Antoni Castells

Laparoscopy-assisted colectomy versus open colectomy for treatment of non-metastatic colon cancer: a randomised trial

BACKGROUND Although early reports on laparoscopy-assisted colectomy (LAC) in patients with colon cancer suggested that it reduces perioperative morbidity, its influence on long-term results is unknown. Our study aimed to compare efficacy of LAC and open colectomy (OC) for treatment of non-metastatic colon cancer in terms of tumour recurrence and survival. METHODS From November, 1993, to July, 1998, all patients with adenocarcinoma of the colon were assessed for entry in this randomised trial. Adjuvant therapy and postoperative follow-up were the same in both groups. The main endpoint was cancer-related survival. Data were analysed according to the intention-to-treat principle. FINDINGS 219 patients took part in the study (111 LAC group, 108 OC group). Patients in the LAC group recovered faster than those in the OC group, with shorter peristalsis-detection (p=0.001) and oral-intake times (p=0.001), and shorter hospital stays (p=0.005). Morbidity was lower in the LAC group (p=0.001), although LAC did not influence perioperative mortality. Probability of cancer-related survival was higher in the LAC group (p=0.02). The Cox model showed that LAC was independently associated with reduced risk of tumour relapse (hazard ratio 0.39, 95% CI 0.19-0.82), death from any cause (0.48, 0.23-1.01), and death from a cancer-related cause (0.38, 0.16-0.91) compared with OC. This superiority of LAC was due to differences in patients with stage III tumours (p=0.04, p=0.02, and p=0.006, respectively). INTERPRETATION LAC is more effective than OC for treatment of colon cancer in terms of morbidity, hospital stay, tumour recurrence, and cancer-related survival.

Surgical resection of hepatocellular carcinoma in cirrhotic patients: prognostic value of preoperative portal pressure.

BACKGROUND & AIMS Although resection of hepatocellular carcinoma complicating cirrhosis is restricted to patients with preserved liver function, postoperative hepatic decompensation develops in some patients. The aim of this study was to determine the value of increased portal pressure in the development of postoperative hepatic decompensation. METHODS Twenty-nine cirrhotic patients with Child-Pughs class A disease and hepatocellular carcinoma (all except one < 5 cm) scheduled to undergo resection were evaluated by conventional criteria and by a systemic and hepatic hemodynamic study. Predictors of decompensation were assessed among a series of 44 clinical, analytical, tumoral, and hemodynamic parameters. RESULTS Eleven patients had unresolved decompensation 3 months after surgery. Bilirubin and blood ureic nitrogen levels, platelet count, wedged hepatic venous pressure, hepatic venous pressure gradient, and indocyanine green intrinsic clearance were significantly associated with unresolved decompensation, but only hepatic venous pressure gradient was significant, in the multivariate analysis (P = 0.0001; odds ratio, 1.90; 95% confidence interval, 1.12-3.22). The preoperative gradient of patients with unresolved decompensation was higher than that of patients without it (13.9 +/- 2.4 and 7.4 +/- 3.5 mm Hg, respectively; P < 0.001). CONCLUSIONS Cirrhotics with increased portal pressure are at high risk of hepatic decompensation after resection of hepatocellular carcinoma. Surgical resection should therefore be restricted to patients without portal hypertension.

Colonoscopy versus Fecal Immunochemical Testing in Colorectal-Cancer Screening

BACKGROUND Colonoscopy and fecal immunochemical testing (FIT) are accepted strategies for colorectal-cancer screening in the average-risk population. METHODS In this randomized, controlled trial involving asymptomatic adults 50 to 69 years of age, we compared one-time colonoscopy in 26,703 subjects with FIT every 2 years in 26,599 subjects. The primary outcome was the rate of death from colorectal cancer at 10 years. This interim report describes rates of participation, diagnostic findings, and occurrence of major complications at completion of the baseline screening. Study outcomes were analyzed in both intention-to-screen and as-screened populations. RESULTS The rate of participation was higher in the FIT group than in the colonoscopy group (34.2% vs. 24.6%, P<0.001). Colorectal cancer was found in 30 subjects (0.1%) in the colonoscopy group and 33 subjects (0.1%) in the FIT group (odds ratio, 0.99; 95% confidence interval [CI], 0.61 to 1.64; P=0.99). Advanced adenomas were detected in 514 subjects (1.9%) in the colonoscopy group and 231 subjects (0.9%) in the FIT group (odds ratio, 2.30; 95% CI, 1.97 to 2.69; P<0.001), and nonadvanced adenomas were detected in 1109 subjects (4.2%) in the colonoscopy group and 119 subjects (0.4%) in the FIT group (odds ratio, 9.80; 95% CI, 8.10 to 11.85; P<0.001). CONCLUSIONS Subjects in the FIT group were more likely to participate in screening than were those in the colonoscopy group. On the baseline screening examination, the numbers of subjects in whom colorectal cancer was detected were similar in the two study groups, but more adenomas were identified in the colonoscopy group. (Funded by Instituto de Salud Carlos III and others; ClinicalTrials.gov number, NCT00906997.).

The Long-term Results of a Randomized Clinical Trial of Laparoscopy-assisted Versus Open Surgery for Colon Cancer

Objective:The aim of this study was to compare the long-term outcome of laparoscopy-assisted colectomy (LAC) and open colectomy (OC) for nonmetastatic colon cancer. Methods:From November 1993 to July 1998 all patients with adenocarcinoma of the colon were assessed for entry in this single center, clinically randomized trial. Adjuvant therapy and postoperative follow-up were similar in both groups. The primary endpoint was cancer-related survival and secondary endpoints were probability of overall survival and probability of being free of recurrence. Data were analyzed according the intention-to-treat principle. Results:Two hundred and nineteen patients entered the study (111 LAC group and 108 OC group). The median follow-up was 95 months (range, 77–133). There was a tendency of higher cancer-related survival (P = 0.07, NS) and overall survival (P = 0.06, NS) for the LAC group. Probability of cancer-related survival was higher in the LAC group (P = 0.02) when compared with OC. The regression analysis showed that LAC was independently associated with a reduced risk of tumor relapse (hazard ratio 0.47, 95% CI 0.23–0.94), death from a cancer-related cause (0.44, 0.21–0.92) and death from any cause (0.59, 0.35–0.98). Conclusions:LAC is more effective than OC in the treatment of colon cancer.

Preoperative Staging and Tumor Resectability Assessment of Pancreatic Cancer: Prospective Study Comparing Endoscopic Ultrasonography, Helical Computed Tomography, Magnetic Resonance Imaging, and Angiography

OBJECTIVES:The objective of this study was to evaluate prospectively the efficacy of different strategies based on endoscopic ultrasonography (EUS), helical computed tomography (CT), magnetic resonance imaging (MRI), and angiography (A) in the staging and tumor resectability assessment of pancreatic cancer.METHODS:All consecutive patients with pancreatic carcinoma judged fit for laparotomy were studied by EUS, CT, MRI, and A. Results of each of the imaging techniques regarding primary tumor, locoregional extension, lymph-node involvement, vascular invasion, distant metastases, tumor TNM stage, and tumor resectability were compared with the surgical findings. Univariate, logistic regression, decision, and cost minimization analyses were performed.RESULTS:Sixty-two patients with pancreatic cancer were included. Helical CT had the highest accuracy in assessing extent of primary tumor (73%), locoregional extension (74%), vascular invasion (83%), distant metastases (88%), tumor TNM stage (46%), and tumor resectability (83%), whereas EUS had the highest accuracy in assessing tumor size (r = 0.85) and lymph node involvement (65%). The decision analysis demonstrated that the best strategy to assess tumor resectability was based on CT or EUS as initial test, followed by the alternative technique in those potentially resectable cases. Cost minimization analysis favored the sequential strategy in which EUS was used as a confirmatory technique in those patients in whom helical CT suggested resectability of the tumor.CONCLUSIONS:Helical CT and EUS are the most useful individual imaging techniques in the staging of pancreatic cancer. In those cases with potentially resectable tumors a sequential approach consisting of helical CT as an initial test and EUS as a confirmatory technique seems to be the most reliable and cost minimization strategy.

EMT-activating transcription factors in cancer: beyond EMT and tumor invasiveness.

Cancer is a complex multistep process involving genetic and epigenetic changes that eventually result in the activation of oncogenic pathways and/or inactivation of tumor suppressor signals. During cancer progression, cancer cells acquire a number of hallmarks that promote tumor growth and invasion. A crucial mechanism by which carcinoma cells enhance their invasive capacity is the dissolution of intercellular adhesions and the acquisition of a more motile mesenchymal phenotype as part of an epithelial-to-mesenchymal transition (EMT). Although many transcription factors can trigger it, the full molecular reprogramming occurring during an EMT is mainly orchestrated by three major groups of transcription factors: the ZEB, Snail and Twist families. Upregulated expression of these EMT-activating transcription factors (EMT-ATFs) promotes tumor invasiveness in cell lines and xenograft mice models and has been associated with poor clinical prognosis in human cancers. Evidence accumulated in the last few years indicates that EMT-ATFs also regulate an expanding set of cancer cell capabilities beyond tumor invasion. Thus, EMT-ATFs have been shown to cooperate in oncogenic transformation, regulate cancer cell stemness, override safeguard programs against cancer like apoptosis and senescence, determine resistance to chemotherapy and promote tumor angiogenesis. This article reviews the expanding portfolio of functions played by EMT-ATFs in cancer progression.

Postoperative Surveillance in Patients With Colorectal Cancer Who Have Undergone Curative Resection: A Prospective, Multicenter, Randomized, Controlled Trial

PURPOSE Although systematic postoperative surveillance of patients with colorectal cancer has been demonstrated to improve survival, it remains unknown whether a more intensive strategy provides any significant advantage. This prospective, multicenter, randomized, controlled trial was aimed at comparing the efficacy of two different surveillance strategies in terms of both survival and recurrence resectability. PATIENTS AND METHODS Patients with stage II or III colorectal cancer were allocated randomly to either a simple surveillance strategy including clinical evaluation and serum carcinoembryonic antigen monitoring, or an intensive strategy in which abdominal computed tomography or ultrasonography, chest radiograph, and colonoscopy were added. RESULTS A total of 259 patients were included: 132 were observed according to the simple strategy and 127 were observed according to the intensive strategy. Both groups were similar with respect to baseline characteristics and rate and type of tumor recurrence. After a median follow-up of 48 months, there was no difference in the probability of overall survival in the whole series (hazard ratio [HR] = 0.87; 95% CI, 0.49 to 1.54; P = .62). However, the intensive strategy was associated with higher overall survival in patients with stage II tumors (HR = 0.34; 95% CI, 0.12 to 0.98; P = .045) and in those with rectal lesions (HR = 0.09; 95% CI, 0.01 to 0.81; P = .03), mainly due to higher rate of resectability for recurrent tumors. Colonoscopy was responsible for the detection of the highest proportion (44%) of resectable tumor recurrence in the intensive arm. CONCLUSION A more intensive surveillance strategy improves the prognosis of patients with stage II colorectal cancer or those with rectal tumors. Inclusion of regular performance of colonoscopy seems justified up to the fifth year of follow-up, at least.

Identification of Lynch syndrome among patients with colorectal cancer.

CONTEXT Lynch syndrome is the most common form of hereditary colorectal cancer (CRC) and is caused by germline mutations in DNA mismatch repair (MMR) genes. Identification of gene carriers currently relies on germline analysis in patients with MMR-deficient tumors, but criteria to select individuals in whom tumor MMR testing should be performed are unclear. OBJECTIVE To establish a highly sensitive and efficient strategy for the identification of MMR gene mutation carriers among CRC probands. DESIGN, SETTING, AND PATIENTS Pooled-data analysis of 4 large cohorts of newly diagnosed CRC probands recruited between 1994 and 2010 (n = 10,206) from the Colon Cancer Family Registry, the EPICOLON project, the Ohio State University, and the University of Helsinki examining personal, tumor-related, and family characteristics, as well as microsatellite instability, tumor MMR immunostaining, and germline MMR mutational status data. MAIN OUTCOME Performance characteristics of selected strategies (Bethesda guidelines, Jerusalem recommendations, and those derived from a bivariate/multivariate analysis of variables associated with Lynch syndrome) were compared with tumor MMR testing of all CRC patients (universal screening). RESULTS Of 10,206 informative, unrelated CRC probands, 312 (3.1%) were MMR gene mutation carriers. In the population-based cohorts (n = 3671 probands), the universal screening approach (sensitivity, 100%; 95% CI, 99.3%-100%; specificity, 93.0%; 95% CI, 92.0%-93.7%; diagnostic yield, 2.2%; 95% CI, 1.7%-2.7%) was superior to the use of Bethesda guidelines (sensitivity, 87.8%; 95% CI, 78.9%-93.2%; specificity, 97.5%; 95% CI, 96.9%-98.0%; diagnostic yield, 2.0%; 95% CI, 1.5%-2.4%; P < .001), Jerusalem recommendations (sensitivity, 85.4%; 95% CI, 77.1%-93.6%; specificity, 96.7%; 95% CI, 96.0%-97.2%; diagnostic yield, 1.9%; 95% CI, 1.4%-2.3%; P < .001), and a selective strategy based on tumor MMR testing of cases with CRC diagnosed at age 70 years or younger and in older patients fulfilling the Bethesda guidelines (sensitivity, 95.1%; 95% CI, 89.8%-99.0%; specificity, 95.5%; 95% CI, 94.7%-96.1%; diagnostic yield, 2.1%; 95% CI, 1.6%-2.6%; P < .001). This selective strategy missed 4.9% of Lynch syndrome cases but resulted in 34.8% fewer cases requiring tumor MMR testing and 28.6% fewer cases undergoing germline mutational analysis than the universal approach. CONCLUSION Universal tumor MMR testing among CRC probands had a greater sensitivity for the identification of Lynch syndrome compared with multiple alternative strategies, although the increase in the diagnostic yield was modest.

Port site metastases and recurrence after laparoscopic colectomy. A randomized trial

AbstractBackground: This study was performed to prospectively assess the impact of the laparoscopic approach to the patterns of port site metastases (PSM) and recurrence rate (RR) of resected colon carcinomas as compared with conventional colectomies. Methods: All patients were included in a prospective randomized trial comparing laparoscopic-assisted colectomy (LAC) versus open colectomy (OC) for colon cancer. The randomization was stratified for localization of the lesion. Patients with metastasic disease at the time of the surgery were excluded. Follow-up in the outpatient clinic was done every 3 months for a minimum of 12 months. Endpoints for the study were metastasis at port site and laparotomy incision as well as recurrence rate. Results: Of 91 segmental colectomies performed from November 1993 to January 1996, there were 44 LAC and 47 OC. Patient data were similar in both groups (age, sex, Dukes stage, type of operation). Mean follow-up was 21.4 months, with a range of 13 to 41 months. There were no wounds or PSM in those series. RR was similar for both groups. For LAC, it was five of 31 (16.1%); for OC, it was six of 40 (15%). Conclusions: The laparoscopic approach has a recurrence rate similar to that for open procedures for colon cancer. However, additional follow-up of these patients is needed before we can determine whether or not the laparoscopic approach influences overall survival.

β-catenin/TCF4 complex induces the epithelial-to-mesenchymal transition (EMT)-activator ZEB1 to regulate tumor invasiveness

In most carcinomas, invasion of malignant cells into surrounding tissues involves their molecular reprogramming as part of an epithelial-to-mesenchymal transition (EMT). Mutation of the APC gene in most colorectal carcinomas (CRCs) contributes to the nuclear translocation of the oncoprotein β-catenin that upon binding to T-cell and lymphoid enhancer (TCF-LEF) factors triggers an EMT and a proinvasive gene expression profile. A key inducer of EMT is the ZEB1 transcription factor whose expression promotes tumorigenesis and metastasis in carcinomas. As inhibitor of the epithelial phenotype, ZEB1 is never present in the epithelium of normal colon or the tumor center of CRCs where β-catenin remains membranous. We show here that ZEB1 is expressed by epithelial cells in intestinal tumors from human patients (familial adenomatous polyposis) and mouse models (APCMin/+) with germline mutations of APC that result in nuclear accumulation of β-catenin. However, ZEB1 is not expressed in the epithelium of hereditary forms of CRCs that carry wild-type APC and where β-catenin is excluded from the nucleus (Lynch syndrome). We found that β-catenin/TCF4 binds directly to the ZEB1 promoter and activates its transcription. Knockdown of β-catenin and TCF4 in APC-mutated CRC cells inhibited endogenous ZEB1, whereas forced translocation of β-catenin to the nucleus in APC-wild-type CRC cells induced de novo expression of ZEB1. Upregulation of MT1-MMP and LAMC2 by β-catenin/TCF4 has been linked to invasiveness in CRCs, and we show here that both proteins are activated by ZEB1 coexpressing with it in primary colorectal tumors with mutated APC. These results set ZEB1 as an effector of β-catenin/TCF4 signaling in EMT and tumor progression.