Expression of cyclin D1a and D1b as predictive factors for treatment response in colorectal cancer.

BACKGROUND: The aim of this study was to investigate the value of the cyclin D1 isoforms D1a and D1b as prognostic factors and their relevance as predictors of response to adjuvant chemotherapy with 5-fluorouracil and levamisole (5-FU/LEV) in colorectal cancer (CRC). METHODS: Protein expression of nuclear cyclin D1a and D1b was assessed by immunohistochemistry in 335 CRC patients treated with surgery alone or with adjuvant therapy using 5-FU/LEV. The prognostic and predictive value of these two molecular markers and clinicopathological factors were evaluated statistically in univariate and multivariate survival analyses. RESULTS: Neither cyclin D1a nor D1b showed any prognostic value in CRC or colon cancer patients. However, high cyclin D1a predicted benefit from adjuvant therapy measured in 5-year relapse-free survival (RFS) and CRC-specific survival (CSS) compared to surgery alone in colon cancer (P=0.012 and P=0.038, respectively) and especially in colon cancer stage III patients (P=0.005 and P=0.019, respectively) in univariate analyses. An interaction between treatment group and cyclin D1a could be shown for RFS (P=0.004) and CSS (P=0.025) in multivariate analysis. CONCLUSION: Our study identifies high cyclin D1a protein expression as a positive predictive factor for the benefit of adjuvant 5-FU/LEV treatment in colon cancer, particularly in stage III colon cancer.

Long-term function after ileal pouch-anal anastomosis - function does not deteriorate with time.

AIM: There are conflicting reports regarding long term function after ileal pouch-anal anastomosis (IPAA). The aim of the present prospective study was to investigate the influence of duration as an independent factor on long-term function results. METHOD: Between 1984 and 2007, 315 patients underwent IPAA and were followed by a standardised interview and endoscopy protocol. There were 1802 interviews. Two hundred and thirty-five patients had three or more visits and these data were analysed by Time-Series-Cross-Section multivariate regression analysis. The mean time follow up was 12 years and the mean interval between visits was 34.5 months. RESULTS: Mean frequency of defecation was 5.2 in the day and 0.55 at night. This did not change with time. Daytime and night incontinence occurred in 13% and 21%. There was no change in incontinence, urgency, soiling or perineal excoriation with time. After 24 years the cumulative incidence of pouchitis was 43.5%. Twenty patients had chronic pouchitis (6.3%). CONCLUSION: The interval from IPAA did not influence the long-term functional outcome.

Failed pelvic pouch substituted by continent ileostomy.

OBJECTIVE: The long-term failure rate of ileal pouch-anal anastomosis (IPAA) is 10-15%. When salvage surgery is unsuccessful, most surgeons prefer pouch excision with conventional ileostomy, thus sacrificing 40-50 cm of ileum. Conversion of a pelvic pouch to a continent ileostomy (CI, Kock pouch) is an alternative that preserves both the ileal surface and pouch properties. The aim of the study was to evaluate clinical outcome after the construction of a CI following a failed IPAA. METHOD: During 1984-2007, 317 patients were operated with IPAA at St Olavs Hospital and evaluated for failure, treatment and outcome. Seven patients with IPAA failure had CI. Four patients with IPAA failure referred from other hospitals underwent conversion to CI and are included in the final analysis. RESULTS: Seven patients had a CI constructed from the transposing pelvic pouch and four had the pelvic pouch removed and a new continent pouch constructed from the distal ileum. Median follow up after conversion to CI was 7 years (0-17 years). Two CI had to be removed due to fistulae. One patient needed a revision of the nipple valve due to pouch loosening. At the end of follow-up, 8 of the 11 patients were fully continent. One patient with Crohn's disease had minor leakage. CONCLUSION: In patients with pelvic pouch failure, the possibility of conversion to CI should be presented to the patient as an alternative to pouch excision and permanent ileostomy. The advantage is the continence and possibly a better body image. Construction of a CI on a new ileal segment may be considered, but the consequences of additional small bowel loss and risk of malnutrition if the Kock pouch fails should be appraised.

Long-term surgical load in patients with ileal pouch-anal anastomosis.

AIM: To evaluate surgical workload and complications in patients who had undergone restorative proctocolectomy, through long-term follow-up in one single institution. METHOD: From 1984 to 2006, 304 consecutive patients underwent Ileal Pouch-Anal Anastomosis (IPAA). There were 182 stapled and 122 hand-sewn anastomoses. A protective loop ileostomy was established in 256 patients (84%), whereas 48 patients (16%) were without a covering stoma. RESULTS: Twenty-nine patients (10%) suffered from early anastomotic leakage. A protective stoma did not prevent early anastomotic dehiscence (P = 0.11) or the number of pelvic abscesses (P = 0.09). Early complications required 20 laparotomies with creation of a diverting stoma in nine patients. There were 16 (6%) complications related to closure of the loop ileostomy. Sixty-six patients needed an additional re-operation related to the IPAA procedure. There were 20 removals of pouches and three permanent diverting stomas. The estimated removal rate at 20 years of a functioning pouch was 11% (CI +/- 6). Altogether 100 (33%) patients had one or more surgical procedures, excluding dilations of anastomotic strictures and closing of a loop ileostomy. These 100 patients underwent 187 surgical procedures. The estimated rate of a first re-operation due to complications was 52% (CI +/- 16) in 20 years. Hand-sewn anastomoses had similar complications and failure rates as stapled anastomoses. CONCLUSIONS: More than half of patients operated with restorative proctocolectomy will need surgical intervention within 20 years and the failure rate is more than 10%. The high risk of complications and failure inherent in the procedure should not be ignored.

Changes of gastric mucosal architecture during long-term omeprazole therapy: results of a randomized clinical trial.

BACKGROUND: The impact of long-term acid suppression on the gastric mucosa remains controversial. AIM: To report further observations on an established cohort of patients with gastro-oesophageal reflux disease, after 7 years of follow-up. METHODS: Of the original cohort randomized to either antireflux surgery or omeprazole, 117 and 98 patients remained in the medical and surgical arms, respectively. Gastric biopsies were taken at baseline and throughout the study. RESULTS: Fifty-three antireflux surgery and 39 omeprazole-treated patients had Helicobacter pylori infection at randomization. Eighty-three omeprazole-treated and 60 antireflux surgery patients remained H. pylori negative over the 7 years, and no change was observed in mucosal morphology except for a change in endocrine cell population (linear and diffuse hyperplasia, P = 0.03). During the 7-year study many patients, who were initially H. pylori infected, had the infection eradicated leaving only 13 omeprazole and 12 antireflux surgery patients still infected. In these patients, omeprazole induced a deterioration of the mucosal inflammation scores (P = 0.01) with a numerical increase of glandular atrophy. CONCLUSIONS: Long-term omeprazole therapy does not alter the exocrine oxyntic mucosal morphology in H. pylori-negative patients, but mucosal endocrine cells appear to be under proliferative stimulation; in H. pylori-positive patients there are changes in mucosal inflammation and atrophy.

Continued (5-year) followup of a randomized clinical study comparing antireflux surgery and omeprazole in gastroesophageal reflux disease.

BACKGROUND: The efficacy of antireflux surgery (ARS) and proton pump inhibitor therapy in the control of gastroesophageal reflux disease is well established. A direct comparison between these therapies is warranted to assess the benefits of respective therapies. STUDY DESIGN: There were 310 patients with erosive esophagitis enrolled in the trial. There were 155 patients randomized to continuous omeprazole therapy and 155 to open antireflux surgery, of whom 144 later had an operation. Because of various withdrawals during the study course, 122 patients originally having an antireflux operation completed the 5-year followup; the corresponding figure in the omeprazole group was 133. Symptoms, endoscopy, and quality-of-life questionnaires were used to document clinical outcomes. Treatment failure was defined to occur if at least one of the following criteria were fulfilled: Moderate or severe heartburn or acid regurgitation during the last 7 days before the respective visit; Esophagitis of at least grade 2; Moderate or severe dysphagia or odynophagia symptoms reported in combination with mild heartburn or regurgitation; If randomized to surgery and subsequently required omeprazole for more than 8 weeks to control symptoms, or having a reoperation; If randomized to omeprazole and considered by the responsible physician to require antireflux surgery to control symptoms; If randomized to omeprazole and the patient, for any reason, preferred antireflux surgery during the course of the study. Treatment failure was the primary outcomes variable. RESULTS: When the time to treatment failure was analyzed by use of the intention to treat approach, applying the life table analysis technique, a highly significant difference between the two strategies was revealed (p < 0.001), with more treatment failures in patients who originally were randomized to omeprazole treatment. The protocol also allowed dose adjustment in patients allocated to omeprazole therapy to either 40 or 60 mg daily in case of symptom recurrence. The curves subsequently describing the failure rates still remained separated in favor of surgery, although the difference did not reach statistical significance (p = 0.088). Quality of life assessment revealed values within normal ranges in both therapy arms during the 5 years. CONCLUSIONS: In this randomized multicenter trial with a 5-year followup, we found antireflux surgery to be more effective than omeprazole in controlling gastroesophageal reflux disease as measured by the treatment failure rates. But if the dose of omeprazole was adjusted in case of relapse, the two therapeutic strategies reached levels of efficacy that were not statistically different.

Long-term management of gastro-oesophageal reflux disease with omeprazole or open antireflux surgery: results of a prospective, randomized clinical trial. The Nordic GORD Study Group.

BACKGROUND AND AIM: The efficacy of antireflux surgery (ARS) and omeprazole treatment in the control of gastrooesophageal reflux disease (GORD) are well established. We have compared these two therapeutic options in a randomized, clinical trial. PATIENTS AND METHODS: Three hundred and ten patients with erosive oesophagitis were enrolled into the trial. After a run-in period when all patients had < or = 40 mg of omeprazole daily to heal the oesophagitis and relieve symptoms, 155 patients were randomized to continuous omeprazole therapy and 155 to open antireflux surgery, of whom 144 later had an operation. One hundred and thirty-nine and 129 in the omeprazole and antireflux surgery groups, respectively, completed the 3-year follow-up. Symptoms, 24-h pH monitoring and endoscopy were used to document the outcome. Quality of life was evaluated by the psychological general well-being (PGWB) index and the gastrointestinal symptom rating scale (GSRS). RESULTS: Analysis of time to treatment failure (defined as moderate to severe GORD symptoms for > or = 3 days during the last 7 days, oesophagitis or changed therapy) revealed a significant difference in favour of antireflux surgery (P = 0.0016). Seventeen patients originally submitted to antireflux surgery experienced symptom relapse alone, 14 had oesophagitis at endoscopy and another six had omeprazole for different reasons, leaving 97 patients in clinical remission after 3 years. The corresponding figures in the omeprazole arm were 50 relapses, 18 with oesophagitis, two had surgery, leaving 77 patients in remission. Allowing a dose adjustment in the case of relapse in those on omeprazole therapy to either 40 or 60 mg, the curves describing the failure rates were not significantly different from each other. Quality of life assessment showed a comparable outcome in the two study groups. CONCLUSION: In this randomized multicentre trial we found antireflux surgery to be very efficacious in controlling GORD, a level of control which could also be achieved by omeprazole provided that advantage was taken of the opportunity of adjusting the dose.

Laparoscopic antiperistaltic versus isoperistaltic gastrojejunostomy for palliation of gastric outlet obstruction in advanced cancer.

The purpose of the study was to compare the impact of the peristaltic orientation of laparoscopic gastrojejunal anastomoses (LGJ) in patients with malignant gastric outlet obstruction (GOO) on postoperative delayed-return gastric emptying (DRGE) rates. GOO was defined as complete holdup of contrast at barium meal and/or failure of gastroscope to pass beyond stricture. DRGE was defined as inability to eat regular diet by day 10. Thirty-four patients undergoing antiperistaltic LGJ were compared with 21 patients undergoing isoperistaltic LGJ at two institutions during the same period. Thirty-day mortality was 5.4%, and median survival was 6.2 months. Thirty-day morbidity was 20%, and conversion rate was 3.6%. DRGE rates were increased after isoperistaltic LGJ (0 vs. 3; P < 0.05), but patient groups were not well matched for type of primary cancer (P < 0.05). All patients with DRGE resumed food intake 12 to 16 days after surgery. There were 21 admissions before death, with a reoperation rate of 11.5% and a recurrent GOO rate of 3.8%. Although no conclusions could be drawn about whether the peristaltic orientation of the anastomosis had a bearing on DRGE rates, LGJ resulted in an overall 6% rate of DRGE.

Colorectal cancer emergencies.

From the variety of operative choices for colorectal cancer emergencies, it is difficult to select the best one for the individual patient, who is often old and frail. Appropriate handling of the emergency situation is essential. Treatment of the patient's malignant disease is secondary. The choice of surgical procedure in colorectal cancer emergencies must be based on sound clinical judgement and should be in keeping with the technical skill and experience of the individual surgeon. Surgical failures have major negative consequences not only for the immediate postoperative course, but also for long-term survival and quality of life of these patients.

Surgical procedures in colorectal cancer emergencies.

About one third of the patients with colorectal cancer presents with large bowel obstruction, perforation or life threatening bleeding. In large bowel obstruction there is a trend towards primary resection and immediate anastomosis, also in cancer of the left colon. Among the techniques used are orthograde irrigation and primary resection with colo-colonic anastomosis, and in selected cases subtotal colectomy with ileosigmoid or ileorectal anastomosis. For sigmoid neoplasms causing obstruction immediate resection and end colostomy is recommended. In perforation at the tumour site, primary resection and immediate anastomosis may be justifiable if the peritonitis is localized. If diffuse peritonitis is present, primary resection with end colostomy seems to be the best choice. Although primary resection with or without immediate anastomosis has its merits, staged resection still remains a good and safe alternative in many cases.

Colonic reservoirs.

During the last decades several types of surgical techniques have been utilized in order to provide the patient with a continent colostomy using the colon as a reservoir. None of the methods have gained wide acceptance and continence is usually dependent upon successful irrigation. By constructing a cecal reservoir with an intussuscepted nipple valve, using the same principle as for the continent ileostomy, a colostomy with perfect continence for both gas and feces can be created. Although improving life quality significantly when successful, the method is hampered by a high rate of complications and malfunction. So far none of the methods introduced offer any great advantage to conventional sigmoidostomy with irrigation. There is, however, evidence that the functional results after coloanal anastomosis may be improved by constructing a pouch-anal anastomosis. The clinical significance of this technical modification is not yet fully evaluated.

Surgical load and long-term outcome for patients with Kock continent ileostomy.

OBJECTIVE: The aim of the study was to evaluate the results of Kock continent ileostomy (CI) during the same period when ileal pouch-anal anastomosis was the preferred operation for patients with ulcerative colitis (UC) or familial adenomatous polyposis (FAP). METHOD: During the period 1983-2002, 50 patients underwent CI. The surgical technique was unchanged during the period. Follow-up included all patients. Forty-eight patients had UC, two of these had the diagnosis later changed to Crohn's disease and two had FAP. RESULTS: Twenty-two patients had 38 reoperations, four (8%) of whom had the pouch removed. The main causes for reoperation included leakage and difficulty in intubation due to sliding of the nipple valve (42%), fistula formation (29%) and stenosis (21%). Seventeen (45%) underwent a revision of the nipple valve and the pouch and nine (24%) a local procedure. The reoperation rate was higher among patients having a conventional ileostomy converted to CI than among those having CI. As a primary procedure (P = 0.016). The risk of a second reoperation was higher for those reoperated within the first year after having a CI, than for those reoperated later (P = 0.007). CONCLUSIONS: The reoperation rate of patients with CI is high but the removal rate of the pouch is low and is not associated with a high rate of revision. CI is a good alternative to conventional ileostomy in patients not suitable for restorative proctocolectomy or where this procedure has failed.

Seven-year follow-up of a randomized clinical trial comparing proton-pump inhibition with surgical therapy for reflux oesophagitis.

BACKGROUND: This randomized clinical trial compared long-term outcome after antireflux surgery with acid inhibition therapy in the treatment of chronic gastro-oesophageal reflux disease (GORD). METHODS: Patients with chronic GORD and oesophagitis verified at endoscopy were allocated to treatment with omeprazole (154 patients) or antireflux surgery (144). After 7 years of follow-up, 119 patients in the omeprazole arm and 99 who had antireflux surgery were available for evaluation. The primary outcome variable was the cumulative proportion of patients in whom treatment failed. Secondary objectives were evaluation of the treatment failure rate after dose adjustment of omeprazole, safety, and the frequency and severity of post-fundoplication complaints. RESULTS: The proportion of patients in whom treatment did not fail during the 7 years was significantly higher in the surgical than in the medical group (66.7 versus 46.7 per cent respectively; P=0.002). A smaller difference remained after dose adjustment in the omeprazole group (P=0.045). More patients in the surgical group complained of symptoms such as dysphagia, inability to belch or vomit, and rectal flatulence. These complaints were fairly stable throughout the study interval. The mean daily dose of omeprazole was 22.8, 24.1, 24.3 and 24.3 mg at 1, 3, 5 and 7 years respectively. CONCLUSION: Chronic GORD can be treated effectively by either antireflux surgery or omeprazole therapy. After 7 years, surgery was more effective in controlling overall disease symptoms, but specific post-fundoplication complaints remained a problem. There appeared to be no dose escalation of omeprazole with time.

Rectal cancer treatment of the elderly.

OBJECTIVE: Life expectancy and incidence of rectal cancer have been increasing. The purpose of this study was to evaluate rectal cancer treatment among very old patients. METHODS: This prospective national cohort study includes all 4875 rectal cancer patients in Norway aged over 65 years treated between November 1993 and December 2001. Patients aged 65-74, 75-79, 80-84 and over 85 years were compared for patient-, tumour- and treatment-characteristics and relative survival. Two thousand eight hundred and forty patients treated for cure with major surgery and TME technique were further evaluated for postoperative mortality, five-year local recurrence, distant metastasis and disease-free survival. RESULTS: There were more palliative surgery and local procedures and less surgery for cure (47%vs 77%, P < 0.001) for patients over 85 years compared to younger patients. Five-year relative survival was 36% for patients aged over 85 years compared to 49% for patients 80-84 years and 60% for patients 65-74 years. Among patients treated for cure with major surgery the rate of anterior resection decreased by age (67%vs 46%, P < 0.001). Postoperative mortality increased from 3% to 8% (P < 0.001). There were no significant differences in the rates of five-year local recurrence, distant metastasis or relative survival. CONCLUSION: Although a slight increase in postoperative mortality, major rectal cancer surgery can be performed in very old patients. These patients had similar rates of local recurrence, distant metastasis and relative survival as younger patients.

Effect of hospital caseload on long-term outcome after standardization of rectal cancer surgery at a national level.

BACKGROUND: The purpose of this prospective study was to examine the influence of hospital caseload on long-term outcome following standardization of rectal cancer surgery at a national level. METHODS: Data relating to all 3388 Norwegian patients with rectal cancer treated for cure between November 1993 and December 1999 were recorded in a national database. Treating hospitals were divided into four groups according to their annual caseload: hospitals in group 1 (n = 4) carried out 30 or more procedures, those in group 2 (n = 6) performed 20-29 procedures, group 3 (n = 16) 10-19 procedures and group 4 (n = 28) fewer than ten procedures. RESULTS: The 5-year local recurrence rates were 9.2, 14.7, 12.5 and 17.5 per cent (P = 0.003) and 5-year overall survival rates were 64.4, 64.0, 60.8 and 57.8 per cent (P = 0.105) respectively in the four hospital caseload groups. An annual hospital caseload of less than ten procedures increased the risk of local recurrence compared with that in hospitals where 30 or more procedures were performed each year (hazard ratio 1.9 (95 per cent confidence interval (c.i.) 1.3 to 2.7); P < 0.001). Overall survival was lower for patients treated at hospitals with an annual caseload of less than ten versus hospitals with 30 or more (hazard ratio 1.2 (95 per cent c.i. 1.0 to 1.5); P = 0.023). CONCLUSION: The rate of local recurrence was higher for hospitals with a low annual caseload of less than ten procedures than for hospitals with a high treatment volume of 30 or more. Patients treated in small hospitals also had a shorter long-term survival than those treated in large hospitals.

Postoperative morbidity and recurrence after local excision of rectal adenomas and rectal cancer by transanal endoscopic microsurgery.

OBJECTIVE: Tumours in the middle and upper part of the rectum are not easy accessible to local excision. Transanal endoscopic microsurgery (TEM) has been recommended for excision of sessile adenomas in the middle and upper part of the rectum, and for small cancers in patients not fit for major surgery. The purpose of this study was to evaluate postoperative morbidity and local recurrence after TEM. MATERIAL AND METHODS: Seventy-nine patients were treated by TEM in the period 1994-2001. The median age was 74 years. The indications for TEM were rectal adenoma in 72 patients and rectal cancer in 7 patients. The tumours were located within 18 cm from the dentate line, median 10 cm. There were performed 69 transmural and 10 mucosal excisions. Mean follow up was 24 months (range 1-95 months). Twenty (25%) patients died during the follow up period, two because of metastases and 18 of other causes. RESULTS: Seven patients had complications. Two (2.5%) patients had peroperative perforation in the intra-abdominal part of the rectum treated by laparotomy. Five (6%) patients had postoperative cardiopulmonal or surgical complications. Eight patients with benign pre-operative histopathological examination had cancer. The local recurrence rate (13%) was similar for adenomas and for carcinomas. CONCLUSION: TEM is a safe technique well tolerated also by high-risk patients, and should be the preferred method in patients with benign tumours in the middle and upper part of the rectum, and in selected cases of early rectal cancer. Benign pre-operative histology does not preclude malignancy and some patients may need further treatment for unexpected malignancy.

Laparoscopic antireflux surgery; the merits and problems.

The development of laparoscopic techniques has enhanced interest in surgical treatment of gastro-oesophageal reflux disease. The goal of laparoscopic surgery in this context is to achieve the same results as in open surgery with fewer complications, shortened hospital stay and reduced sick leave. Several surgical procedures, based on surgical rearrangement of the oesophageal gastric junction or placement of prosthesis, are available. Most of these procedures are applicable in laparoscopic surgery. Surgical treatment of gastro-oesophageal reflux is highly effective although postoperative gas bloat syndrome, dysphagia and recurrence may occur in a small number of patients. In published series short-term results of laparoscopic antireflux surgery have been excellent. The benefits of minimal invasive surgery, such as less painful postoperative course, shortened hospital stay and rapid recovery have been confirmed. Because of the enthusiasm for laparoscopic technique, surgeons not familiar with the surgical treatment of gastro-oesophageal reflux may be tempted to embark on this procedure. This type of surgery is, however, technically demanding and should be performed only by surgeons with significant experience with both laparoscopic surgery in general and open antireflux surgery. A sufficiently long learning period is mandatory if serious complications are to be avoided. Taking into account these premises, laparoscopic antireflux surgery is safe and represents a viable alternative to conventional antireflux surgery.