Randomized clinical trial of laparoscopic colectomy with or without natural-orifice specimen extraction

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1 Randomized clinical trial Randomized clinical trial of laparoscopic colectomy with or without natural-orifice specimen extraction A. M. Wolthuis 1, S. Fieuws 2, A. Van Den Bosch 1, A. de Buck van Overstraeten 1 and A. D Hoore 1 1 Department of Abdominal Surgery, University Hospital Leuven, and 2 Interuniversity Institute for Biostatistics and Statistical Bioinformatics, KU Leuven, Leuven, Belgium Correspondence to: Dr A. M. Wolthuis, Department of Abdominal Surgery, University Hospital Gasthuisberg Leuven, Herestraat 49, 3000 Leuven, Belgium ( albert.wolthuis@uzleuven.be) Background: Although conventional laparoscopic colectomy is a validated technique, laparoscopic natural-orifice specimen extraction (NOSE) colectomy might improve outcome. This randomized clinical trial compared analgesia requirements, postoperative pain, anorectal function, inflammatory response and cosmesis in laparoscopic NOSE colectomy and conventional laparoscopic colectomy. Methods: Patients were randomly assigned to undergo laparoscopic NOSE colectomy or conventional laparoscopic colectomy for left-sided colonic disease. The primary endpoint was analgesia requirement. Secondary endpoints were operative outcome, inflammatory response, anorectal function and cosmesis. Results: Forty patients were enrolled in the study, 20 in each group (15 with diverticulitis and 5 with colorectal cancer in each group). A significant difference was observed in morphine analogue requirements (1 of 20 patients in the NOSE group versus 10 of 20 in the conventional group; P = 0 003). Patient-controlled epidural analgesia was lower in the NOSE group (mean 116 ml versus 221 ml in the conventional group; P < 0 001), as was paracetamol use (mean 11 0 versus 17 0 g respectively; P < 0 001). Postoperative pain scores were lower in the NOSE group: mean maximum visual analogue score of 3 5 versus 2 1(P < 0 001). One week after hospital discharge, pain scores remained higher in the conventional group: 15 of 20 patients in the conventional group reported pain, compared with one of 20 in the NOSE group (P < 0 001). Inflammatory responses were greater in patients undergoing NOSE colectomy: higher peak C-reactive protein and interleukin 6 levels were observed on postoperative day 2 (P < 0 001) and day 1(P = 0 002) respectively. Postoperative anorectal function, complications and hospital stay were similar in the two groups. Conclusion: Laparoscopic NOSE colectomy was associated with less pain and lower analgesia requirements than the conventional laparoscopic extraction. Registration number: NCT ( Paper accepted 26 November 2014 Published online 12 March 2015 in Wiley Online Library ( DOI: /bjs.9757 Introduction Laparoscopic natural-orifice specimen extraction (NOSE) colectomy is assumed to cause less postoperative pain as it avoids extraction-site laparotomy, thus reducing abdominal wall trauma. Subsequently, this reduction in incision length may have an impact on incisional pain. Additional advantages of laparoscopic NOSE colectomy may be less morbidity, shorter hospital stay and better cosmetic outcome 1. To date, only one randomized clinical trial (RCT) 2 has shown less postoperative pain and fewer wound complications. This paper reports the results of a prospective single-blind single-centre RCT of laparoscopic NOSE colectomy versus conventional laparoscopic colectomy, focusing on postoperative pain and analgesia requirements. Methods Patients treated at University Hospital Leuven were eligible if they were to undergo elective laparoscopic left-sided colonic resection. Patients were included if they were older than 18 years and had been diagnosed with sigmoid colonic disease. Exclusion criteria were: contraindication to laparoscopy, previous midline laparotomy, refusal to give consent, having American Society of Anesthesiologists 2015 BJS Society Ltd BJS 2015; 102:

2 Laparoscopic natural-orifice specimen extraction versus conventional laparoscopic colectomy 631 fitness grade III, pregnancy, taking chronic opioid medication, receiving immunosuppressive medication or being immunocompromised, and known coagulopathy. The study was reported according to the principles of the Consolidated Standards of Reporting Trials (CONSORT) statement guidance. Approval was obtained from the medical ethics committee and all patients provided written informed consent. The study was registered under NCT ( Randomization Randomization was performed in the operating theatre at the Department of Abdominal Surgery, University Hospital Leuven. Following induction of general anaesthesia and before laparoscopy, an independent staff nurse randomly assigned patients to undergo either laparoscopic NOSE colectomy or conventional laparoscopic resection by sealed-envelope randomization. Ward nurses, patients and doctors on the ward were blinded to the type of surgical intervention. Surgical procedure All procedures were performed by the same colorectal surgeon. Patients were admitted the day before surgery to undergo evaluation of anorectal function and anal manometry. A phosphate enema was given on the day of surgery. Operating room set-up was the same for all procedures, and pain management was standardized as follows. On the day of surgery, an epidural catheter was inserted and operations were performed under general anaesthesia. The hospital s pain management service provided patient-controlled epidural analgesia (PCEA) catheters as part of an enhanced recovery protocol 3,4.A thoracic PCEA catheter was inserted between T8 and T12. Antibiotic prophylaxis was given intravenously at induction (2 g cefuroxime and 1 5 g metronidazole). The patient was placed in modified Lloyd Davies position on a mouldable beanbag to allow adequate Trendelenburg tilt. The peritoneal cavity was entered with a Veress needle in the left hypochondric region subcostally, and pneumoperitoneum was established to a pressure of 15 mmhg. Three 5-mm trocars were placed in the right and left flanks, and slightly right laterally above the umbilicus. A 12-mm trocar was placed in the right iliac fossa for stapling. A partial mesorectal excision was performed to clean the upper part of the rectum, allowing the rectal ampulla and reservoir function to be saved and leaving rectal capacity intact. In conventional laparoscopic sigmoid resection, the rectum was divided at the level of the promontory using a 60-mm endoscopic linear stapler. The specimen was retrieved through a small left iliac fossa incision of about 3 4 cm using a wound protector. The proximal part of the anastomosis was made by suturing the anvil in place with a purse-string of a monofilament suture. An end-to-end anastomosis was made using a circular stapler in a standard manner. The technical aspects of standard laparoscopic NOSE colectomy have been reported previously 5,6.Briefly,the sigmoid mesentery was divided with a vessel-sealing device. The devascularized specimen was isolated, and both the proximal sigmoid colon and proximal rectum were closed with a non-absorbable suture, determining the proximal and distal resection margins. A rectotomy was then performed to deliver the anvil from a circular stapler. The spike from the circular stapler contained a prefabricated hole and was connected to a monofilament suture. A colotomy was made at the level of the transition between descending colon and proximal sigmoid colon, and the anvil was introduced into the descending colon. The suture on the spike was used to place an antimesenteric stitch, and gentle traction on the suture retrieved the anvil. The spike was disconnected from the anvil and removed via the 12-mm trocar (Fig. 1). The colon was closed and divided with a 60-mm endoscopic linear stapler. The proximal part of the anastomosis was ready for use. The rectum was transected completely and the specimen was extracted transrectally in a specimen retrieval pouch (Fig. 2). The rectum was closed at the level of the promontory with a 60-mm endoscopic linear stapler, and the rim of proximal rectum was extracted through the 12-mm trocar. An end-to-end triple-stapled colorectal anastomosis was made using the circular stapler and an air leak test was performed routinely. In both procedures, no drain was placed and the nasogastric tube was removed at the end of the procedure. Follow-up Postoperative care was standardized in both groups. PCEA catheters were checked daily by the pain management service and removed on postoperative day 2. Postoperative analgesia was provided by continuous epidural infusion of per cent levobupivacaine and 1 mg/ml sufentanil, and supplemented by a patient-controlled bolus capability of 2 ml with a 20-min lock-out period. Patients and nursing staff were blinded to the type of intervention (conventional laparoscopic or laparoscopic NOSE surgery). Therefore, all patients received immediate postoperative dressing of the abdomen with non-transparent bandages until discharge. To eliminate bias from the study, the operating surgeon did not have any direct contact with patients after

3 632 A. M. Wolthuis, S. Fieuws, A. Van Den Bosch, A. de Buck van Overstraeten and A. D Hoore a Anvil insertion via proximal rectotomy b Anvil insertion into colon c Antimesenteric anvil retrieval d Disconnection of spike and anvil Fig. 1 Operative steps of laparoscopic natural-orifice specimen extraction colectomy: a anvil insertion into peritoneal cavity via proximal rectotomy; b anvil insertion into colon; c antimesenteric anvil retrieval; d disconnection of spike and anvil the operation, and surgeons and nursing staff, who were blinded to the surgical details, provided postoperative care. The primary outcome measure was postoperative analgesia requirements. Analgesia requirement was defined as the need for piritramide. An alternative definition for analgesia requirement was the use of tramadol and/or piritramide. Pain scores were assessed twice daily with a validated visual analogue scale (VAS) (0, no pain; 10, worst conceivable pain), rounded to the nearest whole number. All patients were prescribed standard oral postoperative analgesia, which included 1 g paracetamol four times daily, as required. After removal of the PCEA catheter, 100 mg tramadol twice daily was prescribed, as required. Piritramide (a morphine analogue) 20 mg could be administered intramuscularly to patients in either group in case of breakthrough pain, and patients could request piritramide at any point. A clinical trial assistant collected data on postoperative analgesia and pain during the first postoperative week. Secondary endpoints of the study were operative outcome, inflammatory response, anorectal function and cosmetic outcome. All complications were graded

4 Laparoscopic natural-orifice specimen extraction versus conventional laparoscopic colectomy 633 a Specimen in retrieval pouch b Transrectal extraction Fig. 2 Transrectal specimen extraction: a placement of specimen into specimen retrieval pouch; b transrectal extraction. Note: the pouch protects the rectum and anal canal according to Dindo et al. 7 Inflammatory response was determined by measuring C-reactive protein (CRP) levels on the day before surgery and daily after surgery during the hospital stay. Interleukin (IL) 6 concentration was measured on the day before surgery and on postoperative days 1 and 3. Anorectal function was evaluated 1 day before the operation and at 6 weeks and 3 months, using the Cleveland Clinic Incontinence Score (CCIS) 8 and anal manometry. Anal manometry basal and squeeze pressure recordings were performed in the left lateral position. Cosmetic outcome was evaluated at 6 weeks by means of a body image questionnaire, which consisted of a validated body image scale and a cosmetic scale 9. The body image scale contained five questions measuring patients perception of and satisfaction with their own body, and their attitudes towards their bodily appearance (minimum score, 5; maximum score, 20). The cosmetic scale consisted of three questions assessing patients satisfaction with the physical appearance of the scar (minimum score, 3; maximum score, 24). The total body image questionnaire score was calculated by summing the body image scale and the reverse score of the cosmetic scale. Hence, a lower score indicated greater overall cosmetic satisfaction 10. All patients were followed at a dedicated outpatient clinic, 1 week after hospital discharge, at 6 weeks, and at 3 months by the operating surgeon, a clinical nurse specialist to assess functional outcome, and a clinical trial assistant for data collection. Statistical analysis Based on a two-sided χ 2 test with α=5 per cent, 20 patients were needed per arm to have 80 per cent power in order to detect a difference in analgesia requirement of 50 per cent (conventional laparoscopic resection) versus a requirement of 10 per cent (laparoscopic NOSE colectomy). This sample-size calculation was carried out before the start of the study. The proportion of patients with analgesia requirements was compared on an intention-to-treat basis between the two groups using a two-sided Fisher s exact test, with α set at 5 per cent. Secondary outcome measures (analgesia dose, VAS, length of hospital stay, anorectal function, cosmesis) were compared between the groups with Mann Whitney U tests. The evolution of postoperative pain scores during the hospital stay and of the inflammatory response were compared using a linear model for longitudinal measurements, with an unstructured mean evolution and using a likelihood ratio test. P < was considered significant. P values for secondary endpoints were considered significant if less than (to avoid inflation of a type I error). All analyses were performed only after the end of the study using SAS version 9.2 for Windows (SAS Institute, Cary, North Carolina, USA). Results Between December 2009 and September 2013, a total of 43 patients were invited to participate in the study (Fig. 3). Three patients declined and had conventional laparoscopic colectomy. No patient withdrew consent or was lost to follow-up. Of the 40 remaining patients, 20 underwent laparoscopic NOSE colectomy and 20 had conventional laparoscopic colectomy (Table 1). One patient in the NOSE group required conversion to a conventional laparoscopic

5 634 A. M. Wolthuis, S. Fieuws, A. Van Den Bosch, A. de Buck van Overstraeten and A. D Hoore Assessed for eligibility n = 43 Enrolment Excluded (refused to participate) n = 3 Randomized n = 40 Allocation Allocated to laparoscopic NOSE colectomy n = 20 Received intervention n = 19 Conversion owing to inability to extract specimen transrectally n = 1 Allocated to conventional laparoscopic colectomy n = 20 Received intervention n = 20 Follow-up Lost to follow-up n = 0 Lost to follow-up n = 0 Analysis Analysed n = 20 Analysed n = 20 Fig. 3 CONSORT diagram for the trial. NOSE, natural-orifice specimen extraction Table 1 Baseline patient characteristics Laparoscopic NOSE colectomy (n = 20) Conventional laparoscopic colectomy (n = 20) Age (years)* 54 (31 72) 58 (40 73) Sex ratio (M : F) 5 : : 10 BMI (kg/m 2 )* 23 5 (18 29) 24 (20 29) ASA fitness grade I 5 6 II Indication Diverticulitis Tumour 5 5 *Values are median (range). NOSE, natural-orifice specimen extraction; ASA, American Society of Anesthesiologists; BMI, body mass index. approach because the specimen could not be extracted transrectally. Three PCEA catheters did not function properly in each group. Operative data and postoperative complications The median duration of surgery was significantly shorter in the conventional group and median blood loss was comparable in the two groups (Table 2). Fewer technical difficulties were observed in the conventional laparoscopy group (5 versus 8; P = 0 501). In the NOSE colectomy group, technical difficulties included difficult transrectal specimen extraction in four patients, restapling of the rectum in two, splenic flexure mobilization to gain sufficient bowel length in one, and conversion to specimen extraction via the left iliac fossa incision in one patient. In the conventional group, technical difficulties included restapling of the rectum in three patients, difficult anvil insertion owing to proximal diverticular disease in one, and positive air leak test requiring additional sutures in one patient. Median length of the extracted specimen was significantly longer in the NOSE group. Perioperative administration of intravenous fluids and the number of complications were similar in the two groups. In the NOSE colectomy group, complications included intraluminal bleeding from the anastomosis in two patients (grade 3a and 3b) and high fever in one patient (grade 2). In the conventional group, complications included urinary tract infection in one patient (grade 2), postepidural leakage requiring a blood patch in one (grade 3a) and anastomotic leakage requiring a defunctioning loop ileostomy in one patient (grade 3b). Length of hospital stay and readmission rate were similar in the two groups. Analgesia requirements and pain scores The postoperative piritramide requirement was higher in the conventional laparoscopic resection group (Table 3). A significantly greater number of patients in the conventional group required a combination of tramadol and piritramide after surgery. When the analysis was performed as treated, the postoperative piritramide need was higher in the conventional resection group. Both total PCEA dose and the need for paracetamol were higher in the conventional group.

6 Laparoscopic natural-orifice specimen extraction versus conventional laparoscopic colectomy 635 Table 2 Surgical and postoperative data Laparoscopic NOSE colectomy (n = 20) Conventional laparoscopic colectomy (n = 20) P Duration of surgery (min)* 90 (70 125) 75 (50 160) Conversion Blood loss (ml)* 10 (0 100) 0 (0 250) Technical difficulties Length of specimen (cm)* 25 (12 44) 18 (12 33) Lymph node harvest* 12 (7 14) 11 (7 27) Perioperative intravenous fluids (litres)* 1 5 ( ) 1 5 ( ) Procedural cost ( )* ( ) ( ) < Length of hospital stay (days)* 4 (2 8) 4 (3 17) Complications Major 2 2 Minor 1 1 Readmission within 30 days *Values are median (range). NOSE, natural-orifice specimen extraction. Mann Whitney U test, except Fisher s exact test. Table 3 Analgesia requirements Laparoscopic NOSE colectomy (n = 20) Conventional laparoscopic colectomy (n = 20) P Piritramide requirement No. of patients Dose (mg)* 1 0(4 5); 0 (0 20) 16 0(24 1); 7 5 (0 100) Piritramide requirement as treated No. of patients 1 of of Dose (mg)* 1 1(4 6); 0 (0 20) 15 6(23 8); 0 (0 100) Tramadol requirement (mg)* 10 0(44.7); 0 (0 200) 40 0(104 6); 0 (0 400) Combined piritramide + tramadol 2 13 < Paracetamol requirement (g)* 11 0(3 9); 11 (4 18) 17 0(1 2); 17 (15 19) < PCEA dose (ml)* 116(45); 93 (82 247) 221(72); 221 ( ) < *Values are mean(s.d.); median (range). NOSE, natural-orifice specimen extraction; PCEA, patient-controlled epidural analgesia. Mann Whitney U test, except Fisher s exact test. Postoperative pain scores were lower in the NOSE group (mean maximum VAS score 3 5 versus 2.1 in the conventional group) (Fig. 4). There was a significant difference in the evolution of pain scores between the groups. One week after hospital discharge, pain scores remained significantly higher in the conventional group (mean maximum VAS score 2 2 versus 0 3 in the NOSE group), with 15 of 20 patients still reporting pain requiring analgesia compared with one of 20 in the NOSE group (P < 0 001). Inflammatory response There was a significantly different postoperative evolution of CRP values in the two groups (Fig. 5). The serum CRP level was lower after conventional laparoscopic resection. A higher peak CRP concentration was observed in the NOSE colectomy group 2 days after surgery. A significantly higher median peak IL-6 concentration was observed in the NOSE group on postoperative day 1: 68 7 (i.q.r ; range ) pg/ml versus 12.8 ( ; ) pg/ml in the conventional group (P = 0 002). IL-6 levels had normalized in both groups by postoperative day 3: median 5 4 (i.q.r ; range ) and 4 6( ; ) pg/ml in the NOSE and conventional group respectively (P = 0.379). Anorectal function and Cleveland Clinic Incontinence Score Median CCIS values were similar in the two groups before surgery, and at 6 weeks and 3 months after surgery. No patients complained of severe anal dysfunction at 6 weeks or 3 months. Basal and maximum anal squeeze pressures remained comparable before surgery, and at 6 weeks and 3 months (Table 4). Body image and cosmesis There was no significant difference in either body image or cosmetic scores. Median body image score was similar in the two groups: 5 (range 5 9) for NOSE colectomy and 5 (5 9) for conventional laparoscopic resection

7 636 A. M. Wolthuis, S. Fieuws, A. Van Den Bosch, A. de Buck van Overstraeten and A. D Hoore Table 4 Cleveland Clinic Incontinence Scores and anal manometry recordings Laparoscopic NOSE colectomy Conventional laparoscopic colectomy P* CCIS Before surgery 0 9(1 9); 0 (0 6) 0 9(1 7); 0 (0 6) weeks after surgery 2 0(4 1); 0 (0 15) 1 9(4 1); 0 (0 14) months after surgery 0 2(0 5); 0 (0 2) 1 2(2 4); 0 (0 8) Basal pressure (mmhg) Before surgery 91(31); 86 (40 175) 80(23); 81 (38 111) weeks after surgery 79(25); 78 (35 139) 81(22); 83 (44 119) months after surgery 87(20); 81 (54 126) 84(21); 84 (43 126) Maximum squeeze pressure (mmhg) Before surgery 293(90); 255 ( ) 300(121); ( ) weeks after surgery 263(128); 220 ( ) 304(129); 270 ( ) months after surgery 279(145); 221 ( ) 335(179); 338 ( ) Values are mean(s.d.); median (range). NOSE, natural-orifice specimen extraction; CCIS, Cleveland Clinic Incontinence Score. *Mann Whitney U test. 10 Laparoscopic NOSE colectomy Conventional laparoscopic resection Laparoscopic NOSE colectomy Conventional laparoscopic resection VAS score CRP (mg/l) Time after surgery (days) 0 Preop Time after surgery (days) Fig. 4 Evolution of mean (99 per cent c.i.) pain scores in laparoscopic natural-orifice specimen extraction (NOSE) and conventional laparoscopic colectomy groups, determined on a visual analogue scale (VAS; 1 10) on days 1 7 after surgery. χ 2 = 27 1, 7 d.f., P < (likelihood ratio test) (P = 0 462). Median cosmetic score was 21 (14 24) and 18 (8 24) respectively (P = 0 042). Median body image questionnaire score was 26 (i.q.r ; range 20 30) for NOSE colectomy and 24 (21 26; 13 29) for conventional resection (P = 0 029). Discussion This prospective randomized study demonstrates that laparoscopic NOSE colectomy for left-sided colonic disease leads to a significantly lower analgesic requirement, lower pain scores, and a slightly better cosmetic outcome. Apart from standardized perioperative management, Fig. 5 Evolution of mean (99 per cent c.i.) C-reactive protein (CRP) levels in laparoscopic natural-orifice specimen extraction (NOSE) and conventional laparoscopic colectomy groups on days 1 5 after surgery. χ 2 = 26 7, 7 d.f., P < (likelihood ratio test) postoperative analgesia was standardized to minimize bias with regard to pain assessment. Control of postoperative pain is important, because intense postoperative pain is a risk factor for long-term adverse outcome 11. Laparoscopic NOSE colectomy avoids extraction-site laparotomy with subsequent impact on incisional pain. Reduction of postoperative pain and adequate pain control is important in reducing postoperative stress. This neurohumoral stress response consists of inflammatory cascades that, in case of activation, may have a negative influence on postoperative complications, recovery and length of hospital stay 12. Moreover, especially in the first postoperative week, incisional pain dominates over visceral or shoulder pain with regard to incidence and intensity 13.

8 Laparoscopic natural-orifice specimen extraction versus conventional laparoscopic colectomy 637 Apart from postoperative pain reduction, minimization of access trauma is a potential advantage of laparoscopic NOSE colectomy. Reduction of abdominal wall trauma may reduce abdominal wall morbidity, but this was not assessed here. There were more technical difficulties in the NOSE group, indicating that this is a more demanding surgical procedure. Although this study showed significantly lower pain scores and fewer analgesic requirements in the NOSE colectomy group, it did not lead to a shorter hospital stay. The study might have been underpowered to detect a difference, or the greater inflammatory response may have affected postoperative recovery negatively. Laparoscopic NOSE colectomy had significantly higher procedural costs and a longer duration of surgery, reflecting the technical challenges, but, interestingly, a longer specimen was extracted in the NOSE group, as reported in a previous study 5. Long-term outcomes, such as incisional hernias, will be assessed in the future. Acknowledgements The authors thank I. Terrasson, clinical trial assistant, for collecting the data. Disclosure: The authors declare no conflict of interest. References 1 Wolthuis AM, Van Geluwe B, Fieuws S, Penninckx F, D Hoore A. Laparoscopic sigmoid resection with transrectal specimen extraction: a systematic review. Colorectal Dis 2012; 14: Leung AL, Cheung HY, Fok BK, Chung CC, Li MK, Tang CN. Prospective randomized trial of hybrid NOTES colectomy versus conventional laparoscopic colectomy for left-sided colonic tumors. World J Surg 2013; 37: Fierens J, Wolthuis AM, Penninckx F, D Hoore A. Enhanced recovery after surgery (ERAS) protocol: prospective study of outcome in colorectal surgery. Acta Chir Belg 2012; 112: Wind J, Polle SW, Fung Kon Jin PH, Dejong CH, von Meyenfeldt MF, Ubbink DT et al.; Laparoscopy and/or Fast Track Multimodal Management Versus Standard Care (LAFA) Study Group; Enhanced Recovery after Surgery (ERAS) Group. Systematic review of enhanced recovery programmes in colonic surgery. Br J Surg 2006; 93: Wolthuis AM, Meuleman C, Tomassetti C, D Hooghe T, Fieuws S, Penninckx F et al. Laparoscopic sigmoid resection with transrectal specimen extraction: a novel technique for the treatment of bowel endometriosis. Hum Reprod 2011; 26: Wolthuis AM, Penninckx F, D Hoore A. Laparoscopic sigmoid resection with transrectal specimen extraction has a good short-term outcome. Surg Endosc 2011; 25: Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg 2004; 240: Jorge JM, Wexner SD. Etiology and management of fecal incontinence. Dis Colon Rectum 1993; 36: Dunker MS, Stiggelbout AM, van Hogezand RA, Ringers J, Griffioen G, Bemelman WA. Cosmesis and body image after laparoscopic-assisted and open ileocolic resection for Crohn s disease. Surg Endosc 1998; 12: Park SK, Olweny EO, Best SL, Tracy CR, Mir SA, Cadeddu JA. Patient-reported body image and cosmesis outcomes following kidney surgery: comparison of laparoendoscopic single-site, laparoscopic, and open surgery. Eur Urol 2011; 60: Peters ML, Sommer M, de Rijke JM, Kessels F, Heineman E, Patijn J et al. Somatic and psychologic predictors of long-term unfavorable outcome after surgical intervention. Ann Surg 2007; 245: Leung KL, Lai PB, Ho RL, Meng WC, Yiu RY, Lee JF et al. Systemic cytokine response after laparoscopic-assisted resection of rectosigmoid carcinoma: a prospective randomized trial. Ann Surg 2000; 231: Bisgaard T, Klarskov B, Rosenberg J, Kehlet H. Characteristics and prediction of early pain after laparoscopic cholecystectomy. Pain 2001; 90: