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.

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.

Enhancer-derived long non-coding RNAs CCAT1 and CCAT2 at rs6983267 has limited predictability for early stage colorectal carcinoma metastasis.

Up-regulation of long non-coding RNAs (lncRNAs), colon-cancer associated transcript (CCAT) 1 and 2, was associated with worse prognosis in colorectal cancer (CRC). Nevertheless, their role in predicting metastasis in early-stage CRC is unclear. We measured the expression of CCAT1, CCAT2 and their oncotarget, c-Myc, in 150 matched mucosa-tumour samples of early-stage microsatellite-stable Chinese CRC patients with definitive metastasis status by multiplex real-time RT-PCR assay. Expression of CCAT1, CCAT2 and c-Myc were significantly up-regulated in the tumours compared to matched mucosa (p < 0.0001). The expression of c-Myc in the tumours was significantly correlated to time to metastasis [hazard ratio = 1.47 (1.10-1.97)] and the risk genotype (GG) of rs6983267, located within CCAT2. Expression of c-Myc and CCAT2 in the tumour were also significantly up-regulated in metastasis-positive compared to metastasis-negative patients (p = 0.009 and p = 0.04 respectively). Nevertheless, integrating the expression of CCAT1 and CCAT2 by the Random Forest classifier did not improve the predictive values of ColoMet19, the mRNA-based predictor for metastasis previously developed on the same series of tumours. The role of these two lncRNAs is probably mitigated via their oncotarget, c-Myc, which was not ranked high enough previously to be included in ColoMet19.

Results of a colorectal enhanced recovery after surgery (ERAS) programme and a qualitative analysis of healthcare workers' perspectives.

BACKGROUND: Enhanced recovery after surgery (ERAS) is a structured programme using a multimodal, evidence-based approach to improve post-operative outcomes. Successful implementation of ERAS can be challenging. We aimed to evaluate our initial experience with colorectal ERAS and explore the perspectives of specialist doctors and nurses. METHODS: From 1 June 2017 to 31 December 2017, all patients who underwent elective colorectal resection and met the ERAS inclusion criteria at the Department of Colorectal Surgery, Singapore General Hospital, were included in the study. Short-term outcomes were compared between patients with >70% compliance to key ERAS components versus those with ≤70% compliance. Department staff were surveyed via questionnaire in July 2019. RESULTS: Three hundred and fifteen patients were included in study. >70% ERAS compliance rate was achieved in 84 patients (26.7%). A higher compliance rate resulted in a significantly shorter length of stay of 6 (IQR 5-8) days vs. 7 (IQR 6-9.5) days (p = 0.025) and lower readmission rate of 3.6% (n = 3) vs. 4.8% (n = 11) (p = 0.042), as well as a trend towards reduced complication rate of 15.4% (n = 13) vs. 22.0% (n = 51) and earlier return to gastrointestinal function. There was a 100% questionnaire response amongst all 12 colorectal surgeons and 5 colorectal resident nurse practitioners. CONCLUSION: Increased adherence to the components of ERAS results in better early outcomes and may have long-term benefits on survival. Effective communication and professional support for the ERAS multi-disciplinary team, as well as understanding healthcare workers' concerns and addressing long-standing practices, is essential for successful implementation of the programme.

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.

Stenting as a bridge to surgery for obstructed stage IV colorectal cancers - long-term outcomes of a 10-year study.

INTRODUCTION: Successful stenting of an obstructing colorectal tumor can avert upfront emergency surgery in malnourished obstructed patients with metastatic disease and poor physiological condition. This study aims to evaluate the outcomes of stenting followed by primary colorectal tumor resection among patients with obstructed stage IV colorectal cancer at presentation, over a 10-year period. METHODS: From 2007 to 2016, a cohort comprising 25 consecutive patients were retrospectively reviewed from a prospectively collected database. The durability of palliation of bowel obstruction, oncological outcomes and factors influencing overall survival were analyzed. RESULTS: No re-interventions were required for bowel obstruction during the study period. The overall perioperative morbidity rate was 16%, with no postoperative 90-day mortality. Laparoscopic resection rate was 52% and stoma formation rate was 8%. The median overall survival was 24 months for the entire cohort, and the 1-, 3- and 5-year survival rates were 80%, 35% and 23.33% respectively. More than one site of distant metastases, peritoneal involvement, and elevated carcinoembryonic antigen levels were significantly associated with poorer survival outcomes. Patients with peritoneal-only metastasis had worse outcomes, with a median survival of 7 months and no patients surviving beyond 18 months. CONCLUSION: Stenting followed by resection of the primary obstructing colorectal cancer provides durable palliation among patients with stage IV disease, with low perioperative morbidity and stoma formation rates. Superior survival was observed among patients with single-site, non-peritoneal distant metastases.

Prediction of overall survival following colorectal cancer surgery in elderly patients.

BACKGROUND: With advanced age and chronic illness, the life expectancy of a patient with colorectal cancer (CRC) becomes less dependent on the malignant disease and more on their pre-morbid condition. Justifying major surgery for these elderly patients can be challenging. An accurate tool demonstrating post-operative survival probability would be useful for surgeons and their patients. AIM: To integrate clinically significant prognostic factors relevant to elective colorectal surgery in the elderly into a validated pre-operative scoring system. METHODS: In this retrospective cohort study, patients aged 70 and above who underwent surgery for CRC at Singapore General Hospital between 1 January 2005 and 31 December 2012 were identified from a prospectively maintained database. Patients with evidence of metastatic disease, and those who underwent emergency surgery or had surgery for benign colorectal conditions were excluded from the analysis. The primary outcome was overall 3-year overall survival (OS) following surgery. A multivariate model predicting survival was derived and validated against an equivalent external surgical cohort from Kyungpook National University Chilgok Hospital, South Korea. Statistical analyses were performed using Stata/MP Version 15.1. RESULTS: A total of 1267 patients were identified for analysis. The median post-operative length of stay was 8 [interquartile range (IQR) 6-12] d and median follow-up duration was 47 (IQR 19-75) mo. Median OS was 78 (IQR 65-85) mo. Following multivariate analysis, the factors significant for predicting overall mortality were serum albumin < 35 g/dL, serum carcinoembryonic antigen ≥ 20 µg/L, T stage 3 or 4, moderate tumor cell differentiation or worse, mucinous histology, rectal tumors, and pre-existing chronic obstructive lung disease. Advanced age alone was not found to be significant. The Korean cohort consisted of 910 patients. The Singapore cohort exhibited a poorer OS, likely due to a higher proportion of advanced cancers. Despite the clinicopathologic differences, there was successful validation of the model following recalibration. An interactive online calculator was designed to facilitate post-operative survival prediction, available at http://bit.ly/sgh_crc. The main limitation of the study was selection bias, as patients who had undergone surgery would have tended to be physiologically fitter. CONCLUSION: This novel scoring system generates an individualized survival probability following colorectal resection and can assist in the decision-making process. Validation with an external population strengthens the generalizability of this model.

Gracilis pull-through flap for the repair of a recalcitrant recto-vaginal fistula.

Recto-vaginal fistulas are difficult to treat due to their high recurrence rate. Currently, no single surgical intervention is universally regarded as the best treatment option for rectovaginal fistulas. We present a case of recurrent recto-vaginal fistula surgically treated with a gracilis pull-through flap. The surgical goals in this patient were complete excision of the recto-vaginal fistula and introduction of fresh, vascularized muscle to seal the fistula. A defunctioning colostomy was performed 1 month prior to the present procedure. The gracilis muscle and tendon were mobilized, pulled through the freshened recto-vaginal fistula, passed through the anus, and anchored externally. Excess muscle and tendon were trimmed 1 week after the procedure. Follow-up at 4 weeks demonstrated complete mucosal coverage over an intact gracilis muscle, and no leakage. At 8 weeks post-procedure, the patient resumed sexual intercourse with no dyspareunia. At 6 months post-procedure, her stoma was closed. The patient reported transient fecal staining of her vagina after stoma reversal, which resolved with conservative treatment. The fistula had not recurred at 20 months post-procedure. The gracilis pull-through flap is a reliable technique for a scarred vagina with an attenuated rectovaginal septum. It can function as a well-vascularized tissue plug to promote healing.

Totally-laparoscopic versus laparoscopic-assisted low anterior resection for rectal cancer: are outcomes different?

BACKGROUND: Laparoscopic low anterior resection for rectal cancer has superior short-term benefits compared to open surgery. When operative conditions do not favour a totally-laparoscopic (TL) approach, a hybrid operation can be performed. In this laparoscopic-assisted (LA) approach, mobilization and vessel ligation are performed laparoscopically, with total mesorectal excision and distal transection performed either partially or totally in an extra-corporeal fashion. We compared short-term post-operative and oncological outcomes of both approaches. METHODS: A prospectively collected database of patients who underwent laparoscopic low anterior resection for rectal cancer between January 2009 and December 2014 was retrospectively analysed. Demographics, post-operative and oncological outcomes were compared. RESULTS: Of 174 patients, 97 were completed by TL, 62 by LA and the remaining 15 were converted to open. Baseline demographics were similar. LA group compared to TL group had bulkier rectal cancers (6.75 cm3 versus 4.50 cm3 , P = 0.04) which were lower (6 cm versus 7 cm from anal verge, P = 0.02). They were of a more advanced tumour grade and had greater incidence of lymphovascular invasion. Yet, post-operative outcomes such as time to diet, pain scores, hospitalization duration, wound-related and anastomotic complications, 30-day morbidity and mortality were similar. There was no difference in oncological adequacy, including circumferential resection margins, distal margins, lymph node harvest and 2-year local recurrence rates. CONCLUSION: Laparoscopic-assisted low anterior resection enables minimally invasive rectal surgery to be performed despite unfavourable tumour factors and technical challenges; and compares favourably with TL approach in terms of short-term outcomes and oncological safety.

Human colorectal cancer initiation is bidirectional, and cell growth, metabolic genes and transporter genes are early drivers of tumorigenesis.

The role of stem cells in the development of solid tumors remains controversial. In colorectal cancers (CRC), this is complicated by the conflicting "top-down" or "bottom-up" hypotheses of cancer initiation. We profiled the expressions of genes from the top (T) and bottom (B) crypt fractions of normal-appearing human colonic mucosa (M) at least 20 cm away from the tumor as a baseline and compared this to the genes of matched mucosa adjacent to tumors (MT) in twenty-three sporadic CRC patients. In thirteen patients, the genetic distance (M-MT) between the B fractions is smaller than the distance between the T fractions, indicating that the expressions diverge further in the top fractions (B < T). In the remaining patients, the reverse effect is observed (B > T). Assuming that a greater genetic divergence in the top or bottom fractions indicates that position as the initiation site, it is thus equally likely that human CRC initiates from 'top-down' via de-differentiated colonocytes or 'bottom-up' via dysregulated intestinal stem cells. Dysregulated genes that persist until tumor stage are not limited to tumor suppressors or oncogenes but include metabolic and transporter genes such as CA7, PHLPP2, and AQP8.

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.

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.

Evaluation of Long-Term Outcomes of Microsatellite Instability Status in an Asian Cohort of Sporadic Colorectal Cancers.

PURPOSE: Microsatellite instability in colorectal cancer (CRC) and its long-term outcomes remains poorly studied in Asians. We investigate the prognostic significance of microsatellite instability in an Asian population and assess its clinical impact in patients who undergo adjuvant chemotherapy. METHODS: Six hundred fifty-four consecutive CRC patients who underwent surgical resection between January 2010 and December 2012 were recruited. Survival was estimated using the Kaplan-Meier approach. Univariate Cox proportional hazard models were used to estimate the hazard ratios for variables associated with survival. A subgroup analyses was performed for stage III patients who underwent chemotherapy to evaluate the prognostic significance of microsatellite instability in this group. RESULTS: Five hundred ninety-one (90.4%) patients were microsatellite stable (MSS) while 63 (9.6%) were microsatellite instable (MSI). Three years recurrence-free survival (RFS) and disease-specific survival (DSS) were 83.7 versus 73.7% (p = 0.295) and 87.1 versus 91.2% (p = 0.307) in MSS and MSI tumors, respectively. Among stage III patients who received adjuvant therapy, MSI status was found to be an adverse prognostic factor for RFS (HR 2.74 (95% CI 1.43-5.26), p = 0.002). This remained significant on multivariate analysis (HR 2.38 (95% CI 1.15-4.93), p = 0.018). Adjuvant chemotherapy was associated with survival benefit for patients with MSS tumors (HR 0.35, 95% CI 0.17-0.69, p = 0.002) but not MSI tumors (HR 0.67, 95% CI 0.08-8.15, p = 0.750). CONCLUSIONS: MSI status is not a prognostic indicator in the general CRC population but appears to be an adverse prognostic indicator for RFS in stage III CRC patients who received adjuvant chemotherapy.

Rectal Cancer Surveillance-Recurrence Patterns and Survival Outcomes from a Cohort Followed up Beyond 10 Years.

AIM: The intensity and duration of surveillance for rectal cancer after surgical resection remain contentious. We evaluated the pattern of recurrences in a rectal cancer cohort followed up beyond 10 years. METHODS: An analysis was performed on a retrospective database of 326 patients with rectal cancer who underwent curative surgical resection from 1999 to 2007. The above study duration was chosen to ensure at least 10 years of follow-up. Data on patient demographics, peri-operative details, and follow-up outcomes were extracted from the database. The pattern of recurrences and investigative modality that detected recurrences was identified. Patients were followed up until either year 2016 or the day of their demise. RESULTS: Two hundred seventeen patients (66.6%) were male and 109 patients (33.3%) female. Median age was 64 years old. Close to a third of the patients received adjuvant therapy (34%). Among the 326 patients studied, 29.8% of (97/326) patients developed recurrence. 7.7% (25/326) had loco-regional recurrence while 22.1% (72/326) had distant metastasis. Median time to recurrence was 16 months (4-83) and 18 months (3-81), respectively. Computed tomography scan was the best modality to detect both loco-regional and distant recurrences (48% in loco-regional and 41.7% in distant metastasis). The most common site of distant metastasis is the lung (34.7%). The salvage rate for loco-regional and distant recurrences was 52 and 12.5%, respectively. CONCLUSION: The predominant pattern of recurrence in rectal cancer is distant disease. Surveillance regimes may need to be altered to increase early detection of distant metastases.

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.

A formalin-fixed paraffin-embedded (FFPE)-based prognostic signature to predict metastasis in clinically low risk stage I/II microsatellite stable colorectal cancer.

Approximately 20% early-stage (I/II) colorectal cancer (CRC) patients develop metastases despite curative surgery. We aim to develop a formalin-fixed and paraffin-embedded (FFPE)-based predictor of metastases in early-stage, clinically-defined low risk, microsatellite-stable (MSS) CRC patients. We considered genome-wide mRNA and miRNA expression and mutation status of 20 genes assayed in 150 fresh-frozen tumours with known metastasis status. We selected 193 genes for further analysis using NanoString nCounter arrays on corresponding FFPE tumours. Neither mutation status nor miRNA expression improved the estimated prediction. The final predictor, ColoMet19, based on the top 19 genes' mRNA levels trained by Random Forest machine-learning strategy, had an estimated positive-predictive-value (PPV) of 0.66. We tested ColoMet19 on an independent test-set of 131 tumours and obtained a population-adjusted PPV of 0.67 indicating that early-stage CRC patients who tested positive have a 67% risk of developing metastases, substantially higher than the metastasis risk of 40% for node-positive (Stage III) patients who are generally treated with chemotherapy. Predicted-positive patients also had poorer metastasis-free survival (hazard ratios [HR] = 1.92, design-set; HR = 2.05, test-set). Thus, early-stage CRC patients who test positive may be considered for adjuvant therapy after surgery.

Critical evaluation of contemporary management in a new Pelvic Exenteration Unit: The first 25 consecutive cases.

AIM: To critically appraise short-term outcomes in patients treated in a new Pelvic Exenteration (PE) Unit. METHODS: This retrospective observational study was conducted by analysing prospectively collected data for the first 25 patients (16 males, 9 females) who underwent PE for advanced pelvic tumours in our PE Unit between January 2012 and October 2016. Data evaluated included age, co-morbidities, American Society of Anesthesiologists (ASA) score, Eastern Cooperative Oncology Group (ECOG) status, preoperative adjuvant treatment, intra-operative blood loss, procedural duration, perioperative adverse event, lengths of intensive care unit (ICU) stay and hospital stay, and oncological outcome. Quantitative data were summarized as percentage or median and range, and statistically assessed by the χ2 test or Fisher's exact test, as applicable. RESULTS: All 25 patients received comprehensive preoperative assessment via our dedicated multidisciplinary team approach. Long-course neoadjuvant chemoradiotherapy was provided, if indicated. The median age of the patients was 61.9-year-old. The median ASA and ECOG scores were 2 and 0, respectively. The indications for PE were locally invasive rectal adenocarcinoma (n = 13), advanced colonic adenocarcinoma (n = 5), recurrent cervical carcinoma (n = 3) and malignant sacral chordoma (n = 3). The procedures comprised 10 total PEs, 4 anterior PEs, 7 posterior PEs and 4 isolated lateral PEs. The median follow-up period was 17.6 mo. The median operative time was 11.5 h. The median volume of blood loss was 3306 mL, and the median volume of red cell transfusion was 1475 mL. The median lengths of ICU stay and of hospital stay were 1 d and 21 d, respectively. There was no case of mortality related to surgery. There were a total of 20 surgical morbidities, which occurred in 12 patients. The majority of the complications were grade 2 Clavien-Dindo. Only 2 patients experienced grade 3 Clavien-Dindo complications, and both required procedural interventions. One patient experienced grade 4a Clavien-Dindo complication, requiring temporary renal dialysis without long-term disability. The R0 resection rate was 64%. There were 7 post-exenteration recurrences during the follow-up period. No statistically significant relationship was found among histological origin of tumour, microscopic resection margin status and postoperative recurrence (P = 0.67). Four patients died from sequelae of recurrent disease during follow-up. CONCLUSION: By utilizing modern assessment and surgical techniques, our PE Unit can manage complex pelvic cancers with acceptable morbidities, zero-rate mortality and equivalent oncologic outcomes.