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Human papillomavirus (HPV)–driven oropharyngeal carcinoma (OPSCC) is distinct from tobacco- or alcohol-associated OPSCC and has a unique immune landscape. Studies have supported the heterogeneity of T cells, accompanied by a broad repertoire of T-cell responses, within tumors driven by HPV infection. However, the phenotype and function of these HPV-related T cells remain unclear. Using a combination of single-cell RNA sequencing, flow cytometry, pharmacologic inhibition, and immunofluorescence staining, we explored the prognostic implication of HPV-related T cells and further validated our findings in two independent cohorts. Cytotoxic T lymphocytes (CTL) within OPSCC displayed a spectrum of transcriptional signatures. Among which, we identified CD161 receptor, encoded by KLRB1, as a potential marker to distinguish the CTL subsets in HPV-positive OPSCC with a divergent evolutionary trajectory. In-depth analysis revealed that CD161+ CTLs exhibited a more robust immune response over the CD161− counterparts and a T cell–inflamed phenotype that could be further reinvigorated by immune-checkpoint blockade. Despite the high expression of exhaustion markers, reinforcement of CD161+ CTL reactivity was expected to boost immune responses, considering their functional reversibility. We further confirmed that the high level of intratumoral CD161+ CTLs associated with a favorable treatment response and prolonged overall survival. Therefore, our research not only provides an insight into the immune landscape of HPV-driven OPSCC but also sheds light on a special subset of CTLs with prognostic and therapeutic significance.

Context Hypoxia is commonly observed in multiple aggressive cancers. Its role remains unclear in the biology and therapy of dedifferentiated thyroid cancer (DDTC). Objective We aimed to elucidate hypoxia's roles in DDTC tumor biology. Methods We discovered and confirmed hypoxia's correlation with dedifferentiation status, poor prognoses, and immune checkpoints in thyroid cancer using transcriptome data from our center and Gene Expression Omnibus (GEO) database. Then, the effect of targeting hypoxia was investigated via treating anaplastic thyroid cancer (ATC) cells with acriflavine (ACF) in vitro and in vivo, and hypoxia was analyzed for its association with response to immunotherapy in patients. Results Hypoxia score was positively associated with dedifferentiation status, and high hypoxia score significantly correlated with reduced overall survival, TP53 mutation, and elevated expression of immunosuppression-related markers in DDTC. ACF and siRNA targeting HIF-1α significantly suppressed growth and proliferation of thyroid cancer cells in vitro and in vivo, and reduced c-MYC and PDL1 expression in ATC. HIF-1α showed a positive correlation with PDL1 expression in DDTC. Integrated analyses of phosphoproteome and RNA sequencing data revealed that ACF's target was connected with differentiation genes and immune checkpoints via tumor-related kinases in ATC. Furthermore, hypoxia score was associated with immunotherapeutic response in some cancer types. Conclusion Hypoxia score serves as a significant indicator for dedifferentiation status, prognoses, and immunotherapeutic response predicted by Tumor Immune Dysfunction and Exclusion in DDTC patients. Targeting hypoxia by ACF is useful to alleviate aggressive phenotype of ATC in a preclinical model of DDTC.

Purpose: The phase II/III study of donafenib was initiated when there was no available treatment indicated for Chinese patients with progressive radioactive iodine-refractory differentiated thyroid cancer (RAIR-DTC). Donafenib, an oral tyrosine kinase inhibitor (TKI), showed good efficacy and tolerability in the phase II study. We aimed to further evaluate the antitumour activity and safety of donafenib in Chinese RAIR-DTC patients. Patients and Methods: This multicenter, double-blind, placebo-controlled, phase III study enrolled 191 patients with progressive RAIR-DTC and randomized in a ratio of 2:1 to donafenib (300 mg twice daily, n=128) or matched placebo (n=63). An open-label donafenib treatment period was allowed upon disease progression. The primary endpoint was progression-free survival (PFS) assessed by the independent review committee. The second endpoints include objective response rate (ORR), disease control rate (DCR), safety, etc. Results: Donafenib demonstrated prolonged median PFS over placebo (12.9 vs. 6.4 months, HR 0.39, 95% CI 0.25-0.61, p

Supplementary Table 1

Human papillomavirus (HPV)–driven oropharyngeal carcinoma (OPSCC) is distinct from tobacco- or alcohol-associated OPSCC and has a unique immune landscape. Studies have supported the heterogeneity of T cells, accompanied by a broad repertoire of T-cell responses, within tumors driven by HPV infection. However, the phenotype and function of these HPV-related T cells remain unclear. Using a combination of single-cell RNA sequencing, flow cytometry, pharmacologic inhibition, and immunofluorescence staining, we explored the prognostic implication of HPV-related T cells and further validated our findings in two independent cohorts. Cytotoxic T lymphocytes (CTL) within OPSCC displayed a spectrum of transcriptional signatures. Among which, we identified CD161 receptor, encoded by KLRB1, as a potential marker to distinguish the CTL subsets in HPV-positive OPSCC with a divergent evolutionary trajectory. In-depth analysis revealed that CD161+ CTLs exhibited a more robust immune response over the CD161− counterparts and a T cell–inflamed phenotype that could be further reinvigorated by immune-checkpoint blockade. Despite the high expression of exhaustion markers, reinforcement of CD161+ CTL reactivity was expected to boost immune responses, considering their functional reversibility. We further confirmed that the high level of intratumoral CD161+ CTLs associated with a favorable treatment response and prolonged overall survival. Therefore, our research not only provides an insight into the immune landscape of HPV-driven OPSCC but also sheds light on a special subset of CTLs with prognostic and therapeutic significance.

Supplementary figures and legends

Background Surgery is the primary treatment for locally advanced thyroid cancer. For some cases, R0/R1 resection could not be achieved at initial diagnosis and neoadjuvant treatment would be an opt...

TERT reactivation occurs frequently in human malignancies. While BRAF activating mutation widely existed in cancers at various stages, TERT reactivation mainly occurs in advanced tumors. However,in vivoevidence for TERT role in cancer progression and the underlying mechanism is currently lacking. In this study, we induced TERT and/or BRAF V600E expression in mouse thyroid epithelium. TERT overexpression alone had no evident effect on tumor initiation. BRAFVEexpression itself induced mediocre papillary thyroid cancer (PTC). Notably, the co-expression of BRAFVEand TERT resulted in aggressive poorly differentiated thyroid carcinoma (PDTC). Spatial transcriptome revealed that tumors from co-mutant mice were highly heterogeneous and dedifferentiation process significantly correlated with ribosomal pathways. Mechanistically, TERT boosted ribosomal RNA expression and protein synthesis. CX-5461, a rRNA transcription inhibitor, effectively blocked proliferation and induced redifferentiation. Thus, TERT promotes thyroid cancer progression by inducing dedifferentiation, and ribosome biogenesis inhibition represents a potential treatment strategy for TERT-reactivated cancers.Highlights➢TERT accelerated thyroid cancer dedifferentiation and metastasisin vivo➢TERT regulated rRNA metabolism and MTORC1/ S6K/RPS6 activities➢CX-5461 inhibited the progression of TERT-reactivated melanoma and thyroid cancer➢Inhibition of rRNA induced redifferentiation of advanced thyroid cancer with TERT activation

The tumor ecosystem of papillary thyroid carcinoma (PTC) is poorly characterized. Using single-cell RNA sequencing, we profile transcriptomes of 158,577 cells from 11 patients’ paratumors, localized/advanced tumors, initially-treated/recurrent lymph nodes and radioactive iodine (RAI)-refractory distant metastases, covering comprehensive clinical courses of PTC. Our data identifies a “cancer-primed” premalignant thyrocyte population with normal morphology but altered transcriptomes. Along the developmental trajectory, we also discover three phenotypes of malignant thyrocytes (follicular-like, partial-epithelial-mesenchymal-transition-like, dedifferentiation-like), whose composition shapes bulk molecular subtypes, tumor characteristics and RAI responses. Furthermore, we uncover a distinct BRAF-like-B subtype with predominant dedifferentiation-like thyrocytes, enriched cancer-associated fibroblasts, worse prognosis and promising prospect of immunotherapy. Moreover, potential vascular-immune crosstalk in PTC provides theoretical basis for combined anti-angiogenic and immunotherapy. Together, our findings provide insight into the PTC ecosystem that suggests potential prognostic and therapeutic implications., The characterisation of the papillary thyroid carcinoma (PTC) tumour microenvironment remains crucial. Here, the authors perform single-cell RNA sequencing in 11 patients and identify potential opportunities for the use of immunotherapy and its combination with anti-angiogenic therapy in PTC.

Background No available treatment existed in Chinese patients with progressive radioactive iodine–refractory differentiated thyroid cancer (RAIR-DTC) in terms of both affordability and safety upon the initiation of DIRECTION study. Donafenib is an oral tyrosine kinase inhibitor (TKI) with superior efficacy over sorafenib in hepatocellular carcinoma (HCC) phase III study. This study aimed to evaluate its antitumour activity and safety in Chinese RAIR-DTC patients. Methods The sequential phase II/III design as a whole protocol was approved by Center for Drug Evaluation (CDE) of the Chinese National Medical Products Administration (NMPA) by April 25, 2016. The phase II study was finished by March 2018. For the multicenter, double blind, placebo controlled, phase III study, 191 patients with locally advanced or metastatic RAIR-DTC progressed within the past 14 months were enrolled as per protocol design. Along with the approval sorafenib in China during the process of this study, sorafenib was accordingly introduced as an alternative to all the following patients for their option. Two interim analyses were planned. Patients were randomized in a ratio of 2:1 to donafenib (300 mg twice daily, n = 128) or matched placebo (n = 63). An open-label donafenib treatment period was allowed upon disease progression. The primary endpoint was progression-free survival (PFS) assessed by the independent review committee. Analysis was based on the intention-to-treat population (ITT). The second endpoint including (ORR), (OS), (DCR), safety, et al. Results Donafenib demonstrated prolonged median PFS over placebo (12.9 vs 6.4 months, hazard ratio (HR) 0.39, 95% confidence interval (CI) 0.25–0.61, p p = 0.0002). The most common grade ≥ 3 treatment-related adverse events in the donafenib group included hypertension (13.3%) and HFS (12.5%). Of the donafenib group, 6.3% experienced discontinuation and 42.2% for dose reduction or interruption. The average daily dosage accounted for 87.0% of the initial dose, indicating the high adherence of patients to donafenib. Conclusions Donafenib meaningfully improved progression-free survival in patients with RAIR-DTC, particularly in those with prior TKIs. The high adherence of initial dose of donafenib as a result of the low occurrence of grade 3 or above adverse events guaranteed its sustainable anti-tumour effect during treatment.

Background: Sporadic medullary thyroid carcinoma (MTC) is a relatively uncommon neuroendocrine malignancy and the molecular tumorigenesis of its sporadic type (sMTC) is only partially understood. In this study, we performed a study focusing on the genomic and transcriptomic characterization of sMTC. Methods: Twenty-nine sMTC patients were included. Whole-exome sequencing (WES) was carried out in 18 patients, including both tumor samples and matched noncancerous tissues. Whole transcriptome sequencing (RNA-Seq) was performed in all 29 tumors. WES, RNA-Seq, and copy number alteration (CNA) data were analyzed. A Cell Counting Kit-8 (CCK-8) assay was used to evaluate cell proliferation. Results: Among the somatic mutations, RET was the only recurrently cancer-related mutated gene (5/18, 27.8%). In the germline, FAT1 and FAT4, two members of the FAT gene family, were identified as the two most common mutated genes. CNA analysis found that FAT1 and FAT4, both located on chromosome 4q, were also two of the genes most commonly affected by somatic chromosomal deletions (4/18, 22.2%). Using TT and MZ-CRC-1 cell lines, the CCK-8 assay showed that FAT1 and FAT4 knockdown could promote MTC cell proliferation. Based on the gene expression profile, patients were clustered into two molecular subtypes: the mesenchymal-like subtype is characterized by epithelial-mesenchymal transition, while the proliferative-like subtype is associated with enrichment of cell cycle pathways. Most events of structural recurrence (80%) occurred in the proliferative-like subtype. Conclusion: In addition to RET, these findings demonstrate that FAT1/FAT4 genomic alterations appear to be frequent in sMTC. Two molecular subtypes of sMTC with distinct biological behavior could be identified. However, these results need to be validated by larger samples and more comprehensive experiments in the future, especially for the frequency and function of FAT1/FAT4 germline variants.

Objective This study aims to investigate the risk factors of prelaryngeal lymph node metastasis in papillary thyroid carcinoma and its clinical application value. Methods The clinical pathological features and metastatic risks were statistically analyzed by reviewing 254 patients with papillary thyroid carcinoma, who received their first operation and prelaryngeal lymph node dissection in our department. Results The detection of prelaryngeal lymph nodes, tumor size and any paratracheal lymph node metastasis were correlated with the number of paratracheal lymph node metastasis (P 0.05). Conclusion Paratracheal lymph node metastasis indicates a high possibility of prelaryngeal lymph node metastasis. Paratracheal lymph node dissection combined with prelaryngeal lymph node dissection should be simultaneously considered in operations for thyroid papilla carcinoma.

The objective of this study is to demonstrate a novel method for the reconstruction of right recurrent laryngeal nerve (RLN) by transforming into nonrecurrent RLN: the end-to-free vagal laryngeal branch end anastomosis. Here we report a case of locally advanced thyroid carcinoma. The patient underwent radical thyroid surgery with inevitably partial RLN resection and immediate right RLN reconstruction at our institution. With the guidance of intraoperative neuromonitoring (IOMN), we completed a novel end-to-free vagal laryngeal branch end anastomosis. The whole procedure was deliberately monitored by IOMN. Surgeons can procure adequate free nerve for tension-free anastomosis by transforming the right RLN into nonrecurrent nerve. Follow-up laryngoscope showed improved adductory movement of the right arytenoid. The end-to-free vagal end anastomosis is an effective way to reconstruct segmental nerve resection of right RLN. Its long-term postoperative result needs to be further warranted.

Tripartite motif (TRIM)-containing protein 14 (TRIM14) is implicated in many malignancies. Presently, we studied whether TRIM14 played a role in human papillary thyroid carcinoma (PTC). Herein, TRIM14 was up-regulated in tumor tissues when compared with normal thyroid samples. Among PTC patients, enhanced TRIM14 predicted short recurrence free survival (RFS) time. Then, we found that knockdown of TRIM14 in human PTC K1 cells inhibited cell proliferation, induced cell apoptosis and prevented the tumorigenicity in nude mice. On the contrary, TRIM14 overexpression in human PTC TPC1 cells promoted cell proliferation while inhibited cell apoptosis. TRIM14 exerted its oncogenic activities via promoting the activation of signal transducer and activator of transcription 3 (STAT3). Further, TRIM14 interacted with the suppressor of cytokine-signaling-1 (SOCS1), a negative regulator of STAT3 activation, and knockdown of TRIM14 inhibited SOCS1 ubiquitination. In conclusion, TRIM14 may be a prognostic factor and oncogene in PTC, and may be a potential target for PTC intervention.

The impact of Hashimoto's thyroiditis (HT) on the progression of papillary thyroid cancer (PTC) is still unclear. Interleukin-2 (IL-2) is a growth factor and crucial for HT development. This study aimed at investigating the effect of IL-2 on MHC class I expression in PTC cells and immune activation with experimental treatment for PTC using PTC cell lines. We assessed the expression of IL-2, HLA class I, PD-L1, CD3, CD8 and CD16 molecules in paired PTC tissues and HLA-ABC and PD-L1 expression in IL-2 pre-treated K1, TPC-1 and BCPAP cells by immunohistochemistry, qPCR, flow cytometry and Western blotting. The effect of IL-2 on immunogenicity of PTC cells to stimulate activated human T cells was determined for the percentages of activated CD8+ T cells and their cytokine production as well as PD-1 and PD-L1 expression. Compared with non-tumor tissues, we found that IL-2 expression was up-regulated in PTC tissues, particularly in PTC+HT tissues and correlated positively with HLA-class I, CD3 and CD8 expression in PTC+HT tissues. Conversely, PD-L1 expression decreased in PTC+HT tissues. Treatment with IL-2 significantly up-regulated HLA-class I expression, but down-regulated PD-L1 expression in PTC cells. Co-culture with IL-2-pre-treated PTC cells significantly promoted the proliferation of activated CD8+ T cells and their IL-2 secretion, but decreased their PD-1 expression, accompanied by decreased PD-L1 expression in IL-2-treated PTC cells in vitro. In conclusion, IL-2 up-regulated HLA-class I expression and enhanced anti-tumor T cell immunity during the development of PTC and HT. IL-2 may be a promising immunotherapy for PTC.

Background Lymph node yield (LNY) was implemented in the stratification of papillary thyroid cancer (PTC) patients. The effect of LNY may be related to the extent of surgery. This study aims to identify influencing factors for LNY in central compartment neck dissection (CND). Methods Data of 13 712 consecutive PTC patients were analyzed retrospectively. Risk factors for LNY in CND and distribution characteristics of LNY were evaluated. Its relationship with prognosis was studied in another cohort of 136 cases. Results LNY in therapeutic CND was significantly higher than prophylactic CND (Unilateral: 5.55 ± 3.79 vs 3.41 ± 2.77; Bilateral: 8.90 ± 5.10 vs 6.47 ± 4.17, P, Lymph node yield (LNY) in central compartment neck dissection (CND) of papillary thyroid cancer (PTC) is related to preoperative and intraoperative assessment of the disease. Inadequate LNY may lead to poor prognosis.

Background We aimed to explore whether the anatomic extent of lymph node metastases (AE-LNM) could independently predict prognosis of node-positive major salivary gland carcinoma (MaSGC). Methods A total of 376 pathologically node-positive MaSGC patients were identified from the Surveillance, Epidemiology and End Results database and constituted the training cohort. Using the X-Tile program, these patients were divided into three groups based on AE-LNM degrees. Discrimination of overall survival (OS) and disease-specific survival (DSS) was evaluated and compared with the 8th American Joint Committee on Cancer (AJCC) pN classification. The results were externally validated by 220 patients in a Chinese multicenter cohort (Validation cohort). Results Using the training cohort, AE-LNM was divided into Extent 1 (spread to parotid LNs or level I), Extent 2 (spread to level II-IV) and Extent 3 (spread to level V or bilateral LNs or rare LNs). Regarding both OS and DSS, the AE-LNM model revealed clear separation of survival curves, while the pN classification failed to discriminate the prognosis of pN1 and pN2 patients. When we incorporated both the AE-LNM model and AJCC pN classification into the same multivariate Cox analyses, AE-LNM was still an independent prognostic factor, while the AJCC pN classification lost its significance. These results were externally validated by the validation cohort. Conclusion AE-LNM is an independent nodal prognosticator for node-positive MaSGC and may have improved discriminative ability over the current AJCC pN classification. Integration of anatomic extent of LNM into the current AJCC N classification could be considered.

Background: Neuroendocrine tumors (NETs) rarely occur in the mediastinum and their etiology and pathogenesis are still unclear. Objectives: This study assessed inherited or de novo mutations in familial mediastinal NETs. Method: DNA samples from 4 patients were subjected to the whole-exome sequencing, and Sanger sequencing was used to identify Deleted in malignant brain tumor 1 (DMBT1) mutations in all 45 family members. Results: All patients showed a germline DMBT1 mutation at 4971C. Sanger sequencing data showed that 4 NETs and 2 carriers in the first patient’s family and 2 NETs and 4 carriers in the second patient’s family, respectively, had this DMBT1 mutation. The in vitro data showed that the ectopic expression of DMBT1 reduced tumor cell viability and migration by arresting the G1/S phase of the cell cycle. Conclusions: We identified a germline missense mutation in DMBT1D1657E as a susceptibility gene for familial mediastinal NETs.

Background: The status of lymph node metastasis (LNM) is crucial for evaluating prognosis in patients with medullary thyroid cancer (MTC). However, only the compartment of LNM was reflected in the eighth edition (8th) of the American Joint Committee on Cancer (AJCC) N-staging system. Therefore, a more accurate N-staging system is required for MTC. Methods: Two large cohorts were included in this analysis and consisted of 1374 MTC patients from the Surveillance, Epidemiology, and End Results (SEER) database and 164 MTC patients from the Fudan University Shanghai Cancer Center (FUSCC) database. Using metastatic lymph node number (MLNN) and metastatic lymph node ratio (MLNR), a novel N-staging system that predicts the survival of MTC was derived and measured by concordance index (C-index). Results: The cutoff values were 0 and 12 for MLNN and 0.6 (MLNN≤12) and 0.75 (MLNN≥13) for MLNR. Based on the values of MLNN and MLNR, we proposed the following novel N-staging system for MTC: N0, MLNN=0; N1, 1≤MLNN≤12 and MLNR 12 and MLNR 12 and MLNR ≥0.75. Multivariate Cox analysis indicated that the novel N-staging system was an independent prognostic factor for cancerspecific survival. The C-index was higher for the novel N-staging system than for the 8th AJCC N-staging system (SEER cohort: 0.783 vs. 0.756; FUSCC cohort: 0.716 vs. 0.670). Conclusion: With some improvements, the novel N-staging system for MTC suggested from this research may be assessed for potential adoption in the next edition of the AJCC N-staging system. Funding Statement: This work was supported by National Natural Science Foundation of China (81772852), the Science and Technology Commission of Shanghai Municipality (16ZR1406600). Declaration of Interests: The authors report no conflicts of interest in this work. Ethics Approval Statement: This study was approved by the Ethics Committee of FUSCC.

Background: Expression of the programmed death-ligand 1 (PD-L1) in medullary thyroid carcinoma (MTC) has been rarely reported. In this study, we evaluated PD-L1 positivity in MTC and analyzed its c...

Introduction To investigate whether the positive lymph node number (PLNN) and positive lymph node ratio (PLNR) could predict the prognosis of patients with major salivary gland cancer (MSGC) and to identify the optimal cutoff points for these variables that stratify patients according to their risk of survival. Methods We used the Surveillance, Epidemiology, and End Results (SEER) database to identify all patients with MSGC between 1988 and 2014. A logistic regression analysis was carried out to evaluate the risk factors for lymph node metastasis (LNM) in MSGC. The X-tile program was used to identify the cutoff values for the PLNN and PLNR in MSGC patients with LNM. Cox proportional hazards regression models were performed to identify the predictors of cancer-specific survival (CSS). Results In the SEER database, 8668 eligible patients were identified and 3046 of them had LNM. The logistic regression analysis indicated that older age, male sex, larger tumor size, higher grade, tumor extension and high-risk pathology were associated with LNM. The X-tile program showed that a PLNN>4 and a PLNR>0.15 were prognostic indicators of CSS. A multivariable analysis indicated that, after the factors that might potentially affect the prognosis were adjusted for, the PLNN and PLNR were still associated with CSS. Conclusions Our Results demonstrated that the PLNN and PLNR were independent prognostic indicators for MSGC patients with lymph node metastasis.

Context Metabolic reprogramming is a common feature of tumorigenesis. It remains unknown concerning the expression pattern of metabolism-associated genes in dedifferentiated thyroid cancer (DDTC). Objective This study aimed to identify a useful signature to indicate dedifferentiation of papillary thyroid cancer (PTC). Design and Setting We used one discovery and two validation cohorts to screen out aberrant metabolic genes in DDTC, and further used The Cancer Genome Atlas (TCGA) cohort to search for independent risk factors for the low-differentiated phenotype of PTC as a signature of dedifferentiation. The prediction of the signature for DDTC was validated in the TCGA cohort and the combined Gene Expression Omnibus cohort. We also analyzed the correlations of the signature risk score with clinicopathological features of PTC. Gene set enrichment analyses were performed in the TCGA cohort. Results Significant enrichment of metabolic pathways correlated with differentiation status of PTC. A signature of metabolic genes including LPCAT2, ACOT7, HSD17B8, PDE8B, and ST3GAL1 was discovered and validated across three cohorts. The signature was not only predictive of DDTC but also significantly associated with BRAFV600E mutation (P < 0.001), T3/T4 stage (P < 0.001), extrathyroidal extension (P < 0.001), lymph node metastasis (P < 0.001), and tumor/lymph node/metastasis III/IV stage (P < 0.001) in PTC. Downregulations of LPCAT2 expression (P = 0.009) and ST3GAL1 expression (P = 0.005) increased risks of decreased disease-free survival for patients. Furthermore, the signature was implicated in a number of oncogenic biological pathways. Conclusions Our findings suggest that metabolic deregulations mediate dedifferentiation of PTC, and that the metabolic gene signature can be used as a biomarker for DDTC.

Background. Anaplastic thyroid cancer (ATC) responds poorly to conventional therapies and requires a multidisciplinary approach to manage. The aim of the current study is to explore whether aggressive treatment is beneficial, especially the appropriate extent of surgery in ATC. Methods. Patients diagnosed with ATC from 2004 to 2014 were identified from the Surveillance, Epidemiology, and End Results (SEER) database and included in our study. Results. A total of 735 ATC patients were identified. The two-year overall survival (OS) rates for stage IVA, IVB, and IVC patients were 36.5%, 15.6%, and 1.4%, respectively. By directly comparing eight treatment modalities, we found that surgery+radiotherapy RT±chemotherapy was the most effective treatment strategy. surgery+chemotherapy and RT+chemotherapy had comparable results (hazard ratio HR=1.461, 95% confidential interval (CI): 0.843-2.531, P=0.177). Multivariate Cox regression analysis also showed increased mortality risk in patients with increased age (HR=1.022, P<0.001), tumor extension to adjacent structures (HR=1.649, P=0.013), and distant metastasis (HR=2.041, P<0.001), while surgery+RT (HR=0.600, P=0.004) and chemotherapy (HR=0.692, P=0.010) were independently associated with improved OS. Further analysis revealed that patients undergoing total/near-total thyroidectomy (TT) had superior OS to those receiving less than TT (P<0.001). In subgroup analysis, the benefit of TT remained significant in patients with tumors larger than 4.0 cm (HR=0.776, 95% CI: 0.469-0.887, P=0.007), with adjacent structure extension (HR=0.642, 95% CI: 0.472-0.877, P=0.005), including trachea and major vessels, but not in patients with early phase local disease such as tumor≤4.0 cm or tumor within the thyroid or with minimal extrathyroidal extension. Patients with very locally advanced disease or distant metastasis could not benefit from TT as well. Conclusions. In operable cases, surgery+RT±chemotherapy was the optimal treatment modality. Otherwise, RT+chemotherapy was the appropriate strategy. However, TT was not beneficial for very early stage or metastatic ATC.

To evaluate prognostic factors and treatment outcomes of primary squamous cell carcinoma in thyroid (PSCCTh) over the past decades using a large national database. All patients diagnosed with PSCCTh between 1973 and 2015 were identified with the Surveillance, Epidemiology, and End Results Program (SEER) 18-registry database. Relevant clinical data were collected, and prognostic factors of overall survival (OS) and disease-specific survival (DSS) were analyzed. This cohort study included 242 patients, accounting for 0.12% of all primary thyroid carcinomas from 1973 to 2015 nationwide. Of the patients with PSCCTh, 75% were older than 60 years at diagnosis. Patient age older than 60 years (HR 2.242, 95% CI 1.367–3.676, P = 0.001) and a tumor size larger than or equal to 50 mm (HR 1.479, 95% CI 1.011–2.165, P = 0.044) were independent negative prognostic factors. The univariate analysis suggested that the morphological subtype (OS, P = 0.033; DSS, P = 0.048), clinical treatment modality (OS, P

Giant cell tumor of soft tissue (GCT-ST) is a rare benign tumor of low malignant potential. It is thought to be the soft tissue counterpart of giant cell tumors of the bone due to its pathological resemblances. GCT-ST is most commonly found in superficial soft tissue of thigh, trunk and upper extremities. The head and neck region is rarely affected. Here for the first time, we describe a case of GCT-ST in the thyroid region. A 70-year-old female patient presented with a painless swelling in her left neck for the previous three weeks. The condition was initially diagnosed as thyroid goiter and left lobectomy was arranged. Intraoperative findings showed an irregular mass invading the strap muscles and trachea. Complete tumor resection was difficult, and part of the tumor was left in the thyroid bed. Histopathology of the resected specimen showed a mixture of mononuclear round to oval cells and multinucleated osteoclast-like giant cells. The giant cells were CD 68 positive. The patient received a revision surgery 3 months after the first operation to achieve complete resection. There was no recurrence in the first 3-month follow-up. However, 6 months after the revision surgery, the tumor recurred on both sides of the neck. The patient suffered from dysphagia and breathlessness. As further surgery and radiation therapy were not considered, denosumab was used as a novel agent After three months of treatment, the patient showed symptom-relief and tumor-regression. The patient continued to have tumor-regression after 1 year of the denosumab treatment. GCT-ST is a benign tumor, although in this case, it was showing features of malignancy. A review of the literature was conducted to identify previous studies on GCT-ST in the head and neck. We present this case for its rare location and novel treatment with denosumab.

Purpose 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 cancer. In this study, we investigate the prognostic value of lipid metabolism related genes in papillary thyroid cancer (PTC). Methods The in time to recurrence predictive gene signature was developed, 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 by using in-house cohorts which enrolled 97 patients. Kaplan-Meier curve, time-dependent receiver operating characteristic curve, nomogram and decision curve analysis were used to assess the performance of the gene signature. Results We identified four recurrence-related genes, PDZK1IP1, TMC3, LRP2 and KCNJ13, and established a 4-gene signature recurrence risk model. The expression profile of the 4 genes in the TCGA and in-house cohort indicated that stage T1/T2 PTC and locally advanced PTC exhibited notable associations not only with clinicopathological parameters but also with recurrence. Calibration analysis plots indicated the excellent predictive performance of the prognostic nomogram constructed based on the gene signature. GSEA showed that high-risk cases exhibited changes in several important tumorigenesis-related pathways, such as the intestinal immune network and the p53 and Hedgehog signalling pathways. Conclusion Our findings indicate that lipid metabolism-related gene profiling represents a potential marker for prognosis and treatment decisions for PTC patients.

Purpose: Lenvatinib has shown efficacy in treating radioiodine-refractory differentiated thyroid cancer (RR-DTC) in the multinational phase III SELECT study; however, it has not been tested in Chinese patients with RR-DTC. Patients and Methods: Chinese patients with confirmed RR-DTC (n = 151) were randomly assigned 2:1 to receive lenvatinib 24 mg/day or placebo in 28-day cycles. The primary endpoint was progression-free survival, and key secondary endpoints included objective response rate and safety. Analyses for progression-free survival and objective response rate were conducted using Response Evaluation Criteria in Solid Tumors v1.1 and confirmed by independent imaging review. All adverse events were assessed and monitored. Results: Progression-free survival was significantly longer with lenvatinib treatment [n = 103; median 23.9 months; 95% confidence interval (CI), 12.9–not estimable] versus placebo (n = 48; median 3.7 months; 95% CI, 1.9–5.6; hazard ratio = 0.16; 95% CI, 0.10–0.26; P < 0.0001). The objective response rate was 69.9% (95% CI, 61.0–78.8) in the lenvatinib arm and 0% (95% CI, 0–0) in the placebo arm. At data cutoff, 60.2% of patients receiving lenvatinib remained on treatment; treatment-emergent adverse events led to lenvatinib discontinuation in 8.7% of patients. Overall, treatment-emergent adverse events of grade ≥3 occurred in 87.4% of patients in the lenvatinib arm, the most common being hypertension (62.1%) and proteinuria (23.3%). Conclusions: Lenvatinib at a starting dose of 24 mg/day significantly improved progression-free survival and objective response rate in Chinese patients with RR-DTC versus placebo. There were no new or unexpected toxicities. Results are consistent with those from SELECT involving patients with RR-DTC.

Background The techniques of DNA microarray and bioinformatic analysis have exhibited efficiency in identifying dysregulated gene expression in human cancers. In this study, we used integrated bioinformatics analysis to improve our understanding of the pathogenesis of papillary thyroid cancer (PTC). Methods In this study, we integrated four Gene Expression Omnibus (GEO) datasets, GSE33630, GSE35570, GSE60542 and GSE29265, including 136 normal samples and 157 PTC specimens. The contents of the four datasets are based on GPL570, an Affymetrix Human Genome U133 Plus 2.0 array. Gene ontology (GO) analysis was used to identify characteristic the biological attributes of differentially expressed genes (DEGs) between PTC and normal samples. GO annotation was performed on the DEGs obtained, and the process relied on the DAVID online tool. Kyoto Encyclopedia of Genes and Genomes (KEGG) approach enrichment analyses were adopted to obtain the basic functions of the DEGs. The KOBAS online analysis database was used to complete DEG KEGG pathway comparison and analysis. The search tool (STRING) database was mainly used to search for interacting genes and complete the construction of protein-protein interaction (PPI) networks. Results Five hundred-ninety DEGs were consistently expressed in the four datasets; 327 of them were upregulated, while 263 were downregulated. Ten DEGs, including five upregulated (ENTPD1, THRSP, KLK10, ADAMTS9, MIR31HG) and five downregulated (SCARA5, EPHB1, CHRDL1, LOC440934, FOXP2) genes, were randomly selected for q-PCR in our own tissue samples to validate the integrated data. The most highly enriched GO terms were extracellular exosome (GO:0070062), cell adhesion (GO:0070062), positive regulation of gene expression (GO:0010628), and extracellular matrix (ECM) organization (GO:0030198). KEGG pathway analysis was performed, and it was found that abnormally expressed genes effectively participated in pathways such as tyrosine metabolism, complement and coagulation cascades, cell adhesion molecules (CAMs), transcriptional misregulation and ECM-receptor interaction pathways. Conclusions Five hundred-ninety DEGs were identified in PTC by integrated microarray analysis. The GO and KEGG analyses presented here suggest that the DEGs were enriched in extracellular exosome, tyrosine metabolism, CAMs, complement and coagulation cascades, transcriptional misregulation and ECM-receptor interaction pathways. Functional studies of PTC should focus on these pathways.