Nigel Scott

Role of circumferential margin involvement in the local recurrence of rectal cancer

Local recurrence after resection for rectal cancer remains common despite growing acceptance that inadequate local excision may be implicated. In a prospective study of 190 patients with rectal cancer, we examined the circumferential margin of excision of resected specimens for tumour presence, to examine its frequency and its relation to subsequent local recurrence. Tumour involvement of the circumferential margin was seen in 25% (35/141) of specimens for which the surgeon thought the resection was potentially curative, and in 36% (69/190) of all cases. After a median 5 years follow-up (range 3.0-7.7 years), the frequency of local recurrence after potentially curative resection was 25% (95% CI 18-33%). The frequency of local recurrence was significantly higher for patients who had had tumour involvement of the circumferential margin than for those without such involvement (78 [95% CI 62-94] vs 10 [4-16]%). By Coxs regression analysis tumour involvement of the circumferential margin independently influenced both local recurrence (hazard ratio = 12.2 [4.4-34.6]) and survival (3.2 [1.6-6.53]). These results show the importance of wide local excision during resection for rectal cancer, and the need for routine assessment of the circumferential margin to assess prognosis.

Rates of Circumferential Resection Margin Involvement Vary Between Surgeons and Predict Outcomes in Rectal Cancer Surgery

ObjectiveTo analyze the potential variability in rates of circumferential resection margin (CRM) involvement between different surgeons and time periods and to determine the suitability of using CRM status as an immediate predictor of outcome after rectal cancer surgery. Summary Background DataAfter disease stage has been taken into account, survival in rectal cancer has been shown to be very variable between surgeons and institutions. One of the major factors influencing survival is local recurrence, and this in turn is strongly related to inadequate tumor excision, particularly at the CRM. MethodsIn a study involving 608 patients who underwent surgery for rectal cancer in Leeds during the 12-year period 1986 to 1997, the authors examined the role of CRM status as an immediate predictor of likely outcome, paying particular attention to its relationships with different surgeons and time periods. ResultsOf 586 patients on whom full clinical follow-up was obtained, 165 (28.2%) had CRM involvement by carcinoma on pathologic examination. Up to the end of 1998, 105 (17.9%) patients had developed local recurrence. A significantly higher proportion (38.2%) of CRM-positive patients developed local recurrence than CRM-negative ones (10.0%). Kaplan-Meier survival analysis showed significant improvements in survival for CRM-negative patients over CRM-positive patients. Survival analysis in relation to two gastrointestinal surgeons and a group of other surgeons showed survival improvements that paralleled a reduction in the rates of CRM involvement for the two gastrointestinal surgeons during the period of the study. No improvement in survival or reduction in rates of CRM involvement was seen in the group of other surgeons. ConclusionsThese results show that CRM status may be used as an immediate predictor of survival after rectal cancer surgery and serves as a useful indicator of the quality of surgery. The frequency of CRM involvement can be used both for overall surgical audit and for monitoring the value of training programs in improving rectal surgery by individual surgeons. Its use in the current MRC CR07 study is valid and the best indicator of a requirement for further local therapy.

The Modern Abdominoperineal Excision: The Next Challenge After Total Mesorectal Excision

Objectives:Examine the cause of local recurrence (LR) and patient survival (S) following abdominoperineal resection (APR) and anterior resection (AR) for rectal carcinoma and the effect of introduction of total mesorectal excision (TME) on APR. Methods:A total of 608 patients underwent surgery for rectal cancer in Leeds from 1986 to 1997. CRM status and follow-up data of local recurrence and patient survival were available for 561 patients, of whom 190 underwent APR (32.4%) and 371 AR (63.3%). Also, a retrospective study of pathologic images of 93 specimens of rectal carcinoma. Results:Patients undergoing APR had a higher LR and lower survival (LR, 22.3% versus 13.5%, P = 0.002; S, 52.3% versus 65.8%, P = 0.003) than AR. LR free rates were lower in the APR group and cancer specific survival was lowered (LR, 66% versus 77%, log rank P = 0.03; S, 48% versus 59%, log rank P = 0.02). Morphometry: total area of surgically removed tissue outside the muscularis propria was smaller in APR specimens (n = 27) than AR specimens (n = 66) (P < 0.0001). Linear dimensions of transverse slices of tissue containing tumor, median posterior, and lateral measurements were smaller (P < 0.05) in the APR than the AR group. APR specimens with histologically positive CRM (n = 11) had a smaller area of tissue outside the muscularis propria (P = 0.04) compared with the CRM-negative APR specimens (n = 16). Incidence of CRM involvement in the APR group (41%) was higher than in the AR group (12%) (P = 0.006) in the 1997 to 2000 cohort. Similar results (36% and 22%) were found in the 1986 to 1997 cohort (P = 0.002). Conclusions:Patients treated by APR have a higher rate of CRM involvement, a higher LR, and poorer prognosis than AR. The frequency of CRM involvement for APR has not diminished with TME. CRM involvement in the APR specimens is related to the removal of less tissue at the level of the tumor in an APR. Where possible, a more radical operation should be considered for all low rectal cancer tumors.

Prognostic value of p53 overexpression and c-Ki-ras gene mutations in colorectal cancer

BACKGROUNDnMutations in Ki-ras codon 12 and the p53 gene are common abnormalities in colorectal cancer. The occurrence of p53 overexpression and/or Ki-ras codon 12 mutations were analyzed in 100 colorectal adenomas to determine if they were related to patient survival.nnnMETHODSnp53 overexpression was identified by immunohistochemistry, and Ki-ras codon 12 mutations were detected using the polymerase chain reaction and a restriction enzyme digestion method.nnnRESULTSnp53 overexpression was identified in 45% of tumors, with a higher frequency identified in DNA aneuploid and left-sided tumors than in DNA diploid and right-sided tumors. Mutations in Ki-ras codon 12 were identified in 24% of carcinomas. Individually, mutations in Ki-ras codon 12 or p53 overexpression were not prognostic indicators of survival. However, a statistically significant difference in survival was identified when these two oncogenic abnormalities were analyzed together. The median survival of patients whose tumors contained both oncogenic abnormalities was less than half of that of patients with either alteration alone or without either abnormality.nnnCONCLUSIONSnScreening for multiple genetic abnormalities in colorectal cancers excised at surgery may prove to be a useful tool in determining prognosis.

Ileal Pouch—anal Anastomosis: Reoperation for Pouch-related Complications

The aim was to assess the value of reoperative surgery for pouch-related complications after ileal pouch-anal anastomosis (IPAA) for chronic ulcerative colitis and familial adenomatous polyposis. Between January 1981 and August 1989, 114 of 982 IPAA patients (12%) seen at the Mayo Clinic had complications directly related to IPAA that required reoperation. Among the 114 patients, the complications prevented initial ileostomy closure in 33 patients (25%), occurred after ileostomy closure in 68 patients (60%), and delayed ileostomy closure in the remaining patients. The salvage procedures performed included anal dilatation under anesthesia for anastomotic strictures, placement of setons and/or fistulotomy for perianal fistulae, unroofing of anastomotic sinuses, simple drainage and antibiotics for perianal abscesses, abdominal exploration with drainage of intra-abdominal abscesses with or without establishment of ileostomy, and complete or partial reconstruction of the reservoir for patients with inadequate emptying. None of the reoperated patients died. Reoperation led to restoration of pouch function in two thirds of patients and, of these, 70% had an excellent clinical outcome. However approximately 20% of the 114 pouches required excision. Excision was common, especially among patients who had pelvic sepsis. Salvage procedures for pouch-specific complications can be done safely and will restore pouch function in two thirds of patients. Complications after reoperation, however, may ultimately lead to loss of the reservoir in one in five patients.

Outcome of reconstructive surgery for intestinal fistula in the open abdomen.

Objective:To determine factors which influence the outcome of surgical techniques to close enterocutaneous fistulas within the open abdomen. Summary Background Data:Enterocutaneous fistulation within an open abdominal wound is associated with considerable morbidity and mortality. The factors that influence the outcome of reconstructive surgery are unclear. Methods:Sixty-one patients undergoing 63 operations to close enterocutaneous fistulas associated with open abdominal wounds were referred to a national center for further management. Once sepsis had been eradicated, nutritional status restored and local conditions in the abdomen judged to be suitable, fistulas were resected and the abdominal wall reconstructed by suture repair with and without component separation, or by suture repair in combination with absorbable or nonabsorbable prosthetic mesh. Patients were followed up for 16 to 84 months postoperatively. Results:There were 3 postoperative deaths (4.8%). Major complications, including postoperative respiratory and surgical site infection occurred in 52 of 63 (82.5%) procedures. Refistulation occurred in 7 cases (11.1%) but was more common when the abdominal wall was reconstructed with prosthetic mesh (7 of 29, 24.1%) than with sutures (0 of 34, 0%). Porcine collagen mesh was associated with a particularly high rate of refistulation (5 of 12, 41.7%). Conclusions:Simultaneous reconstruction of the intestinal tract and abdominal wall remains associated with a high complication rate, justifying the management of such patients in specialized units. Simultaneous reconstruction of the abdominal wall with prosthetic mesh is associated with a particularly high incidence of recurrent postoperative fistulation and should be avoided if possible.

p53 expression and K-ras mutation in colorectal adenomas.

The frequency of p53 overexpression and K-ras codon 12 mutation was investigated in a series of colorectal adenomas. p53 was detected by immunohistochemistry in only 5% of tumours, whereas K-ras mutation was found in eight of 30 adenomas examined. In vitro, mutant p53 and ras genes cooperate to transform primary rat cells into a tumourigenic cell line. The presence of both p53 overexpression and K-ras mutation in a benign tubulovillous polyp in the present series suggests that in vivo this combination of events is insufficient to cause malignant transformation of a large bowel adenoma.

Flow Cytometric DNA Patterns From Colorectal Cancers—How Reproducible Are They?

The heterogeneity of DNA ploidy patterns within individual colorectal carcinomas was investigated by analyzing 261 different samples from 30 fresh colorectal cancers. The results of DNA analysis of multiple superficial cup biopsy specimens, of multiple full-thickness fresh tumor slices, and of nuclei extracted from paraffin-embedded pathologic archival specimens with use of the Hedley technique were compared. The same DNA ploidy pattern was found in all specimens of 19 (63%) of the 30 tumors studied. Minimal heterogeneity for DNA ploidy pattern was noted in seven carcinomas (23%), and moderate to marked heterogeneity was found in an additional four tumors (13%). The DNA pattern of a full-thickness specimen from 79% of the carcinomas studied was the same when samples were obtained from any one of five possible sites. In addition, the DNA ploidy pattern of the majority of the carcinomas could have been accurately predicted by flow cytometric DNA analysis of superficial cup biopsy specimens. These results demonstrate that most colorectal carcinomas are DNA ploidy homogeneous. Therefore, measurement of this tumor property can be used in future clinical research studies with some degree of confidence.

A study of indefinite for dysplasia in Barrett’s oesophagus: reproducibility of diagnosis, clinical outcomes and predicting progression with AMACR (α-methylacyl-CoA-racemase)

Sonwalkar S A, Rotimi O, Scott N, Verghese E, Dixon M, Axon A T R A & Everett S Mu2028(2010) Histopathologyu200256, 900–907u2028A study of indefinite for dysplasia in Barrett’s oesophagus: reproducibility of diagnosis, clinical outcomes and predicting progression with AMACR (α‐methylacyl‐CoA‐racemase)

Molecular biology of colorectal neoplasia.

Large bowel cancer is a major cause of morbidity and mortality in the western world. In England and Wales approximately 8500 men and 9000 women die of the disease every year. Yet despite this, relatively little is known of its pathogenesis in the vast majority of sporadic cases. In 1954, Armitage and Doll proposed that common cancers arise as a result of the accumulation of as many as seven events.2 Most scientists now believe that the molecular substrate for these critical events in tumorigenesis are genes that regulate cell proliferation and differentiation that is, oncogenes and tumour suppressor genes. Alterations to the expression or structure of these genes may result in the perturbation of cell growth, which is the hallmark of neoplasia. The past 10 years has seen an explosion in our knQwledge of the molecular biology ofcancer, and nowhere has this been as exciting as in the field of large bowel cancer. Research into colorectal tumours has directly or indirectly contributed to the discovery of three new tumour suppressor genes; APC, DCC, and p53, the latter probably representing the commonest genetic abnormality so far described in human cancer.3 Therefore, despite being unclear about the environmental agents that promote genetic changes in the large bowel, in few other tumour systems are we as close to identifying the critical events which underlie malignant, neoplastic behaviour as we are in colorectal cancer.