Consensus-led recommendations defining practical principles of achieving optimal surgical outcomes in robotic colorectal surgery in the Asia-Pacific region.

Recent innovations within the field of robotic surgery have particular relevance to colorectal surgery. Although a robotic approach has been associated with satisfactory outcomes, there remains a wide variation in levels of adoption. In particular, this study focuses on patient positioning, docking, and table placement, with the intent of understanding the strength of opinion of colorectal surgeons in the Asia-Pacific region to the practical application of these developments to achieve optimal surgical outcomes. Using a modified Delphi methodology, a steering group of colorectal surgeons with experience in robotic surgery from across the Asia-Pacific region identified 35 consensus statements. An online 4-point Likert scale questionnaire was distributed to surgeons in the Asia-Pacific region using convenience sampling. Respondents were excluded from further analysis if they did not perform colorectal surgery or had no experience in robotic surgery. A total of 140 responses (71.8% response rate) were received between August and October 2021. 22 statements attained a very high degree of agreement (≥ 90%). High agreement (< 90% and ≥ 75%) was achieved in another 12, and one failed to meet the consensus threshold (< 75%). A set of five recommendations were developed based on these results. The high levels of agreement demonstrate recognition amongst colorectal surgeons within the Asia-Pacific region of the potential advantage of recent improvements in robotic surgery technology to further improve surgical outcomes. The recommendations may inform a set of practical principles to help standardise the use of colorectal robotic surgery, which may also be relevant to other surgical fields.

Prognostic implication of the neoadjuvant rectal score and other biomarkers of clinical outcome in Hong Kong Chinese patients with locally advanced rectal cancer undergoing neoadjuvant chemoradiotherapy.

BACKGROUND: Neoadjuvant chemoradiotherapy is a standard treatment for locally advanced rectal cancer, for which pathological complete response is typically used as a surrogate survival endpoint. Neoadjuvant rectal score is a new biomarker that has been shown to correlate with survival. The main objectives of this study were to investigate factors contributing to pathological complete response, to validate the prognostic significance of neoadjuvant rectal score, and to investigate factors associated with a lower neoadjuvant rectal score in a cohort of Hong Kong Chinese. METHODS: Data of patients with locally advanced rectal cancer who received neoadjuvant chemoradiotherapy from August 2006 to October 2018 were retrieved from hospital records and retrospectively analysed. RESULTS: Of 193 patients who had optimal response to neoadjuvant chemoradiotherapy and surgery, tumour down-staging was the only independent prognostic factor that predicted pathological complete response (P<0.0001). Neoadjuvant rectal score was associated with overall survival (hazard ratio [HR]=1.042, 95% confidence interval [CI]=1.021-1.064; P<0.0001), disease-free survival (HR=1.042, 95% CI=1.022-1.062; P<0.0001), locoregional recurrence-free survival (HR=1.070, 95% CI=1.039-1.102; P<0.0001) and distant recurrence-free survival (HR=1.034, 95% CI=1.012-1.056; P=0.002). Patients who had pathological complete response were associated with a lower neoadjuvant rectal score (P<0.0001), but pathological complete response was not associated with survival. For patients with intermediate neoadjuvant rectal scores, late recurrences beyond 72 months from diagnosis were observed. CONCLUSION: Neoadjuvant rectal score is an independent prognostic marker of survival and disease recurrence in a cohort of Hong Kong Chinese patients who received neoadjuvant chemoradiotherapy for locally advanced rectal cancer.

A structural equation model of the relationship between muscle strength, balance performance, walking endurance and community integration in stroke survivors.

PURPOSE: To use structural equation modelling (SEM) to determine (1) the direct and indirect associations of strength of paretic lower limb muscles with the level of community integration, and (2) the direct association of walking endurance and balance performance with the level of community integration in community-dwelling stroke survivors. MATERIALS AND METHODS: In this cross-sectional study of 105 stroke survivors, the Subjective Index of Physical and Social Outcome (SIPSO) was used to measure the level of community integration. Lower-limb strength measures included isometric paretic ankle strength and isokinetic paretic knee peak torque. The Berg Balance Scale (BBS) and the 6-minute walk test (6MWT) were used to evaluate balance performance and walking endurance, respectively. RESULTS: SEM revealed that the distance walked on the 6MWT had the strongest direct association with the SIPSO score (ß = 0.41, p <0.001). An increase of one standard deviation in the 6MWT distance resulted in an increase of 0.41 standard deviations in the SIPSO score. Moreover, dorsiflexion strength (ß = 0.18, p = 0.044) and the BBS score (ß = 0.21, p = 0.021) had direct associations with the SIPSO score. CONCLUSIONS: The results of the proposed model suggest that rehabilitation training of community-dwelling stroke survivors could focus on walking endurance, balance performance and dorsiflexor muscle strengthening if the aim is to augment the level of community integration.

Pre-45s rRNA promotes colon cancer and is associated with poor survival of CRC patients.

One characteristic of cancer cells is the abnormally high rate of cell metabolism to sustain their enhanced proliferation. However, the behind mechanism of this phenomenon is still elusive. Here we find that enhanced precursor 45s ribosomal RNA (pre-45s rRNA) is one of the core mechanisms in promoting the pathogenesis of colorectal cancer (CRC). Pre-45s rRNA expression is significantly higher in primary CRC tumor tissues samples and cancer cell lines compared with the non-tumorous colon tissues, and is associated with tumor sizes. Knockdown of pre-45s rRNA inhibits G1/S cell-cycle transition by stabilizing p53 through inducing murine double minute 2 (MDM2) and ribosomal protein L11 (RpL11) interaction. In addition, we revealed that high rate of cancer cell metabolism triggers the passive release of calcium ion from endoplasmic reticulum to the cytoplasm. The elevated calcium ion in the cytoplasm activates the signaling cascade of calcium/calmodulin-dependent protein kinase II, ribosomal S6 kinase (S6K) and ribosomal S6K (CaMKII-S6K-UBF). The activated UBF promotes the transcription of rDNA, which therefore increases pre-45s rRNA. Disruption of CaMKII-S6K-UBF axis by either RNAi or pharmaceutical approaches leads to reduction of pre-45s rRNA expression, which subsequently suppresses cell proliferation in colon cancer cells by causing cell-cycle arrest. Knockdown of APC activates CaMKII-S6K-UBF cascade and thus enhances pre-45s rRNA expression. Moreover, the high expression level of pre-45s rRNA is associated with poor survival of CRC patients in two independent cohorts. Our study identifies a novel mechanism in CRC pathogenesis mediated by pre-45s rRNA and a prognostic factor of pre-45s rRNA in CRC patients.

Reduced prostate cancer risk with green tea and epigallocatechin 3-gallate intake among Hong Kong Chinese men.

BACKGROUND: In vitro and in vivo studies suggested that polyphenol epigallocatechin 3-gallate (EGCG) in tea may have anti-carcinogenic effect on prostate cells, but this protective effect has less been examined in epidemiology studies. We aimed to investigate the association between prostate cancer (PCA) risk and habitual green tea intake among Chinese men in Hong Kong; meanwhile, the relationship with EGCG was also explored. METHODS: We consecutively recruited 404 PCA cases and 395 controls from the same hospital who had complete data on habitual tea consumption, including green, oolong, black and pu'er tea. We reconstructed the level of EGCG intake according to a standard questionnaire and the analytic values for EGCG extracted from the literature published by Lin et al. in 2003. We calculated odds ratios (ORs) for tea consumption and EGCG intake using unconditional multiple logistic regression, and examined their exposure--response relationships with PCA risk. RESULTS: A total of 32 cases and 50 controls reported habitual green tea drinking, showing an adjusted OR of 0.60 (95% confidence interval (CI): 0.37, 0.98). A moderate excess risk was observed among the habitual pu'er tea drinkers (OR=1.44, 95% CI: 1.02, 1.91). A significantly lower intake of EGCG was observed among cases (54.4 mg) than the controls (72.5 mg), which resulted in an inverse gradient of PCA risk with the increasing intake of EGCG (test for trend, P=0.015). CONCLUSION: PCA risk among Chinese men in Hong Kong was inversely associated with green tea consumption and EGCG intake, but these results need to be replicated in larger studies.

Disruption of NCOA2 by recurrent fusion with LACTB2 in colorectal cancer.

Whole-genome and transcriptome sequencing were used to discover novel gene fusions in a case of colon cancer. A tumor-specific LACTB2-NCOA2 fusion originating from intra-chromosomal rearrangement of chromosome 8 was identified at both DNA and RNA levels. Unlike conventional oncogenic chimeric proteins, the fusion product lacks functional domain from respective genes, indicative of an amorphic rearrangement. This chimeric LACTB2-NCOA2 transcript was detected in 6 out of 99 (6.1%) colorectal cancer (CRC) cases, where NCOA2 was significantly downregulated. Enforced expression of wild-type NCOA2 but not the LACTB2-NCOA2 fusion protein impaired the pro-tumorigenic phenotypes of CRC cells, whereas knockdown of endogenous NCOA2 in normal colonocytes had opposite effects. Mechanistically, NCOA2 inhibited Wnt/ß-catenin signaling through simultaneously upregulating inhibitors and downregulating stimulators of Wnt/ß-catenin pathway. Collectively, our data supports that NCOA2 is a novel negative growth regulatory gene repressing the Wnt/ß-catenin pathway in CRC, where recurrent fusion with LACTB2 contributes to its disruption.

An updated Asia Pacific Consensus Recommendations on colorectal cancer screening.

OBJECTIVE: Since the publication of the first Asia Pacific Consensus on Colorectal Cancer (CRC) in 2008, there are substantial advancements in the science and experience of implementing CRC screening. The Asia Pacific Working Group aimed to provide an updated set of consensus recommendations. DESIGN: Members from 14 Asian regions gathered to seek consensus using other national and international guidelines, and recent relevant literature published from 2008 to 2013. A modified Delphi process was adopted to develop the statements. RESULTS: Age range for CRC screening is defined as 50-75 years. Advancing age, male, family history of CRC, smoking and obesity are confirmed risk factors for CRC and advanced neoplasia. A risk-stratified scoring system is recommended for selecting high-risk patients for colonoscopy. Quantitative faecal immunochemical test (FIT) instead of guaiac-based faecal occult blood test (gFOBT) is preferred for average-risk subjects. Ancillary methods in colonoscopy, with the exception of chromoendoscopy, have not proven to be superior to high-definition white light endoscopy in identifying adenoma. Quality of colonoscopy should be upheld and quality assurance programme should be in place to audit every aspects of CRC screening. Serrated adenoma is recognised as a risk for interval cancer. There is no consensus on the recruitment of trained endoscopy nurses for CRC screening. CONCLUSIONS: Based on recent data on CRC screening, an updated list of recommendations on CRC screening is prepared. These consensus statements will further enhance the implementation of CRC screening in the Asia Pacific region.

DACT2 is a functional tumor suppressor through inhibiting Wnt/ß-catenin pathway and associated with poor survival in colon cancer.

Dapper homolog (DACT) 2 is one of the Dact gene family members, which are important modulators of Wnt signaling pathway. We aim to clarify its epigenetic inactivation, biological function and clinical implication in colon cancer. DACT2 was silenced in five out of eight colon cancer cell lines, but robustly expressed in normal colon tissues. The loss of DACT2 expression was regulated by promoter hypermethylation. Restoring DACT2 expression in colon cancer cell lines suppressed tumor cell growth by inducing cell apoptosis and inhibiting cell proliferation both in vitro and in vivo. Moreover, DACT2 overexpression effectively reduced lung metastasis of colon cancer cells in nude mice. These effects by DACT2 were attributed to inhibition of Wnt/ß-catenin signaling. Reexpression of DACT2 significantly suppressed the transcriptional activity of both wild-type ß-catenin and degradation-resistant form mutant ß-catenin (S33Y). DACT2 could actively shuttle into and out of nuclei, with its predominant steady-state localization in the cytoplasm dependent on its nuclear export signal. Co-immunoprecipitation results indicated that DACT2 strongly associated ß-catenin as well as lymphoid enhancer-binding factor 1 (LEF1) and directly disrupted the formation of the ß-catenin-LEF1 complex in the nucleus. Whereas in the cytoplasm, DACT2 restored junctional localization of E-cadherin-ß-catenin complexes and prevented ß-catenin nuclear translocation through direct interaction with ß-catenin. DACT2 methylation was detected in 43.3% (29/67) of colon cancer tissues, but none in normal controls. Multivariate analysis revealed that patients with DACT2 methylation had a significant decrease in overall survival (P=0.006). Kaplan-Meier survival curves showed that DACT2 methylation was significantly associated with shortened survival in stage I-III colon cancer patients. In conclusion, DACT2 acts as a functional tumor suppressor in colon cancer through inhibiting Wnt/ß-catenin signaling. Its methylation at early stages of colon carcinogenesis is an independent prognostic factor.

microRNA-221 and microRNA-18a identification in stool as potential biomarkers for the non-invasive diagnosis of colorectal carcinoma.

BACKGROUND: The detection of microRNA (miRNA) dysregulation in stool is a novel approach for the diagnosis of colorectal carcinoma (CRC). The aim of this study is to investigate the use of miR-221 and miR-18a in stool samples as non-invasive biomarkers for CRC diagnosis. METHODS: A miRNA expression array containing 667 miRNAs was performed to identify miRNA dysregulation in CRC tissues. We focused on miR-221 and miR-18a, two significantly upregulated miRNAs which were subsequently verified in 40 pairs of CRC tissues and 595 stool samples (198 CRCs, 199 polyps and 198 normal controls). RESULTS: miR-221 and miR-18a were upregulated in the miRNA expression array. miR-221 and miR-18a levels were also significantly higher in 40 CRC tumours compared with their respective adjacent normal tissues. In stool samples, miR-221 and miR-18a showed a significant increasing trend from normal controls to late stages of CRC (P<0.0001). The levels of stool miR-221 and miR-18a were both significantly higher in subjects with stages I+II (miR-221: P<0.0001, miR-18a: P<0.0001) and stages III+IV of CRC (miR-221: P=0.0004, miR-18a: P<0.0001) compared with normal controls. The AUC of stool miR-221 and miR-18a were 0.73 and 0.67 for CRC patients as compared with normal controls, respectively. No significant differences in stool miR-221 and miR-18a levels were found between patients with proximal and distal CRCs. The use of antibiotics did not influence stool miRNA-221 and miRNA-18a levels. CONCLUSIONS: Stool-based miR-221 can be used as a non-invasive biomarker for the detection of CRC.

The Janus face of cathelicidin in tumorigenesis.

Cathelicidin is a host defense peptide with multiple innate immunity-related functions. Recent findings indicate that cathelicidin is frequently dysregulated in human cancers where it plays a paradoxical yet dominant role in the regulation of tumor malignancy. In this review, the regulation of malignant phenotypes by cathelicidin in relation to the activation of its receptors and intracellular signaling is discussed.

Diagnostic accuracy of faecal immunochemical test for screening individuals with a family history of colorectal cancer.

BACKGROUND: The role of a faecal immunochemical test (FIT) in screening individuals with a positive family history of colorectal cancer (CRC) is not clear. AIM: To assess the diagnostic accuracy of FIT using colonoscopy findings as the gold standard in identifying colorectal neoplasms. METHODS: We analysed data from 4539 asymptomatic subjects aged 50-70 years who had both colonoscopy and FIT (Hemosure; W.H.P.M., Inc, El Monte, CA, USA) at our bowel cancer screening centre between 2008 and 2012. A total of 572 subjects (12.6%) had a family history of CRC. Our primary outcome was the sensitivity of FIT in detecting advanced neoplasms and cancers in subjects with a family history of CRC. A family history of CRC was defined as any first-degree relative with a history of CRC. RESULTS: Among 572 subjects with a family history of CRC, adenoma, advanced neoplasm and cancer were found at screening colonoscopy in 29.4%, 6.5% and 0.7% individuals, respectively. The sensitivity of FIT in detecting adenoma, advanced neoplasm and cancer was 9.5% [95% confidence interval (CI), 5.7-15.3], 35.1% (95% CI, 20.7-52.6) and 25.0% (95% CI, 1.3-78.1), respectively. Among FIT-negative subjects who have a family history of CRC, adenoma was found in 152 (29.6%), advanced neoplasm in 24 (4.7%) and cancer in 3 (0.6%) individuals. CONCLUSION: Compared with colonoscopy, FIT is more likely to miss advanced neoplasms or cancers in individuals with a family history of CRC.

microRNA-7 is a novel inhibitor of YY1 contributing to colorectal tumorigenesis.

Using microRNA (miRNA) expression array, we identified that miR-7 was deregulated in colorectal cancer (CRC). We studied the biological role and molecular target of miR-7 in CRC. miR-7 was downregulated in six out of seven colon cancer cell lines. Ectopic expression of miR-7 suppressed colon cancer cell proliferation (P<0.05), induced apoptosis (P<0.05) and caused cell-cycle arrest in G1 phase (P<0.05). The tumor suppressive function of miR-7 was further confirmed in nude mice (P<0.05). The 3'-untranslated region (3'UTR) of Yin Yang 1 (YY1) mRNA contains an evolutionarily conserved miR-7 binding site using in silico searches, luciferase reporter assay and western blot analysis confirmed that miR-7 directly bound to YY1 3'UTR to negatively regulate the protein expression of YY1 in colon cancer cell lines HCT116 and LOVO. Intriguingly, knock-down of YY1 in three colon cancer cell lines (HCT116, LOVO and DLD1) consistently suppressed cell proliferation (P<0.01) and induced apoptosis (P<0.01), indicating the opposite functions of miR-7 and YY1 in CRC. Consistent with these data, ectopic expression of YY1 promoted cell growth by increasing proliferation (P<0.01) and suppressing apoptosis (P<0.001). The tumorigenic ability of YY1 was further confirmed in vivo in xenograft-nude mouse model (P<0.01). In addition, pathway analyses revealed that the oncogenic effect by YY1 was associated with inhibiting p53 and modulating its downstream effectors p15, caspase cascades and C-Jun, and activating Wnt signaling pathway through activating ß-catenin, anti-apoptotic survivin and fibroblast growth factor 4. Furthermore, multivariate analysis revealed that patients with YY1 protein high expression had a significant decrease in overall survival, and Kaplan-Meier survival curves showed that these patients had significantly shorter survival than others (P<0.0001). In conclusion, MiR-7 is a novel miRNA with tumor suppressive function in colon cancer by targeting oncogenic YY1. YY1 promotes colon cancer growth through inhibiting p53 and promoting Wnt signaling pathways and serves as an independent prognostic biomarker for CRC patients.

Electroacupuncture for ileus after laparoscopic colorectal surgery: a randomised sham-controlled study.

1. Electroacupuncture at acupoints of Zusanli, Sanyinjiao, Hegu, and Zhigou is more effective than no acupuncture and sham acupuncture in stimulating early return of bowel function and reducing analgesic requirement after laparoscopic colorectal surgery. 2. Electroacupuncture is more effective than no acupuncture in reducing the duration of hospital stay. 3. Receipt of electroacupuncture is an independent predictor of shorter duration of ileus and hospital stay after laparoscopic colorectal surgery.

Clinical significance of CDX2-positive circulating tumour cells in colorectal cancer patients.

BACKGROUND: Our recent work has shown the feasibility of using a refined immunomagnetic enrichment (IE) assay to detect cytokeratin 20-positive circulating tumour cells (CK20 pCTCs) in colorectal cancer (CRC) patients. We attempted to improve the sensitivity for CRC by detecting another intestinal-type differentiation marker, CDX2 pCTCs, using the same methodology. METHODS: CDX2 pCTCs were detected in patients with CRC, colorectal adenoma (CAD), benign colorectal diseases (BCD), other common cancers (OCC) and normal subjects (NS). Statistical analysis was used to correlate CDX2 pCTCs to the clinicohistopathological factors, recurrence, metastasis and survival after follow-up for 42 months in CRC patients. RESULTS: CDX2 pCTCs were detected in 81% CRC patients (73 out of 90, median number=21.5 CTCs), 7.5% CAD patients (3 out of 40), 0% patients with BCD (0 out of 90), 2.5% patients with OCC (2 out of 80) and 0% NS (0 out of 40). Furthermore, statistical analysis showed that CDX2 pCTC numbers were associated with tumour- node-metastasis stage and lymph node status. Using the median CDX2 pCTC numbers as the cutoff points, stratified groups of CRC patients had significant differences in their recurrence and survival. CONCLUSIONS: This study showed that the refined IE assay can detect CDX2 pCTCs with high sensitivity and that CDX2 pCTCs can generate clinically important information for CRC patients.

MicroRNA dysregulation in colorectal cancer: a clinical perspective.

Recent researches have shed light on the biological importance of microRNAs (miRNAs) in colorectal cancer (CRC) genesis, progression and response to treatments. The potential utility of miRNAs in the preclinical stage have been explored and investigated. In this review, we explored the literature and reviewed the cutting edge progress in the discovery of noninvasive plasma and faecal miRNAs for CRC early diagnosis, as well as their measurability and predictability. We also discussed the utility of miRNAs as novel prognostic and predictive markers, and their association with CRC clinical phenotypes including recurrence, metastasis and therapeutic outcomes. Finally, we summarised miRNA-related single-nucleotide polymorphisms and their potential influence on sporadic CRC susceptibility and therapeutic response. In conclusion, the use of miRNAs as biomarker for CRC is still in its infancy and need further characterisation and evaluation.