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Clinical Epigenetics Jun 2024The major challenge in routine endocervical curettage (ECC) among Human Papillomavirus (HPV) 16/18-positive patients is that only a small fraction benefit. Nevertheless,...
PAX1 methylation as a robust predictor: developing and validating a nomogram for assessing endocervical curettage (ECC) necessity in human papillomavirus16/18-positive women undergoing colposcopy.
OBJECTIVE
The major challenge in routine endocervical curettage (ECC) among Human Papillomavirus (HPV) 16/18-positive patients is that only a small fraction benefit. Nevertheless, current reported models often overestimate the validity and necessity of ECC, making it difficult to improve benefits for patients. This research hypothesized that assessing paired boxed gene 1 methylation levels (PAX1) and clinical characteristics could enhance the predictive accuracy of detecting additional high-grade squamous intraepithelial lesions or worse (HSIL +) through ECC that were not identified by colposcopy-directed biopsy (CDB).
METHODS
Data from 134 women with HPV16/18 positivity undergoing CDB and ECC between April 2018 and April 2022 were collected and analyzed. Quantitative methylation-specific polymerase chain reaction (qMSP) was utilized to measure PAX1, expressed as ΔCp. Univariate and multivariate regression analyses were conducted to screen variables and select predictive factors. A nomogram was constructed using multivariate logistic regression to predict additional HSIL + detected by ECC. The discrimination, calibration, and clinical utility of the nomogram were evaluated using receiver operating characteristic curves (ROC) and the calibration plot.
RESULTS
Age (odds ratio [OR], 5.654; 95% confidence interval [CI], 1.131-37.700), cytology (OR, 24.978; 95% CI, 3.085-540.236), and PAX1 methylation levels by grade (PAX1 grade) (OR, 7.801; 95% CI, 1.548-44.828) were independent predictive factors for additional detection of HSIL + by ECC. In HPV16/18-positive women, the likelihood of additional detection of HSIL + through ECC increased with the severity of cytological abnormalities, peaking at 43.8% for high-grade cytological lesions. Moreover, when cytological findings indicated low-grade lesions, PAX1 methylation levels were positively correlated with the additional detection of HSIL + by ECC (P value < 0.001). A nomogram prediction model was developed (area under curve (AUC) = 0.946; 95% CI, 0.901-0.991), demonstrating high sensitivity (90.9%) and specificity (90.5%) at the optimal cutoff point of 107. Calibration analysis confirmed the model's strong agreement between predicted and observed probabilities.
CONCLUSION
The clinical nomogram presented promising predictive performance for the additional detection of HSIL + through ECC among women with HPV16/18 infection. PAX1 methylation level could serve as a valuable tool in guiding individualized clinical decisions regarding ECC for patients with HPV 16/18 infection, particularly in cases of low-grade cytological findings.
Topics: Humans; Female; Paired Box Transcription Factors; Human papillomavirus 16; Nomograms; Adult; DNA Methylation; Middle Aged; Human papillomavirus 18; Papillomavirus Infections; Colposcopy; Uterine Cervical Neoplasms; Curettage; ROC Curve; Uterine Cervical Dysplasia; Cervix Uteri
PubMed: 38849868
DOI: 10.1186/s13148-024-01691-1 -
BMC Women's Health Jun 2024This study aims to analyze factors associated with positive surgical margins following cold knife conization (CKC) in patients with cervical high-grade squamous...
Development of a machine learning-based model for predicting positive margins in high-grade squamous intraepithelial lesion (HSIL) treatment by Cold Knife Conization(CKC): a single-center retrospective study.
OBJECTIVES
This study aims to analyze factors associated with positive surgical margins following cold knife conization (CKC) in patients with cervical high-grade squamous intraepithelial lesion (HSIL) and to develop a machine-learning-based risk prediction model.
METHOD
We conducted a retrospective analysis of 3,343 patients who underwent CKC for HSIL at our institution. Logistic regression was employed to examine the relationship between demographic and pathological characteristics and the occurrence of positive surgical margins. Various machine learning methods were then applied to construct and evaluate the performance of the risk prediction model.
RESULTS
The overall rate of positive surgical margins was 12.9%. Independent risk factors identified included glandular involvement (OR = 1.716, 95% CI: 1.345-2.189), transformation zone III (OR = 2.838, 95% CI: 2.258-3.568), HPV16/18 infection (OR = 2.863, 95% CI: 2.247-3.648), multiple HR-HPV infections (OR = 1.930, 95% CI: 1.537-2.425), TCT ≥ ASC-H (OR = 3.251, 95% CI: 2.584-4.091), and lesions covering ≥ 3 quadrants (OR = 3.264, 95% CI: 2.593-4.110). Logistic regression demonstrated the best prediction performance, with an accuracy of 74.7%, sensitivity of 76.7%, specificity of 74.4%, and AUC of 0.826.
CONCLUSION
Independent risk factors for positive margins after CKC include HPV16/18 infection, multiple HR-HPV infections, glandular involvement, extensive lesion coverage, high TCT grades, and involvement of transformation zone III. The logistic regression model provides a robust and clinically valuable tool for predicting the risk of positive margins, guiding clinical decisions and patient management post-CKC.
Topics: Humans; Female; Retrospective Studies; Machine Learning; Adult; Margins of Excision; Conization; Middle Aged; Uterine Cervical Neoplasms; Squamous Intraepithelial Lesions; Risk Factors; Squamous Intraepithelial Lesions of the Cervix; Uterine Cervical Dysplasia; Papillomavirus Infections; Aged; Logistic Models; Cryosurgery; Young Adult
PubMed: 38849836
DOI: 10.1186/s12905-024-03180-2 -
Journal of Translational Medicine Jun 2024Despite significant advancements in treatment strategies, multiple myeloma remains incurable. Additionally, there is a distinct lack of reliable biomarkers that can...
Progression of monoclonal gammopathy of undetermined significance to multiple myeloma is associated with enhanced translational quality control and overall loss of surface antigens.
BACKGROUND
Despite significant advancements in treatment strategies, multiple myeloma remains incurable. Additionally, there is a distinct lack of reliable biomarkers that can guide initial treatment decisions and help determine suitable replacement or adjuvant therapies when relapse ensues due to acquired drug resistance.
METHODS
To define specific proteins and pathways involved in the progression of monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma (MM), we have applied super-SILAC quantitative proteomic analysis to CD138 + plasma cells from 9 individuals with MGUS and 37 with MM.
RESULTS
Unsupervised hierarchical clustering defined three groups: MGUS, MM, and MM with an MGUS-like proteome profile (ML) that may represent a group that has recently transformed to MM. Statistical analysis identified 866 differentially expressed proteins between MM and MGUS, and 189 between MM and ML, 177 of which were common between MGUS and ML. Progression from MGUS to MM is accompanied by upregulated EIF2 signaling, DNA repair, and proteins involved in translational quality control, whereas integrin- and actin cytoskeletal signaling and cell surface markers are downregulated.
CONCLUSION
Compared to the premalignant plasma cells in MGUS, malignant MM cells apparently have mobilized several pathways that collectively contribute to ensure translational fidelity and to avoid proteotoxic stress, especially in the ER. The overall reduced expression of immunoglobulins and surface antigens contribute to this and may additionally mediate evasion from recognition by the immune apparatus. Our analyses identified a range of novel biomarkers with potential prognostic and therapeutic value, which will undergo further evaluation to determine their clinical significance.
Topics: Humans; Multiple Myeloma; Monoclonal Gammopathy of Undetermined Significance; Disease Progression; Proteomics; Male; Female; Protein Biosynthesis; Middle Aged; Aged; Cluster Analysis; Plasma Cells; Signal Transduction; Proteome; Quality Control
PubMed: 38849800
DOI: 10.1186/s12967-024-05345-x -
Clinical Oral Investigations Jun 2024Diagnosing oral potentially malignant disorders (OPMD) is critical to prevent oral cancer. This study aims to automatically detect and classify the most common...
OBJECTIVES
Diagnosing oral potentially malignant disorders (OPMD) is critical to prevent oral cancer. This study aims to automatically detect and classify the most common pre-malignant oral lesions, such as leukoplakia and oral lichen planus (OLP), and distinguish them from oral squamous cell carcinomas (OSCC) and healthy oral mucosa on clinical photographs using vision transformers.
METHODS
4,161 photographs of healthy mucosa, leukoplakia, OLP, and OSCC were included. Findings were annotated pixel-wise and reviewed by three clinicians. The photographs were divided into 3,337 for training and validation and 824 for testing. The training and validation images were further divided into five folds with stratification. A Mask R-CNN with a Swin Transformer was trained five times with cross-validation, and the held-out test split was used to evaluate the model performance. The precision, F1-score, sensitivity, specificity, and accuracy were calculated. The area under the receiver operating characteristics curve (AUC) and the confusion matrix of the most effective model were presented.
RESULTS
The detection of OSCC with the employed model yielded an F1 of 0.852 and AUC of 0.974. The detection of OLP had an F1 of 0.825 and AUC of 0.948. For leukoplakia the F1 was 0.796 and the AUC was 0.938.
CONCLUSIONS
OSCC were effectively detected with the employed model, whereas the detection of OLP and leukoplakia was moderately effective.
CLINICAL RELEVANCE
Oral cancer is often detected in advanced stages. The demonstrated technology may support the detection and observation of OPMD to lower the disease burden and identify malignant oral cavity lesions earlier.
Topics: Humans; Mouth Neoplasms; Precancerous Conditions; Lichen Planus, Oral; Leukoplakia, Oral; Sensitivity and Specificity; Photography; Diagnosis, Differential; Carcinoma, Squamous Cell; Male; Female; Photography, Dental; Image Interpretation, Computer-Assisted
PubMed: 38849649
DOI: 10.1007/s00784-024-05762-8 -
Archives of Dermatological Research Jun 2024Topical tirbanibulin is a highly effective and well tolerated novel treatment option for actinic keratoses (AKs). This study aimed to characterize the mode of action of...
Topical tirbanibulin is a highly effective and well tolerated novel treatment option for actinic keratoses (AKs). This study aimed to characterize the mode of action of tirbanibulin in keratinocytes (NHEK) and cutaneous squamous cell carcinoma (cSCC) cell lines (A431, SCC-12) in vitro. Tirbanibulin significantly reduced proliferation in a dose-dependent manner in all investigated cell lines, inhibited migration, and induced G2/M-cell cycle arrest only in the cSCC cell lines analyzed, and induced apoptosis solely in A431, which showed the highest sensitivity to tirbanibulin. In general, we detected low basal expression of phosphorylated SRC in all cell lines analyzed, therefore, interference with SRC signaling does not appear to be the driving force regarding the observed effects of tirbanibulin. The most prominent tirbanibulin-mediated effect was on β-tubulin-polymerization, which was especially impaired in A431. Additionally, tirbanibulin induced an increase of the proinflammatory cytokines IL-1α, bFGF and VEGF in A431. In conclusion, tirbanibulin mediated anti-tumor effects predominantly in A431, while healthy keratinocytes and more dedifferentiated SCC-12 were less influenced. These effects of tirbanibulin are most likely mediated via dysregulation of β-tubulin-polymerization and may be supported by proinflammatory aspects.
Topics: Humans; Carcinoma, Squamous Cell; Keratinocytes; Cell Line, Tumor; Tubulin; Skin Neoplasms; Apoptosis; Cell Proliferation; Cell Movement; Antineoplastic Agents; Polymerization; Keratosis, Actinic; Signal Transduction; Acetamides; Morpholines; Pyridines
PubMed: 38847867
DOI: 10.1007/s00403-024-03032-x -
Endoscopy International Open Jun 2024Gastric adenocarcinoma of the fundic gland type (GA-FG) is characterized by an elevated lesion with vessel dilation exhibiting branching architecture (DVBA). However,...
Gastric adenocarcinoma of the fundic gland type (GA-FG) is characterized by an elevated lesion with vessel dilation exhibiting branching architecture (DVBA). However, this feature is also found in fundic gland polyps (FGPs), posing a challenge in their differentiation. In this study, we aimed to investigate the clinicopathological features of gastric elevated lesions with DVBA and assess the efficacy of the white ring sign (WRS) as a novel marker for distinguishing between FGPs and GA-FGs. We analyzed 159 gastric elevated lesions without DVBA and 51 gastric elevated lesions with DVBA, further dividing the latter into 39 in the WRS-positive group and 12 in the WRS-negative group. The clinicopathological features, diagnostic accuracy, and inter-rater reliability were analyzed. Univariate and multivariate analyses for gastric elevated lesions with DVBA identified the histological type consistent with FGPs and GA-FGs, along with the presence of round pits in the background gastric mucosa, as independent predictors. FGPs were present in 92.3% (36/39) of the WRS-positive group and GA-FGs were observed in 50.0% (6/12) of the WRS-negative group. WRS positivity and negativity exhibited high diagnostic accuracy, with 100% sensitivity, 80.0% specificity, and 94.1% accuracy for FGPs, and 100% sensitivity, 86.7% specificity, and 88.2% accuracy for GA-FGs. Kappa values for WRS between experts and nonexperts were 0.891 and 0.841, respectively, indicating excellent agreement. WRS positivity and negativity demonstrate high diagnostic accuracy and inter-rater reliability for FGPs and GA-FGs, respectively, suggesting that WRS is a useful novel marker for distinguishing between FGPs and GA-FGs.
PubMed: 38847014
DOI: 10.1055/a-2301-6248 -
Endoscopy International Open Jun 2024Endoscopic resection has traditionally involved electrosurgical cautery (hot snare) to resect premalignant polyps. Recent data have suggested superior safety of cold...
Endoscopic resection has traditionally involved electrosurgical cautery (hot snare) to resect premalignant polyps. Recent data have suggested superior safety of cold resection. We aimed to assess the safety of cold compared with traditional (hot) resection for non-ampullary duodenal polyps. We performed a systematic review ending in September 2022. The primary outcome of interest was the adverse event (AE) rate for cold compared with hot polyp resection. We reported odds ratios with 95% confidence intervals (CIs). Secondary outcomes included rates of polyp recurrence and post-polypectomy syndrome. We assessed publication bias with the classic fail-safe test and used forest plots to report pooled effect estimates. We assessed heterogeneity using I index. Our systematic review identified 1,215 unique citations. Eight of these met inclusion criteria, seven of which were published manuscripts and one of which was a recent meeting abstract. On random effect modeling, cold resection was associated with significantly lower odds of delayed bleeding compared with hot resection. The difference in the odds of perforation (odds ratio [OR] 0.31 [95% confidence interval [CI] 0.05-2.87], =0.2, I =0) and polyp recurrence (OR 0.75 [95% CI 0.15-3.73], =0.72, I =0) between hot and cold resection was not statistically significant. There were no cases of post-polypectomy syndrome reported with either hot or cold techniques. Cold resection is associated with lower odds of delayed bleeding compared with hot resection for duodenal tumors. There was a trend toward higher odds of perforation and recurrence following hot resection, but this trend was not statistically significant.
PubMed: 38847013
DOI: 10.1055/a-2306-6535 -
PeerJ 2024The objective of this study was to delineate the profile of peripheral blood lymphocytic indices in patients afflicted with high-grade squamous intraepithelial lesions...
Peripheral blood immune cell parameters in patients with high-grade squamous intraepithelial lesion (HSIL) and cervical cancer and their clinical value: a retrospective study.
OBJECTIVE
The objective of this study was to delineate the profile of peripheral blood lymphocytic indices in patients afflicted with high-grade squamous intraepithelial lesions (HSIL) and cervical neoplasms, and to elucidate the correlation of these hematologic markers with the clinicopathological spectra in individuals diagnosed with cervical carcinoma.
METHODS
We adopted a retrospective case-control modality for this investigation. An aggregate of 39 HSIL patients and 42 cervical carcinoma patients, who were treated in our facility from July 2020 to September 2023, were meticulously selected. Each case of cervical malignancy was confirmed through rigorous histopathological scrutiny. Concomitantly, 31 healthy female individuals, who underwent prophylactic health evaluations during the corresponding timeframe, were enlisted as the baseline control group. We systematically gathered and analyzed clinical demographics, as well as the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR), from peripheral blood samples. Pearson's correlation coefficient was deployed to dissect the interrelation between peripheral NLR and PLR concentrations and the clinicopathological features in the cervical cancer group.
RESULTS
Inter-group comparative analysis unveiled statistically substantial variances in the PLR and NLR values among the tripartite clusters ( = 36.941, 14.998, < 0.001, respectively). Although discrepancy in NLR ( = 0.061) and PLR ( = 0.759) measures between the groups of cervical carcinoma and HSIL was not statistically appreciable, these indices were markedly elevated in the cervical carcinoma faction as juxtaposed with the normative control group ( = 5.094, 5.927; < 0.001 for both parameters). A discernible gradation in peripheral blood PLR and NLR concentrations was noted when stratified by clinical stage and the profundity of myometrial invasion in cervical cancer subjects ( < 0.001). The correlation matrix demonstrated a positive liaison between peripheral blood PLR and the clinical gradation, as well as the invasiveness of the neoplastic cells into the muscularis propria ( < 0.05); a similar trend was observed with the NLR values ( < 0.05).
CONCLUSION
Augmented NLR and PLR levels in peripheral blood specimens are indicative of HSIL and cervical malignancy. These hematological parameters exhibit a pronounced interconnection with clinical staging and muscular wall penetration depth, serving as potential discriminative biomarkers for the diagnosis and prognosis of cervical cancer.
Topics: Humans; Female; Uterine Cervical Neoplasms; Retrospective Studies; Adult; Middle Aged; Neutrophils; Case-Control Studies; Lymphocytes; Squamous Intraepithelial Lesions; Lymphocyte Count; Blood Platelets; Squamous Intraepithelial Lesions of the Cervix
PubMed: 38846752
DOI: 10.7717/peerj.17499 -
Skin Health and Disease Jun 2024Actinic keratoses (AK) are pre-malignant skin lesions caused by chronic sun exposure. Progression from an AK to intraepidermal carcinoma (IEC) and a cutaneous squamous...
BACKGROUND
Actinic keratoses (AK) are pre-malignant skin lesions caused by chronic sun exposure. Progression from an AK to intraepidermal carcinoma (IEC) and a cutaneous squamous cell carcinoma (SCC) is well known but the rate of transformation to an invasive SCC is highly variable. Since no definitive biomarkers are available, treatment decisions are made ad hoc.
OBJECTIVES
To fully characterise our AK to SCC progression series, we performed microRNA (miRNA) microarray expression profiling of normal and photodamaged skin, as well as AKs, IEC, and invasive SCCs.
METHODS
The study recruited 27 patients who donated fresh biopsies of normal skin, photodamaged skin, AK, IEC, and SCC ( = 67 specimens). All miRbase (v.21) miRNAs were profiled to identify miRNAs related to SCC progression. miRNAs were validated using qRT-PCR and in vitro phenotypic assays.
RESULTS
There were 234 robustly expressed miRNAs across the tissue collection, which resulted in 20 miRNA that were differentially expressed ((cor) ≤ 0.05 and ≥ 10 fold) between normal skin and SCC. Hierarchical clustering all samples illustrated that AKs, IEC, and SCCs were largely indistinguishable, which confirms the premalignant status of an AK. A panel of miRNAs showed significant dysregulation between normal and photodamaged skin and AK. Importantly, we found miR-34a-5p and miR-31-5p had significant differential expression between AKs and IEC and IEC and SCC respectively. Phenotypic assays determined that the miR-31 duplex had opposing effects on SCC cell lines which suggests that dysregulation of this duplex may be related to the dynamic control of progression of transformed keratinocytes.
CONCLUSIONS
This study confirmed the continuum of AK with IEC and SCC highlighting that miRNA expression plays a role in keratinocyte transformation. Development of our putative miRNA biomarker candidates is warranted to aid in clinical management of patients experiencing high AK load to determine the most appropriate treatment.
PubMed: 38846701
DOI: 10.1002/ski2.360 -
Skin Health and Disease Jun 2024Actinic keratoses (AKs) are common pre-malignant lesions. There are numerous management options including active surveillance, multiple topical therapies, cryotherapy,...
Actinic keratoses (AKs) are common pre-malignant lesions. There are numerous management options including active surveillance, multiple topical therapies, cryotherapy, curettage and cautery, and photodynamic therapy, each with their own risks, benefits and efficacy. Best practice currently involves shared decision-making between patient and clinician, particularly in the setting of multiple management options. Patient decision aids have been shown to be beneficial in the shared decision-making process. In view of this, we have developed and validated a decision aid for the management of AKs, in concordance with the International Patient Decision Aids Standards.
PubMed: 38846696
DOI: 10.1002/ski2.388