Functional outcome and quality of life after restorative proctocolectomy and ileo-anal pouch anastomosis.

OBJECTIVE: Reconstructive proctocolectomy with ileal pouch-anal anastomosis (IPAA) is the surgical treatment of ulcerative colitis (UC) and familial adenomatous polyposis (FAP). The aim of our study was to evaluate the functional results of this procedure and to assess its impact upon patient quality of life (QoL). METHODS: We evaluated QoL and functional results in patients who had undergone IPAA using two self-rating questionnaires: 1) Medical Outcome 36 item Health Survey (SF-36); and 2) a specific questionnaire evaluating various aspects of anorectal and urogenital function. RESULTS: 107 patients (median age 38 [range 17-69] years) underwent reconstructive proctocolectomy with IPAA between 1981 and 2002. Median duration of follow-up was 83 (range 4-230) months. 66 patients (61%) answered both questionnaires. Two thirds of patients have more than five bowel movements per day and one bowel movement at night. Whilst true faecal incontinence is exceptional, episodes of soiling are reported by 25% of patients. Regarding QoL in this population, the two scores of the SF-36, which summarise physical and mental health status (Physical Component Summary and Mental Component Summary) were 54.6 and 45.8, respectively (both are 50 in the general population). CONCLUSION: Our data indicate that, as measured with SF-36 questionnaire, QoL after IPAA is close to normal. However, good quality of life is not a surrogate for good functional results. Despite excellent control of continence during the day, IPAA is often associated with night time bowel movements and soiling.

Preoperative hyperfractionated radiotherapy for locally advanced rectal cancers: a phase I-II trial.

PURPOSE: To assess the toxicity, pathologic response rates, type of surgery, and oncologic results in a prospective Phase I-II trial using pure hyperfractionated radiotherapy (RT) preoperatively in locally advanced rectal cancer. METHODS AND MATERIALS: Between September 1997 and April 2000, 50 patients with T3-T4 or N1 rectal cancers were treated preoperatively with 50 Gy (45 Gy to the pelvis and a 5-Gy tumor boost) in 40 fractions of 1.25 Gy during 4 weeks. The pretreatment tumor stage as determined by CT and endorectal ultrasonography (80% of patients) included 1 Stage T2 (2%), 45 T3 (90%), and 4 T4 (8%). Nodal involvement (N1) was documented in 26 patients (52%). Surgery was performed at a median interval of 45 days (range 26-114 days) after RT completion. Seventeen patients who presented with pT4 or pN1 and/or pM1 received 5-fluorouracil-based chemotherapy postoperatively. RESULTS: All patients completed the RT schedule as planned. Severe acute toxicities included two Grade 3 skin reactions (4%) that did not require a break. The other acute toxicities were Grade 2 or less (skin, diarrhea, urinary, rectal tenesmus, and fatigue). A complete pathologic response was observed in 7 patients (14%), and microscopic residual cancer was found in 10 (20%). Of the 20 patients presenting with tumor located < or = 6 cm from the anal verge, sphincter-saving surgery was performed in 14 (70%). At 3 years, the actuarial locoregional control rate was 90.5%, and the disease-free survival rate was 74.6%. At a median follow-up of 32 months, 4 patients (8%) presented with severe late complications (Grade 3-4) that might have been RT related (one rectovaginal fistula, two chronic perineal fistulas, and one bilateral ureteral stenosis). CONCLUSION: In locally advanced rectal cancer, preoperative hyperfractionated RT to a total dose of 50 Gy is feasible, with acceptable acute and late toxicity and an objective downstaging effect. In view of these results, this schedule might be used as a basis for additional investigation regarding RT dose escalation or the addition of concomitant chemotherapy.

Peroxisome proliferator-activated receptors (PPARs) and associated transcription factors in colon cancer: reduced expression of PPARgamma-coactivator 1 (PGC-1).

Peroxisome proliferator-activated receptors (PPARs) alpha,beta/delta and gamma are fatty acid sensitive transcription factors that have been implicated in colorectal cancer. To better understand their role, we studied the expression levels of all PPAR-isoforms and transcriptional partners such as the retinoid X receptor alpha (RXRalpha) and PPARgamma-coactivator-1 (PGC-1) by means of real-time PCR in 17 patients with colon cancer. While a heterogeneous pattern was observed for the expression level of the PPAR-isoforms alpha,beta/delta and gamma, the coactivator PGC-1 was significantly decreased in 15 of 17 tumors. Taken together our data suggest that the transcriptional activity of PPARgamma may not only be decreased by mutation but also by downregulation of the coactivator PGC-1 of PPARgamma.

Does mechanical bowel preparation have a role in preventing postoperative complications in elective colorectal surgery?

BACKGROUND: mechanical bowel preparation (MBP) consists of orthograde fluid preparation to clean the bowel. MBP is considered to prevent postoperative complications. METHODS: meta-analysis of prospective randomised clinical trials (RCT) evaluating MBP versus no MBP. RESULTS: following a medline search we retrieved 15 prospective trials of which only 5 where RCT comparing MBP versus no MBP in elective colorectal surgery. For the randomised studies, there were respectively 186, 179, 149, 267 and 380 patients, including all type of resections. The total number of patients in these 5 studies was 1144 (565 with MBP and 579 with no preparation). All patients received perioperative antibiotic prophylaxis. Only one of these RCT show a significant decrease in anastomotic leak (AL), but among all the patients enrolled, AL is significantly more frequent in the group with MBP (Odds Ratio 1.8). Wound infection, re-operation and intra-abdominal abscess rates were more frequent in the MBP group but the difference did not reach statistical significance and the odds ratios for a 95% confidence interval were extremely large. CONCLUSION: there is limited evidence in the literature to support the use of MBP in patient undergoing elective colorectal surgery. Available data tend to suggest that MBP could be harmful with respect to the incidence of anastomotic leak. Moreover, MBP does not reduce the incidence of other infectious complications. Further RCTs are needed to establish an evidence-based rationale for the use of MBP in elective colorectal surgery.

Laparoscopic robotic-assisted gastrointestinal surgery: the Geneva experience.

The continuing development of robotic surgery supports its use in laparoscopic gastrointestinal surgery. Our study retrospectively reviewed the surgical outcome and patient's satisfaction of gastrointestinal laparoscopic robotic procedures. From January 2003 to September 2007, 94 patients (27 women, 67 men) with a mean age of 53 years (range 19-84 years) underwent laparoscopic surgery with a da Vinci robotic system. There were 40 colorectal cases (43%), 31 anti-reflux surgery cases (33%) and 14 obesity surgery cases (15%); the remaining cases consisted of gastric and gallbladder surgery, intra-abdominal tumour excisions, and hepatic cyst resections. The majority of the cases (88, 94%) were performed for benign disease. The mean operative time was 153 min (range 60-330 min). One patient needed a blood transfusion. The mean body mass index was 25 (range 16-47). No death occurred. Five cases (5.3%) were converted to conventional laparoscopic surgery (n = 3) or to laparotomy (n = 2). Morbidity consisted of one Nissen redo surgery to loosen a tight anti-reflux valve 6 days after robotic surgery, a robotic left ureter repair and pelvic haemorrhage following proctectomy requiring re-operation to control haemostasis and to remove pelvic haematoma. Mean follow-up time was 11 months (range 15 days to 34 months). One case of incisional trocar hernia needed re-operation. Overall patient's satisfaction was high: few scars were cheloïd, while functional surgical outcome was rated high by most of the patients. Our preliminary experience was encouraging, with minimal morbidity and very high acceptance by patients.

Morphologic alterations associated with mechanical bowel preparation before elective colorectal surgery: a randomized trial.

PURPOSE: The feasibility and safety of left-sided colorectal procedures with avoidance of mechanical bowel preparation has recently been demonstrated. Moreover, mechanical preparation has been associated with an increased risk for abdominal septic complications, including anastomotic leakage. This study was designed to determine whether mechanical bowel preparation is associated with histologic alterations in the colon. METHODS: Fifty patients (mean age, 61 (range, 45-78) years) scheduled to undergo elective colorectal surgery were prospectively randomized to receive mechanical preparation (polyethylene glycol; Group 1) or no preparation (Group 2) preoperatively. A macroscopically healthy segment of the bowel was excised at the proximal margin of the colectomy piece. A pathologist, blinded to the patient's group allocation, assessed various morphologic parameters. RESULTS: Indications for colectomy (cancer and complicated diverticulosis) did not differ between groups. Bowel wall alterations were more frequent in patients who received a preparation. The most striking alterations associated with mechanical preparation were loss of superficial mucus (moderate-to-severe in 96 and 52 percent in Groups 1 and 2, respectively; P < 0.001) and epithelial cells (moderate-to-severe in 88 and 40 percent in Groups 1 and 2, respectively; P < 0.01). In addition, inflammatory changes, i.e., lymphocytes (severe in 48 and 12 percent in Groups 1 and 2, respectively; P < 0.02) and polymorphonuclear cells infiltration (severe in 52 and 8 percent in Groups 1 and 2, respectively; P < 0.02), were more prevalent after mechanical preparation. CONCLUSIONS: Mechanical bowel preparation is associated with structural alteration and inflammatory changes in the large bowel wall. Although bowel wall inflammation is a known risk factor for anastomotic leak, it remains to be elucidated whether these changes have a direct relation to the deleterious effect of mechanical bowel preparation in terms of abdominal morbidity.

Double frameshift mutations in APC and MSH2 in the same individual.

Heterozygous germline DNA mismatch repair gene mutations are typically associated with HNPCC. Here we report the case of a proband whose father was known for familial adenomatous polyposis. The number of polyps (less than ten) was not typical of polyposis; therefore, the diagnosis of HNPCC was entertained. Microsatellite instability analyses were performed on peripheral blood and biopsy of a right-sided dysplastic adenoma. The tumor tissue showed high-grade instability, and a subsequent, immunohistochemistry showed that neither MSH2 nor MSH6 proteins were expressed in tumor cells. Prophylactic colectomy was performed, and an adenocarcinoma developing within the adenoma was diagnosed (pT1N0). Genomic DNA analysis revealed a novel mutation in MSH2 as a frameshift mutation in exon 7 (c.1191_1192dupG). Both parents of the proband were analysed for MSH2 and APC mutations, and in the father, a truncating mutation in exon 15 of APC was identified as del3471-3473GAGA. This mutation was found to be present in the proband. His mother was found to bear the MSH2 exon 7 mutation. At the follow-up, the proband was diagnosed with fundic, antral and duodenal adenomas (one fundic adenoma showed low-grade dysplasia). Several tubular rectal adenomas with low-grade dysplasia were excised. The patient later developed an intra-abdominal desmoid tumor.

Proximal location of colon cancer is a risk factor for development of metachronous colorectal cancer: a population-based study.

PURPOSE: This study was undertaken to assess the incidence of 1) metachronous colorectal cancer and 2) subsequent extracolonic cancers, in relation to the location (proximal or distal to the splenic flexure) of the first primary colorectal tumor. METHODS: In this population-based study, a cancer registry database was used to identify patients diagnosed with colorectal adenocarcinoma between 1970 and 1999. Patients with familial adenomatous polyposis and those with hereditary nonpolyposis colorectal cancer syndrome were excluded from the study, as were patients with nonepithelial tumors. Location of the first tumor was established according to International Classification of Diseases-Oncology-02 classification. The registry covers a population of 500,000 residents. RESULTS: A total of 5,006 patients had sporadic adenocarcinoma of the colon or rectum during this period of time, with 1,703 first primary tumors (34 percent) being located proximal to the splenic flexure. One hundred twenty occurrences of second primary colorectal cancer were observed in this population (2.39 percent). The risk for developing a second incidence of primary colorectal cancer was higher in patients whose initial tumor was located in the proximal colon (3.4 percent vs. 1.8 percent; odds ratio, 1.92; 95 percent confidence interval, 1.33-2.77; P < 0.001). The risk for each segment of the large bowel was as follows: cecum, 3.4 percent; right colon, 3 percent; transverse colon, 3.8 percent; left colon, 2.8 percent; sigmoid colon, 1.7 percent; and rectum, 1.8 percent. By contrast, the risk for developing a second, extracolonic tumor did not differ between patients with proximal and distal tumors (13.7 percent vs. 13.4 percent, P = 0.73). CONCLUSION: Patients with a first tumor located within the proximal colon are at twice the risk for developing metachronous colorectal cancer. From an epidemiologic standpoint, these data are in accordance with 1) the increasing incidence and 2) the better prognosis of proximal colon cancer in various populations. Our results confirm that proximal colon cancer is a distinct entity, which justifies the reporting of cases of colon cancer according to their location proximal or distal to the splenic flexure.

Long-term outcome of mesocolic and pelvic diverticular abscesses of the left colon: a prospective study of 73 cases.

PURPOSE: The aim of of this study was to evaluate prospectively the long-term outcome of mesocolic and pelvic diverticular abscesses of the left colon. METHODS: Between October 1986 and October 1997, a total of 465 patients urgently admitted to our hospital with a suspected diagnosis of acute left-sided colonic diverticulitis had a CT scan. Of 76 patients (17 percent) who had an associated mesocolic or pelvic abscess, 3 were lost to follow-up. The remaining 73 patients (45 with a mesocolic abscess and 28 with a pelvic abscess) were followed for a median of 43 months. RESULTS: of the 45 patients with a mesocolic abscess, 7 (15 percent) required surgery during their first hospitalization versus 11 (39 percent) of the 28 patients with a pelvic abscess (P = 0.04). At the end of follow-up, 22 (58 percent) of the 38 patients with a mesocolic abscess who had successful conservative treatment during their first hospitalization did not need surgical treatment vs. 8 (47 percent) of the 17 who had a pelvic abscess. Altogether, 51 percent of the patients with a mesocolic abscess had surgical treatment versus 71 percent of those with a pelvic abscess (P = 0.09). CONCLUSIONS: Considering the poor outcome of pelvic abscess associated with acute left-sided colonic diverticulitis, percutaneous drainage followed by secondary colectomy seems justified. Mesocolic abscess by itself is not an absolute indication for colectomy.

Preoperative concomitant hyperfractionated radiotherapy and gemcitabine for locally advanced rectal cancers: a phase I-II trial.

PURPOSE: The purpose of this study was to determine the maximum tolerated dose of gemcitabine when it was administered concomitantly with hyperfractionated radiotherapy before surgery in patients with locally advanced rectal cancers and to investigate the midterm efficacy of such a regimen. PATIENTS AND METHODS: Thirty-seven patients with stage II-III tumors as assessed by computed tomography/echoendoscopy were enrolled. Radiotherapy consisted of 50 Gy given in two daily fractions of 1.25 Gy over 4 weeks. The starting dose of gemcitabine was 10 mg/m(2)/day (in a 30-minute i.v. perfusion) twice weekly with planned escalation steps of 5 mg/m(2)/day. Surgery was planned at 6 weeks after the end of radiotherapy. Main end-points of the study were complete pathological tumor response, the rate of clear margin resection, and actuarial locoregional control and disease-free survival. The median follow-up for all patients was 32 months (range: 10-51 months). RESULTS: At the level of 45 mg/m(2), two of four patients presented with dose-limiting rectal toxicities (severe acute proctitis requiring hospitalization in the immediate postradiotherapy period). Thus, the gemcitabine biweekly dose of 40 mg/m(2) was considered to be the maximum tolerated dose. Among the 36 patients who underwent surgery, 17 (47%) had a marked pathological response, including six patients (17%) with a microscopically complete response and 11 (30%) with only microscopically residual carcinoma of less than 1 cm. All of them had clear surgical margins. At 3 years, actuarial overall survival rate was 85%, locoregional control was 94.5%, and disease-free survival was 67%. DISCUSSION: The present study determined the recommended dose of gemcitabine to be 40 mg/m(2) when administered concurrently twice a week with 50 Gy hyperfractionated radiotherapy for the preoperative treatment of locally advanced rectal cancers. The encouraging pathological response rate and the very low locoregional recurrence rate suggest that this innovative approach merits further investigation.

Double frameshift mutations in APC and MSH2 in the same individual.

Heterozygous germline DNA mismatch repair gene mutations are typically associated with HNPCC. Here we report the case of a proband whose father was known for familial adenomatous polyposis. The number of polyps (less than ten) was not typical of polyposis; therefore, the diagnosis of HNPCC was entertained. Microsatellite instability analyses were performed on peripheral blood and biopsy of a right-sided dysplastic adenoma. The tumour tissue showed high-grade instability, and subsequently, immunohistochemistry showed that neither MSH2 nor MSH6 proteins were expressed in tumour cells. Prophylactic colectomy was performed, and an adenocarcinoma developing within the adenoma was diagnosed (pT1N0). Genomic DNA analysis revealed a novel mutation in MSH2 as a frameshift mutation in exon 7 (c.1,191_1,192dupG). Both parents of the proband were analyzed for MSH2 and APC mutations, and in the father, a truncating mutation in exon 15 of APC was identified as del3471-3473GAGA. This mutation was found to be present in the proband. His mother was found to bear the MSH2 exon 7 mutation. At follow-up, the proband was diagnosed with fundic, antral and duodenal adenomas (one fundic adenoma showed low-grade dysplasia). Several tubular rectal adenomas with low-grade dysplasia were excised. The patient later developed an intra-abdominal desmoid tumour.

Early prediction of acute pancreatitis: prospective study comparing computed tomography scans, Ranson, Glascow, Acute Physiology and Chronic Health Evaluation II scores, and various serum markers.

The aim of this study was to assess the predictability of the outcome of acute pancreatitis using the Ranson, Glascow, and Acute Physiology and Chronic Health Evaluation (APACHE) II scores, the computed tomography (CT) scan, and several serum markers. Altogether, 137 consecutive patients with acute pancreatitis confirmed by CT scan were prospectively included. Blood samples were obtained daily for 6 days. The predictive value of each parameter was studied by univariate and multivariate analyses comparing mild and severe pancreatitis. A total of 111 attacks were graded as mild (81%) and 26 as severe (19%). Ranson (p = 0.3) and APACHE II (p = 0.049) scores appeared insufficiently predictive in the univariate analysis. Pancreatic imaging by CT scan was insufficiently predictive (p > 0.05), whereas the presence of extrapancreatic fluid collections was more indicative of outcome (p <0.05). With the univariate analysis, the four most reliable serum markers were pancreatic amylase (p <0.001), neutrophil elastase (p <0.05), albumin (p <0.002), and C-reactive protein (p <0.001). Results became homogeneous when the CT results were added; serum albumin plus extrapancreatic fluid collections (negative predictive value 92%-96% and positive predictive value 67%-100%) comprised the best indicator of severity. None of the parameters tested achieved sufficient predictability when used alone. Serum albumin plus extrapancreatic fluid collections comprise the best indicator of severity at the time of admission.

Prostate cancer is part of the hereditary non-polyposis colorectal cancer (HNPCC) tumor spectrum.

The recognized urologic tumor spectrum in hereditary non-polyposis colon cancer includes ureteral and renal pelvis malignancies. Here, we report a family in which the proband, who had three metachronous adenocarcinomas of the colon and rectum (at ages 54, 57, and 60), presented with an adenocarcinoma of the prostate at age 61. Immunohistochemical (IHC) staining of colonic, rectal, and prostatic tumor tissues demonstrated lack of expression of both MSH2 and MSH6. Accordingly, microsatellite instability (MSI) was found in the rectal, colonic, and prostatic tumors. The kindred complies with the Amsterdam criteria for HNPCC, as five members over three generations had colorectal cancer. Molecular investigations were initiated when the proband's son presented with an adenocarcinoma of the colon at age 35. Southern blotting analysis of genomic DNA led to identification of a novel genomic deletion encompassing exon 5 of the MSH2 gene. Although prostate cancer has occasionally been described in HNPCC families, to the best of our knowledge, this is the first report where the MSI and IHC analysis of the prostatic adenomcarcinoma clearly link its aetiology to the germline mismatch repair mutation. Hence, prostate cancer should be included in the HNPCC tumor spectrum.