John W. Lumley

Effect of Laparoscopic-Assisted Resection vs Open Resection on Pathological Outcomes in Rectal Cancer: The ALaCaRT Randomized Clinical Trial

IMPORTANCE Laparoscopic procedures are generally thought to have better outcomes than open procedures. Because of anatomical constraints, laparoscopic rectal resection may not be better because of limitations in performing an adequate cancer resection. OBJECTIVE To determine whether laparoscopic resection is noninferior to open rectal cancer resection for adequacy of cancer clearance. DESIGN, SETTING, AND PARTICIPANTS Randomized, noninferiority, phase 3 trial (Australasian Laparoscopic Cancer of the Rectum; ALaCaRT) conducted between March 2010 and November 2014. Twenty-six accredited surgeons from 24 sites in Australia and New Zealand randomized 475 patients with T1-T3 rectal adenocarcinoma less than 15 cm from the anal verge. INTERVENTIONS Open laparotomy and rectal resection (n = 237) or laparoscopic rectal resection (n = 238). MAIN OUTCOMES AND MEASURES The primary end point was a composite of oncological factors indicating an adequate surgical resection, with a noninferiority boundary of Δ = -8%. Successful resection was defined as meeting all the following criteria: (1) complete total mesorectal excision, (2) a clear circumferential margin (≥1 mm), and (3) a clear distal resection margin (≥1 mm). Pathologists used standardized reporting and were blinded to the method of surgery. RESULTS A successful resection was achieved in 194 patients (82%) in the laparoscopic surgery group and 208 patients (89%) in the open surgery group (risk difference of -7.0% [95% CI, -12.4% to ∞]; P = .38 for noninferiority). The circumferential resection margin was clear in 222 patients (93%) in the laparoscopic surgery group and in 228 patients (97%) in the open surgery group (risk difference of -3.7% [95% CI, -7.6% to 0.1%]; P = .06), the distal margin was clear in 236 patients (99%) in the laparoscopic surgery group and in 234 patients (99%) in the open surgery group (risk difference of -0.4% [95% CI, -1.8% to 1.0%]; P = .67), and total mesorectal excision was complete in 206 patients (87%) in the laparoscopic surgery group and 216 patients (92%) in the open surgery group (risk difference of -5.4% [95% CI, -10.9% to 0.2%]; P = .06). The conversion rate from laparoscopic to open surgery was 9%. CONCLUSIONS AND RELEVANCE Among patients with T1-T3 rectal tumors, noninferiority of laparoscopic surgery compared with open surgery for successful resection was not established. Although the overall quality of surgery was high, these findings do not provide sufficient evidence for the routine use of laparoscopic surgery. Longer follow-up of recurrence and survival is currently being acquired. TRIAL REGISTRATION anzctr.org Identifier: ACTRN12609000663257.

Laparoscopic-assisted colorectal surgery

PURPOSE: To audit the development and outcomes of laparoscopic colorectal surgery at the Royal Brisbane Hospital. METHODS: Since July 1991, laparoscopic-assisted colectomy for benign and malignant colorectal disease has been performed on more than 300 patients at the Royal Brisbane Hospital. This paper summarizes the outcome for the first 240 patients who underwent a laparoscopic colorectal procedure. All laparoscopic data were collected prospectively, and for selected studies, data were compared with open surgical controls. RESULTS: Nineteen patients required open conversion (7.9 percent). There was a significant decrease in wound infection rates in patients having a laparoscopic-assisted colectomy (3.6 percent) compared with historical controls (7.9 percent) (P<0.05; chisquared). There were five anastomotic leaks, five laparotomies for postoperative adhesive obstruction, and four perioperative deaths. A total of 103 patients had a procedure for colorectal cancer. Of the 79 potentially curative procedures, there have been 5 (6.3 percent) recurrences to date. CONCLUSION: The overall morbidity and mortality in this series seem to be acceptable compared with that of open procedures.

laparoscopic Colorectal Surgery for Cancer : intermediate to Long-term Outcomes

AbstractPURPOSE: Since 1991, a laparoscopic-assisted resection has been used at the Royal Brisbane Hospital selectively for patients with colorectal cancer. This article audits the intermediate to long-term postoperative complications and cancer follow-up data. METHODS: All patients undergoing a laparoscopic resection for cancer were prospectively followed up with regard to long-term outcomes. RESULTS: One hundred eighty-one patients have been studied. One hundred fifty-four patients had potentially curative procedures performed in the study period. Median follow up was 71 (range, 7–108) months. The overall recurrence rate in this group was 6 percent (21 recurrences). There was one port site recurrence after a potentially curative procedure (0.6 percent) and one port site recurrence after a palliative resection. Perioperative mortality was 1 percent (2 patients). Only six patients suffered an adhesive small-bowel obstruction postoperatively. There was one incisional hernia. Unadjusted five-year median survival data for Australian Clinico-pathological Staging A was 91 percent (3.5 percent recurrence); for Australian Clinico-pathological Staging B, 83 percent (15 percent recurrence); and for Australian Clinico-pathological Staging C, 74 percent (26 percent recurrence). CONCLUSION: In selected patients a laparoscopic resection for colorectal cancer produces acceptable intermediate to long-term oncologic outcomes and a low long-term complication rate.

Laparoscopically assisted anterior resection for diverticular disease: follow-up of 100 consecutive patients.

PURPOSE The objectives of this study were to refine the technique of laparoscopically assisted anterior resection (LAR) for diverticular disease and to analyze the morbidity and mortality rates, and longer term follow-up of the first 100 consecutive patients. METHODS Data were collected prospectively, and follow-up was performed by an independent assessor using a standardized questionnaire. RESULTS The median duration of surgery was 180 minutes, the median time for passage of flatus was 2 days after surgery, and the median length of hospital stay was 4 days. Overall, the morbidity rate was 21%, and the wound infection rate was 5%. There were no deaths. Eight patients underwent open laparotomy. The rate of complications was significantly greater in the latter group of patients (75%) than in those who underwent laparoscopy (16%, p = 0.002). The comparison between the first 20 cases and the last 20 patients revealed a significantly shorter duration of surgery (median 225 min. vs. 150 min.; p < 0.0001) and decreased length of stay (6 days vs. 4 days, p < 0.0001). Apart from a nonsignificant increase in the length of surgery, there were no differences in other study parameters when comparisons were made between those patients who underwent LAR for complicated diverticular disease and those patients who underwent uncomplicated diverticular disease. FOLLOW-UP Ninety patients were available for follow-up at a median time of 37 months. Ninety-three percent of the patients reported that the surgery had improved their symptoms. No patient required hospitalization, and no one was treated with antibiotics for recurrent symptoms. CONCLUSION Laparoscopically assisted anterior resection for diverticular disease has acceptable morbidity and mortality rates and a median postoperative hospital stay of only 4 days. Follow-up investigations revealed no recurrence of diverticulitis, and patients reported satisfaction regarding cosmetic and functional results.

Laparoscopic resection for diverticular disease: follow-up of 500 consecutive patients.

Objective:To examine morbidity, mortality, conversion rates, and disease recurrence after laparoscopic resection of complicated and uncomplicated diverticular disease in a single center. Summary Background Data:In contrast to colorectal cancer, there are few large studies of laparoscopic or open resection for diverticular disease. Methods:This study represents a retrospective analysis of a prospectively collected database of all laparoscopic resections for uncomplicated and complicated diverticulitis from a single center. Results:Five hundred patients (305 female) were identified (median age 58; range, 26–89). Recurrent diverticulitis was the most common indication for surgery (77%), followed by perforation (10%) and fistulation (9%). Median operating time was 120 minutes (range, 45–285) and median length of hospital stay was 4 (2–33) days. The splenic flexure was routinely mobilized. There was 1 (0.2%) 30-day and in-hospital death and 55 (11%) patients had major morbidity after the procedure. Conversion to an open operation was performed in 14 (2.8%) cases. Dense adhesions were the most common cause for conversion (6 patients). Among patients with complicated diverticulitis, the conversion rate was 5.3%, whereas for those with uncomplicated disease, it was 2.1% (P = ns). Operating time and length of hospital stay do not differ significantly between patients with complicated and uncomplicated diverticulitis. The conversion rate has come down from 8% for the first 100 cases to 1.5% for the last 400 cases (P = 0.002). To our knowledge, there have been no cases of recurrent diverticulitis. Conclusions:Laparoscopic resection even in complicated cases of diverticulitis is safe and effective. It can be achieved with short operating times and length of stay in conjunction with very low rates of morbidity and mortality. Adherence to surgical principles including routine mobilization of the splenic flexure and anastomosis onto the rectum may explain the absence of disease recurrence in our experience.

Laparoscopic-assisted resection-rectopexy for rectal prolapse: Early and medium follow-up

PURPOSE: Objectives of this study were to describe the technique of laparoscopic-assisted resection rectopexy and audit the clinical outcomes, including review of functional results. METHODS: Data were prospectively collected for duration of operation, time to passage of flatus and feces postoperatively, hospital stay, morbidity, and mortality. Follow-up was performed by an independent assessor using a standardized questionnaire. Patients were also assessed by clinical review or telephone interview. RESULTS: During a four-year period, 34 patients underwent laparoscopic repair for rectal prolapse, of which 30 patients underwent laparoscopic-assisted resection rectopexy. Median duration of the operations was 185 minutes, median time for passage of flatus was two days postoperatively, and median length of hospital stay was five days. Morbidity was 13 percent and mortality rate was 3 percent. Comparison between the first ten patients who underwent laparoscopic-assisted resection rectopexy and the last ten revealed a significant reduction in both median duration of operating time (224vs. 163 minutes;P<0.005) and length of stay (6vs. 4 days;P<0.015). Follow-up study conducted at a median time of 18 months revealed that most patients (92 percent) felt that the operation had improved their symptoms, that incontinence was improved in 14 of 20 patients with impaired continence (70 percent), and that constipation was improved in 64 percent. Symptoms of incomplete emptying and the need to strain at stool were both improved in 62 and 59 percent of patients, respectively. No full-thickness recurrences have occurred, but two patients have had mucosal prolapse detected (7 percent) and treated. CONCLUSION: Laparoscopic-assisted resection rectopexy is feasible and safe, with acceptable recurrence rates and functional results compared with the open procedure in the surgical literature. There is rapid return of intestinal function associated with an early discharge from hospital.

Laparoscopically-Assisted Resection Rectopexy for Rectal Prolapse: Ten Years’ Experience

PURPOSEThis study has been undertaken to audit a single-center experience with laparoscopically-assisted resection rectopexy for full-thickness rectal prolapse. The clinical outcomes and long-term results were evaluated.METHODSThe data were prospectively collected for the duration of the operation, time to passage of flatus postoperatively, hospital stay, morbidity, and mortality. For follow-up, patients received a questionnaire or were contacted. The data were divided into quartiles over the study period, and the differences in operating time and length of hospital stay were tested using the Kruskal-Wallis test.RESULTSBetween March 1992 and October 2003, a total of 117 patients underwent laparoscopic resection rectopexy for rectal prolapse. The median operating time during the first quartile (representing the early experience) was 180 minutes compared with 110 minutes for the fourth quartile (Kruskal-Wallis test for operating time = 35.523, 3 df, P < 0.0001). Overall morbidity was 9 percent (ten patients), with one death (<1 percent). One patient had a ureteric injury requiring conversion. One minor anastomotic leak occurred, necessitating laparoscopic evacuation of a pelvic abscess. Altogether, 77 patients were available for follow-up. The median follow-up was 62 months. Eighty percent of the patients reported alleviation of their symptoms after the operation. Sixty-nine percent of the constipated patients experienced an improvement in bowel frequency. No patient had new or worsening symptoms of constipation after surgery. Two (2.5 percent) patients had full-thickness rectal prolapse recurrence. Mucosal prolapse recurred in 14 (18 percent) patients. Anastomotic dilation was performed for stricture in five (4 percent) patients.CONCLUSIONSLaparoscopically-assisted resection rectopexy for rectal prolapse provides a favorable functional outcome and low recurrence rate. Shorter operating time is achieved with experience. The minimally invasive technique benefits should be considered when offering rectal prolapse patients a transabdominal approach for repair, and emphasis should now be on advanced training in the laparoscopic approach.

Preservation of sexual and bladder function after laparoscopic rectal surgery

Background  There have recently been reports of higher levels of bladder and sexual dysfunction in men after laparoscopic rectal surgery when compared with those undergoing open surgery. This has led some surgeons to question the role of the laparoscopic approach to rectal surgery.

Cellular Settings Mediating Src Substrate Switching between Focal Adhesion Kinase Tyrosine 861 and CUB-domain-containing protein 1 (CDCP1) Tyrosine 734

Background: Focal adhesion kinase (FAK) and CUB-domain-containing protein 1 (CDCP1) are Src family kinase (SFK) substrates. Results: SFK switching between FAK-Tyr-861 and CDCP1-Tyr-734 is induced by increased CDCP1 expression and changes in cell attachment. Conclusion: SFK switching between FAK and CDCP1 may be relevant to malignant transformation. Significance: Targeting of this switch may be a rational approach to treat diseases such as cancer. Reciprocal interactions between Src family kinases (SFKs) and focal adhesion kinase (FAK) are critical during changes in cell attachment. Recently it has been recognized that another SFK substrate, CUB-domain-containing protein 1 (CDCP1), is differentially phosphorylated during these events. However, the molecular processes underlying SFK-mediated phosphorylation of CDCP1 are poorly understood. Here we identify a novel mechanism in which FAK tyrosine 861 and CDCP1-Tyr-734 compete as SFK substrates and demonstrate cellular settings in which SFKs switch between these sites. Our results show that stable CDCP1 expression induces robust SFK-mediated phosphorylation of CDCP1-Tyr-734 with concomitant loss of p-FAK-Tyr-861 in adherent HeLa cells. SFK substrate switching in these cells is dependent on the level of expression of CDCP1 and is also dependent on CDCP1-Tyr-734 but is independent of CDCP1-Tyr-743 and -Tyr-762. In HeLa CDCP1 cells, engagement of SFKs with CDCP1 is accompanied by an increase in phosphorylation of Src-Tyr-416 and a change in cell morphology to a fibroblastic appearance dependent on CDCP1-Tyr-734. SFK switching between FAK-Tyr-861 and CDCP1-Tyr-734 also occurs during changes in adhesion of colorectal cancer cell lines endogenously expressing these two proteins. Consistently, increased p-FAK-Tyr-861 levels and a more epithelial morphology are seen in colon cancer SW480 cells silenced for CDCP1. Unlike protein kinase Cδ, FAK does not appear to form a trimeric complex with Src and CDCP1. These data demonstrate novel aspects of the dynamics of SFK-mediated cell signaling that may be relevant during cancer progression.

The cell surface glycoprotein CUB domain containing protein 1 (CDCP1) contributes to Epidermal Growth Factor Receptor-mediated cell migration

Background: Epidermal growth factor (EGF) activates EGF receptor (EGFR) to promote cell migration and cancer. Results: EGF/EGFR up-regulates the cell surface glycoprotein CDCP1, and blockade of CDCP1 reduces EGF/EGFR-induced migration of ovarian cancer cells lines. CDCP1 is expressed by ovarian tumors. Conclusion: CDCP1 contributes to EGF/EGFR-induced cell migration. Significance: Targeting of CDCP1 may be a rational approach to inhibit cancers mediated by EGFR. Epidermal growth factor (EGF) activation of the EGF receptor (EGFR) is an important mediator of cell migration, and aberrant signaling via this system promotes a number of malignancies including ovarian cancer. We have identified the cell surface glycoprotein CDCP1 as a key regulator of EGF/EGFR-induced cell migration. We show that signaling via EGF/EGFR induces migration of ovarian cancer Caov3 and OVCA420 cells with concomitant up-regulation of CDCP1 mRNA and protein. Consistent with a role in cell migration CDCP1 relocates from cell-cell junctions to punctate structures on filopodia after activation of EGFR. Significantly, disruption of CDCP1 either by silencing or the use of a function blocking antibody efficiently reduces EGF/EGFR-induced cell migration of Caov3 and OVCA420 cells. We also show that up-regulation of CDCP1 is inhibited by pharmacological agents blocking ERK but not Src signaling, indicating that the RAS/RAF/MEK/ERK pathway is required downstream of EGF/EGFR to induce increased expression of CDCP1. Our immunohistochemical analysis of benign, primary, and metastatic serous epithelial ovarian tumors demonstrates that CDCP1 is expressed during progression of this cancer. These data highlight a novel role for CDCP1 in EGF/EGFR-induced cell migration and indicate that targeting of CDCP1 may be a rational approach to inhibit progression of cancers driven by EGFR signaling including those resistant to anti-EGFR drugs because of activating mutations in the RAS/RAF/MEK/ERK pathway.