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Background Surgical-site infection (SSI) is associated with significant healthcare costs. To reduce the high rate of SSI among patients undergoing colorectal surgery at a cancer centre, a comprehensive care bundle was implemented and its efficacy tested. Methods A pragmatic study involving three phases (baseline, implementation and sustainability) was conducted on patients treated consecutively between 2013 and 2016. The intervention included 13 components related to: bowel preparation; oral and intravenous antibiotic selection and administration; skin preparation, disinfection and hygiene; maintenance of normothermia during surgery; and use of clean instruments for closure. SSI risk was evaluated by means of a preoperative calculator, and effectiveness was assessed using interrupted time-series regression. Results In a population with a mean BMI of 30 kg/m2, diabetes mellitus in 17·5 per cent, and smoking history in 49·3 per cent, SSI rates declined from 11·0 to 4·1 per cent following implementation of the intervention bundle (P = 0·001). The greatest reductions in SSI rates occurred in patients at intermediate or high risk of SSI: from 10·3 to 4·7 per cent (P = 0·006) and from 19 to 2 per cent (P < 0·001) respectively. Wound care modifications were very different in the implementation phase (43·2 versus 24·9 per cent baseline), including use of an overlying surface vacuum dressing (17·2 from 1·4 per cent baseline) or leaving wounds partially open (13·2 from 6·7 per cent baseline). As a result, the biggest difference was in wound-related rather than organ-space SSI. The median length of hospital stay decreased from 7 (i.q.r. 5–10) to 6 (5–9) days (P = 0·002). The greatest reduction in hospital stay was seen in patients at high risk of SSI: from 8 to 6 days (P < 0·001). SSI rates remained low (4·5 per cent) in the sustainability phase. Conclusion Meaningful reductions in SSI can be achieved by implementing a multidisciplinary care bundle at a hospital-wide level.

Numerous studies have demonstrated the persistent localization of matrix metalloproteinase (MMP) expression to the interface between invading human colorectal cancer (CRC) cells and surrounding stroma supporting a role for MMPs in CRC invasion and metastasis. The present study sought to determine whether CRC cells of varying metastatic potential would have differential effects on host MMP release. Subcutaneous CRC tumors were generated in BALB/c nude mice using three CRC cell lines: SW480, SW620, and the highly metastatic SW620S5 clone. Representative samples from the subcutaneous CRC were then orthotopically implanted on the cecum of recipient nude mice. Subcutaneous and cecal tumors were analyzed for MMP expression via zymography, western blot, and RT-PCR. In vitro, none of the three cell lines expressed MMP-2 nor MMP-9. In contradistinction, the subcutaneous tumors expressed limited amounts of MMP-2 and MMP-9 while the cecal tumors expressed significant amounts of MMP-2 and MMP-9 as well as other smaller members of the MMP family. MMP-9 mRNA and protein was confirmed as host in origin by RT-PCR with mouse specific primers and a mouse MMP-9 molecular weight of 105 kDa as determined by zymography and western blot analysis. In situ hybridization also localized the mRNA for MMP-9 to the host stromal cells. In conclusion, CRC cells appear incapable of producing MMP-2 and MMP-9 in vitro but are capable of up-regulating host MMP production in vivo. Enhanced host MMP-9 production in metastatic CRC cell-derived subcutaneous and cecal tumors suggests that metastatic colon cells may acquire the expression of important MMP regulating factor(s) in vivo.

Increased understanding of the pathology and natural history of colorectal cancer has led to significant advances in the management of this disease. Surgical management of rectal cancer currently includes a spectrum of operative procedures ranging from radical operations to innovative sphincter-preserving techniques. At one end of the spectrum, 5% to 10% of patients present with small, superficially invasive rectal cancers amenable to a curative local excision. At the other end, a subset of patients present with locally advanced rectal cancers that require multimodality therapy, including sharp pelvic dissection with en-bloc resection of involved organs. However, the majority of rectal cancer patients present with nonfixed, yet deeply invasive, lesions requiring either a low anterior resection (LAR) or an abdominal perineal resection (APR). This report will address the controversies in the surgical management of colorectal cancer.

To determine the local control, survival, and functional outcome of local excision plus postoperative therapy for patients with rectal cancer.A total of 39 patients underwent a local excision (2 with snare excision of a T1 polyp and 37 with full-thickness local excision) followed by postoperative radiation therapy +/- 5-FU-based chemotherapy. The median follow-up was 41 months, and 11 patients had positive margins.The 5-year actuarial colostomy-free survival was 87% and overall survival was 70%. Crude local failure increased with T stage: 0% T1, 24% T2, and 25% T3. Of the 8 patients (21%) who developed local failure, 5 underwent salvage APR and were locally controlled. Actuarial local failure at 5 years was 31% for T2 disease and 27% for the total patient group. In the 32 patients with an intact sphincter, 94% had good to excellent sphincter function.Although local failure in patients with T2 tumors has increased since our prior report, the survival, sphincter function, and local salvage rates are acceptable. Local excision and postoperative therapy remains a reasonable alternative to APR in selected patients.

There are a subset of patients with invasive anal cancers who undergo an excisional biopsy either before or after combined-modality therapy (CMT). The objective of this study is to determine whether these patients can be adequately treated with a lower dose of pelvic radiation therapy.A total of 25 patients were treated with CMT either before or after an excisional biopsy. The four subsets included 8 patients with initial excision followed by CMT with 30-34 Gy (EX/30), 6 patients with initial excision followed by CMT with 45-50.4 Gy (EX/45), 10 patients treated by CMT with 30 Gy followed by an excision (30/EX), and 1 patient by CMT with 45 Gy followed by an excision (45/EX).For the total group, the actuarial 5-year disease-free survival was 78%, overall survival was 86%, colostomy-free survival was 91%, and local control was 82%. When patients received CMT either before or following an excision, the actuarial local control and survival results with 30-34 Gy vs. 45-50.4 Gy were similar. In contrast to radiation dose, in patients who received 30-34 Gy, the sequence of the excision (before or after CMT) did appear to have a borderline significant impact on local control. Actuarial 5-year local control was 100% for EX/30 vs. 67% for 30/EX (P = 0.08).Because of the small number of patients in each group and the retrospective nature of the analysis, it is difficult to draw definitive conclusions from this study. However, our data suggest that in patients who are selected to undergo an initial excisional biopsy followed by CMT, 30 Gy may be an adequate radiation dose. Local control may be higher in patients who undergo an excisional biopsy followed by CMT compared with the converse.

Tissue inhibitor of metalloproteinase (TIMP) inhibits the proteolytic activity of several matrix metalloproteinases centrally involved in tumor invasion and metastases. The purpose of this study was to determine the origin of TIMP-1 mRNA production in both human colorectal cancer (CRC) and metastatic liver lesions as well as define the relationships between TIMP-1 RNA expression and standard clinicopathological variables of CRC. Total cellular RNA, extracted from 56 CRC and 10 liver metastases, were examined by Northern blot hybridization. The mean/normal mucosa fold increase of TIMP-1 RNA was significantly elevated in both CRC (12.1 +/- 1.7) and liver metastases (10.0 +/- 3.6). No relationship was noted between TIMP-1 expression and tumor size, location nor differentiation. Based on lymph node metastases status, significantly higher TIMP-1 RNA levels were found in CRC with metastases than in those without metastases (15.6 +/- 3.3 versus 7.9 +/- 1.3) (P = 0.04). Similarly, TIMP-1 RNA levels were higher in primary CRC with distant metastases than those without distant metastases (17.6 +/- 4.1 versus 9.3 +/- 1.9) (P = 0. 04). In situ hybridization localized TIMP-1 mRNA predominantly in tumor stroma within spindle fibroblast-like cells rather than in cancer cells themselves. The correlation between the increased TIMP-1 mRNA level and advanced CRC stage noted in this study reflects a possible growth-promoting function for TIMP-1 in human CRC.

Transrectal ultrasonography (TRUS) supplements clinical evaluation of early carcinoma of the rectum in selecting patients for local operative therapy, such as transanal excision (TAE).This study was done to evaluate the accuracy of ultrasonographic staging of tumor depth (T stage) in patients with suspected early carcinoma of the rectum, to compare ultrasonographic with clinical T-staging accuracies within this patient group, to determine if any specific tumor characteristics (configuration, size, location) predispose toward ultrasonographic T-staging inaccuracy, and to examine the role of TRUS in operative selection for patients with early carcinoma of the rectum.Between April 1990 and December 1992, 62 patients with primary carcinoma of the rectum underwent ultrasonographic staging (uT), whereby three uT4, 27 uT3, 24 uT2 and eight uT1 carcinomas were identified. Of the 32 patients with suspected intramural (uT1 or uT2) disease, 27 underwent prompt operative excision or resection at our institution, allowing comparative histopathologic staging. In this highly selected patient subset, uT1 staging was correct in all instances; uT2 staging was incorrect in 45 percent of instances, with 30 percent having unpredicted transmural penetration. Ultrasonographic and clinical staging accuracies were quantitatively similar, and no tumor characteristics were consistently associated with ultrasonographic imprecision.Among patients with clinically suspected early carcinoma of the rectum, the decision to perform TAE is supported by ultrasonographic T1 staging. By contrast, the decision to perform TAE cannot be based solely on ultrasonographic T2 staging, because of the possibility for transmural penetration of tumor.

CRA4030 Background: In the absence of symptoms (bleeding, perforation, obstruction) or resectable metastatic disease, primary tumor resection in patients who present with synchronous metastatic colorectal cancer (CRC) is of uncertain benefit. The purpose of this study was to describe the frequency of intervention necessary to palliate the intact primary tumor in patients who present with synchronous stage IV CRC and receive up-front modern combination chemotherapy without prophylactic surgery. Methods: Using a prospective institutional database, we identified 233 consecutive patients from 2000 through 2006 with synchronous metastatic CRC and an unresected primary tumor who received oxaliplatin- or irinotecan-based, triple-drug chemotherapy (FOLFOX, IFL, or FOLFIRI) with or without bevacizumab as their initial treatment. The incidence of subsequent use of surgery, radiotherapy, and/or endoluminal stenting to manage primary tumor complications was recorded. Results: Of 233 patients, 217 (93%) never required surgical palliation of their primary tumor. Sixteen patients (7%) required emergent surgery for primary tumor obstruction or perforation, 10 patients (4%) required nonoperative intervention (stent or radiotherapy), whereas 213 (89%) never required any direct symptomatic management for their intact primary. Of those, 47 (20%) ultimately underwent elective colon resection at the time of metastasectomy and 8 (3%) during laparotomy for hepatic artery infusion pump placement. Neither use of bevacizumab, location of the primary tumor in the rectum, or metastatic disease burden were associated with increased intervention rate. In addition, when included as a time-varying covariate in a Cox regression model, the need for emergent intervention did not correlate with overall survival. Conclusions: Most patients with synchronous stage IV CRC who receive up-front modern combination chemotherapy never require palliative surgery for their intact primary. These data support the use of chemotherapy, without routine prophylactic resection, as the appropriate standard practice for patients with neither obstructed nor hemorrhaging primary colorectal tumors in the setting of metastatic disease. [Table: see text]

We have found that in 15 of 15 primary human colon tumors there was a significant decrease (by about 40%) in the levels of diacylglycerol when compared to paired adjacent normal mucosa samples. Assays on the same samples indicated that this decrease was seen both in tumors that did and did not display mutations in codon 12 of c-K-ras. These results, taken together with previous studies on protein kinase C, suggest that the protein kinase C signal transduction pathway is suppressed in human colon cancer.

Although dietary lipids have been implicated in colon cancer causation, the underlying mechanisms are not known. This paper indicates that when bacteria obtained from normal human feces are incubated with 14C-labeled phosphatidylcholine there is appreciable production of diacylglycerol (DAG), monoacylglycerol, and free fatty acid. Curiously, the production of DAG and monoacylglycerol, but not fatty acid, is strictly dependent on addition of certain bile acids to the incubation system. Among the bile acids tested deoxycholic acid is the most active. Assays of fecal specimens from 10 normal individuals demonstrate a 27-fold interindividual variation in the production of DAG in the in vitro assay system, and also in the absolute levels of DAG present in the same fecal samples. On the other hand, both parameters of DAG are quite constant in repeated fecal samples obtained from the same individual over a period of about 4 months. DAG is a normal physiological activator of protein kinase C, an enzyme that plays a key role in growth control and tumor promotion. We speculate, therefore, that DAG produced by the intestinal microflora might stimulate growth of colonic epithelial cells. Thus an interaction between dietary lipids, bile acids, and specific bacteria in the intestinal lumen could contribute to the risk of colon cancer development in humans.

3568 Background: Although CRT has emerged as the preferred treatment for T3 and/or lymph node (LN) positive rectal cancer, Sauer et al (NEJM 2004) demonstrated that 18% of patients deemed suitable for preop CRT via endorectal ultrasound (ERUS) were overstaged and therefore received unnecessary preoperative CRT. Since data also suggest that LN negative rectal cancer s/p TME may not need adjuvant therapy, it is reasonable to consider the omission of radiotherapy for the cT3N0 subset. We therefore determined the accuracy of pre-CRT ERUS/MRI staging in order to explore the validity of a non-radiation approach for cT3N0 disease. Methods: 188 ERUS/MRI staged T3N0 rectal cancer patients from 6 insitutions in the US, Europe and Asia received preoperative CRT (5-FU based and 45–52.5 Gy) followed by radical resection. Rates of pathologic complete response (pCR) and mesorectal LN involvement were determined. Results: Tumors were located a median of 5 centimeters from the anal verge. Sphincter-preserving surgery was performed in 135 (81%) patients. Overall pCR was 19%. Median number of LN sampled was 9 (range 0–38). Rate of positive LN was significantly associated with T-stage: pT0: 3%, pT1: 7%, pT2: 20%, pT3–4: 36%(p=0.001). 41 patients (22%) had pathologically positive mesorectal LN. There was no significant difference in rate of positive LN between those staged by ERUS and MRI(25% vs 16%, p=0.19). Conclusions: Accuracy of preoperative ERUS/MRI for identifying mid to distal T3N0 rectal cancer is limited, as 22% will have undetected mesorectal LN involvement despite CRT. Therefore, ERUS/MRI staged T3N0 patients should continue to receive preoperative CRT. Although 19% are overstaged and therefore overtreated, our data suggest that an even larger number would be understaged and require postoperative CRT, which is associated with inferior local control, higher toxicity, and poor functional outcome. No significant financial relationships to disclose.

The possible roles in experimental colon carcinogenesis of two protooncogenes (c-myc and c-H-ras), two endogenous retrovirus-related DNA sequences [rat leukemia virus (RaLV) and the 30S sequence], and two cell cycle related genes (beta-actin and ornithine decarboxylase) were studied by analyzing the levels of their corresponding RNAs during the course of azoxymethane induced and high fat promoted colon carcinogenesis. F-344 male rats received three s.c. injections of azoxymethane (15 mg/kg) or normal saline and were then subdivided into high or low fat diet groups. During subsequent serial sacrifices normal colon mucosa, adenomas, and carcinomas were harvested for histology and RNA extraction. Seventy-one RNA samples were analyzed by the Northern blot hybridization procedure using the appropriate 32P-labeled DNA probes. A marked increase in the abundance of c-myc, RaLV, and 30S RNAs were seen in all of the colon tumors, including adenomas and invasive carcinomas. No or a very low level of expression of RaLV and c-myc RNA was found in the flat grossly normal mucosa adjacent to the tumors and in the mucosa of the control rats. Some of the colon tumors also displayed increased levels of c-H-ras, ornithine decarboxylase and beta-actin RNAs but these findings were less striking and more variable than those seen with c-myc, RaLV, and 30S RNAs. These results suggest that increased expression of the c-myc protooncogene and of the endogenous retrovirus-like sequences (RaLV) and 30S are hallmarks of colon carcinogenesis in this model system.

First-degree relatives of colon cancer patients are at elevated risk for developing colorectal neoplasms. In order to assess the potential usefulness of screening by colonoscopy in this high-risk population, we reviewed the records of 48 colonoscopies performed on asymptomatic patients who were self- or physician-referred for colonoscopy because of a history of one or more first-degree relatives with colon cancer. Twelve (25%) had at least one adenomatous polyp, but no significant atypia was detected. No cancers were detected. One third of the lesions were beyond the reach of a flexible sigmoidoscope. This apparent increase in the prevalence of adenomas was most striking (46%) among men over the age of 50. These preliminary results demonstrate that colonoscopy is effective in detecting and removing adenomatous polyps in a substantial fraction of asymptomatic patients whose sole risk-factor is being a first-degree relative of a patient with colon cancer. Further studies in larger populations are warranted to determine the use of colonoscopy in screening these high-risk individuals.

Protein kinase C (PKC) is a Ca2+- and phospholipid-dependent protein kinase which is implicated in tumor promotion, since it has been demonstrated to be a high affinity receptor for tumor promoters such as 12-O-tetradecanoylphorbol-13-acetate. Colon carcinogenesis appears to proceed through distinct stages of initiation and promotion. The present studies show that PKC and calcium-dependent protein kinase specific activities are reduced in human colon carcinomas when compared to their normal adjacent colon mucosa. There were significantly higher Ca2+-dependent protein kinase and PKC specific activities observed in both the cytosolic and particulate fractions of the normal mucosa relative to the corresponding values obtained with the carcinoma fractions. The average specific activity ratios were 5.1 (normal cytosolic/carcinoma cytosolic) and 3.7 (normal particulate/carcinoma particulate) for PKC. PKC activity was reduced in the carcinoma tissues with respect to both protein and tissue weight. The percentage of Ca2+-dependent protein kinase and PKC activities that were present in the particulate fraction of each of the samples varied considerably among tissues, and in general there was no systematic difference between the carcinoma and normal mucosa samples. However, in the carcinoma samples that contained an extensive admixture of benign adenomatous tissue, the particulate fractions consistently contained greater than 60% of the total Ca2+-dependent protein kinase and PKC activities. The present studies indicate that colon carcinogenesis is associated with alterations in cellular levels of protein kinase activities.

This review focuses on specific effects of diet on cancer risk and the relevance of these dietary effects to the risk of cancer in the elderly. The authors address the impact of certain dietary factors on cancer risk by reviewing their roles in two distinct phases of carcinogenesis: "imitation" and "promotion."

We have developed a rapid, nonradioactive large scale method for the detection of ras oncogenes in human tumors. DNA is amplified by the polymerase chain reaction (PCR), and then digested with specific restriction enzymes to detect either endogenous or primer-mediated Restriction Fragment Length Polymorphisms (RFLPs). We report here that three of 15 colon tumors tested contain K-ras codon 12 aspartic acid mutations and one, along with the HCT 116 colon carcinoma cell line, contains a K-ras codon 13 aspartic acid mutation. On the other hand, we did not detect H- or K-ras codon 12 mutations or the K-ras codon 13 aspartic acid mutation in 25 esophageal and 27 gastric cardia tumors isolated from patients in Lin-xing County, China. By incorporating nucleotide substitutions in PCR primers, this method can be applied towards the rapid, non-radioactive screening of virtually any genetic disease caused by known point mutations.