Risk factors for anastomotic leak and postoperative morbidity after right hemicolectomy for colon cancer: results from a prospective, multi-centre, snapshot study in China.

BACKGROUND: Right hemicolectomy is the standard treatment for right-sided colon cancer. There is variation in the technical aspects of performing right hemicolectomy as well as in short-term outcomes. It is therefore necessary to explore best clinical practice following right hemicolectomy in expert centres. METHODS: This snapshot study of right hemicolectomy for colon cancer in China was a prospective, multicentre cohort study in which 52 tertiary hospitals participated. Eligible patients with stage I-III right-sided colon cancer who underwent elective right hemicolectomy were consecutively enrolled in all centres over 10 months. The primary endpoint was the incidence of postoperative 30-day anastomotic leak. RESULTS: Of the 1854 patients, 89.9 per cent underwent laparoscopic surgery and 52.3 per cent underwent D3 lymph node dissection. The overall 30-day morbidity and mortality were 11.7 and 0.2 per cent, respectively. The 30-day anastomotic leak rate was 1.4 per cent. In multivariate analysis, ASA grade > II (P < 0.001), intraoperative blood loss > 50 ml (P = 0.044) and D3 lymph node dissection (P = 0.008) were identified as independent risk factors for postoperative morbidity. Extracorporeal side-to-side anastomosis (P = 0.031), intraoperative blood loss > 50 ml (P = 0.004) and neoadjuvant chemotherapy (P = 0.004) were identified as independent risk factors for anastomotic leak. CONCLUSION: In high-volume expert centres in China, laparoscopic resection with D3 lymph node dissection was performed in most patients with right-sided colon cancer, and overall postoperative morbidity and mortality was low. Further studies are needed to explore the optimal technique for right hemicolectomy in order to improve outcomes further.

Squalene epoxidase promotes the chemoresistance of colorectal cancer via (S)-2,3-epoxysqualene-activated NF-κB.

BACKGROUND: While de novo cholesterol biosynthesis plays a crucial role in chemotherapy resistance of colorectal cancer (CRC), the underlying molecular mechanism remains poorly understood. METHODS: We conducted cell proliferation assays on CRC cells with or without depletion of squalene epoxidase (SQLE), with or without 5-fluorouracil (5-FU) treatment. Additionally, a xenograft mouse model was utilized to explore the impact of SQLE on the chemosensitivity of CRC to 5-FU. RNA-sequencing analysis and immunoblotting analysis were performed to clarify the mechanism. We further explore the effect of SQLE depletion on the ubiquitin of NF-κB inhibitor alpha (IκBα) and (S)-2,3-epoxysqualene on the binding of IκBα to beta-transducin repeat containing E3 ubiquitin protein ligase (BTRC) by using immunoprecipitation assay. In addition, a cohort of 272 CRC patients were selected for our clinical analyses. RESULTS: Mechanistically, (S)-2,3-epoxysqualene promotes IκBα degradation and subsequent NF-κB activation by enhancing the interaction between BTRC and IκBα. Activated NF-κB upregulates the expression of baculoviral IAP repeat containing 3 (BIRC3), sustains tumor cell survival after 5-FU treatment and promotes 5-FU resistance of CRC in vivo. Notably, the treatment of terbinafine, an inhibitor of SQLE commonly used as antifungal drug in clinic, enhances the sensitivity of CRC to 5-FU in vivo. Additionally, the expression of SQLE is associated with the prognosis of human CRC patients with 5-FU-based chemotherapy. CONCLUSIONS: Thus, our finding not only demonstrates a new role of SQLE in chemoresistance of CRC, but also reveals a novel mechanism of (S)-2,3-epoxysqualene-dependent NF-κB activation, implicating the combined potential of terbinafine for 5-FU-based CRC treatment.

Conditional survival and the prognostic value of serum carcinoembryonic antigen level in oldest old with colorectal cancer.

BACKGROUND: To evaluate the clinical value of serum CEA levels and their implications on the diagnostic value of the conventional TNM staging system in the oldest-old patients with colorectal cancer (CRC). METHODS: The recruited subjects were colorectal cancer patients aged 85 and older. The cutoff value for normal CEA level is 5 ng/mL. Patients with elevated CEA levels were categorized as stage C1, and those with normal CEA levels as stage C0. A number of Cox proportional hazard regression models were established to evaluate the prognosis of different prognostic factors with hazard ratios (HRs) and 95% confidence intervals (CIs). The Kaplan-Meier method was utilized to display the disparate prognostic impact of multiple clinicopathological factors with the log-rank test. RESULTS: A total of 17,359 oldest-old patients diagnosed with CRC were recruited from the SEER database. The conditional survival of oldest-old patients with CRC was dismal with a 1-year conditional survival of only 11%, 18%, and 30% for patients surviving 1, 3, and 5 years, respectively. Patients with stage C1 exhibited a 48.5% increased risk of CRC-specific mortality compared with stage C0 (HR = 1.485, 95%CI = 1.393-1.583, using stage C0 patients as the reference, P < 0.001). All the stage C0 patients indicated lower HRs relative to the corresponding stage C1 patients. CONCLUSIONS: Dismal conditional survival of oldest-old patients with CRC should be given additional consideration. C stage influences the prognosis of oldest-old patients with CRC.

Integrated metagenomic and metabolomic analysis reveals distinct gut-microbiome-derived phenotypes in early-onset colorectal cancer.

OBJECTIVE: The incidence of early-onset colorectal cancer (EO-CRC) is steadily increasing. Here, we aimed to characterise the interactions between gut microbiome, metabolites and microbial enzymes in EO-CRC patients and evaluate their potential as non-invasive biomarkers for EO-CRC. DESIGN: We performed metagenomic and metabolomic analyses, identified multiomics markers and constructed CRC classifiers for the discovery cohort with 130 late-onset CRC (LO-CRC), 114 EO-CRC subjects and age-matched healthy controls (97 LO-Control and 100 EO-Control). An independent cohort of 38 LO-CRC, 24 EO-CRC, 22 LO-Controls and 24 EO-Controls was analysed to validate the results. RESULTS: Compared with controls, reduced alpha-diversity was apparent in both, LO-CRC and EO-CRC subjects. Although common variations existed, integrative analyses identified distinct microbiome-metabolome associations in LO-CRC and EO-CRC. Fusobacterium nucleatum enrichment and short-chain fatty acid depletion, including reduced microbial GABA biosynthesis and a shift in acetate/acetaldehyde metabolism towards acetyl-CoA production characterises LO-CRC. In comparison, multiomics signatures of EO-CRC tended to be associated with enriched Flavonifractor plauti and increased tryptophan, bile acid and choline metabolism. Notably, elevated red meat intake-related species, choline metabolites and KEGG orthology (KO) pldB and cbh gene axis may be potential tumour stimulators in EO-CRC. The predictive model based on metagenomic, metabolomic and KO gene markers achieved a powerful classification performance for distinguishing EO-CRC from controls. CONCLUSION: Our large-sample multiomics data suggest that altered microbiome-metabolome interplay helps explain the pathogenesis of EO-CRC and LO-CRC. The potential of microbiome-derived biomarkers as promising non-invasive tools could be used for the accurate detection and distinction of individuals with EO-CRC.

Utility of Circulating Free DNA Fragmentomics in the Prediction of Pathological Response after Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer.

BACKGROUND: A "Watch and Wait" (W&W) approach has become an alternative to surgery for locally advanced rectal cancer (LARC) after neoadjuvant chemoradiotherapy (nCRT). Precise prediction of pathological complete response (pCR) will improve patient selection for W&W. We investigated the utility of cell-free DNA (cfDNA) fragmentomics in predicting pCR. METHODS: We recruited 119 LARC patients and evaluated nCRT response by pCR status and pathological or MRI tumor regression grade (mrTRG). Plasma samples before, during, and after nCRT were applied to deep targeted-panel sequencing, with 103 patients having complete samples. cfDNA fragment and 5'-end motif profiles were used to construct elastic-net logistic regression models to predict non-pCR. Predictive performance was measured by area under the receiver operator characteristic curve (AUC), sensitivity, and specificity. RESULTS: In the training cohort, the model based on 5'-end motif profile plus mrTRG achieved the highest cross-validation AUC (0.92, 95% CI, 0.91-0.93). The AUC in a testing cohort was 0.96 (95% CI, 0.90-1.00). The models based on 5'-end motif profile alone or in combination with mrTRG both maintained good predictive ability for patients without detectable circulating tumor DNA (AUC 0.94, 95% CI, 0.93-0.95; AUC 0.95, 95% CI, 0.94-0.96). In an external validation cohort, the model trained with a local 5'-end motif profile obtained an AUC of 0.878 (95% CI, 0.801-0.956) in discriminating colorectal cancer from healthy subjects. CONCLUSIONS: The combination of a 5'-end motif profile with mrTRG has the potential to predict the response to nCRT, and therefore may improve the patient selection for a W&W approach.

Use of lymph node ratio to guide clinical decision-making concerning adjuvant radiotherapy in pT1-2N1 rectal cancer.

PURPOSE: Lymph node metastases are uncommon in pT1-2 rectal cancer. pT1-2N1 are often characterized with low tumor burden and intermediate prognosis. Therefore, adjuvant radiotherapy (ART) is controversial in these patients. This study aimed to investigate the value of ART in pT1-2 rectal cancer and evaluate the guiding role of lymph node ratio (LNR) for utilization of ART. METHODS: pT1-2N1 rectal cancer patients who received surgery without neoadjuvant radiotherapy between 2000 and 2018 with at least 12 lymph node harvest were extracted from the Surveillance, Epidemiology and End Results (SEER) database. We used time-dependent receiver operating characteristic (ROC) analysis to determine the optimal cutoff of LNR. Kaplan-Meier methods and Cox proportional hazards regression models were performed to determine the prognostic value of ART in pT1-2N1 rectal cancer patients and subgroups stratified by LNR. RESULTS: A total of 674 and 1321 patients with pT1N1 and pT2N1 rectal cancer were eligible for analysis. There was no statistical cancer-specific survival (CSS) difference in pT1N1 rectal cancer patients between receiving and not receiving ART (P = 0.464). The 5-year CSS was 89.6% and 83.2% in pT2N1 rectal cancer patients between receiving and not receiving ART, respectively (P = 0.003). A total of 7.0% was identified as the optimal cutoff value of LNR. Survival improvement offered by ART was only found in LNR ≥ 7.0% subgroup (5-year CSS: 89.5% versus 79.6%, P = 0.003) instead of LNR < 7.0% subgroup (5-year CSS: 89.9% versus 86.3%, P = 0.208). CONCLUSION: ART show substantial survival benefit in pT2N1 rectal cancer patients with LNR ≥ 7.0%, warranting the conventional adoption of ART in this subgroup.

HER2 status is positively associated with vessel invasion of colorectal cancer: a retrospective large cohort study.

PURPOSE: HER2-positive colorectal cancer was drawn increasing attention in recent years. Accumulating evidence showed HER2-positive metastatic colorectal cancer could benefit from HER2-targeted therapy. While HER2 expression and the relationship between HER2 status and clinicopathological characteristics of overall colorectal cancer remains largely unknown. The aim of this study was to evaluate HER2 expression in colorectal cancer and compare the clinicopathological features between HER2-positive and HER2-negative colorectal cancer. METHODS: We retrospectively analyzed 3910 primary colorectal cancer patients treated in our institution from January 2016 to December 2019. Medical records and pathology reports after surgery were collected to provide information about HER2 status and other clinicopathological characteristics. RESULTS: We identified 3347 HER2-negative and 79 HER2-positive colorectal cancer patients in our cohort. The chi-square test showed that vessel invasion was significantly more common in HER2-positive colorectal cancer patients. Crude analysis showed HER2 positive was associated with vessel invasion in colorectal cancer [OR and 95% CI 0.534 (0.341, 0.835), p = 0.006]. After adjusting for N stage, a significant association was still observed between HER2 status and vessel invasion in colorectal cancer [OR and 95% CI 0.550 (0.322, 0.941), p = 0.029]. Survival analysis showed that there was no significant difference in 3-year overall survival rate between HER2 positive and HER2 negative group (p = 0.603). CONCLUSION: Our findings indicate that the rate of HER2 positivity in colorectal cancer was relatively low, and HER2 status was strongly associated with vessel invasion while having no significant influence on the 3-year overall survival rate in colorectal cancer patients.

A novel epithelial-mesenchymal transition molecular signature predicts the oncological outcomes in colorectal cancer.

Epithelial-mesenchymal transition (EMT), a biological process involving the transformation of epithelial cells into mesenchymal cells, promotes tumour initiation and metastasis. The aim of this study was to construct an EMT molecular signature for predicting colorectal cancer (CRC) prognosis and evaluate the efficacy of the model. The risk scoring system, constructed by log-rank test and multivariate Cox regression analysis according to EMT-related gene expression in CRC patients from TCGA database, demonstrated the highest correlation with prognosis compared with other parameters in CRC patients. The risk scores were significantly correlated with more lymph node metastasis, distal metastasis and advanced clinical stage of CRC. The model was further successfully validated in two independent external cohorts from GEO database. Furthermore, we developed a nomogram to integrate the EMT signature with the pathological stage of CRC, which was found to perform well in predicting the overall survival. Additionally, this risk scoring model was found to be associated with immune cell infiltration, implying a potential role of EMT involved in immunity regulation in tumour microenvironment. Taken together, our novel EMT molecular model may be useful in identifying high-risk patients who need an intensive follow-up and more aggressive therapy, finally contributing to more precise individualized therapeutic strategies.

Utility of ctDNA in predicting response to neoadjuvant chemoradiotherapy and prognosis assessment in locally advanced rectal cancer: A prospective cohort study.

BACKGROUND: For locally advanced rectal cancer (LARC) patients who receive neoadjuvant chemoradiotherapy (nCRT), there are no reliable indicators to accurately predict pathological complete response (pCR) before surgery. For patients with clinical complete response (cCR), a "Watch and Wait" (W&W) approach can be adopted to improve quality of life. However, W&W approach may increase the recurrence risk in patients who are judged to be cCR but have minimal residual disease (MRD). Magnetic resonance imaging (MRI) is a major tool to evaluate response to nCRT; however, its ability to predict pCR needs to be improved. In this prospective cohort study, we explored the value of circulating tumor DNA (ctDNA) in combination with MRI in the prediction of pCR before surgery and investigated the utility of ctDNA in risk stratification and prognostic prediction for patients undergoing nCRT and total mesorectal excision (TME). METHODS AND FINDINGS: We recruited 119 Chinese LARC patients (cT3-4/N0-2/M0; median age of 57; 85 males) who were treated with nCRT plus TME at Fudan University Shanghai Cancer Center (China) from February 7, 2016 to October 31, 2017. Plasma samples at baseline, during nCRT, and after surgery were collected. A total of 531 plasma samples were collected and subjected to deep targeted panel sequencing of 422 cancer-related genes. The association among ctDNA status, treatment response, and prognosis was analyzed. The performance of ctDNA alone, MRI alone, and combining ctDNA with MRI was evaluated for their ability to predict pCR/non-pCR. Ranging from complete tumor regression (pathological tumor regression grade 0; pTRG0) to poor regression (pTRG3), the ctDNA clearance rate during nCRT showed a significant decreasing trend (95.7%, 77.8%, 71.1%, and 66.7% in pTRG 0, 1, 2, and 3 groups, respectively, P = 0.008), while the detection rate of acquired mutations in ctDNA showed an increasing trend (3.8%, 8.3%, 19.2%, and 23.1% in pTRG 0, 1, 2, and 3 groups, respectively, P = 0.02). Univariable logistic regression showed that ctDNA clearance was associated with a low probability of non-pCR (odds ratio = 0.11, 95% confidence interval [95% CI] = 0.01 to 0.6, P = 0.04). A risk score predictive model, which incorporated both ctDNA (i.e., features of baseline ctDNA, ctDNA clearance, and acquired mutation status) and MRI tumor regression grade (mrTRG), was developed and demonstrated improved performance in predicting pCR/non-pCR (area under the curve [AUC] = 0.886, 95% CI = 0.810 to 0.962) compared with models derived from only ctDNA (AUC = 0.818, 95% CI = 0.725 to 0.912) or only mrTRG (AUC = 0.729, 95% CI = 0.641 to 0.816). The detection of potential colorectal cancer (CRC) driver genes in ctDNA after nCRT indicated a significantly worse recurrence-free survival (RFS) (hazard ratio [HR] = 9.29, 95% CI = 3.74 to 23.10, P < 0.001). Patients with detectable driver mutations and positive high-risk feature (HR_feature) after surgery had the highest recurrence risk (HR = 90.29, 95% CI = 17.01 to 479.26, P < 0.001). Limitations include relatively small sample size, lack of independent external validation, no serial ctDNA testing after surgery, and a relatively short follow-up period. CONCLUSIONS: The model combining ctDNA and MRI improved the predictive performance compared with the models derived from individual information, and combining ctDNA with HR_feature can stratify patients with a high risk of recurrence. Therefore, ctDNA can supplement MRI to better predict nCRT response, and it could potentially help patient selection for nonoperative management and guide the treatment strategy for those with different recurrence risks.

Development and validation of a novel epigenetic signature for predicting prognosis in colon cancer.

Epigenetic factors play a critical role in carcinogenesis by imparting a distinct feature to the chromatin architecture. The present study aimed to develop a novel epigenetic signature for evaluating the relapse-free survival of colon cancer patients. Public microarray datasets were acquired from the Gene Expression Omnibus databases: GSE39582, GSE17538, GSE33113, and GSE37892 set. Patients from GSE39582 set were randomized 1:1 into training and internal validation series. Patients were divided into high-risk and low-risk groups in training series based on a set of 11 epigenetic factors (p < .001). The good reproducibility for the prognostic value of the epigenetic signature was confirmed in the internal validation series (p < .001), external validation series (a combination of GSE17538 set, GSE33113 set, and GSE37892 set; p = .018), and entire series (p < .001). Furthermore, a nomogram, which integrated the epigenetic signature, pathological stage, and postoperative chemotherapy, was developed based on the GSE39582 set. The time-dependent receiver operating characteristic curve at 1 year demonstrated that the comprehensive signature presented superior prognostic value than the pathological stage. In conclusion, an epigenetic signature, which could be utilized to divide colon cancer patients into two groups with significantly different risk of relapse, was established. This biomarker would aid in identifying patients who require an intensive follow-up and aggressive therapeutic intervention.

MiR-126 targets IL-17A to enhance proliferation and inhibit apoptosis in high-glucose-induced human retinal endothelial cells.

Diabetic retinopathy (DR) is a common complication of diabetes mellitus (DM), which results in vision loss. This study explored the role of miR-126 in high-glucose-induced human retinal endothelial cells (HRECs) and its underlying molecular mechanisms. The results showed that the expression levels of miR-126 and interleukin-17A (IL-17A) in high-glucose-induced HRECs were downregulated and upregulated, respectively. Functionally, overexpression of miR-126 promoted proliferation and suppressed apoptosis in high-glucose-induced HRECs, while IL-17A reversed the effects induced by miR-126. However, overexpression of IL-17A inhibited the proliferation and induced apoptosis, while knockdown of IL-17A accelerated the proliferation and repressed apoptosis. In addition, miR-126 repressed the expression of IL-17A, Bax, and caspase-3, while promoting the expression of survivin and phosphorylation of PI3K and AKT; restoration of IL-17A rescued these effects. Furthermore, IL-17A was identified as a target of miR-126. This indicates that miR-126 enhances proliferation and inhibits apoptosis in high-glucose-induced HRECs by activating the PI3K-AKT pathway, increasing survivin levels, and decreasing Bax and caspase-3 expression by targeting IL-17A, suggesting that miR-126 could be a novel target for preventing DR.

Large-Scale Genome-Wide Association Study of East Asians Identifies Loci Associated With Risk for Colorectal Cancer.

BACKGROUND & AIMS: Genome-wide association studies (GWASs) have associated approximately 50 loci with risk of colorectal cancer (CRC)-nearly one third of these loci were initially associated with CRC in studies conducted in East Asian populations. We conducted a GWAS of East Asians to identify CRC risk loci and evaluate the generalizability of findings from GWASs of European populations to Asian populations. METHODS: We analyzed genetic data from 22,775 patients with CRC (cases) and 47,731 individuals without cancer (controls) from 14 studies in the Asia Colorectal Cancer Consortium. First, we performed a meta-analysis of 7 GWASs (10,625 cases and 34,595 controls) and identified 46,554 promising risk variants for replication by adding them to the Multi-Ethnic Global Array (MEGA) for genotype analysis in 6445 cases and 7175 controls. These data were analyzed, along with data from an additional 5705 cases and 5961 controls genotyped using the OncoArray. We also obtained data from 57,976 cases and 67,242 controls of European descent. Variants at identified risk loci were functionally annotated and evaluated in correlation with gene expression levels. RESULTS: A meta-analyses of all samples from people of Asian descent identified 13 loci and 1 new variant at a known locus (10q24.2) associated with risk of CRC at the genome-wide significance level of P < 5 × 10-8. We did not perform experiments to replicate these associations in additional individuals of Asian ancestry. However, the lead risk variant in 6 of these loci was also significantly associated with risk of CRC in European descendants. A strong association (44%-75% increase in risk per allele) was found for 2 low-frequency variants: rs201395236 at 1q44 (minor allele frequency, 1.34%) and rs77969132 at 12p11.21 (minor allele frequency, 1.53%). For 8 of the 13 associated loci, the variants with the highest levels of significant association were located inside or near the protein-coding genes L1TD1, EFCAB2, PPP1R21, SLCO2A1, HLA-G, NOTCH4, DENND5B, and GNAS. For other intergenic loci, we provided evidence for the possible involvement of the genes ALDH7A1, PRICKLE1, KLF5, WWOX, and GLP2R. We replicated findings for 41 of 52 previously reported risk loci. CONCLUSIONS: We showed that most of the risk loci previously associated with CRC risk in individuals of European descent were also associated with CRC risk in East Asians. Furthermore, we identified 13 loci significantly associated with risk for CRC in Asians. Many of these loci contained genes that regulate the immune response, Wnt signaling to ß-catenin, prostaglandin E2 catabolism, and cell pluripotency and proliferation. Further analyses of these genes and their variants is warranted, particularly for the 8 loci for which the lead CRC risk variants were not replicated in persons of European descent.

The safety and effectiveness of carbon nanoparticles suspension in tracking lymph node metastases of colorectal cancer: a prospective randomized controlled trial.

OBJECTIVE: This study was to evaluate the safety and effectiveness of carbon nanoparticles suspension in tracking lymph node metastases of colorectal cancer. METHODS: Eligible patients diagnosed with stages I-III colorectal cancer in Fudan University Shanghai Cancer Center between 1 May 2017 and 31 May 2018 fulfilling the inclusion criteria were included in this prospective randomized controlled study. All the patients were randomly allocated to two groups: the nanocarbon group and the control group. Patients' clinicopathological characteristics were compared between the nanocarbon group and the control group. For continuous variables, data were presented as mean (±SD) and differences between the two groups were compared by the Mann-Whitney U test; for categorical variables, data was presented as frequency (%) and the Pearson's chi-squared test was used to compare the differences between two groups. RESULTS: All the patients' characteristics between two groups did not achieve statistical significance (P > 0.05). Patients in nanocarbon group were more likely to be associated with more lymph nodes retrieved totally compared with control group (19.84 ± 6.428 vs. 17.41 ± 7.229, P < 0.001). The number of lymph nodes retrieved in nanocarbon group were more likely to be ≥12 than that in the control group (P = 0.005). CONCLUSIONS: Our study confirmed the safety of using carbon nanoparticles suspension as a tracer in colorectal cancer. More importantly, nanocarbon could significantly increase the detected number of lymph nodes in colorectal cancer, which can help improve the accuracy of lymph node staging and even improve patients' survival.

Anatomical characteristics and classifications of gastrocolic trunk of Henle in laparoscopic right colectomy: preliminary results of multicenter observational study.

BACKGROUND: As a key landmark during laparoscopic right colectomy, the classification and variation of the gastrocolic trunk of Henle (GTH) remains to be clarified. The aim of this nationwide multicenter study was to describe the characteristics of the GTH intra-operatively during laparoscopic right colectomies. METHODS: Three hundred seventy-one patients who underwent laparoscopic right colectomies from January 2018 to March 2019 in 25 hospitals across China were enrolled in the study. The length of the GTH, the classification with a precise description of confluent tributaries, and other variations were analyzed. RESULTS: Of the 371 patients, 363 had a GTH. The proportion of type-0, type-I, type-II, and type-III was 15.2% (n = 55), 54.8% (n = 199), 25.3% (n = 92), and 4.7% (n = 17), respectively. The average length of the GTH was 8.5 mm, ranging from 2 to 30 mm. CONCLUSIONS: This is the first multicenter study with a large sample by which the GTH was classified based on laparoscopic intraoperative observation. Variations in the GTH were classified into four types based on the number of colic drainage veins (right colic, superior right colic, middle colic, accessory middle colic, and ileocolic veins), among which the right colic vein was the most common. The length of the GTH was relatively short, and thus might carry a risk of bleeding. Further clinical data should be correlated with the characteristics of the GTH.

Overexpression of Orange Carotenoid Protein Protects the Repair of PSII under Strong Light in Synechocystis sp. PCC 6803.

Orange carotenoid protein (OCP) plays a vital role in the thermal dissipation of excitation energy in the photosynthetic machinery of the cyanobacterium Synechocystis sp. PCC 6803. To clarify the role of OCP in the protection of PSII from strong light, we generated an OCP-overexpressing strain of Synechocystis and examined the effects of overexpression on the photoinhibition of PSII. In OCP-overexpressing cells, thermal dissipation of energy was enhanced and the extent of photoinhibition of PSII was reduced. However, photodamage to PSII, as monitored in the presence of lincomycin, was unaffected, suggesting that overexpressed OCP protects the repair of PSII. Furthermore, the synthesis de novo of proteins in thylakoid membranes, such as the D1 protein which is required for the repair of PSII, was enhanced in OCP-overexpressing cells under strong light, while the production of singlet oxygen was suppressed. Thus, the enhanced thermal dissipation of energy via overexpressed OCP might support the repair of PSII by protecting protein synthesis from oxidative damage by singlet oxygen under strong light, with the resultant mitigation of photoinhibition of PSII.

ACRNaCT trial protocol: efficacy of adjuvant chemotherapy in patients with clinical T3b/T4, N+ rectal Cancer undergoing Neoadjuvant Chemoradiotherapy: a pathology-oriented, prospective, multicenter, randomized, open-label, parallel group clinical trial.

BACKGROUND: The CAO/ARO/AIO-94 demonstrated that neoadjuvant chemoradiotherapy (CRT) could decrease the rate of local recurrence rather than distal metastases in advanced rectal cancer. Adjuvant chemotherapy (ACT) can eliminate micrometastasis, and render a better prognosis to rectal cancer. However, adoption of ACT mainly depends on the evidence from colon cancer. Neoadjuvant CRT can lead to tumor shrinkage in a number of patients with advanced rectal cancer. The administration of adjuvant therapy depending on pretreatment clinical stage or postoperative yield pathological (yp) stage remains controversial. At present, the clinical guidelines recommend ACT for patients with stage II/III (ypT3-4 N0 or ypTanyN1-2) rectal cancer following neoadjuvant CRT and surgery. However, the yp stage may influence the guidance of ACT. METHODS: According to the postoperative pathological stage, the present study was divided into two parts with different study design procedures. Patients will undergo different therapeutic strategies after collecting data related to postoperative pathological stage. For patients with pathologic complete response or yp stage I, the study was designed as a non-inferiority trial to compare the patients' long-term outcomes in observational group and those in treatment group with 5-fluorouracil. For patients at yp stage II or III, the study was designed as a superiority trial to compare the oncological effect of oxaliplatin combined with 5-fluorouracil, in addition to 5-fluorouracil alone in ACT. The primary endpoint is 3-year disease-free survival (DFS). Secondary endpoints are 3-year, 5-year overall survival, 5-year DFS, and the rate of local recurrence and adverse events resulted from chemotherapy and the patients' quality of life postoperatively. DISCUSSION: The ACRNaCT trial aims to investigate whether observation is not inferior than 5-fluorouracil for pathologic complete response or yp stage I, and indicate whether combined chemotherapy contains superior outcomes than 5-fluorouracil alone for yp stage II or III in patients receiving neoadjuvant CRT and surgery for locally advanced rectal cancer (LARC). This trial is expected to provide individualized adjuvant treatment strategies for LARC patients following neoadjuvant CRT and surgery. TRIAL REGISTRATION: The trial has been registered in ClinicalTrials.gov on January 30, 2018 (Registration No. NCT03415763), and also, that was registered in Chinese Clinical Trial Registry on November 12, 2018 (Registration No. ChiCTR1800019445).

Klotho negatively regulated aerobic glycolysis in colorectal cancer via ERK/HIF1α axis.

BACKGROUND: Klotho (KL) was originally characterized as an aging suppressor gene, and has been identified as a tumor suppressor gene in a variety of cancers, including colorectal cancer. Recent years have witnessed the importance of metabolism transformation in cancer cell malignancies maintenance. Aberrant cancer cell metabolism is considered to be the hallmark of cancer. Our previous studies demonstrated that KL played negative roles in colon cancer cell proliferation and metastasis. However, its role in the cancer cell reprogramming has seldom been reported. The aim of this study was to examine the role of KL in aerobic glycolysis in colorectal cancer. METHODS: Combining maximum standardized uptake value (SUVmax), which was obtained preoperatively via a PET/CT scan, with immunohistochemistry staining, we analyzed the correlation between SUVmax and KL expression in colorectal cancer tissues. The impact of KL on glucose metabolism and its mechanisms were further validated in vitro and in vivo. RESULTS: Patients with lower KL expression exhibited higher 18F-FDG uptake (P < 0.05), indicating that KL might participate in aerobic glycolysis regulation. In vitro assay by using colon cancer cell lines further supported this observation. By overexpressing KL in HTC116 and SW480 cells, we observed that the glycolysis was inhibited and the mitochondrial respiration increased, indicating that KL was a negative regulator of aerobic glycolysis. To seek for the underlying mechanisms, we tried to dig out the relation between KL and HIF1α signaling pathway, and found that KL negatively regulated HIF1α protein level and transcriptional activity. Western blot analysis showed that KL overexpression negatively regulated ERK pathway, and KL regulated aerobic glycolysis in part through its regulation of ERK/ HIF1α axis. CONCLUSIONS: Taken together, KL is a negative regulator of aerobic glycolysis and KL inhibited glucose metabolism transformation via the ERK/ HIF1α axis.

Prognostic Impact of Hypochloremia in Patients With Stage I to III Colorectal Cancer After Radical Resection.

BACKGROUND: Recent studies have suggested that electrolyte disorders might be a negative prognostic factor for some diseases. OBJECTIVE: The purpose of this study was to systematically evaluate the prognostic role of electrolyte disorders in patients with stage I to III colorectal cancer who received radical surgical resection. DESIGN: This study was retrospectively performed. SETTINGS: The study was conducted at a single tertiary care center. PATIENTS: Patients with colorectal cancer who underwent radical resection in between April 2007 and April 2014 were included. MAIN OUTCOME MEASURES: The Kaplan-Meier method was adopted to estimate the overall and disease-free survival with and without propensity score matching. RESULTS: In total, our study recruited 5089 eligible patients. In prematching analysis, patients with hypochloremia showed both shorter overall survival (HR = 0.943 (95% CI, 0.908-0.980); p = 0.003) and disease-free survival (HR = 0.957 (95% CI, 0.933-0.981); p < 0.001) than those with normal serum chloride levels. In postmatching analysis, 770 patients from each group were compared, and the results further confirmed that hypochloremia was significantly associated with worse overall survival (HR = 0.646 (95% CI, 0.489-0.855); p = 0.002) and disease-free survival (HR = 0.782 (95% CI, 0.647-0.944); p = 0.01), with the hypochloremia group as a reference. LIMITATIONS: The study was limited by its retrospective nature. CONCLUSIONS: Hypochloremia diagnosed before treatment can independently prognosticate the overall and disease-free survival for patients with stage I to Ш colorectal cancer after radical resection. Intensive surveillance and management might improve the survival outcome for patients with hypochloremia. See Video Abstract at http://links.lww.com/DCR/A727.

Real-world study of a novel prognostic scoring system: for a more precise prognostication and better clinical treatment guidance in stages II and III colon cancer.

PURPOSE: This study aimed to improve the American Joint Committee on Cancer (AJCC) Tumor Node Metastases (TNM) staging system and demonstrate the improvement in prognostic accuracy and clinical management guidance in colon cancer using the novel prognostic score (P score). METHODS: Eligible patients were identified using the Surveillance, Epidemiology, and End Results database. A P score (based on age, tumor size, and tumor grade) was assigned to each patient. The Cox proportional hazards regression analyses were performed to identify independent factors associated with prognosis. The Kaplan-Meier survival curves were used to analyze the prognosis of patients with colon cancer with different P scores. The TNM staging system was compared with the P score in stages I-IV by calculating the concordance index. RESULTS: The multivariate Cox analysis indicated that a higher P score was independently associated with a higher risk of cancer-specific mortality. The Kaplan-Meier survival curves showed that the survival benefit gradually increased as the P score decreased. The concordance index rose from 0.5, 0.593, 0.633, and 0.551 of AJCC TNM staging system to 0.709, 0.651, 0.691, and 0.623 of P score in stages I-IV, respectively. CONCLUSIONS: The P score was an independent prognostic factor of colon cancer and had a much better prognostic accuracy than the AJCC TNM staging system in all patients with colon cancer. It may help in identifying patients with high-risk stage II colon cancer who were candidates for adjuvant therapy and differentiating patients with stage III colon cancer for adjuvant therapy.

Prognostic value of distant metastasis sites and surgery in stage IV colorectal cancer: a population-based study.

PURPOSE: We investigated the prognostic value of distant metastasis sites among patients with metastatic colorectal cancer (CRC) and the significance of metastasectomy and resection of the primary CRC. METHODS: Between 2010 and 2014, patients diagnosed with metastatic colorectal adenocarcinoma were selected using the surveillance, epidemiology, and end results (SEER) database. The prognosis of these patients was compared according to the site of metastasis (liver, lung, bone, and brain). A total of 15,133 patients suffered from isolated organ involvement, while 5135 patients experienced multiple organ metastases. RESULTS: In the isolated organ metastasis cohort, median overall survival (OS) for patients with liver, lung, bone, and brain metastases was 16, 20, 7, and 5 months, respectively. Patients with isolated lung metastases had better cancer-specific survival (CSS) and OS as compared to patients with metastases at any other sites (p < 0.0001 for both CSS and OS). Patients with isolated liver metastases had better prognosis as compared to patients with isolated bone or brain metastases (p < 0.0001 for both CSS and OS). Moreover, patients with a single metastatic site had better prognosis than patients with multiple organs involved (p < 0.0001 for both CSS and OS). Multivariate analysis in patients with isolated organ metastases demonstrated that age ≤ 60 years, rectal cancer, being married, non-black race, N0 stage, and surgery of the primary and distant lesions showed more favorable prognosis. CONCLUSIONS: The metastatic site was an independent prognostic factor in stage IV colorectal cancer. Also, carefully chosen patients may benefit from surgery.