Resectional surgery for malignant disease of abdominal digestive organs is not surgery of the organ itself, but also that of the mesenteric organ.

Despite large strides in molecular oncology, surgery remains the bedrock in the management of visceral cancer. The primacy of surgery cannot be understated and a mesenteric (i.e. ontogenetic) approach is particularly beneficial to patients. Heald greatly advanced the management of rectal cancer with his description of the anatomical foundation of total mesorectal excision (TME), dramatically improving outcomes worldwide with this mesenteric-based approach. Moreover, complete mesocolic excision (CME) based on similar principles is becoming popular. Introduced by Hohenberger, CME resembles TME insofar as it emphasises strictly anatomical dissection along embryological planes to detach an intact (i.e. "complete") mesentery with peritoneal envelope. CME also incorporates "central" vascular ligation (CVL) which broadly correlates with the "D3 lymphadenectomy" of Eastern literature. As many surgeons already practise anatomical and mesenteric-based surgery, it is unclear how the putative benefits of CME (including CVL) arise. Herein, we argue that these may relate to a more extensive resection of the mesentery, and thus mesenteric tumour deposits within the connective tissue lattice of the mesentery, and not necessarily the lymphadenectomy alone. We believe the connective tissue interface between the bowel wall and mesentery provides an alternative mode of spread of pathogenic elements. Whilst this remains a suggestion only, it would explain the histological independence of tumour deposits and why a greater mesenterectomy could be associated with benefits in survival. If this argument holds, it follows that resectional surgery for digestive organ malignancy is not surgery of the organ itself (or lymphatics only), but also that of the contiguous mesentery.

The relationship between mesorectal grading and oncological outcome in rectal adenocarcinoma.

AIM: The prognostic association between mesorectal grading and oncological outcome in patients undergoing resection for rectal adenocarcinoma is controversial. The aim of this retrospective chart review was to determine the individual impact of mesorectal grading on rectal cancer outcomes. METHOD: We compared oncological outcomes in patients with complete, near-complete and incomplete mesorectum who underwent rectal excision with curative intent from 2009 to 2014 for Stage cI-III rectal adenocarcinoma. We also assessed the independent association of mesorectal grading and oncological outcome using multivariate models including other relevant variables. RESULTS: Out of 505 patients (339 men, median age of 60 years), 347 (69%) underwent a restorative procedure. There were 452 (89.5%), 33 (6.5%) and 20 (4%) patients with a complete, near-complete and incomplete mesorectum, respectively. Local recurrence was seen in 2.4% (n = 12) patients after a mean follow-up of 3.1 ± 1.7 years. Unadjusted 3-year Kaplan-Meier analysis by mesorectal grade showed decreased rates of overall, disease-free and cancer-specific survival and increased rates of overall and distant recurrence with a near-complete mesorectum, while local recurrence was increased in cases of an incomplete mesorectum (all P < 0.05). On multivariate analyses, a near-complete mesorectum was independently associated with decreased cancer-specific survival (hazard ratio 0.26, 95% CI 0.1-0.7; P = 0.007). There were no associations between mesorectal grading and overall survival, disease-free survival, overall recurrence or distant recurrence (all P > 0.05). CONCLUSION: Mesorectal grading is independently associated with oncological outcome. It provides unique information for optimizing surgical quality in rectal cancer.

Colorectal surveillance after segmental resection for young-onset colorectal cancer: is there evidence for extended resection?

AIM: Although sporadic colorectal cancer (CRC) usually occurs in patients aged over 50, recent evidence suggests that the incidence is increasing in younger patients. Such patients are theoretically at high risk of metachronous neoplasia and may be candidates for extended prophylactic colectomy. This study aimed to define the risk of metachronous cancer/adenomas during follow-up of younger patients who underwent segmental colectomy for CRC. METHOD: A CRC database was used to identify patients aged under 50 who underwent surgery for CRC between 1994 and 2010. Patients diagnosed with hereditary cancer or inflammatory bowel disease were excluded. The primary end-points were frequency of extended resection and the rates of metachronous cancer and high-risk adenomas during follow-up. RESULTS: There were 284 young patients with a resectable primary tumour, of whom 280 (98.6%) underwent segmental resection, 3 (1%) extended resection and 1 (0.4%) local resection. Endoscopic follow-up was available for 150 of the patients who had segmental colectomy, with a mean age of 42.6 (±5.8) years at diagnosis and median follow-up time of 68 months (interquartile range 45-105). Out of these 150 patients, 4 (2.7%) developed metachronous colonic adenocarcinoma at 24, 71, 151 and 228 months after index surgery. Thirty additional patients had at least one adenoma identified during surveillance, and three had sessile serrated polyps. Out of the three patients undergoing extended resection, none had metachronous cancer or advanced adenomas at an average follow-up of 17 years. CONCLUSION: A segmental colectomy or proctectomy is adequate treatment for patients presenting with CRC under the age of 50.

Robotic versus conventional laparoscopic rectal cancer surgery in obese patients.

AIM: Obesity adds to the technical difficulty of laparoscopic colorectal surgery. The robotic approach has the potential to overcome this limitation because of its proposed technical advantages over laparoscopy. The aim of this retrospective study was to compare the short-term outcomes of robotic surgery (RS) vs conventional laparoscopy surgery (LS) in this patient population. METHOD: Patients with a body mass index ≥ 30 kg/m2 undergoing RS or LS for rectal cancer between January 2011 and June 2014 were identified from an institutional database. Perioperative parameters, oncological findings and postoperative 30-day short-term outcomes were compared between the RS and LS groups. RESULTS: The RS and LS groups included 29 and 27 patients, respectively. Groups were comparable in terms of patient demographics, body mass index (34.9 ± 7.2 vs 35.2 ± 5.0 kg/m2 , P = 0.71), comorbidities, surgical and tumour characteristics. Comparison of the intra-operative findings revealed no significant differences between the groups including operative time (329.0 ± 102.2 vs 294.6 ± 81.1 min, P = 0.13), blood loss (434.0 ± 612.4 vs 339.4 ± 271.9 ml, P = 0.68), resection margin involvement (6.9% vs 7.4%, P = 0.99), conversions (3.4% vs 18.5%, P = 0.09) and complications (6.9% vs 0%, P = 0.49). Regarding postoperative outcomes, there were no significant differences in morbidity except that robotic surgery was associated with a quicker return of bowel function (median 3 vs 4 days, P = 0.01) and shorter hospital stay (median 6 vs 7 days, P = 0.02). CONCLUSION: Robotic surgery for rectal cancer in obese patients has short-term outcomes similar to laparoscopy, but accelerated postoperative recovery.

Transcriptomic profiles differentiate normal rectal epithelium and adenocarcinoma.

Adenocarcinoma is a histologic diagnosis based on subjective findings. Transcriptional profiles have been used to differentiate normal tissue from disease and could provide a means of identifying malignancy. The goal of this study was to generate and test transcriptomic profiles that differentiate normal from adenocarcinomatous rectum. Comparisons were made between cDNA microarrays derived from normal epithelium and rectal adenocarcinoma. Results were filtered according to standard deviation to retain only highly dysregulated genes. Genes differentially expressed between cancer and normal tissue on two-groups t test (P < 0.05, Bonferroni P value adjustment) were further analyzed. Genes were rank ordered in terms of descending fold change. For each comparison (tumor versus normal epithelium), those 5 genes with the greatest positive fold change were grouped in a classifier. Five separate tests were applied to evaluate the discriminatory capacity of each classifier. Genetic classifiers derived comparing normal epithelium with malignant rectal epithelium from pooled stages had a mean sensitivity and specificity of 99.6% and 98.2%, respectively. The classifiers derived from comparing normal and stage I cancer had comparable mean sensitivities and specificities (97% and 98%, respectively). Areas under the summary receiver-operator characteristic curves for each classifier were 0.981 and 0.972, respectively. One gene was common to both classifiers. Classifiers were tested in an independent Gene Expression Omnibus-derived dataset. Both classifiers retained their predictive properties. Transcriptomic profiles comprising as few as 5 genes are highly accurate in differentiating normal from adenocarcinomatous rectal epithelium, including early-stage disease.

Assessment of a novel, full-thickness incisional biopsy model to restage rectal tumours after neoadjuvant chemoradiotherapy: results of an ex vivo pilot study.

BACKGROUND: There is currently no reliable means to restage rectal cancers after neoadjuvant chemoradiation. Recent histological evidence shows that the epicentre for residual cancer cells is focussed directly underneath any residual mucosal abnormality (RMA). This proof-of-concept study aimed to determine the utility of a novel, minimally invasive method of incisional biopsy as a restaging tool. A secondary aim was to compare its performance to clinical response assessment. METHODS: After surgical resection, 0.5 × 0.5 cm, full-thickness incisional biopsy was performed in 15 rectal cancers. Of these, 13 had RMA and 2 had mucosal cCR but a palpable intramural abnormality. In all patients, a full-thickness incisional biopsy was taken through the centre of these areas. The ypT stage of the incisional biopsy and the final total specimen were compared. Complete mucosal clinical response was deemed to have occurred when either no residual tumour or only a flat mucosal scar remained. RESULTS: Incisional biopsy correctly identified all patients that had been downstaged to ypT0; however, it also falsely identified 5 of 10 patients (50%) with yp residual disease as ypT0. Overall performance of incisional biopsy to detect residual cancer was 50% sensitivity, 100 % specificity, 100% PPV, and 50% NPV with an accuracy of 66%. A complete mucosal clinical response occurred in only one of five patients downstaged to ypT0 (20% sensitive). It also occurred in one patient, which was ultimately staged as ypT3. CONCLUSION: This prospective data demonstrates that incisional biopsy is not suitable as a stand-alone method to restage rectal cancer after CRT. Alternate or complementary means of restaging are needed.

Genotype-defined cancer risk in juvenile polyposis syndrome.

BACKGROUND: Germline mutations in SMAD4 and BMPR1A disrupt the transforming growth factor ß signal transduction pathway, and are associated with juvenile polyposis syndrome. The effect of genotype on the pattern of disease in this syndrome is unknown. This study evaluated the differential impact of SMAD4 and BMPR1A gene mutations on cancer risk and oncological phenotype in patients with juvenile polyposis syndrome. METHODS: Patients with juvenile polyposis syndrome and germline SMAD4 or BMPR1A mutations were identified from a prospectively maintained institutional registry. Medical records were reviewed and the clinical patterns of disease were analysed. RESULTS: Thirty-five patients had germline mutations in either BMPR1A (8 patients) or SMAD4 (27). Median follow-up was 11 years. Colonic phenotype was similar between patients with SMAD4 and BMPR1A mutations, whereas SMAD4 mutations were associated with larger polyp numbers (number of patients with 50 or more gastric polyps: 14 versus 0 respectively). The numbers of patients with rectal polyps was comparable between BMPR1A and SMAD4 mutation carriers (5 versus 17). No patient was diagnosed with cancer in the BMPR1A group, whereas four men with a SMAD4 mutation developed gastrointestinal (3) or extraintestinal (1) cancer. The gastrointestinal cancer risk in patients with juvenile polyposis syndrome and a SMAD4 mutation was 11 per cent (3 of 27). CONCLUSION: The SMAD4 genotype is associated with a more aggressive upper gastrointestinal malignancy risk in juvenile polyposis syndrome.

Depth and lateral spread of microscopic residual rectal cancer after neoadjuvant chemoradiation: implications for treatment decisions.

AIM: The aim of this study was to determine the distribution of residual tumour within the bowel wall in relation to residual mucosal abnormalities (RMAs) and surrounding normal mucosa in patients with rectal cancer who underwent neoadjuvant chemoradiation followed by curative surgery. METHOD: Archived pathological slides from a cohort of 60 patients with residual tumour were retrieved. The incidence, distance and depth of tumour spread (ypT) under RMAs and adjacent normal mucosa were reviewed and recorded. RESULTS: Histological sections containing both RMA and adjacent normal mucosa were available for 45 of 60 patients with ypT1 (n = 6), ypT2 (n = 18) and ypT3 (n = 21) disease. The maximal depth of invasion, as measured by ypT stage, was found underneath the RMA in 44 of 45 (98%) patients. Microscopic tumour spread lateral to the RMA and under adjacent normal mucosa was found in 32 of 45 (71%) patients. The median and maximum distances of lateral spread for ypT1 tumours were 0 and 4 mm; for ypT2 were 2.5 and 9 mm; and for ypT3 were 4 and 9 mm respectively. CONCLUSION: Lateral tumour spread under normal mucosa adjacent to RMAs is a common finding and extended up to 9 mm in this study. The epicentre for maximum depth of invasion was directly underneath the RMAs in nearly all cases. These data have clinical and technical implications if local excision is to be considered.

Results from an American Society of Colon and Rectal Surgeons survey on the management of young-onset colorectal cancer.

BACKGROUND: Young patients with colorectal cancer (CRC) present a diagnostic and clinical challenge. The aim of our study was to survey the approaches to preoperative evaluation and clinical management of young patients with CRC by colorectal surgeons in North America. METHODS: A standard electronic survey was sent to the members of the American Society of Colon and Rectal Surgeons. The survey polled management decisions in various clinical scenarios for CRC patients less than 50 years old. Survey responses were collated and analyzed. RESULTS: One hundred ninety surgeons responded and 140 completed the entire survey (response rate 10%). Eighty percent of surgeons would offer preoperative genetic testing if the patient's family met the Amsterdam criteria compared to only 67% if the criteria were not met. Of those offering preoperative tumor testing, 48% test microsatellite instability, 19% mismatch repair protein expression by immunohistochemistry, and 24% offer both. Decisions regarding the extent of the resection for cancer were dependent on family history: Most members (86%) would perform a segmental colectomy for CRC in a patient without family history. Eighty-four percent of respondents would offer a total abdominal colectomy if preoperative tests indicated Lynch syndrome. When questioned about MYH-associated polyposis, only 27% recognized the appropriate diagnosis. CONCLUSIONS: Among the American Society of Colon and Rectal Surgeons, family history influences preoperative testing and surgical management decisions. A significant portion of surgeons do not offer preoperative genetic testing, despite implications on operative management, postoperative surveillance, and screening of family members.

Gene expression profile is associated with chemoradiation resistance in rectal cancer.

AIM: Patients with rectal cancer who achieve a complete pathological response after preoperative chemoradiation (CRT) have an improved oncological outcome. Identifying factors associated with a lack of response could help our understanding of the underlying biology of treatment resistance. This study aimed to develop a gene expression signature for CRT-resistant rectal cancer using high-throughput nucleotide microarrays. METHOD: Pretreatment biopsies of rectal adenocarcinomas were prospectively collected and freshly frozen according to an institutional review board-approved protocol. Total tumour mRNA was extracted and gene expression levels were measured using microarrays. Patients underwent proctectomy after completing standard long-course CRT and the resected specimens were graded for treatment response. Gene expression profiles for nonresponders were compared with those of responders. Differentially expressed genes were analyzed for functional significance using the Ingenuity Pathway Analysis (IPA) software. RESULTS: Thirty-three patients treated between 2006 and 2009 were included. We derived 812-gene and 183-gene signatures separating nonresponders from responders. The classifiers were able to identify nonresponders with a sensitivity and specificity of 100% using the 812-gene signature, and sensitivity and specificity of 33% and 100% using the 183-gene signature. IPA canonical pathway analysis revealed a significant ratio of differentially expressed genes in the 'DNA double-strand break repair by homologous recombination' pathway. CONCLUSION: Certain rectal cancer gene profiles are associated with poor response to CRT. Alterations in the DNA double-strand break repair pathway could contribute to treatment resistance and provides an opportunity for further studies.

BRAF mutation is associated with distinct clinicopathological characteristics in colorectal cancer: a systematic review and meta-analysis.

AIM: Colorectal cancer is a heterogeneous disease with multiple underlying genetic mutations resulting in different phenotypes. Mutation in the v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) proto-oncogene is an important event in the methylator pathway. There is no consensus, however, on the clinicopathological characteristics associated with BRAF mutation. METHOD: A comprehensive search for published studies examining the effect of BRAF mutation on colorectal cancer was performed. Random effects methods were used to combine data. RESULTS: Data were retrieved from 21 studies describing 9885 patients. BRAF associated colorectal cancer is associated with proximal tumour location (OR 5.222, 95% CI 3.801-7.174, P < 0.001), T4 tumours (OR 1.761, 95% CI 1.164-2.663, P = 0.007) and poor differentiation (OR 3.816, 95% CI 2.714-5.365, P < 0.001) and is negatively associated with male sex (OR 0.623, 95% CI 0.505-0.769, P < 0.001), age of diagnosis under 60 years (OR 0.453, 95% CI 0.280-0.733, P = 0.001) and rectal cancer (OR 0.266, 95% CI 0.122-0.422, P < 0.001). CONCLUSION: BRAF mutation appears to be associated with distinct, unfavourable clinicopathological characteristics in colorectal cancer.

Serrated polyps: new classifications highlight clinical importance.

AIM: Many lesions previously classified as hyperplastic polyps and therefore thought to be innocuous have been reclassified as sessile serrated adenomas/polyps (SSA/Ps), establishing their place in the serrated pathway and underscoring their malignant potential. The clinical relevance of this new nomenclature is incompletely defined. This study examines the incidence and characteristics of colorectal SSA/Ps and describes other associated colorectal neoplasia. METHOD: A single institution pathology database was searched for the diagnosis of SSA/Ps between January 2004 and October 2007. SSA/Ps found by colonoscopy were included. Patient demographics, SSA/P characteristics and associated colonoscopic findings were retrospectively recorded. RESULTS: A total of 585 SSA/Ps were removed during 519 colonoscopies in 483 patients performed by 64 different endoscopists. This represented an overall incidence of SSA/Ps per colonoscopy of 2.1% in the 28,054 colonoscopies performed during the study period. The median SSA/P size was 0.8 cm (range 0.2-4.5) and 188 (69%) were ≥ 1.0 cm. Of the 585 SSA/Ps, 366 (63%) were right-sided, 129 (22%) were in the left colon and 90 (15%) were in the rectum. Also, 439 synchronous polyps of other histology (mainly adenomas and hyperplastic polyps) were found during the same 519 colonoscopies. CONCLUSION: SSA/Ps are rare lesions found during colonoscopy that may coexist with small hyperplastic polyps. Because SSA/Ps are part of the serrated oncogenic pathway, all, even those appearing to be hyperplastic, should be removed or biopsied for diagnosis. Careful review of historical lesions with application of new definitions may redefine risk for malignancy.

Serrated polyp detection rate during screening colonoscopy.

AIM: The adenoma detection rate is an important quality indicator for colonoscopy, but recently, serrated polyps of the large bowel have been recognized as important premalignant lesions. As they are often more difficult to see than adenomas, the detection rate of serrated polyps is set to become a more stringent indicator of quality in colonoscopy than adenoma detection rate. Here we aim to provide preliminary data on serrated polyp detection. METHOD: This is a retrospective review of prospectively collected data. Colonoscopies were stratified by one of six colorectal surgeons, each of whom had performed more than 1000 colonoscopies. Exams were separated by indication and the number of patients with at least one adenoma or one serrated polyp recorded. Time of withdrawal in normal examinations was noted. RESULTS: Eighteen thousand and three colonoscopies were included. Average completion rate was 96.3 ± 1.2%. Mean serrated detection rate for all examinations was 20.6 ± 4.8% and for screening examinations only was 13.9 ± 5.0%. Corresponding means for adenoma detection were 31.5 ± 6.7% and 20.7 ± 4.1%, respectively. Simple regression of overall adenoma detection rate versus overall serrated detection rate was not significant (R = 0.571, P = 0.237), but was significant for screening exams (R = 0.854, P = 0.031). There was a strong relationship between time of withdrawal and serrated detection rate (screening, R = 0.908, P = 0.012; overall, R = 0.956, P = 0.003). CONCLUSION: Taking time to withdraw the colonoscope is essential for maximum detection of serrated polyps. The ability to find adenomas does not necessarily correlate with an ability to find serrated polyps.

The mesocolon: a prospective observational study.

AIM: The aim of this study was to characterize formally the mesocolic anatomy during and following total mesocolic excision. Total mesocolic excision may improve survival in patients with colon cancer. Although this requires a detailed knowledge of normal and variant mesocolic anatomy, the latter is poorly characterized. No studies have prospectively characterized the anatomy of the entire mesocolon. METHOD: Total mesocolic excision was performed in 109 patients undergoing total abdominal colectomy. The mesocolon was maintained intact thereby permitting a precise anatomical characterization from ileocaecal to mesorectal levels. Two- and three-dimensional schematic reconstructions were generated to illustrate in situ conformation. RESULTS: Several previously undocumented findings emerged, including: (i) the mesocolon was continuous from ileocaecal to rectosigmoid level; (ii) a mesenteric confluence occurred at the ileocaecal and rectosigmoid junction as well as at the hepatic and splenic flexures; (iii) each flexure (and ileocaecal junction) was a complex of peritoneal and omental attachments to the colon centred on a mesenteric confluence; (iv) the proximal rectum originated at the confluence of the mesorectum and mesosigmoid; and (v) a plane occupied by Toldt's fascia separated the entire apposed mesocolon from the retroperitoneum. CONCLUSION: When the mesocolon is fully mobilized during a total mesocolic excision of the colon, several anatomical findings that have not been previously documented emerge. These findings provide a rationalization of the surgical, embryological and anatomical approaches to the mesocolon. This has implications for all related sciences.

Clinical implications of acellular mucin pools in resected rectal cancer with pathological complete response to neoadjuvant chemoradiation.

AIM: Approximately 20% of rectal cancers treated with neoadjuvant chemoradiation achieve a pathological complete response (pCR), which is associated with an improved oncological outcome. However, in a proportion of patients with a pCR, acellular pools of mucin are present in the surgical specimen. The aim of this study was to evaluate the clinical implications of acellular mucin pools in patients with rectal adenocarcinoma achieving a pCR after neoadjuvant chemoradiation followed by proctectomy. METHOD: A single-centre colorectal cancer database was searched for patients with clinical Stage II and Stage III rectal adenocarcinoma who achieved a pCR (i.e. ypT0N0M0) after neoadjuvant chemoradiation followed by proctectomy between 1997 and 2007. Patients were categorized according to the presence or absence of acellular mucin pools in the resected specimen, and groups were compared. Patient demographics, tumour and treatment characteristics, and oncological outcomes were recorded. Primary outcomes were 3-year local and distant recurrences, and disease-free and overall survivals. RESULTS: Two hundred and fifty-eight patients with clinical Stage II or Stage III rectal adenocarcinoma were treated by neoadjuvant chemoradiation. Fifty-eight of these patients had a 58 pCR. Eleven of the 58 patients with a pCR had acellular mucin pools in the surgical specimen. The median follow up was 40 months. The groups were statistically similar with respect to demographics, chemoradiation regimens, distance of tumour from the anal verge, clinical stage and surgical procedure. No patient had local recurrence. Patients with acellular mucin pools had increased distant recurrence (21%vs 5%), decreased disease-free survival (79%vs 95%) and decreased overall survival (83%vs 95%) rates, although none of these differences was statistically significant. CONCLUSION: The presence of acellular mucin pools in a proctectomy specimen with a pCR does not affect local recurrence, but may suggest a more aggressive tumour biology.

Minimally invasive colon resection for malignant colonic conditions is associated with a transient early increase in plasma sVEGFR1 and a decrease in sVEGFR2 levels after surgery.

INTRODUCTION: Plasma VEGF levels increase after minimally invasive colorectal resection (MICR) and remain elevated for 2-4 weeks. VEGF induces physiologic and pathologic angiogenesis by binding to endothelial cell (EC) bound VEGF-Receptor-1 (VEGFR1) and VEGFR2. Soluble forms of these receptors sequester plasma VEGF, decreasing the amount available to bind to EC-bound receptors. Ramifications of surgery-related plasma VEGF changes partially depend on plasma levels of sVEGFR1 and sVEGFR2. This study assessed perioperative sVEGFR1 and sVEGFR2 levels after MICR in patients with colorectal cancer. METHODS: Forty-five patients were studied; blood samples were taken from all patients preoperatively (preop) and on postoperative days (POD) 1 and 3; in most a fourth sample was drawn between POD 7-30. Late samples were bundled into two time points: POD 7-13 and POD 14-30. sVEGFR1 and sVEGFR2 levels were measured via ELISA. sVEGFR2 data are reported as mean +/- SD and were assessed with the paired samples t test. sVEGFR1 data were not normally distributed. They are reported as median and 95% confidence interval (CI) and were assessed with the Wilcoxon signed-Rank test (p < 0.05). RESULTS: Preoperatively, the mean plasma sVEGFR2 level (7583.9 pg/ml) was greater than the sVEGFR1 result (98.3 pg/ml). Compared with preop levels, sVEGFR2 levels were significantly lower on POD 1 (6068.2 pg/ml, +/-2034.5) and POD 3 (6227.6 pg/ml, +/-2007.0), whereas sVEGFR1 levels were significantly greater on POD 1 (237.5 pg/ml; 95% CI, 89.6-103.5), POD 3 (200.2 pg/ml; 95% CI, 159-253), and POD 7-13 (102.9 pg/ml; 95% CI, 189.7-253). No differences were found on POD 7-13 for sVEGFR2 or POD 14-30 for either protein. CONCLUSIONS: sVEGFR2 values decreased and sVEGFR1 levels increased early after MICR; sVEGFR2 changes dominate due to their much larger magnitude. The net result is less plasma VEGF bound by soluble receptors and more plasma VEGF available to bind to ECs early after surgery.

Genetic and epigenetic classifications define clinical phenotypes and determine patient outcomes in colorectal cancer.

BACKGROUND: A molecular classification of colorectal cancer has been proposed based on microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and mutations in the KRAS and BRAF oncogenes. This study examined the prevalence of these molecular classes, and differences in clinical presentation and outcome. METHODS: Demographics, tumour characteristics and survival were recorded for 391 subjects with colorectal cancer. Tumour DNA was analysed for MSI (high (MSI-H) or microsatellite stable (MSS)), CIMP (high (CIMP-H) or no (CIMP-neg)) and BRAF and KRAS mutations. Clinical differences between four phenotypes were examined. RESULTS: Most tumours were MSS/CIMP-neg (69.8 per cent), with a nearly equal distribution of MSI-H/CIMP-H, MSI-H/CIMP-neg and MSS/CIMP-H types. MSS/CIMP-neg tumours were less likely to be poorly differentiated (P = 0.009). CIMP-H tumours were more common in older patients (P < 0.001). MSI-H/CIMP-H tumours had a high frequency of BRAF mutation and a low rate of KRAS mutation; the opposite was true for MSS/CIMP-neg tumours (P < 0.001). The four molecular phenotypes tended towards divergent survival (P = 0.067 for stages 1-III). MSI-H cancers were associated with better disease-free survival (hazard ratio 2.00 (95 per cent confidence interval 1.03 to 3.91); P = 0.040). CONCLUSION: Colorectal cancers are molecularly and clinically heterogeneous. These different molecular phenotypes may reflect variable prognosis.