Overexpression of protein S100A4 is independently associated with overall survival in stage C colonic cancer but only in cytoplasm at the advancing tumour front.

PURPOSE: S100A4, a multifunctional protein, has been linked to the invasive growth and metastases of several human cancers. This study investigated the association between S100A4 and overall survival and other clinicopathological features in patients with stage C colonic cancer. METHODS: Clinical and pathological data were obtained from a prospective hospital registry of 409 patients who had a resection for stage C colonic cancer. Tissue microarrays for immunohistochemistry were constructed from archived tissue. S100A4 staining intensity and percentage of stained cells were assessed in nuclei and cytoplasm for both the central part of the tumour and at the advancing front. Overall survival was analysed by the Kaplan-Meier method and Cox regression. RESULTS: Only a high percentage of cells with S100A4 cytoplasmic staining in frontal tissue was associated with poor survival (hazard ratio, 1.6; 95 % CI 1.1-2.2; p = 0.008) after adjustment for other prognostic variables. There was no association between frontal cytoplasmic S100A4 expression and any of 13 other clinicopathological variables. CONCLUSIONS: High expression of S100A4 in cytoplasm at the advancing front of stage C colonic tumours indicates a poor prognosis. Whether S100A4 can predict response to adjuvant chemotherapy remains to be investigated in a randomised clinical trial.

Understanding the anatomy of lymphatic drainage and the use of blue-dye mapping to determine the extent of lymphadenectomy in rectal cancer surgery: unresolved issues.

OBJECTIVE: This paper reviews the literature on the pathways of lymphatic drainage of the rectum and their significance in radical cancer surgery. METHOD: This paper reviews some of the seminal works on the lymphatic drainage of the rectum and its surgical implications when operating on patients with rectal cancer. Publications were searched via Medline, sourced from reference lists and by cross referencing with the most widely cited papers. RESULTS: The classical European description of the anatomy of the lymphatic drainage of the rectum is presented. Early lymphatic mapping techniques and the role of newer technologies in lymphatic mapping, including sentinel lymph node mapping are discussed. The differing philosophies between Western practice, of dissection in the plane of the fascia propria and the Japanese wider pelvic lymphadenectomy are discussed. CONCLUSIONS: A clear understanding of the regional lymphatic drainage of the rectum and precise anatomical mobilisation of the rectum is the surgical cornerstone to excellent locoregional control of rectal cancer. The success of the differing Western and Japanese philosophies on the degree of pelvic lymphadenectomy suggests a possible role for 'selective wide pelvic lymphadectomy'. Mapping lateral lymphatic drainage pathways could augment the selection process for radiotherapy.

The importance of tumor stage and relative survival analysis for the association between sex and survival after resection of colorectal cancer.

OBJECTIVE: The aim of this study was to determine whether the previously noted poorer survival of men after resection of colorectal cancer varied among clinicopathological tumor stages. SUMMARY BACKGROUND DATA: The question of whether sex is independently associated with prognosis after resection of colorectal cancer has been examined in numerous studies over the past 2 decades, but with conflicting results. METHODS: Data on 3,301 patients were drawn from a comprehensive, prospective hospital registry of all resections for colorectal cancer performed between January 1971 and December 2005. Statistical analysis employed Kaplan Meier estimation and relative survival analysis to adjust for differential male/female life expectancy in the general population. RESULTS: The relative survival of males was significantly less than that of females (P = 0.004) only in stage B. This was not accounted for by other negative pathology features and cause of death did not differ significantly between males and females. However, men with stage B tumor were more likely than women to experience postoperative morbidity, particularly a respiratory complication or a surgical complication requiring urgent reoperation. The sex difference in relative survival persisted among patients who had either a respiratory complication or an urgent reoperation (P = 0.003) but disappeared among those who had neither (P = 0.193). CONCLUSION: The poorer survival of men with stage B tumor was attributable to their greater postoperative morbidity which led to the earlier death of some due to causes unrelated to their colorectal cancer.

Anastomotic leakage after resection of colorectal cancer generates prodigious use of hospital resources.

OBJECTIVE: The aim of this study was to determine the demand for hospital resources generated by anastomotic leakage, including surgical, medical, imaging, pathology, and other allied health consultations or services and length of postoperative hospital stay. METHOD: Data were obtained from a comprehensive, prospective hospital registry of all resections for colorectal cancer from January 1995 to December 2004 and from retrospective review of patients' notes. RESULTS: Forty-one patients with a leak spent 92 days in intensive care, required 129 days of total parenteral nutrition, 69 days of enteric feeding and 41 days on ventilation and had a median postoperative hospital stay of 28 days (range 11-104). These patients required 24 re-operations and 2273 separate medical consultations or allied services. CONCLUSION: Anastomotic leakage generates a very considerable demand for hospital resources and diverts these resources from the hospital population at large.

The significance of involvement of a free serosal surface for recurrence and survival following resection of clinicopathological stage B and C rectal cancer.

OBJECTIVE: To determine whether the presence of tumour at a free serosal surface was independently associated with pelvic recurrence or survival in patients who had a resection for clinicopathological stage B or stage C rectal cancer and who had not received adjuvant therapy. METHOD: Data were drawn from a comprehensive, prospective hospital registry of all resections for rectal cancer from January 1971 to December 1998 with follow up to December 2003. Statistical analysis employed the chi(2) test or Fisher's exact probability, Kaplan-Meier estimation and proportional hazards regression, with a significance level of < or =0.05 and 95% confidence intervals (CI). RESULTS: In 665 patients with stages B or C tumour, 35 (5.3%; CI 3.7-7.2%) had tumour at a free serosal surface. These comprised 6/332 (1.8%; CI 0.8-3.7%) patients with stage B tumour and 29/333 (8.7%; CI 6.1-12.2%) with stage C tumour. After adjustment for other relevant variables, involvement of a free serosal surface was significantly associated with pelvic recurrence [hazard ratio (HR) 2.7; CI 1.3-5.5] and diminished survival (HR 1.6; CI 1.1-2.4) but not with systemic (only) recurrence. CONCLUSION: This study has confirmed that direct tumour spread to a free serosal surface independently predicts pelvic recurrence and diminished survival after resection of clinicopathological stage B and C rectal cancer. This feature should always be sought by the pathologist and reported when present, and noted by the surgeon and oncologist. Serosal involvement should be evaluated further for its utility in selecting patients for adjuvant therapy.

Promoter methylation of the mutated in colorectal cancer gene is a frequent early event in colorectal cancer.

The mutated in colorectal cancer (MCC) gene is in close linkage with the adenomatous polyposis coli (APC) gene on chromosome 5, in a region of frequent loss of heterozygosity in colorectal cancer. The role of MCC in carcinogenesis, however, has not been extensively analysed, and functional studies are emerging, which implicate it as a candidate tumor suppressor gene. The aim of this study was to examine loss of MCC expression due to promoter hypermethylation and its clinicopathologic significance in colorectal cancer. Correspondence of MCC methylation with gene silencing was demonstrated using bisulfite sequencing, reverse transcription-polymerase chain reaction and Western blotting. MCC methylation was detected in 45-52% of 187 primary colorectal cancers. There was a striking association with CDKN2A methylation (P<0.0001), the CpG island methylator phenotype (P<0.0001) and the BRAF V600E mutation (P<0.0001). MCC methylation was also more common (P=0.0084) in serrated polyps than in adenomas. In contrast, there was no association with APC methylation or KRAS mutations. This study demonstrates for the first time that MCC methylation is a frequent change during colorectal carcinogenesis. Furthermore, MCC methylation is significantly associated with a distinct spectrum of precursor lesions, which are suggested to give rise to cancers via the serrated neoplasia pathway.

Assessing the evidence for an association between circumferential tumour clearance and local recurrence after resection of rectal cancer.

OBJECTIVE: Circumferential resection margin involvement (CRMI) after resection of rectal cancer is regarded as a risk factor for local recurrence. We have been able to identify only nine peer-reviewed English-language publications which focus primarily on this association, and they report widely differing rates of local recurrence. The aims of this study were to review possible reasons for this variability and to assess the evidence for the micrometrically measured threshold defining CRMI. METHOD: Methodological and statistical evaluation of relevant literature. RESULTS: Several factors which could account for this variability are discussed including the nature of the patient series, surgical technique, curative vs palliative resections, pathology technique, the definition of CRMI, adjuvant therapy, tumour stage, definition and ascertainment of local recurrence, length of follow-up and method of analysis. The objective evidence for the conventional definition of CRMI as tumour 1 mm or less from a circumferential margin is considered along with the evidence supporting a recent proposal that the margin be extended to 2 mm or less. The evidence is numerically weak in both cases and we believe that neither definition should be set in concrete at this stage. CONCLUSION: Pending further research, we recommend that routine pathology reports should record frank tumour transection, if present, or otherwise report the histological width of the margin between the tumour and the nearest circumferential line of resection in millimetres. The definition of CRMI should be simply histological evidence of tumour in a line of resection, that is, a margin of 0 mm. The definition of CRMI as a margin of

Risk factors for tumour present in a circumferential line of resection after excision of rectal cancer.

BACKGROUND: Transected tumour in a circumferential line of resection after excision of rectal cancer carries a high likelihood of local recurrence. The aim of this study was to identify independent risk factors for transected tumour and to examine their temporal variability. METHODS: Data were drawn from a comprehensive, prospective hospital registry of all resections for rectal cancer from January 1971 to July 2004. Transected tumour was defined as tumour present histologically in a line of resection and was assessed in all specimens. RESULTS: Transection occurred in 129 of 1613 patients (8.0 (95 per cent confidence interval 6.7 to 9.4) per cent). The following variables were independently associated with transected tumour: tumour perforation, a non-restorative operation, tumour adherence, non-standardized operative technique, preoperative radiotherapy, male sex, histological involvement of an adjacent organ or tissue, high-grade tumour and venous invasion. The mean number of risk factors per patient per year and the annual percentage of patients with transection varied distinctly over the history of the database. CONCLUSION: The varying prevalence of risk factors, both within and between hospitals and patient series, should be taken into account if the rate of transection is to be regarded as an index of the quality of surgery.

Local recurrence after curative resection for rectal cancer is associated with anterior position of the tumour.

BACKGROUND: Mobilization of rectal cancer can be difficult if the tumour is located anteriorly and may result in a higher incidence of local recurrence. The aim of this study was to determine whether local recurrence and survival following curative resection of rectal cancer were associated with the position of the tumour. METHODS: Data were drawn from a comprehensive, prospective hospital registry of all resections for rectal cancer from January 1990 to December 1998, with follow-up to December 2003. RESULTS: The 5-year local recurrence rate was 15.9 (95 per cent confidence interval (c.i.) 11.0 to 22.8) per cent in 176 patients with tumours that had an anterior component compared with 5.8 (95 per cent c.i. 2.8 to 11.9) per cent in 132 patients with tumours without an anterior component (P = 0.009). This association persisted after adjustment for other factors linked to local recurrence (hazard ratio (HR) 2.4 (95 per cent c.i. 1.1 to 5.4)). Similarly, anterior position had a significant negative independent association with survival (HR 1.4 (95 per cent c.i. 1.0 to 2.00)). CONCLUSION: Anterior position is an independent negative prognostic factor for both local recurrence and survival after curative resection of rectal cancer.

Effect of supervised surgical training on outcomes after resection of colorectal cancer.

BACKGROUND: The process of training surgeons in technique for resection of colorectal cancer should not compromise patient care or outcomes. The aim of this study was to compare morbidity, mortality and survival rates after resection performed by trainees with those for a consultant surgeon. METHODS: Outcomes for 150 patients operated on by a single colorectal surgeon at a private hospital were compared with those of 344 patients admitted under the same surgeon and operated on by closely supervised trainee surgeons in a public teaching hospital between 1995 and 2002. RESULTS: Co-morbidity was significantly more common in patients operated on by trainees; their American Society of Anesthesiologists grades were higher and tumours were more advanced. Of 16 postoperative complications evaluated, only respiratory and cardiac problems were significantly more common in patients operated on by trainees. There was no difference in operative mortality, local recurrence or 2-year survival rate after adjustment for age and tumour stage. CONCLUSION: Outcomes after resection for colorectal cancer did not differ between the consultant and trainees in the context of a closely supervised training programme.

What factors influence survival in patients with unresected synchronous liver metastases after resection of colorectal cancer?

OBJECTIVE: The aim of this study was to determine whether the survival of patients with untreated synchronous liver metastases after resection of a colorectal cancer was associated with any features of the primary tumour. METHODS: Information for 398 consecutive patients with unresected liver metastases in the period 1971-2001 was examined by multivariate survival analysis. RESULTS: Of 19 clinical and pathological variables considered, survival was independently associated only with residual tumour in a line of resection (hazard ratio (HR) 1.95), venous invasion (HR 1.87), right colonic tumour (HR 1.68), lymph node metastasis (HR 1.54), and extra-hepatic metastasis (HR 1.16); 8.3% of patients had none of these adverse features. Their 2-year overall survival rate was 39.2%, compared with only 16.5% (P < 0.001) in those with one or more adverse features. CONCLUSIONS: These findings may assist in selecting patients most likely to benefit from treatment of hepatic metastases and in counselling patients and their relatives.

Low level microsatellite instability may be associated with reduced cancer specific survival in sporadic stage C colorectal carcinoma.

BACKGROUND: Colorectal cancers (CRCs) may be categorised according to the degree of microsatellite instability (MSI) exhibited, as MSI-high (MSI-H), MSI-low (MSI-L), or microsatellite stable (MSS). MSI-H status confers a survival advantage to patients with sporadic CRC. AIMS: To determine if low levels of MSI are related to the clinicopathological features and prognosis of sporadic stage C CRC. PATIENTS: A total of 255 patients who underwent resection for sporadic stage C CRC were studied. No patient received chemotherapy. Minimum follow up was five years. METHODS: DNA extracted from archival malignant and non-malignant tissue was amplified by polymerase chain reaction using a panel of 11 microsatellites. MSI-H was defined as instability at > or =40% of markers, MSS as no instability, and MSI-L as instability at >0% but <40% of markers. Patients with MSI-H CRC were excluded from analysis as they have previously been shown to have better survival. RESULTS: Thirty three MSI-L and 176 MSS CRCs were identified. There was no difference in biological characteristics or overall survival of MSI-L compared with MSS CRC but MSI-L was associated with poorer cancer specific survival (hazard ratio 2.0 (95% confidence interval 1.1-3.6)). CONCLUSIONS: Sporadic MSI-L and MSS CRCs have comparable clinicopathological features. Further studies are required to assess the impact of MSI-L on prognosis.

Adverse histopathological findings as a guide to patient management after curative resection of node-positive colonic cancer.

BACKGROUND: The aim of this study was to identify patient and tumour characteristics that might assist in developing an improved approach to patient selection for chemotherapy after resection of clinicopathological stage C colonic cancer. METHODS: Clinical, pathological and follow-up data have been collected prospectively for all patients undergoing resection for colorectal cancer at Concord Hospital since 1971. From an initial 2980 patients, after exclusions 378 remained who had a potentially curative operation for colonic cancer with nodal metastases and did not receive adjuvant chemotherapy. Associations between several pathological features and survival were examined by proportional hazards regression. RESULTS: In a multivariate model, both overall and colonic cancer-specific survival rates were negatively associated with serosal surface involvement, apical node metastasis, high histological grade and venous invasion. The survival of patients with stage C disease who had none of these adverse features was not significantly different from that of patients with stage B lesions. However, survival diminished significantly when one or more of the adverse features were present. CONCLUSION: Patients with a stage C tumour but with none of the identified adverse features experience relatively good survival and are unlikely to benefit from adjuvant chemotherapy. In this series such patients accounted for 40.5 per cent of patients with stage C disease.

Anastomotic leakage after curative anterior resection results in a higher prevalence of local recurrence.

BACKGROUND: The aim of this study was to determine whether leakage from a colorectal anastomosis following potentially curative anterior resection for rectal cancer is an independent risk factor for local recurrence. METHODS: The study included all patients who had a potentially curative anterior resection with anastomosis for adenocarcinoma of the rectum between 1971 and 1991 at Concord Hospital. The data were collected prospectively, with complete follow-up for at least 5 years. The Kaplan-Meier method was used to compare time to recurrence between strata of categorical variables. Proportional hazards regression was used in multivariate modelling. RESULTS: There were 403 patients in the study. After adjustment for lymph node metastases, the distal resection margin of resection, non-total anatomical dissection of the rectum and the level of anastomosis, multivariate analysis identified a significant association between anastomotic leakage and local recurrence (hazard ratio 3.8, 95 per cent confidence interval 1.8 to 7.9). CONCLUSION: Leakage following a colorectal anastomosis after potentially curative resection for adenocarcinoma of the rectum is an independent predictor of local recurrence.

Surgical technique and survival in patients having a curative resection for colon cancer.

PURPOSE: This study was performed to determine whether the adoption of a standardized technique for resection of colon cancer, based on mobilization along anatomic planes, resulted in improved survival after adjustment for other known prognostic factors. METHODS: Patients undergoing a potentially curative, elective colonic resection at Concord Hospital from 1971 to 1995 were included. None received adjuvant therapy. Data were recorded prospectively. Overall survival and colon-cancer-specific survival were examined by the Kaplan-Meier method and proportional-hazards regression in relation to patient and tumor characteristics and the introduction of a standardized surgical technique in 1980. RESULTS: Overall five-year survival rose from 48.1 percent before 1980 to 63.7 percent after 1980 (P < 0.0001); cancer-specific survival rose from 66.4 percent to 76.6 percent (P = 0.002). Factors that did not change significantly before and after 1980 were patient age and gender, tumor site, stage, grade, serosal surface involvement, and apical node metastases. The proportion of tumors > or =5 cm in diameter decreased after 1980 (61.9 to 49.2 percent, P = 0.001) but survival was unrelated to size. Venous invasion rose after 1980 (9 to 15.8 percent, P = 0.014). Multiple regression with adjustment for age, stage, grade, venous invasion, serosal surface involvement, and apical node metastases showed significantly shorter overall survival before the introduction of the standardized technique (hazard ratio, 1.5; 95 percent confidence interval, 1.2-1.8) and significantly shorter colon-cancer-specific survival (hazard ratio, 1.7; 95 percent confidence interval, 1.3-2.2). The proportion of patients having a noncurative operation because of residual tumor in a line of resection (excluded from the survival analyses) fell from 10.6 percent (confidence interval, 7-15.3 percent) before 1980 to 3.2 percent (confidence interval, 2-4.9 percent) after 1980. CONCLUSION: As in rectal cancer surgery, mobilization of the colon along anatomic planes is an important principle that influences outcome and needs to be emphasized.

A systematic review of stapled hemorrhoidectomy.

HYPOTHESIS: Use of circular stapled hemorrhoidectomy will result in the same or improved safety and efficacy outcomes as those of the conventional methods for hemorrhoidectomy in patients with hemorrhoids. DATA SOURCES: Studies on stapled hemorrhoidectomy were identified using PREMEDLINE and MEDLINE (June 1966-June 2001), EMBASE (January 1980-June 2001), Current Contents (June 1993-June 2001), Ovid HEALTHSTAR (January 1975-June 2001), the National Institutes of Health Clinical Trials database (searched June 13, 2001), and The National Coordinating Centre for Health Technology Assessment database (searched June 14, 2001). The search terms were as follows: haemorrhoid* and (stapl* or convent*) or hemorrhoid* and (stapl* or convent*). The Cochrane Library (2001, issue 2) was searched using the search terms haemorrhoid* or hemorrhoid*. STUDY SELECTION: Articles detailing randomized controlled trials were included if they compared circular stapled with conventional hemorrhoidectomy and provided relevant safety and efficacy outcome information. DATA EXTRACTION: Data from all included studies were extracted using standardized data extraction tables that were developed a priori. In addition, the randomized controlled trials were examined with respect to the adequacy of allocation concealment, handling of those unavailable for follow-up, and any other aspect of the study design or execution that may have introduced bias. DATA SYNTHESIS: Seven randomized controlled trials met the inclusion criteria. A meta-analysis was conducted when the studies had comparable outcomes, inclusion criteria, and follow-up. There was reasonably clear evidence in favor of the stapled procedure for bleeding at 2 weeks (relative risk, 0.55; 95% confidence interval, 0.37-0.82) and length of hospital stay (weighted mean difference, -0.89 days; 95% confidence interval, -1.42 to -0.36). Other less robust results in favor of the stapled hemorrhoidectomy related to pain, bleeding, anal discharge, wound healing, tenderness to per rectal examination, incontinence scores, earlier return of bowel function, analgesic requirement, and resumption of normal activities. One trial showed that prolapse occurred at significantly higher rates in the stapled hemorrhoidectomy group. However, the outcomes were poorly reported and generally showed statistically significant heterogeneity. CONCLUSIONS: Stapled hemorrhoidectomy may be at least as safe as conventional hemorrhoidal surgical techniques. However, the efficacy of the stapled procedure compared with the conventional techniques could not be determined. More rigorous studies with longer follow-up periods and larger sample sizes need to be conducted.

Laparoscopy for colon cancer.

Laparoscopic resection of the colon is certainly feasible. There are conflicting reports regarding decreased postoperative pain, resumption of gastrointestinal function, and earlier return to work. There is no change in either mortality or morbidity when compared with open resection. For benign disease laparoscopic colonic resection is ideal if performed by a surgeon who performs the operation frequently. For malignant disease, [table: see text] at this stage, laparoscopic colonic resection should only be performed in the setting of a randomized controlled trial. The future of laparoscopic surgery for colon cancer will be decided by oncologic parameters. There is good evidence that a laparoscopic resection can be technically equivalent to its open counterpart. The data on recurrence, both local and distant, and long-term survival will become clearer when results of randomized controlled trials currently underway become available. The issue of port-site recurrence is a major concern in laparoscopic colorectal cancer surgery. The reported incidence is low; however, its cause remains unexplained and its presence in patients with early stage tumors cannot be ignored.