Scoping review: The terminology used to describe major abdominal surgical procedures.

BACKGROUND: Major abdominal surgery (MAS) can have a profound impact on the patient but there is currently no consensus as to which surgical procedures constitute MAS. The main objective of this work is to ascertain the terminology used to describe MAS procedures and to apply these findings in order to propose a definition of MAS. METHODS: The following databases were searched: Ovid MEDLINE (R) ALL, Embase Classic and Embase (via OvidSP), Global Health (via OvidSP), Health Management Information Consortium (via OvidSP), APA PsycInfo (via OvidSP), PubMed and Web of Science. Original research articles, published between 1980 and April 26, 2022 that contained a description of MAS procedure were included in this study. Article screening and data extraction was undertaken independently by 3 authors. Content analysis was performed to identify key terminology used to describe MAS. RESULTS: Five thousand six hundred and sixty three articles were identified, of which 767 underwent full-text review and 312 were included in the scoping review. Content analysis resulted in 4 main categories: (1) pre-operative factors, (2) intraoperative factors, (3) operation-related factors, (4) post-operative factors. Operation-related factors was the predominant category (1137 references coded). The gastrointestinal resection made the vast majority of the references coded (591). CONCLUSIONS: Based on these results, the term "major abdominal surgery" should be defined as an intra-peritoneal operation with no primary involvement of the thorax, involving either luminal resection and/or resection of a solid organ associated with the gastrointestinal tract. However, further work is required to verify this definition using real world data.

Analysis of colorectal cancers in British Bangladeshi identifies early onset, frequent mucinous histotype and a high prevalence of RBFOX1 deletion.

BACKGROUND: Prevalence of colorectal cancer (CRC) in the British Bangladeshi population (BAN) is low compared to British Caucasians (CAU). Genetic background may influence mutations and disease features. METHODS: We characterized the clinicopathological features of BAN CRCs and interrogated their genomes using mutation profiling and high-density single nucleotide polymorphism (SNP) arrays and compared findings to CAU CRCs. RESULTS: Age of onset of BAN CRC was significantly lower than for CAU patients (p=3.0 x 10-5) and this difference was not due to Lynch syndrome or the polyposis syndromes. KRAS mutations in BAN microsatellite stable (MSS) CRCs were comparatively rare (5.4%) compared to CAU MSS CRCs (25%; p=0.04), which correlates with the high percentage of mucinous histotype observed (31%) in the BAN samples. No BRAF mutations was seen in our BAN MSS CRCs (CAU CRCs, 12%; p=0.08). Array data revealed similar patterns of gains (chromosome 7 and 8q), losses (8p, 17p and 18q) and LOH (4q, 17p and 18q) in BAN and CAU CRCs. A small deletion on chromosome 16p13.2 involving the alternative splicing factor RBFOX1 only was found in significantly more BAN (50%) than CAU CRCs (15%) cases (p=0.04). Focal deletions targeting the 5' end of the gene were also identified. Novel RBFOX1 mutations were found in CRC cell lines and tumours; mRNA and protein expression was reduced in tumours. CONCLUSIONS: KRAS mutations were rare in BAN MSS CRC and a mucinous histotype common. Loss of RBFOX1 may explain the anomalous splicing activity associated with CRC.

HSP27 expression in primary colorectal cancers is dependent on mutation of KRAS and PI3K/AKT activation status and is independent of TP53.

Colorectal adenomas display features of senescence, but these are often lost upon progression to carcinoma, indicating that oncogene induced senescence (OIS) could be a roadblock in colorectal cancer (CRC) development. Heat shock proteins (HSPs) have been implicated in the prognosis of CRC and HSP based therapy is a current interest for drug development. Recent cell culture studies have suggested that in the absence of a TP53 mutation, OIS mediated by PI3K/AKT activation can be circumvented by high expression of HSPs. Furthermore, while PI3K/AKT activation and KRAS mutations are independent inducers of OIS, PI3K/AKT activation can suppress KRAS-induced OIS when both are present in cultured cells. As KRAS mutations, PI3K/AKT activation and TP53 mutations are all common features of CRC, it is possible that the requirement for HSP to inhibit OIS in CRC is dependent on the mutation spectrum of a tumour. However, work on HSP that utilised mutation profiled human tumour tissues has been limited. Here, we characterised the expression of two major HSP proteins (HSP27 and 72) by immunohistochemistry (IHC), the mutation status of TP53, KRAS and PIK3CA genes by direct sequencing and the activation status of AKT by IHC in a cohort of unselected primary CRC (n=74). We compare our data with findings generated from cell-based studies. Expression of HSP27 and HSP72 was correlated to clinicopathological and survival data but no significant association was found. We also established the mutation status of TP53, KRAS and PIK3CA genes and the activation status of AKT in our CRC panel. We did not detect any associations between HSP27 or HSP72 expression with TP53 mutation status. However, HSP27 expression in CRCs was strongly associated with the co-presence of wildtype KRAS and activated PI3K/AKT (p=0.004), indicating a possible role of HSP27 in overcoming PI3K/AKT induced OIS in tumours. Our studies suggest a role for using archival tissues in validating hypotheses generated from cell culture based investigations.

A distinct DNA methylation profile associated with microsatellite and chromosomal stable sporadic colorectal cancers.

Aberrant DNA methylation, microsatellite instability (MSI) and chromosomal instability (CIN) are well-characterised molecular features of sporadic colorectal cancers (CRCs). In addition to CpG island methylator phenotype (CIMP) associated with MSI, an intermediate methylation subgroup is also a feature of non-MSI cancers. A large proportion of CRCs have no evidence of either MSI or CIN, here called Microsatellite and Chromosomal Stable (MACS), and require their methylation profile to be established. The clinical and molecular features of 170 sporadic CRC patients were investigated and stratified into MSI, CIN and MACS groups. MACS were most often found in the left colon and had a significantly lower BRAF mutation frequency (p < 0.001) compared with MSI. MACS had better survival [hazard ratio (HR) = 0.244, p = 0.017] compared with CIN, but were similar to MSI. The methylation status of 1,505 CpG loci from cancer-related genes was analysed in a subset of CRCs (n = 44 normal-tumour pairs) and compared with CIN, MSI and MACS status. Using two-way hierarchical clustering, three subgroups were identified, which associated with CIN, MSI and MACS status. Using significance analysis of microarray, 16 CpG loci demonstrating methylation changes associated with MACS were identified. A combination of six loci identified MACS with 81% sensitivity and 93% specificity. This result now requires independent validation. Hypomethylation of a CpG locus within the sonic hedgehog (SHH) promoter correlated with increased gene expression and was associated significantly with MACS cancers. In conclusion, we propose that MACS have distinct clinicopathological features and can be distinguished from other CRCs by a specific set of methylation loci.

Right colonic transposition technique: when the left colon is unavailable for achieving a pelvic anastomosis.

PURPOSE: On occasion, the left colon is not available for rectal or low pelvic anastomosis either because of synchronous pathology, previous resections, or inadequate blood supply. The short middle colic pedicle prevents use of the transverse colon for this purpose. In this situation, the right colon is a good anastomotic conduit. The aim of this video is to demonstrate the right colonic transposition technique. METHODS: Intraoperative footage was filmed and edited in a multimedia format. Operative details were as follows: the diseased left colon and transverse colon are excised; the right colon is fully mobilized and transposed 180 degrees anticlockwise around the axis of the ileocolic pedicle, so the hepatic flexure reaches into the pelvis without tension. The hepatic flexure is then used for anastomosis within the pelvis either to the residual rectum or anus (see Supplemental Digital Content, Videos 1-3, http://links.lww.com/DCR/A46, http://links.lww.com/DCR/A47, and http://links.lww.com/DCR/A48). Case notes were reviewed to analyze clinical outcome and bowel function. RESULTS: Three patients underwent the technique, 2 females and 1 male (median age, 45 (range, 30-55) years). Median operating time was 98 (range, 95-114) minutes. There were no anastomotic failures or other major complications. One patient had a superficial wound infection. The median in-hospital stay was 7 (range, 7-8) days. The median time to first bowel movement was 3 (range, 3-4) days; the median daily stool frequency was 4 (range, 3-4) on discharge, decreasing to 2 daily stools 12 months after surgery. Stoma formation and total colectomy were successfully avoided in each patient. CONCLUSIONS: Right colonic transposition is a useful technique to enable the construction of a tension-free rectal anastomosis with a good blood supply. The use of the right colon in these clinicopathological situations can be achieved with low morbidity and results in good short- and long-term bowel function in these patients. Careful preservation of the ileocolic pedicle and division of the right colic vessels are essential to facilitate successful anastomosis.

Platelet-leucocyte aggregates form in the mesenteric vasculature in patients with ulcerative colitis.

BACKGROUND AND AIMS: Inflammation and thrombosis are closely related processes, which may play a role in the pathogenesis, as well as complications, of inflammatory bowel disease (IBD). Platelet activation and platelet-leucocyte aggregation are increased and platelet aggregation is known to occur in the mesenteric vasculature in IBD. The aims of this study were to test the hypotheses that platelet-leucocyte aggregation, platelet activation and neutrophil activation occur in the mesenteric vessels of patients with ulcerative colitis (UC). PATIENTS AND METHODS: Platelet-leucocyte aggregates (PLAs), platelet activation (P-selectin expression) and neutrophil activation (L-selectin expression, which decreases on neutrophil activation) were assessed flow cytometrically in mesenteric arterial, and venous blood sampled in eight patients with UC and eight controls with colonic carcinoma undergoing intestinal resections. RESULTS: In the patients with UC, the number of PLAs in the mesenteric vein exceeded that in the artery, the median rise being 38% (P=0.02). In UC, arterial PLA numbers were 0.17 (0.02-0.32) (median, range) x 10(9)/l versus venous 0.26 (0.09-1.6) x 10(9)/l (P=0.02). The median percentage increase was 45%. Mesenteric PLA formation did not occur in patients with colonic carcinoma [arterial 0.06 (0.03-0.49) x 10(9)/l vs. venous 0.05 (0.02-0.35) x 10(9)/l; P=0.55]. The median percentage change was +45% for UC patients and -5% for controls. No arteriovenous gradient was observed in P-selectin expression, but L-selectin expression (arbitrary units), increased in the mesenteric vasculature of the UC patients [arterial 839 (503-995), venous 879 (477-1035); P=0.03] and fell in those with colonic carcinoma [arterial 900 (660-959), venous 850 (546-957); P=0.04]. The median percentage change was +4% for UC and -7% for controls. CONCLUSION: The finding of increased numbers of PLAs in the venous mesenteric circulation supports the hypothesis that activated vascular endothelium stimulates PLA formation in UC.

MRI demonstration of the effect of neoadjuvant radiotherapy on rectal carcinoma.

BACKGROUND AND PURPOSE: In patients with locally advanced rectal cancer, neoadjuvant long course (45-54 Gy in 25-30 fractions) chemoradiotherapy (CRT) may reduce tumour size and result in downstaging. In patients with primary resectable tumour short course (25 Gy in 5 fractions) radiotherapy (SCRT) reduces local recurrence but downstaging the disease or altering tumour size has not been described. We aimed to assess change in tumour size on MRI after SCRT or CRT. MATERIALS AND METHODS: Nineteen patients with rectal carcinoma underwent MRI before and after SCRT or CRT. In each case, tumour length and width were documented and number of locoregional lymph nodes recorded. Total mesorectal excision was performed in 15 patients and MR findings correlated with histopathology. RESULTS: Ten patients received SCRT and nine CRT. Tumour length reduced by 19% overall (15% following SCRT, 23% following CRT). Greater than 30% reduction (partial response) in maximum tumour thickness was seen in 4/10 (40%) following SCRT and 5/9 (56%) following CRT. CONCLUSIONS: Significant reduction in tumour size can be achieved with preoperative long course CRT and SCRT. This unexpected finding following SCRT has not been previously described.

Molecular staging of colorectal cancer: new paradigm or waste of time?

Colorectal cancer staging describes disease spread by assessing tumour penetration of the bowel wall and the presence of lymph node involvement and distant metastases. Although useful for stratifying patients into risk groups that indicate prognosis as well as treatment, conventional staging frequently fails to predict the biological behaviour of individual tumours within the same stage. Accordingly, up to a third of patients undergoing apparently curative surgery develop systemic disease and die from cancer-related causes. This heterogeneity of clinical outcome is mirrored by similarly extensive molecular diversity, where progression to systemic disease is associated with a range of genetic and epigenetic alterations. This has led to the idea that tumour stratification based on molecular taxonomy might increase the prognostic accuracy for the individual patient. However, despite the description of many putative individual and multiple molecular biomarkers, the data generated by molecular diagnostic assays have not proved to be either robust or consistently reproducible. Experimental bias exists throughout the entire process, starting with sample collection and ending with data interpretation. There is an urgent need to integrate clinical, biochemical, genetic and molecular data, and findings must be validated in prospective, well-controlled clinical studies of large numbers of diverse patients across multiple institutions. Only then can the implementation of molecular staging assays into clinical practice be considered.

Immunogenic hsp-70 is overexpressed in colorectal cancers with high-degree microsatellite instability.

PURPOSE: Colorectal cancers that display high-degree mi-crosatellite instability are associated with an improved prognosis and evidence of an activated host immune response. Molecular analyses have suggested that heat shock proteins, a family of proteins that have key immunologic functions, are upregulated in these cancers. We aimed to explore the expression of heat shock proteins 70 and 110 and their relationship to microsatellite instability, survival, and other clinicopathologic parameters. METHODS: Twenty-six colorectal cancers that displayed microsatellite instability were matched by age, stage, and site in the colorectum to 26 microsatellite-stable cancers. Immunohistochemistry was used to detect expression of both markers. RESULTS: The microsatellite-unstable group showed significantly higher expression of heat shock protein 70 than the microsatellite-stable group (P = 0.006), and patients undergoing curative resections for unstable cancers had improved prognosis compared with their stable counterparts (P = 0.026). Significantly, in a multivariate survival analysis, low or absent heat shock protein 70 expression was independently associated with a poor outcome (P = 0.001). CONCLUSIONS: Heat shock protein 70 has known functions that promote antitumor immune responses. Its overexpression in colorectal cancers with microsatellite instability may be pivotal to explaining these tumors' enhanced immunogenicity and improved prognosis.

The immunogenicity of colorectal cancers with high-degree microsatellite instability.

BACKGROUND: High-degree microsatellite instability (MSI-H) is a feature of approximately 15% of sporadic colorectal cancers. Patients with MSI-H cancers have been reported to have a better prognosis than those with non-MSI-H cancers. The MSI-H subset is also characterised by a dense infiltrate of intra-epithelial lymphocytes and the hypothesis that the latter represents an efficacious immune response contributing to improved outcome is very attractive. METHODS: Data for this review were identified by searches of MEDLINE, PubMed, and cross references from relevant articles using the search terms 'microsatellite instability', 'colorectal cancer' and 'immunology', 'immune response' or 'immunogenicity'. RESULTS: A total of 38 articles were identified by the search criteria and a further 95 articles by cross-referencing. The relevance of the articles to be interviewed was established by hand searching. Out of a total of 133 articles identified, 47 articles were rejected due to lack of relevance. A total of 86 articles were included in the review, pertaining to microsatellite instability in colorectal cancer, and immune mechanisms in colorectal cancer. CONCLUSION: It is suggested that this distinct group of colorectal cancers may have inherent immunogenic properties and that further elucidation of these may be invaluable to the development of successful immunotherapy.

Gene expression profiling for molecular staging and prognosis prediction in colorectal cancer.

A key issue for patients undergoing surgery for colorectal cancer is the accurate prediction of treatment outcome. Currently, classification of a tumor by histopathologic stage is the most accurate prognostic factor for the risk assessment of treatment failure. However, despite improved histologic techniques and the application of novel immunohistochemical and molecular techniques, it is still not possible to delineate the underlying biochemical and genetic events that predict clinical outcome for individual cancer patients. One reason for this lack of progress is that the factors which determine the metastatic potential of a primary tumor are still unknown. This reality, coupled to dramatic technological developments in the field of expression profiling, has started a paradigm shift in the staging of colorectal cancers. It has raised expectations that genetic and/or transcriptome profiling of the primary tumor will result in the identification of prognostic determinants relevant to the individual patient. In turn, this may allow a clinically relevant definition of patient subgroups based on individual molecular parameters for rational decision making regarding choice of therapy.

Colorectal cancers with microsatellite instability display mRNA expression signatures characteristic of increased immunogenicity.

BACKGROUND: Colorectal cancers displaying high-degree microsatellite instability (MSI-H) have an improved prognosis compared to microsatellite stable (MSS) cancers. The observation of pronounced lymphocytic infiltrates suggests that MSI-H cancers are inherently more immunogenic. We aimed to compare the gene expression profiles of MSI-H and MSS cancers to provide evidence for an activated immune response in the former. RESULTS: We analysed tissue from 133 colorectal cancer patients with full consent and Local Ethics Committee approval. Genomic DNA was analysed for microsatellite instability in BAT-26. High-quality RNA was used for microarray analysis on the Affymetrix HG-U133A chip. Data was analysed on GeneSpring software version 6.0. Confirmatory real-time RT-PCR was performed on 28 MSI-H and 26 MSS cancers. A comparison of 29 MSI-H and 104 MSS cancers identified 2070 genes that were differentially expressed between the two groups [P < 0.005]. Significantly, many key immunomodulatory genes were up-regulated in MSI-H cancers. These included antigen chaperone molecules (HSP-70, HSP-110, Calreticulin, gp96), pro-inflammatory cytokines (Interleukin (IL)-18, IL-15, IL-8, IL-24, IL-7) and cytotoxic mediators (Granulysin, Granzyme A). Quantitative RT-PCR confirmed up-regulation of HSP-70 [P = 0.016], HSP-110 [P = 0.002], IL-18 [P = 0.004], IL-8 [0.002] and Granulysin [P < 0.0001]. CONCLUSIONS: The upregulation of a large number of genes implicated in immune response supports the theory that MSI-H cancers are immunogenic. The novel observation of Heat Shock Protein up-regulation in MSI-H cancer is highly significant in light of the recognised roles of these proteins in innate and antigen-specific immunogenicity. Increased mRNA levels of pro-inflammatory cytokines and cytotoxic mediators also indicate an activated anti-tumour immune response.

Differential expression patterns of the insulin-like growth factor 2 gene in human colorectal cancer.

Tumour development and metastasis are associated with altered gene expression profiles. The aim of this study was to identify the transcriptional differences in normal, tumour and metastatic tissue. We used oligonucleotide arrays to identify differential expression patterns of insulin-like growth factor 2 (IGF 2) between 139 primary colorectal tumour specimens and 42 tumour-adjacent mucosa specimens from colorectal cancer (CRC) patients. The expression levels of the IGF 2 gene were significantly increased in primary tumours compared with adjacent mucosae. This was concordant with our real-time RT-PCR quantification of 48 matched tumour mucosa samples. IGF 2 expression levels were also measured by RT-PCR quantitative analysis in 18 liver metastases and 10 normal tissues from patients without cancer. The mRNA levels were significantly under-expressed in liver metastases compared with either colorectal tumours or adjacent normal mucosae. The non- malignant normal tissue expressed significantly lower IGF 2 levels than adjacent normal tissue, and this was not due to a field effect originating from the tumour. In addition, our microarray data demonstrated that IGF 2 expression was down-regulated in sporadic microsatellite instability (MSI-H) CRC and parallels under-expression of hMLH1 and IGF 2 receptor genes in these patients. We conclude that IGF 2 plays an important role in CRC development. Also, individuals with loss of genomic imprinting (LOI) causing over-expression of IGF 2 may be at greater risk of developing CRC. However, this LOI may be reversed in MSI-H patients.

Quantification of cytokeratin 20, carcinoembryonic antigen and guanylyl cyclase C mRNA levels in lymph nodes may not predict treatment failure in colorectal cancer patients.

Conventional histopathologic staging of primary colorectal cancers does not allow accurate prognostic stratification within a given tumour stage. Therefore, PCR-based assays are increasingly used to try to predict more accurately the likelihood of disease progression for the individual patient. Real-time reverse transcription PCR (RT-PCR) assays were used to detect and quantitate cytokeratin 20 (ck20), carcinoembryonic antigen (CEA) and guanylyl cyclase C (GCC) mRNA in 149 lymph nodes (LN) from 17 patients with benign disease and 302 LN from 42 patients with colorectal cancer who had curative (R0) resections. None of the markers were specific, with ck20, CEA and GCC mRNA detected in 47%, 89% and 13% of 149 LN, respectively, from patients with benign disease. The sensitivity of all 3 markers was very high, with mRNA detected in 93%, 100% and 97% of 30 histologically involved LN, respectively. There was significant overlap in the mRNA levels of all 3 markers between histologically involved and uninvolved LN. There was no association between mRNA levels and distant recurrence (median follow-up: 3.94 years, range 3.35-5.12). We conclude that the use of molecular techniques to detect occult disease in LN may suffer from the same limitations as conventional methods. Instead, accurate prognostic stratification requires careful assessment of the likely metastatic potential of the primary cancer.

Identification of differentially expressed genes associated with colorectal cancer liver metastasis.

The molecular mechanisms underlying successful metastasis of primary colorectal tumour to the liver remain unknown. We have used suppression subtractive hybridisation (SSH) and reverse Northern dot blot analysis to profile the mRNA expression patterns of a primary colorectal cancer and its liver metastasis. After SSH and reverse Northern dot blot analysis, differential expression was confirmed in 17 clones from the forward, and 13 clones from the reverse subtracted cDNA library. Four clones showed no significant sequence identities with any known sequences in the GenBank data base and likely to represent novel genes whose up- or down-regulation is associated with colorectal liver metastasis. Interestingly, one of the 13 down-regulated clones displayed 99% sequence identity with the BRCA1 tumour suppressor gene. Since promoter methylation is a direct cause of transcription silencing of the BRCA1 gene in approximately 10-20% of human breast cancer we further investigated its promoter methylation status in ten primary colorectal tumour samples, but revealed no evidence of promoter methylation.

Surgery for colorectal cancer.

Colorectal cancer remains the second commonest cause of cancer death in North America and Western Europe. Surgery remains the mainstay of treatment. The aim of surgery should be to achieve cure and to avoid locoregional recurrence. The fixity of the primary tumour determines resectability, and the extent of spread determines ultimate survival. Patients with rectal cancer present a particular problem. There is good evidence that lower local recurrence rates may be achieved both by improvements in surgical technique and the use of adjuvant radiotherapy. The importance of adequate treatment of the circumferential tumour margin cannot be over-emphasised; meticulous attention is required to ensure an adequate circumferential excision. The lowest incidences of locoregional recurrence are reported by surgeons who perform total mesorectal excision. Anorectal function, sexual and urinary dysfunction may occur after rectal excision. Both postoperative and pre-operative radiotherapy can reduce the incidence of local recurrence. However, in view of the low recurrence rates obtained with TME alone, the role of adjuvant radiotherapy requires further evaluation. Several aspects of the surgical management of colorectal cancer, for example, the role of transanal local excision of selected rectal cancers and laparoscopic surgery, the management of obstructed cases and the role of follow-up remain to be defined clearly.