Advanced Papillary Thyroid Cancer Research Articles

Prophylactic Central Compartment Dissection on the Long-Term Outcome of Advanced (N0-T3/T4) Papillary Thyroid Cancer

Prophylactic Central Compartment Dissection on the Long-Term Outcome of Advanced (N0-T3/T4) Papillary Thyroid Cancer

The emerging role and clinical significance of circRNAs in papillary thyroid cancer.

Papillary thyroid cancer (PTC) is the most common type of thyroid malignancy, and its global incidence has been gradually increasing. For advanced PTC, the mortality rates are also increasing yearly. Despite advancements in diagnosis and treatment, some advanced PTC exhibit aggressive behaviors, leading to a poor prognosis. CircRNAs are a class of non-coding RNAs characterized by a covalently closed loop structure. Their stability and abundance have positioned them as promising diagnostic and prognostic biomarkers. Numerous studies have identified dysregulated circRNAs in PTC tissues and cell lines, suggesting their involvement in PTC initiation and progression. In this review, we provide an overview of circRNAs and systematically discuss their role in PTC. CircRNAs affect cancer progression by regulating the Wnt/β-catenin, PI3K/AKT, MAPK pathways, and others. Furthermore, circRNAs have been implicated in PTC metastasis and chemoresistance. We highlight their potential value as diagnostic markers, therapeutic targets, and prognostic indicators. In conclusion, circRNAs play a critical role in PTC, and dysregulated circRNAs influence multiple signaling pathways and cellular processes involved in tumorigenesis and metastasis. It represents a promising avenue for advancing the diagnosis, management, and treatment of PTC.

METTL3 inhibition induced by M2 macrophage-derived extracellular vesicles drives anti-PD-1 therapy resistance via M6A-CD70-mediated immune suppression in thyroid cancer.

The treatment options for advanced papillary thyroid cancer (PTC) and anaplastic thyroid cancer (ATC) refractory to standard therapies are limited. Although anti-PD-1 therapy has a manageable safety profile and has been effective in a small percentage of patients with advanced PTC and refractory ATC, the majority of the patients either do not respond or develop resistance to anti-PD-1 therapy. N6-methyladenosine (m6A) modification is a critical determinant of the complexity of the tumor microenvironment (TME). However, it is unclear whether and how m6A modification in tumor cells shapes the immune landscape of PTC and ATC. In this study, we performed bulk and single cell RNA sequencing analysis of PTC and ATC tissues, and found that low METTL3 expression not only correlated to poor response to immune checkpoint blockade (ICB) but was also associated with increased TNF family-related ligand-receptor interactions in the immunosuppressive Tregs and exhausted T cells. Furthermore, overexpression of METTL3 in PTC and ATC cells enhanced the efficacy of anti-PD-1 therapy in a peripheral blood mononuclear cell humanized NCG (huPBMC-NCG) mouse model. Mechanistically, M2 macrophage-derived extracellular vesicles (M2 EVs) inhibited METTL3 expression in PTC and ATC cells via miR-21-5p. Downregulation of METTL3 promoted demethylation of CD70 mRNA, which prevented YTHDF2-mediated degradation of the transcripts. The stabilization of CD70 mRNA, and the subsequent upregulation in CD70 protein levels increased the abundance of the immunosuppressive Tregs and terminally exhausted T cells, thereby inducing resistance to anti-PD-1 therapy. Furthermore, blocking CD70 using cusatuzumab, a high-affinity monoclonal antibody, reversed the anti-PD-1 therapy resistance induced by M2 EVs in vivo. Finally, we demonstrated that METTL3 expression negatively correlated with CD70 expression and M2 macrophages and Tregs infiltration in PTC and ATC tissues. Our findings provide new insights into developing novel therapies for advanced PTC and ATC.

Overall survival trends of papillary thyroid cancer: A Surveillance, Epidemiology, and End Results (SEER) population-based data (2002-2016).

e18108 Background: In the United States, the 5-year survival rate for patients with thyroid cancer is 98%. However, survival rates are mainly influenced by the type of thyroid cancer and the stage of the disease. The tremendous research in the area and the need to assess outcomes of recently implemented treatments necessitate the evaluation of the epidemiology and overall survival rates of the most common type of this malignancy, papillary thyroid cancer (PTC). Although the cause-specific survival (CSS) of Papillary Thyroid Cancer (PTC) patients has been extensively investigated, the overall survival (OS) of these patients is unclear. In this study, we aim to conduct an evaluation of survival trends after PTC diagnosis by stage of disease for the years 2002 through 2016 in the United States. Methods: We used the SEER 9 database to study PTC cases during 2002-2016. The patient survival data for the three disease stages (local, regional, and distal) were compared for the two time periods of interest, (2002-2008) and (2009-2016). The data for each cohort were split into six groups, (those whose deaths were in each of the five one-year intervals and those surviving the five-year follow-up period). These categorical counts were compared by the chi-square test of contingency table data. Statistical significance was taken as a p-value less than 0.05. Results: We reviewed 73,333 PTC cases in the United States from 2002 through 2016. There was an overall survival improvement with the exception of the distal stage, which did not demonstrate any statistical difference in the 2-time frames of interest. For local sites, there was a highly significant difference between the survival distributions of patients in the two time periods of interest (p = 0.0095; chi-square test statistic = 15.20 with 5 degrees of freedom). For regional sites, there was a highly significant difference between the survival distributions of patients in the two time periods of interest (p = 0.0077; chi-square test statistic = 15.72 with 5 degrees of freedom). For the distant stage, there was no significant difference between the survival distributions of patients in the two time periods of interest (p = 0.28; chi-square test statistic = 6.25 with 5 degrees of freedom). Conclusions: PTC’s survival rates have shown an improvement over the years 2002 through 2016, mostly noted in the local and regional stages. Although most patients with PTC have a favorable prognosis when conventional treatments are implemented, local recurrence and distant metastasis of advanced PTCs still hamper the survival and clinical management in certain patients.

Initial Experiences of Selective RET Inhibitor Selpercatinib in Adults with Metastatic Differentiated Thyroid Carcinoma and Medullary Thyroid Carcinoma: Real-World Case Series in Korea

Recently, selpercatinib, a highly selective inhibitor of RET receptor tyrosine kinase, has been used for RET-altered thyroid cancer. We present four cases of patients with advanced thyroid cancer who were treated with selpercatinib. The first patient was a 63-year-old male with advanced medullary thyroid cancer (MTC) treated with vandetanib. Six months ago, he had an intracranial hemorrhage and swallowing difficulty. He started selpercatinib with percutaneous endoscopic gastrostomy (PEG). For 11 months, a partial response (PR) was observed stably with PEG administration without any more cardiovascular events. The second patient was a 67-year-old female with advanced MTC treated with vandetatib. After selpercatinib treatment, a PR was observed for most metastatic sites, including choroidal metastasis. The third patient was a 32-year-old female with advanced papillary thyroid cancer (PTC) without history of systematic treatment. For six months, a PR was observed at her metastatic site with manageable adverse events. The last patient was a 59-year-old female with advanced PTC treated with lenvatinib. She suffered from a panic disorder and pleural pain due to metastasis during lenvatinib treatment. After selpercatinib treatment, her pain and panic symptoms were improved. Facing varying clinical obstacles of the real world, selpercatinib safely proved remarkable therapeutic efficacy regardless of previous treatment or metastatic site.

BCL2L11 Induction Mediates Sensitivity to Src and MEK1/2 Inhibition in Thyroid Cancer.

Patients with advanced thyroid cancer, including advanced papillary thyroid cancer and anaplastic thyroid cancer (ATC), have low survival rates because of the lack of efficient therapies available that can combat their aggressiveness. A total of 90% of thyroid cancers have identifiable driver mutations, which often are components of the MAPK pathway, including BRAF, RAS, and RET-fusions. In addition, Src is a non-receptor tyrosine kinase that is overexpressed and activated in thyroid cancer, which we and others have shown is a clinically relevant target. We have previously demonstrated that combined inhibition of Src with dasatinib and the MAPK pathway with trametinib synergistically inhibits growth and induces apoptosis in BRAF- and RAS-mutant thyroid cancer cells. Herein, we identified the pro-apoptotic protein BCL2L11 (BIM) as being a key mediator of sensitivity in response to combined dasatinib and trametinib treatment. Specifically, cells that are sensitive to combined dasatinib and trametinib treatment have inhibition of FAK/Src, MEK/ERK, and AKT, resulting in the dramatic upregulation of BIM, while cells that are resistant lack inhibition of AKT and have a dampened induction of BIM. Inhibition of AKT directly sensitizes resistant cells to combined dasatinib and trametinib but will not be clinically feasible. Importantly, targeting BCL-XL with the BH3-mimeitc ABT-263 is sufficient to overcome lack of BIM induction and sensitize resistant cells to combined dasatinib and trametinib treatment. This study provides evidence that combined Src and MEK1/2 inhibition is a promising therapeutic option for patients with advanced thyroid cancer and identifies BIM induction as a potential biomarker of response.

Total Laryngectomy in Advanced Papillary Thyroid Cancer Infiltrating into Larynx: A Case Report & review of Literature

Abstract: Among differentiated thyroid cancer (DTC), papillary thyroid cancer (PTC) is the most commonly encountered histological type. Patients with papillary thyroid carcinoma (PTC) show an excellent prognosis. Infiltration of PTC into the larynx is very rare and can worsen the disease prognosis. We are reporting one such rare case in which PTC showed invasion in the larynx causing narrowing of the airway. We performed total thyroidectomy with total laryngectomy and neck dissection.

Analysis of the key ligand receptor CADM1_CADM1 in the regulation of thyroid cancer based on scRNA-seq and bulk RNA-seq data.

Advanced papillary thyroid cancer (PTC) has a poor prognosis, 60~70% of which become radio iodine refractory (RAI-R), but the molecular markers that assess PTC progress to advanced PTC remain unclear. Meanwhile, current targeted therapies are badly effective due to drug resistance and adverse side effects. Ligand-receptor pairs (L/R pairs) play an important role in the interactions between tumor cells and other cells in the tumor microenvironment (TME). Nowadays, therapies targeting ligand-receptor pairs in the TME are advancing rapidly in the treatment of advanced cancers. However, therapies targeting L/R pairs applied to advanced PTC remains challenging because of limited knowledge about L/R pairs in PTC. We screened the critical L/R pair: CADM1-CADM1 using 65311 single-cell RNA sequencing (scRNA-seq) samples from 7 patients in different stage of PTC and bulk RNA-seq datasets containing data from 487 tumor samples and 58 para-carcinoma samples. Moreover, the expression levels of CADM1-CADM1 was assessed by quantitative real time polymerase chain reaction (qRT-PCR) and the function was analyzed using Transwell immigration assay. We found that CADM1_CADM1 could be regarded as a biomarker representing a good prognosis of PTC. In addition, the high expression of CADM1_CADM1 can strongly increase the sensitivity of many targeted drugs, which can alleviate drug resistance. And the results of qRT-PCR showed us that the expression of CADM1_CADM1 in PTC was down-regulated and overexpression of CADM1 could suppresses tumor cell invasion migration. Our study identified that CADM1_CADM1 played an essential role in the progression of PTC for the first time and our findings provide a new potential prognostic and therapeutic ligand-receptor pair for advanced PTC.

Clinical significance of extrathyroidal extension to major vessels in papillary thyroid carcinoma.

Gross extrathyroidal extension (gETE) into major vessel is considered the most advanced stage of the locally advanced papillary thyroid cancer (PTC). Surgical intervention may not benefit some patients at this disease stage or even result in intraoperative death due to massive hemorrhage; however, it is still considered an effective strategy for most cases. The lack of description for this challenging invasion in PTC warrants detailed characterization of its pattern, risk factors, optimal surgical method, and prognostic value. In total, 3127 patients diagnosed as having PTC were enrolled and categorized into two the following groups, namely the major vessel invasion (MVI) group (n = 30) and the control group (n = 3097). Data regarding clinicopathological and demographic characteristics, vascular invasion sites, postoperative complications, locoregional recurrence, distant metastasis, and surgical strategies were collected. Predictive disease-free survival (DFS) was also compared between the two groups. MVI was independently associated with invasion of the esophageal extension, age < 55years, tumor size > 1cm, lateral lymph node metastasis, and distant metastasis (P = 0.00; P = 0.01; 0.05; P = 0.00; P = 0.00, respectively). The difference in the predictive DFS between the two groups was significant (P = 0.00), and the difference remained significant even in patients with ETE when compared with patients without ETE (P = 0.00). Additionally, predictive DFS did not differ significantly between patients who received vessel repairment and those who received vessel resection (P = 0.28). This study first characterized the gross MVI pattern exhibited by PTC and the risk factors for MVI. Additionally, it demonstrated the DFS of patients with PTC. Extensive gross MVI significantly worsened the biological characteristics of PTC. Regardless of the high risk and difficulty of the operation, patients still benefited from the surgical intervention, and vessel repairment may be the optimal surgical strategy.

162 (PB042) - The effects of Aurora Kinase inhibition on thyroid cancer growth and sensitivity to MAPK-directed therapies

Background: Advanced papillary thyroid cancer (PTC) and anaplastic thyroid cancer (ATC) are the leading causes of endocrine cancer death. Mutations in the MAP kinase (MAPK) pathway are common in PTC and ATC. Recently, the combination of dabrafenib (BRAFi) and trametinib (MEKi) was approved for treatment of BRAF-mutant ATC. However, combined BRAF/ MEK inhibition is rarely curative for ATC patients and has had limited responses in PTC. Here, we identify an induction of Aurora Kinase B (AURKB) in response to MEKi in cells that are resistant to combined BRAF/MEK inhibition.

Facility Volume as a Prognosticator of Survival in Locally Advanced Papillary Thyroid Cancer.

To evaluate the influence of facility case-volume on survival in patients with locally advanced papillary thyroid cancer (PTC), and to identify prognostic case-volume thresholds for facilities managing this patient population. Retrospective database study. The 2004-2017 National Cancer Database was queried for patients receiving definitive surgery for locally advanced PTC. Using K-means clustering and multivariable Cox proportional-hazards (CPH) regression, two groups with distinct spectrums of facility case-volumes were generated. Multivariable CPH regression and Kaplan-Meier analysis assessed for the influence of facility case-volume and the prognostic value of its stratification on overall survival (OS). Of 48,899 patients treated at 1304 facilities, there were 34,312 (70.2%) females and the mean age was 48.0 ± 16.0 years. Increased facility volume was significantly associated with reduced all-cause mortality (HR 0.996; 95% CI, 0.992-0.999; p=0.008). Five facility clusters were generated, from which two distinct cohorts were identified: low (LVF; <27 cases/year) and high (HVF; ≥27 cases/year) facility case-volume. Patients at HVFs were associated with reduced mortality compared to those at LVFs (HR 0.791; 95% CI, 0.678-0.923, p=0.003). Kaplan-Meier analysis of propensity score-matched N0 and N1 patients demonstrated higher OS in HVF cohorts (all p < 0.001). Facility case-volume was an independent predictor of improved OS in locally advanced PTC, indicating a possible survival benefit at high-volume medical centers. Specifically, independent of a number of sociodemographic and clinical factors, facilities that treated ≥27 cases per year were associated with increased OS. Patients with locally advanced PTC may, therefore, benefit from referrals to higher-volume facilities. 4 Laryngoscope, 133:443-450, 2023.

Pralsetinib: chemical and therapeutic development with FDA authorization for the management of RET fusion-positive non-small-cell lung cancers.

Pralsetinib (PRL) is a selective Rearranged during Transfection (RET) inhibitor, developed by Blueprint Medicines Corporation for the treatment of RET fusion non-small-cell lung cancer (NSCLC), papillary thyroid cancer (PTC), and medullary thyroid carcinoma (MTC). RET is a known proto-oncogene found in NSCLC, PTC, and MTC. PRL was recently granted accelerated USFDA approval with the brand name GAVRETO™ on 4 September 2020 to treat metastatic RET fusion-positive NSCLC and was updated on 1 December 2020 with the addition of advanced and metastatic RET-altered MTC and PTC in the USA. On 19 November 2021, the European Commission granted conditional marketing authorization to PRL for use as a single agent in adult patients with RET fusion-positive advanced NSCLC. They were not previously treated with an RET inhibitor. This review article summarizes the milestones in the development of PRL, chemistry, chemical (synthesis) research and development, characterization and identification of PRL-resistant RET mutants, the structural basis of resistance to PRL, mechanism of action, pharmacokinetics, pharmacodynamic, adverse effects, and regulatory status, including ongoing clinical trial of PRL and other potential drug candidates, leading to this first approval of PRL for the treatment of various solid tumors (RET fusion NSCLC, MTC, and PTC).

Transcriptomic Analysis of Papillary Thyroid Cancer: A Focus on Immune-Subtyping, Oncogenic Fusion, and Recurrence.

ObjectivesThyroid cancer is the most common endocrine tumor, with rapidly increasing incidence worldwide. However, its transcriptomic characteristics associated with immunological signatures, driver fusions, and recurrence markers remain unclear. We aimed to investigate the transcriptomic characteristics of advanced papillary thyroid cancer.MethodsThis study included 282 papillary thyroid cancer tumor samples and 155 normal samples from Chungnam National University Hospital and Seoul National University Hospital. Transcriptomic quantification was determined by high-throughput RNA sequencing. We investigated the associations of clinical parameters and molecular signatures using RNA sequencing. We validated predictive biomarkers using the Cancer Genome Atlas database.ResultsThrough a comparison of differentially expressed genes, gene sets, and pathways in papillary thyroid cancer compared to normal tumor-adjacent tissue, we found increased immune signaling associated with cytokines or T cells and decreased thyroid hormone synthetic pathways. In addition, patients with recurrence presented increased CD8+ T-cell and Th1-cell signatures. Interestingly, we found differentially overexpressed genes related to immune-escape signaling such as CTLA4, IDO1, LAG3, and PDCD1 in advanced papillary thyroid cancer with a low thyroid differentiation score. Fusion analysis showed that the PI3K and mitogen-activated protein kinase (MAPK) signaling pathways were regulated differently according to the RET fusion partner genes (CCDC6 or NCOA4). Finally, we identified HOXD9 as a novel molecular biomarker that predicts the recurrence of thyroid cancer in addition to known risk factors (tumor size, lymph node metastasis, and extrathyroidal extension).ConclusionWe identified a high association with immune-escape signaling in the immune-hot group with aggressive clinical characteristics among Korean thyroid cancer patients. Moreover, RET fusion differentially regulated PI3K and MAPK signaling depending on the partner gene of RET, and HOXD9 was found to be a recurrence marker for advanced papillary thyroid cancer.

Identification of lipid metabolism-related genes as prognostic indicators in papillary thyroid cancer.

Lipid metabolism plays important roles not only in the structural basis and energy supply of healthy cells but also in the oncogenesis and progression of cancers. In this study, we investigated the prognostic value of lipid metabolism-related genes in papillary thyroid cancer (PTC). The recurrence predictive gene signature was developed and internally and externally validated based on PTC datasets including The Cancer Genome Atlas (TCGA) and GSE33630 datasets. Univariate, LASSO, and multivariate Cox regression analysis were applied to assess prognostic genes and build the prognostic gene signature. The expression profiles of prognostic genes were further determined by immunohistochemistry of tissue microarray using in-house cohorts, which enrolled 97 patients. Kaplan-Meier curve, time-dependent receiver operating characteristic curve, nomogram, and decision curve analyses were used to assess the performance of the gene signature. We identified four recurrence-related genes, PDZK1IP1, TMC3, LRP2 and KCNJ13, and established a four-gene signature recurrence risk model. The expression profiles of the four genes in the TCGA and in-house cohort indicated that stage T1/T2 PTC and locally advanced PTC exhibit notable associations not only with clinicopathological parameters but also with recurrence. Calibration analysis plots indicate the excellent predictive performance of the prognostic nomogram constructed based on the gene signature. Single-sample gene set enrichment analysis showed that high-risk cases exhibit changes in several important tumorigenesis-related pathways, such as the intestinal immune network and the p53 and Hedgehog signaling pathways. Our results indicate that lipid metabolism-related gene profiling represents a potential marker for prognosis and treatment decisions for PTC patients.

RAC1 Alterations Induce Acquired Dabrafenib Resistance in Association with Anaplastic Transformation in a Papillary Thyroid Cancer Patient.

Simple SummaryWe identified an acquired RAC1 (P34R) mutation in the metastatic tumor of a BRAF-mutated papillary thyroid cancer patient treated with the BRAF inhibitor dabrafenib. Further investigations uncovered a high RAC1 copy number in the metastatic sample and its derived cell line. We demonstrated that an increase in RAC1 copy numbers could lead to increased tumor cell growth independently of the RAC1 (P34R) mutation. Further, we identified polyploidy of chromosome 7 in the metastatic sample and derived cell line, which accounted for amplification of other genes, their increased expression and therefore their ability to also induce resistance to therapy.BRAF-activating mutations are the most frequent driver mutations in papillary thyroid cancer (PTC). Targeted inhibitors such as dabrafenib have been used in advanced BRAF-mutated PTC; however, acquired resistance to the drug is common and little is known about other effectors that may play integral roles in this resistance. In addition, the induction of PTC dedifferentiation into highly aggressive KRAS-driven anaplastic thyroid cancer (ATC) has been reported. We detected a novel RAC1 (P34R) mutation acquired during dabrafenib treatment in a progressive metastatic lesion with ATC phenotype. To identify a potential functional link between this novel mutation and tumor dedifferentiation, we developed a cell line derived from the metastatic lesion and compared its behavior to isogenic cell lines and primary tumor samples. Our data demonstrated that RAC1 mutations induce changes in cell morphology, reorganization of F-actin almost exclusively at the cell cortex, and changes in cell adhesion properties. We also established that RAC1 amplification, with or without mutation, is sufficient to drive cell proliferation and resistance to BRAF inhibition. Further, we identified polyploidy of chromosome 7, which harbors RAC1, in both the metastatic lesion and its derived cell line. Copy number amplification and overexpression of other genes located on this chromosome, such as TWIST1, EGFR, and MET were also detected, which might also lead to dabrafenib resistance. Our study suggests that polyploidy leading to increased expression of specific genes, particularly those located on chromosome 7, should be considered when analyzing aggressive thyroid tumor samples and in further treatments.

Identifying the tumor-progressive gene expression profile in high-risk papillary thyroid cancer.

Papillary thyroid cancer (PTC) is generally associated with a favorable prognosis. However, some patients have fatal disease, with locally infiltrating tumors or progressive distant metastases; yet few studies have investigated the characteristics of the tumor-progressive gene expression profile in advanced PTC. We conducted this study to clarify the gene expression status in advanced PTC and identify candidate molecules for prognostic biomarkers. We analyzed 740 tumor-progressive gene expression levels from formalin-fixed paraffin-embedded blocks of samples from six patients with low-risk PTC and six patients with high-risk PTC, using the nCounter PanCancer Progression panel. Then, we investigated the association between the expression levels of focused genes and pathological factors in PTC patients in The Cancer Genome Atlas (TCGA) database. The expression levels of 14 genes in the high-risk PTC specimens were more than two-fold those in the low-risk PTC specimens. In the TCGA database, expression levels of four genes (CCL11, COL6A3, INHBA, and SRPX2) were significantly higher in patients with advanced PTC. Among the patients with advanced PTC, those with high SRPX2 expression levels had poor disease-free survival. Univariate and multivariate analyses revealed that high SRPX2 expression was an independent prognostic factor. Based on the findings of this study, CCL11, COL6A3, INHBA, and SRPX2 are potential biomarkers that indicate advanced PTC. SRPX2, in particular, is considered a prognostic biomarker.

Perioperative Management of Advanced Papillary Thyroid Cancer in an Elderly Dementia Patient

Perioperative Management of Advanced Papillary Thyroid Cancer in an Elderly Dementia Patient

Characterization of immune landscape in papillary thyroid cancer reveals distinct tumor immunogenicity and implications for immunotherapy

ABSTRACT Although the vast majority of patients with papillary thyroid cancer (PTC) have a favorable prognosis when conventional treatments are implemented, local recurrence and distant metastasis of advanced PTCs still hamper the survival and clinical management in certain patients. As immune checkpoint blockade (ICB) therapy achieves a great success in some advanced cancers, we aimed to investigate the immune landscape in PTC and its potential implications for prognosis and immunotherapy. In this study, different algorithms were conducted to estimate immune infiltration in PTC samples. A series of bioinformatic and machine learning approaches were performed to identify PTC-specific immune-related genes (IRGs) and distinct immune clusters. Differences in intrinsic tumor immunogenicity and potential immunotherapy response were observed between distinct immune clusters. A prognostic immune-related signature (IRS) was established to predict progression-free survival (PFS). IRS exhibited more powerful prognostic capacity and accurate survival prediction compared to conventional clinicopathological features. Furthermore, an integrated survival decision tree and a scoring nomogram were constructed to improve prognostic stratification and predictive accuracy for individual patients. In addition, altered pathways, mutational patterns, and potential applicable drugs were analyzed in different immune-related risk groups. Our study gained some insight into the immune landscape of PTC, and provided some useful clues for introducing immune-based molecular classification into risk stratification and guiding ICB decision-making.

Radical neck dissection with advancement flap in advanced papillary thyroid cancer: a therapeutic option

Papillary thyroid cancer (TC) is the most common TC subtype with a global incidence of 80–90% and an annual rate of increase of 5% in the last ten years.Papillary TC has the peculiar tendency to spread to the central and lateral lymph nodes (LNs) of the neck, and recurrence occurs in 60–75% of cases. The most affected site is the central compartment.Total thyroidectomy with radical dissection achieved the best results for differentiated TC with LN involvement, with a complication rate of 6%.Classic radical dissection is an effective surgical approach when performed by experienced surgeons in cases in which there is a good knowledge of local anatomy, decreasing recurrence and improving survival.

MON-453 Dramatic Clinical Response to Lenvatinib in a Pediatric Patient with Advanced Metastatic Papillary Thyroid Carcinoma

Introduction: Papillary thyroid cancer (PTC) is the most common thyroid tumor in childhood. Most patients are referred with locally advanced and/or distant disease at the time of diagnosis. Whenever possible, these patients should be offered total thyroidectomy and radioiodine remnant ablation; however, this approach is not always feasible, rendering these tumors unresectable. These critical cases could benefit from neoadjuvant treatment with multikinase inhibitors (MKI) so that standard treatment can be performed. Lenvatinib is an MKI recently approved in many countries throughout the world for the treatment of radioiodine refractory adult differentiated thyroid cancer. Only few pediatric cases have been reported. Case report: A 10-year-old female patient with locally advanced PTC and metastasis to the lungs, who required 3 liters of oxygen due to respiratory failure caused by bilateral miliary lung disease, mistakenly treated as tuberculosis two months previously and referred to our Hospital. A large thyroid mass adhered to deep tissues was confirmed on CT scan, showing a large heterogeneous neck mass with multiple microcalcifications associated with multiple lymph nodes. Both lungs had multiple micro-nodular disease with interstitial involvement. Total thyroidectomy together with lymph-node dissection was planned, but extensive local infiltration made the lesion unresectable and surgery was limited to a thyroid biopsy. The patient required respiratory assistance. Histopathology confirmed the presence of a PTC (diffuse sclerosing variant) with a RET-PTC3 oncogene rearrangement. Eight days after surgery the patient was critical and we decided to indicate the compassionate use of Lenvatinib. The patient was started on oral lenvatinib at a dose of 14 mg daily (14 mg/m/day). Three days later, she clinically improved and nine days post-lenvatinib initiation, the patient was discharged from hospital without need for oxygen therapy. Lab studies showed a rise in thyroglobulin levels in the first month of treatment followed by a significant drop. All Lung Function Test parameters significantly improved. The patient initially had severe restrictive breathing and due to the resting dyspnea with hypoxemia she could not perform the walking test. Two months after treatment onset she could walk 360 meters in six minutes with 96% oxygen saturation. After 4 months on Lenvatinib, imaging studies showed a stable thyroid mass while the pulmonary nodules appeared stable to slightly smaller without evidence of new or progressive disease. Conclusion: On lenvatinib treatment, our patient showed significant clinical improvement, arrest of disease progression, and stable disease on imaging studies. This case shows that lenvatinib may be a beneficial option for children with advanced PTC not amenable to surgery/RAI treatment and may be used as a bridge to these first-line therapies.