H. Jaap Bonjer

Minimally invasive versus open oesophagectomy for patients with oesophageal cancer: a multicentre, open-label, randomised controlled trial

BACKGROUND Surgical resection is regarded as the only curative option for resectable oesophageal cancer, but pulmonary complications occurring in more than half of patients after open oesophagectomy are a great concern. We assessed whether minimally invasive oesophagectomy reduces morbidity compared with open oesophagectomy. METHODS We did a multicentre, open-label, randomised controlled trial at five study centres in three countries between June 1, 2009, and March 31, 2011. Patients aged 18-75 years with resectable cancer of the oesophagus or gastro-oesophageal junction were randomly assigned via a computer-generated randomisation sequence to receive either open transthoracic or minimally invasive transthoracic oesophagectomy. Randomisation was stratified by centre. Patients, and investigators undertaking interventions, assessing outcomes, and analysing data, were not masked to group assignment. The primary outcome was pulmonary infection within the first 2 weeks after surgery and during the whole stay in hospital. Analysis was by intention to treat. This trial is registered with the Netherlands Trial Register, NTR TC 2452. FINDINGS We randomly assigned 56 patients to the open oesophagectomy group and 59 to the minimally invasive oesophagectomy group. 16 (29%) patients in the open oesophagectomy group had pulmonary infection in the first 2 weeks compared with five (9%) in the minimally invasive group (relative risk [RR] 0·30, 95% CI 0·12-0·76; p=0·005). 19 (34%) patients in the open oesophagectomy group had pulmonary infection in-hospital compared with seven (12%) in the minimally invasive group (0·35, 0·16-0·78; p=0·005). For in-hospital mortality, one patient in the open oesophagectomy group died from anastomotic leakage and two in the minimally invasive group from aspiration and mediastinitis after anastomotic leakage. INTERPRETATION These findings provide evidence for the short-term benefits of minimally invasive oesophagectomy for patients with resectable oesophageal cancer. FUNDING Digestive Surgery Foundation of the Unit of Digestive Surgery of the VU University Medical Centre.

A Randomized Trial of Laparoscopic versus Open Surgery for Rectal Cancer

BACKGROUND Laparoscopic resection of colorectal cancer is widely used. However, robust evidence to conclude that laparoscopic surgery and open surgery have similar outcomes in rectal cancer is lacking. A trial was designed to compare 3-year rates of cancer recurrence in the pelvic or perineal area (locoregional recurrence) and survival after laparoscopic and open resection of rectal cancer. METHODS In this international trial conducted in 30 hospitals, we randomly assigned patients with a solitary adenocarcinoma of the rectum within 15 cm of the anal verge, not invading adjacent tissues, and without distant metastases to undergo either laparoscopic or open surgery in a 2:1 ratio. The primary end point was locoregional recurrence 3 years after the index surgery. Secondary end points included disease-free and overall survival. RESULTS A total of 1044 patients were included (699 in the laparoscopic-surgery group and 345 in the open-surgery group). At 3 years, the locoregional recurrence rate was 5.0% in the two groups (difference, 0 percentage points; 90% confidence interval [CI], -2.6 to 2.6). Disease-free survival rates were 74.8% in the laparoscopic-surgery group and 70.8% in the open-surgery group (difference, 4.0 percentage points; 95% CI, -1.9 to 9.9). Overall survival rates were 86.7% in the laparoscopic-surgery group and 83.6% in the open-surgery group (difference, 3.1 percentage points; 95% CI, -1.6 to 7.8). CONCLUSIONS Laparoscopic surgery in patients with rectal cancer was associated with rates of locoregional recurrence and disease-free and overall survival similar to those for open surgery. (Funded by Ethicon Endo-Surgery Europe and others; COLOR II ClinicalTrials.gov number, NCT00297791.).

Fewer intraperitoneal adhesions with use of hyaluronic acid-carboxymethylcellulose membrane: a randomized clinical trial.

ObjectiveTo assess the effectiveness of bioresorbable Seprafilm membrane in preventing abdominal adhesions in a prospective clinical randomized multicenter trial. Summary Background DataAdhesions occur frequently after abdominal operations and are a common cause of bowel obstruction, chronic abdominal pain, and infertility. To reduce the formation of adhesions, a mechanical barrier composed of hyaluronic acid and carboxymethylcellulose was developed, preventing adherence of tissues after abdominal surgery. MethodsBetween April 1996 and September 1998, all patients requiring a Hartmann procedure for sigmoid diverticulitis or obstructed rectosigmoid were randomized to either intraperitoneal placement of the antiadhesions membrane under the midline during laparotomy and in the pelvis, or as a control. Direct visual evaluation of the incidence and severity of adhesions was performed laparoscopically at second-stage surgery for restoration of the continuity of the colon. ResultsA total of 71 patients were randomized; of these, 42 could be evaluated. The incidence of adhesions did not differ significantly between the two groups, but the severity of adhesions was significantly reduced in the Seprafilm group both for the midline incision and for the pelvic area. Complications occurred in similar numbers in both groups. ConclusionsSeprafilm antiadhesions membrane appears effective in reducing the severity of postoperative adhesions after major abdominal surgery, although the incidence of adhesions was not diminished. The authors recommend using Seprafilm when relaparotomy or second-look intervention is planned. Long-term studies are needed to assess the cost-effectiveness and value of Seprafilm in preventing bowel obstruction, chronic abdominal pain, and infertility.

Endoscopic Retroperitoneal Adrenalectomy: Lessons Learned From 111 Consecutive Cases

ObjectiveTo evaluate the effectiveness of endoscopic retroperitoneal adrenalectomy (ERA). Summary Background DataMinimally invasive adrenalectomy has become the procedure of choice for benign adrenal pathology. Although the adrenal glands are located in the retroperitoneum, most surgeons prefer the transperitoneal laparoscopic approach to adrenal tumors. MethodsClinical characteristics and outcomes of 111 ERAs from January 1994 to December 1999 were evaluated. ResultsNinety-five patients underwent 111 ERAs (79 unilateral, 16 bilateral). Indications were Cushing syndrome (n = 22), Cushing disease (n = 8), ectopic adrenocorticotropic hormone syndrome (n = 6), Conn’s adenoma (n = 25), pheochromocytoma (n = 19), incidentaloma (n = 11), and other (n = 4). Tumor size varied from 0.1 to 8 cm. Median age was 50 years. Unilateral ERA required 114 minutes, with median blood loss of 65 mL. Bilateral ERA lasted 214 minutes, with median blood loss of 121 mL. The conversion rate to open surgery was 4.5%. The complication rate was 11%. Median postoperative hospital stay was 2 days for unilateral ERA and 5 days for bilateral ERA. The death rate was 0.9%. At a median follow-up of 14 months, the recurrence rate of disease was 0.9%. ConclusionFor benign adrenal tumors less than 6 cm, ERA is recommended.

Losses of Chromosomes 1p and 3q Are Early Genetic Events in the Development of Sporadic Pheochromocytomas

Despite several loss of heterozygosity studies, a comprehensive genomic survey of pheochromocytomas is still lacking. To identify DNA copy number changes which might be important in tumor development and progression and which may have diagnostic utility, we evaluated genetic aberrations in 29 sporadic adrenal and extra-adrenal pheochromocytomas (19 clinically benign tumors and 10 malignant lesions). Comparative genomic hybridization was performed using directly fluorochrome-conjugated DNA extracted from frozen (16) and paraffin-embedded (13) tumor tissues. The most frequently observed changes were losses of chromosomes 1p11-p32 (86%), 3q (52%), 6q (34%), 3p, 17p (31% each), 11q (28%), and gains of chromosomes 9q (38%) and 17q (31%). No amplification was identified and no difference between adrenal and extra-adrenal tumors was detected. Progression to malignant tumors was strongly associated with deletions of chromosome 6q (60% versus 21% in clinically benign lesions, P = 0.0368) and 17p (50% versus 21%). Fluorescence in situ hybridization confirmed the comparative genomic hybridization data of chromosomes 1p, 3q, and 6q, and revealed aneuploidy in some tumors. Our results suggest that the development of pheochromocytomas is associated with specific genomic aberrations, such as losses of 1p, 3q, and 6q and gains of 9q and 17q. In particular, tumor suppressor genes on chromosomes 1p and 3q may be involved in early tumorigenesis, and deletions of chromosomes 6q and 17p in progression to malignancy.

Right-sided laparoscopic live-donor nephrectomy: Is reluctance still justified?

Background. Laparoscopic donor nephrectomy (LDN) of the right kidney is performed with great reluctance because of the shorter renal vein and possible increased incidence of venous thrombosis. Methods. In this retrospective, clinical study, right LDN and left LDN were compared. Between December 1997 and May 2001, 101 LDN were performed. Seventy-three (72%) right LDN were compared with 28 (28%) left LDN for clinical characteristics, operative data, and graft function. Results. There were no significant differences between the two groups regarding conversion rate, complications, hospital stay, thrombosis, graft function, and graft survival. Operating time was significantly shorter in the right LDN group (218 vs. 280 min). Conclusion. In this study, right LDN was not associated with a higher number of complications, conversions, or incidence of venous thrombosis compared with the left LDN. Thus, reluctance toward right LDN is not justified, and therefore, right LDN should not be avoided.

Proliferative index in phaeochromocytomas: does it predict the occurrence of metastases?

Evaluation of the malignant potential of phaeochromocytomas in the absence of metastases presents a formidable challenge to both clinicians and pathologists. Until now, no widely accepted clinical, histological, immunohistochemical or molecular method has become available to discriminate malignant from benign phaeochromocytomas. In other endocrine tumours, estimation of proliferative activity by MIB‐1 immunostaining has emerged as a promising approach for the determination of metastatic potential. In this study, the utility of MIB‐1 immunostaining as a predictive marker for the occurrence of metastases in phaeochromocytomas was evaluated. In addition, the density of S100‐positive sustentacular cells was studied, since their depletion has been identified as a negative predictive marker in smaller series. Furthermore, several clinicopathological parameters were evaluated. One hundred and ten patients operated on for a total of 99 benign and 37 malignant phaeochromocytomas were studied. All malignant tumours had documented metastases. The histopathological diagnosis of primary tumours and metastases was reviewed and graded for angioinvasion, capsular extension, and intra‐tumoural necrosis. The proliferative index (percentage of MIB‐1‐positive cells) and the density of S100‐positive cells were assessed. In addition, age at resection, associated familial tumour syndromes, tumour size, and tumour location were recorded. Univariate analysis revealed statistically significant correlations between malignancy and proliferative index (p<0.0005) and depletion of S100‐positive sustentacular cells (p<0.0005). Fifty per cent of the malignant, but none of the benign phaeochromocytomas had a proliferative index greater than 2.5%. Higher age at resection (p=0.03), sporadic occurrence (p<0.0005), extra‐adrenal location (p<0.0005), tumour size (p<0.0005), and necrosis (p=0.03) were also significantly associated with malignancy. Logistic regression showed that proliferative index (p=0.0072), size (p=0.0022), and extra‐adrenal location (p=0.0012) of the primary tumour were independently predictive for malignancy. In conclusion, this study indicates that assessing the proliferative activity of phaeochromocytomas by MIB‐1 immunohistochemistry can predict the occurrence of metastases. The predictive value of S100 immunostaining, tumour size, and extra‐adrenal location of the tumour was also confirmed. Copyright

Laparoscopic vs open incisional hernia repair a randomized clinical trial

IMPORTANCE Incisional hernia is the most frequent surgical complication after laparotomy. Up to 30% of all patients undergoing laparotomy develop an incisional hernia. OBJECTIVE To compare laparoscopic vs open ventral incisional hernia repair with regard to postoperative pain and nausea, operative results, perioperative and postoperative complications, hospital admission, and recurrence rate. DESIGN Multicenter randomized controlled trial between May 1999 and December 2006 with a mean follow-up period of 35 months. SETTING All patients were operated on in a clinical setting at 1 of the 2 participating university medical centers or at the other 8 teaching hospitals. PARTICIPANTS Two hundred six patients from 10 hospitals were randomized equally to laparoscopic or open mesh repair. Patients with an incisional hernia larger than 3 cm and smaller than 15 cm, either primary or recurrent, were included. Patients were excluded if they had an open abdomen treatment in their medical histories. INTERVENTION Laparoscopic or open ventral incisional hernia repair. MAIN OUTCOME MEASURES The primary outcome of the trial was postoperative pain. Secondary outcomes were use of analgesics, perioperative and postoperative complications, operative time, postoperative nausea, length of hospital stay, recurrence, morbidity, and mortality. RESULTS Median blood loss during the operation was significantly less (10 mL vs 50 mL; P = .05) as well as the number of patients receiving a wound drain (3% vs. 45%; P < .001) in the laparoscopic group. Operative time for the laparoscopic group was longer (100 minutes vs. 76 minutes; P = .001). Perioperative complications were significantly higher after laparoscopy (9% vs. 2%). Visual analog scale scores for pain and nausea, completed before surgery and 3 days and 1 and 4 weeks postoperatively, showed no significant differences between the 2 groups. At a mean follow-up period of 35 months, a recurrence rate of 14% was reported in the open group and 18%, in the laparoscopic group (P = .30). The size of the defect was found to be an independent predictor for recurrence (P < .001). CONCLUSIONS AND RELEVANCE During the operation, there was less blood loss and less need for a wound drain in the laparoscopic group. However, operative time was longer during laparoscopy. Perioperative complications were significantly higher in the laparoscopic group. Visual analog scores for pain and nausea did not differ between groups. The incidence of a recurrence was similar in both groups. The size of the defect was found to be an independent factor for recurrence of an incisional hernia.

Traditional invasive vs. minimally invasive esophagectomy: a multi-center, randomized trial (TIME-trial)

BackgroundThere is a rise in incidence of esophageal carcinoma due to increasing incidence of adenocarcinoma. Probably the only curative option to date is the use of neoadjuvant therapy followed by surgical resection. Traditional open esophageal resection is associated with a high morbidity and mortality rate. Furthermore, this approach involves long intensive care unit stay, in-hospital stay and long recovery period. Minimally invasive esophagectomy could reduce the morbidity and accelerate the post-operative recovery.Methods/DesignComparison between traditional open and minimally invasive esophagectomy in a multi-center, randomized trial. Patients with a resectable intrathoracic esophageal carcinoma, including the gastro-esophageal junction tumors (Siewert I) are eligible for inclusion. Prior thoracic surgery and cervical esophageal carcinoma are indications for exclusion. The surgical technique involves a right thoracotomy with lung blockade and laparotomy either with a cervical or thoracic anastomosis for the traditional group. The minimally invasive procedure involves a right thoracoscopy in prone position with a single lumen tube and laparoscopy either with a cervical or thoracic anastomosis. All patients in both groups will undergo identical pre-operative and post-operative protocol. Primary endpoint of this study are post-operative respiratory complications within the first two post-operative weeks confirmed by clinical, radiological and sputum culture data. Secondary endpoints are the operative data, the post-operative data and oncological data such as quality of the specimen and survival. Operative data include duration of the operation, blood loss and conversion to open procedure. Post-operative data include morbidity (major and minor), quality of life tests and hospital stay.Based on current literature and the experience of all participating centers, an incidence of pulmonary complications for 57% in the traditional arm and 29% in the minimally invasive arm, it is estimated that per arm 48 patients are needed. This is based on a two-sided significance level (alpha) of 0.05 and a power of 0.80. Knowing that approximately 20% of the patients will be excluded, we will randomize 60 patients per arm.DiscussionThe TIME-trial is a prospective, multi-center, randomized study to define the role of minimally invasive esophageal resection in patients with resectable intrathoracic and junction esophageal cancer.Trial registration (Netherlands Trial Register)NTR2452

COLOR III: a multicentre randomised clinical trial comparing transanal TME versus laparoscopic TME for mid and low rectal cancer

IntroductionTotal mesorectal excision (TME) is an essential component of surgical management of rectal cancer. Both open and laparoscopic TME have been proven to be oncologically safe. However, it remains a challenge to achieve complete TME with clear circumferential resections margin (CRM) with the conventional transabdominal approach, particularly in mid and low rectal tumours. Transanal TME (TaTME) was developed to improve oncological and functional outcomes of patients with mid and low rectal cancer.MethodsAn international, multicentre, superiority, randomised trial was designed to compare TaTME and conventional laparoscopic TME as the surgical treatment of mid and low rectal carcinomas. The primary endpoint is involved CRM. Secondary endpoints include completeness of mesorectum, residual mesorectum, morbidity and mortality, local recurrence, disease-free and overall survival, percentage of sphincter-saving procedures, functional outcome and quality of life. A Quality Assurance Protocol including centralised MRI review, histopathology re-evaluation, standardisation of surgical techniques, and monitoring and assessment of surgical quality will be conducted.DiscussionThe difference in involvement of CRM between the two treatment strategies is thought to be in favour of the TaTME. TaTME is therefore expected to be superior to laparoscopic TME in terms of oncological outcomes in case of mid and low rectal carcinomas.