clinical results of the field. Rationale for islet transplantation in type 1 diabetes mellitus, current patient selection criteria, clinical data, technical aspects of organ procurement, islet isolation and transplantation are highlighted. The current challenges are also presented and analysed. Significant advances in clinical islet transplantation have been achieved recently. New immunosuppressive strategies were introduced, there were considerable changes in the patient selection criteria. International collaborations were established in order to standardize islet isolation and transplantation procedures. The spectacular results, recently reported by the Edmonton-group, represent a major breakthrough of the field and the outcomes are comparable with the results of whole pancreas transplantation. Islet transplantation became one of the most promising fields of tolerance induction research. Although still considered experimental, within the frameworks of expanding international collaborations, pancreatic islet allotransplantation gains more and more recognition in the clinical practice. These elements give hope that diabetes might be in the near future treated by islet cell transplantation.

Objective: To evaluate the cost of islet transplantation in type 1 diabetic patients with a functional renal graft in a multicenter network., Research Design and Methods: The study involved nine diabetic patients transplanted in the Swiss-French Groupe Rhône-Alpes, Rhin et Geneve pour la transplantation d'Ilots Langerhans (GRAGIL) consortium between March 1999 and June 2000. The direct medical costs were estimated from Social Security's perspective from the inclusion of the patient to 1 year after transplantation. All cost components were computed separately and included evaluation, screening and candidacy, organ retrieval, islet processing, pancreas and islet transportation, hospitalization for transplantation, follow-up, medications (immunosuppressive, antidiabetic, and adjuvant drugs), and adverse events requiring hospitalization., Results: During the study period, 56 pancreata were processed and 14 islet preparations were transplanted. The average cost of an islet transplantation (procedure and 1-year follow-up) was 77,745 euro (French rate, year 2000). The four main cost components were islet preparation (30% of the total cost), adverse events (24%), drugs (14%), and hospitalization (13%)., Conclusions: Overall costs of islet transplantation are slightly higher than those of pancreas transplantation. The cell isolation process is a critical point; a reduction in overall cost will require more efficient ways of isolating high yields of viable islets. Costs generated by shipments within the GRAGIL network did not represent an economic burden. It can be expected that the costs will decrease with growing experience and improving technology.

During transplantation, pancreatic islets release chemokines which promote macrophage attraction, hampering engraftment of islets. The aim of this study was to modulate chemotaxis and the immune response of human macrophages induced by islets. Human monocyte-derived macrophages of healthy subjects were exposed to supernatants of human islets. Chemotaxis, tumour necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) release were evaluated. To modulate migration, human macrophages were incubated in the presence of aminooxypentane-regulated on activation, normal, T-cell expressed, and secreted (AOP-RANTES), a potent antagonist of CCR5. Chemotactic activity of islets supernatant was modulated by the addition of heparin or heparinoids [pentosan and calix[8S]arene (C8S)]. AOP-RANTES significantly reduced, in a dose-dependent manner, macrophage chemotaxis and cytokine release induced by islets supernatant. The chemotactic index was reduced from 3.05 +/- 0.27 to 0.71 +/- 12, TNF-alpha from 1205 +/- 52 to 202 +/- 12 pg/ml, and IL-1beta from 234 +/- 12 to 10 +/- 6 pg/ml. The trapping of chemokines by heparinoids reduced the chemotactic activity of islets supernatant from 3.05 +/- 0.27 to 1.2 +/- 0.1 with heparin or pentosan and to 1.72 +/- 0.22 with C8S, and also decreased the TNF-alpha release by human macrophages from 1205 +/- 35 to 1000 +/- 26 (C8S), 250 +/- 21 (heparin) and 320 +/- 19 (pentosan) pg/ml, and IL-1beta from 234 +/- 13 to 151 +/- 5 (C8S), 50 +/- 3 (heparin) and 57 +/- 4 (pentosan) pg/ml. In conclusion, AOP-RANTES and heparinoids inhibit human macrophage activation and migration induced by islets supernatant.

Gastrointestinal stromal tumours (GIST) are the most common mesenchymal tumours of the digestive tract. Most gastrointestinal soft tissue neoplasms, previously classified as leiomyomas, schwannomas, leiomyoblastomas or leiomyosarcomas, are today classified as GIST on the basis of molecular and immunohistological features. They originate from gastrointestinal pacemaker cells and are characterised by over-expression of the tyrosine kinase receptor KIT. Overall 5-year survival after surgical resection of GIST is approximately 60%. However, these tumours span a wide clinical spectrum from benign to highly malignant. Prognostic factors have recently been identified for GIST and include tumour size, mitotic rate and other minor factors. At present, surgery is the standard treatment for primary resectable GIST. Benign GIST have an excellent prognosis after primary surgical treatment, with over 90% 5-year survival. While recurrent or malignant GIST, which are resistant to radiotherapy and chemotherapy, had until recently an extremely poor prognosis even after surgical resection, with median survival of 12 months. The development of a tyrosine kinase inhibitor has changed the management of unresectable malignant cases. This new tyrosine kinase inhibitor, imatinib mesylate, which inhibits the c-kit receptor, has proved highly effective against GIST and has improved survival in metastatic GIST. This paper reviews the literature and our experience of GIST, including: diagnosis, pathology, treatment and prognosis.

Background: mechanical bowel preparation (MBP) consists of orthograde fluid preparation to clean the bowel. MBP is considered to prevent postoperative complications., Methods: meta-analysis of prospective randomised clinical trials (RCT) evaluating MBP versus no MBP., Results: following a medline search we retrieved 15 prospective trials of which only 5 where RCT comparing MBP versus no MBP in elective colorectal surgery. For the randomised studies, there were respectively 186, 179, 149, 267 and 380 patients, including all type of resections. The total number of patients in these 5 studies was 1144 (565 with MBP and 579 with no preparation). All patients received perioperative antibiotic prophylaxis. Only one of these RCT show a significant decrease in anastomotic leak (AL), but among all the patients enrolled, AL is significantly more frequent in the group with MBP (Odds Ratio 1.8). Wound infection, re-operation and intra-abdominal abscess rates were more frequent in the MBP group but the difference did not reach statistical significance and the odds ratios for a 95% confidence interval were extremely large., Conclusion: there is limited evidence in the literature to support the use of MBP in patient undergoing elective colorectal surgery. Available data tend to suggest that MBP could be harmful with respect to the incidence of anastomotic leak. Moreover, MBP does not reduce the incidence of other infectious complications. Further RCTs are needed to establish an evidence-based rationale for the use of MBP in elective colorectal surgery.

Insulinoma is a rare, almost always benign endocrine tumor of the pancreas, clinically characterized by hyperinsulinemic, hypoglycemic episodes. Surgical excision is the therapy of choice, which may lead to postpancreatectomy diabetes mellitus in the case of extensive pancreatic resection. We present the cases and the metabolic follow up of two patients, 81 and 73 years old, with insulinoma localized close to the main duct in the pancreatic neck. Both patients underwent an 80% left pancreatectomy, avoiding a pancreatico-enteric anastomosis. In order to prevent postpancreatectomy diabetes, the islets from the tumor-free part of the resected pancreas were isolated and injected via a right colic vein into the portal system. After a follow up of 6 and 3 years respectively, both patients remained insulin-independent without any dietary restrictions. Fasting and glucagon-stimulated C-peptide-levels and glycosylated hemoglobin remained within normal range. There were no signs of recurrent insulinoma. Liver biopsy performed in one patient at 1 year after autotransplantation, showed intact, insulin-producing islets within the portal spaces. In conclusion, autologous islet transplantation can preserve the insulin secretory reserve after extended left pancreatectomy for the treatment of benign tumors in the pancreatic neck.

Objective: To compare the glycemic profiles of patients with type 1 diabetes treated with either an implantable insulin pump or pancreas or islet transplantation by the means of the continuous glucose monitoring system (CGMS; Minimed, Sylmar, CA)., Research Design and Methods: The CGMS enabled recording of subcutaneous glucose concentrations (range 2.2-22 mmol/l) over 72 h (288 measurements per day). Over 3 days, 26 patients with type 1 diabetes were connected to a CGMS: 10 patients were treated with intraperitoneal insulin infusion through an implantable pump (IPII), 9 patients were treated with simultaneous pancreas-kidney transplantation (SPK), and 7 patients were treated with pancreatic islet transplantation after kidney grafting (IAK). All SPK patients and four IAK patients were insulin independent, whereas three IAK patients had partial graft function and reduced exogenous insulin needs. Glucose control was evaluated by the mean glucose concentration, glucose variability, and the number and duration of hypoglycemic events (<3.3 mmol/l) over 3 days., Results: The mean glucose concentration and the glucose variability in SPK and IAK patients were significantly lower than those observed in patients treated with IPII: 5.38 +/- 1.12 and 5.83 +/- 0.81 vs. 7.81 +/- 1.55 mmol/l (P < 0.001) and 1.40 +/- 0.42 and 1.32 +/- 0.53 vs. 3.47 +/- 1.66 mmol/l (P < 0.001), respectively. Furthermore, the mean glucose concentration and the glucose variability were comparable between SPK and IAK patients. Over 3 days, no hypoglycemic events were observed in SPK patients and insulin-independent IAK patients. A total of 4.12 +/- 1.66 hypoglycemic events were detected in the IPII patient group, whereas only 0.66 +/- 0.57 events were observed in IAK patients with partial graft function (P < 0.001). The duration of the hypoglycemic events was significantly longer in IPII patients as compared with IAK patients: 64 +/- 33 vs. 30 +/- 15 min for the day period and 130 +/- 62 vs. 30 +/- 27 min for the night period (P < 0.001)., Conclusions: Use of subcutaneous CGMS confirms that islet transplantation can be as efficient as pancreas transplantation in restoring good metabolic control and reducing blood glucose variability. Metabolic improvement due to use of an implantable insulin pump requires insulin delivery by a closed loop.