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Actinic keratosis (AK) is a common precancerous skin condition predominantly affecting older males with fair skin and significant UV exposure. The clinical significance of AK is related to its potential for malignant transformation and progression to squamous cell carcinoma (SCC). Accurate diagnosis of AK is essential for adequate treatment, evaluation of therapeutic efficacy, and mitigating the risk of developing SCC. However, clinician variability due to the subjective nature of current diagnostic tools presents significant challenges to achieving consistent and reliable AK diagnoses. Thus, there is no universally accepted standard for measuring AK.This review evaluates current methods for evaluating and diagnosing AK, focusing on clinician variability through inter- and intraobserver agreement. Eight peer-reviewed studies investigating the reliability of various approaches for AK evaluation show substantial variability in interobserver or intraobserver agreement, with most methods demonstrating only slight to moderate reliability. Some suggest that consensus discussions and simplified rating scales can modestly improve diagnostic reliability. However, remaining variability and the lack of a universally accepted standard for measuring AK underscore the need for more robust and standardized diagnostic and evaluation methods.The review emphasizes the need for improved diagnostic tools and standardized methods to enhance the accuracy and reliability of AK assessments. It also proposes applying a novel examination approach using 1,3-dihydroxyacetone (DHA) staining which may improve the visualization and identification of AK lesions. Advancements in these areas have significant potential, promising better clinical practices and patient outcomes in AK management.

Background: Persistent infection with high-risk human papillomavirus (HPV) is a significant risk factor for cervical cancer. HPV typing and cytology are conducted in women of appropriate age to assess the risk of cervical lesions and to guide the need for further diagnostic procedures such as colposcopy, cervical biopsy, or treatment. This article explores methods to predict the risks of high-grade precancerous cervical lesions based on high-risk HPV typing. Methods: We conducted a retrospective analysis of HPV typing data from 158,565 women, including 19,707 who underwent ThinPrep cytologic testing (TCT), 7,539 who had colposcopy examinations, and 4,762 who had biopsies. We evaluated the sensitivity, specificity, and risk parameters of high-grade lesions associated with high-risk HPV types. Results: (1) The overall prevalence of HPV infection was 17.89%, with the most prevalent types being HPV52 (4.44%), HPV58 (2.10%), HPV53 (1.96%), HPV81 (1.85%), HPV42 (1.75%), and HPV16 (1.44%). (2) The sensitivity and specificity of detecting high-grade lesions in TCT, colposcopy, and biopsy, based on high-risk HPV typing, demonstrated a strong linear correlation with the infection rate of each type. (3) HPV16 was confirmed to have a higher risk of CIN2 + in biopsies using a self-defined risk parameter. (4) The top five HPV types with the highest PPVs and pathogenicity risks in biopsies were HPV45, HPV16, HPV58, HPV33, and HPV18. Conclusion: In Changsha, China, HPV52, HPV58, and HPV53 were the most prevalent and contributed significantly to high-grade lesions. After adjusting for infection rates, a self-defined risk parameter was proposed as a measure of the intrinsic risks of high-grade lesions associated with high-risk HPV types. Focused monitoring of prevalent high-risk HPV types such as HPV45, HPV16, HPV58, HPV33, and HPV18, which show the highest pathogenicity risks, is recommended in our region. [ABSTRACT FROM AUTHOR]

Pancreatic intraepithelial neoplasia (PanIN) is the most common precursor lesion of pancreatic ductal adenocarcinoma (PDAC), which has poor prognosis with a short median overall survival of 6-12 months and a low 5-year survival rate of approximately 3%. It is crucial to remove PanIN lesions to prevent the development of invasive PDAC, as PDAC spreads rapidly outside the pancreas. This review aims to provide the latest knowledge on PanIN risk, pathology, cellular origin, genetic susceptibility, and diagnosis, while identifying research gaps that require further investigation in this understudied area of precancerous lesions. PanINs are classified into PanIN 1, PanIN 2, and PanIN 3, with PanIN 3 having the highest likelihood of developing into invasive PDAC. Differentiating between PanIN 2 and PanIN 3 is clinically significant. Genetic alterations found in PDAC are also present in PanIN and increase with the grade of PanIN. Imaging methods alone are insufficient for distinguishing PanIN, necessitating the use of genetic and molecular tests for identification. In addition, metabolomics technologies and miRNAs are playing an increasingly important role in the field of cancer diagnosis, offering more possibilities for efficient identification of PanIN. Although detecting and stratifying the risk of PanIN poses challenges, the combined utilization of imaging, genetics, and metabolomics holds promise for improving patient survival in this field. [ABSTRACT FROM AUTHOR]

Background: Cervical screening, aimed at detecting precancerous lesions and preventing cancer, is based on cytology and HPV testing. Both methods have limitations, the main ones being the variable diagnostic sensitivity of cytology and the moderate specificity of HPV testing. Various molecular biomarkers are proposed in recent years to improve cervical cancer management, including a number of mRNAs encoded by human genes involved in carcinogenesis. Many scientific papers have shown that the expression patterns of cellular mRNAs reflect the severity of the lesion, and their analysis in cervical smears may outperform HPV testing in terms of diagnostic specificity. However, such analysis has not yet been implemented in broad clinical practice. Our aim was to devise an assay detecting severe cervical lesions (≥HSIL) via analysis of cellular mRNA expression in cytological smears. Methods: Through logistic regression analysis of a reverse-transcription quantitative PCR (RT-qPCR) dataset generated from analysis of six mRNAs in 167 cervical smears with various cytological diagnoses, we generated a family of linear classifiers based on paired mRNA concentration ratios. Each classifier outputs a dimensionless decision function (DF) value that increases with lesion severity. Additionally, in the same specimens, the HPV genotyping, viral load assessment, diagnosis of cervicovaginal microbiome imbalance and profiling of some relevant mRNAs and miRNAs were performed by qPCR-based methods. Results: The best classifiers were obtained with pairs of mRNAs whose expression changes in opposite directions during lesion progression. With this approach based on a five-mRNA combination (CDKN2A , MAL , TMPRSS4 , CRNN , and ECM1), we generated a classifier having ROC AUC 0.935, diagnostic sensitivity 89.7%, and specificity 87.6% for ≥HSIL detection. Based on this classifier, a two-tube RT-qPCR based assay was developed and it confirmed the preliminary characteristics on 120 cervical smears from the test sample. DF values weakly correlated with HPV loads and cervicovaginal microbiome imbalance, thus being independent markers of ≥HSIL risk. Conclusion: Thus, we propose a high-throughput method for detecting ≥HSIL cervical lesions by RT-qPCR analysis of several cellular mRNAs. The method is suitable for the analysis of cervical cytological smears prepared by a routine method. Further clinical validation is necessary to clarify its clinical potential. [ABSTRACT FROM AUTHOR]

Introduction: The current understanding of colorectal carcinogenesis is based on the adenoma-carcinoma sequence, where genetics, intestinal microbiota changes and local immunity shifts seem to play the key roles. Despite the emerging evidence of dysbiotic intestinal state and immune-cell infiltration changes in patients with colorectal adenocarcinoma, early and advanced adenoma as precursors of colorectal cancer, and carcinoma in situ as the following progression, are rather less studied. The newly colon-site adapted AI-based analysis of immune infiltrates is able to predict long-term outcomes of colon carcinoma. Though it could also facilitate the pathologic evaluation of precancerous lesion's potential to progress. Therefore, the purpose of this prospective cohort study (MIMICA-1) is, firstly, to identify the intestinal microbiota and immune infiltration patterns around the normal bowel tissue, early and advanced adenoma, carcinoma in situ, and adenocarcinoma, and secondly, to analyze the immune – microbiome interplay along the steps of conventional colorectal tumorigenesis. Methods and analyses: This study aims to prospectively recruit 40 patients (10 per group) with confirmed colorectal dysplasia undergoing endoscopic polypectomy, endoscopic mucosal resection for colorectal small (≤1cm), and large (>1cm) adenoma or carcinoma in situ, or biopsy and subsequent colon resection for invasive colorectal cancer, and 10 healthy patients undergoing screening colonoscopy. Stool samples will be collected prior to bowel preparation for the analysis of fecal (luminal) microbiota composition. Biopsy specimens will be taken from the terminal ileum, right colon, left colon, and a pathological lesion in the colon (if present) to assess mucosa-associated microbiota composition and intestinal immunity response. DNA will be extracted from all samples and sequenced using the Illumina MiSeq platform. Unifrac and Bray-Curtis methods will be used to assess microbial diversity. The intestinal immune system response will be examined using digital image analysis where primarily immunohistochemistry procedures for CD3, CD8, CD20 and CD68 immune cell markers will be performed. Thereafter, the count, density and distribution of immunocompetent cells in epithelial and stromal tissue compartments will be evaluated using AI-based platform. The interaction between the microbial shifts and intestinal immune system response in adenoma-carcinoma sequence and the healthy patients will be examined. In addition, fecal samples will be explored for gut microbiota's composition, comparing fecal- and tissue-derived bacterial patterns in healthy gut and along the adenoma-carcinoma sequence. Discussion: We hypothesize that changes within the human gut microbiota led to detectable alterations of the local immune response and correlate with the progression from normal mucosa to colorectal adenoma and invasive carcinoma. It is expectable to find more severe gut immune infiltration at dysplasia site, though analyzing invasive colorectal cancer we expect to detect broader mucosa-associated and luminal microbiota changes with subsequent local immune response at near-lesion site and possibly throughout the entire colon. We believe that specific compositional differences detected around premalignant colorectal lesions are critically important for its primary role in initiation and acceleration of colorectal carcinogenesis. Thus, these microbial patterns could potentially supplement fecal immunohistochemical tests for the early non-invasive detection of colorectal adenoma. Moreover, AI-based analysis of immune infiltrates could become additional diagnostic and prognostic tool in precancerous lesions prior to the development of colorectal cancer. Registration: The study is registered at the Australian New Zealand Clinical Trials Registry (ACTRN12624000976583) https://www.anzctr.org.au/. [ABSTRACT FROM AUTHOR]

Endoscopy is vital for detecting and diagnosing gastrointestinal diseases. Systematic examination protocols are key to enhancing detection, particularly for the early identification of premalignant conditions. Publicly available endoscopy image databases are crucial for machine learning research, yet challenges persist, particularly in identifying upper gastrointestinal anatomical landmarks to ensure effective and precise endoscopic procedures. However, many existing datasets have inconsistent labeling and limited accessibility, leading to biased models and reduced generalizability. This paper introduces GastroHUN, an open dataset documenting stomach screening procedures based on a systematic protocol. GastroHUN includes 8,834 images from 387 patients and 4,729 labeled video sequences, all annotated by four experts. The dataset covers 22 anatomical landmarks in the stomach and includes an additional category for unqualified images, making it a valuable resource for AI model development. By providing a robust public dataset and baseline deep learning models for image and sequence classification, GastroHUN serves as a benchmark for future research and aids in the development of more effective algorithms. [ABSTRACT FROM AUTHOR]

Objective: To compare the performance of cytology, HPV16/18 genotyping and PAX1/SOX1 methylation for the triage of high‐risk HPV‐positive cervical samples. Design: Retrospective analyses of archival samples collected from a large‐scale prospective randomised controlled trial. Setting/Sample: HPV‐positive women recruited from the general cervical screening population. Methods: 403 HPV‐positive samples including 113 normal, 173 low‐grade cervical intraepithelial neoplasia (LG‐CIN), 114 HG‐CIN and three cervical cancers. All samples were assessed by liquid‐based cytology, HPV genotyping and PAX1/SOX1 methylation. Main Outcome Measures: AUC (area under the curve), sensitivity and specificity for cytology, HPV16/18 genotyping and PAX1/SOX1 methylation for high‐grade (HG) premalignant cervical lesions. Results: PAX1 was more sensitive than cytology and HPV16/18 genotyping in detecting a HG lesion (CIN2+). The sensitivity for PAX1, SOX1, cytology and HPV16/18 were 73.5% (95% CI: 65.5–81.5), 41.9% (95% CI: 32.9–50.8), 48.7% (95% CI: 39.7–57.8) and 36.8% (95% CI: 28.0–45.5), respectively, and their respective specificities were 70.3% (95% CI: 65.0–75.6), 83.6% (95% CI: 79.3–87.9), 77.6% (95% CI: 72.8–82.5) and 67.1% (95% CI: 61.7–72.6), respectively. Overall, PAX1 gave the best AUC at 0.72. Adding SOX1 to PAX1 did not improve the AUC (0.68). Three hundred and twenty‐two women who did not have a HG lesion at baseline were followed up for two rounds of screening. Fewer women developed a HG lesion with a normal baseline PAX1 compared to women with a normal baseline cytology or negative HPV16/18 (8.4% vs. 14.5% and 17.5%, respectively). Conclusion: PAX1 triage for referral to colposcopy in HPV‐positive women may be superior to cytology and HPV16/18 genotyping. [ABSTRACT FROM AUTHOR]

Cervical cancer remains a major global health concern, with a specially alarming incidence in younger women. Traditional detection techniques such as the Pap smear and colposcopy often lack sensitivity and specificity and are highly dependent on the experience of the gynaecologist. In response, this study proposes the use of Hyperspectral Imaging, a pioneering technology that combines traditional imaging with spectroscopy to provide detailed spatial and spectral information. Over a period of six-months, our custom-designed hyperspectral colposcope was used on 62 patients. The gathered data underwent a specialized preprocessing workflow using a PCA-based strategy for unsupervised segmentation of the cervical region. This process extracted spectral signatures from various tissue types, and our subsequent statistical analysis highlighted its ability to detect differences and alterations in the cervical tissue. This offers a promising avenue for improving the precision of cervical lesion diagnosis. [ABSTRACT FROM AUTHOR]

Introduction: India ranks second in the total incidence of oral cancer. The purpose of the present study is to identify the predictive risk factors for potentially premalignant oral mucosal lesions among a vulnerable Indigenous community in Bhopal. Materials and Methods: A cross-sectional study design with a prevalidated questionnaire including the demographic characteristics, tobacco usage, and other predictive risk factors was used to survey subjects aged between 15 and 75 years, both males and females of the Gond community in the Bhopal division. Type III Oral examination was conducted to determine oral mucosal changes. Statistical Analysis: Descriptive statistics were done to estimate the prevalence of oral premalignant mucosal lesions (OPMLs) and the demographic characteristics of participants. Chi-square statistics was employed to analyze the association between predictive risk factors and with the prevalence of oral premalignant lesions. Linear logistic regression was done to correlate the significance of predictive risk factors of OPMLs. P ≤ 0.05 was considered statistically significant. Results: A statistically significant association for OPMLs was observed with tobacco use, alcohol, and tobacco with alcohol usage and gender (P = 0.00). OPMLs do not show any significant association with trauma, oral ulcers, or dentures (P ≥ 0.05). The most common lesion identified was leukoplakia (39.1%), followed by Oral sub mucous fibrosis (33.33%) and both (16.66%). Lesions were most commonly seen on the buccal mucosa (60.3%), followed by the tongue (21.8%) and alveolar ridge/gingiva (9.6%). Logistic regression of predictive risk factors showed a significant correlation of OPMLs with smokeless, smoking, alcohol, and tobacco with alcohol usage. Conclusion: There is a higher burden of OPMLs and increased tobacco consumption observed in the Gond community residing in the rural areas of Bhopal. The increased burden of tobacco usage and oral mucosal lesions needs to be addressed, and interventions, including tobacco cessation counseling and awareness of oral hygiene practices, should be made feasible for the problem. [ABSTRACT FROM AUTHOR]

The incidence rate of cervical cancer (CC) is three times greater in Southeast Asia (SEA), where screening tests are less common than in Northern America, underlining a need for convenient self-diagnostic methods. The expression pattern of microRNAs (miRNAs) has been considered a molecular tool for non-invasive cancer diagnosis and prognosis. This study aimed at the development of the first miRNA biomarker panel for early detection of CC in Thai women. Genome-wide miRNA expression profiling was performed on cervical tissue and discharge samples from high-grade squamous intraepithelial lesion (HSIL) and adenocarcinoma in situ (AIS) subjects. Machine learning was used for handling imbalanced data and feature selection before differential expression analysis to identify significantly dysregulated miRNA panels. Pathway analysis was conducted to provide the cellular functions involved in CC progression. The study identified a shared 18-miRNA panel for both tissue and discharge, with which the prediction model distinguished HSIL and AIS from normal samples with an accuracy of 90.9%. Three dysregulated miRNAs comprised of miR-125b-1-3p, miR-487b-3p, and miR-1180-3p in CC were first described. Most of the miRNAs in the panel were down-regulated, whereas merely miR-142-3p was significantly up-regulated in HSIL and AIS, suggesting a convenient biomarker for detecting precancerous conditions. Moreover, our miRNA panel highlighted important roles played by the cell-cell interaction pathways in CC. Together, our miRNA panel hold promise as a biomarker for the early detection of cervical cancer with cervical discharge, offering the possibility for developing non-invasive diagnostic tools. [ABSTRACT FROM AUTHOR]

The continuous rise in skin cancer incidence highlights an imperative for improved skin cancer prevention. Topical calcipotriol-plus-5-fluorouracil (calcipotriol-plus-5-FU) immunotherapy effectively eliminates precancerous skin lesions and prevents squamous cell carcinoma (SCC) in patients. However, its mechanism of action remains unclear. Herein, we demonstrate that calcipotriol-plus-5-FU immunotherapy induces T helper type 2 (Th2) immunity, eliminating premalignant keratinocytes in humans. CD4+ Th2 cells were required and were sufficient downstream of thymic stromal lymphopoietin cytokine induction by calcipotriol to suppress skin cancer development. Th2-associated cytokines induced IL-24 expression in cancer cells, resulting in toxic autophagy and anoikis followed by apoptosis. Calcipotriol-plus-5-FU immunotherapy was dependent on IL-24 to suppress skin carcinogenesis in vivo. Collectively, our findings establish a critical role for Th2 immunity in cancer immunoprevention and highlight the Th2/IL-24 axis as an innovative target for skin cancer prevention and therapy. [ABSTRACT FROM AUTHOR]

Background: Colorectal cancer (CRC) claims 900,000 lives per year. Colonoscopy offers reliable detection, but with low patient adherence rates. To significantly reduce CRC incidence and mortality, a more convenient screening measure for advanced precancerous lesions (APL) and CRC is urgently needed. Methods: In this study, the clinical performance of a multitarget stool DNA (mt-sDNA) test combining fecal immunochemical test (FIT) with the analysis of genetic biomarkers by real-time PCR was evaluated in a cohort of 208 subjects. Results: The mt-sDNA test showed a sensitivity of 84.2% for CRC (all stages) and 39.6% sensitivity for APL detection with a specificity of 91.5%. Within the APL group, high-grade dysplasia, characterized by the highest risk of further cancer progression, were detected with 75% sensitivity. Conclusions: The mt-sDNA test represents a significant advancement for non-invasive detection of APL and CRC and bears great potential to enhance CRC prevention, incidence, and mortality. [ABSTRACT FROM AUTHOR]

Surveillance recommendations for gastric cancer (GC) in current guidelines focused on advanced precancerous lesions and were based on precise diagnosis of severity/extent of baseline lesions. We aimed to develop a less endoscopy-related equipment-dependent risk-stratification tool, and assessed whether mild-precursor-lesion patients can be safely exempt from surveillance. In the multicenter community-based cohort, 75,051 participants receiving baseline endoscopy were enrolled during 2015–2017 and followed-up until 2021. Cumulative incidence rates (CIRs) of GC for precancerous-conditions were calculated by Kaplan-Meier method and compared by Log-rank tests. Mixed-effects Cox regression models were used to detect potential factors for progression towards GC. A risk score was calculated as counts of selected factors. An independent cohort, including 26,586 participants was used for external validation. During a median follow-up of 6.25 years, CIRs of GC were 0.302%, 0.436%, and 4.756% for normal group, non-neoplastic (atrophic gastritis/intestinal metaplasia) and neoplastic lesions (low-grade/high-grade dysplasia), respectively (Ptrend<0.001). Four predictors, including male, ⩾60 years, smoking, and limited vegetable consumption, were selected for risk-stratification. High-risk patients (⩾3 risk factors) with non-neoplastic lesions showed higher GC risks (adjusted HR=7.73, 95%CI: 4.29–13.92), and their four-year CIR reached the one-year CIR of neoplastic lesions. Further categorizing non-neoplastic lesions by histological grade, both patients with moderate-to-severe lesions (aHR=3.07, 95%CI: 1.67–5.64) and high-risk patients with mild lesions (aHR=7.29, 95%CI: 3.58–14.86) showed higher risks. Consistent trends were observed in validation cohort. High-risk mild-precursor-lesion patients should receive surveillance within 3–5 years after baseline screening. Our study provides evidence on supplementing current guideline recommendations. [ABSTRACT FROM AUTHOR]

Background: Use of combustible cigarettes (CCs) and smokeless oral tobacco products are well documented risk factors for a variety of oral diseases. However, the potential oral health risks of using recently introduced (since about 2000) non-combustible tobacco/nicotine products (NCPs: electronic cigarettes (ECs), heated tobacco products (HTPs) and oral nicotine pouches (ONPs), remain poorly established. Methods: This review evaluates published human studies on detrimental oral health effects in people who use NCPs compared to those smoking cigarettes and those not using any tobacco/nicotine product (NU). We identified 52 studies, predominantly focusing on adults who used electronic cigarettes as an NCP. The studies exhibited significant heterogeneity regarding design, populations, endpoints and quality. Reported outcomes, based on both single and grouped endpoints were qualitatively evaluated by comparing people who use NCPs with NU and with people smoking CCs. Significant increases (indicating a worsening in oral health), significant decreases (indicating a lower level of detrimental effects) and no significant difference between groups were assigned scores of + 1, -1 and 0, respectively. Scores from studies belonging to the same single or grouped endpoints were averaged to a summary score ranging from − 1 to + 1. Results: The qualitative meta-analysis revealed that comparisons of EC versus NU groups yielded mean scores of 0.29 for pre-cancerous lesions (N = 14 observations), 0.27 for inflammatory processes (N = 83), 0.43 for oral clinical parameters (N = 93) and 0.70 for shifts in the oral microbiome (N = 10). The corresponding values for the EC versus CC group comparisons amounted to -0.33 (N = 15), -0.14 (N = 76), -0.27 (N = 78) and 0.57 (N = 7). Most studies had significant limitations regarding group sizes, duration of NCP use (mostly only a few years) and validity of self-reported exclusive NCP use. Notably, the implications of dual use (EC + CC) and prior CC use were often not adequately considered. Conclusions: The evaluated studies suggest that use of ECs is associated with relatively fewer detrimental oral health effects compared to smoking, yet oral health status remains poorer compared to not using any tobacco/nicotine products. These results have to be interpreted with caution due to a number of limitations and uncertainties in the underlying studies, particularly the potential biases and confounding factors inherent in cross-sectional study designs. [ABSTRACT FROM AUTHOR]

Few studies have demonstrated the interplay between human immunodeficiency virus (HIV), anal human papillomavirus (HPV), and anal microbiota, especially in persons living with HIV who are men who have sex with men. We, therefore, explored these interrelationships in a cohort of persons living with HIV, mainly comprising men who have sex with men. HPV genotyping using a commercial genotyping kit and ThinPrep cytology interpreted by Bethesda systems was performed on samples from 291 patients. Samples were characterized by high-throughput sequencing of dual-index barcoded 16s rRNA (V3–4). Bacterial diversity was diminished in individuals living with HIV with CD4+ T cells <500 cells/μL and anal cytology yielding atypical squamous cells of undetermined significance or higher grades (ASCUS+) with detectable HPV 16/18 compared with those with CD4+ T cells ≥500 cells/μL with ASCUS+ and HPV 16/18 and those with normal anal cytology or inflammation without HPV 16/18. Enterobacteriaceae, Ruminococcus, and Bacilli were significantly abundant in persons living with HIV with CD4+ T cells <500 cells/μL with ASCUS+ and HPV 16/18. Bacterial diversity, composition, and homogeneity of dispersion were different in individuals living with HIV with low CD4+ T cells with ASCUS+ and HPV 16/18, and understanding the interaction among immunocompromised hosts, oncogenic HPVs, and microbiota is essential, and the contribution of these factors to anal precancerous lesions needs more in-depth exploration. [ABSTRACT FROM AUTHOR]

Environmental chemicals and toxins are known to impact human health and contribute to cancer developments. Among these, genotoxins induce genetic mutations critical for cancer initiation. In the liver, proliferation serves not only as a compensatory mechanism for tissue repair but also as a potential risk factor for the progression of premalignant lesions. The role of Human Liver DnaJ-Like Protein (DNAJB4/HLJ1), a stress-responsive heat shock protein 40, in genotoxin-induced liver carcinogenesis remains unexplored. Using whole-genome transcriptomic analysis, we demonstrate that HLJ1 deficiency in mice results in altered gene signatures enriched in pathways associated with chemically induced liver cancer and IL-6/STAT3 signaling activation. Employing diethylnitrosamine (DEN) as a carcinogen, we further reveal that STAT3 and H2AX phosphorylation induced by short-term DEN treatment are amplified in HLJ1-deficient mice. In long-term DEN experiments, HLJ1 deletion enhances tumor proliferation and progression, accompanied by pronounced STAT3 phosphorylation in normal tissues rather than in tumor regions. The tumor-suppressive role of peritumoral HLJ1 is validated through the transplantation of HLJ1-wildtype B16F1 and LLC cancer cell lines into syngeneic HLJ1-deficient mice, which exhibits an augmented tumorigenic phenotype compared to wildtype controls. This study uncovers a previously unrecognized role of HLJ1 in suppressing liver carcinogenesis via the downregulation of STAT3 signaling in peritumoral normal cells. These findings suggest that HLJ1 reinforcement represents a promising strategy for liver cancer treatment and prevention. [ABSTRACT FROM AUTHOR]

In recent years, the incidence of ground-glass nodular lung adenocarcinoma has gradually increased. Preoperative evaluation of the tumor invasiveness is very important, but there is a lack of effective methods. Plasma samples of ground-glass nodular lung adenocarcinoma and healthy volunteers were collected. Pulmonary nodules with different densities were compared by metabolomics. Different invasive degrees of lung adenocarcinoma were contrasted as well. Multivariate statistical methods were applied to search for significant metabolites from comparisons between two groups. The common metabolites among the different comparisons were selected and then assessed by various indices. Five metabolites were discovered for lung adenocarcinoma with different invasive degrees. Significant metabolites were selected for pulmonary nodules with different densities as well. When these metabolites were cross-compared, only the level of lysoPC(18:3) was significantly lower in ground-glass nodular lung adenocarcinoma than healthy population, as opposed to other metabolites. After identifying the invasive degree of pulmonary ground-glass nodules, lysoPC(18:3) showed a satisfactory sensitivity and specificity, both greater than 0.85. Metabolomics analysis has favorable advantages in the study of ground-glass nodular lung adenocarcinoma. LysoPC(18:3) may have the potential to differentiate precancerous lesions from invasive lung cancer, which could help clinicians to make proper judgment before surgery. [ABSTRACT FROM AUTHOR]

Background: A ground glass nodule (GGN) is a radiologically descriptive term for a lung parenchymal area with increased attenuation and preserved bronchial and vascular structures. GGNs are further divided into pure versus subsolid lesions. The differential diagnosis for GGNs is wide and contains a malignant possibility for a lung adenocarcinoma precursor or tumor. Clinical and pathological staging of GGNs is based on the lesions' solid component and falls into a specific classification including T0 for TIS, T1mi for minimally invasive adenocarcinoma (MIA) and T1abc for lepidic predominant adenocarcinoma (LPA) according to the eighth edition of the TNM classification of lung cancer. Correlation between solid parts seen on a CT scan and the tumor pathological invasive component is not absolute. Methods: This retrospective study collected the data of 68 GGNs that were operated upon in Carmel Medical Center. A comparison between preoperative clinical staging and post-surgery pathological staging was conducted. Results: Over a third of the lesions, twenty-four (35.3%), were upstaged while only four (5.9%) lesions were downstaged. Another third of the lesions, twenty-three (33.8%), kept their stage. In three (4.4%) cases, premalignant lesion atypical adenomatous hyperplasia (AAH) was diagnosed. Ten (14.7%) cases were diagnosed as non-malignant on final pathology. These findings show an overall low agreement between the clinical and pathological stages of GGNs. Conclusions: The relatively high percentage of upstaging tumors detected in this study and the overall safe and short surgical procedure advocate for surgical resection even in the presence of a significant number of non-malignant lesions that retrospectively do not mandate intervention at all. [ABSTRACT FROM AUTHOR]

Simple Summary: Pancreatic cystic lesions (PCLs) can range from harmless growths to precursors of pancreatic cancer, making accurate diagnosis crucial for patient care. Traditional methods for managing PCLs, such as imaging and biopsies, often depend on the skill of the doctor interpreting the images, leading to variability in diagnosis and treatment. This review highlights the challenges in diagnosing and managing PCLs and discusses the potential for artificial intelligence (AI) to improve accuracy. AI techniques, such as automated image analysis and deep learning algorithms, can provide more consistent and reliable assessments of pancreatic cysts. These tools could help doctors better identify high-risk lesions that need treatment, while avoiding unnecessary procedures for benign cysts. AI-driven methods show promise in improving patient outcomes, offering earlier detection and more precise management, and ultimately helping to prevent pancreatic cancer. Pancreatic cystic lesions (PCLs) represent a spectrum of non-neoplasms and neoplasms with varying malignant potential, posing significant challenges in diagnosis and management. While some PCLs are precursors to pancreatic cancer, others remain benign, necessitating accurate differentiation for optimal patient care. Conventional approaches to PCL management rely heavily on radiographic imaging, and endoscopic ultrasound (EUS) guided fine-needle aspiration (FNA), coupled with clinical and biochemical data. However, the observer-dependent nature of image interpretation and the complex morphology of PCLs can lead to diagnostic uncertainty and variability in patient management strategies. This review critically evaluates current PCL diagnosis and surveillance practices, showing features of the different lesions and highlighting the potential limitations of conventional methods. We then explore the potential of artificial intelligence (AI) to transform PCL management. AI-driven strategies, including deep learning algorithms for automated pancreas and lesion segmentation, and radiomics for analyzing heterogeneity, can improve diagnostic accuracy and risk stratification. These advanced techniques can provide more objective and reproducible assessments, aiding clinicians in decision-making regarding follow-up intervals and surgical interventions. Early results suggest that AI-driven methods can significantly improve patient outcomes by enabling earlier detection of high-risk lesions and reducing unnecessary procedures for benign cysts. Finally, this review emphasizes that AI-driven approaches could potentially reshape the landscape of PCL management, ultimately leading to improved pancreatic cancer prevention. [ABSTRACT FROM AUTHOR]

Objective: Unusual clinical course Background: Recent studies have shown that peribiliary glands may be the potential cell origin of cholangiocarcinoma, and that precancerous lesions such as biliary intraepithelial neoplasms and intraductal papillary neoplasms of the bile duct may arise from these peribiliary glands. However, whether and how these precancerous lesions progress to cholangiocarcinoma is controversial. Case Report: Herein, an autopsy case of perihilar cholangiocarcinoma, exclusively periductal-infiltrating, is reported. Since repeated transpapillary biopsies and cytology showed no carcinoma cells, the patient was treated for sclerosing cholangitis until death. The findings at cholelithiasis treatment 1 year earlier had not aroused suspicion of the presence of precancerous lesions. The changes in the spread of bile duct stenoses on cholangiography and the unique findings at autopsy, namely (i) the distribution of cancer growing locally within the peribiliary gland compartment without invading the bile duct mucosa and (ii) the existence of in situ-like carcinoma cells replacing the epithelium of the peribiliary glands throughout the extrahepatic bile duct, suggested that cholangiocarcinoma arose from the peribiliary glands in the hilum without a detectable precancerous lesion and then spread to the lower end of the common bile duct via the peribiliary gland network. Conclusions: This case report may help further our understanding of the natural history of cholangiocarcinoma and provide clues about cholangiocarcinogenesis and progression. In addition, histological and cytological diagnosis could be theoretically difficult by sampling tissue from the bile duct lumen in cholangiocarcinoma, as in this case. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effects of Xinwei granules on the METTL16/CyclinD1 pathway and proliferation, apoptosis, and cell cycle of gastric cancer cells, and to elucidate the molecular mechanisms underlying its therapeutic potential in gastric cancer. Methods: Cell viability of the MKN-45 gastric cancer cell line was assessed using the CCK-8 assay following treatment with various concentrations of gastric-derived granules. Flow cytometry was employed to analyze apoptosis and cell cycle distribution. Western blot and RT-qPCR analyses were used to measure the expression of key molecules in the METTL16/CyclinD1 pathway. Spot hybridization was performed to detect m6A methylation modifications of CyclinD1. Results: Compared to the control group, gastric-derived granules significantly increased apoptosis in MKN-45 cells, elevated the proportion of cells in the G1 phase, reduced the proportion in the S phase, and downregulated the expression of CyclinD1, CDK4, E2F1, and METTL16 proteins as well as the p-Rb/Rb ratio (P<0.01) . Additionally, gastric-derived granules significantly decreased the mRNA expression levels of METTL16 and CyclinD1, and inhibited CyclinD1 m6A methylation modifications (P<0.01). Conclusion: Xinwei granules exert their effects by inhibiting METTL16-mediated m6A methylation of CyclinD1, thereby blocking the transition from the G1 phase to the S phase, suppressing cell proliferation, and promoting apoptosis. [ABSTRACT FROM AUTHOR]

Background: Human papillomavirus (HPV) testing of self-collected vaginal samples has potential to improve coverage of cervical screening programmes, but current guidelines mostly require those HPV positive on a self-sample to attend for routine screening. Methods and findings: A pragmatic modified stepped-wedge implementation feasibility trial was conducted at primary care practices in England. Individuals aged 25 to 64 years who were at least 6 months overdue for cervical screening could provide a self-collected sample. The primary outcomes included the monthly proportion of non-attenders screened, changes in coverage, and uptake within 90 days. Self-samples from 7,739 individuals were analysed using Roche Cobas 4800. Individuals with a positive self-sample were encouraged to attend clinical screening. In this post hoc study of the trial, we related the HPV type (HPV16, HPV18, or other high-risk type) and cycle threshold (Ct) value on the self-sample to the results of clinician-collected sample and cervical intraepithelial neoplasia grade 2 or worse (CIN2+). We wished to triage HPV–positive individuals to immediate colposcopy, clinician sampling, or 12-month recall depending on risk. A total of 1,001 women tested positive through self-samples, and 855 women who had both an HPV–positive self-sample and a subsequent clinician-sample were included in this study. Of these, 71 (8.3%) had CIN2+. Self-sample Ct values were highly predictive of HPV in the clinician sample. Combining HPV type and Ct value allowed stratification into 3 risk groups; 44/855 (5%) were high-risk of whom 43% (19/44, 95% confidence interval [29.7%, 57.8%]) had CIN2+. The majority (52.9%, 452/855) were low-risk, of whom 4% (18/452, 95% CI [2.5%, 6.2%]) had CIN2+. The main limitation of our study was the colposcopy assessment was restricted to individuals who had abnormal cytology after positive results of both self-sample and clinician-collected sample. Conclusions: HPV type and Ct value on HPV–positive self-samples may be used for triage. The difference in the risk of CIN2+ in these groups appears sufficient to justify differential clinical management. A prospective study employing such triage to evaluate laboratory workflow, acceptability, and follow-up procedure and to optimise clinical performance seems warranted. Trial Registration: ISRCTN12759467. In a post-hoc analysis of the YouScreen trial, Jiayao Lei and colleagues investigate whether HPV Ct levels and HPV types from self-samples can be used to stratify HPV-positive individuals into distinct risk groups. Author summary: Why was this study done?: Human papillomavirus (HPV) testing of self-collected vaginal samples has potential to improve coverage of cervical screening programmes, but current guidelines mostly require those HPV positive on a self-sample to attend for routine screening. The association between HPV cycle threshold (Ct) values (as a proxy for viral load), HPV genotypes, and the risk of high-grade cervical precancerous lesions and cancers has been well established. However, most of the existing studies are based on practitioner-collected cervical samples, with limited research focusing on self-collected samples. What did the researcher do and find?: We propose a stratification approach, dividing HPV–positive individuals into 3 distinct risk groups based on HPV Ct values and genotypes (HPV16, HPV18, or other high-risk type) from HPV self-samples. We classified 5% (44/855) of the individuals (HPV-16 Ct <30) who tested HPV-positive on their self-sample as high-risk, with 43.2% (19/44) of them having CIN2+, which is comparable to those referred in England with HPV positive and abnormal cytology results. The low-risk group (HPV non-16/18 Ct ≥30), comprising half of those with HPV on their self-sample have a risk of CIN2+ of 4.0% (18/452) which is lower than in those who are HPV positive but cytology normal on a routine clinician screen. What do these findings mean?: The proposed classifier allows those at greatest risk (high-risk group) to be sent directly to colposcopy and detects 3 quarters of CIN2+ without delay while allowing half of individuals (low-risk group) to be managed by repeat self-sampling. The intermediate risk group could be referred to their general practises for clinical sampling. Findings support the potential use of this risk classifier in the management of HPV–positive self-samples within organised cervical screening programmes. Limitations of the study include that the colposcopy assessment was restricted to individuals who had abnormal cytology after positive results of both self-samples and clinician-collected samples. Additionally, different HPV assays were used for primary screening and follow-up tests. [ABSTRACT FROM AUTHOR]

Aloe-emodin, an anthraquinone compound naturally derived from Rheum undulatum L., has gained extensive research attention owing to its various pharmacological effects, including its potential as an anticancer, antivirus, anti-inflammatory, antibacterial, and anti-parasitic agent. It has demonstrated notable inhibitory effects against various types of cancer and cancer cells. Prostate cancer is among the most commonly identified cancers globally and remains a leading cause of cancer-associated deaths in men, often presenting challenges in early detection due to its asymptomatic nature during initial stages. The aim of present study was to determine the biological activity of aloe-emodin obtained from Rheum undulatum L. involving activation of the p53-dependent pathway in certain human prostate cancer cell lines. We explored the mechanisms underlying the anticancer effects of aloe-emodin using LNCaP cells, which include p53-wild type and phosphatase and tensin homolog-deficient mutated genes, a widely studied model in genomic research. Aloe-emodin induced apoptosis in LNCaP cells through several mechanisms, including upregulation of the cleavage of caspase-8 (a cross-linked promoter of cell death signals), phosphorylation of p53 at serine 15, DNA fragmentation, cleavage of poly [ADP-ribose] polymerase, and promotion of cell death. These findings strongly indicated that aloe-emodin's anticancer properties in human prostate cancer involve the activation of p53-induced cellular senescence. Conclusively, the findings of this study imply that aloe-emodin extracted from Rheum undulatum L. is a potential therapeutic compound for adjuvant chemotherapy that induces apoptosis and pyroptosis, an innate immune response, in preventing the progression of precancerous lesions in patients with prostate cancer. [ABSTRACT FROM AUTHOR]

The present investigation explores into the influence of dietary nutrients, particularly alpha-linolenic acid (ALA), a plant-derived omega-3 fatty acid abundant in perilla seed oil (PSO), on the development of colitis-associated colorectal cancer (CRC). The study employs a mouse model to scrutinize the effects of ALA-rich PSO in the context of inflammation-driven CRC. Perilla seeds were subjected to oil extraction, and the nutritional composition of the obtained oil was analysed. Male ICR mice, initiated at four weeks of age, were subjected to diets comprising 5%, 10%, or 20% PSO, 10% fish oil, or 5% soybean oil. All groups, with the exception of the control group (5% soybean oil), underwent induction with azoxymethane (AOM) and dextran sulphate sodium (DSS) to instigate CRC. Disease development, colon samples, preneoplastic lesions, dysplasia, and biomarkers were meticulously evaluated. Furthermore, gut microbiota composition was elucidated through 16S rRNA sequencing. The analysis revealed that PSO contained 61.32% ALA and 783.90 mg/kg tocopherols. Mice subjected to diets comprising 5% soybean or 10% fish oil exhibited higher tumour incidence, burden, multiplicity, and aberrant crypt counts. Remarkably, these parameters were significantly reduced in mice fed a 5% PSO diet. Additionally, 5% PSO-fed mice displayed reduced proliferative and pro-inflammatory markers in colon tissues, coupled with an alleviation of AOM/DSS-induced gut dysbiosis. Notably, PSO demonstrated inhibitory effects on colitis-associated CRC in the AOM/DSS mice model, achieved through the suppression of proliferative and pro-inflammatory protein levels, and mitigation of gut dysbiosis, with discernible efficacy observed at a 5% dietary concentration. [ABSTRACT FROM AUTHOR]

Background: Inflammation is the most important deriving force for the development of colitis-associated colorectal cancer (CAC) through the Inflammation-Pretumor dysplasia-CAC sequence. T helper (Th) subsets Th9 and Th17 cells can potentially stimulate inflammation in the ulcerative colitis (UC). Therefore, Th9 and Th17 cells may play a promoting role in the colitis-associated dysplasia (CAD). Methods: Using immunohistochemistry (IHC), we evaluated the presentation patterns and densities of T lymphocytes, Th9 and Th17 cells in human UC and CAD tissues. Results: A general increasing trend of CD3-positive T lymphocytes, P.U.1-positive Th9 and interleukin (IL)-17A-positive Th17 cells was illustrated throughout the normal-UC-CAD sequence, IHC images showed that these cells were very prominent in the lamina propria, and some cells were also observed in the epithelium in the CAD tissues. Density analysis revealed that numbers of Th9 and Th17 cells were progressively increased in the CAD tissues as compared with the UC and control tissues. In general, densities of Th9 and Th17 cells in the lamina propria were slightly higher in the non-adenoma-like dysplasia (NALD) tissues than that in the adenoma-like dysplasia (ALD) tissues. However, densities of neither Th9 nor Th17 cells in both the ALD and NALD subgroups were associated with the degree of dysplasia in CAD lesions. Conclusion: Accumulated Th9 and Th17 cells contribute to the immune cellular composition in the CAD tissues and may represent the early conditional change for the Dysplasia-CAC transition. [ABSTRACT FROM AUTHOR]

Objective Methods Results Conclusion This study assessed the prevalence and factors associated with detecting cervical intraepithelial neoplasia grade 2 or higher (CIN2+) via endocervical curettage (ECC) during colposcopy.Between December 2020 and September 2023, a prospective, cross‐sectional study involving women with abnormal cervical cancer screening results who underwent colposcopy was conducted. ECC was performed via a Kevorkian endocervical curette following colposcopy‐directed biopsy. The exclusion criteria were glandular cytology abnormalities, pregnancy, post‐hysterectomy status, and cervical cancer.The study included 569 women, with a mean age of 41.6 ± 11.7 years. Among the participants, 78.9% presented with low‐grade cytology, whereas 21.1% presented with high‐grade cytology. All of the patients underwent ECC, with 0.4% (two patients) yielding inadequate samples. ECC detected CIN2+ lesions in 11.6% of the patients (95% confidence interval [CI], 9–14.3). Univariable analysis revealed that age, menopausal status, history of CIN2+, high‐grade cytology, and high‐grade colposcopy impression were significant factors for CIN2+ detection by ECC. Multivariable analysis confirmed high‐grade cytology as the sole independent factor (adjusted odds ratio [OR], 13.81 [95% CI, 4.60–41.42], P < 0.001). ECC added a diagnostic yield of 2.9% (95% CI, 1.5–4.3) for detecting CIN2+ lesions missed by colposcopy‐directed biopsy. Multivariable analysis demonstrated an independent association between human papillomavirus 16 (HPV‐16) infection and the additional diagnostic benefit of ECC, with an adjusted odds ratio (OR) of 6.26 (95% CI, 1.49–26.23, P = 0.012).This study highlights the critical role of ECC in detecting CIN2+ lesions, particularly in patients with high‐grade cytology or HPV‐16 positivity. [ABSTRACT FROM AUTHOR]