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Frontiers in Endocrinology 2024Medullary thyroid cancer (MTC) is a challenging malignancy. The survival outcome of MTC based on AJCC staging system does not render a discriminant classifier among...
BACKGROUND
Medullary thyroid cancer (MTC) is a challenging malignancy. The survival outcome of MTC based on AJCC staging system does not render a discriminant classifier among early stages.
METHODS
3601 MTC patients from 2000 to 2018 were identified from the Surveillance, Epidemiology, and End Results (SEER) database. Smooth curve fitting, Cox proportional hazard regression and competing risk analysis were applied.
RESULTS
A linear correlation between age and log RR (relative risk of overall death) was detected. Overlaps were observed between K-M curves representing patients aged 45-50, 50-55, and 55-60. The study cohort was divided into 3 subgroups with 2 age cutoffs set at 45 and 60. Each further advanced age cutoff population resulted in a roughly "5%" increase in MTC-specific death risks and an approximately "3 times" increase in non-MTC-specific death risks.
CONCLUSIONS
The survival outcome disparity across age cutoffs at 45 and 60 for MTC has been well defined.
Topics: Humans; Thyroid Neoplasms; Middle Aged; Male; Female; Carcinoma, Neuroendocrine; Retrospective Studies; Age Factors; SEER Program; Survival Rate; Aged; Prognosis; Adult; Cohort Studies; Follow-Up Studies
PubMed: 38948527
DOI: 10.3389/fendo.2024.1393904 -
Journal of Cell Communication and... Jun 2024lncRNA ZFAS1 was identified to facilitate thyroid cancer, but its role in medullary thyroid carcinoma (MTC) remains unknown. This study aimed to unravel the potential...
lncRNA ZFAS1 was identified to facilitate thyroid cancer, but its role in medullary thyroid carcinoma (MTC) remains unknown. This study aimed to unravel the potential function of this lncRNA in MTC by investigating the involvement of the lncRNA ZFAS1 in a ceRNA network that regulates MTC invasion. Proliferation, invasion, and migration of cells were evaluated using EdU staining and Transwell assays. Immunoprecipitation (IP) assays, dual-fluorescence reporter, and RNA IP assays were employed to examine the binding interaction among genes. Nude mice were used to explore the role of lncRNA ZFAS1 in MTC in vivo. ZFAS1 and EPAS1 were upregulated in MTC. Silencing ZFAS1 inhibited MTC cell proliferation and invasion under hypoxic conditions, which reduced EPAS1 protein levels. UCHL1 knockdown increased EPAS1 ubiquitination. ZFAS1 positively regulated UCHL1 expression by binding to miR-214-3p. Finally, silencing ZFAS1 significantly repressed tumor formation and metastasis in MTC. LncRNA ZFAS1 promotes invasion of MTC by upregulating EPAS1 expression via the miR-214-3p/UCHL1 axis.
PubMed: 38946718
DOI: 10.1002/ccs3.12021 -
Annals of Agricultural and... Jun 2024Multiple endocrine neoplasia type 2B (MEN 2B) is a rare autosomal dominant hereditary cancer syndrome which is characterized by the appearance of medullary thyroid...
Multiple endocrine neoplasia type 2B (MEN 2B) is a rare autosomal dominant hereditary cancer syndrome which is characterized by the appearance of medullary thyroid carcinoma (MTC), pheochromocytoma, parathyroid adenomas, ganglioneuromas of the digestive tract, and musculoskeletal abnormalities. The case is presented of a 31-year-old male patient with numerous polyps in the colon described as ganglioneuromas which are ectodermal neoplasms emerging from a proliferation of ganglionic cells of the sympathetic nervous system. The results show elevated levels of normetanephrine, which is an endogenous catecholamine metabolite, and has high diagnostic sensitivity as well as specificity in pheochromocytoma detection. The patient underwent partial thyreoidectomy due to a nodular goiter. He was admitted to the Department of Gastroenterology to lead a diagnostic pathway towards MEN 2B.
Topics: Humans; Male; Adult; Multiple Endocrine Neoplasia Type 2b; Ganglioneuroma
PubMed: 38940117
DOI: 10.26444/aaem/171736 -
Frontiers in Endocrinology 2024Medullary thyroid carcinoma (MTC) accounts for only 3% of all thyroid carcinomas: 75% as sporadic MTC (sMTC) and 25% as hereditary MTC (hMTC) in the context of multiple... (Review)
Review
Medullary thyroid carcinoma (MTC) accounts for only 3% of all thyroid carcinomas: 75% as sporadic MTC (sMTC) and 25% as hereditary MTC (hMTC) in the context of multiple endocrine neoplasia type 2 (MEN2). Early diagnosis is possible by determining the tumour marker calcitonin (Ctn) when clarifying nodular goitre and by detecting the mutation in the proto-oncogene RET in the MEN2 families. If the Ctn level is only slightly elevated, up to 30 pg/ml in women and up to 60 pg/ml in men, follow-up checks are advisable. At higher levels, surgery should be considered; at a level of > 100 pg/ml, surgery is always advisable. The treatment of choice is total thyroidectomy, possibly with central lymphadenectomy. In the early stage, cure is possible with adequate surgery; in the late stage, treatment with tyrosine kinase inhibitors is an option. RET A mutation analysis should be performed on all patients with MTC. During follow-up, a biochemical distinction is made between: healed (Ctn not measurably low), biochemically incomplete (Ctn increased without tumour detection) and structural tumour detection (metastases on imaging). After MTC surgery, the following results should be available for classification in follow-up care: (i) histology, Ctn immunohistology if necessary, (ii) classification according to the pTNM scheme, (iii) the result of the RET analysis for categorisation into the hereditary or sporadic variant and (iiii) the postoperative Ctn value. Tumour progression is determined by assessing the Ctn doubling time and the RECIST criteria on imaging. In most cases, "active surveillance" is possible. In the case of progression and symptoms, the following applies: local (palliative surgery, radiotherapy) before systemic (tyrosine kinase inhibitors).
Topics: Humans; Thyroid Neoplasms; Proto-Oncogene Mas; Carcinoma, Medullary; Multiple Endocrine Neoplasia Type 2a; Proto-Oncogene Proteins c-ret; Thyroidectomy; Mutation; Calcitonin; Biomarkers, Tumor; Carcinoma, Neuroendocrine
PubMed: 38919477
DOI: 10.3389/fendo.2024.1412942 -
JAMA Internal Medicine Jun 2024Current approaches to classify the hepatotoxic potential of medications are based on cumulative case reports of acute liver injury (ALI), which do not consider the size...
IMPORTANCE
Current approaches to classify the hepatotoxic potential of medications are based on cumulative case reports of acute liver injury (ALI), which do not consider the size of the exposed population. There is little evidence from real-world data (data relating to patient health status and/or the delivery of health care routinely collected from sources outside of a research setting) on incidence rates of severe ALI after initiation of medications, accounting for duration of exposure.
OBJECTIVE
To identify the most potentially hepatotoxic medications based on real-world incidence rates of severe ALI and to examine how these rates compare with categorization based on case reports.
DESIGN, SETTING, AND PARTICIPANTS
This series of cohort studies obtained data from the US Department of Veterans Affairs on persons without preexisting liver or biliary disease who initiated a suspected hepatotoxic medication in the outpatient setting between October 1, 2000, and September 30, 2021. Data were analyzed from June 2020 to November 2023.
EXPOSURES
Outpatient initiation of any one of 194 medications with 4 or more published reports of hepatotoxicity.
MAIN OUTCOMES AND MEASURES
Hospitalization for severe ALI, defined by either inpatient: (1) alanine aminotransferase level greater than 120 U/L plus total bilirubin level greater than 2.0 mg/dL or (2) international normalized ratio of 1.5 or higher plus total bilirubin level greater than 2.0 mg/dL recorded within the first 2 days of admission. Acute or chronic liver or biliary disease diagnosis recorded during follow-up or as a discharge diagnosis of a hospitalization for severe ALI resulted in censoring. This study calculated age- and sex-adjusted incidence rates of severe ALI and compared observed rates with hepatotoxicity categories based on cumulative published case reports.
RESULTS
The study included 7 899 888 patients across 194 medication cohorts (mean [SD] age, 64.4 [16.4] years, 7 305 558 males [92.5%], 4 354 136 individuals [55.1%] had polypharmacy). Incidence rates of severe ALI ranged from 0 events per 10 000 person-years (candesartan, minocycline) to 86.4 events per 10 000 person-years (stavudine). Seven medications (stavudine, erlotinib, lenalidomide or thalidomide, chlorpromazine, metronidazole, prochlorperazine, and isoniazid) exhibited rates of 10.0 or more events per 10 000 person-years, and 10 (moxifloxacin, azathioprine, levofloxacin, clarithromycin, ketoconazole, fluconazole, captopril, amoxicillin-clavulanate, sulfamethoxazole-trimethoprim, and ciprofloxacin) had rates between 5.0 and 9.9 events per 10 000 person-years. Of these 17 medications with the highest observed rates of severe ALI, 11 (64%) were not included in the highest hepatotoxicity category when based on case reports.
CONCLUSIONS AND RELEVANCE
In this study, incidence rates of severe ALI using real-world data identified the most potentially hepatotoxic medications and can serve as a tool to investigate hepatotoxicity safety signals obtained from case reports. Case report counts did not accurately reflect the observed rates of severe ALI after medication initiation.
PubMed: 38913369
DOI: 10.1001/jamainternmed.2024.1836 -
Frontiers in Oncology 2024Aurora kinase A (AURKA) and tumor-infiltrating lymphocytes (TILs) are both known to play an essential role in tumorigenesis. However, the expression and prognostic value...
BACKGROUND
Aurora kinase A (AURKA) and tumor-infiltrating lymphocytes (TILs) are both known to play an essential role in tumorigenesis. However, the expression and prognostic value of the AURKA and TILs in medullary thyroid carcinoma (MTC) have not yet been investigated.
PATIENTS AND METHODS
Surgical specimens and clinical data of 137 patients diagnosed with MTC were collected. AURKA expression and TILs infiltration were quantified by immunohistochemistry and hematoxylin-eosin staining. Subsequently, the prognostic value of AURKA expression and TIL infiltration in MTC was evaluated.
RESULTS
AURKA was highly expressed in patients with multifocal tumor, cervical lymph node metastasis, and an advanced TNM stage, indicating a high probability of recurrence. AURKA further exhibited a positive correlation with TILs (R = 0.44, < 0.001). High expression of AURKA combined with a low numbers of TILs (AURKA/TILs) was identified as an independent prognostic factor for biochemical recurrence (odds ratio: 4.57, 95% confidence interval: 1.54-14.66, < 0.01) and recurrence-free survival (hazard ratio: 3.64, 95% confidence interval: 1.52-8.71, < 0.001). The combination of AURKA and TILs apparently improves the prognostic value for biochemical recurrence (area under the curve: 0.751) and structural recurrence (area under the curve: 0.836) of MTC. Notably, AURKA/TILs demonstrated a high value for prediction of distant or unresectable locoregional recurrence, with an overall accuracy of 86.9%.
CONCLUSION
AURKA is associated with the MTC malignancy. The combination of AURKA/TILs was identified as novel independent prognostic marker in MTC, predicting incurable disease recurrence with high accuracy.
PubMed: 38903715
DOI: 10.3389/fonc.2024.1379420 -
Cells May 2024N-acetyl-selenomethionine (NASeLM), a representative of the selenium compounds, failed to convince in clinical studies and cell cultures that it neither inhibits cancer... (Comparative Study)
Comparative Study
UNLABELLED
N-acetyl-selenomethionine (NASeLM), a representative of the selenium compounds, failed to convince in clinical studies and cell cultures that it neither inhibits cancer growth nor has a chemoprotective effect. This study aims to find out whether NASeLM shows a growth-inhibiting property compared to the carrier substance N-Acetyl-L-methionine (NALM) on two different cancer cells, namely Jurkat cells and MTC-SK cells.
METHODS
Jurkat and MTC-SK cells were cultured in the absence or presence of varying concentrations (0-500 µg/mL) of NASeLM and NALM solutions. After 0, 24, 48, and 72 h, mitochondrial activity, cancer cell membrane CP levels, cell growth, and caspase-3 activity were assessed in aliquots of Jurkat and MTC-SK cells.
RESULTS
Both substances, NASeLM and NALM, were similarly able to inhibit cell growth and mitochondrial activity of Jurkat cells in a concentration-dependent and time-dependent manner up to 70%. Only the determination of caspase activity showed that only NASeLM was able to increase this to almost 40% compared to the control as well as the same lack of NALM. However, the experiments on MTC-SK cells showed a clear difference in favor of NASeLM compared to NALM. While NASeLM was able to reduce cell growth to up to 55%, the same amount of NALM was only at around 15%, which turned out to be highly significant ( < 0.001). The same could also be measured for the reduction in MTC-SK mitochondrial activity. Time dependence could also be recognized: the longer both substances, NASeLM and NALM, were incubated, the higher the effect on cell growth and mitochondrial activity, in favour of NASeLM. Only NASeLM was able to increase caspase-3 activity in MTC-SK cells: at 250 µg/mL NASeLM, caspase-3 activity increased significantly to 28% after 24 and 48 h compared to the control (14%) or the same NALM concentration (14%). After 72 h, this could still increase to 37%. A further increase in the NASeLM concentration did not result in higher caspase-3 activity.
CONCLUSION
NASeLM could clearly increase caspase-3 activity in both cell types, Jurkat or MTC-SK cells, and thus induce cell death. NALM and NASeLM showed a reduction in cell growth and mitochondrial activity in both cell lines: While NALM and NASeLM showed almost identical measurements on Jurkat cells, NASeLM was much more effective on MTC-SK than the non-selenium-containing carrier, indicating that it has additional anti-chemoprotective effects.
Topics: Humans; Selenomethionine; Jurkat Cells; Methionine; Cell Proliferation; Mitochondria; Caspase 3; Cell Line, Tumor; Apoptosis
PubMed: 38891069
DOI: 10.3390/cells13110937 -
Chinese Clinical Oncology May 2024Thyroid cancer is the most common endocrine malignancy. It presents a significant challenge despite advances in treatment. Immunotherapy, which harnesses the body's...
Thyroid cancer is the most common endocrine malignancy. It presents a significant challenge despite advances in treatment. Immunotherapy, which harnesses the body's immune system to fight cancer, has emerged as a potential solution. The immune system's interaction with cancer cells follows a complex process involving immune surveillance, equilibrium, and escape. On the other hand, cancer cells develop mechanisms, such as loss of antigenicity and immunogenicity, as well as creating an immunosuppressed tumor microenvironment, to evade immune response. Immunotherapy modalities, including immune checkpoint inhibitors like anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and anti-programmed cell death protein 1/programmed cell death protein-ligand 1 (PD-1/PD-L1), have shown promising results in various cancers. In the context of thyroid cancer, immunotherapy, particularly PD-1/PD-L1 blockade, has been explored in patients with follicular cell-derived thyroid carcinomas and medullary thyroid carcinomas (MTCs). Clinical trials using PD-1/PD-L1 inhibitors, such as pembrolizumab and nivolumab, have been conducted for these cases, with varying degrees of success. Although preclinical studies have suggested the potential benefit of immunotherapy modalities for patients with follicular cell-derived thyroid carcinoma, to date, clinical studies have failed to demonstrate clear clinical benefits in patients with advanced thyroid cancer. Additionally, other approaches like dendritic cell vaccination and radioimmunotherapy have been explored mainly for MTC, showing potential but requiring further investigation. While immunotherapy holds promise, especially in combination with other treatments, further research, and high-quality clinical trials are necessary to establish its effectiveness in treating advanced thyroid cancers.
PubMed: 38859604
DOI: 10.21037/cco-23-133 -
Heliyon Jun 2024Selpercatinib is effective in the treatment of RET-altered medullary thyroid carcinoma (MTC). This study aimed to evaluate the efficacy and safety of selpercatinib in...
BACKGROUND
Selpercatinib is effective in the treatment of RET-altered medullary thyroid carcinoma (MTC). This study aimed to evaluate the efficacy and safety of selpercatinib in the treatment of patients with RET-altered MTC.
METHODS
PubMed, Embase, the Cochrane Library, and ClinicalTrials.gov were searched from their inception to April 5, 2024. Outcomes included complete response (CR), partial response (PR), stable disease (SD), objective response rate (ORR), disease control rate (DCR), and adverse events (AEs). We carried out a meta-analysis of these studies and exploratory subgroup analyses. The effect sizes for all pooled results were presented as 95% confidence intervals with upper and lower limits.
RESULTS
The pooled CR, PR, and SD rates for all patients were 10%, 59%, and 26%, respectively. The pooled ORR in all patients was 70%, while the pooled ORR in pre-treated and non-pre-treated groups were 67% and 70%, respectively. The pooled DCR in all patients was 95%, while the pooled DCR in pre-treated and non-pre-treated groups were 96% and 95%, respectively. The most common AEs associated with selpercatinib were hypertension, alanine aminotransferase (ALT) increased and aspartate aminotransferase (AST) increased.
CONCLUSION
Selpercatinib offers significant benefits to patients with RET-altered MTC with assessable CR, PR, SD, ORR, and grade 3-4 AEs; however, treatment-related AEs should be considered.
PubMed: 38841496
DOI: 10.1016/j.heliyon.2024.e31681 -
Oncology Research 2024This review aimed to describe the inculpation of microRNAs (miRNAs) in thyroid cancer (TC) and its subtypes, mainly medullary thyroid carcinoma (MTC), and to outline... (Review)
Review
This review aimed to describe the inculpation of microRNAs (miRNAs) in thyroid cancer (TC) and its subtypes, mainly medullary thyroid carcinoma (MTC), and to outline web-based tools and databases for bioinformatics analysis of miRNAs in TC. Additionally, the capacity of miRNAs to serve as therapeutic targets and biomarkers in TC management will be discussed. This review is based on a literature search of relevant articles on the role of miRNAs in TC and its subtypes, mainly MTC. Additionally, web-based tools and databases for bioinformatics analysis of miRNAs in TC were identified and described. MiRNAs can perform as oncomiRs or antioncoges, relying on the target mRNAs they regulate. MiRNA replacement therapy using miRNA mimics or antimiRs that aim to suppress the function of certain miRNAs can be applied to correct miRNAs aberrantly expressed in diseases, particularly in cancer. MiRNAs are involved in the modulation of fundamental pathways related to cancer, resembling cell cycle checkpoints and DNA repair pathways. MiRNAs are also rather stable and can reliably be detected in different types of biological materials, rendering them favorable diagnosis and prognosis biomarkers as well. MiRNAs have emerged as promising tools for evaluating medical outcomes in TC and as possible therapeutic targets. The contribution of miRNAs in thyroid cancer, particularly MTC, is an active area of research, and the utility of web applications and databases for the biological data analysis of miRNAs in TC is becoming increasingly important.
Topics: Humans; Thyroid Neoplasms; MicroRNAs; Biomarkers, Tumor; Carcinoma, Neuroendocrine; Prognosis; Computational Biology; Gene Expression Regulation, Neoplastic; Internet; Molecular Targeted Therapy
PubMed: 38827323
DOI: 10.32604/or.2024.049235