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Frontiers in Endocrinology 2023Clinical management of papillary thyroid cancer depends on estimations of prognosis. Standard care, which relies on prognostication based on clinicopathologic features,...
Clinical management of papillary thyroid cancer depends on estimations of prognosis. Standard care, which relies on prognostication based on clinicopathologic features, is inaccurate. We applied a machine learning algorithm () to 502 cases annotated by The Cancer Genome Atlas Project to derive an accurate molecular prognostic classifier. Unsupervised analysis of the 82 genes that were most closely associated with recurrence after surgery enabled the identification of three unique molecular subtypes. One subtype had a high recurrence rate, an immunosuppressed microenvironment, and enrichment of the EZH2-HOTAIR pathway. Two other unique molecular subtypes with a lower rate of recurrence were identified, including one subtype with a paucity of BRAF mutations and a high rate of RAS mutations. The genomic risk classifier, in addition to tumor size and lymph node status, enabled effective prognostication that outperformed the American Thyroid Association clinical risk stratification. The genomic classifier we derived can potentially be applied preoperatively to direct clinical decision-making. Distinct biological features of molecular subtypes also have implications regarding sensitivity to radioactive iodine, EZH2 inhibitors, and immune checkpoint inhibitors.
Topics: Humans; Thyroid Cancer, Papillary; Thyroid Neoplasms; Carcinoma, Papillary; Iodine Radioisotopes; Proto-Oncogene Proteins B-raf; Genomics; Tumor Microenvironment
PubMed: 37772080
DOI: 10.3389/fendo.2023.1220617 -
Journal of Gastroenterology Oct 2023Trajectories of serological and morphological signatures have not been documented in pancreatic carcinogenesis related to intraductal papillary mucinous neoplasms...
Clinical trajectory of intraductal papillary mucinous neoplasms progressing to pancreatic carcinomas during long-term surveillance: a prospective series of 100 carcinoma cases.
BACKGROUND
Trajectories of serological and morphological signatures have not been documented in pancreatic carcinogenesis related to intraductal papillary mucinous neoplasms (IPMNs).
METHODS
Using a prospective cohort of 3437 IPMN patients, we identified 100 IPMN patients who developed pancreatic carcinomas during long-term surveillance. We examined serial changes of blood markers (carbohydrate antigen 19-9 [CA19-9], hemoglobin A1c [HbA1c], and pancreatic enzymes) and morphological features (worrisome features and high-risk stigmata) during the prediagnostic period of pancreatic carcinomas, overall and by carcinoma types (IPMN-derived vs. concomitant pancreatic carcinomas).
RESULTS
CA19-9 elevation was observed in 39 patients and was associated with a metastatic stage. Compared to IPMN-derived carcinomas, concomitant carcinomas were more likely to represent CA19-9 elevation (60% vs. 30%, respectively; P = 0.005). HbA1c levels elevated only in 3 patients. Pancreatic enzyme elevation was observed in 18 patients with no differences in frequencies between the carcinoma types. All patients with elevated levels of blood markers had positive findings on cross-sectional imaging. High-risk stigmata or worrisome features were observed in all patients but one with concomitant carcinoma. The most common types of worrisome features were the main pancreatic duct dilatation and CA19-9 elevation in IPMN-derived and concomitant carcinomas, respectively. Compared to IPMN-derived carcinomas, concomitant carcinomas were less likely to harbor high-risk stigmata (16% vs. 86%, respectively; P < 0.001).
CONCLUSIONS
The usefulness of currently available blood biomarkers was limited in early detection of pancreatic carcinomas related to IPMNs. Morphological alterations were well correlated with long-term risk of IPMN-derived carcinomas, but not with that of concomitant carcinomas.
Topics: Humans; Carcinoma, Pancreatic Ductal; Pancreatic Intraductal Neoplasms; CA-19-9 Antigen; Glycated Hemoglobin; Adenocarcinoma, Mucinous; Retrospective Studies; Pancreatic Neoplasms; Pancreatic Ducts
PubMed: 37507590
DOI: 10.1007/s00535-023-02028-0 -
Hormone and Metabolic Research =... Sep 2023Suppression of TSH levels associated with levothyroxine treatment is a known risk factor for fracture. However, it is unclear whether patients with papillary thyroid...
Suppression of TSH levels associated with levothyroxine treatment is a known risk factor for fracture. However, it is unclear whether patients with papillary thyroid carcinoma (PTC) have a higher risk of vertebral fracture (VF) before TSH suppression. The aim of the study was to examine whether the risk of VF is higher in PTC than in healthy subjects. A hospital-based, matched case-control study was conducted comparing PTC and healthy individuals. We enrolled 43 postoperative patients with PTC scheduled for radioiodine therapy and 43 age- and sex-matched healthy controls. Serum and urinary biological parameters, bone mineral density (BMD), and presence of VFs were evaluated in both groups. We compared these indices using χ2 and Mann-Whitney U-test and analyzed the association between PTC and VF by logistic regression analysis. The PTC group had higher BMI, HbA1c and phosphorus, and lower intact PTH than the control group. Lumbar and femoral neck BMD did not differ between the two groups. Prevalence of VFs was significantly higher in the PTC group (44.1%) than in the control group (16.3%). Multivariate logistic regression analyses adjusted for age, sex, and BMI identified PTC as being associated with the presence of VFs (odds ratio, 5.63; 95% confidence interval: 1.82 to 17.5). This relationship remained significant after additional adjustment for HbA1c and BMD. There is an association between PTC and a risk of VF independent of sex, BMI, glucose metabolism, and BMD, suggesting the importance of fracture risk assessment before TSH suppression.
Topics: Humans; Spinal Fractures; Thyroid Cancer, Papillary; Case-Control Studies; Glycated Hemoglobin; Iodine Radioisotopes; Bone Density; Thyroid Neoplasms; Thyrotropin
PubMed: 37068493
DOI: 10.1055/a-2059-8830 -
Annals of Medicine Dec 2023This study aims to evaluate the prognostic value of m6A-associated long noncoding RNAs (lncRNAs) and their interaction with tumour microenvironment in thyroid cancer...
OBJECTIVE
This study aims to evaluate the prognostic value of m6A-associated long noncoding RNAs (lncRNAs) and their interaction with tumour microenvironment in thyroid cancer (THCA).
METHODS
The clinical and gene expression data of tumours from 502 patients with THCA and 58 adjacent normal tissues were retrieved from The Cancer Genome Atlas (TCGA)-THCA dataset. The Pearson test was utilized to identify potential m6A-associated lncRNAs ( < 0.001 and Pearson correlation coefficient > 0.4). Quantitative real-time polymerase chain reaction was performed to verify the expression levels of lncRNAs in tissues. MTT, EdU, colony formation and wound-healing assays were performed to determine the functions of m6A-associated lncRNAs in THCA cell proliferation and metastasis.
RESULTS
M6A-associated lncRNAs were identified in three cluster groups. A significant survival difference was found among them, with cluster 1 patients showing worse survival. Moreover, lower immune and estimate scores were correlated to poorer prognosis, and CD8+ T cell and memory CD4+ T cell levels were increased in cluster 1. Cluster 2, with better overall survival, had high expression of PD-L1 and CTLA-4. Eleven of the m6A-associated lncRNAs were screened to establish the risk model, including AC007365.1, AC008555.1, AC040160.1, AC064807.1, AC126773.4, AL023583.1, AL512306.2, EIF2AK3-DT, LINC00667, LYPLAL1-DT and MIR181A2HG. Based on the median risk score, THCA patients were stratified into low-risk and high-risk groups. Overall survival analysis showed a dramatic difference between the two groups. qRCR was performed to verify the expression levels of lncRNA (LYPLAL1-DT, EIF2AK3-DT and MIR181A2HG) in THCA and adjacent normal tissues. Furthermore, functional experiments showed that knockdown of MIR181A2HG obviously inhibited the proliferation and migration of papillary thyroid cancer (PTC) cells , whereas LYPLAL1-DT overexpression promoted PTC cell proliferation and migration.
CONCLUSIONS
Eleven of the m6A-associated lncRNAs were identified as a risk model to predict clinical outcomes and provide a novel and efficient immunotherapeutic strategy for THCA patients.Key messagesm6A-associated lncRNAs can be used to predict the clinical outcomes of thyroid cancer patients.An m6A-associated lncRNAs risk model, which can accurately evaluate the immune status and risk stratification in individual thyroid cancer patients, was established.Knockdown/overexpression of representative lncRNAs in the risk model significantly affected the proliferation and migration of papillary thyroid cancer cells.
Topics: Humans; RNA, Long Noncoding; Thyroid Cancer, Papillary; Thyroid Neoplasms; Prognosis; CD8-Positive T-Lymphocytes; Tumor Microenvironment
PubMed: 36974635
DOI: 10.1080/07853890.2023.2192049 -
Cell Reports Dec 2023Lung adenocarcinoma (LUAD) is the most prevalent subtype of lung cancer and presents clinically with a high degree of biological heterogeneity and distinct clinical...
Lung adenocarcinoma (LUAD) is the most prevalent subtype of lung cancer and presents clinically with a high degree of biological heterogeneity and distinct clinical outcomes. The current paradigm of LUAD etiology posits alveolar epithelial type II (AT2) cells as the primary cell of origin, while the role of AT1 cells in LUAD oncogenesis remains unknown. Here, we examine oncogenic transformation in mouse Gram-domain containing 2 (Gramd2) AT1 cells via oncogenic KRAS. Activation of KRAS in AT1 cells induces multifocal LUAD, primarily of papillary histology. Furthermore, KRT8 intermediate cell states were observed in both AT2- and AT1-derived LUAD, but SCGB3A2, another intermediate cell marker, was primarily associated with AT1 cells, suggesting different mechanisms of tumor evolution. Collectively, our study reveals that Gramd2 AT1 cells can serve as a cell of origin for LUAD and suggests that distinct subtypes of LUAD based on cell of origin be considered in the development of therapeutics.
Topics: Animals; Mice; Adenocarcinoma of Lung; Cell Transformation, Neoplastic; Lung Neoplasms; Proto-Oncogene Proteins p21(ras)
PubMed: 37995179
DOI: 10.1016/j.celrep.2023.113286 -
Nature Communications Mar 2024The existing Intraductal Papillary Mucinous Neoplasm (IPMN) risk stratification relies on clinical and histological factors, resulting in inaccuracies and leading to...
The existing Intraductal Papillary Mucinous Neoplasm (IPMN) risk stratification relies on clinical and histological factors, resulting in inaccuracies and leading to suboptimal treatment. This is due to the lack of appropriate molecular markers that can guide patients toward the best therapeutic options. Here, we assess and confirm subtype-specific markers for IPMN across two independent cohorts of patients using two Spatial Transcriptomics (ST) technologies. Specifically, we identify HOXB3 and ZNF117 as markers for Low-Grade Dysplasia, SPDEF and gastric neck cell markers in borderline cases, and NKX6-2 and gastric isthmus cell markers in High-Grade-Dysplasia Gastric IPMN, highlighting the role of TNFα and MYC activation in IPMN progression and the role of NKX6-2 in the specific Gastric IPMN progression. In conclusion, our work provides a step forward in understanding the gene expression landscapes of IPMN and the critical transcriptional networks related to PDAC progression.
Topics: Humans; Carcinoma, Pancreatic Ductal; Pancreatic Intraductal Neoplasms; Adenocarcinoma, Mucinous; Pancreatic Neoplasms; Hyperplasia; Homeodomain Proteins
PubMed: 38553466
DOI: 10.1038/s41467-024-46994-2 -
Frontiers in Endocrinology 2023Thyroid cancer is the most prevalent endocrine malignancy, with its global incidence increasing annually in recent years. Papillary carcinoma is the most common subtype,...
INTRODUCTION
Thyroid cancer is the most prevalent endocrine malignancy, with its global incidence increasing annually in recent years. Papillary carcinoma is the most common subtype, frequently accompanied by cervical lymph node metastasis early on. Central lymph node metastasis (CLNM) is particularly the common metastasis form in this subtype, and the presence of lymph node metastasis correlates strongly with tumor recurrence. However, effective preoperative assessment methods for CLNM in patients with papillary thyroid carcinoma (PTC) remain lacking.
METHODS
Data from 400 patients diagnosed with PTC between January 1, 2018, and January 1, 2022, at the Shandong Provincial Hospital were retrospectively analyzed. This data included clinicopathological information of the patients, such as thyroid function, BRAF V600E mutation, whether complicated with Hashimoto's thyroiditis, and the presence of capsular invasion. Univariate and multivariate logistic regression analyses were performed to assess the risk factors associated with cervical CLNM in patients with PTC. Subsequently, a clinical prediction model was constructed, and prognostic risk factors were identified based on univariate and multivariate Cox regression analyses.
RESULTS
Univariate and multivariate analyses identified that age >45 years (P=0.014), body mass index ≥25 (P=0.008), tumor size ≥1 cm (P=0.001), capsular invasion (P=0.001), and the presence of BRAF V600E mutation (P<0.001) were significantly associated with an increased risk of CLNM. Integrating these factors into the nomogram revealed an area-under-the-curve of 0.791 (95% confidence interval 0.735-0.846) and 0.765 (95% confidence interval: 0.677-0.852) for the training and validation sets, respectively, indicating strong discriminative abilities. Subgroup analysis further confirmed that patients with papillary thyroid microcarcinoma and BRAF V600E mutations who underwent therapeutic central compartment neck dissection had significantly better 3-year disease-free survival than those who had prophylactic central compartment neck dissection (P<0.001).
CONCLUSION
The study revealed that age >45 years, body mass index ≥25, tumor size ≥1 cm, BRAF V600E mutation, and capsular invasion are the related risk factors for CLNM in patients with PTC. For patients with clinically nodal-negative (cN0) papillary thyroid microcarcinoma, accurately identifying the BRAF V600E mutation is essential for guiding the central lymph node dissection approach and subsequent treatments.
Topics: Humans; Middle Aged; Thyroid Cancer, Papillary; Retrospective Studies; Lymphatic Metastasis; Proto-Oncogene Proteins B-raf; Models, Statistical; Prognosis; Neoplasm Recurrence, Local; Thyroid Neoplasms; Risk Factors
PubMed: 38047112
DOI: 10.3389/fendo.2023.1288527 -
Medicine Aug 2023Inflammation plays an important role in the pathogenesis of many cancer types and is associated with thyroid malignancy. The systemic immune-inflammation index (SII) is...
Inflammation plays an important role in the pathogenesis of many cancer types and is associated with thyroid malignancy. The systemic immune-inflammation index (SII) is a new inflammation marker that can be calculated from routine complete blood count (CBC). This study investigated the association between SII, a marker derived from routine CBC, and different thyroid diseases. The objective was to determine if this simple inflammation marker can distinguish between benign and malignant thyroid diseases. The medical records of all patients who underwent surgical treatment for thyroid disease between January 2018 and January 2022 were systematically evaluated. The routine preoperative CBC parameters' demographic, clinical, and laboratory data were recorded. A total of 241 patients were included in the study, and the patients were grouped as having multinodular goiter (n = 125), lymphocytic thyroiditis (n = 44), and papillary thyroid carcinoma (PTC) (n = 73) according to pathological results. The SII was defined as the ratio of the total count of neutrophils × platelets divided by the lymphocyte count. Subgroup analysis of patients was performed according to the presence of follicular variant or thyroiditis, micro or macro carcinoma, or bilaterality of the tumor. The SII level was significantly higher in the PTC group than in the lymphocytic thyroiditis and multinodular goiter groups (P < .001). When we grouped the patients according to the presence of PTC as benign or malignant, the optimum cutoff point for SII level was found 654.13, with 73.8% sensitivity and 72.3% specificity from ROC analysis. In the subgroup analysis of patients with PTC, the SII level was similar according to the clinicopathological characteristics of the tumor. The differential diagnosis of thyroid diseases is important for patient management. We found that preoperative SII levels were significantly elevated in patients with PTC compared to those with benign thyroid disorders, and this simple marker can be used for the differentiation of benign and malignant thyroid disease.
Topics: Humans; Thyroiditis, Autoimmune; Carcinoma, Papillary; Thyroid Neoplasms; Thyroid Cancer, Papillary; Hashimoto Disease; Inflammation; Goiter; Retrospective Studies; Lymphocytes
PubMed: 37543770
DOI: 10.1097/MD.0000000000034596 -
BMC Cancer Sep 2023Guidelines recommend total thyroidectomy (TT) to facilitate radioactive ablation and serological follow-up for intermediate- to high-risk papillary thyroid carcinoma...
BACKGROUND
Guidelines recommend total thyroidectomy (TT) to facilitate radioactive ablation and serological follow-up for intermediate- to high-risk papillary thyroid carcinoma (PTC). However, the association between surgical extent and tumor recurrence in these patients has not been well validated. We aimed to examine the association between the extent of surgery and recurrence in patients with completely resected unilateral intermediate- to high-risk PTC.
METHODS
Patients with completely resected unilateral PTC from 2000 to 2017 in a single institute were reviewed. Those who had extrathyroidal extension (ETE) or lymph node metastasis (LNM, cN1 or pN1 > 5 lymph nodes involved) were included for analysis. Cox proportional hazards models were applied to measure the association between surgical extent and recurrence-free survival (RFS) while adjusting for patient demographic, clinicopathological and treatment variables.
RESULTS
A total of 4550 patients (mean[SD] age, 43.0[11.7] years; 3379 women[74.3%]) were included. Of these patients, 2262(49.7%), 656(14.4%), 1032(22.7%), and 600 (13.2%) underwent lobectomy, TT, lobectomy + neck dissection (ND) and TT + ND, respectively. With a median follow-up period of 68 months, after multivariate adjustment, lobectomy was associated with a compromised RFS compared with other surgical extents (HR[95%CI], TT 0.537[0.333-0.866], P = 0.011, lobectomy + ND 0.531[0.392-0.720] P < 0.0001, TT + ND 0.446[0.286-0.697] P < 0.0001). RFS was similar between the two extents with ND (lobectomy + ND, HR [95%CI], 1.196 [0.759-1.885], P = 0.440).
CONCLUSION
Lobectomy alone is associated with an elevated recurrence risk in patients with unilateral intermediate- to high-risk PTC compared with larger surgical extents. However, lobectomy and ND may provide similar tumor control compared with the conventional approach of TT and ND.
Topics: Humans; Female; Adult; Thyroid Cancer, Papillary; Thyroidectomy; Lymph Nodes; Lymphatic Metastasis; Thyroid Neoplasms
PubMed: 37723469
DOI: 10.1186/s12885-023-11307-1 -
Frontiers in Endocrinology 2023
Topics: Humans; Thyroid Cancer, Papillary; Thyroid Neoplasms; Thyroid Nodule
PubMed: 37786792
DOI: 10.3389/fendo.2023.1283397