Stump closure reinforcement with absorbable fibrin collagen sealant sponge (TachoSil) does not prevent pancreatic fistula after distal pancreatectomy: the FIABLE multicenter controlled randomized study.

BACKGROUND: The aim of this study is to evaluate the effectiveness of TachoSil sponge on distal pancreatectomy remnant stump in reducing the rate and severity of postoperative pancreatic fistula (POPF). METHODS: All consecutive patients requiring distal pancreatectomy were randomized in 45 centers. The principal end point was onset of "clinically relevant" POPF. Univariate and multivariate analyses were searched for predictive factors. RESULTS: Of the 270 patients randomized (134 with TachoSil; 136 without), 150 (55.6%) patients sustained a POPF [74 clinically relevant and 76 clinically silent (27.4% and 28.1%), respectively]: no statistically significant difference was found between patients sustaining clinically relevant POPF [41 (30.6%) with vs 33 (24.3%) without TachoSil (P = .276)], or overall POPF [73 (54.5%) with vs 77 (56.6%) without TachoSil, (P = .807)], but there were more clinically relevant POPF after hand-sewn (32.3%) versus mechanical closure (19.8%) (P = .025) and, in case of splenic preservation, after splenic vessel ligation (15/32, 46.9%) versus vascular preservation (17/72, 23.6%) (P = .024). Hand-sewn pancreatic remnant closure (P = .023) and splenic vessel ligation in splenic preservation (P = .035) were independent predictive factors for the onset of clinically relevant POPF. CONCLUSION: TachoSil sponge reinforcement of the proximal remnant after distal pancreatectomy reduced neither the rate nor the severity of POPF.

Guidelines for time-to-event end-point definitions in trials for pancreatic cancer. Results of the DATECAN initiative (Definition for the Assessment of Time-to-event End-points in CANcer trials).

BACKGROUND: Using potential surrogate end-points for overall survival (OS) such as Disease-Free- (DFS) or Progression-Free Survival (PFS) is increasingly common in randomised controlled trials (RCTs). However, end-points are too often imprecisely defined which largely contributes to a lack of homogeneity across trials, hampering comparison between them. The aim of the DATECAN (Definition for the Assessment of Time-to-event End-points in CANcer trials)-Pancreas project is to provide guidelines for standardised definition of time-to-event end-points in RCTs for pancreatic cancer. METHODS: Time-to-event end-points currently used were identified from a literature review of pancreatic RCT trials (2006-2009). Academic research groups were contacted for participation in order to select clinicians and methodologists to participate in the pilot and scoring groups (>30 experts). A consensus was built after 2 rounds of the modified Delphi formal consensus approach with the Rand scoring methodology (range: 1-9). RESULTS: For pancreatic cancer, 14 time to event end-points and 25 distinct event types applied to two settings (detectable disease and/or no detectable disease) were considered relevant and included in the questionnaire sent to 52 selected experts. Thirty experts answered both scoring rounds. A total of 204 events distributed over the 14 end-points were scored. After the first round, consensus was reached for 25 items; after the second consensus was reached for 156 items; and after the face-to-face meeting for 203 items. CONCLUSION: The formal consensus approach reached the elaboration of guidelines for standardised definitions of time-to-event end-points allowing cross-comparison of RCTs in pancreatic cancer.

Optimal duration and timing of adjuvant chemotherapy after definitive surgery for ductal adenocarcinoma of the pancreas: ongoing lessons from the ESPAC-3 study.

PURPOSE: Adjuvant chemotherapy improves patient survival rates after resection for pancreatic adenocarcinoma, but the optimal duration and time to initiate chemotherapy is unknown. PATIENTS AND METHODS: Patients with pancreatic ductal adenocarcinoma treated within the international, phase III, European Study Group for Pancreatic Cancer-3 (version 2) study were included if they had been randomly assigned to chemotherapy. Overall survival analysis was performed on an intention-to-treat basis, retaining patients in their randomized groups, and adjusting the overall treatment effect by known prognostic variables as well as the start time of chemotherapy. RESULTS: There were 985 patients, of whom 486 (49%) received gemcitabine and 499 (51%) received fluorouracil; 675 patients (68%) completed all six cycles of chemotherapy (full course) and 293 patients (30%) completed one to five cycles. Lymph node involvement, resection margins status, tumor differentiation, and completion of therapy were all shown by multivariable Cox regression to be independent survival factors. Overall survival favored patients who completed the full six courses of treatment versus those who did not (hazard ratio [HR], 0.516; 95% CI, 0.443 to 0.601; P < .001). Time to starting chemotherapy did not influence overall survival rates for the full study population (HR, 0.985; 95% CI, 0.956 to 1.015). Chemotherapy start time was an important survival factor only for the subgroup of patients who did not complete therapy, in favor of later treatment (P < .001). CONCLUSION: Completion of all six cycles of planned adjuvant chemotherapy rather than early initiation was an independent prognostic factor after resection for pancreatic adenocarcinoma. There seems to be no difference in outcome if chemotherapy is delayed up to 12 weeks, thus allowing adequate time for postoperative recovery.

Pancreatic cancer hENT1 expression and survival from gemcitabine in patients from the ESPAC-3 trial.

BACKGROUND: Human equilibrative nucleoside transporter 1 (hENT1) levels in pancreatic adenocarcinoma may predict survival in patients who receive adjuvant gemcitabine after resection. METHODS: Microarrays from 434 patients randomized to chemotherapy in the ESPAC-3 trial (plus controls from ESPAC-1/3) were stained with the 10D7G2 anti-hENT1 antibody. Patients were classified as having high hENT1 expression if the mean H score for their cores was above the overall median H score (48). High and low hENT1-expressing groups were compared using Kaplan-Meier curves, log-rank tests, and Cox proportional hazards models. All statistical tests were two-sided. RESULTS: Three hundred eighty patients (87.6%) and 1808 cores were suitable and included in the final analysis. Median overall survival for gemcitabine-treated patients (n = 176) was 23.4 (95% confidence interval [CI] = 18.3 to 26.0) months vs 23.5 (95% CI = 19.8 to 27.3) months for 176 patients treated with 5-fluorouracil/folinic acid (χ(2) 1=0.24; P = .62). Median survival for patients treated with gemcitabine was 17.1 (95% CI = 14.3 to 23.8) months for those with low hENT1 expression vs 26.2 (95% CI = 21.2 to 31.4) months for those with high hENT1 expression (χ(2)1= 9.87; P = .002). For the 5-fluorouracil group, median survival was 25.6 (95% CI = 20.1 to 27.9) and 21.9 (95% CI = 16.0 to 28.3) months for those with low and high hENT1 expression, respectively (χ(2)1 = 0.83; P = .36). hENT1 levels were not predictive of survival for the 28 patients of the observation group (χ(2)1 = 0.37; P = .54). Multivariable analysis confirmed hENT1 expression as a predictive marker in gemcitabine-treated (Wald χ(2) = 9.16; P = .003) but not 5-fluorouracil-treated (Wald χ(2) = 1.22; P = .27) patients. CONCLUSIONS: Subject to prospective validation, gemcitabine should not be used for patients with low tumor hENT1 expression.

Effect of adjuvant chemotherapy with fluorouracil plus folinic acid or gemcitabine vs observation on survival in patients with resected periampullary adenocarcinoma: the ESPAC-3 periampullary cancer randomized trial.

CONTEXT: Patients with periampullary adenocarcinomas undergo the same resectional surgery as that of patients with pancreatic ductal adenocarcinoma. Although adjuvant chemotherapy has been shown to have a survival benefit for pancreatic cancer, there have been no randomized trials for periampullary adenocarcinomas. OBJECTIVE: To determine whether adjuvant chemotherapy (fluorouracil or gemcitabine) provides improved overall survival following resection. DESIGN, SETTING, AND PATIENTS: The European Study Group for Pancreatic Cancer (ESPAC)-3 periampullary trial, an open-label, phase 3, randomized controlled trial (July 2000-May 2008) in 100 centers in Europe, Australia, Japan, and Canada. Of the 428 patients included in the primary analysis, 297 had ampullary, 96 had bile duct, and 35 had other cancers. INTERVENTIONS: One hundred forty-four patients were assigned to the observation group, 143 patients to receive 20 mg/m2 of folinic acid via intravenous bolus injection followed by 425 mg/m2 of fluorouracil via intravenous bolus injection administered 1 to 5 days every 28 days, and 141 patients to receive 1000 mg/m2 of intravenous infusion of gemcitabine once a week for 3 of every 4 weeks for 6 months. MAIN OUTCOME MEASURES: The primary outcome measure was overall survival with chemotherapy vs no chemotherapy; secondary measures were chemotherapy type, toxic effects, progression-free survival, and quality of life. RESULTS: Eighty-eight patients (61%) in the observation group, 83 (58%) in the fluorouracil plus folinic acid group, and 73 (52%) in the gemcitabine group died. In the observation group, the median survival was 35.2 months (95%% CI, 27.2-43.0 months) and was 43.1 (95%, CI, 34.0-56.0) in the 2 chemotherapy groups (hazard ratio, 0.86; (95% CI, 0.66-1.11; χ2 = 1.33; P = .25). After adjusting for independent prognostic variables of age, bile duct cancer, poor tumor differentiation, and positive lymph nodes and after conducting multiple regression analysis, the hazard ratio for chemotherapy compared with observation was 0.75 (95% CI, 0.57-0.98; Wald χ2 = 4.53, P = .03). CONCLUSIONS: Among patients with resected periampullary adenocarcinoma, adjuvant chemotherapy, compared with observation, was not associated with a significant survival benefit in the primary analysis; however, multivariable analysis adjusting for prognostic variables demonstrated a statistically significant survival benefit associated with adjuvant chemotherapy. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00058201.

[The death of Ignatius Loyola]. / De quoi Ignace de Loyola est-il mort?

A recent examination of a bilioportal fistula led us to suspect a link between this case and the death of Ignatius of Loyola. Realdo Colombo, professor of anatomy, eviscerated Ignatius prior to his embalming In his book De re anatomica, published in 1559, he wrote that he extracted stones from the portal vein of the venerable Ignatius. Before his death, Ignatius suffered from epigastric pain and fever (Monumenta historica societatis Jesu). Colombo latin text is difficult to interpret and the data are meager. Other possible causes of Ignatius' death include gastroduodenal ulcer, tuberculosis and hyperparathyroidism, but despite of rarity bilioportal fistula is the best guess.

Ischemic colitis.

BACKGROUND: Ischemic colitis almost always occurs in older patients. Because life expectancy is increasing, more and more often physicians will face this problem. The aim of this study was to identify factors leading to surgery in the acute phase of the disease, and to evaluate mortality and long-term follow-up evaluation. METHODS: We performed a retrospective study of 73 patients (mean age, 73 y) in the Department of General and Digestive Surgery. Diagnosis was obtained by endoscopic and pathologic procedures. The median follow-up period was 4.5 years (range, 2-9 y). RESULTS: Thirty-six patients had 1 or more co-existing medical diseases. All the patients had either lower intestinal bleeding (45 patients) or diarrhea (28 patients). Thirty-three patients had undergone surgery (45%). In the surgical group, 13 patients underwent immediate surgery for abdominal tenderness and/or shock. Eight of these patients died (62%). Out of 60 patients undergoing nonsurgical immediate management, 1 patient died (septic shock). Delayed surgery was indicated in 20 out of the 59 remaining patients for clinical or endoscopic aggravation. Six of these patients died (30%). Multivariate analysis selected 4 factors of severity: age younger than 80 years, male sex, absence of bleeding, and abdominal tenderness. In the follow-up period 13 patients died from a cardiovascular disease. The 2- and 5-year actuarial survival rates of patients who survived the initial hospitalization were 88% and 68%, respectively. CONCLUSIONS: Multivariate analysis selected the risk factors of severity. In severely ill patients serial endoscopic evaluations are the best indicator for surgery before appearance of tenderness, septic shock, full-thickness gangrene, and perforation. At discharge, anticoagulant or anti-arrhythmic therapy should be considered for patients who have cardiovascular disease.

Stage II colon cancer prognosis prediction by tumor gene expression profiling.

PURPOSE: This study mainly aimed to identify and assess the performance of a microarray-based prognosis predictor (PP) for stage II colon cancer. A previously suggested 23-gene prognosis signature (PS) was also evaluated. PATIENTS AND METHODS: Tumor mRNA samples from 50 patients were profiled using oligonucleotide microarrays. PPs were built and assessed by random divisions of patients into training and validation sets (TSs and VSs, respectively). For each TS/VS split, a 30-gene PP, identified on the TS by selecting the 30 most differentially expressed genes and applying diagonal linear discriminant analysis, was used to predict the prognoses of VS patients. Two schemes were considered: single-split validation, based on a single random split of patients into two groups of equal size (group 1 and group 2), and Monte Carlo cross validation (MCCV), whereby patients were repeatedly and randomly divided into TS and VS of various sizes. RESULTS: The 30-gene PP, identified from group 1 patients, yielded an 80% prognosis prediction accuracy on group 2 patients. MCCV yielded the following average prognosis prediction performance measures: 76.3% accuracy, 85.1% sensitivity, and 67.5% specificity. Improvements in prognosis prediction were observed with increasing TS size. The 30-gene PS were found to be highly-variable across TS/VS splits. Assessed on the same random splits of patients, the previously suggested 23-gene PS yielded a 67.7% mean prognosis prediction accuracy. CONCLUSION: Microarray gene expression profiling is able to predict the prognosis of stage II colon cancer patients. The present study also illustrates the usefulness of resampling techniques for honest performance assessment of microarray-based PPs.

Gene expression profiling of nonneoplastic mucosa may predict clinical outcome of colon cancer patients.

PURPOSE: This study assessed the possibility to build a prognosis predictor, based on microarray gene expression measures, in Stage II and III colon cancer patients. METHODS: Tumor and nonneoplastic mucosa mRNA samples from 12 colon cancer patients were profiled using the Affymetrix HGU133A GeneChip. Six of 12 patients experienced a metachronous metastasis, whereas the 6 others remained disease-free for more than five years. Three datasets were constituted, including, respectively, the gene expression measures in tumor samples (T), in adjacent nonneoplastic mucosa samples (A), and the log-ratio of the gene expression measures (L). The step-down procedure of Westfall and Young and the k-nearest neighbor class prediction method were applied on T, A, and L. Leave-one-out cross-validation was used to estimate the generalization error of predictors based on different numbers of genes and neighbors. RESULTS: The most frequent results were one false prediction with the A-based predictors (95 percent) and two false predictions with the T- and L: -based predictors (65 and 60 percent, respectively). A-based predictors were more stable (i.e., less sensitive to changes of parameters, such as numbers of genes and neighbors) than T- and L: -based predictors. Informative genes in A-based predictors included genes involved in the oxidative and phosphorylative mitochondrial metabolism and genes involved in cell-signaling pathways and their receptors. CONCLUSIONS: This study suggests that one can build a prognosis predictor for Stage II and III colon cancer patients, based on microarray gene expression measures, and suggests the potential usefulness of nonneoplastic mucosa for this purpose.

Colon cancer prognosis prediction by gene expression profiling.

This study assessed the possibility to build a prognosis predictor, based on microarray gene expression measures, in stage II and III colon cancer patients. Tumour (T) and non-neoplastic mucosa (NM) mRNA samples from 18 patients (nine with a recurrence, nine with no recurrence) were profiled using the Affymetrix HGU133A GeneChip. The k-nearest neighbour method was used for prognosis prediction using T and NM gene expression measures. Six-fold cross-validation was applied to select the number of neighbours and the number of informative genes to include in the predictors. Based on this information, one T-based and one NM-based predictor were proposed and their accuracies were estimated by double cross-validation. In six-fold cross-validation, the lowest numbers of informative genes giving the lowest numbers of false predictions (two out of 18) were 30 and 70 with the T and NM gene expression measures, respectively. A 30-gene T-based predictor and a 70-gene NM-based predictor were then built, with estimated accuracies of 78 and 83%, respectively. This study suggests that one can build an accurate prognosis predictor for stage II and III colon cancer patients, based on gene expression measures, and one can use either tumour or non-neoplastic mucosa for this purpose.

Evidence-based medicine in surgical decision making.

There are now five classic steps for analysis of diagnostic and therapeutic medical decision-making policies: (1) formulate a clear clinical question based on a particular patient's problem; (2) search the literature for relevant clinical articles; (3) evaluate the evidence for its validity and usefulness; (4) implement useful findings into clinical practice; (5) audit the validity of the process. The clinician must have the necessary skills to appraise critically the information retrieved. Rather than focusing on the discussion and conclusion sections of articles, the reader should concentrate on the review of the methods and results sections to formulate an opinion regarding the strength of evidence presented in the paper. The process is intellectually demanding and difficult to achieve. This particular step in the validation of evidence implies that each clinician must be methodologically and statistically sound, an "expert," capable of analyzing the method used in that particular publication to achieve the published result.

Cardio-esophageal cancer. Is 18Fluorodeoxyglucose positron emission tomography worthwhile?

BACKGROUND/AIMS: 18Fluorodeoxyglucose positron emission tomography has been proposed for the preoperative staging of carcinomas of the esophagus and gastric cardia. The aim of this study was to assess its diagnostic value and its influence on therapeutical decisions. METHODOLOGY: Twenty-eight patients with a cancer of the esophagus or gastric cardia underwent a 18Fluorodeoxyglucose positron emission tomography on a gamma camera with coincidence detection electronics, in addition to our standard preoperative procedures (barium swallow, liver ultrasonography, chest X-ray). Four types of lesions were searched for: primary tumor, abdominal and mediastinal lymph nodes, and distant metastases. Results of 18Fluorodeoxyglucose positron emission tomography were compared to pathological findings. RESULTS: Sensitivity for the primary tumor was 86%. Sensitivity for mediastinal and abdominal lymph nodes was 75 and 54%, respectively, whereas specificity was 100%. Distant metastases were detected in 4 patients: liver metastasis in 2 patients and bone metastasis in 2 patients. Results of 18Fluorodeoxyglucose positron emission tomography influenced therapeutical decisions for 2 patients. CONCLUSIONS: 18Fluorodeoxyglucose positron emission tomography seems to be worthwhile in the preoperative staging of carcinomas of the esophagus and gastric cardia, mainly because it may detect distant metastases.

A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer.

BACKGROUND: The effect of adjuvant treatment on survival in pancreatic cancer is unclear. We report the final results of the European Study Group for Pancreatic Cancer 1 Trial and update the interim results. METHODS: In a multicenter trial using a two-by-two factorial design, we randomly assigned 73 patients with resected pancreatic ductal adenocarcinoma to treatment with chemoradiotherapy alone (20 Gy over a two-week period plus fluorouracil), 75 patients to chemotherapy alone (fluorouracil), 72 patients to both chemoradiotherapy and chemotherapy, and 69 patients to observation. RESULTS: The analysis was based on 237 deaths among the 289 patients (82 percent) and a median follow-up of 47 months (interquartile range, 33 to 62). The estimated five-year survival rate was 10 percent among patients assigned to receive chemoradiotherapy and 20 percent among patients who did not receive chemoradiotherapy (P=0.05). The five-year survival rate was 21 percent among patients who received chemotherapy and 8 percent among patients who did not receive chemotherapy (P=0.009). The benefit of chemotherapy persisted after adjustment for major prognostic factors. CONCLUSIONS: Adjuvant chemotherapy has a significant survival benefit in patients with resected pancreatic cancer, whereas adjuvant chemoradiotherapy has a deleterious effect on survival.

Rectal cancer surgery in patients more than 80 years of age.

BACKGROUND: This retrospective study aimed to compare the prognosis for rectal cancer in patients more than 80 years old with that observed in younger patients. METHODS: Patients operated on for a rectal adenocarcinoma, from 1980 to 1998, were divided into two groups: group 1 (>80 years, n = 92); group 2 (<80 years, n = 276). RESULTS: There were significant differences between the two groups with regard to the sex ratio, the American Society of Anesthesiologists (ASA) classification, the emergency presentation, and the curative operation rate. The operative mortality rate was 8% in group 1, 4% in group 2 (P = 0.26). The overall 5-year survival rate was 35% in group 1, 53% in group 2 (P = 0.0004). In patients operated on for cure, the cancer-specific 5-year survival rate was 50% in group 1, 59% in group 2 (P = 0.08). CONCLUSIONS: The prognosis for rectal cancer in patients over 80 years is not significantly different from that of younger patients. Surgery should not be restricted on the basis of age.