Bas P. L. Wijnhoven

An evaluation of prognostic factors and tumor staging of resected carcinoma of the esophagus

Objective:To evaluate prognostic factors and tumor staging in patients after esophagectomy for cancer. Summary Background Data:Several reports have questioned the appropriateness of the sixth edition of the International Union Against Cancer (UICC) TNM guidelines for staging esophageal cancer. Additional pathologic characteristics, besides the 3 basic facets of anatomic spread (tumor, node, metastases), might also have prognostic value. Methods:All patients who underwent resection of the esophagus for carcinoma between January 1995 and March 2003 were extracted from a prospective database. Univariate and multivariate analysis was performed to identify prognostic factors for survival. The goodness of fit and accuracy of 3 staging models (UICC-TNM, Korst classification, Rice classification) predicting survival were assessed. Results:A total of 292 patients (mean age, 63 years) underwent esophagectomy. The 5-year overall survival rate was 29% (median, 21 months). pT-, pN-, pm-stage, and radicality of the resection were independent prognostic factors. Subdivision of T1 tumors into mucosal and submucosal showed significant differences in 5-year survival between both groups: 90% versus 47%, respectively (P = 0.01). Subdivision of pN-stage into 3 groups based on the number of positive nodes (0, 1–2, and >3 nodes positive) or the lymph node ratio (0, 0.01–0.2, and >0.2) also refined staging (P = 0.001 and P < 0.001, respectively). The current subclassification of M1 (M1a and M1b) is not warranted (P = 0.41). The staging model of Rice was more accurate than the UICC-TNM classification in predicting survival. Conclusion:This study supports the view that the current (6th edition) UICC-TNM staging model for esophageal cancer needs to be revised.

High-Volume versus Low-Volume for Esophageal Resections for Cancer: The Essential Role of Case-Mix Adjustments based on Clinical Data

BackgroundMost studies addressing the volume–outcome relationship in complex surgical procedures use hospital mortality as the sole outcome measure and are rarely based on detailed clinical data. The lack of reliable information about comorbidities and tumor stages makes the conclusions of these studies debatable.The purpose of this study was to compare outcomes for esophageal resections for cancer in low- versus high-volume hospitals, using an extensive set of variables concerning case-mix and outcome measures, including long-term survival.MethodsClinical data, from 903 esophageal resections performed between January 1990 and December 1999, were retrieved from the original patients’ files. Three hundred and forty-two patients were operated on in 11 low-volume hospitals (<7 resections/year) and 561 in a single high-volume center.ResultsMortality and morbidity rates were significantly lower in the high-volume center, which had an in-hospital mortality of 5 vs 13% (P < .001). On multivariate analysis, hospital volume, but also the presence of comorbidity proved to be strong prognostic factors predicting in-hospital mortality (ORs 3.05 and 2.34). For stage I and II disease, there was a significantly better 5-year survival in the high-volume center. (P = .04).ConclusionsHospital volume and comorbidity patterns are important determinants of outcome in esophageal cancer surgery. Strong clinical endpoints such as in-hospital mortality and survival can be used as performance indicators, only if they are joined by reliable case-mix information.

Centralization of Esophageal Cancer Surgery: Does It Improve Clinical Outcome?

BackgroundThe volume–outcome relationship for complex surgical procedures has been extensively studied. Most studies are based on administrative data and use in-hospital mortality as the sole outcome measure. It is still unknown if concentration of these procedures leads to improvement of clinical outcome. The aim of our study was to audit the process and effect of centralizing oesophageal resections for cancer by using detailed clinical data.MethodsFrom January 1990 until December 2004, 555 esophagectomies for cancer were performed in 11 hospitals in the region of the Comprehensive Cancer Center West (CCCW); 342 patients were operated on before and 213 patients after the introduction of a centralization project. In this project patients were referred to the hospitals which showed superior outcomes in a regional audit. In this audit patient, tumor, and operative details as well as clinical outcome were compared between hospitals. The outcome of both cohorts, patients operated on before and after the start of the project, were evaluated.ResultsDespite the more severe comorbidity of the patient group, outcome improved after centralizing esophageal resections. Along with a reduction in postoperative morbidity and length of stay, mortality fell from 12% to 4% and survival improved significantly (Pxa0=xa00.001). The hospitals with the highest procedural volume showed the biggest improvement in outcome.ConclusionVolume is an important determinant of quality of care in esophageal cancer surgery. Referral of patients with esophageal cancer to surgical units with adequate experience and superior outcomes (outcome-based referral) improves quality of care.

Small bites versus large bites for closure of abdominal midline incisions (STITCH): A double-blind, multicentre, randomised controlled trial

BACKGROUNDnIncisional hernia is a frequent complication of midline laparotomy and is associated with high morbidity, decreased quality of life, and high costs. We aimed to compare the large bites suture technique with the small bites technique for fascial closure of midline laparotomy incisions.nnnMETHODSnWe did this prospective, multicentre, double-blind, randomised controlled trial at surgical and gynaecological departments in ten hospitals in the Netherlands. Patients aged 18 years or older who were scheduled to undergo elective abdominal surgery with midline laparotomy were randomly assigned (1:1), via a computer-generated randomisation sequence, to receive small tissue bites of 5 mm every 5 mm or large bites of 1 cm every 1 cm. Randomisation was stratified by centre and between surgeons and residents with a minimisation procedure to ensure balanced allocation. Patients and study investigators were masked to group allocation. The primary outcome was the occurrence of incisional hernia; we postulated a reduced incidence in the small bites group. We analysed patients by intention to treat. This trial is registered at Clinicaltrials.gov, number NCT01132209 and with the Nederlands Trial Register, number NTR2052.nnnFINDINGSnBetween Oct 20, 2009, and March 12, 2012, we randomly assigned 560 patients to the large bites group (n=284) or the small bites group (n=276). Follow-up ended on Aug 30, 2013; 545 (97%) patients completed follow-up and were included in the primary outcome analysis. Patients in the small bites group had fascial closures sutured with more stitches than those in the large bites group (mean number of stitches 45 [SD 12] vs 25 [10]; p<0·0001), a higher ratio of suture length to wound length (5·0 [1·5] vs 4·3 [1·4]; p<0·0001) and a longer closure time (14 [6] vs 10 [4] min; p<0·0001). At 1 year follow-up, 57 (21%) of 277 patients in the large bites group and 35 (13%) of 268 patients in the small bites group had incisional hernia (p=0·0220, covariate adjusted odds ratio 0·52, 95% CI 0·31-0·87; p=0·0131). Rates of adverse events did not differ significantly between groups.nnnINTERPRETATIONnOur findings show that the small bites suture technique is more effective than the traditional large bites technique for prevention of incisional hernia in midline incisions and is not associated with a higher rate of adverse events. The small bites technique should become the standard closure technique for midline incisions.nnnFUNDINGnErasmus University Medical Center and Ethicon.

MicroRNA profiling of Barrett's oesophagus and oesophageal adenocarcinoma

The genetic changes that drive metaplastic progression from squamous oesophageal mucosa toward intestinal metaplasia and adenocarcinoma are unclear. The aberrant expression of microRNAs (miRNAs) is involved in the development of cancer. This study examined whether miRNAs play a role in the development of oesophageal adenocarcinoma.

The comprehensive complication index: a novel and more sensitive endpoint for assessing outcome and reducing sample size in randomized controlled trials

Objective:To test whether the newly developed comprehensive complication index (CCI) is more sensitive than traditional endpoints for detecting between-group differences in randomized controlled trials (RCTs). Background:A major challenge in RCTs is the choice of optimal endpoints to detect treatment effects. Mortality is no longer a sufficient marker in studies, and morbidity is often poorly defined. The CCI, integrating all complications including their severity in a linear scale ranging from 0 (no complication) to 100 (death), is a new tool, which may be more sensitive than other traditional endpoints to detect treatment effects on postoperative morbidity. Methods:The CCI was tested in 3 published RCTs from European centers evaluating pancreas, esophageal and colon resections. To compare the sensitivity of the CCI with traditional morbidity endpoints, for example, presence of any (yes/no) or only the most severe complications, all postoperative events were assessed, and the CCI calculated. Treatment effects and sample size calculations were compared using the CCI and traditional endpoints. Results:Although RCTs failed to show between-group differences using any or most severe complications, the CCI revealed significant differences between treatment groups in 2 RCTs—after pancreas (P = 0.009) and esophageal surgery (P = 0.014). The CCI in the RCT on colon resections confirmed the absence of between-group differences (P = 0.39). The required sample sizes in trials are up to 9 times lower for the CCI than for traditional morbidity endpoints. Conclusions:This study demonstrates superiority of the CCI to traditional endpoints. The CCI may serve as an appealing endpoint for future RCTs and may reduce the sample size.

MicroRNAs and cancer

MicroRNAs (miRNAs) are small sequences of RNA, 21 to 22 nucleotides long, that have been discovered recently. They are produced from areas of the human genome that were previously thought to have no function. These sequences now appear to be important in the regulation of many fundamental processes. Evidence has recently emerged that deregulated miRNA activity is associated with human cancers.

Increased incidence of adenocarcinomas at the gastro-oesophageal junction in Dutch males since the 1990s

Background Worldwide population-based studies suggest that the incidence of oesophageal and gastric cardia adenocarcinomas has increased since the 1970s. Objective and methods We studied time trends in mortality and incidence rates of oesophageal and gastric carcinomas according to subsite and histology in the south-east Netherlands since 1978. Results The age-adjusted mortality and incidence rates for oesophageal cancer doubled in males over the entire 19-year study period from 2.7 to 5.6 and from 2.4 to 4.8 per 100 000 person years, respectively. In females, a similar trend for the mortality and incidence rates was seen, but at a lower level. The age-adjusted mortality and incidence rates for gastric cancer decreased with time from 20.7 to 12.8 and from 21.6 to 15.9 per 100 000 person years in males, respectively. In females, age-adjusted mortality and incidence rates for gastric cancer also decreased. Analysis of incidence rates by subsite and subtype showed an increase in adenocarcinomas of the oesophagus and gastric cardia, largely restricted to males. In females, the rise in incidence of squamous cell carcinoma of the oesophagus appeared to be more marked than the rise in adenocarcinomas, whereas the incidence of gastric cardia carcinomas has remained stable over the last 10 years. Neither the decrease in the number of unspecified tumours with time, nor the increase in the use of diagnostic endoscopy and imaging techniques, is likely to explain completely the observed increases. Conclusion The increase in incidence of adenocarcinomas at the gastro-oesophageal junction in the south-eastern Netherlands seems, at least in part, to represent a true underlying increase that is restricted largely to males.

Improving the Accuracy of TNM Staging in Esophageal Cancer: A Pathological Review of Resected Specimens

BackgroundControversy exists over the Sixth Edition of the International Union Against Cancer (UICC) TNM staging system for esophageal cancer. Inclusion of additional information such as the number of metastatic lymph nodes and extracapsular lymph node invasion may improve the current staging system and lead to optimization of patient treatment.MethodsAll patients in Adelaide who underwent resection for esophageal cancer between 1997 and 2007 were identified from a prospective database. Two independent observers then reexamined all pathology slides from the original resection. Univariate and multivariate analysis was performed to identify significant prognostic factors. The goodness of fit and accuracy of additional prognostic factors were assessed, and the staging system was modified according to this information.ResultsThere were 240 patients (mean age, 62xa0years) who met the inclusion criteria. The 5-year overall survival rate was 36% (median, 24xa0months). Only histological grade and a refined pN stage were found to be independent prognostic factors that could then be used to improve current TNM staging. Subdivision of pN stage into three groups (0, 1–2, and >2 positive nodes) showed significant differences in 5-year survival between all three groups: 53% vs 27% vs 6%, respectively (Pxa0<xa0.01). The optimal staging model was the same for patients who received neoadjuvant therapy and surgery (nxa0=xa0116), and those who underwent surgery alone (nxa0=xa0124).ConclusionA staging model that incorporates a refined pN stage and histological grade appears to be more accurate than the current UICC-TNM staging system. This staging model is still applicable in patients who receive neoadjuvant therapy.

End-to-end versus end-to-side esophagogastrostomy after esophageal cancer resection: a prospective randomized study.

Objective: To compare single-layered hand-sewn cervical end-to-side (ETS) anastomosis with end-to-end (ETE) anastomosis in a prospective randomized fashion. Background: The preferred organ used for reconstruction after esophagectomy for cancer is the stomach. Previous studies attempted to define the optimal site of anastomosis and anastomotic techniques. However, anastomotic stricture formation and leakage still remain an important clinical problem. Methods: From May 2005 to September 2007, 128 patients (64 in each group) were randomized between ETE and ETS anastomosis after esophagectomy for cancer with gastric tube reconstruction. Routine contrast swallow studies and endoscopy were performed. Anastomotic stricture within 1 year, requiring dilatation, was the primary endpoint. Secondary endpoints were anastomotic leak rate and mortality. Results: Ninety-nine men and 29 women underwent esophagectomy and gastric tube reconstruction. Benign stenosis of the anastomosis, for which dilatation was required, occurred more often in the ETE group (40% vs. ETS 18%, P < 0.01) after 1 year of follow-up. The overall (clinical and radiological) anastomotic leak rate was lower in the ETE group (22% vs. ETS 41%, P = 0.04). Patients with an ETE anastomosis suffered less often from pneumonia; 17% versus ETS 44%, P = 0.002 and had subsequently significantly shorter in-hospital stay (15 days vs. 22 days, P = 0.02). In-hospital mortality did not differ between both groups. Conclusion: ETS anastomosis is associated with a lower anastomotic stricture rate, compared to ETE anastomosis. However, prevention of stricture formation was at high costs with increased anastomotic leakage and longer in-hospital stay. This study is registered with the Dutch Trial Registry and carries the ID number OND1317772.