Risk factors for synchronous high-risk polyps in patients with colorectal cancer.

Purpose: Colorectal cancer (CRC) patients may experience inadequate preoperative colonoscopy due to bowel obstruction or inadequate bowel preparation, leading to potential oversight of other polyps. We aimed to identify risk factors for CRC complicated with synchronous high-risk polyps. Methods: A retrospective analysis of 6,674 CRC patients from December 2014 to September 2018 was conducted. High-risk polyps were defined as adenomas or serrated polyps that were ≥10 mm, or with tubulovillous/villous components or high-grade dysplasia. All other polyps were defined as low-risk polyps. Patients with complete pathological and clinical information were categorized into three groups: the no polyp group, the low-risk polyp group, and the high-risk polyp group. Univariate and multivariate logistic regression analyses were performed to calculate the odds ratios (ORs) and corresponding 95% confidence intervals (CIs) for all potential risk factors. Results: Among the 4,659 eligible patients, 848 (18.2%) were found to have low-risk polyps, while 675 (14.5%) were diagnosed with high-risk polyps. In a multivariate logistic regression model, compared to patients without polyps, those with synchronous high-risk polyps were more likely to be male (OR = 2.07), aged 50 or older (OR = 2.77), have early-stage tumors (OR = 1.46), colon tumors (OR = 1.53), NRAS mutant tumors (OR = 1.66), and BRAF wild-type tumors (OR = 2.43). Conclusion: Our study has identified several risk factors associated with the presence of synchronous high-risk polyps in CRC patients. Based on these findings, we recommend that patients who exhibit these high-risk factors undergo early follow-up of colonoscopy to detect synchronous polyps early.

Adipose-derived mesenchymal stromal cells alleviate intestinal fibrosis: The role of tumor necrosis factor-stimulated gene 6 protein.

BACKGROUND: The therapeutic potential of adipose-derived mesenchymal stromal cells (AMSCs) in the treatment of intestinal fibrosis occured in patients with Crohn's disease (CD) remains unclear. Tumor necrosis factor-stimulated gene 6 (TSG6) protein plays a critical role in inflammation regulation and tissue repair. This study aimed to determine if AMSCs attenuate intestinal fibrosis by secreting paracrine TSG6 protein and explore the underlying mechanisms. METHODS: Two murine models for intestinal fibrosis were established using 2,4,6-trinitrobenzene sulfonic acid in BALB/c mice and dextran sulfate sodium in C57BL/6 mice. Primary human fibroblasts and CCD-18co cells were incubated with transforming growth factor (TGF)-ß1 to build two fibrosis cell models in vitro. RESULTS: Intraperitoneally administered AMSCs attenuated intestinal fibrosis in the two murine models, as evidenced by significant alleviation of colon shortening, collagen protein deposits, and submucosal thickening, and also decrease in the endoscopic and fibrosis scores (P < 0.001). Although intraperitoneally injected AMSCs did not migrate to the colon lesions, high levels of TSG6 expression and secretion were noticed both in vivo and in vitro. Similar to the role of AMSCs, injection of recombinant human TSG6 attenuated intestinal fibrosis in the mouse models, which was not observed with the administration of AMSCs with TSG6 knockdown or TSG6 neutralizing antibody. Mechanistically, TSG6 alleviates TGF-ß1-stimulated upregulation of α-smooth muscle actin (αSMA) and collagen I by inhibiting Smad2 phosphorylation. Furthermore, the expression of TSG6 is lower in intestinal fibrosis tissue of patients with Crohn's disease and can reduce pro-fibrotic protein (αSMA) secretion from primary ileal fibrotic tissue. CONCLUSIONS: AMSCs attenuate intestinal fibrosis by secreting paracrine TSG6 protein, which inhibits Smad2 phosphorylation. TSG6, a novel anti-fibrotic factor, could potentially improve intestinal fibrosis treatments.

Risk of advanced neoplasia after removal of colorectal adenomas with high-grade dysplasia.

BACKGROUND: Many studies reported the presence of adenomas with high-grade dysplasia (HGD) at index colonoscopy increased the incidence of advanced neoplasia (AN) and colorectal cancer (CRC) following. However, the conclusion remains obscure due to lack of studies on the specific population of adenomas with HGD. This study aimed to assess the long-term risk of AN and CRC after removal of adenomas with HGD. METHODS: A total of 814 patients who underwent adenomas with HGD removal between 2010 and 2019 were retrospectively analyzed. The outcomes were the incidences of AN and CRC during surveillance colonoscopy. Cox proportional hazards models were utilized to identify risk factors associated with AN and CRC. RESULTS: During more than 2000 person-years of follow-up, we found that AN and CRC incidence densities were 44.3 and 4.4 per 1000 person-years, respectively. The 10-year cumulative incidence of AN and CRC were 39.1% and 5.5%, respectively. In the multivariate model, synchronous low-risk polyps (HR 1.80, 95% CI 1.10-2.93) and synchronous high-risk polyps (HR 3.99, 95% CI 2.37-6.72) were risk factors for AN, whereas participation in surveillance colonoscopy visits (HR 0.56, 95% CI 0.36-0.88 for 1 visit; HR 0.10, 95% CI 0.06-0.19 for ≥ 2 visits) were associated with decreased AN incidence. Additionally, elevated baseline carcinoembryonic antigen (CEA) level (HR 10.19, 95% CI 1.77-58.59) was a risk factor for CRC, while participation in ≥ 2 surveillance colonoscopy visits (HR 0.11, 95% CI 0.02-0.56) were associated with decreased CRC incidence. Interestingly, for 11 patients who developed CRC after removal of adenomas with HGD, immunohistochemistry revealed that 8 cases (73%) were deficient mismatch repair CRCs. CONCLUSIONS: Patients who have undergone adenoma with HGD removal are at higher risk of developing AN and CRC, while surveillance colonoscopy can reduce the risk. Patients with synchronous polyps, or with elevated baseline CEA level are considered high-risk populations and require more frequent surveillance.

ELMO1 ameliorates intestinal epithelial cellular senescence via SIRT1/p65 signaling in inflammatory bowel disease-related fibrosis.

Background: Intestinal fibrosis is a common complication in inflammatory bowel disease (IBD), which still lacks of reliable markers and therapeutic options. Cellular senescence has been considered an important mechanism of intestinal fibrosis, but the underlying molecular link remains elusive. Methods: Tissues were stained using α-smooth muscle actin (α-SMA), fibronectin, and collagen I as markers of myofibroblastic differentiation. Cellular senescence was confirmed through Lamin B1 staining, senescence-associated ß-galactosidase staining, and the expression of senescence-associated secretory phenotype (SASP) factors. We explored the relationship between senescence of intestinal epithelial cells (IECs) and intestinal fibrosis, as well as the molecular mechanism underlying this interaction. The effects of irisin on cellular senescence and fibrosis were determined. Results: Here, we identify engulfment and cell motility protein 1 (ELMO1) as a novel biomarker for intestinal cellular senescence and fibrosis. In fibrostrictured tissues from patients and murine models with IBD, significantly high levels of cellular senescence score and factors were noted, which positively correlated with the fibrotic regulator fibronectin. Senescent IECs, not fibroblast itself, released SASP factors to regulate fibroblast activation. Prolonging exposure to severe and persistent injurious stimuli decreased ELMO1 expression, which dampened SIRT1 deacetylase activity, enhanced NF-κB (p65) acetylation, and thereby accelerated cellular senescence. Deletion of ELMO1 led to senescent IECs accumulation and triggered premature fibrosis in murine colitis. Furthermore, irisin, inhibiting the degradation of ELMO1, could downregulate p65 acetylation, reduce IECs senescence, and prevent incipient intestinal fibrosis in murine colitis models. Conclusions: This study reveals ELMO1 downregulation is an early symbol of intestinal senescence and fibrosis, and the altered ELMO1-SIRT1-p65 pathway plays an important role in intestinal cellular senescence and IBD-related fibrosis.

A new clinical model for predicting lymph node metastasis in T1 colorectal cancer.

PURPOSE: Lymph node metastasis (LNM) is a crucial factor that determines the prognosis of T1 colorectal cancer (CRC) patients. We aimed to develop a practical prediction model for LNM in T1 CRC. METHODS: We conducted a retrospective analysis of data from 825 patients with T1 CRC who underwent radical resection at a single center in China. All enrolled patients were randomly divided into a training set and a validation set at a ratio of 7:3 using R software. Risk factors for LNM were identified through multivariate logistic regression analyses. Subsequently, a prediction model was developed using the selected variables. RESULTS: The lymph node metastasis (LNM) rate was 10.1% in the training cohort and 9.3% in the validation cohort. In the training set, risk factors for LNM in T1 CRC were identified, including depressed endoscopic gross appearance, sex, submucosal invasion combined with tumor grade (DSI-TG), lymphovascular invasion (LVI), and tumor budding. LVI emerged as the most potent predictor for LNM. The prediction model based on these factors exhibited good discrimination ability in the validation sets (AUC: 79.3%). Compared to current guidelines, the model could potentially reduce over-surgery by 48.9%. Interestingly, we observed that sex had a differential impact on LNM between early-onset and late-onset CRC patients. CONCLUSIONS: We developed a clinical prediction model for LNM in T1 CRC using five factors that are easily accessible in clinical practice. The model has better predictive performance and practicality than the current guidelines and can assist clinicians in making treatment decisions for T1 CRC patients.

The depth of perineural invasion is an independent prognostic factor for stage II colorectal cancer.

BACKGROUND: Perineural invasion (PNI) is the invasion of nerves by cancer cells and is associated with poor survival in stage II colorectal cancer. However, PNI can be further subdivided according to the depth of invasion, and the depth of PNI has not been clearly linked to prognosis. METHOD: This study aimed to assess the prognostic value of different depths of PNI in stage II colorectal cancer. We defined PNI in the submucosal plexus and myenteric plexus as superficial perineural invasion (sup-PNI) and PNI in the subserous plexus as deep perineural invasion (deep-PNI). Patients were divided into three groups based on the depth of PNI: sup-PNI, deep-PNI and non-PNI. Then, univariate and multivariate Cox regression analyses were conducted to evaluate the role of PNI in the prognosis of stage II colorectal cancer. RESULTS: This study enrolled 3508 patients with stage II colorectal cancer who underwent resection for primary colorectal lesions between January 2013 and September 2019. Clinicopathological features, including elevated carcinoembryonic antigen (CEA) levels, T4 stage, poor differentiation, deficient DNA mismatch repair (dMMR), and vascular invasion, were correlated with deep-PNI. Multivariate analyses revealed that deep-PNI was associated with worse overall survival (OS; hazard ratio [HR], 3.546; 95% confidence interval [CI], 2.307-5.449; P < 0.001) and disease-free survival (DFS; HR, 2.921; 95% CI, 2.032-4.198; P < 0.001), compared with non-PNI. Conversely, no significant difference in OS or DFS was observed between the sup-PNI and non-PNI groups in multivariate analyses. CONCLUSIONS: The study demonstrated that the depth of PNI was an independent prognostic factor for patients with stage II colorectal cancer, and patients with deep PNI had a worse prognosis. Thus, patients with PNI require further subdivision according to the depth of invasion.

Amino acids analysis reveals serum methionine contributes to diagnosis of the Kawasaki disease in mice and children.

BACKGROUND: Kawasaki disease (KD) patients often lack early and definitive diagnosis due to insufficient clinical criteria, whereas biomarkers might accelerate the diagnostic process and treatment. METHODS: The KD mouse models were established and thirteen amino acids were determined. A total of 551 serum samples were collected including KD patients (n = 134), HCs (n = 223) and KD patients after intravascular immunoglobulin therapy (IVIG, n = 194). A paired analysis of pre- and post-IVIG was employed in 10 KD patients. RESULTS: The pathological alterations of the aorta, myocardial interstitium and coronary artery vessel were observed in KD mice; the serum levels of methionine in KD mice (n = 40) were markedly altered and negatively correlated with the C-reactive protein levels. Consistent with the mouse model, serum methionine were significantly decreased in KD children, with the relative variation ratio of KD with HCs above 30% and AUROC value of 0.845. Serum methionine were correlated with Z-Score and significantly restored to the normal ranges after KD patient IVIG treatment. Another case-control study with 10 KD patients with IVIG sensitivity and 20 healthy controls validated serum methionine as a biomarker for KD patients with AUROC of 0.86. Elevation of serum DNMT1 activities, but no differences of DNMT3a and DNMT3b, were observed in KD patients when comparing with those in the HCs. CONCLUSIONS: Our study validated that serum methionine was a potential biomarker for KD, the alteration of which is associated with the activation of DNMT1 in KD patients.

An immunomodulatory role of Fc receptor γ chain independent of FcγR ligation by IgG in acute neuroinflammation triggered by MPTP intoxication.

Aberrant microglial activation is a prominent feature of neuroinflammation, which is implicated in the pathogenesis of neurological disorders. Fc receptor common γ-chain (FcRγ), one of the two immunoreceptor tyrosine-based activation motif-bearing adaptor proteins, is abundantly expressed in microglia. It couples with different receptors, such as receptors for the Fc portion of IgG. In this study, we observed increased FcRγ expression along with increased IgG-binding during acute neuroinflammation triggered by MPTP intoxication, where adaptive immune responses should not be involved. Notably, FcRγ was expressed not only in the cell membrane but also in the cytoplasm in the activated microglia. FcRγ deficiency exacerbated microglial activation, pro-inflammatory factor upregulation, nigral dopaminergic neuronal loss and motor deficits, implicating a beneficial role of FcRγ in this model. Blockade of Fcγ receptor ligation by IgG in mice by Endoglycosidase S treatment, a bacterial endo-ß-N-acetylglucosaminidase cleaving specifically the Asn297-linked glycan of IgG, or by using the mice deficient in mature B cells (muMT) with IgG production defects, did not show similar phenotypes to those observed in FcRγ-deficient mice, indicating that the beneficial effect mediated by FcRγ did not depend on FcγR ligation by IgG. Further, FcRγ knockout aggravated the expression and activation of STAT1 in microglia, suggesting FcRγ modulated neuroinflammation by dampening STAT1 signaling. Collectively, these results revealed that FcRγ-associated receptors could function as negative regulators of neuroinflammation and dopaminergic neurodegeneration.

Effect of Vitamin D on the HMGB1/RAGE Pathway and Adipokines Levels in Obese Asthmatic Mice.

Compared to common asthma, obese asthma is difficult to control. Previous studies have shown that vitamin D (Vit D) has a therapeutic effect on asthma. Nevertheless, the action mechanism of Vit D for obese asthma are not well known. In this study, we, therefore, induced obesity and established an obese asthma mouse model using ovalbumin (OVA) stimulation and applied treatment with Vit D (100 ng/kg). Accordingly, thirty mice were randomly divided into 5 equal groups of normal control, asthma, obese asthma, asthma+Vit D, and obese asthma+ Vit D. The levels of inflammatory factors and adipokines were measured by the ELISA assay; then the quantitative reverse transcription PCR (qRT-PCR) method was used to evaluate the expression of high mobility group box 1(HMGB1) and receptor for advanced glycation end products [RAGE] genes.T he results showed that OVA sensitization significantly increased airway resistance, the levels of inflammatory cytokines, and HMGB and RAGE expression in asthmatic and obese asthmatic mice, as compared to the control group. Also, these changes in the obese asthmatic group were notably higher than those in the asthmatic one. In addition, the treatment of asthmatic and obese asthmatic mice with Vit D significantly reduced the raw, serum and BALF levels of inflammatory cytokines, as well as the expression of HMGB1 and RAGE mRNA. To conclude, the present study showed that vitamin D might attenuate lung injury by up-regulating HMGB1 and RAGE expression. Our findings, thus, may offer new concepts and approaches for the treatment and prevention of obese asthma.

Senescence-based colorectal cancer subtyping reveals distinct molecular characteristics and therapeutic strategies.

Cellular senescence has been listed as a hallmark of cancer, but its role in colorectal cancer (CRC) remains unclear. We comprehensively evaluated the transcriptome, genome, digital pathology, and clinical data from multiple datasets of CRC patients and proposed a novel senescence subtype for CRC. Multi-omics data was used to analyze the biological features, tumor microenvironment, and mutation landscape of senescence subtypes, as well as drug sensitivity and immunotherapy response. The senescence score was constructed to better quantify senescence in each patient for clinical use. Unsupervised learning revealed three transcriptome-based senescence subtypes. Cluster 1, characterized by low senescence and activated proliferative pathways, was sensitive to chemotherapeutic drugs. Cluster 2, characterized by intermediate senescence and high immune infiltration, exhibited significant immunotherapeutic advantages. Cluster 3, characterized by high senescence, high immune, and stroma infiltration, had a worse prognosis and maybe benefit from targeted therapy. We further constructed a senescence scoring system based on seven senescent genes through machine learning. Lower senescence scores were highly predictive of longer disease-free survival, and patients with low senescence scores may benefit from immunotherapy. We proposed the senescence subtypes of CRC and our findings provide potential treatment interventions for each CRC senescence subtype to promote precision treatment.

CD51 Intracellular Domain Promotes Cancer Cell Neurotropism through Interacting with Transcription Factor NR4A3 in Colorectal Cancer.

The abundant nervous system in intestine provides the basis for perineural invasion (PNI) of colorectal cancer (CRC). PNI is defined as the invasion of the nerves by cancer cells. Although PNI is already known to be an independent prognostic factor in CRC, the molecular mechanism underlying PNI remains obscure. In this study, we first demonstrated that CD51 could promote the neurotropism of tumor cells through cleavage with γ-secretase to generate an intracellular domain (ICD). Mechanistically, ICD of CD51 could bind to the transcription factor NR4A3, and act as a coactivator to promote the expression of downstream effectors, such as NTRK1, NTRK3, and SEMA3E. Pharmacological inhibition of γ-secretase impedes PNI mediated by CD51 in CRC both in vitro and in vivo and may become a potential therapeutic target for PNI in CRC.

Clinical significance of neoadjuvant chemotherapy for locally advanced colorectal cancer patients with deficient mismatch repair: possibly residual value in the era of immunotherapy.

Background: Deficient mismatch repair (dMMR) or microsatellite instability is one of the well-established molecular biomarkers in colorectal cancer (CRC). The efficiency of neoadjuvant chemotherapy (NAC) in locally advanced colorectal cancer (LACC) patients with dMMR is unclear. Objectives: We assessed the tumor response and clinical outcome in LACC patients with dMMR received NAC. Design: Retrospective, single-center analysis. Methods: From 2013 to 2018, a total of 577 LACC patients with dMMR who underwent radical surgery were identified. Among them, 109 patients who received adjuvant chemotherapy were further screened out for analysis. According to whether receiving NAC or not, 109 patients were divided into two groups with the purpose of retrospectively analyzing their characteristics, treatment, and survival results, especially the 5-year disease-free survival (DFS) and 5-year overall survival. Results: Baseline characteristics were matched between the two groups. One of 40 patients in NAC group recurred, while 13 of 69 patients in non-NAC group recurred. Univariate and multivariate analyses showed that NAC (hazard ratio: 0.115; 95% confidence interval: 0.015-0.897; p = 0.039) was independent influence factor for DFS. In NAC group, there were 13/40 (32.5%) patients for tumor regression grade 1 and 27/40 (67.5%) patients converted clinical positive N-stage into negative N-stage. Conclusion: In this study, NAC was associated with better tumor downstaging and longer 5-year DFS in LACC patients with dMMR. Consequently, NAC might be an additional treatment choice when it comes to such patients in the future.

Nomogram for predicting overall survival time of patients with stage IV colorectal cancer.

Background: Prognosis varies among stage IV colorectal cancer (CRC). Our study aimed to build a robust prognostic nomogram for predicting overall survival (OS) of patients with stage IV CRC in order to provide evidence for individualized treatment. Method: We collected the information of 16,283 patients with stage IV CRC in the Surveillance, Epidemiology, and End Results (SEER) database and then randomized these patients in a ratio of 7:3 into a training cohort and an internal validation cohort. In addition, 501 patients in the Sixth Affiliated Hospital of Sun Yat-sen University (Guangzhou, China) database were selected and used as an external validation cohort. Univariate and multivariate Cox analyses were used to screen out significant variables for nomogram establishment. The nomogram model was assessed using time-dependent receiver-operating characteristic curve (time-dependent ROC), concordance index (C-index), calibration curve, and decision curve analysis. Survival curves were plotted using the Kaplan-Meier method. Result: The C-index of the nomogram for OS in the training, internal validation, and external validation cohorts were 0.737, 0.727, and 0.655, respectively. ROC analysis and calibration curves pronounced robust discriminative ability of the model. Further, we divided the patients into a high-risk group and a low-risk group according to the nomogram. Corresponding Kaplan-Meier curves showed that the prediction of the nomogram was consistent with the actual practice. Additionally, model comparisons and decision curve analysis proved that the nomogram for predicting prognosis was significantly superior to the tumor-node-metastasis (TNM) staging system. Conclusions: We constructed a nomogram to predict OS of the stage IV CRC and externally validate its generalization, which was superior to the TNM staging system.

Predicting pathologic complete response in locally advanced rectal cancer patients after neoadjuvant therapy: a machine learning model using XGBoost.

PURPOSE: Watch and wait strategy is a safe and effective alternative to surgery in patients with locally advanced rectal cancer (LARC) who have achieved pathological complete response (pCR) after neoadjuvant therapy (NAT); present restaging methods do not meet clinical needs. This study aimed to construct a machine learning (ML) model to predict pCR preoperatively. METHODS: LARC patients who received NAT were included to generate an extreme gradient boosting-based ML model to predict pCR. The group was divided into a training set and a tuning set at a 7:3 ratio. The SHapley Additive exPlanations value was used to quantify feature importance. The ML model was compared with a nomogram model developed using independent risk factors identified by conventional multivariate logistic regression analysis. RESULTS: Compared with the nomogram model, our ML model improved the area under the receiver operating characteristics from 0.72 to 0.95, sensitivity from 43 to 82.2%, and specificity from 87.1 to 91.6% in the training set, the same trend applied to the tuning set. Neoadjuvant radiotherapy, preoperative carbohydrate antigen 125 (CA125), CA199, carcinoembryonic antigen level, and depth of tumor invasion were significant in predicting pCR in both models. CONCLUSION: Our ML model is a potential alternative to the existing assessment tools to conduct triage treatment for patients and provides reference for clinicians in tailoring individual treatment: the watch and wait strategy is used to avoid surgical trauma in pCR patients, and non-pCR patients receive surgical treatment to avoid missing the optimal operation time window.

Endoscopy-Based Deep Convolutional Neural Network Predicts Response to Neoadjuvant Treatment for Locally Advanced Rectal Cancer.

Background and Aims: Although the wait and watch (W&W) strategy is a treatment choice for locally advanced rectal cancer (LARC) patients who achieve clinical complete response (cCR) after neoadjuvant therapy (NT), the issue on consistency between cCR and pathological CR (pCR) remains unsettled. Herein, we aimed to develop a deep convolutional neural network (DCNN) model using endoscopic images of LARC patients after NT to distinguish tumor regression grade (TRG) 0 from non-TRG0, thus providing strength in identifying surgery candidates. Methods: A total of 1000 LARC patients (6,939 endoscopic images) who underwent radical surgery after NT from April 2013 to April 2021 at the Sixth Affiliated Hospital, Sun Yat-sen University were retrospectively included in our study. Patients were divided into three cohorts in chronological order: the training set for constructing the model, the validation set, and the independent test set for validating its predictive capability. Besides, we compared the model's performance with that of three endoscopists on a class-balanced, randomly selected subset of 20 patients' LARC images (10 TRG0 patients with 70 images and 10 non-TRG0 patients with 72 images). The measures used to evaluate the efficacy for identifying TRG0 included overall accuracy, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and area under the receiver operating characteristic curve (AUROC). Results: There were 219 (21.9%) cases of TRG0 in the included patients. The constructed DCNN model in the training set obtained an excellent performance with good accuracy of 94.21%, specificity of 94.39%, NPV of 98.11%, and AUROC of 0.94. The validation set showed accuracy, specificity, NPV, and AUROC of 92.13%, 93.04%, 96.69%, and 0.95, respectively; the corresponding values in the independent set were 87.14%, 92.98%, 91.37%, and 0.77, respectively. In the reader study, the model outperformed the three experienced endoscopists with an AUROC of 0.85. Conclusions: The proposed DCNN model achieved high specificity and NPV in detecting TRG0 LARC tumors after NT, with a better performance than experienced endoscopists. As a supplement to radiological images, this model may serve as a useful tool for identifying surgery candidates in LARC patients after NT.

Risk factors for recurrence of colorectal conventional adenoma and serrated polyp.

Background: Removal of colorectal polyps during screening could reduce the incidence of colorectal cancer (CRC). However, there is a lack of data on risk factors associated with recurrence of polyps, including conventional adenomas and serrated polyps (SPs). This study aimed to determine risk factors for recurrence of colorectal polyps and their subtypes based on the characteristics of the patients and polyps. Methods: A total of 1,165 patients diagnosed with conventional adenoma or SP in the Sixth Affiliated Hospital of Sun Yat-sen University between January 2013 and December 2019 were enrolled in this study, including 668 cases with conventional adenomas, 385 with SPs, and 112 with coexistence of adenomas and SPs. Univariate analysis and multivariate logistic regression were used to identify potential risk factors for polyp recurrence. A nomogram was established according to risk factors and the performance was evaluated using calibration plots. Results: During a median follow-up of 24 months, recurrent polyps were observed in 531 (45.6%) cases. Male, age ≥50 years, body mass index (BMI) ≥24 kg/m2, at least three polyps, smoking, alcohol consumption, family history of polyps, and family history of CRC were independent risk factors for polyp recurrence. The Harrell's C-index of the nomogram developed with these parameters was 0.69 and the calibration plots showed good agreement between actual polyp recurrence and nomogram-predicted recurrence probability. In the subtype analyses, conventional adenomas had the same risk factors for recurrence as all polyps, while smoking, alcohol consumption, family history of polyps, and family history of CRC were not risk factors for SP recurrence. Conclusions: We identified several risk factors for recurrence of colorectal polyps and found that some of them could increase the risk of adenoma recurrence but not SP recurrence, including smoking, alcohol consumption, and family history of polyps/CRC, which might help us to understand different etiology and biology between conventional adenomas and SPs.

Mitolysosome exocytosis, a mitophagy-independent mitochondrial quality control in flunarizine-induced parkinsonism-like symptoms.

Mitochondrial quality control plays an important role in maintaining mitochondrial homeostasis and function. Disruption of mitochondrial quality control degrades brain function. We found that flunarizine (FNZ), a drug whose chronic use causes parkinsonism, led to a parkinsonism-like motor dysfunction in mice. FNZ induced mitochondrial dysfunction and decreased mitochondrial mass specifically in the brain. FNZ decreased mitochondrial content in both neurons and astrocytes, without affecting the number of nigral dopaminergic neurons. In human neural progenitor cells, FNZ also induced mitochondrial depletion. Mechanistically, independent of ATG5- or RAB9-mediated mitophagy, mitochondria were engulfed by lysosomes, followed by a vesicle-associated membrane protein 2- and syntaxin-4-dependent extracellular secretion. A genome-wide CRISPR knockout screen identified genes required for FNZ-induced mitochondrial elimination. These results reveal not only a previously unidentified lysosome-associated exocytosis process of mitochondrial quality control that may participate in the FNZ-induced parkinsonism but also a drug-based method for generating mitochondria-depleted mammal cells.

Increased risk of colorectal neoplasia in inflammatory bowel disease patients with post-inflammatory polyps: A systematic review and meta-analysis.

BACKGROUND: Inflammatory bowel disease (IBD) patients with post-inflammatory polyps (PIPs) may carry an increased risk of colorectal neoplasia (CRN) including dysplasia and cancer. Current guidelines recommend active colonoscopy follow-up for these patients. However, the evidence for guidelines is still poor. In addition, some recent high-quality reports present a different view, which challenges the current guidelines. We hypothesize that IBD patients with PIPs are at increased risk of CRN. AIM: To evaluate the risk of CRN in IBD patients with and without PIPs. METHODS: A systematic search of PubMed, Embase, Cochrane Library, and Web of Science was performed to identify studies that compared the risk of CRN in IBD patients with and without PIPs. In addition, we screened the reference lists and citation indices of the included studies. Quality assessment was performed using the Newcastle-Ottawa Scale. Pooled odds ratio (OR) was calculated using the random-effects model to explore the final pooled effect size of the included studies and determine whether PIPs increase the risk of CRN. Sensitivity analysis, subgroup analysis, and assessment of publication bias were performed to examine the sources of heterogeneity. RESULTS: Twelve studies with 5819 IBD patients, including 1281 (22.01%) with PIPs, were considered eligible for this meta-analysis. We found that IBD patients with PIPs were at an increased risk of CRN as compared to those without PIPs [OR 2.01; 95% confidence interval (CI): 1.43-2.83]. The results were similar when colorectal cancer was used as the study endpoint (OR 2.57; 95%CI: 1.69-3.91). Furthermore, the risk of CRN was still increased (OR 1.80; 95%CI: 1.12-2.91) when restricted to ulcerative colitis patients. Heterogeneity was high among the included studies (I² = 75%). Subgroup analysis revealed that the high heterogeneity was due to the study design. Sensitivity analysis showed that the main statistical outcomes did not essentially change after excluding any one of the included studies. No significant publication bias was found in the funnel plots. CONCLUSION: IBD patients with PIPs have an increased risk of CRN as compared with those without PIPs, which support the current guidelines. However, a high-quality randomized controlled trial is warranted.

Orthodontic Rubber Band-Assisted Endoscopic Submucosal Dissection: An Efficient Method for Treating Superficial Colorectal Tumors.

BACKGROUND: Colorectal endoscopic submucosal dissection (ESD) is a complex operation. Effective traction is crucial. We have successfully used an orthodontic rubber band (ORB) combined with the clip traction method to assist ESD (ORB-ESD). The aim of this retrospective study is to describe the method and to compare the efficacy and safety of ORB-ESD versus conventional ESD in the treatment of superficial colorectal tumors. METHODS: We retrospectively analyzed the data of patients with superficial colorectal tumor (with diameter ≥ 20 mm) who received either ORB-ESD (n = 34) or conventional ESD (n = 90) between January 2019 and September 2020. Propensity score matching (PSM) was used to match the clinical data of 31 pairs of patients in each group. RESULTS: Operation time was significantly shorter for ORB-ESD than for conventional ESD (34.5 minutes vs. 56 minutes, P ≤ 0.001). In the propensity-matched cohorts, the operation time remained significantly shorter in the ORB-ESD patients (35 minutes vs. 50 minutes, P = 0.001). Postoperative adverse events, en bloc resection rate, and R0 resection rate were comparable between the two groups (P > 0.05), both before and after propensity score matching. In the ORB subgroup analysis, the trainee and expert ESD operation times were similar (37 (26-53) vs. 33.5 (26-37) minutes, respectively; P = 0.274). CONCLUSION: ORB-ESD appears to be an effective technique for ESD of colorectal cancer. Our findings need to be confirmed in large prospective multicenter studies.