Human Innate Lymphoid Cell Subsets Possess Tissue-Type Based Heterogeneity in Phenotype and Frequency.

Animal models have highlighted the importance of innate lymphoid cells (ILCs) in multiple immune responses. However, technical limitations have hampered adequate characterization of ILCs in humans. Here, we used mass cytometry including a broad range of surface markers and transcription factors to accurately identify and profile ILCs across healthy and inflamed tissue types. High dimensional analysis allowed for clear phenotypic delineation of ILC2 and ILC3 subsets. We were not able to detect ILC1 cells in any of the tissues assessed, however, we identified intra-epithelial (ie)ILC1-like cells that represent a broader category of NK cells in mucosal and non-mucosal pathological tissues. In addition, we have revealed the expression of phenotypic molecules that have not been previously described for ILCs. Our analysis shows that human ILCs are highly heterogeneous cell types between individuals and tissues. It also provides a global, comprehensive, and detailed description of ILC heterogeneity in humans across patients and tissues.

Functional annotation with expression validation identifies novel metastasis-relevant genes from post-GWAS risk loci in sporadic colorectal carcinomas.

BACKGROUND: Colorectal cancer (CRC) is the third highest incidence cancer and is the leading cause of cancer mortality worldwide. Metastasis to distal organ is the major cause of cancer mortality. However, the underlying genetic factors are unclear. This study aimed to identify metastasis-relevant genes and pathways for better management of metastasis-prone patients. METHODS: A case-case genome-wide association study comprising 2677 sporadic Chinese CRC cases (1282 metastasis-positive vs 1395 metastasis-negative) was performed using the Human SNP6 microarray platform and analysed with the correlation/trend test based on the additive model. SNP variants with association testing -log10 p value ≥5 were imported into Functional Mapping and Annotation (FUMA) for functional annotation. RESULTS: Glycolysis was uncovered as the top hallmark gene set. Transcripts from two of the five genes profiled, hematopoietic substrate 1 associated protein X 1 (HAX1) and hyaluronan-mediatedmotility receptor (HMMR), were significantly upregulated in the metastasis-positive tumours. In contrast to disease-risk variants, HAX1 appeared to act synergistically with HMMR in significantly impacting metastasis-free survival. Examining the subtype datasets with FUMA and Ingenuity Pathway Analysis (IPA) identified distinct pathways demonstrating sexual dimorphism in CRC metastasis. CONCLUSIONS: Combining genome-wide association testing with in silico functional annotation and wet-bench validation identified metastasis-relevant genes that could serve as features to develop subtype-specific metastasis-risk signatures for tailored management of patients with stage I-III CRC.

The orphan nuclear receptor NR0B2 could be a novel susceptibility locus associated with microsatellite-stable, APC mutation-negative early-onset colorectal carcinomas with metabolic manifestation.

Colorectal cancer (CRC) is a high incidence cancer and major cause of cancer mortality. Though disease-causing tumor suppressors for major syndromes are well characterized, about 10% of CRC is familial but without mutations in known tumor suppressors. We exhaustively screened 100 polyposis families for APC germline mutations and identified 13, which are APC mutation-negative, microsatellite-stable (MSS), and with undetectable mutation in known tumor suppressors. Whole exome sequencing in three probands uncovered two with germline frameshift NR0B2 mutations, c.293_301delTTGGGTTGGinsAC and c.227delT. Sanger Sequencing identified a third proband with NR0B2 c.157_166delCATCGCACCT frameshift mutation. All three mutations deleted the C-terminus activation/repression domain of NR0B2, thus are loss-of-function mutations. Real-time RT-PCR performed on tumor and matched mucosa of one patient revealed that NR0B2 downstream targets, SMAD3 was derepressed while GLI1 was downregulated in the colonic mucosa compared to healthy controls. Truncated NR0B2 molecule was predicted to have weakened binding with interacting partners SMAD3, GLI1, BCL2, and RXRα, implying perturbation of TGF-ß, Hedgehog, anti-apoptotic and nuclear hormone receptor signaling pathways. Immunostaining also revealed nuclear retention of the most severely truncated NR0B2 molecule compared to the wildtype. Microsatellite and sequencing analysis did not detect loss of wildtype allele in probands' tumors. The patient who acquired somatic KRAS mutation progressed rapidly whist the other two patients manifested with late-onset obesity and diabetes. We propose that haploinsufficiency of NR0B2 is associated with a novel CRC syndrome with metabolic phenotypes.

Genome-wide association study identified copy number variants associated with sporadic colorectal cancer risk.

BACKGROUND: Multiple single nucleotide polymorphisms (SNPs) have been associated with colorectal cancer (CRC) risk. The role of structural or copy number variants (CNV) in CRC, however, remained unclear. We investigated the role of CNVs in patients with sporadic CRC. METHODS: A genome-wide association study (GWAS) was performed on 1000 Singapore Chinese patients aged 50 years or more with no family history of CRC and 1000 ethnicity-matched, age-matched and gender-matched healthy controls using the Affymetrix SNP 6 platform. After 16 principal component corrections, univariate and multivariate segmentations followed by association testing were performed on 1830 samples that passed quality assurance tests. RESULTS: A rare CNV region (CNVR) at chromosome 14q11 (OR=1.92 (95% CI 1.59 to 2.32), p=2.7e-12) encompassing CHD8, and common CNVR at chromosomes 3q13.12 (OR=1.54 (95% CI 1.33 to 1.77), p=2.9e-9) and 12p12.3 (OR=1.69 (95% CI 1.41 to 2.01), p=2.8e-9) encompassing CD47 and RERG/ARHGDIB, respectively, were significantly associated with CRC risk. CNV loci were validated in an independent replication panel using an optimised copy number assay. Whole-genome expression data in matched tumours of a subset of cases demonstrated that copy number loss at CHD8 was significantly associated with dysregulation of several genes that perturb the Wnt, TP53 and inflammatory pathways. CONCLUSIONS: A rare CNVR at 14q11 encompassing the chromatin modifier CHD8 was significantly associated with sporadic CRC risk. Copy number loss at CHD8 altered expressions of genes implicated in colorectal tumourigenesis.

Systematic review and meta-analysis of the use of serum procalcitonin levels to predict intra-abdominal infections after colorectal surgery.

PURPOSE: There has been much recent interest in the use of procalcitonin (PCT) as a marker of intra-abdominal infection (IAI) following colorectal surgery. However, the literature remains divided on the value of PCT in this setting. This meta-analysis aims to evaluate the value of PCT in predicting IAI after colorectal surgery. METHODS: Systemic literature search was performed using MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials (CENTRAL) and the Cochrane Database of Systematic Reviews to identify studies evaluating the diagnostic accuracy of PCT as a predictor for detecting IAI on postoperative days (POD) 3 to 5 following colorectal surgery. A meta-analysis was performed using random effect model and pooled predictive parameters as well as cut-off values for POD 3 to 5 were derived. RESULTS: Eight studies consisting 1629 patients were included. The pooled prevalence of IAI was 5.7% on POD 3, 9.7% on POD 4, and 6.3% on POD 5. The pooled AUC for POD 3 to 5 were 0.83 (95% CI 0.78-0.88), 0.79 (95% CI 0.64-0.93), and 0.94 (95% CI 0.91-0.97), respectively. The derived PCT cut-off values were 1.45 ng/ml on POD 3, 1.28 ng/ml on POD 4, and 1.26 ng/ml on POD 5. PCT had the highest diagnostic capability on POD 5 with diagnostic odds ratio of 32.9 (95% CI 15.01-69.88), sensitivity of 0.78 (95% CI 0.65-0.89), and specificity of 0.88 (95% CI 0.85-0.90). CONCLUSIONS: PCT is a useful diagnostic predictor of IAI after colorectal surgery. It has the greatest diagnostic accuracy on POD 5 and can help guide safe discharge of patients after colorectal surgery.

Amino-terminal p53 mutations lead to expression of apoptosis proficient p47 and prognosticate better survival, but predispose to tumorigenesis.

Whereas most mutations in p53 occur in the DNA-binding domain and lead to its functional inactivation, their relevance in the amino-terminal transactivation domain is unclear. We show here that amino-terminal p53 (ATp53) mutations often result in the abrogation of full-length p53 expression, but concomitantly lead to the expression of the amino-terminally truncated p47 isoform. Using genetically modified cancer cells that only express p47, we demonstrate it to be up-regulated in response to various stimuli, and to contribute to cell death, through its ability to selectively activate a group of apoptotic target genes. Target gene selectivity is influenced by K382 acetylation, which depends on the amino terminus, and is required for recruitment of selective cofactors. Consistently, cancers capable of expressing p47 had a better overall survival. Nonetheless, retention of the apoptotic function appears insufficient for tumor suppression, because these mutations are also found in the germ line and lead to Li-Fraumeni syndrome. These data from ATp53 mutations collectively demonstrate that p53's apoptosis proficiency is dispensable for tumor suppression, but could prognosticate better survival.

A Novel Derivation Predicting Survival After Primary Tumor Resection in Stage IV Colorectal Cancer: Validation of a Prognostic Scoring Model and an Online Calculator to Provide Individualized Survival Estimation.

BACKGROUND: A prognostic scoring model has been devised previously to predict survival following primary tumor resection in patients with metastatic colorectal cancer and unresectable metastases. This has yet to be validated. OBJECTIVE: The main objectives of this study are to validate the proposed prognostic scoring model and create an interactive online calculator to estimate an individual's survival after primary tumor resection. DESIGN: Clinical data and survival outcomes of patients were extracted from a prospectively maintained database. Patients were categorized into good, moderate, or poor survivor groups based on the previously proposed scoring algorithm. Discrimination was assessed and recalibration was performed, with the recalibrated model implemented as an interactive Web application to provide individualized survival probability. SETTINGS: This study was conducted at a tertiary referral center. PATIENTS: The study included 324 consecutive patients with metastatic colorectal carcinoma and unresectable metastases who underwent primary tumor resection between January 2008 and December 2013. MAIN OUTCOME MEASURES: The primary outcome measured was overall survival. RESULTS: Three hundred twenty-four patients were included in the study. Median survival in the good, moderate, and poor prognostic groups was 56.8, 25.7, and 19.9 months (log rank test, p = 0.003). The κ statistic was 0.638 and RD was 0.101. Significant differences in survival were found between the moderate and good prognostic groups (HR, 2.79; 95% CI, 1.51-5.15; p = 0.001) and between poor and good prognostic groups (HR, 4.12; 95% CI, 1.98-8.55; p < 0.001). The model was implemented as an interactive online calculator to provide individualized survival estimation after primary tumor resection (http://bit.ly/Stage4PrognosticScore). LIMITATIONS: Selection bias and single-center data preclude the generalizability of the proposed model. Information regarding the severity or likelihood of developing symptoms from the primary tumor were also not accounted for in the prognostic scoring model proposed. CONCLUSIONS: The prognostic scoring model provides good prognostic stratification of survival after primary tumor resection and may be a useful tool to predict survival after primary tumor resection. See Video Abstract at http://links.lww.com/DCR/A330.

Analysis of colorectal cancer glyco-secretome identifies laminin ß-1 (LAMB1) as a potential serological biomarker for colorectal cancer.

The high mortality rate in colorectal cancer is mostly ascribed to metastasis, but the only clinical biomarker available for disease monitoring and prognosis is the carcinoembryonic antigen (CEA). However, the prognostic utility of CEA remains controversial. In an effort to identify novel biomarkers that could be potentially translated for clinical use, we collected the secretomes from the colon adenocarcinoma cell line HCT-116 and its metastatic derivative, E1, using the hollow fiber culture system, and utilized the multilectin affinity chromatography approach to enrich for the secreted glycoproteins (glyco-secretome). The HCT-116 and E1 glyco-secretomes were compared using the label-free quantitative SWATH-MS technology, and a total of 149 glycoproteins were differentially secreted in E1 cells. Among these glycoproteins, laminin ß-1 (LAMB1), a glycoprotein not previously known to be secreted in colorectal cancer cells, was observed to be oversecreted in E1 cells. In addition, we showed that LAMB1 levels were significantly higher in colorectal cancer patient serum samples as compared to healthy controls when measured using ELISA. ROC analyses indicated that LAMB1 performed better than CEA at discriminating between colorectal cancer patients from controls. Moreover, the diagnostic performance was further improved when LAMB1 was used in combination with CEA.

Risk prediction score in laparoscopic colorectal surgery training: experience from the English National Training Program.

OBJECTIVE: The overall aim was to develop and validate a risk prediction score for laparoscopic colorectal surgery training cases. BACKGROUND: Published risk prediction scores are not transferable between hospitals because they are derived from a single institution's data and are not designed for use in training situations. METHODS: Cases from the prospectively collected database of the National Training Programme in Laparoscopic Colorectal Surgery, between July 2008 and July 2012, were analyzed. Independent risk factors for conversion were identified by the logistic regression. Converting the odds ratios into integers created a risk prediction score for conversion. The clinical impact of this score was investigated by comparing postoperative complications and the level of trainer input in high- and low-risk cases. To study whether adverse outcomes in predicted high-risk cases occur outside the National Training Programme in Laparoscopic Colorectal Surgery, 2 external data sets were examined. RESULTS: A total of 2341 cases carried out in 42 hospitals were analyzed. Significant risk factors for conversion were body mass index, American Society of Anesthesiology classification, male sex, prior abdominal surgery, and resection type. At a risk score of more than 6, complication rates increased, including mortality (2.9% vs 0.5%, P < 0.001), anastomotic leak (4.3% vs 1.4%, P = 0.002), and a higher level of trainer input (32.2% vs 19.9% of cases, P < 0.001). Analysis of 786 external cases showed that high-risk cases had higher conversion (18.8% vs 7.1%, P < 0.001), overall complication (36.4% vs 15.0%, P < 0.001), and leak rates (4.0% vs 1.3%, P = 0.015). CONCLUSIONS: A risk predication score to facilitate case selection in laparoscopic colorectal surgery training was developed and validated.

Short and long-term outcomes of a randomised controlled trial of vertical periumbilical wound versus transverse left iliac fossa wound for specimen retrieval in laparoscopic anterior resections.

BACKGROUND: The ideal incision for laparoscopic specimen extraction is not known. There has been no randomised study thus far evaluating extraction site in laparoscopic colorectal surgery. The aim of our study was to compare post-operative outcomes, pain scores and quality of life scores of vertical periumbilical (VW) versus transverse left iliac fossa (TW) incisions for specimen extraction in laparoscopic anterior resections. METHODS: Using an assumption of pain score of 5 in the VW group versus pain score of 2 in the TW group, on day one post-operatively, and based on a 80% statistical power of analysis to achieve a statistical difference with reduction in pain scores, the sample size per arm calculated was 16. Forty patients undergoing laparoscopic anterior resection were randomised to VW (n = 20) or TW (n = 20). Primary endpoint was post-operative pain. Secondary endpoints were post-operative outcomes, wound cosmesis using Hollander Cosmesis Score and quality of life assessment using EQ-5D at 2 weeks and 2 months post-operatively. RESULTS: Median pain score on the first post-operative day was 2 in both groups (p = 0.360). There was no significant difference in wound infection rates, operative time or post-operative recovery. Cosmesis scores and EQ-5D scores were also similar in both groups. At a median follow-up of 30 months, the incidence of extraction site incisional hernia was similar. CONCLUSION: Transverse and vertical incisions in laparoscopic colorectal surgery have similar post-operative outcomes, with similar pain scores, cosmesis scores, quality of life scores and incisional hernia rates.

Serum methylation levels of TAC1. SEPT9 and EYA4 as diagnostic markers for early colorectal cancers: a pilot study.

OBJECTIVE: To identify methylated genes in serum with diagnostic potentials for early colorectal cancer (CRC). METHODS: Serum methylation levels of up to 12 genes were measured in two sets of serum samples with the second set from 26 stage I CRC patients and 26 age/gender-matched controls. RESULTS: Serum methylation levels of TAC1, SEPT9, and EYA4 were significant discriminants between stage I CRC and healthy controls. Combination of TAC1 and SEPT9 rendered 73.1% sensitivity with 92.3% specificity. CONCLUSION: Serum methylation levels of TAC1. SEPT9 and EYA4 may be useful biomarkers for early detection of CRC though a validation study is necessary.

Conventional laparoscopic versus single-incision laparoscopic right hemicolectomy: a case cohort comparison of short-term outcomes in 144 consecutive cases.

BACKGROUND: Single-incision laparoscopic surgery (SILS) is a recent development of minimally invasive surgery for colorectal disease. The literature comparing it against conventional laparoscopic colectomy remains limited. METHODS: A retrospective case-cohort study compared the benefits and outcomes of SILS right hemicolectomy (SRH) with those of conventional laparoscopic right hemicolectomy (LRH). The medical records of consecutive patients from a prospectively collected database were reviewed. Demographic data, operative details, recovery parameters, and details of resected specimens were obtained and analyzed in an intention-to-treat manner. RESULTS: From January 2006 to March 2011, 104 elective LRHs (72 %) and 40 elective SRHs (28 %) were performed. The demographics for these two groups were comparable in terms of gender, age, ethnicity, body mass index (BMI), comorbidities and American Society of Anesthesiology score. As the records showed, 62 % of the LRHs and 57 % of the SRHs were performed for malignancies (p = 0.536). Seven of the LRH cases (7 %) were converted to open procedure, whereas two of the SILS cases (5 %) were converted. Three SILS cases (7 %) were completed with additional laparoscopic ports. The two groups did not differ significantly in terms of wound length, mean operative time, lymph node clearance, or margins of resected specimen. The recovery parameters (pain score, hospital length of stay, and complications rate) also were equivalent between the two groups. CONCLUSION: As a feasible and safe procedure with early postoperative outcomes equivalent to those for LRH, SRH is a suitable alternative. The possible advantages of SILS over conventional laparoscopic surgery may be validated only with randomized controlled trials in the future.

Mismatch repair deficiency screening via immunohistochemical staining in young Asians with colorectal cancers.

BACKGROUND: The incidence of mismatch repair deficiency in colorectal cancer (CRC) in young people remains unknown in Asians. The present study assessed the clinicopathological features and efficacy of immunohistochemistry screening for Lynch syndrome in young Asian CRC patients. MATERIAL AND METHODS: This was a retrospective review conducted in Singapore General Hospital between January 2006 and December 2010 of 240 unrelated patients under the age of 50. All patients had immunohistochemical (IHC) staining for mismatch repair proteins in resected CRC specimen data retrieved from a prospective computerized database. RESULTS: A total of 21 % (n = 51) of the patients had abnormal IHC staining. Loss of staining for MLH1, MSH2, MSH6, and PMS2 proteins was observed in 10, 4, 6, and 13 % of tumors, respectively. Of the 22 patients who had abnormal staining of MLH1, 13 had concomitant abnormal staining for PMS2. One tumor specimen had abnormal staining in all four proteins. If the Amsterdam criteria alone were to be used, 86 % (n = 44) of the cohort would have not been detected for mismatch repair gene defects. CONCLUSIONS: The overall burden of germline mismatch repair deficiency in the Singapore population may be as high as 21 %. The Amsterdam criteria alone are inadequate to detect Lynch syndrome patients. The use of IHC staining of at least four mismatch repair proteins is a useful screening strategy for Lynch syndrome diagnosis. Routine screening of mismatch repair deficiency may be recommended for all young Asian CRC patients.

Endoscopic stenting and elective surgery versus emergency surgery for left-sided malignant colonic obstruction: a prospective randomized trial.

PURPOSE: This study aims to evaluate the role of colonic stenting as a bridge to surgery in acutely obstructed left-sided colon cancer. METHODS: Patients with acute left-sided malignant colonic obstruction with no evidence of peritonitis were recruited. After informed consent, patients were randomized to colonic stenting followed by elective surgery or immediate emergency surgery. Patients who had successful colonic stenting underwent elective surgery 1 to 2 weeks later, while the other group had emergency surgery. Patients in whom stenting was unsuccessful also underwent emergency surgery. RESULTS: Twenty patients were randomized to stenting and 19 to emergency surgery. Fourteen patients (70%) had successful stenting and underwent elective surgery at a median of 10 days later; the rest underwent emergency surgery. Technical stent failure occurred in five patients (25%). One patient failed to decompress after successful stent deployment. All patients underwent definitive colonic resection with primary anastomosis. Two of 20 patients in the stenting group required defunctioning stomas compared to 6 of 19 in emergency surgery group, p = 0.127. Overall complication rate was 35% versus 58% (p = 0.152) and mortality was 0% versus 16% (p = 0.106) in the stenting group and emergency surgery group, respectively. Postoperatively, the stenting group was discharged from hospital earlier (median of 6 versus 8 days, p = 0.028) than the emergency surgery group. CONCLUSION: Colonic stenting followed by interval elective surgery may be safer, with a trend towards lower morbidity and mortality when compared with the current practice of emergency surgery for left-sided malignant colonic obstruction.

Close distal margins do not increase rectal cancer recurrence after sphincter-saving surgery without neoadjuvant therapy.

PURPOSE: The oncological results of close distal resection margins (DM) have been mixed due to variations in perioperative treatment protocols and surgical expertise. With the increased application of sphincter-saving surgery in the management of rectal cancer, "close shave" DM is an increasingly encountered phenomenon. Our center aims to examine the oncological outcomes of "close shave" DM in the absence of neoadjuvant therapy in the surgical treatment of rectal cancer. METHODS: A prospective database of 320 patients who underwent curative surgical resection for primary rectal cancer between 1999 and 2007 was reviewed. One hundred forty-eight patients had "close shave" DM (DM <1 cm) and 70 (22 %) patients had stage 1, 102 (32 %) patients had stage 2, and 148 (46 %) patients presented with stage 3 disease. Median follow-up was 45 months. RESULTS: The overall recurrence rate for the entire study cohort was 29 % (n = 94), with 6.6 % of patients developing locoregional recurrence. Recurrence was noted to be significantly associated with decreasing circumferential resection margin (p = 0.008) and increasing American Joint Committee on Cancer stage (p < 0.001). Five-year cancer-specific survival (CSS) for patients with DM <1 cm was 75.6 % and is higher compared to patients with longer DM (p = 0.041). Multivariate analysis showed that CSS was worsened with T stage, N stage, and perineural invasion status. Decreasing DM, however, was not significantly associated with poorer CSS or recurrence rates. CONCLUSION: Close distal resection margins do not negatively impact long-term disease control, even without the use of neoadjuvant therapy, provided that safe, optimal surgical resection is performed. Circumferential radial margin may be a more important indicator for outcomes.

Evaluation of laparoscopic versus open colorectal surgery in elderly patients more than 70 years old: an evaluation of 727 patients.

BACKGROUND: With longer life expectancy, surgeons can expect to operate on older patients. Laparoscopic colorectal (LC) surgery has been demonstrated to be superior to open surgery. Controversy persists, however, regarding benefits of LC in the elderly due to increase in operative time. The aim of our study was to compare short-term outcomes of LC versus open colorectal (OC) surgery in elderly patients. MATERIALS AND METHODS: Patients ≥70 years old that underwent elective LC between 2005 and 2008 were compared with controls who underwent OC. Data was extracted from a prospectively collected database. RESULTS: Seven hundred and twenty-seven patients underwent colorectal resection in this study period (LC n = 225, OC n = 502). The laparoscopic arm was characterised by shorter incisions (LC 6.0 cm vs. OC 12.0 cm, p < 0.001) but longer operating times (LC 125 min vs. OC 85 min, p < 0.001). Median use of narcotics and length of stay were significantly shorter in the laparoscopic group (LC 2 days vs. OC 3 days, p < 0.001 and LC 6 days vs. OC 7 days, p < 0.001, respectively). There was no significant difference in median recovery of bowel function (LC 4 days vs. OC 4 days, p = 0.14) and post-operative morbidity (p = 0.725). Thirty-day mortality was significantly lower in the laparoscopic arm (LC 1.3% vs. OC 4.6%, p = 0.03) CONCLUSION: This is the largest series from a single institution comparing LC and OC in elderly patients. In our series, LC in elderly patients was safe and not associated with a higher morbidity. LC was also associated with less narcotic use and shorter length of stay.

KRAS mutation-independent downregulation of MAPK/PI3K signaling in colorectal cancer.

KRAS is a gatekeeper gene in human colorectal tumorigenesis. KRAS is 'undruggable'; hence, efforts have been diverted to inhibit downstream RAF/MEK/ERK and PI3K/Akt signaling. Nevertheless, none of these inhibitors has progressed to clinical use despite extensive trials. We examined levels of phospho-ERK1/2(T202/Y204) and phospho-Akt1/2/3(S473) in human colorectal tumor compared to matched mucosa with semi-quantitative near-infrared western blot and confocal fluorescence immunohistochemistry imaging. Surprisingly, 75.5% (25/33) of tumors had lower or equivalent phospho-ERK1/2 and 96.9% (31/32) of tumors had lower phospho-Akt1/2/3 compared to matched mucosa, irrespective of KRAS mutation status. In contrast, we discovered KRAS-dependent SOX9 upregulation in 28 of the 31 (90.3%) tumors. These observations were substantiated by analysis of the public domain transcriptomics The Cancer Genome Atlas (TCGA) and NCBI Gene Expression Omnibus (GEO) datasets and proteomics Clinical Proteomic Tumor Analysis Consortium (CPTAC) dataset. These data suggest that RAF/MEK/ERK and PI3K/Akt signaling are unlikely to be activated in most human colorectal cancer.

A prognostic score predicting survival following emergency surgery in patients with metastatic colorectal cancer.

BACKGROUND: Survival of patients with metastatic colorectal cancer (mCRC) varies. We aim to develop a prognostic score for mCRC after emergency surgery to guide treatment decisions. METHODS: Newly diagnosed mCRC patients who presented with primary tumor-related complications and underwent emergency surgery between January 1999 and December 2013 were included. Univariate and multivariate Cox regression analyses were performed to identify covariates significantly associated with the time to death following surgery. A survival score was derived using the Cox regression equation. RESULTS: The study cohort comprised 248 patients. Median patient age was 66 ± 13 years. Primary tumor was located in the left colon and rectum in 211 patients (85.1%) while 37 patients (14.9%) had primaries in the right colon. Liver, lung, and peritoneal metastases occurred in 161 patients (64.9%), 59 patients (23.8%), and 96 patients (38.7%), respectively. Majority of patients presented with either obstruction (174 patients, 70.1%) or perforation (52 patients, 21%). On multivariate analysis, age of 60 years or older (p = 0.007), carcinoembryonic antigen levels greater than 45 ng/ml (p = 0.022), presence of liver metastases (p = 0.024), and peritoneal carcinomatosis (p < 0.001) were found to be significantly associated with overall survival. A simplified score was derived with good survivors (score 0-2), moderate survivors (score 3-4), and poor survivors (score 5 and above) experiencing median survival of 7, 14, and 23 months, respectively (p < 0.001). CONCLUSION: The management of mCRC presenting with an emergency is challenging. A prognostic score that estimates survival after emergency surgery may aid clinical decision-making.