Outcomes of Robot-Assisted Versus Laparoscopic Surgery for Colorectal Cancer in Adults ≥ 75 Years Old: A Propensity Score Matched Analysis of the US Nationwide Inpatient Sample.

BACKGROUND: Robot-assisted surgery has been increasingly adopted in colorectal cancer resection. OBJECTIVE: The study aimed to compare the inpatient outcomes of robot-assisted versus conventional laparoscopic colorectal cancer resection in patients ≥ 75 years. DESIGN: A retrospective, population-based study. SETTINGS: This study analyzed data from the United States Nationwide Inpatient Sample from 2005 to 2018. PATIENTS: Colorectal cancer patients ≥ 75 years old and underwent robot-assisted or conventional laparoscopic resection. MAIN OUTCOME MEASURES: Postoperative complication, prolonged length of stay, and total hospital costs were assessed. RESULTS: Data from 14,108 patients were analyzed. After adjustment, any postoperative complications (aOR = 0.87, 95% CI: 0.77-0.99, p = 0.030) and prolonged length of stay (aOR = 0.78, 95% CI: 0.67-0.91, p = 0.001) were significantly less in the robotic than the laparoscopic group. In addition, robotic surgery was associated with significantly higher total hospital costs ($26.06 USD greater cost; 95% CI: 21.35-30.77 USD, p < 0.001). LIMITATIONS: The analysis was limited by its retrospective and observational nature, potential coding errors, and the lack of intraoperative factors such as operative time, laboratory measures, and information on surgeons' experience. CONCLUSIONS: In United States, patients with colorectal cancer ≥ 75 years who were undergoing tumor resections, compared to conventional laparoscopic surgery, robotic surgery is associated with better inpatient outcomes in terms of complication rate and risk of prolonged length of stay, especially among patients with colon cancer. However, robotic surgery is associated with higher total hospital costs.

The Cerebral Protective Effect of Novel Erinacines from Hericium erinaceus Mycelium on In Vivo Mild Traumatic Brain Injury Animal Model and Primary Mixed Glial Cells via Nrf2-Dependent Pathways.

Hericium erinaceus, a consumable mushroom, has shown a potential to enhance the production of neuroprotective bioactive metabolites. Traumatic brain injury (TBI) often leads to cognitive, physical, and psychosocial impairments, resulting in neuroinflammation and the loss of cortical neurons. In this research, the effects of H. erinaceus mycelium, its derivative erinacine C, along with the underlying mechanisms, were examined in terms of oxidative stress modulation and neurological improvement in a rat model of mild traumatic brain injury (mTBI). Male Sprague-Dawley rats were administered diets containing H. erinaceus mycelium and erinacine C following experimental brain injury; these supplements were continued throughout the recovery phase. The binding activity of NF-E2-related factor 2 (Nrf2) near antioxidant genes in mixed glial cells was measured by chromatin immunoprecipitation-quantitative polymerase chain reaction (ChIP-qPCR). The motor beam walking test revealed that dietary supplementation of H. erinaceus mycelium resulted in modest improvements in spatial memory while inhibiting neuron cell death and microglial activation according to brain histological examination. These findings were further corroborated by the upregulation of several antioxidant enzymes (catalase, glutathione reductase, thioredoxin reductase, and superoxide dismutase) and phospho-CAMP-response element-binding (p-CREB) levels in the mTBI model treated with H. erinaceus mycelium. Erinacine C treatment led to significantly reduced brain inflammation and normalization of mTBI-induced deficits through the modulation of the Nrf2 activation pathway and upregulated expression of numerous Nrf2-binding antioxidant genes such as catalase, thioredoxin reductase, superoxide dismutase, and brain-derived neurotrophic factor. This study demonstrates the potential of H. erinaceus mycelium and erinacine C in facilitating recovery following mTBI, including the prevention of neuronal injury and inactivation of microglia through the Nrf2-mediated antioxidant pathway in vivo.

Potential beneficial effects of long-term aspirin use on the prevalence of colorectal cancer: a population-based study of the US Nationwide Inpatient Sample.

PURPOSE: Whether long-term aspirin usage is associated with colorectal cancer (CRC) risk needs more evidence. The study evaluated the association between long-term aspirin use and prevalence of CRC in a large, nationally representative database. METHODS: Hospitalized patients aged ≥ 50 years during 2018 were identified in the United States (US) National Inpatient Sample (NIS). Patients without complete information of age, sex, race, income, and insurance status were excluded, as well as those with inflammatory bowel disease (IBD) or malignancies other than CRC. Propensity score matching (PSM) was applied to balance the characteristics between patients with and without long-term aspirin use. Logistic regressions were performed to determine the relationship between long-term aspirin use and the presence of CRC. CRC and aspirin use were identified through the administrative International Classification of Diseases (ICD) codes. RESULTS: Data from 3,490,226 patients were included, in which 688,018 (19.7%) had a record of long-term aspirin use. After 1:1 PSM, there remained 1,376,006 patients, representing 6,880,029 individuals in the US after weighting. After adjusting for confounders, long-term aspirin use was significantly associated with lower CRC odds (adjusted odds ratio [aOR] = 0.64, 95% confidence interval [CI] 0.62, 0.67). This association was not changed when stratified by age, sex, race, body mass index (BMI), and smoking. CONCLUSIONS: From a national inpatient dataset, US adults ≥ 50 years on long-term aspirin are less likely to have CRC, regardless of age, sex, race, BMI, and smoking status.

Survival Evidence of Local Control for Colorectal Cancer Liver Metastases by Hepatectomy and/or Radiofrequency Ablation.

Hepatectomy and/or local ablation therapy have been recommended for colorectal cancer liver metastases (CRLM). However, they still lack strong evidence for their survival benefits, in addition to systemic therapy. This study aims to evaluate the survival evidence of hepatectomy and/or radiofrequency ablation (RFA) therapy in CRLM patients from a large multi-institutional database. A total of 20,251 patients with colorectal cancer, 4521 of whom were with CRLM, were screened for eligibility. Finally, 2612 patients (637 hepatectomy, 93 RFA, 92 combined hepatectomy and RFA, and 1790 non-aggressive treatment) were enrolled. Frequency matching analysis was used to adjust for baseline differences. The 5-year overall survival (OS) was as follows: hepatectomy alone was 47.8%, combined hepatectomy plus RFA was 35.9%, RFA alone was 29.2%, and the non-aggressive treatment group was 7.4%. Kaplan-Meier curves showed that hepatectomy, RFA, and combination were significantly associated with a better OS compared to those without aggressive local therapy (p < 0.001). Multivariate Cox regression analysis showed that male gender (hazard ratio (HR) 0.89; 95% confidence interval (CI), 0.81-0.97; p = 0.011), old age (≥60 years) (HR 1.20; 95% CI, 1.09-1.32; p < 0.001), high CEA level (>5 ng/mL) (HR 2.14; 95% CI, 1.89-2.42; p < 0.001), primary right-sided cancer (HR 1.35; 95% CI, 1.22-1.51; p < 0.001), extrahepatic metastasis (HR 1.46; 95% CI, 1.33-1.60; p < 0.001), systemic therapy (HR 0.7; 95% CI, 0.62-0.79; p < 0.001), and aggressive local therapy (hepatectomy vs. non-local therapy HR 0.22; 95% CI, 0.20-0.26; p < 0.001; RFA vs. non-local therapy HR 0.29; 95% CI, 0.29-0.41; p < 0.001) were independent factors associated with OS. In the frequency matching analysis, patients receiving hepatectomy and/or RFA resulted in a better OS than those without (p < 0.001). In conclusion, aggressive local treatment provides survival advantages over systemic therapy alone among CRLM patients.

Use of iTRAQ-based quantitative proteomic identification of CHGA and UCHL1 correlated with lymph node metastasis in colorectal carcinoma.

Metastatic dissemination of colorectal cancer (CRC), the third most common cancer type, is responsible for CRC deaths. Understanding the transition of lymph node metastasis (LNM) from Stage II to Stage III is beneficial in the prognosis and intervention of CRC. In this study, a quantitative proteomic survey was conducted to investigate the LNM-associated proteins and evaluate the clinicopathological characteristics of these target proteins in CRC. By using the LC-MS/MS iTRAQ technology, we analysed the proteomic changes between LMN II and LMN III. Fresh tumours from the CRC specimens consisting of 12 node-negative (Stage II) and 12 node-positive (Stage III) cases were analysed by LC-MS/MS iTRAQ proteome analysis. Subsequently, tissue microarray with immunohistochemistry staining was conducted to access the clinicopathological characteristics of these proteins in 116 paraffin-embedded CRC samples, each for non-LNM and LNM CRC. To study the effects of the differentially expressed proteins on the potential mechanism, Boyden chamber assay, flow cytometry and shRNA-based assessments were conducted to examine the role of the epithelial-mesenchymal transition (EMT) and the invasiveness of CRC cells and others in vivo xenograft mouse model experiments. Forty-eight proteins were found differentially expressed between non-LNM and LNM CRC tissues. Protein abundances of chromogranin-A (CHGA) and ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCHL1) were observed in node-positive CRC (p < 0.05). Knockdown of CHGA and UCHL1 significantly regulate cancer behaviours of HCT-116, including inhibition of cell migration, invasiveness, cell cycle G1/S arrest and reactive oxygen species (ROS) generation. Mechanistically, the CHGA and UCHL1 inactivation displayed decreased levels of UCH-L1, chromogranin A, ß-catenin, cyclin E, twist-1/2, vimentin, MMP-9, N-cadherin and PCNA through the activation of the Rho-GTPase/AKT/NFκB pathways. Histone modification of H3K4 trimethylation of CHGA and UCHL1 promoter were increased to activate their transcription through the signalling transduction such as Rho-GTPase, AKT and NFκB pathways. Our results indicated that UCHL1 and chromogranin A are novel regulators in CRC lymph node metastasis to potentially provide new insights into the mechanism of CRC progression and serve as biomarkers for CRC diagnosis at the metastatic stage.

Outcomes of robot-assisted versus laparoscopic surgery for colorectal cancer in morbidly obese patients: A propensity score-matched analysis of the US Nationwide Inpatient Sample.

BACKGROUND AND AIM: Morbid obesity is associated with poorer postoperative outcomes in colorectal cancer (CRC) patients. We aimed to evaluate short-term outcomes after robotic versus conventional laparoscopic CRC resection in morbidly obese patients. METHODS: This population-based, retrospective study extracted data from the US Nationwide Inpatient Sample during 2005-2018. Adults ≥ 20 years old, with morbid obesity and CRC, and undergoing robotic or laparoscopic resections were identified. Propensity score matching (PSM) was applied to minimize the confounding. Univariate and multivariable regression was conducted to evaluate the associations between outcomes and study variables. RESULTS: After PSM, 1296 patients remained. The risks of any postoperative complication (adjusted odds ratio [aOR] = 0.99, 95% confidence interval [CI]: 0.80, 1.22), prolonged length of stay (LOS) (aOR = 0.80, 95% CI: 0.63, 1.01), death (aOR = 0.57, 95% CI: 0.11, 3.10), or pneumonia (aOR = 1.13, 95% CI: 0.73, 1.77) were not significantly different between the two procedures after adjustment. Robotic surgery was significantly associated with greater hospital cost (aBeta = 26.26, 95% CI: 16.08, 36.45) than laparoscopic surgery. Stratified analyses revealed that, in patients with tumor located at the colon, robotic surgery was associated with lower risk of prolonged LOS (aOR = 0.72, 95% CI: 0.54, 0.95). CONCLUSIONS: In patients with morbid obesity, risks of postoperative complication, death, or pneumonia are not significantly different between robotic and laparoscopic CRC resection. Among patients with tumor located at the colon, robotic surgery is associated with lower risk of prolonged LOS. These findings fill the knowledge gap and provide useful information for clinicians on risk stratification and treatment choice.

Antrodin C Isolated from Antrodia Cinnamomea Induced Apoptosis through ROS/AKT/ERK/P38 Signaling Pathway and Epigenetic Histone Acetylation of TNFα in Colorectal Cancer Cells.

BACKGROUND: Antrodin C, a maleimide derivative compound isolated from the ethanol extract of the mycelium of Antrodia cinnamomea, is an endemic fungus of Taiwan and a potential chemoprotective agent. However, the molecular mechanisms underlying the mode of action of antrodin C on cancer cells, especially in human colorectal cancer (CRC), remain unclear. METHODS: The cell death and ROS of the antrodin-C-treated HCT-116 cells were measured by annexin V-FITC/propidium iodide staining, DCFDA, and Fluo-3 fluorescence staining assays. Moreover, signaling molecules regulating TNFα cell death pathways and ROS/AKT/ERK/P38 pathways were also detected in cells treated with antrodin C by Western blotting and chromatin immunoprecipitation. The effects of antrodin C were determined in HCT-116 cell xenograft animal models in terms of tumor volumes and histopathological evaluation. RESULTS: Treatment with antrodin C triggered the activation of extrinsic apoptosis pathways (TNFα, Bax, caspase-3, and -9), and also suppressed the expression of anti-apoptotic molecules Bcl-2 in HCT-116 cells in a time-dependent manner. Antrodin C also decreased cell proliferation and growth through the inactivation of cyclin D1/cyclin for the arrest of the cell cycle at the G1 phase. The activation of the ROS/AKT/ERK/P38 pathways was involved in antrodin-C-induced transcriptional activation, which implicates the role of the histone H3K9K14ac (Acetyl Lys9/Lys14) of the TNFα promoters. Immunohistochemical analyses revealed that antrodin C treatment significantly induced TNFα levels, whereas it decreased the levels of PCNA, cyclin D1, cyclin E, and MMP-9 in an in vivo xenograft mouse model. Thus, antrodin C induces cell apoptosis via the activation of the ROS/AKT/ERK/P38 signaling modules, indicating a new mechanism for antrodin C to treat CRC in vitro and in vivo.

A Retrospective Single-Arm Cohort Study in a Single Center of Radiofrequency Ablation in Treatment of Chronic Radiation Proctitis.

BACKGROUND: Chronic radiation proctitis (CRP) may develop in patients within months to years after undergoing pelvic radiotherapy. Numerous treatment modalities are available to achieve hemostasis in CRP, but the optimal treatment remains controversial. We report our clinical experience and long-term outcomes using radiofrequency ablation (RFA) in patients with CRP. METHODS: We retrospectively reviewed patients who underwent RFA for CRP at Kaohsiung Chang Gung Memorial Hospital between October 2015 and March 2021. The patient characteristics, endoscopic findings, and clinical outcomes were collected and analyzed. RESULTS: 35 total patients were enrolled in the study. The mean age was 70.5 ± 12.4 years. All patients sustained repeated rectal bleeding before RFA, and 15 of 35 patients needed blood transfusion. Bleeding cessation was achieved in all patients. Mean follow-up time was 18.6 months (ranging from 2 to 52 months). The hemoglobin (Hb) levels at 6 months after RFA revealed significant improvement from 11.0 ± 2.3 to 11.8 ± 1.9 g/dL (p = 0.048). The rectal telangiectasia density (RTD) scores also showed significant improvement from 2.96 ± 0.2 to 0.85 ± 0.7 (p < 0.0001). In conclusion, RFA treatment is safe and effective in controlling rectal bleeding in CRP without serious complications and can be considered as a first-line or alternative endoscopic treatment for patients with CRP.

Association between metabolic syndrome and colorectal cancer incidence and all-cause mortality: a hospital-based observational study.

BACKGROUND: Metabolic syndrome (MetS) is a worldwide pandemic and complex disorder associated with colorectal cancer (CRC). This study aims to identify the influence of number of MetS components on CRC incidence and mortality, using a national, longitudinal dataset of hospital care in Taiwan. METHODS: Patient data from the Taiwan National Health Insurance Research Database (NHIRD) from 2001 to 2008 were extracted. Individuals with at least one inpatient diagnosis or 2 outpatient visits with any MetS component found within one year were identified and included. Subjects died within 12 months after the presence of MetS components or had any prior cancer were excluded. The study cohort were then divided into two groups: subjects who had more (i.e., 3 to 4) MetS components and those who had fewer (i.e., 1 to 2) MetS components. An 2:1 propensity score (PS) matching were performed to balance the baseline characteristics between the groups. Cox regression analyses were conducted to compare the CRC incidence and all-cause mortality at follow-up between subjects with more MetS components versus fewer components. RESULTS: After matching, a total of 119,843 subjects (78,274 with 1-2 and 41,569 with 3-4 MetS components) were analyzed. After adjusting for confounders, subjects with 3-4 MetS components had a significantly higher risk of CRC [adjusted hazard ratio (aHR), 1.28; 95% confidence interval (CI), 1.15-1.43, p < 0.001) and all-cause mortality (aHR, 1.13; 95% CI, 1.08-1.17, p < 0.001) than those with only 1-2 MetS components. In stratified analyses, the greatest increased risk of CRC incidence that 3-4 MetS components posed as compared to 1-2 MetS components was seen in subjects without CHD history (aHR, 1.41, 95% CI, 1.23-1.62, p < 0.001). In addition, 3-4 MetS components (vs. 1-2) led to greater all-cause mortality among the subjects < 65y, both genders, with or without CHD, subjects without CKD hisotry, both aspirin users and non-users, users of nonsteroidal anti-inflammatory drugs (NSAIDs), and users of statin. CONCLUSION: Compared with 1-2 components, subjects with 3-4 MetS components are at greater risk of CRC and death at follow-up. This study also demonstrates the risks for CRC and all-cause mortality in certain subgroups of individuals with 3-4 MetS components compared to 1-2 components. These findings may help clinicians on the CRC risk stratification according to individuals' characteristics, as well as to optimize the strategy of MetS surveillance and control in order to prevent CRC.

Risk factors of delayed hemorrhage after LigaSure hemorrhoidectomy.

BACKGROUND: As one of the most popular methods for treating hemorrhoidal diseases, hemorrhoidectomy with LigaSure devices has been proven to have less postoperative pain and has gained in popularity among surgeons. However, our previous study found higher incidence of delayed post-hemorrhoidectomy bleeding (DPHB) in patients who underwent LigaSure hemorrhoidectomy compared to those who underwent the traditional Ferguson's method. This follow-up study aimed to reveal the relationship between DPHB and the surgeon's experience. METHODS: This retrospective study included 437 consecutive patients with symptomatic grade II to IV hemorrhoids who received hemorrhoidectomy by LigaSure devices from March 2009 to December 2017. Twenty-two patients who experienced DPHB were analyzed to identify risk factors. Cumulative incidence of DPHB were calculated and visualized to assess the improvement of DPHB rate by time. RESULTS: All operations were performed by a single surgeon. The most common postoperative complication was constipation, followed by urinary retention. DPHB developed in 22 patients (5%). Multivariate analysis showed that the male sex was an independent risk factor for DPHB in patients who underwent hemorrhoidectomy with LigaSure devices. The cumulative incidence was initially higher (about 10%) in the earlier cases and stabilized at around 5% with more cases. The change in cumulative incidence indicated a lower complication rate as the surgeon's experience increased. CONCLUSION: Male sex is an independent risk factor for DHBP. The risk of DPHB is higher in patients undergoing hemorrhoidectomy with LigaSure in a surgeon's earlier cases, and decreases to a rate similar to that for the traditional hemorrhoidectomy once the surgeon becomes more familiar with the procedure and postoperative care.

Fermented Ginger Extract in Natural Deep Eutectic Solvent Enhances Cytotoxicity by Inhibiting NF-κB Mediated CXC Chemokine Receptor 4 Expression in Oxaliplatin-Resistant Human Colorectal Cancer Cells.

Ginger extracts have been shown to have health-promoting pharmacological activity and beneficial effects, including antioxidant and anticancer properties. The extraction of ginger by natural deep eutectic solvents (NaDES) has been shown to enhance bioactivity, but the cytotoxicity of NaDES extracts needs to be further determined. Signaling through the CXC chemokine receptor 4 (CXCR4) expressed on colorectal cancer (CRC) cells has a pivotal role in tumor cell chemosensitivity. Oxaliplatin is a third-generation platinum compound used as an effective chemotherapeutic drug for CRC treatment. However, whether ginger extract and oxaliplatin could induce a synergistic cytotoxic effect in oxaliplatin-resistant CRC cells through modulating CXCR4 expression is not known. In this study, oxaliplatin-resistant HCT-116 (HCT-116/R) cells were generated first. Ginger was extracted using the NaDES mixture betaine/lactate/water (1:2:2.5). Lactobacillus reuteri fermentation of NaDES-ginger extract increased the total polyphenol content (12.42 mg gallic acid/g in non-fermented NaDES-ginger extract and 23.66 mg gallic acid/g in fermented NaDES-ginger extract). It also increased the antioxidant activity by about 20−30% compared to non-fermented NaDES-ginger extract. In addition, it achieved low cytotoxicity to normal colonic mucosal cells and enhanced the anticancer effect on HCT-116/R cells. On the other hand, the inhibition of NF-κB activation by fermented NaDES-ginger extract significantly decreased the CXCR4 expression (p < 0.05) in HCT-116/R cells. The inactivation of NF-κB by pharmacological inhibitor pyrrolidine dithiocarbamate further enhanced the fermented NaDES-ginger extract-reduced CXCR4 expression levels (p < 0.05). Moreover, fermented NaDES-ginger extract could synergistically increase the cytotoxicity of oxaliplatin by inhibiting CXCR4 expression and inactivating NF-κB, resulting in HCT-116/R cell death. These findings demonstrate that fermented NaDES-ginger extract reduces the NF-kB-mediated activation of CXCR4 and enhances oxaliplatin-induced cytotoxicity in oxaliplatin-resistant CRC cells.

Inhibition of NLRP3 by Fermented Quercetin Decreases Resistin-Induced Chemoresistance to 5-Fluorouracil in Human Colorectal Cancer Cells.

The drug resistance of colorectal cancer (CRC) cells against 5-fluorouracil (5-FU) therapy is a major challenge to successful cancer treatment. While previous studies have proposed several 5-FU resistance mechanisms, the effects of the adipokines on cancer cells remain unclear. Thus, this study investigated the effect of resistin on 5-FU-treated CRC cell lines. The upregulation of NLRP3 can regulate the inflammatory responses in cancer cells and then enhance cancer progression. This study investigated the expression level and the function of NLRP3 on 5-FU-induced cytotoxicity in CRC cells and found that resistin-induced ERK activation and increased NLRP3 expression in CRC HCT-116 and DLD-1 cells were mediated by Toll-like receptor 4 (TLR4). The inhibition of TLR4 and ERK by pharmacological inhibitors attenuated the resistin-induced NLRP3 mRNA and protein levels. In contrast, the knockdown of NLRP3 enhanced the cytotoxic effects of 5-FU. Furthermore, quercetin is an effective chemopreventive compound. This study showed that quercetin fermented by Lactobacillus could exhibit low cytotoxicity on normal mucosa cells and improve the function of inhibiting CRC cells. The treatment of CRC cells with fermented quercetin increased the cytotoxicity and enhanced cell death in the presence of resistin. In this study, fermented quercetin induced the cytotoxicity and cell death of 5-FU in resistin-treated CRC cells, which is associated with the downregulation of NLRP3 expression and ERK phosphorylation. These results indicate the role of NLRP3 in the development of drug resistance to 5-FU in CRC cells. Elucidating the mechanism regarding the cytotoxicity effect of quercetin may provide another vision for the development of a chemotherapy strategy for CRC in the future.

2D-DIGE-MS Proteomics Approaches for Identification of Gelsolin and Peroxiredoxin 4 with Lymph Node Metastasis in Colorectal Cancer.

BACKGROUND/AIMS: A combination of fluorescence two-dimensional difference gel electrophoresis (2D-DIGE) and matrix-assisted laser desorption/ionization time of flight mass spectrometry approach was used to search for potential markers for prognosis and intervention of colorectal cancer (CRC) at different stages of lymph node metastasis (LMN). This quantitative proteomic survey aimed to investigate the LNM-associated proteins and evaluate the clinicopathological characteristics of these target proteins in CRC from stage I to stage IV. METHODS: Sixteen CRC cases were categorized into paired non-LNM and LNM groups, and two-dimensional difference gel electrophoresis and MS proteome analysis were performed. Differential protein expression between non-LNM and LNM CRC was further validated in a tissue microarray, including 40 paraffin-embedded samples by immunohistochemistry staining. Moreover, a Boyden chamber assay, flow cytometry, and shRNA were used to examine the epithelial-mesenchymal transition and mechanism invasiveness of the differentially expressed proteins in DLD-1 cells and in vivo xenograft mouse model. RESULTS: Eighteen differentially expressed proteins were found between non-LNM and LNM CRC tissues. Among them, protein levels of Gelsolin (GSN) and peroxiredoxin 4 (PRDX4) were abundant in node-positive CRC. Downregulation of GSN and PRDX4 markedly suppressed migration and invasiveness and also induced cell cycle G1/S arrest in DLD-1. Mechanistically, the EGFR/RhoA/PKCα/ERK pathways are critical for transcriptional activation of histone modification of H3 lysine 4 trimethylation (H3K4me3) of GSN and PRDX4 promoters, resulting in upregulation of GSN, PRDX4, Twist-1/2, cyclinD1, proliferating cell-nuclear antigen, ß-catenin, N-cadherin, and matrix metalloprotein-9. CONCLUSIONS: GSN and PRDX4 are novel regulators in CRC lymph node metastasis to potentially provide new insights into the mechanism of CRC progression and serve as a biomarker for CRC diagnosis at the metastatic stage.

Suppression of the Proliferation of Huh7 Hepatoma Cells Involving the Downregulation of Mutant p53 Protein and Inactivation of the STAT 3 Pathway with Ailanthoidol.

Ailanthoidol (ATD) has been isolated from the barks of Zanthoxylum ailanthoides and displays anti-inflammatory, antioxidant, antiadipogenic, and antitumor promotion activities. Recently, we found that ATD suppressed TGF-ß1-induced migration and invasion of HepG2 cells. In this report, we found that ATD exhibited more potent cytotoxicity in Huh7 hepatoma cells (mutant p53: Y220C) than in HepG2 cells (wild-type p53). A trypan blue dye exclusion assay and colony assay showed ATD inhibited the growth of Huh7 cells. ATD also induced G1 arrest and reduced the expression of cyclin D1 and CDK2. Flow cytometry analysis with Annexin-V/PI staining demonstrated that ATD induced significant apoptosis in Huh7 cells. Moreover, ATD increased the expression of cleaved PARP and Bax and decreased the expression of procaspase 3/8 and Bcl-xL/Bcl-2. In addition, ATD decreased the expression of mutant p53 protein (mutp53), which is associated with cell proliferation with the exploration of p53 siRNA transfection. Furthermore, ATD suppressed the phosphorylation of the signal transducer and activator of transcription 3 (STAT3) and the expression of mevalonate kinase (MVK). Consistent with ATD, the administration of S3I201 (STAT 3 inhibitor) reduced the expression of Bcl-2/Bcl-xL, cyclin D1, mutp53, and MVK. These results demonstrated ATD's selectivity against mutp53 hepatoma cells involving the downregulation of mutp53 and inactivation of STAT3.

High Red Cell Distribution Width Is Associated with Worse Prognosis in Early Colorectal Cancer after Curative Resection: A Propensity-Matched Analysis.

The red blood cell distribution width (RDW) is a simple and widely available parameter obtained from a complete blood cell count test and is usually used in the analysis of anemia. Recently, studies have discovered the association between RDW and the host inflammatory response of cancer patients. We aimed to determine the prognostic value of RDW in colorectal cancer (CRC) patients. 5315 total patients with stage I-II CRC from the Chang Gung Memorial Hospital between 2001 and 2018 were enrolled. The study cohort was divided into two groups using RDW = 13.8 as the cutoff value as determined by receiver operating curve. High RDW had worse overall survival (OS), disease-free survival (DFS), and cancer-specific survival (CSS), and was also independently related to older age, more advanced tumor stage, lower albumin level, lower hemoglobin level, and more co-morbidities including diabetes, hypertension, and chronic kidney disease. We performed a propensity-score matched analysis to balance the heterogeneity between the two groups and to reduce the influence of confounding factors that may have compromised the prognosis. High RDW remained a negative predictor of OS (HR = 1.49, 95% CI: 1.25-1.78), as well as DFS and CSS. In conclusion, this is the first report using propensity matching to demonstrate the relationship between RDW and the prognosis of early-stage CRC patients.

The impact of obesity on postoperative outcomes in colorectal cancer patients: a retrospective database study.

PURPOSE: Obesity is an independent risk factor for worse outcomes in various surgical settings. Whether obesity is a prognostic factor for postoperative morbidity and mortality of colorectal cancer (CRC) is inconclusive. This study aimed to determine the impact of obesity on short-term postoperative outcomes in CRC patients undergoing laparoscopic surgery. METHODS: Data of a total of 23,898 CRC patients aged ≥ 20 years and undergoing laparoscopic resection were extracted from the US National Inpatient Sample (NIS) database and analyzed. The study endpoints were in-hospital mortality, any postoperative complications, infection/sepsis, acute kidney injury (AKI), deep vein thrombosis (DVT)/pulmonary embolisms (PE), and extended hospital stay. Univariate and multivariate logistic regression analyses were performed to examine the associations between patients' obesity status (morbid obese: BMI > = 40 kg/m2; obese: BMI 30-39.9 kg/m2) and the study outcomes. RESULTS: In 23,898 CRC patients undergoing laparoscopic resection, the prevalence of obesity prevalence was 11.8%. After adjustment, the results revealed that morbid obesity was significantly associated with increased risk for in-hospital mortality (aOR = 2.06, 95%CI: 1.11-3.83), AKI (aOR = 1.78, 95%CI = 1.34-2.36), DVT/PE (aOR = 2.88, 95%CI = 1.70-4.88), and extended LOS (aOR = 1.21, 95%CI = 1.02-1.43), while non-morbid obesity was significantly associated with more DVT/PE (aOR = 2.12, 95%CI = 1.32-3.41) as compared with non-obesity. CONCLUSION: In patients with CRC undergoing laparoscopic surgery, morbid obesity is strongly associated with worse postoperative outcomes, including increased in-hospital mortality, postoperative AKI and DVT/PE, and extended LOS. The findings of the present study highlight the importance of obesity status in risk stratification for laparoscopic CRC surgery.

Visfatin and Resveratrol Differentially Regulate the Expression of Thymidylate Synthase to Control the Sensitivity of Human Colorectal Cancer Cells to Capecitabine Cytotoxicity.

Colorectal cancer (CRC) is a highly lethal malignant cancer. Capecitabine, a 5-fluororacil (5-FU) derivate, is its first-line drug, but the resistance of CRC to capecitabine is still the most challenging factor for curing patients. It has been suggested that thymidylate synthase (TYMS) level might affect the capecitabine efficacy in CRC patients, but the mechanism still needs more elucidation. Obesity is a risk factor for CRC. Recently, a correlation between serum visfatin, an obesity-elicited adipokine, and CRC development has been found. Thus, the aim of present study is to examine the visfatin capacity in TYMS expression and in the development of capecitabine resistance of CRC. Moreover, an attractive natural component, i.e., resveratrol, has been proposed in anticancer therapy and has hence been examined in the present study to see its potential capacity in the alleviation of CRC resistance. Our results found that visfatin significantly reduces the CRC sensitivity to capecitabine by controlling the TYMS expression via p38 signaling and Sp1 transcription factor. Moreover, resveratrol could significantly alleviate the visfatin effect on capecitabine-treated CRC cells. These results provided new insights to understand the capecitabine susceptibility of CRC under a visfatin-containing environment and a possible therapeutic application of resveratrol in CRC patients with obesity.

Development and Validation of a Novel Serum Prognostic Marker for Patients with Metastatic Colorectal Cancer on Regorafenib Treatment.

(1) Background: To investigate the prognostic value of cancer-inflammation prognostic index (CIPI) in patients with metastatic colorectal cancer (mCRC) on regorafenib treatment; (2) Methods: Patients with mCRC who were given regorafenib as later-line treatment at Kaohsiung and Linkou Chang-Gung Memorial Hospital between November 2014 and January 2021 were consecutively enrolled. All relevant clinicopathologic, laboratory data and survival status were recorded. Independent prognostic factors were determined by the multivariate Cox regression method; (3) Results: In total, 106 patients in the training cohort and 250 in the validation cohort were enrolled. The median OS for patients with CIPI ≥ 300 and < 300 in the training cohort was 3.8 and 9.0 months, respectively (hazard ratio (HR) 2.78, 95% confidence interval (CI) 1.82-4.23; p < 0.0001). Time to regorafenib, liver metastasis and CIPI were independent factors by multivariate Cox regression analyses. A new scoring model demonstrated a good discriminatory ability to risk stratification of a patient's survival; (4) Conclusions: We identified CIPI as a novel serum marker highly associated with overall survival in patients with mCRC receiving regorafenib treatment. Further confirmatory studies are warranted.

6-Shogaol Antagonizes the Adipocyte-Conditioned Medium-Initiated 5-Fluorouracil Resistance in Human Colorectal Cancer Cells through Controlling the SREBP-1 Level.

The resistance of colorectal cancer (CRC) to chemotherapy, e.g., 5-fluorouracil (5-FU), is an impediment to successful cancer treatment. Although many mechanisms have been proposed to explain the occurrence of resistance, little is known concerning the role of the adipocyte-containing microenvironment of CRC. Accumulating data have proposed that the combined therapy of clinical drugs with ginger derivatives, e.g., 6-shogaol, might improve resistance development. In the present study, we examined the effect of adipocyte-conditioned medium (ACM) on 5-FU-treated CRC cells (human DLD-1 and SW480 cells) and further examined the possible antagonized role of 6-shogaol in this situation. It was shown that the level of sterol-regulatory element-binding protein-1 (SREBP-1), a critical transcription factor involved in lipid synthesis and metabolism, would be upregulated through Akt and p70S6K signaling pathways while CRC cells are cultured in ACM, which subsequently decreases the cell sensitivity to 5-FU cytotoxicity. Moreover, our results also demonstrated the antagonized role of 6-shogaol in attenuating the ACM effects on CRC cells through activating AMPK signaling. Overall, the present study elucidated the role of adipocyte-containing microenvironment in 5-FU resistance development of CRC through controlling the SREBP-1 level and further enhanced the concept of clinical application of 6-shogaol and AMPK signaling in CRC therapy.

Ailanthoidol, a Neolignan, Suppresses TGF-ß1-Induced HepG2 Hepatoblastoma Cell Progression.

Ailanthoidol (ATD), a neolignan, possessed an antitumor promotion effect in the mouse skin model in our previous investigation. However, other antitumor properties remain to be elucidated. Liver cancer is a major cause of death in the world, and its prognosis and survival rate are poor. Therefore, the prevention and therapy of liver cancer have received much attention. TGF (transforming growth factor)-ß1, a cytokine, plays a critical role in the progression of liver cancer. This study determined the inhibitory effects of ATD on the migration and invasion induced by TGF-ß1 in HepG2 hepatoblastoma cells. Furthermore, ATD reduced the TGF-ß1-promoted colony number of HepG2 hepatoblastoma cells. In addition to reversing TGF-ß1-induced cell scattering, ATD suppressed TGF-ß1-induced expression of integrin α3, vimentin, N-cadherin, and matrix metalloproteinase 2 (MMP2). Finally, this study found that ATD significantly inhibited TGF-ß1-promoted phosphorylation of p-38 mitogen-activated protein kinase (MAPK) and Smad 2. Furthermore, the administration of SB203580 (p38MAPK inhibitor) suppressed TGF-ß1-induced expression of integrin α3, N-cadherin, and MMP2. These results demonstrate a novel mechanism of ATD against progression of liver cancer.