Premalignant Research Articles

The Role of Inflammatory Markers in Distinguishing Endometrial Polyp: Single Center Results

Objective: To investigate the role of inflammatory markers in predicting the presence of endometrial polyps in patients undergoing endometrial sampling due to abnormal uterine bleeding. Methods: The pathology results of patients who presented to Akçakoca State Hospital with abnormal uterine bleeding and underwent endometrial sampling between May 2023 and July 2023 were retrospectively examined. The demographic characteristics of the patients, platelet-lymphocyte, neutrophil-lymphocyte and lymphocyte-monocyte ratios and systemic immune inflammation index were calculated. Patients were categorized into endometrial polyps and other benign pathologies according to the pathological diagnosis. Malignant and premalignant lesions were not included in the study. The examination results and inflammatory markers were compared between these two groups. Results: 89 patients were included in the study. While the pathological finding in 38 patients was an endometrial polyp, other benign pathologies were found in 51 patients. No significant difference was found in terms of hemoglobin, hematocrit, lymphocytes, monocytes, platelets, neutrophils and PDW variables in patients with endometrial polyps (p>0.05). PLR (platelet-to-lymphocyte ratio) and SII (systemic immune-inflammatory index) were significantly higher in the endometrial polyp group compared to other benign pathologies (p

Could Clinically Suspicious Cervix Predict Cervical Premalignant and Malignant Lesions in Postmenopausal Women?

Could Clinically Suspicious Cervix Predict Cervical Premalignant and Malignant Lesions in Postmenopausal Women?

Endometrial Atypical Hyperplasia and Risk of Endometrial Cancer

Endometrial atypical hyperplasia (EAH) is a premalignant condition with a substantial risk of progression to endometrial cancer (EC), with the endometrioid subtype being the most common. EAH is characterized by abnormal endometrial gland proliferation and cellular atypia, often resulting from prolonged unopposed estrogen exposure. This review aims to explore the clinical significance of EAH, its risk of progression to EC, and the current approaches to management. The risk of EAH progressing to EC ranges from 20 to 50%, influenced by factors such as histopathology and genetic mutations including PTEN and KRAS. Key risk factors include obesity, polycystic ovary syndrome, and postmenopausal status. Abnormal uterine bleeding is a hallmark symptom of EAH and early-stage EC, necessitating diagnostic evaluation through endometrial biopsy and transvaginal ultrasonography. Therapeutic management strategies depend on patient risk and fertility considerations. Hormonal therapy, particularly progestins, is the mainstay for fertility preservation, while hysterectomy is preferred for higher-risk patients. Regular monitoring with biopsies is essential for those undergoing conservative treatment. Recent advancements in the management of EAH and EC have shifted towards incorporation of molecular diagnostics and targeted therapies, enabling better risk stratification and individualized care. Biomarkers and minimally invasive surgical techniques are emerging as promising approaches in improving outcomes for women with EAH. This review underscores the importance of early diagnosis and personalized management in preventing the progression of EAH to EC, highlighting current clinical practices and potential future developments in this field.

Evaluation of the Use of Methylation as a New Tool for the Diagnostics and Progression of Squamous Intraepithelial Lesions

Vaccination against human papillomavirus (HPV) significantly reduces the incidence of HPV-related lesions worldwide. Considering the increasingly young age of patients in gynecological offices and earlier sexual initiation and potential contact with the HPV virus, doctors need the tools to verify diagnoses. Currently, women plan to pursue motherhood later, so it is necessary to consider whether sexual treatment in the form of, among others, loop electrosurgical excision procedures (LEEPs) may increase the risk of premature birth or difficulty dilating the cervix during labour. For this reason, to avoid the overtreatment of low-grade squamous intraepithelial lesions (LSILs), methylation testing may be considered. In patients with histopathologically confirmed high-grade squamous intraepithelial lesions (HSILs) during biopsy and, ultimately, a lower diagnosis, i.e., LSIL or no signs of atypia, methylation was found to be a useful tool. We performed a Pap smear, HPV genotyping, a punch biopsy, LEEP-conization (if needed), and methylation tests on 108 women admitted to the District Public Hospital in Poland. Women with a negative methylation test result were significantly more likely to be ultimately diagnosed with LSIL (p = 0.013). This means that in 85.7% of the patients with HSIL, major cervical surgery could be avoided if the methylation test was negative. Methylation testing, as well as dual-staining and diagnostics detecting the mRNA transcripts of highly oncogenic types of HPV, might be used in the future in the diagnosis of pre-cancerous conditions, mainly of the cervix, and in HPV-dependent cervical cancer screening. The methylation test may also be used in the diagnosis and identification of lesions within the cervical canal, including those located deep within the frontal crypts, not visible even during a professional colposcopic evaluation of the cervix.

Precancerous Lesions of HPV-independent Vulvar Squamous Cell Carcinoma: Clinicopathologic Consideration of an Evolving Spectrum.

HPV-independent squamous cell carcinomas of the vulva comprise the majority of vulvar cancers, but their putative precancers represent only a small proportion of the vulvar squamous intraepithelial lesions that are encountered in routine practice. The precancerous lesions of HPV-independent vulvar squamous cell carcinoma encompass a spectrum of lesions that, collectively, may pose significant diagnostic challenges. Included in this spectrum are differentiated vulvar intraepithelial neoplasia [dVIN], the prototypical lesion of the group, which is characterized by a high propensity for progression, a relatively short duration to progression, frequent association with lichen sclerosus, and according to our review of the recent literature, TP53/p53 aberration in 50% to 95% (mean 77.4%) of cases. Regarding the latter, some authors consider TP53/p53 aberration to be a diagnostic requirement for dVIN, although this is controversial, as discussed further herein. Also included in the spectrum of lesions that are considered in this review are possibly related HPV-independent, p53-wild type lesions that have historically been reported as "vulvar acanthosis with altered differentiation" (VAAD), "differentiated exophytic vulvar intraepithelial lesion" (DEVIL), "verruciform lichen simplex chronicus" (vLSC), and which more recently, have collectively been described as "verruciform acanthotic vulvar intraepithelial neoplasia (vaVIN)" or "vulvar aberrant maturation (VAM)." In this review, we perform a comprehensive clinicopathologic review of putative precancerous lesions of HPV-independent squamous cell carcinomas of the vulva, with an emphasis on recent developments in terminology, practical diagnostic issues, biomarkers, and pathogenesis.

Acute non peurperal uterine inversion caused by leiomyma associated with precancerous lesions: a case report

Introduction and importance: Acute nonpuerperal uterine inversion (Acute NPUI) is a rare clinical entity that is usually associated with a polypoid uterine tumor, usually a leiomyoma, but its occurrence due to combined leiomyoma with precancerous lesions is quite exceptional. Case presentation: Here, the authors present the case of a 65-year-old woman who was diagnosed with acute NPUI as an unusual complication of prolapsed fibroid. Clinical discussion: On abdominal examination, palpation of the lower abdomen was very painful. On pelvic examination, a huge hemorrhagic mass was noticed, with necrotic areas protruding at a level 10 cm above the introitus. The cervix could not be palpated or visualized, and the uterus was difficult to appreciate on a bimanual examination due to tenderness. By transabdominal sonography, the uterus could not be clearly identified. Routine blood tests were completely normal, including hemoglobin concentrations. First of all, the authors manually replaced the inverted uterus in its normal position and then performed a total hysterectomy and a bilateral adnexectomy. Pathological findings demonstrated a leiomyoma with areas of complex hyperplasia with atypia! Conclusion: When the authors encounter a case of nonpuerperal uterine inversion, the authors must consider fibroids as the most common cause, and the authors must act quickly so that the patient does not go into neurogenic shock and die. Although leiomyoma is the most common cause of NPUI, a pathological study should be performed in all cases.

A Multicenter Cohort Study on DNA Methylation for Endometrial Cancer Detection in Cervical Scrapings.

The increasing incidence of endometrial cancer (EC) has highlighted the need for improved early detection methods. This study aimed to develop and validate a novel DNA methylation classifier, EMPap, for EC detection using cervical scrapings. EMPap incorporated the methylation status of BHLHE22 and CDO1, along with age and body mass index (BMI), into a logistic regression model to calculate the endometrial cancer methylation (EM) score for identifying EC in cervical scrapings. We enrolled 1297 patients with highly suspected EC, including 196 confirmed EC cases, and assessed the EMPap performance in detecting EC. EMPap demonstrated robust diagnostic accuracy, with an area under the curve of 0.93, sensitivity of 90.3%, and specificity of 89.3%. It effectively detected EC across various disease stages, grades, and histological subtypes, and consistently performed well across patient demographics and symptoms. EMPap correctly identified 87.5% of the type II ECs and 53.8% of premalignant lesions. Notably, compared with transvaginal ultrasonography (TVS) in patients with postmenopausal bleeding, EMPap exhibited superior sensitivity (100% vs. 82.0%) and specificity (85.2% vs. 38.5%). In asymptomatic postmenopausal women, EMPap maintained high sensitivity (89.5%) and negative predictive value (NPV) (98.3%). This study demonstrated the potential of EMPap as an effective tool for EC detection. Despite the limited sample size, EMPap showed promise for identifying type II EC and detecting over 50% of premalignant lesions. As a DNA methylation classifier, EMPap can reduce unnecessary uterine interventions and improve diagnosis and outcomes.

Isolation and Characterization of a Bacteriophage with Potential for the Control of Multidrug-Resistant Salmonella Strains Encoding Virulence Factors Associated with the Promotion of Precancerous Lesions

Background: Antimicrobial-resistant bacteria represent a serious threat to public health. Among these bacteria, Salmonella is of high priority because of its morbidity levels and its ability to induce different types of cancer. Aim: This study aimed to identify Salmonella strains encoding genes linked to the promotion of precancerous lesions and to isolate a bacteriophage to evaluate its preclinical potential against these bacteria. Methodology: An epidemiological approach based on wastewater analysis was employed to isolate Salmonella strains and detect genes associated with the induction of precancerous lesions. Antimicrobial susceptibility was assessed by the disk diffusion method. A bacteriophage was isolated via the double agar technique, and its morphological characteristics, stability, host range, replication dynamics, and ability to control Salmonella under different conditions were evaluated. The bacteriophage genome was sequenced and analyzed using bioinformatics tools. Results: Thirty-seven Salmonella strains were isolated, seventeen of which contained the five genes associated with precancerous lesions’ induction. These strains exhibited resistance to multiple antimicrobials, including fluoroquinolones. A bacteriophage from the Autographiviridae family with lytic activity against 21 bacterial strains was isolated. This phage exhibited a 20 min replication cycle, releasing 52 ± 3 virions per infected cell. It demonstrated stability and efficacy in reducing the Salmonella concentration in simulated gastrointestinal conditions, and its genome lacked genes that represent a biosafety risk. Conclusion: This bacteriophage shows promising preclinical potential as a biotherapeutic agent against Salmonella.

Lamin A and Emerin Protein Expression Remains Consistently Low and Nuclear Size is Unchanged in Normal Endometrium, Precancerous Lesions, and Endometrioid Carcinoma.

Nuclear laminar or inner nuclear membrane proteins, including lamin A, B1, and B2 and emerin, are involved in maintaining nuclear morphology. However, their expression patterns vary among tumors and remain incompletely understood. Endometrioid carcinoma (EC) exhibits mild nuclear atypia, although the underlying reasons have not been thoroughly explored. In this study, we quantitatively analyzed emerin and lamin A, B1, and B2 expression levels in normal endometrium (NE), precancerous lesions, and EC using computer-assisted image analysis to assess the proteins' roles in nuclear morphologic change during tumorigenesis. From NE to EC, nuclear size remained unchanged, and lamin A and emerin were consistently expressed at low levels, whereas lamin B1 and B2 expression gradually decreased. Given the association between lamin A and emerin as well as their roles in nuclear morphology, these results indicate that their consistent low expression may underlie the preservation of nuclear size and shape in EC relative to NE. Conversely, lamin B1 and B2 are implicated in tumor progression rather than nuclear morphology maintenance. As lamin A and emerin are expressed in many organs and tumors, the consistently low expression of these proteins from NE to EC highlights a notable feature of the endometrium and endometrial carcinogenesis.

Prevalence and predictors of precancerous cervical lesions among women living with HIV in Libreville, Gabon

BackgroundHIV-infected women are at an increased risk of developing precancerous cervical lesions (PCL) than non-infected women. In Gabon, no data exists on the prevalence of PCL among women living with HIV. The aim of this study was to assess the prevalence and risk factors associated with the development of PCL among HIV-positive women in Libreville, Gabon.MethodologiesThis was a retrospective study carried out within the Gynecology and Obstetrics Department of University Hospital Center of Libreville (CHUL) from January to August 2016. It included women registered at the HIV Clinic of Nkembo, and screened for PCL or cervical cancer (CC). Descriptive statistics were used to characterize sociodemographic data and the prevalence of PCL. The chi square and odd-ratio tests were used to evaluate the associations between PCL, CD4 count, antiretroviral use, age at first sexual intercourse, number of sexual partner tobacco, and contraception use.ResultsAmong the 115 HIV-positive women recruited, 33 (28.70%; SD ± 0.45) were diagnosed with PCL. 79.1% of them were on antiretroviral therapy (ART), and the mean CD4 cell count value was 411.74 cells/mm3 (SD ± 241.77). Being on ART, age, number of sexual partners, contraceptive use and smoking were not risk-factors linked with the development of PCL. CD4 cell count was the only associated risk-factors (p-value: 0.02).ConclusionThe incidence of PCL among HIV-infected is high in Libreville, Gabon, especially among those with baseline CD4 counts < 200 cells/mm3. This study recommends screening for cervical cancer for all HIV-infected women.

Evaluation of BUBR1, MCM2, and GMNN as oral cancer biomarkers.

Oral cancer is a public health problem worldwide. Late diagnosis results in a low survival rate. However, this tumor can arise from oral precancerous lesions and identification of biomarkers in precursor lesions has the potential for early diagnosis, improving patient survival. In this context, proteins involved in the cell cycle control are potentially promising. This study aimed to evaluate the importance of immunohistochemical expression of BUBR1, MCM2, and GMNN as biomarkers of oral carcinogenesis considering different oral sites. Sixty-six samples of oral epithelial dysplasia (from 33 males and 33 females) and 63 samples of oral squamous cell carcinoma (from 44 males and 19 females) were subjected to immunohistochemistry to detect some human proteins. Ki67 expression was included as a marker of cell proliferation. Marker expression was quantified by manually counting at least 1000 cells, and the labeling index was used in all statistical analyses. GMNN, MCM2, BUBR1 (nuclear and cytoplasmic labeling), and Ki67 expression levels were higher in carcinomas than in dysplasia (P < 0.05). Cytoplasmic BUBR1 was a good marker of malignancy (AUC = 0.8525, P < 0.05), but Ki67 was not (AUC = 0.5943, P = 0.0713). GMNN, MCM2, BUBR1, and Ki67 had higher expression in carcinoma than in dysplasia, regardless of the site of the lesion. Cytoplasmic BUBR1 has the potential to be used as a marker of tumor progression.

HPV and HCMV in Cervical Cancer: A Review of Their Co-Occurrence in Premalignant and Malignant Lesions

Cervical cancer remains a significant global health concern, particularly in low- and middle-income countries. While persistent infection with high-risk human papillomavirus (HR-HPV) is essential for cervical cancer development, it is not sufficient on its own, suggesting the involvement of additional cofactors. The human cytomegalovirus (HCMV) is a widespread β-herpesvirus known for its ability to establish lifelong latency and reactivate under certain conditions, often contributing to chronic inflammation and immune modulation. Emerging evidence suggests that HCMV may play a role in various cancers, including cervical cancer, through its potential to influence oncogenic pathways and disrupt host immune responses. This review explores clinical evidence regarding the co-presence of HR-HPV and HCMV in premalignant lesions and cervical cancer. The literature reviewed indicates that HCMV is frequently detected in cervical lesions, particularly in those co-infected with HPV, suggesting a potential synergistic interaction that could enhance HPV’s oncogenic effects, thereby facilitating the progression from low-grade squamous intraepithelial lesions (LSIL) to high-grade squamous intraepithelial lesions (HSIL) and invasive cancer. Although the precise molecular mechanisms were not thoroughly investigated in this review, the clinical evidence suggests the importance of considering HCMV alongside HPV in the management of cervical lesions. A better understanding of the interaction between HR-HPV and HCMV may lead to improved diagnostic, therapeutic, and preventive strategies for cervical cancer.

Polyclonal-to-monoclonal transition in colorectal precancerous evolution.

Unravelling the origin and evolution of precancerous lesions is crucial for effectively preventing malignant transformation, yet our current knowledge remains limited1-3. Here we used a base editor-enabled DNA barcoding system4 to comprehensively map single-cell phylogenies in mouse models of intestinal tumorigenesis induced by inflammation or loss of the Apc gene. Through quantitative analysis of high-resolution phylogenies including 260,922 single cells from normal, inflamed and neoplastic intestinal tissues, we identified tens of independent celllineages undergoing parallel clonal expansions within each lesion. We also found polyclonal origins of human sporadic colorectal polyps through bulk whole-exome sequencing and single-gland whole-genome sequencing. Genomic and clinical data support a model of polyclonal-to-monoclonal transition, with monoclonal lesions representing a more advanced stage. Single-cell RNA sequencing revealed extensive intercellular interactions in early polyclonal lesions, but there was significant loss of interactions during monoclonal transition. Therefore, our data suggest that colorectal precancer is often founded by many different lineages and highlight their cooperative interactions in the earliest stages of cancer formation. These findings provide insights into opportunities for earlier intervention in colorectal cancer.

Gastric neoplasm detection of computer-aided detection-assisted esophagogastroduodenoscopy changes with implement scenarios: a real-world study.

The implementation of computer-aided detection (CAD) devices in esophagogastroduodenoscopy (EGD) could autonomously identify gastric precancerous lesions and neoplasms and reduce the miss rate of gastric neoplasms in prospective trials. However, there is still insufficient evidence of their use in real-life clinical practice. A real-world, two-center study was conducted at Wenzhou Central Hospital (WCH) and Renmin Hospital of Wuhan University (RHWU). High biopsy rate and low biopsy rate strategies were adopted, and CAD devices were applied in 2019 and 2021 at WCH and RHWU, respectively. We compared differences in gastric precancerous and neoplasm detection of EGD before and after the use of CAD devices in the first half of the year. A total of 33 885 patients were included and 32 886 patients were ultimately analyzed. In WCH of which biopsy rate >95%, with the implementation of CAD, more the number of early gastric cancer divided by all gastric neoplasm (EGC/GN) (0.35% vs 0.59%, P=0.028, OR [95% CI]=1.65 [1.0-2.60]) was found, while gastric neoplasm detection rate (1.39% vs 1.36%, P=0.897, OR [95% CI]=0.98 [0.76-1.26]) remained stable. In RHWU of which biopsy rate <20%, the gastric neoplasm detection rate (1.78% vs 3.23%, P<0.001, OR [95% CI]=1.84 [1.33-2.54]) nearly doubled after the implementation of CAD, while there was no significant change in the EGC/GN. The application of CAD devices devoted to distinct increases in gastric neoplasm detection according to different biopsy strategies, which implied that CAD devices demonstrated assistance on gastric neoplasm detection while varied effectiveness according to different implementation scenarios.

Factors associated with actinic keratoses in people with albinism in the Albivoire program

Abstract Background People with albinism (PWA) face health inequalities partly due to barriers in accessing health care, consequently delaying the diagnosis of skin precancerous and cancerous lesions. Actinic keratoses (AK), are common precancerous lesions, indicating a high risk of skin cancer. Given the scarcity of research on skin cancer prevention among PWA in Africa, this study aimed to determine the prevalence and factors associated with AK in PWA followed in the Albivoire program. Methods This cross-sectional analytical study was conducted within the ongoing Albivoire program in Ivory Cost. Initiated in Ivory Coast in 2021, Albivoire is the largest comprehensive preventive and care initiative with and for PWA, offering medical consultation campaigns in dermatology, ophthalmology, and psychology. Dermatological records of consenting patients were analyzed. The prevalence (95%CI) of AK was estimated, and the associated factors assessed using logistic model. Results To date, a total of 1978 PWA received care across four regions (Abidjan, Bouaké, Korhogo and Man). Available data from 475 PWA were analyzed, among whom 247 (52%) were women. The median age was 14 years (interquartile range [IQR]: 7-25). Of these, 181 individuals (38.1%, 95% CI [33.7 - 42.6]) presented with actinic keratoses (AK). The median age of PWA with AK was 22 years (vs 11 years for without AK (p &amp;lt; 0.001). Among PWA with AK, 87.8% were daily exposed to sun (vs 12.2% for those exposed occasionally, p = 0.026). In the multivariate analysis, factors significantly associated with AK included age 22 years or older (vs age &amp;lt; 22 years, aOR=4.83, p &amp;lt; 0.001), the presence of ephelides (vs absence; aOR=2.08, p = 0.003) and presence of xerosis (vs absence aOR=4.88, p &amp;lt; 0.001). Conclusions This study highlights the high prevalence of AK in PWA in Ivory Cost, and identifies specific modifiable associated factors which should be targeted in global health strategies to prevent skin cancer among this vulnerable population. Key messages • Prevalence of skin precancerous lesions (actinic keratoses) in people with albinism in Ivory Cost is high (38%) and associated with modifiable risk factors. • Tailored public health interventions needed to prevent skin cancers in vulnerable populations, targeting lesions like xerosis, ephelides, and actinic keratoses through skin protection.

Oncogenic H-RAS induces metformin resistance in head and neck cancer by promoting glycolytic metabolism.

Metformin administration has recently emerged as a candidate strategy for the prevention of head and neck squamous cell carcinoma (HNSCC). However, the intricate relationship between genetic alterations in HNSCC and metformin sensitivity is still poorly understood, which prevents the stratifications of patients harboring oral premalignant lesions that may benefit from the chemopreventive activity of metformin. In this study, we investigate the impact of prevalent mutations in HNSCC in response to metformin. Notably, we found that the expression of oncogenic HRAS mutants confers resistance to metformin in isogenic HNSCC cell systems and that HNSCC cells harboring endogenous HRAS mutations display limited sensitivity to metformin. Remarkably, we found that metformin fails to reduce activation of the mTOR pathway in HRAS oncogene expressing HNSCC cells in vitro and in vivo, correlating with reduced tumor suppressive activity. Mechanistically, we found that this process depends on the ability of HRAS to enhance glycolytic metabolism, thereby suppressing the requirement of oxidative phosphorylation to maintain the cellular energetic balance. Overall, our study revealed that HNSCC cells with oncogenic HRAS mutations exhibit diminished metformin sensitivity, thus shedding light on a potential mechanism of treatment resistance. This finding may also help explain the limited clinical responses to metformin in cancers with RAS mutations. Ultimately, our study underscores the importance of understanding the impact of the genetic landscape in tailoring precision cancer preventive approaches in the context of HNSCC and other cancers that are characterized by the presence of a defined premalignant state and, therefore, amenable for cancer interception strategies.

Application of mass cytometry in multiparametric characterization of precancerous cervical lesions.

Cervical cancer (CC) is the fourth most common malignant tumor in women worldwide. Detecting different biomarkers together on single cells by novel method mass cytometry could contribute to more precise screening. Liquid-based cytology (LBC) cervical samples were collected (N = 53) from women categorized as normal and precancerous lesions. Human papillomavirus was genotyped by polymerase chain reaction, while simultaneous examination of the expression of 29 proteins was done by mass cytometry (CyTOF). Differences in cluster abundances were assessed with Spearman's rank correlation as well as high dimensional data analysis (t-SNE, FlowSOM). Cytokeratin (ITGA6, Ck5, Ck10/13, Ck14, Ck7) expression patterns allowed determining the presence of different cells in the cervical epithelium. FlowSOM analysis enabled to phenotype cervical cells in five different metaclusters and find new markers that could be important in CC screening. The markers Ck18, Ck18, and CD63 (Metacluster 3) showed significantly increasing associated with severity of the precancerous lesions (Spearman rank correlation rho 0.304, p = 0.0271), while CD71, KLF4, LRIG1, E-cadherin, Nanog and p53 (Metacluster 1) decreased with severity of the precancerous lesions (Spearman rank correlation rho -0.401, p = 0.0029). Other metaclusters did not show significant correlation, but metacluster 2 (Ck17, MCM, MMP7, CD29, E-cadherin, Nanog, p53) showed higher abundance in low- and high-grade intraepithelial lesion cases. CyTOF appears feasible and should be considered when examining novel biomarkers on cervical LBC samples. This study enabled us to characterize different cells in the cervical epithelium and find markers and populations that could distinguish precancerous lesions.

Anti-VEGFR2 neutralising antibody slows the progression of multistep oral carcinogenesis.

Angiogenesis plays an important role in cancer growth and metastasis, and it is considered a therapeutic target to control tumour growth following anti-angiogenic therapy. However, it is still unclear when tissues initiate angiogenesis during malignant transformation from premalignant condition and whether this premalignant condition could be a therapeutic target of anti-angiogenic therapy. In this study, we aimed to analyse the onset of angiogenesis by evaluating morphological and functional alterations of microvessels during oral multistep carcinogenesis using a 4-nitroquinoline 1-oxide (4NQO)-induced oral carcinogenesis mouse model. In the study, we initially confirmed that with the use of 4NQO, oral lesions develop in a stepwise manner from normal mucosa through oral epithelial dysplasia (OED) to oral squamous cell carcinoma (OSCC). Evaluation of CD31-immunostained specimens revealed that microvessel density (MVD) increases in a stepwise manner from OEDs. Histological and functional analyses revealed the structural abnormalities and leakage of blood vessels had already taken place in OED. Then we evaluated the expression profiles of Hif1a and Vegfa along with hypoxic status and found that OED exhibited increased Vegfa expression under hypoxic conditions. Finally, we tested the possibility of OEDs as a target of anti-angiogenic therapy and found that anti-VEGFR2 neutralising antibody in OED slowed the disease progression from OED to OSCC. These data indicate that an angiogenic switch occurs at the premalignant stage and morphological, and functional alterations of microvessels already exist in OED. These findings also elucidate the tumour microenvironment, which gradually develops along with carcinogenic processes, and highlight usefulness of the 4NQO-induced carcinogenesis model in the study of epithelial and stromal components, which will support epithelial carcinogenesis. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Proteomic and serological markers for diagnosing cardia gastric cancer and precursor lesions in a Chinese population

Cardia gastric cancer (CGC) is prevalent in East Asia, and noninvasive, cost-effective screening methods are needed. This study investigated the diagnostic value of serum pepsinogen (PG), gastrin-17 (G-17), Helicobacter pylori (H. pylori) antibodies, and proteomic profiling for CGC and precancerous lesions. We conducted a case-control study involving biopsy-confirmed patients with CGC (n = 60), low-grade intraepithelial neoplasia (CLGD, n = 60), high-grade intraepithelial neoplasia (CHGD, n = 64), and healthy controls (n = 120) matched for age and sex from high-incidence areas in China. Serological markers including PGI, PGII, G-17, and H. pylori were measured using ELISA and Western blot, while plasma protein markers were assessed using Olink® technology. The VSOLassoBag algorithm and nine machine learning (ML) algorithms were employed to identify crucial features and construct predictive models. Various evaluation metrics, including the area under the receiver-operating-characteristic curve (AUC), were utilized to compare predictive performance. Elevated PGII levels, decreased PGR, and H. pylori infection were significantly associated with an increased risk of CGC and precancerous lesions (P for trend < 0.05). The eXtreme Gradient Boosting (XGBoost) model performed best in discriminative ability among the 9 ML models. Following feature reduction based on predictive performance, a final explainable XGBoost model was developed, incorporating five protein biomarkers (CDHR2, ICAM4, PTPRM, CDC27, and FLT1). This model exhibited excellent performance in distinguishing individuals with CGC and precancerous lesions from healthy controls (AUC = 0.931 for CGC, 0.867 for CHGD, and 0.763 for CLGD), surpassing the traditional serological marker-based model. This study underscores the diagnostic potential of serological markers and proteomic profiling in the detection of CGC. Further validation and exploration of combined biomarker approaches are warranted to enhance early diagnosis and improve outcomes in high-risk populations.

Tissue pool of hypersegmented neutrophils in patients with precancerous and tumor diseases of the larynx and laryngopharynx

The presence of neutrophils in a tumor often correlates with an unfavorable prognosis, however, there is still no clear answer about the role of tumor-associated neutrophils and the relationship of their morphofunctional features with the prognosis of the course of the disease. The aim of the study was to evaluate the structural features of tissue neutrophil nuclei in the pathological zone in patients with precancerous changes and malignant neoplasms in the larynx. Eight people with precancerous changes in the larynx, 18 patients with localized cancer of the larynx (stages II and III of the tumor process and the absence of metastases – T2- 3N0M0), and 12 patients with advanced cancer (stage III of tumor diseases and regional metastases – T3N1- 2M0) were examined. Blood slides and smear prints of tissue biopsies from three localizations were examined: 1 – zones of the pathological focus; 2 – boundaries between the pathological focus and conditionally healthy tissue; and 3 – conditionally healthy tissue. In the blood of patients with precancerous changes in the larynx and cancer patients, the main part of neutrophils was represented by cells with a 4-segment nucleus, and the number of hypersegmented forms (5 or more segments) was higher than in the blood of healthy volunteers (p 0.002). The same type of changes in smear prints of biopsies from different areas of the pathological focus in patients with precancerous and malignant neoplasms were revealed: as they approached the pathological focus, an increase the cells with 4-5 or more segments was observed. The content of hypersegmented forms was maximum in the pathological focus. Only in patients with a widespread tumor process, neutrophils with a 4-segment nucleus dominated the immediate environment of the tumor. As the tumor spreads and metastases form, the proportion of hypersegmented cells increases in the population of intra-tumor neutrophils. It is very likely that the morphological features of tissue neutrophils in different zones of the pathological focus reflect their functional heterogeneity, and hypersegmetation of nuclei can be considered as a potential predictor of the development and progression of the tumor process.