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Annals of Oncology : Official Journal... Dec 2023Detection of circulating tumor DNA (ctDNA) is a minimally invasive and convenient blood-based screening strategy that may increase effectiveness of colorectal cancer...
BACKGROUND
Detection of circulating tumor DNA (ctDNA) is a minimally invasive and convenient blood-based screening strategy that may increase effectiveness of colorectal cancer (CRC) screening.
PATIENTS AND METHODS
A novel multimodal ctDNA-based blood assay that integrates genomics, epigenomics and fragmentomics, as well as proteomics in a refined version, was tested in blood samples from two cohorts: (i) consecutive fecal immunochemical test (FIT)-positive individuals from the CRC Barcelona stool-based screening program; (ii) patients diagnosed with CRC. Primary endpoint was the performance of the test to detect CRC at different tumor-node-metastasis (TNM) stages. Secondary endpoint was the ability of the test to detect advanced precancerous lesions (advanced adenoma or advanced serrated lesion).
RESULTS
A total of 623 blood samples were analyzed in the primary analysis. Sensitivity and specificity of the assay to detect CRC was 93% and 90%, respectively. The sensitivity of CRC detection according to TNM stages was 84% for stage I, 94% for stage II and 96% for stage III (70/73) (P< 0.024). Sensitivity to detect advanced precancerous lesions was 23% with a refined version of the test (including protein and updating bioinformatic thresholding).
CONCLUSION
A blood-based multimodal ctDNA assay detected CRC with high accuracy. This minimally invasive, accessible and convenient assay may help to increase the effectiveness of CRC screening.
Topics: Humans; Sensitivity and Specificity; Mass Screening; Proteins; Colorectal Neoplasms; Early Detection of Cancer; Precancerous Conditions
PubMed: 37805131
DOI: 10.1016/j.annonc.2023.09.3113 -
Ugeskrift For Laeger Jul 2023Immunocompromised women are at increased risk of having HPV detected and developing HPV-related diseases such as genital warts, anogenital dysplasia, and cancer. This... (Review)
Review
Immunocompromised women are at increased risk of having HPV detected and developing HPV-related diseases such as genital warts, anogenital dysplasia, and cancer. This review aims to summarize the current literature regarding the immunogenicity of the HPV vaccine in immunocompromised women and to discuss whether HPV vaccination may be able to reduce the risk of cervical dysplasia and cancer. HPV vaccination induces an immune response in these women; however, it is unknown whether vaccination is effective in reducing the risk of cervical dysplasia and cancer. Further research is needed.
Topics: Humans; Female; Papillomavirus Infections; Uterine Cervical Neoplasms; Condylomata Acuminata; Uterine Cervical Dysplasia; Papillomavirus Vaccines; Vaccination
PubMed: 37539796
DOI: No ID Found -
Gastroenterology May 2024Gastric carcinogenesis develops within a sequential carcinogenic cascade from precancerous metaplasia to dysplasia and adenocarcinoma, and oncogenic gene activation can...
BACKGROUND & AIMS
Gastric carcinogenesis develops within a sequential carcinogenic cascade from precancerous metaplasia to dysplasia and adenocarcinoma, and oncogenic gene activation can drive the process. Metabolic reprogramming is considered a key mechanism for cancer cell growth and proliferation. However, how metabolic changes contribute to the progression of metaplasia to dysplasia remains unclear. We have examined metabolic dynamics during gastric carcinogenesis using a novel mouse model that induces Kras activation in zymogen-secreting chief cells.
METHODS
We generated a Gif-rtTA;TetO-Cre;Kras (GCK) mouse model that continuously induces active Kras expression in chief cells after doxycycline treatment. Histologic examination and imaging mass spectrometry were performed in the GCK mouse stomachs at 2 to 14 weeks after doxycycline treatment. Mouse and human gastric organoids were used for metabolic enzyme inhibitor treatment. The GCK mice were treated with a stearoyl- coenzyme A desaturase (SCD) inhibitor to inhibit the fatty acid desaturation. Tissue microarrays were used to assess the SCD expression in human gastrointestinal cancers.
RESULTS
The GCK mice developed metaplasia and high-grade dysplasia within 4 months. Metabolic reprogramming from glycolysis to fatty acid metabolism occurred during metaplasia progression to dysplasia. Altered fatty acid desaturation through SCD produces a novel eicosenoic acid, which fuels dysplastic cell hyperproliferation and survival. The SCD inhibitor killed both mouse and human dysplastic organoids and selectively targeted dysplastic cells in vivo. SCD was up-regulated during carcinogenesis in human gastrointestinal cancers.
CONCLUSIONS
Active Kras expression only in gastric chief cells drives the full spectrum of gastric carcinogenesis. Also, oncogenic metabolic rewiring is an essential adaptation for high-energy demand in dysplastic cells.
Topics: Animals; Stomach Neoplasms; Humans; Fatty Acids; Proto-Oncogene Proteins p21(ras); Energy Metabolism; Organoids; Mice; Metaplasia; Disease Models, Animal; Carcinogenesis; Chief Cells, Gastric; Cell Transformation, Neoplastic; Mice, Transgenic; Glycolysis; Adenocarcinoma; Disease Progression; Precancerous Conditions
PubMed: 38272100
DOI: 10.1053/j.gastro.2024.01.027 -
Nature Communications Aug 2023Esophageal squamous precancerous lesions (ESPL) are the precursors of esophageal squamous cell carcinoma (ESCC) including low-grade and high-grade intraepithelial...
Esophageal squamous precancerous lesions (ESPL) are the precursors of esophageal squamous cell carcinoma (ESCC) including low-grade and high-grade intraepithelial neoplasia. Due to the absence of molecular indicators, which ESPL will eventually develop into ESCC and thus should be treated is not well defined. Indicators, for predicting risks of ESCC at ESPL stages, are an urgent need. We perform spatial whole-transcriptome atlas analysis, which can eliminate other tissue interference by sequencing the specific ESPL regions. In this study, the expression of TAGLN2 significantly increases, while CRNN expression level decreases along the progression of ESCC. Additionally, TAGLN2 protein level significantly increases in paired after-progression tissues compared with before-progression samples, while CRNN expression decreases. Functional studies suggest that TAGLN2 promotes ESCC progression, while CRNN inhibits it by regulating cell proliferation. Taken together, TAGLN2 and CRNN are suggested as candidate indicators for the risk of ESCC at ESPL stages.
Topics: Humans; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Carcinoma, Squamous Cell; Transcriptome; Precancerous Conditions; Cell Line, Tumor; Gene Expression Regulation, Neoplastic
PubMed: 37553345
DOI: 10.1038/s41467-023-40343-5 -
ELife Dec 2023Cutaneous squamous cell carcinoma (cSCC) is the second most frequent of the keratinocyte-derived malignancies with actinic keratosis (AK) as a precancerous lesion. To...
Cutaneous squamous cell carcinoma (cSCC) is the second most frequent of the keratinocyte-derived malignancies with actinic keratosis (AK) as a precancerous lesion. To comprehensively delineate the underlying mechanisms for the whole progression from normal skin to AK to invasive cSCC, we performed single-cell RNA sequencing (scRNA-seq) to acquire the transcriptomes of 138,982 cells from 13 samples of six patients including AK, squamous cell carcinoma in situ (SCCIS), cSCC, and their matched normal tissues, covering comprehensive clinical courses of cSCC. We identified diverse cell types, including important subtypes with different gene expression profiles and functions in major keratinocytes. In SCCIS, we discovered the malignant subtypes of basal cells with differential proliferative and migration potential. Differentially expressed genes (DEGs) analysis screened out multiple key driver genes including transcription factors along AK to cSCC progression. Immunohistochemistry (IHC)/immunofluorescence (IF) experiments and single-cell ATAC sequencing (scATAC-seq) data verified the expression changes of these genes. The functional experiments confirmed the important roles of these genes in regulating cell proliferation, apoptosis, migration, and invasion in cSCC tumor. Furthermore, we comprehensively described the tumor microenvironment (TME) landscape and potential keratinocyte-TME crosstalk in cSCC providing theoretical basis for immunotherapy. Together, our findings provide a valuable resource for deciphering the progression from AK to cSCC and identifying potential targets for anticancer treatment of cSCC.
Topics: Humans; Carcinoma, Squamous Cell; Keratosis, Actinic; Skin Neoplasms; Keratinocytes; Transcriptome; Tumor Microenvironment
PubMed: 38099574
DOI: 10.7554/eLife.85270 -
European Journal of Obstetrics,... Nov 2023Following the publication of the European consensus statement on standards for essential colposcopy in 2020, the need for standards relating to more complex and... (Review)
Review
BACKGROUND
Following the publication of the European consensus statement on standards for essential colposcopy in 2020, the need for standards relating to more complex and challenging colposcopy practice was recognised. These standards relate to colposcopy undertaken in patients identified through cervical screening and tertiary referrals from colposcopists who undertake standard colposcopy only. This set of recommendations provides a review of the current literature and agreement on care for recognised complex cases. With good uptake of human papillomavirus (HPV) immunisation, we anticipate a marked reduction in cervical disease over the next decade. Still, the expert colposcopist will continue to be vital in managing complex cases, including previous cervical intraepithelial neoplasia (CIN)/complex screening histories and multi-zonal disease.
AIMS
To provide expert guidance on complex colposcopy cases through published evidence and expert consensus.
MATERIAL & METHODS
Members of the EFC and ESGO formed a working group to identify topics considered to be the remit of the expert rather than the standard colposcopy service. These were presented at the EFC satellite meeting, Helsinki 2021, for broader discussion and finalisation of the topics.
RESULTS & DISCUSSION
The agreed standards included colposcopy in pregnancy and post-menopause, investigation and management of glandular abnormalities, persistent high-risk HPV+ with normal/low-grade cytology, colposcopy management of type 3 transformation zones (TZ), high-grade cytology and normal colposcopy, colposcopy adjuncts, follow-up after treatment with CIN next to TZ margins and follow-up after treatment with CIN with persistent HPV+, and more. These standards are under review to create a final paper of consensus standards for dissemination to all EFC and ESGO members.
Topics: Female; Pregnancy; Humans; Uterine Cervical Neoplasms; Colposcopy; Papillomavirus Infections; Early Detection of Cancer; Uterine Cervical Dysplasia; Papillomaviridae
PubMed: 37716200
DOI: 10.1016/j.ejogrb.2023.08.369 -
Gastroenterology Jan 2024Precancerous metaplasia progression to dysplasia can increase the risk of gastric cancers. However, effective strategies to specifically target these precancerous...
BACKGROUNDS & AIMS
Precancerous metaplasia progression to dysplasia can increase the risk of gastric cancers. However, effective strategies to specifically target these precancerous lesions are currently lacking. To address this, we aimed to identify key signaling pathways that are upregulated during metaplasia progression and critical for stem cell survival and function in dysplasia.
METHODS
To assess the response to chemotherapeutic drugs, we used metaplastic and dysplastic organoids derived from Mist1-Kras mice and 20 human precancerous organoid lines established from patients with gastric cancer. Phospho-antibody array analysis and single-cell RNA-sequencing were performed to identify target cell populations and signaling pathways affected by pyrvinium, a putative anticancer drug. Pyrvinium was administered to Mist1-Kras mice to evaluate drug effectiveness in vivo.
RESULTS
Although pyrvinium treatment resulted in growth arrest in metaplastic organoids, it induced cell death in dysplastic organoids. Pyrvinium treatment significantly downregulated phosphorylation of ERK and signal transducer and activator of transcription 3 (STAT3) as well as STAT3-target genes. Single-cell RNA-sequencing data analyses revealed that pyrvinium specifically targeted CD133/CD166 stem cell populations, as well as proliferating cells in dysplastic organoids. Pyrvinium inhibited metaplasia progression and facilitated the restoration of normal oxyntic glands in Mist1-Kras mice. Furthermore, pyrvinium exhibited suppressive effects on the growth and survival of human organoids with dysplastic features, through simultaneous blocking of the MEK/ERK and STAT3 signaling pathways.
CONCLUSIONS
Through its dual blockade of MEK/ERK and STAT3 signaling pathways, pyrvinium can effectively induce growth arrest in metaplasia and cell death in dysplasia. Therefore, our findings suggest that pyrvinium is a promising chemotherapeutic agent for reprogramming the precancerous milieu to prevent gastric cancer development.
Topics: Humans; Mice; Animals; Proto-Oncogene Proteins p21(ras); Stomach Neoplasms; STAT3 Transcription Factor; Carcinogenesis; Hyperplasia; Precancerous Conditions; Mitogen-Activated Protein Kinase Kinases; Metaplasia; Stem Cells; RNA
PubMed: 37802423
DOI: 10.1053/j.gastro.2023.09.040 -
Cell Death & Disease Aug 2023Tumor is a representative of cell immortalization, while senescence irreversibly arrests cell proliferation. Although tumorigenesis and senescence seem contrary to each... (Review)
Review
Tumor is a representative of cell immortalization, while senescence irreversibly arrests cell proliferation. Although tumorigenesis and senescence seem contrary to each other, they have similar mechanisms in many aspects. Pancreatic ductal adenocarcinoma (PDA) is highly lethal disease, which occurs and progresses through a multi-step process. Senescence is prevalent in pancreatic premalignancy, as manifested by decreased cell proliferation and increased clearance of pre-malignant cells by immune system. However, the senescent microenvironment cooperates with multiple factors and significantly contributes to tumorigenesis. Evidently, PDA progression requires to evade the effects of cellular senescence. This review will focus on dual roles that senescence plays in PDA development and progression, the signaling effectors that critically regulate senescence in PDA, the identification and reactivation of molecular targets that control senescence program for the treatment of PDA.
Topics: Humans; Pancreas; Pancreatic Neoplasms; Carcinogenesis; Cell Transformation, Neoplastic; Carcinoma, Pancreatic Ductal; Tumor Microenvironment
PubMed: 37591827
DOI: 10.1038/s41419-023-06040-3 -
Clinical Gastroenterology and... Aug 2023
Topics: Humans; Stomach Diseases; Gastric Mucosa; Precancerous Conditions; Metaplasia; Stomach Neoplasms; Helicobacter pylori
PubMed: 37086748
DOI: 10.1016/j.cgh.2023.03.010 -
Microbiology Spectrum Aug 2023Metabolites and their interactions with microbiota may be involved in Helicobacter pylori-associated gastric lesion development. This study aimed to explore metabolite...
Metabolites and their interactions with microbiota may be involved in Helicobacter pylori-associated gastric lesion development. This study aimed to explore metabolite alterations upon H. pylori eradication and possible roles of microbiota-metabolite interactions in progression of precancerous lesions. Targeted metabolomics assays and 16S rRNA gene sequencing were conducted to investigate metabolic and microbial alterations of paired gastric biopsy specimens in 58 subjects with successful and 57 subjects with failed anti-H. pylori treatment. Integrative analyses were performed by combining the metabolomics and microbiome profiles from the same intervention participants. A total of 81 metabolites were significantly altered after successful eradication compared to failed treatment, including acylcarnitines, ceramides, triacylglycerol, cholesterol esters, fatty acid, sphingolipids, glycerophospholipids, and glycosylceramides, with values of <0.05 for all. The differential metabolites showed significant correlations with microbiota in baseline biopsy specimens, such as negative correlations between and glycerophospholipids, glycosylceramide, and triacylglycerol (0.05 for all), which were altered by eradication. The characteristic negative correlations between glycosylceramides and , Streptococcus, and in H. pylori-positive baseline biopsy specimens were further noticed in active gastritis and intestinal metaplasia (0.05 for all). A panel including differential metabolites, genera, and their interactions may help to discriminate high-risk subjects who progressed from mild to advanced precancerous lesions in short-term and long-term follow-up periods with areas under the curve (AUC) of 0.914 and 0.801, respectively. Therefore, our findings provide new insights into the metabolites and microbiota interactions in H. pylori-associated gastric lesion progression. In this study, a panel was established including differential metabolites, genera, and their interactions, which may help to discriminate high-risk subjects for progression from mild lesions to advanced precancerous lesions in short-term and long-term follow-up.
Topics: Humans; Helicobacter pylori; RNA, Ribosomal, 16S; Stomach Neoplasms; Helicobacter Infections; Microbiota; Precancerous Conditions
PubMed: 37358459
DOI: 10.1128/spectrum.05347-22