Combined targeted therapy and immunotherapy in anaplastic thyroid carcinoma with distant metastasis: A case report

BACKGROUND Anaplastic thyroid carcinoma(ATC),also called undifferentiated thyroid cancer,is the least common but most aggressive and deadly thyroid gland malignancy of all thyroid cancers[1].It has poor prognosis,and is the leading cause of death from malignant thyroid tumors.The one-year survival rate is 20%,with a median overall survival(OS)of only 5 mo[2].The aim of this report is to provide our experience in the diagnosis and treatment of ATC.CASE SUMMARY A patient with a thyroid mass underwent surgical treatment after developing symptoms of hoarseness.The resected tumor was pathologically diagnosed as ATC.Imaging examination revealed organ and lymph node metastasis.After multiple cycles of chemotherapy and local radiotherapy,the metastases were not relieved and gradually increased in size and new metastases appeared.The patient immediately received immunotherapy combined with targeted therapy.During treatment,immune-related adverse reactions occurred,which were improved after symptomatic treatment,and tolerated by the patient.The OS of the patient was more than 30 mo after immunotherapy combined with targeted therapy.CONCLUSION For metastatic ATC,surgical treatment,radiotherapy and chemotherapy have no significant effect on remission of the disease.However,immunotherapy has made a breakthrough in the treatment of ATC。

TMEM158 May Serve as a Diagnostic Biomarker for Anaplastic Thyroid Carcinoma:An Integrated Bioinformatic Analysis

Anaplastic thyroid carcinoma(ATC)is a rare but extremely lethal malignancy.However,little is known about the pathogenesis of ATC.Given its high mortality,it is critical to improve our understanding of ATC pathogenesis and to find new diagnostic biomarkers.In the present study,two gene microarray profiles(GSE53072 and GSE65144),which included 17 ATC and 17 adjacent non-tumorous tissues,were obtained.Bioinformatic analyses were then performed.Immunohistochemistry(IHC)and receiver operating characteristic(ROC)curves were then used to detect transmembrane protein 158(TMEM158)expression and to assess diagnostic sensitivity.A total of 372 differentially expressed genes(DEGs)were identified.Through protein-protein interaction(PPI)analysis,we identified a significant module with 37 upregulated genes.Most of the genes in this module were related to cell-cycle processes.After co-expression analysis,132 hub genes were selected for further study.Nine genes were identified as both DEGs and genes of interest in the weighted gene co-expression network analysis(WGCNA).IHC and ROC curves confirmed that TMEM158 was overexpressed in ATC tissue as compared with other types of thyroid cancer and normal tissue samples.We identified 8 KEGG pathways that were associated with high expression of TMEM158,including aminoacyl-tRNA biosynthesis and DNA replication.Our results suggest that TMEM158 may be a potential oncogene and serve as a diagnostic indicator for ATC.

Aberrant DNA repair as a potential contributor for the clonal evolution in subsets of anaplastic thyroid carcinomas arising through dedifferentiation: implications for future therapeutic algorithms?

Well-differentiated thyroid carcinoma(WDTC,including papillary thyroid carcinoma and follicular thyroid carcinoma)are fairly slow-growing tumors with an overall low mortality due to the efficacy of combinatory surgery and postoperative radioiodine therapy.Subsets of WDTCs may dedifferentiate into poorly differentiated thyroid carcinoma(PDTC)and anaplastic thyroid carcinoma(ATC),of which especially the latter has an exceptionally poor patient outcome.The underlying genetics responsible for this tumor progression is only partly understood,and is complicated by the fact that subgroups of ATCs are thought to arise de novo without a demonstrable,pre-existing WDTC.Even so,recent advances using next generation sequencing(NGS)techniques have identified a genetic link between WDTCs and ATCs,suggesting a step-wise accumulation of mutations driving the loss of differentiation for most cases.In this Commentary,recent findings from an NGS study on synchronous FTC,PDTC,and ATC tumor components from the same patient are highlighted.By using whole-genome data,clonality analyses identified a chief ancestral clone carrying mutations in TP53-associated signaling networks regulating genes involved in DNA repair,with sub-clones in each tumor component that were identified also in the less differentiated,neighboring tumor.Moreover,mutational signatures suggested a general mismatch repair(MMR)deficiency along with microsatellite instability.These findings support the chained progression model of dedifferentiation in thyroid cancer,and pinpoint a central role for defective DNA repair.Since effective treatment modalities for ATCs are urgently needed,studies regarding therapeutic agents specifically targeting defective MMR in dedifferentiated thyroid carcinoma could be pursued.

Capsaicin restores sodium iodine symportermediated radioiodine uptake through bypassing canonical TSH–TSHR pathway in anaplastic thyroid carcinoma cells

Anaplastic thyroid cancer(ATC)is a rare but highly lethal disease.ATCs are resistant to standard therapies and are extremely difficult to manage.The stepwise cell dedifferentiation results in the impairment of the iodine-metabolizing machinery and the infeasibility of radioiodine treatment in ATC.Hence,reinducing iodine-metabolizing gene expression to restore radioiodine avidity is considered as a promising strategy to fight against ATC.In the present study,capsaicin(CAP),a natural potent transient receptor potential vanilloid type 1(TRPV1)agonist,was discovered to reinduce ATC cell differentiation and to increase the expression of thyroid transcription factors(TTFs including TTF-1,TTF-2,and PAX8)and iodine-metabolizing proteins,including thyroidstimulating hormone receptor(TSHR),thyroid peroxidase,and sodium iodine symporter(NIS),in two ATC cell lines,8505C and FRO.Strikingly,CAP treatment promoted NIS glycosylation and its membrane trafficking,resulting in a significant enhancement of radioiodine uptake of ATC cells in vitro.Mechanistically,CAP-activated TRPV1 channel and subsequently triggered Ca2þinflux,cyclic adenosine monophosphate(cAMP)generation,and cAMP-responsive element-binding protein(CREB)signal activation.Next,CREB recognized and bound to the promoter of SLC5A5 to facilitate its transcription.Moreover,the TRPV1 antagonist CPZ,the calcium chelator BAPTA,and the PKA inhibitor H-89 effectively alleviated the redifferentiation exerted by CAP,demonstrating that CAP might improve radioiodine avidity through the activation of the TRPV1–Ca2þ/cAMP/PKA/CREB signaling pathway.In addition,our study indicated that CAP might trigger a novel cascade to redifferentiate ATC cells and provide unprecedented opportunities for radioiodine therapy in ATC,bypassing canonical TSH–TSHR pathway.