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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.

The consensus molecular subtype (CMS) classification of colorectal cancer is based on bulk transcriptomics. The underlying epithelial cell diversity remains unclear. We analyzed 373,058 single-cell transcriptomes from 63 patients, focusing on 49,155 epithelial cells. We identified a pervasive genetic and transcriptomic dichotomy of malignant cells, based on distinct gene expression, DNA copy number and gene regulatory network. We recapitulated these subtypes in bulk transcriptomes from 3,614 patients. The two intrinsic subtypes, iCMS2 and iCMS3, refine CMS. iCMS3 comprises microsatellite unstable (MSI-H) cancers and one-third of microsatellite-stable (MSS) tumors. iCMS3 MSS cancers are transcriptomically more similar to MSI-H cancers than to other MSS cancers. CMS4 cancers had either iCMS2 or iCMS3 epithelium; the latter had the worst prognosis. We defined the intrinsic epithelial axis of colorectal cancer and propose a refined ‘IMF’ classification with five subtypes, combining intrinsic epithelial subtype (I), microsatellite instability status (M) and fibrosis (F). A single-cell transcriptomic analysis of 63 patients with colorectal cancer classifies tumor cells into two epithelial subtypes. An improved tumor classification based on epithelial subtype, microsatellite stability and fibrosis reveals differences in pathway activation and metastasis.

BackgroundOncological outcomes of stenting as a bridge to surgery (SBTS) remain a major concern, despite perioperative benefits it offers. This study aims to evaluate the differences in recurrence patterns and survival in patients with non-metastatic, obstructing left sided colon cancers treated by SBTS versus upfront emergency surgery (ES).MethodsThis is a retrospective, single-centre cohort study of 227 consecutive patients with non-metastatic, obstructing left sided colon cancer between 2007 and 2016. Primary outcomes were pattern of recurrence, and survival. Univariate, bivariate and multivariate logistic regression were done to determine relationships between factors and recurrence. Kaplan Meier curves and log rank tests were used to analyse survival outcomes.ResultsOf the 227 patients included, 62 underwent SBTS and 165 underwent upfront ES. There was a higher rate of peritoneal recurrence in SBTS group (27.4 vs 15.2% p = 0.034), with no difference observed in overall, liver or lung recurrences. No significant difference in overall survival (p = 0.11), cancer specific survival (p = 0.35), or recurrence free survival (p = 0.107) was observed.Univariate analysis showed that SBTS (OR 2.12, p = 0.036), diabetes mellitus (DM) (OR 2.58, p = 0.013), T4 (OR 2.81, p = 0.001), N + (OR 4.02, p = 0.001), lymphovascular invasion (OR 2.43, p = 0.011) contributed to a higher rate of peritoneal recurrence.Bivariate analysis showed synergistic relationship between T4 tumors and SBTS: in T4 tumors that underwent SBTS, the odds of having peritoneal recurrence was 6.8 times higher when compared to ES (p = 0.004); whilst in T2/3 tumors there was no significant difference observed (OR 1.33, p = 0.55).Multivariable analysis showed SBTS (OR 2.60, p = 0.04), DM (OR 2.88, p = 0.012), N + (OR 2.97, p = 0.026) were significant predictors for peritoneal recurrence.ConclusionsThere are concerns over oncological safety of SBTS even with low rates of stent-related perforation. Higher rates of peritoneal recurrence are seen especially with T4 colon cancers treated with SBTS. SBTS, DM and nodal stage were significant predictors for peritoneal recurrence.

Minimally invasive abdominal surgery (MAS) can exert a physical cost. Surgical trainees spend years assisting minimally-invasive surgeries, increasing the risk of workplace injury. This prospective questionnaire-based cohort study was conducted amongst general surgery residents in Singapore. Residents assisting major MAS surgery were invited to complete anonymous online survey forms after surgery. The Phase 1 survey assessed physical discomfort scores and risk factors. Intraoperative measures to improve ergonomics were administered and evaluated in Phase 2. During Phase 1 (October 2021 to April 2022), physical discomfort was reported in at least one body part in 82.6% (n = 38) of respondents. Over a third of respondents reported severe discomfort in at least one body part (n = 17, 37.0%). Extremes of height, training seniority, longer surgical duration and operative complexity were significant risk factors for greater physical discomfort. In Phase 2 (October 2022 to February 2023), the overall rate of physical symptoms and severe discomfort improved to 81.3% (n = 52) and 34.4% (n = 22) respectively. The ergonomic measure most found useful was having separate television monitors for the primary surgeon and assistants, followed by intraoperative feedback on television monitor angle or position. Close to 20% of survey respondents felt that surgeon education was likely to improve physical discomfort.

Aim Natural orifice specimen extraction (NOSE) is an alternative to conventional transabdominal retrieval. We aimed to compare outcomes following transvaginal specimen extraction (TVSE) and transabdominal specimen extraction (TASE) in minimally invasive abdominal surgery. Methods An electronic database search of PubMed, Embase and CENTRAL was performed from inception until March 2023. Comparative studies evaluating TVSE versus TASE in adult female patients were included. Studies involving transanal NOSE, endoluminal surgery, or TVSE with concomitant hysterectomy were excluded. Weighted mean differences (WMD) and odds ratio were estimated for continuous and dichotomous outcomes respectively. Primary outcomes were postoperative day 1 (POD1) pain and length of stay (LOS). Secondary outcomes were operative time, rescue analgesia, morbidity, and cosmesis. A review of sexual, oncological, and technical outcomes was performed. Results Thirteen studies (2 randomised trials, 11 retrospective cohort studies), involving 1094 patients (TASE 583, TVSE 511), were included in the analysis. Seven studies involved colorectal disease and six assessed gynaecological conditions. TVSE resulted in significantly decreased POD1 pain (WMD 1.08, 95% CI: 0.49, 1.68) and shorter LOS (WMD 1.18 days, 95% CI: 0.14, 2.22), compared to TASE. Operative time was similar between both groups, with fewer patients requiring postoperative rescue analgesia with TVSE. Overall morbidity rates, as well as both wound-related and non-wound related complication rates were better with TVSE, while anastomotic morbidity rates were comparable. Cosmetic scores were higher with TVSE. TVSE did not result in worse sexual or oncological outcomes. Conclusion TVSE may be feasible and beneficial compared to TASE when performed by proficient laparoscopic operators, using appropriate selection criteria. Continued evaluation with prospective studies is warranted.

Wnts, cholesterol, and MAPK signaling are essential for development and adult homeostasis. Here, we report that fatty acid hydroxylase domain containing 2 (FAXDC2), a previously uncharacterized enzyme, functions as a methyl sterol oxidase catalyzing C4 demethylation in the Kandutsch-Russell branch of the cholesterol biosynthesis pathway. FAXDC2, a paralog of MSMO1, regulated the abundance of the specific C4-methyl sterols lophenol and dihydro-T-MAS. Highlighting its clinical relevance, FAXDC2 was repressed in Wnt/β-catenin-high cancer xenografts, in a mouse genetic model of Wnt activation, and in human colorectal cancers. Moreover, in primary human colorectal cancers, the sterol lophenol, regulated by FAXDC2, accumulated in the cancerous tissues and not in adjacent normal tissues. FAXDC2 linked Wnts to RTK/MAPK signaling. Wnt inhibition drove increased recycling of RTKs and activation of the MAPK pathway, and this required FAXDC2. Blocking Wnt signaling in Wnt-high cancers caused both differentiation and senescence; and this was prevented by knockout of FAXDC2. Our data show the integration of 3 ancient pathways, Wnts, cholesterol synthesis, and RTK/MAPK signaling, in cellular proliferation and differentiation.

Background and Objectives: During the COVID-19 pandemic, many countries implemented lockdowns and social distancing measures, which may delay the early diagnosis of colorectal cancer (CRC). This study aims to review the impact of the pandemic on the diagnosis and treatment outcomes of CRC. Materials and Methods: Patients who underwent colonoscopy or surgery for CRC were included. The study was divided into the pre-COVID-19 (January 2019–January 2020), early COVID-19 (February–May 2020), recovery (June–December 2020), and heightened alert (January–December 2021) periods. Cox regression was used to model the waiting time to colonoscopy. Multivariable logistic regression identified associations between time periods and incidence of CRC diagnosed. The characteristics and outcomes of the surgical procedures that were performed were compared across the time periods. Results: A total of 18,662 colonoscopies and 1462 surgical procedures were performed in the study period. Compared to the pre-COVID-19 period, there was a longer time to colonoscopy during the recovery (HR: 0.91; 95% CI: 0.87, 0.94) and heightened alert periods (HR: 0.88; 95% CI 0.85, 0.91). The early COVID-19 (OR: 1.36; 95% CI: 1.04, 1.77) and recovery (OR: 1.20; 95% CI: 1.01, 1.43) periods were associated with higher odds of diagnosing CRC. Compared to the pre-COVID-19 period, there was a higher proportion of ASA 4 patients (4.3% vs. 1.3%; p < 0.001) and stage 4 CRC patients (22.2% vs. 16.9%; p = 0.001) that required surgery during the heightened alert period. Similarly, there was a higher proportion of emergency surgeries (22% vs. 13.3%; p = 0.002); diverting stomas (13.5% vs. 10.5%; p = 0.005), and Hartmann’s procedures (4.4% vs. 0.4%; p = 0.001) performed during the heightened alert period. Conclusions: The pandemic was associated with a higher proportion of metastatic CRC patients requiring surgery. Healthcare policies should facilitate early cancer screening, diagnosis, and treatment to reduce cancer-related morbidity for future pandemics.

Colorectal cancer (CRC) incidence and mortality in those aged 50 years and above have decreased over the past 2 decades. However, there is a rising incidence of CRC among individuals under 50 years of age, termed early-onset colorectal cancer (EOCRC). Patients with EOCRC are diagnosed at an advanced stage and may be in more psychosocial, emotional, and financial distress. Our study examined the epidemiological shifts in CRC in Singapore, a multiethnic country. CRCs diagnosed at age 20 years and above were identified from the Singapore Cancer Registry (SCR) from 1968 to 2019. Patient characteristics included gender, ethnicity, and age of CRC diagnosis. Population information was obtained from the Department of Statistics Singapore (SingStat). Age-specific incidence rates (ASRs) and age-standardized incidence rates (ASIRs) were calculated. The cohort was divided into 3 age groups: 20-49, 50-64, and ≥65 years. Temporal trends in incidence rates were modeled with joinpoint regression. Birth cohort models were fitted using the National Cancer Institute (NCI) age-period-cohort analysis tool. Cancer-specific survival analysis was performed with the Cox proportional hazards model. In total, 53,044 CRCs were included, and 6183 (11.7%) adults aged 20-49 years were diagnosed with EOCRC. The ASR of EOCRC rose from 5 per 100,000 population in 1968 to 9 per 100,000 population in 1996 at 2.1% annually and rose to 10 per 100,000 population in 2019 at 0.64% annually. The ASR for CRC among adults aged 50-64 years rose at 3% annually from 1968 to 1987 and plateaued from 1987, while the ASR for adults aged 65 years and above rose at 4.1% annually from 1968 to 1989 and 1.3% annually from 1989 to 2003 but decreased from 2003 onwards at 1% annually. The ASR of early-onset rectal cancer increased significantly at 1.5% annually. There was a continued rise in the ASR of EOCRC among males (annual percentage change [APC] 1.5%) compared to females (APC 0.41%). Compared to the 1950-1954 reference birth cohort, the 1970-1984 birth cohort had a significantly higher incidence rate ratio (IRR) of 1.17-1.36 for rectal cancer, while there was no significant change for colon cancer in later cohorts. There were differences in CRC trends across the 3 ethnic groups: Malays had a rapid and persistent rise in the ASR of CRC across all age groups (APC 1.4%-3%), while among young Chinese, only the ASR of rectal cancer was increasing (APC 1.5%). Patients with EOCRC had better survival compared to patients diagnosed at 65 years and above (hazard ratio [HR] 0.73, 95% CI 0.67-0.79, P<.001) after adjusting for covariates. The rise in the incidence of rectal cancer among young adults, especially among Chinese and Malays, in Singapore highlights the need for further research to diagnose CRC earlier and reduce cancer-related morbidity and mortality.

Lateral pelvic lymph-node metastases occur in 10–25% of patients with rectal cancer, and are associated with higher local recurrence and reduced survival rates. A meta-analysis was undertaken to assess the value of extended lateral pelvic lymphadenectomy in the operative management of rectal cancer. We searched Medline, Embase, Ovid, Cochrane Library, and Google Scholar for studies published between 1965 and 2009 that compared extended lymphadenectomy (EL) with standard rectal resection. 20 studies, which included 5502 patients from one randomised, three prospective non-randomised, and 14 retrospective case–control studies published between 1984 and 2009, met our search criteria and were assessed. 2577 patients underwent EL and 2925 underwent non-EL for rectal cancer. Random and fixed-effects meta-analytical models were used where indicated, and between-study heterogeneity was assessed. End-points evaluated included peri-operative outcomes, 5-year survival and recurrence rates. Operating time was significantly longer in the EL group by 76·7 min (95% CI 18·77–134·68; p=0·0096). Intra-operative blood loss was greater in the EL group by 536·5 mL (95% CI 353·7–719·2; p<0·0001). Peri-operative mortality (OR 0·81, 95% CI 0·34–1·93; p=0·63) and morbidity (OR 1·45, 95% CI 0·89–2·35; p=0·13) were similar between the two groups. Data from individual studies showed that male sexual dysfunction and urinary dysfunction (three studies: OR 3·70, 95% CI 1·66–8·23; p=0·0012) were more prevalent in the EL group. There were no significant differences in 5-year survival (hazard ratio [HR] 1·09, 95% CI 0·78–1·50; p=0·62), 5-year disease-free survival (HR 1·23, 95% CI 0·75–2·03, p=0·41), and local (OR 0·83, 95% CI 0·61–1·13; p=0·23) or distant recurrence (OR 0·93, 95% CI 0·72–1·21; p=0·60). Extended lymphadenectomy does not seem to confer a significant overall cancer-specific advantage, but does seem to be associated with increased urinary and sexual dysfunction. The National Institute for Health Research Biomedical Research Centre, London, UK.

Background Fast-track (FT) protocols accelerate patient's recovery and shorten hospital stay as a result of the optimization of the perioperative care they offer. The aim of this review is to examine the latest evidence for fast-track protocols when compared with standard care in elective colorectal surgery involving segmental colonic and/or rectal resection. Materials and methods All randomized controlled trials and controlled clinical trials on FT colorectal surgery were reviewed systematically. The main end points were short-term morbidity, length of primary postoperative hospital stay, length of total postoperative stay, readmission rate, and mortality. Quality assessment and data extraction were performed independently by two observers. Results Eleven studies were eligible for analysis (four randomized controlled trials (RCTs) and seven controlled clinical trials (CCT)), including 1,021 patients. Primary hospital stay (weighted mean difference -2.35 days, 95% confidence interval (CI) -3.24 to -1.46 days, P < 0.00001) and total hospital stay (weighted mean difference -2.46 days, 95% CI -3.43 to -1.48 days, P < 0.00001) were significantly lower for FT programs. Morbidity was also lower in the FT group. Readmission rates were not significantly different. No increase in mortality was found. Conclusions FT protocols show high-level evidence on reducing primary and total hospital stay without compromising patients' safety offering lower morbidity and the same readmission rates. Enhanced recovery programs should become a mainstay of elective colorectal surgery.