Differential pre-malignant programs and microenvironment chart distinct paths to malignancy in human colorectal polyps.

Colorectal cancers (CRCs) arise from precursor polyps whose cellular origins, molecular heterogeneity, and immunogenic potential may reveal diagnostic and therapeutic insights when analyzed at high resolution. We present a single-cell transcriptomic and imaging atlas of the two most common human colorectal polyps, conventional adenomas and serrated polyps, and their resulting CRC counterparts. Integrative analysis of 128 datasets from 62 participants reveals adenomas arise from WNT-driven expansion of stem cells, while serrated polyps derive from differentiated cells through gastric metaplasia. Metaplasia-associated damage is coupled to a cytotoxic immune microenvironment preceding hypermutation, driven partly by antigen-presentation differences associated with tumor cell-differentiation status. Microsatellite unstable CRCs contain distinct non-metaplastic regions where tumor cells acquire stem cell properties and cytotoxic immune cells are depleted. Our multi-omic atlas provides insights into malignant progression of colorectal polyps and their microenvironment, serving as a framework for precision surveillance and prevention of CRC.

On the covalent nature of lysine polyphosphorylation.

Post-translational modifications of proteins (PTMs) introduce an extra layer of complexity to cellular regulation. Although phosphorylation of serine, threonine, and tyrosine residues is well-known as PTMs, lysine is, in fact, the most heavily modified amino acid, with over 30 types of PTMs on lysine having been characterized. One of the most recently discovered PTMs on lysine residues is polyphosphorylation, which sees linear chains of inorganic polyphosphates (polyP) attached to lysine residues. The labile nature of phosphoramidate bonds raises the question of whether this modification is covalent in nature. Here, we used buffers with very high ionic strength, which would disrupt any non-covalent interactions, and confirmed that lysine polyphosphorylation occurs covalently on proteins containing PASK domains (polyacidic, serine-, and lysine-rich), such as the budding yeast protein nuclear signal recognition 1 (Nsr1) and the mammalian protein nucleolin. This Matters Arising Response paper addresses the Neville et al. (2024) Matters Arising paper, published concurrently in Molecular Cell.

Cryo-EM structure of the polyphosphate polymerase VTC reveals coupling of polymer synthesis to membrane transit.

The eukaryotic vacuolar transporter chaperone (VTC) complex acts as a polyphosphate (polyP) polymerase that synthesizes polyP from adenosine triphosphate (ATP) and translocates polyP across the vacuolar membrane to maintain an intracellular phosphate (Pi ) homeostasis. To discover how the VTC complex performs its function, we determined a cryo-electron microscopy structure of an endogenous VTC complex (Vtc4/Vtc3/Vtc1) purified from Saccharomyces cerevisiae at 3.1 Å resolution. The structure reveals a heteropentameric architecture of one Vtc4, one Vtc3, and three Vtc1 subunits. The transmembrane region forms a polyP-selective channel, likely adopting a resting state conformation, in which a latch-like, horizontal helix of Vtc4 limits the entrance. The catalytic Vtc4 central domain is located on top of the pseudo-symmetric polyP channel, creating a strongly electropositive pathway for nascent polyP that can couple synthesis to translocation. The SPX domain of the catalytic Vtc4 subunit positively regulates polyP synthesis by the VTC complex. The noncatalytic Vtc3 regulates VTC through a phosphorylatable loop. Our findings, along with the functional data, allow us to propose a mechanism of polyP channel gating and VTC complex activation.

Cellular and molecular characteristics of stromal Lkb1 deficiency-induced gastrointestinal polyposis based on single-cell RNA sequencing.

Liver kinase B1 (Lkb1), encoded by serine/threonine kinase (Stk11), is a serine/threonine kinase and tumor suppressor that is strongly implicated in Peutz-Jeghers syndrome (PJS). Numerous studies have shown that mesenchymal-specific Lkb1 is sufficient for the development of PJS-like polyps in mice. However, the cellular origin and components of these Lkb1-associated polyps and underlying mechanisms remain elusive. In this study, we generated tamoxifen-inducible Lkb1flox/flox;Myh11-Cre/ERT2 and Lkb1flox/flox;PDGFRα-Cre/ERT2 mice, performed single-cell RNA sequencing (scRNA-seq) and imaging-based lineage tracing, and aimed to investigate the cellular complexity of gastrointestinal polyps associated with PJS. We found that Lkb1flox/+;Myh11-Cre/ERT2 mice developed gastrointestinal polyps starting at 9 months after tamoxifen treatment. scRNA-seq revealed aberrant stem cell-like characteristics of epithelial cells from polyp tissues of Lkb1flox/+;Myh11-Cre/ERT2 mice. The Lkb1-associated polyps were further characterized by a branching smooth muscle core, abundant extracellular matrix deposition, and high immune cell infiltration. In addition, the Spp1-Cd44 or Spp1-Itga8/Itgb1 axes were identified as important interactions among epithelial, mesenchymal, and immune compartments in Lkb1-associated polyps. These characteristics of gastrointestinal polyps were also demonstrated in another mouse model, tamoxifen-inducible Lkb1flox/flox;PDGFRα-Cre/ERT2 mice, which developed obvious gastrointestinal polyps as early as 2-3 months after tamoxifen treatment. Our findings further confirm the critical role of mesenchymal Lkb1/Stk11 in gastrointestinal polyposis and provide novel insight into the cellular complexity of Lkb1-associated polyp biology. © 2024 The Pathological Society of Great Britain and Ireland.

Murine model of eosinophilic chronic rhinosinusitis with nasal polyposis inducing neuroinflammation and olfactory dysfunction.

BACKGROUND: Chronic rhinosinusitis (CRS) is a common inflammatory condition affecting the nasal and paranasal sinus mucosa, often accompanied by olfactory dysfunction. Eosinophilic CRS with nasal polyps (ECRSwNP) is a subtype of CRS characterized by eosinophilic infiltration. Animal models for ECRSwNP with olfactory dysfunction are necessary for exploring potential therapeutic strategies. OBJECTIVE: The aim of this study was to establish a mouse model of ECRSwNP combined with olfactory dysfunction in a shorter time frame using intranasal ovalbumin and Aspergillus protease (AP) administration. The efficacy of the model was validated by evaluating sinonasal inflammation, cytokine levels, olfactory function, and neuroinflammation in the olfactory bulb. METHODS: Male BALB/c mice were intranasally administered ovalbumin and AP for 6 and 12 weeks to induce ECRSwNP. The resultant ECRSwNP mouse model underwent histologic assessment, cytokine analysis of nasal lavage fluid, olfactory behavioral tests, and gene expression profiling to identify neuroinflammatory markers within the olfactory bulb. RESULTS: The developed mouse model exhibited substantial eosinophil infiltration, increased levels of inflammatory cytokines in nasal lavage fluid, and confirmed olfactory dysfunction through behavioral assays. Furthermore, olfactory bulb inflammation and reduced mature olfactory sensory neurons were observed in the model. CONCLUSION: This study successfully established a validated mouse model of ECRSwNP with olfactory dysfunction within a remarkably short span of 6 weeks, providing a valuable tool for investigating the pathogenesis and potential therapies for this condition. The model offers an efficient approach for future research in CRS with nasal polyps and olfactory dysfunction.

Galectin-10 in serum extracellular vesicles reflects asthma pathophysiology.

BACKGROUND: Novel biomarkers (BMs) are urgently needed for bronchial asthma (BA) with various phenotypes and endotypes. OBJECTIVE: We sought to identify novel BMs reflecting tissue pathology from serum extracellular vesicles (EVs). METHODS: We performed data-independent acquisition of serum EVs from 4 healthy controls, 4 noneosinophilic asthma (NEA) patients, and 4 eosinophilic asthma (EA) patients to identify novel BMs for BA. We confirmed EA-specific BMs via data-independent acquisition validation in 61 BA patients and 23 controls. To further validate these findings, we performed data-independent acquisition for 6 patients with chronic rhinosinusitis without nasal polyps and 7 patients with chronic rhinosinusitis with nasal polyps. RESULTS: We identified 3032 proteins, 23 of which exhibited differential expression in EA. Ingenuity pathway analysis revealed that protein signatures from each phenotype reflected disease characteristics. Validation revealed 5 EA-specific BMs, including galectin-10 (Gal10), eosinophil peroxidase, major basic protein, eosinophil-derived neurotoxin, and arachidonate 15-lipoxygenase. The potential of Gal10 in EVs was superior to that of eosinophils in terms of diagnostic capability and detection of airway obstruction. In rhinosinusitis patients, 1752 and 8413 proteins were identified from EVs and tissues, respectively. Among 11 BMs identified in EVs and tissues from patients with chronic rhinosinusitis with nasal polyps, 5 (including Gal10 and eosinophil peroxidase) showed significant correlations between EVs and tissues. Gal10 release from EVs was implicated in eosinophil extracellular trapped cell death in vitro and in vivo. CONCLUSION: Novel BMs such as Gal10 from serum EVs reflect disease pathophysiology in BA and may represent a new target for liquid biopsy approaches.

IL-4Rα signaling promotes barrier-altering oncostatin M and IL-6 production in aspirin-exacerbated respiratory disease.

BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is a severe disease involving dysregulated type 2 inflammation. However, the role other inflammatory pathways play in AERD is poorly understood. OBJECTIVE: We sought to broadly define the inflammatory milieu of the upper respiratory tract in AERD and to determine the effects of IL-4Rα inhibition on mediators of nasal inflammation. METHODS: Twenty-two AERD patients treated with dupilumab for 3 months were followed over 3 visits and compared to 10 healthy controls. Nasal fluid was assessed for 45 cytokines and chemokines using Olink Target 48. Blood neutrophils and cultured human mast cells, monocytes/macrophages, and nasal fibroblasts were assessed for response to IL-4/13 stimulation in vitro. RESULTS: Of the nasal fluid cytokines measured, nearly one third were higher in AERD patients compared to healthy controls, including IL-6 and the IL-6 family-related cytokine oncostatin M (OSM), both of which correlated with nasal albumin levels, a marker of epithelial barrier dysregulation. Dupilumab significantly decreased many nasal mediators, including OSM and IL-6. IL-4 stimulation induced OSM production from mast cells and macrophages but not from neutrophils, and OSM and IL-13 stimulation induced IL-6 production from nasal fibroblasts. CONCLUSION: In addition to type 2 inflammation, innate and IL-6-related cytokines are also elevated in the respiratory tract in AERD. Both OSM and IL-6 are locally produced in nasal polyps and likely promote pathology by negatively affecting epithelial barrier function. IL-4Rα blockade, although seemingly directed at type 2 inflammation, also decreases mediators of innate inflammation and epithelial dysregulation, which may contribute to dupilumab's therapeutic efficacy in AERD.

Comprehensive single-cell analysis deciphered microenvironmental dynamics and immune regulator olfactomedin 4 in pathogenesis of gallbladder cancer.

OBJECTIVE: Elucidating complex ecosystems and molecular features of gallbladder cancer (GBC) and benign gallbladder diseases is pivotal to proactive cancer prevention and optimal therapeutic intervention. DESIGN: We performed single-cell transcriptome analysis on 230 737 cells from 15 GBCs, 4 cholecystitis samples, 3 gallbladder polyps, 5 gallbladder adenomas and 16 adjacent normal tissues. Findings were validated through large-scale histological assays, digital spatial profiler multiplexed immunofluorescence (GeoMx), etc. Further molecular mechanism was demonstrated with in vitro and in vivo studies. RESULTS: The cell atlas unveiled an altered immune landscape across different pathological states of gallbladder diseases. GBC featured a more suppressive immune microenvironment with distinct T-cell proliferation patterns and macrophage attributions in different GBC subtypes. Notably, mutual exclusivity between stromal and immune cells was identified and remarkable stromal ecosystem (SC) heterogeneity during GBC progression was unveiled. Specifically, SC1 demonstrated active interaction between Fibro-iCAF and Endo-Tip cells, correlating with poor prognosis. Moreover, epithelium genetic variations within adenocarcinoma (AC) indicated an evolutionary similarity between adenoma and AC. Importantly, our study identified elevated olfactomedin 4 (OLFM4) in epithelial cells as a central player in GBC progression. OLFM4 was related to T-cell malfunction and tumour-associated macrophage infiltration, leading to a worse prognosis in GBC. Further investigations revealed that OLFM4 upregulated programmed death-ligand 1 (PD-L1) expression through the MAPK-AP1 axis, facilitating tumour cell immune evasion. CONCLUSION: These findings offer a valuable resource for understanding the pathogenesis of gallbladder diseases and indicate OLFM4 as a potential biomarker and therapeutic target for GBC.

Optimal glycaemic control and the reduced risk of colorectal adenoma and cancer in patients with diabetes: a population-based cohort study.

OBJECTIVE: Whether varying degrees of glycaemic control impact colonic neoplasm risk in patients with diabetes mellitus (DM) remains uncertain. DESIGN: Patients with newly diagnosed DM were retrieved from 2005 to 2013. Optimal glycaemic control at baseline was defined as mean haemoglobin A1c (HbA1c)<7%. Outcomes of interest included colorectal cancer (CRC) and colonic adenoma development. We used propensity score (PS) matching with competing risk models to estimate subdistribution HRs (SHRs). We further analysed the combined effect of baseline and postbaseline glycaemic control based on time-weighted mean HbA1c during follow-up. RESULTS: Of 88 468 PS-matched patients with DM (mean (SD) age: 61.5 (±11.7) years; male: 47 127 (53.3%)), 1229 (1.4%) patients developed CRC during a median follow-up of 7.2 (IQR: 5.5-9.4) years. Optimal glycaemic control was associated with lower CRC risk (SHR 0.72; 95% CI 0.65 to 0.81). The beneficial effect was limited to left-sided colon (SHR 0.71; 95% CI 0.59 to 0.85) and rectum (SHR 0.71; 95% CI 0.57 to 0.89), but not right-sided colon (SHR 0.86; 95% CI 0.67 to 1.10). Setting suboptimal glycaemic control at baseline/postbaseline as a reference, a decreased CRC risk was found in optimal control at postbaseline (SHR 0.79), baseline (SHR 0.71) and both time periods (SHR 0.61). Similar associations were demonstrated using glycaemic control as a time-varying covariate (HR 0.75). A stepwise greater risk of CRC was found (Ptrend<0.001) with increasing HbA1c (SHRs 1.34, 1.30, 1.44, 1.58 for HbA1c 7.0% to <7.5%, 7.5% to <8.0%, 8.0% to <8.5% and ≥8.5%, respectively). Optimal glycaemic control was associated with a lower risk of any, non-advanced and advanced colonic adenoma (SHRs 0.73-0.87). CONCLUSION: Glycaemic control in patients with DM was independently associated with the risk of colonic adenoma and CRC development with a biological gradient.

Current Approaches in Managing Colonic Serrated Polyps and Serrated Polyposis.

For decades, conventional adenomas were the only known precursor lesions of colorectal cancer (CRC). Accordingly, education and research regarding CRC prevention were mainly focused on adenomas. The groundbreaking discovery that serrated polyps (SPs) also have the potential to develop into CRCs, and seem to account for a considerable proportion of sporadic CRCs, has led to a paradigm shift in the prevention, diagnosis, and treatment of CRC. Studies in recent years have led to our current understanding of SPs and associated CRC, but a lot of work is still to be done to further improve knowledge about this serrated neoplasia pathway and the clinical management of SPs and serrated polyposis syndrome (SPS). In this review, we reflect on the current understanding of SPs with respect to terminology, detection, resection, and surveillance and reflect on the management of SPS.

AGA Clinical Practice Update on Appropriate and Tailored Polypectomy: Expert Review.

DESCRIPTION: In this Clinical Practice Update (CPU), we provide guidance on the appropriate use of different polypectomy techniques. We focus on polyps <2 cm in size that are most commonly encountered by the practicing endoscopist, including use of classification systems to characterize polyps and various polypectomy methods. We review characteristics of polyps that require complex polypectomy techniques and provide guidance on which types of polyps require more advanced management by a therapeutic endoscopist or surgeon. This CPU does not provide a detailed review of complex polypectomy techniques, such as endoscopic submucosal dissection, which should only be performed by endoscopists with advanced training. METHODS: This expert review was commissioned and approved by the American Gastroenterological Association (AGA) Institute CPU Committee and the AGA Governing Board to provide timely guidance on a topic of high clinical importance to the AGA membership, and underwent internal peer review by the CPU Committee and external peer review through standard procedures of Clinical Gastroenterology and Hepatology. These Best Practice Advice statements were drawn from a review of the published literature and from expert opinion. Because systematic reviews were not performed, these Best Practice Advice statements do not carry formal ratings regarding the quality of evidence or strength of the presented considerations. BEST PRACTICE ADVICE 1: A structured visual assessment using high-definition white light and/or electronic chromoendoscopy and with photodocumentation should be conducted for all polyps found during routine colonoscopy. Closely inspect colorectal polyps for features of submucosally invasive cancer. BEST PRACTICE ADVICE 2: Use cold snare polypectomy for polyps <10 mm in size. Cold forceps polypectomy can alternatively be used for 1- to 3-mm polyps where cold snare polypectomy is technically difficult. BEST PRACTICE ADVICE 3: Do not use hot forceps polypectomy. BEST PRACTICE ADVICE 4: Clinicians should be familiar with various techniques, such as cold and hot snare polypectomy and endoscopic mucosal resection, to ensure effective, safe, and optimal resection of intermediate-size polyps (10-19 mm). BEST PRACTICE ADVICE 5: Consider using lifting agents or underwater endoscopic mucosal resection for removal of sessile polyps 10-19 mm in size. BEST PRACTICE ADVICE 6: Serrated polyps should be resected using cold resection techniques. Submucosal injection may be helpful for polyps >10 mm if margins cannot be well delineated. BEST PRACTICE ADVICE 7: Use hot snare polypectomy to remove pedunculated lesions >10 mm in size. BEST PRACTICE ADVICE 8: Do not routinely use clips to close resection sites for polyps <20 mm. BEST PRACTICE ADVICE 9: Refer patients with polyps to endoscopic referral centers in the context of size ≥20 mm, challenging polypectomy location, or recurrent polyp at a prior polypectomy site. BEST PRACTICE ADVICE 10: Tattoo lesions that may need future localization at endoscopy or surgery. Tattoos should be placed in a location that will not interfere with subsequent attempts at endoscopic resection. BEST PRACTICE ADVICE 11: Refer patients with nonpedunculated polyps with clear evidence of submucosally invasive cancer for surgical evaluation. BEST PRACTICE ADVICE 12: Understand the endoscopy suite's electrosurgical generator settings appropriate for polypectomy or postpolypectomy thermal techniques.

Effect of Real-Time Computer-Aided Polyp Detection System (ENDO-AID) on Adenoma Detection in Endoscopists-in-Training: A Randomized Trial.

BACKGROUND: The effect of computer-aided polyp detection (CADe) on adenoma detection rate (ADR) among endoscopists-in-training remains unknown. METHODS: We performed a single-blind, parallel-group, randomized controlled trial in Hong Kong between April 2021 and July 2022 (NCT04838951). Eligible subjects undergoing screening/surveillance/diagnostic colonoscopies were randomized 1:1 to receive colonoscopies with CADe (ENDO-AID[OIP-1]) or not (control) during withdrawal. Procedures were performed by endoscopists-in-training with <500 procedures and <3 years' experience. Randomization was stratified by patient age, sex, and endoscopist experience (beginner vs intermediate level, <200 vs 200-500 procedures). Image enhancement and distal attachment devices were disallowed. Subjects with incomplete colonoscopies or inadequate bowel preparation were excluded. Treatment allocation was blinded to outcome assessors. The primary outcome was ADR. Secondary outcomes were ADR for different adenoma sizes and locations, mean number of adenomas, and non-neoplastic resection rate. RESULTS: A total of 386 and 380 subjects were randomized to CADe and control groups, respectively. The overall ADR was significantly higher in the CADe group than in the control group (57.5% vs 44.5%; adjusted relative risk, 1.41; 95% CI, 1.17-1.72; P < .001). The ADRs for <5 mm (40.4% vs 25.0%) and 5- to 10-mm adenomas (36.8% vs 29.2%) were higher in the CADe group. The ADRs were higher in the CADe group in both the right colon (42.0% vs 30.8%) and left colon (34.5% vs 27.6%), but there was no significant difference in advanced ADR. The ADRs were higher in the CADe group among beginner (60.0% vs 41.9%) and intermediate-level (56.5% vs 45.5%) endoscopists. Mean number of adenomas (1.48 vs 0.86) and non-neoplastic resection rate (52.1% vs 35.0%) were higher in the CADe group. CONCLUSIONS: Among endoscopists-in-training, the use of CADe during colonoscopies was associated with increased overall ADR. (ClinicalTrials.gov, Number: NCT04838951).

Inorganic polyphosphate: from basic research to diagnostic and therapeutic opportunities in ALS/FTD.

Inorganic polyphosphate (polyP) is a simple, negatively charged biopolymer with chain lengths ranging from just a few to over a thousand ortho-phosphate (Pi) residues. polyP is detected in every cell type across all organisms in nature thus far analyzed. Despite its structural simplicity, polyP has been shown to play important roles in a remarkably broad spectrum of biological processes, including blood coagulation, bone mineralization and inflammation. Furthermore, polyP has been implicated in brain function and the neurodegenerative diseases amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer's disease and Parkinson's disease. In this review, we first address the challenges associated with identifying mammalian polyP metabolizing enzymes, such as Nudt3, and quantifying polyP levels in brain tissue, cultured neural cells and cerebrospinal fluid. Subsequently, we focus on recent studies that unveil how the excessive release of polyP by human and mouse ALS/FTD astrocytes contributes to these devastating diseases by inducing hyperexcitability, leading to motoneuron death. Potential implications of elevated polyP levels in ALS/FTD patients for innovative diagnostic and therapeutic approaches are explored. It is emphasized, however, that caution is required in targeting polyP in the brain due to its diverse physiological functions, serving as an energy source, a chelator for divalent cations and a scaffold for amyloidogenic proteins. Reducing polyP levels, especially in neurons, might thus have adverse effects in brain functioning. Finally, we discuss how activated mast cells and platelets also can significantly contribute to ALS progression, as they can massively release polyP.

The Role of Tumor Location on Endoscopic and Surgical Management of Malignant Colon Polyps.

BACKGROUND: Endoscopic polypectomy could be an appropriate, definitive treatment for pathologic T1 (pT1) colon polyps without high-risk features. Prior studies suggested worse prognosis for proximal versus distal advanced-stage colon cancers following curative treatment. However, there is limited evidence on the prognostic impact of tumor location for pT1s. PATIENTS AND METHODS: This was a retrospective cohort study using the Surveillance, Epidemiology, and End Results database to identify adults with T1NxMx or T1N0-3M0/x colon adenocarcinoma from 2000 to 2019. RESULTS: A total of 3398 patients underwent endoscopic polypectomy (17% proximal) and 28,334 had a partial colectomy (49% proximal) for pT1 adenocarcinoma. Following endoscopic polypectomy, 5-year overall and cancer-specific survival rates were 64% and 91% for proximal versus 83% and 96% for distal polyps, compared with 82% and 95% for proximal versus 88% and 97% for distal tumors after colectomy. In multivariable models, there was a greater difference in overall survival between proximal and distal polyps for those who underwent endoscopic versus surgical resection [hazard ratio (HR) 1.73, 95% confidence interval (CI) 1.49-2.02 vs. HR 1.13, 95% CI 1.08-1.18]. Patients with proximal versus distal polyps who underwent polypectomy also exhibited increased cancer-specific mortality (HR 1.94, 95% CI 1.37-2.75). However, cancer-specific survival variations based on tumor location were no longer observed in patients undergoing partial colectomy (HR 1.09, 95% CI 0.98-1.21). CONCLUSIONS: Proximal tumor location was independently associated with worse overall and cancer-specific survival following endoscopic polypectomy. However, after colectomy, the cancer-specific disparity based on tumor laterality was mitigated. These findings suggest that proximal location may be considered a high-risk feature in endoscopic polypectomy.

Nonlinear correlation between serum vitamin D levels and the incidence of endometrial polyps in infertile women.

STUDY QUESTION: Are serum vitamin D levels associated with the incidence of endometrial polyps (EPs) in infertile patients? SUMMARY ANSWER: Serum 25(OH)D levels were nonlinearly correlated with the incidence of EPs in infertile women. WHAT IS KNOWN ALREADY: EPs are a common condition that may affect the receptivity of the endometrium in women of reproductive age. Vitamin D regulates cell proliferation and differentiation, apoptosis, angiogenesis, anti-inflammation, and immunomodulation, in addition to its well-known functions in balancing calcium and phosphorus. Previous studies have shown that vitamin D concentrations are associated with reproductive outcomes, and that low vitamin D levels are associated with the incidence of colorectal polyps and nasal polyps. There is little evidence regarding the relationship between EPs and serum vitamin D levels. STUDY DESIGN, SIZE, DURATION: We conducted a cross-sectional study using data from Guangdong Women and Children Hospital from January 2019 to October 2023, enrolling 3107 patients. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 3107 infertile patients who underwent hysteroscopy were included in this study; 642 patients had endometrial polyps and 2465 had a normal uterine cavity. Hysteroscopy findings included risk of EPs, polyp size, percentage of multiple polyps, and incidence of chronic endometritis (CE). Serum vitamin D were assessed by measuring total 25(OH)D using chemiluminescence. According to international guideline recommendations for vitamin D deficiency, patients were divided into two groups: the <50 nmol/l group and the ≥50 nmol/l group. Univariable and multivariable logistic regression models, stratified analyses, and smooth curve fitting were used to examine the relationship between serum 25(OH)D levels and risk of EPs. MAIN RESULTS AND THE ROLE OF CHANCE: Of all patients, 23.8% (740/3107) were vitamin D deficient (<50 nmol/l). The incidence of EPs was significantly higher in the 25(OH)D < 50 nmol/l group than in the ≥50 nmol/l group (24.9% vs 19.3%; P = 0.001). However, there were no differences in polyp size, proportion of multiple polyps, and presence of CE between the two groups. After controlling for confounders, 25(OH)D ≥ 50 nmol/l (compared with <50 nmol/l) was negatively associated with risk of EPs (adjusted OR, 0.733; 95% CI, 0.598-0.898). Other variables that had an impact on polyp incidence included BMI, type of infertility, CA125, and CD138-positive plasma cells. In addition, a linear regression model between age and serum 25(OH)D levels showed a positive linear association. Subgroup analyses were performed for different age groups, and the risk of EPs was significantly higher in the 25(OH)D < 50 nmol/l group than in the ≥50 nmol/l group, both in the younger subgroup (23.8% vs 19.1%) and in the older subgroup (28.0% vs 19.9%). The smooth curve fitting model showed a nonlinear correlation between 25(OH)D levels and risk of EPs (nonlinear P-value = 0.020), with an optimal threshold of 51.8 nmol/l for 25(OH)D levels. Moreover, subgroup smooth curve fitting models showed a nonlinear correlation between 25(OH)D levels and polyp risk in patients aged <35 years (nonlinear P-value = 0.010), whereas a linear correlation between 25(OH)D levels and polyp risk was found in patients aged ≥35 years (nonlinear P-value = 0.682). LIMITATIONS, REASONS FOR CAUTION: Caution should be exercised in interpreting our findings as this is a correlational study and causality cannot be inferred from our results. In addition, because of strict inclusion and exclusion criteria, our results may not be generalizable to unselected populations, including premenopausal women or women of other races. WIDER IMPLICATIONS OF THE FINDINGS: This study demonstrated for the first time that vitamin D deficiency is an independent risk factor for the incidence of EPs in infertile patients. Identifying modifiable risk factors (e.g. vitamin D deficiency) can help in the development of new strategies for treating polyps or to protect against polyp development. Further clinical intervention trials and laboratory studies are needed to evaluate the effect of vitamin D on the development of EPs and to elucidate the mechanisms. STUDY FUNDING/COMPETING INTEREST(S): The study was funded by the National Natural Science Foundation of China (82101718) and Natural Science Foundation of Guangdong Province, China (2022A1515010776). No competing interest was involved in this study. TRIAL REGISTRATION NUMBER: N/A.

A deep learning approach to case prioritisation of colorectal biopsies.

AIMS: To create and validate a weakly supervised artificial intelligence (AI) model for detection of abnormal colorectal histology, including dysplasia and cancer, and prioritise biopsies according to clinical significance (severity of diagnosis). MATERIALS AND METHODS: Triagnexia Colorectal, a weakly supervised deep learning model, was developed for the classification of colorectal samples from haematoxylin and eosin (H&E)-stained whole slide images. The model was trained on 24 983 digitised images and assessed by multiple pathologists in a simulated digital pathology environment. The AI application was implemented as part of a point and click graphical user interface to streamline decision-making. Pathologists assessed the accuracy of the AI tool, its value, ease of use and integration into the digital pathology workflow. RESULTS: Validation of the model was conducted on two cohorts: the first, on 100 single-slide cases, achieved micro-average model specificity of 0.984, micro-average model sensitivity of 0.949 and micro-average model F1 score of 0.949 across all classes. A secondary multi-institutional validation cohort, of 101 single-slide cases, achieved micro-average model specificity of 0.978, micro-average model sensitivity of 0.931 and micro-average model F1 score of 0.931 across all classes. Pathologists reflected their positive impressions on the overall accuracy of the AI in detecting colorectal pathology abnormalities. CONCLUSIONS: We have developed a high-performing colorectal biopsy AI triage model that can be integrated into a routine digital pathology workflow to assist pathologists in prioritising cases and identifying cases with dysplasia/cancer versus non-neoplastic biopsies.

Sedated Colonoscopy may not be Beneficial for Polyp/Adenoma Detection.

BACKGROUND: Sedated colonoscopy has been increasingly selected. However, the effect of sedated colonoscopy on polyp/adenoma detection rate (PDR/ADR) remains controversial among studies. METHODS: In this retrospective study, the medical records of 11 504 consecutive patients who underwent colonoscopy at our department from July 1, 2021 to December 31, 2022 were collected. Patients were divided into sedated and unsedated groups according to the use of intravenous sedation during colonoscopy. Overall PDR/ADR, right-side, transverse, and left-side colon PDR/ADR, and single and multiple PDR/ADR were calculated. By adjusting for age, gender, body mass index, inpatient, screening/surveillance, cecal intubation time, colonoscopy withdrawal time ≥6 min, and an endoscopist's experience ≥5 years, multivariate logistic regression analyses were performed to evaluate the association of sedated colonoscopy with overall PDR/ADR, right-side, transverse, and left-side colon PDR/ADR, and single and multiple PDR/ADR, where the absence of PDR/ADR was used as reference. Odds ratios (ORs) with their 95% confidence intervals (CIs) were calculated. RESULTS: Overall, 2275 patients were included, of whom 293 and 1982 underwent sedated and unsedated colonoscopy, respectively. Multivariate logistic regression analyses showed that sedated colonoscopy was independently associated with lower overall PDR/ADR (OR = 0.640, 95% CI = 0.460-0.889, P = 0.008), right-side colon PDR/ADR (OR = 0.591, 95% CI = 0.417-0.837, P = 0.003), single PDR/ADR (OR = 0.659, 95% CI = 0.436-0.996, P = 0.048), and multiple PDR/ADR (OR = 0.586, 95% CI = 0.402-0.855, P = 0.005), but not transverse or left-side colon PDR/ADR. CONCLUSION: Sedated colonoscopy may not be beneficial in terms of overall PDR/ADR, right-side colon PDR/ADR, and number of polyps/adenomas. Thus, it should be selectively recommended. Additionally, it should be necessary to explore how to improve the quality of sedated colonoscopy.

Local recurrence rates after resection of large colorectal serrated lesions with or without margin thermal ablation.

INTRODUCTION: Serrated lesions (SLs) including traditional serrated adenomas (TSA), large hyperplastic polyps (HP) and sessile serrated lesions (SSLs) are associated with high incomplete resection rates. Margin ablation combined with EMR (EMR-T) has become routine to reduce local recurrence while cold snare polypectomy (CSP) is becoming recognized as equally effective for large SLs. Our aim was to evaluate local recurrence rates (LRR) and the use of margin ablation in preventing recurrence in a retrospective cohort study. METHODS: Patients undergoing resection of ≥15 mm colorectal SLs from 2010-2022 were identified through a pathology database and electronic medical records search. Hereditary CRC syndromes, first follow-up > 18 months or no follow-up, surgical resection were excluded. Primary outcome was LRRs (either histologic or visual) during the first 18-month follow-up. Secondary outcomes were LRRs according to size, and resection technique. RESULTS: 191 polyps in 170 patients were resected (59.8% women; mean age, 65 years). The mean size of polyps was 22.4 mm, with 107 (56.0%) ≥20 mm. 99 polyps were resected with EMR, 39 with EMR-T, and 26 with CSP. Mean first surveillance was 8.2 mo. Overall LRR was 18.8% (36/191) (16.8% for ≥20 mm, 17.9% for ≥30 mm). LRR was significantly lower after EMR-T when compared with EMR (5.1% vs. 23.2%; p = 0.013) or CSP (5.1% vs. 23.1%; p = 0.031). There was no difference in LRR between EMR without margin ablation and CSP (p = 0.987). CONCLUSION: The local recurrence rate for SLs ≥15 mm is high with 18.8% overall recurrence. EMR with thermal ablation of the margins is superior to both no ablation and CSP in reducing LRRs.

Hyperplastic polyp-like adenoma: a subtype of colonic adenoma with a proliferative zone confined to the lower two-thirds of the crypt.

BACKGROUND: The proliferative zone of colonic adenomas is confined to the upper third of the crypt or is scattered along its entire axis. In contrast, there are unusual adenomas with proliferative zones confined to the lower two-thirds of the crypt. We investigated the frequency and endoscopic features of adenomas with lower proliferative zones. METHODS: We retrospectively reviewed consecutive patients who underwent colonoscopies between September 2022 and March 2023 at the Toyoshima Endoscopy Clinic. Colorectal polyps were endoscopically assessed using the Japan Narrow-Band Imaging Expert Team (JNET) classification. All resected polyps were histologically examined, and the proliferative zone locations were assessed in the adenomas. RESULTS: The frequency of adenomas with a lower proliferative zone was 1.8% (44/2420) in adenomas. Among these adenomas, JNET type 1 incidence was 43.2% (19/44), which was significantly higher than that in adenomas with a normal proliferative zone. Adenomas with a lower proliferative zone were diminutive (mean size: 2.5 mm) and prone to develop in the proximal colon. CONCLUSION: Colonic adenomas with proliferative zones confined to the lower two-thirds of the crypt often appear as diminutive, hyperplastic polyps.

Association between colonic adenoma size and proliferative zone in the crypt.

BACKGROUND: We previously reported unusual adenomas with proliferative zones confined to the lower two-thirds of the crypt. The proliferative zones of colorectal adenomas have three patterns: 'lower,' 'superficial' and 'entire'. This study aimed to clarify the characteristics of each adenoma pattern. METHODS: We investigated 2925 consecutive patients who underwent colonoscopy at our institute. All polyps that were removed were histologically examined using hematoxylin and eosin staining. The location of the proliferative zone was assessed for adenomas. Data were compared using Dunn's and Kruskal-Wallis tests. RESULTS: Colorectal adenomas with 'lower' proliferative zone often appeared similar to hyperplastic polyps (42.8%), and the frequency was significantly higher than that of adenomas with 'superficial' and 'entire' proliferative zones (p < 0.001). The mean sizes of adenomas were 2.4, 3.0 and 3.9 mm for 'lower,' 'superficial' and 'entire' proliferative zones, respectively. A significant gradual increase was observed. Regarding morphology, the proportion of type 0-I in adenomas with an 'entire' proliferative zone was significantly higher than that in adenomas with 'superficial' proliferative zone (p < 0.001). CONCLUSION: While colorectal adenomas develop and increase in size, the proliferative zone appears to shift upward and become scattered.