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Jin-Xing Gong,1 Jian-Wei Gu,1 Feng Ji,1 Kun Li,1 Qi Zhu,1 Fang-Ying Gu,1 Yan Chen,1 Qing-Hai Ji2 1Department Four of Surgery, Kunshan Hospital of Traditional Chinese Medicine, Kunshan 215300, People’s Republic of China; 2Head & Neck Surgery, Fudan University Shanghai Cancer Center, Shanghai 200000, People’s Republic of ChinaCorrespondence: Jian-Wei GuDepartment Four of Surgery, Kunshan Hospital of Traditional Chinese Medicine, No. 189 of Chaoyang Street, Yushan Town, Kunshan 215300, People’s Republic of ChinaTel +86-051257310000-3698Email jwgdr_999@163.comObjective: 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), but these were not correlated with age, gender, multiple foci, tumor size, any paratracheal lymph node metastasis, metastatic location, or foci location (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.Keywords: papillary thyroid cancer, delphian lymph node, lymph node metastasis, lymph node dissection, tumor

Lu-Lu Ye,1,2,* Jia Rao,2,3,* Xing-Wen Fan,1,2 Qing-Hai Ji,2,4 Chao-Su Hu,1,2 Hong-Mei Ying1,2 1Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China; 2Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China; 3Department of Pathology, 4Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China *These authors contributed equally to this work Purpose: To analyze the potential variables affecting the survival of patients undergoing primary surgery for hypopharyngeal squamous cell carcinoma.Patients and methods: Between August 2007 and December 2016, 93 patients with primary hypopharyngeal squamous cell carcinomas undergoing radical surgery at Fudan University Shanghai Cancer Center were reviewed. The clinicopathological features were analyzed retrospectively. The optimal cutoff values were determined based on the receiver operating characteristic curve analysis. Pearson correlation coefficients were used to assess the correlations between variables. The Kaplan–Meier and Cox proportional hazard methods were used to evaluate the impact of variables on overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS).Results: Cox multivariate analysis revealed that a depth of invasion (DOI) ≥ 4.3 mm was correlated with inferior OS (P=0.045), DSS (P=0.046), and DFS (P=0.046). A primary tumor volume (PTV) ≥0.36 mL was related to poor OS (P=0.018), DSS (P=0.026), and DFS (P=0.036). A lymph node density (LND) ≥0.07 was also associated with worse OS (P=0.014) and DSS (P=0.045). Moreover, additional prognostic value was observed in the combined use of PTV and LND.Conclusion: The DOI, PTV, and LND obtained from the surgical specimens could provide additional valuable information for prognostic stratification and allowed the more appropriate selection of suitable candidates for more aggressive adjuvant therapy. Keywords: hypopharynx, surgery, depth of invasion, primary tumor volume, lymph node density, survival

Xiao Shi,1,2,* Nai-Si Huang,1,2,* Rong-Liang Shi,1,2,* Wen-Jun Wei,1,2 Yu-Long Wang,1,2 Qing-Hai Ji1,2 1Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center, 2Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China *These authors contributed equally to this work Purpose: The prognostic value of primary tumor surgery (PTS) in minor salivary-gland carcinoma (MiSGC) with distant metastasis (DM) at diagnosis has never been investigated. In this study, we aimed to provide the first evidence.Patients and methods: The Surveillance, Epidemiology, and End Results (SEER) database was employed to identify MiSGC patients with DM at diagnosis. The prognostic value of PTS was evaluated by Kaplan–Meier methods, log-rank analyses, and multivariate Cox proportional-hazard regression models.Results: Of the 152 eligible patients included in our study, 50 (32.9%) had undergone PTS. Kaplan–Meier analyses showed that the PTS group had >20% increase in 1- and 2-year overall survival (OS) and cancer-specific survival (CSS) compared with their counterparts without PTS (PTS group vs no-PTS group, 1-year OS 66.1% vs 43.9%, 1-year CSS 69.9% vs 44.9%, 2-year OS 56.6% vs 24.2%, 2-year CSS 59.9% vs 25.7%). Compared with the no-PTS group, multivariate analyses also demonstrated a significantly decreased risk of overall mortality (HR 0.601, 95% CI 0.379–0.952; P=0.031) and cancer-specific mortality (HR 0.547, 95% CI 0.336–0.891; P=0.015) in the PTS group. Subgroup multivariate analyses revealed patients with T1–T3 oropharynx, nasal cavity, or paranasal sinus primary MiSGC, especially adenoid cystic carcinoma, might benefit from PTS (all P

Background: Papillary thyroid cancer (PTC) with the BRAF V600E mutation is associated with a poorer prognosis. BRAF inhibitors may demonstrate limited efficacy due to emerging drug resistance. The Warburg effect may have cancer therapeutic implications. It is not known if the BRAF V600E mutation is associated with altered glucose metabolism in PTC. Methods: This study examined the effect of BRAF V600E and dynamin-related protein 1 (DRP1) on various cellular processes in PTC cells, including cell proliferation, migration, invasion, mitochondrial fission, glucose metabolism, reactive oxygen species (ROS) generation, and apoptosis. We used RT-qPCR to assess the expression of key glycolytic enzymes in thyroid cancer tissues. Additionally, the regulatory interaction between BRAF V600E and DRP1 was investigated through Western blot and immunohistochemical staining. We further evaluated the impact of DRP1 in PTC and the inhibitory effects of dabrafenib and 2-deoxy-d-glucose (2-DG) in vitro and in vivo . Results: We found that the BRAF V600E mutation significantly augments aerobic glycolysis while suppressing oxidative phosphorylation in PTC. We identified the BRAF V600E /p-ERK/p-DRP1(Ser616) signaling pathway as a critical mediator in PTC progression. First, the BRAF V600E /p-ERK/p-DRP1(Ser616) signaling pathway enhances cell proliferation by upregulating hexokinase 2 expression and thereby increasing aerobic glycolysis. Second, it inhibits apoptosis by promoting mitochondrial fission and reducing ROS levels. Moreover, we demonstrated that the combination therapy of 2-DG and dabrafenib markedly impedes the progression of BRAF V600E -positive PTC. Conclusion: The BRAF V600E /p-ERK/p-DRP1(Ser616) signaling pathway plays a pivotal role in glucose metabolism reprogramming, contributing to the aggressiveness and progression of BRAF V600E -positive PTC. Our findings suggest that a combined therapeutic approach using 2-DG and dabrafenib has the potential to improve the outcome of PTC patients with BRAF V600E .

Background: Papillary thyroid carcinoma (PTC) and follicular thyroid carcinoma (FTC) contribute to more than 95% of thyroid malignancies. However, synchronous PTC and FTC are less common; it is most commonly discovered incidentally as synchronous malignancies during operation, which adds difficulties to intraoperative decision-making and postoperative treatment. Therefore, we analyzed the clinicopathological characteristics and prognosis of patients with PTC and FTC in our center., Methods: We conducted a search of single PTC, single FTC, and synchronous PTC/FTC patients who received initial surgery treatment at Fudan University Shanghai Cancer Center from 2006 to 2018 and collected paraffin-embedded samples of synchronous patients. Clinicopathological characteristics were collected from the electronic medical record system. Follow-up was performed through telephone contact or medical records. Exome sequencing was performed by ThyroLead panel., Results: Total of 42 synchronous PTC/FTC patients, 244 single FTC patients, and 2,959 single PTC patients were included. It showed a similarity between the clinicopathological features of synchronous thyroid cancer patients and single PTC patients, with a greater proportion of females, higher probabilities of lymph node metastasis, and higher rate of concurrence of Hashimoto's disease. The disease-free survival (DFS) curve indicated a worse prognosis of the synchronous group and single PTC group compared to the single FTC group, who had a propensity for neck lymph node recurrence; however, logistic multivariate regression analysis did not find any factor related to recurrence in the synchronous group. After re-checking pathology, DNA extraction, and quality control, genetic alteration information of 62 samples including primary tumors and metastatic lymph nodes from 35 synchronous cancer patients was displayed. In total, 81 mutations and 1 fusion gene were identified, including mutations related to outcomes and targeted therapy. Besides, some rare mutations in thyroid cancer were found in these patients., Conclusions: To conclude, synchronous PTC/FTC tend to be incidentally discovered during or after operation, behaving more like single PTC. The prognosis of synchronous patients is worse than that of single FTC patients and supplemental cervical lymph node dissection, total thyroidectomy, and postoperative radioiodine therapy should be taken into consideration after diagnosis. The next-generation sequencing (NGS) showed a unique molecular feature of synchronous patients with some rare mutations., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-23-1526/coif). Z.T.K. is an employee from the Department of Bioinformatics, Zhejiang Shaoxing Topgen Biomedical Technology Co., Ltd. R.J.L. is an employee from the Department of Technology, Zhejiang Topgen Clinical Laboratory Co., Ltd. L.S.H. is an employee from Department of Bioinformatics, Zhejiang Shaoxing Topgen Biomedical Technology Co., Ltd. S.E.T. is an employee from AO Vector-Best, Novosibirsk, Russian Federation. The other authors have no conflicts of interest to declare., (2024 Translational Cancer Research. All rights reserved.)

Both anaplastic thyroid cancer (ATC) and papillary thyroid cancer (PTC) originate from thyroid follicular epithelial cells, but ATC has a significantly worse prognosis and shows resistance to conventional therapies. However, clinical trials found that immunotherapy works better in ATC than late-stage PTC. Here, we used single-cell RNA sequencing (scRNA-Seq) to generate a single-cell atlas of thyroid cancer. Differences in ATC and PTC tumor microenvironment components (including malignant cells, stromal cells, and immune cells) leading to the polarized prognoses were identified. Intriguingly, we found that CXCL13+ T lymphocytes were enriched in ATC samples and might promote the development of early tertiary lymphoid structure (TLS). Last, murine experiments and scRNA-Seq analysis of a treated patient's tumor demonstrated that famitinib plus anti-PD-1 antibody could advance TLS in thyroid cancer. We displayed the cellular landscape of ATC and PTC, finding that CXCL13+ T cells and early TLS might make ATC more sensitive to immunotherapy.

Objectives: To establish a computed tomography (CT)-based scale to evaluate the resectability of locally advanced thyroid cancer., Methods: This twin-centre retrospective study included 95 locally advanced thyroid cancer patients from the 1 st centre as the training cohort and 31 patients from the 2 nd centre as the testing cohort, who were categorised into the resectable and unresectable groups. Three radiologists scored the CT scans of each patient by evaluating the extension to the recurrent laryngeal nerve (RLN), trachea, oesophagus, artery, vein, soft tissue, and larynx. A 14-score scale (including all comprised structures) and a 12-score scale (excluding larynx) were developed. Receiver-operating characteristic (ROC) analysis was used to evaluate the performance of the scales. Stratified fivefold cross-validation and external verification were used to validate the scale., Results: In the training cohort, compromised RLN (p < 0.001), trachea (p = 0.001), oesophagus (p = 0.002), artery (p < 0.001), vein (p = 0.005), and soft tissue (p < 0.001) were predictors for unresectability, while compromised larynx (p = 0.283) was not. The 12-score scale (AUC = 0.882, 95%CI: 0.812-0.952) was not inferior to the 14-score scale (AUC = 0.891, 95%CI: 0.823-0.960). In subgroup analysis, the AUCs of the 12-score scale were 0.826 for treatment-naïve patients and 0.976 for patients with prior surgery. The 12-score scale was further validated with a fivefold cross-validation analysis, with an overall accuracy of 78.9-89.4%. Finally, external validation using the testing cohort showed an AUC of 0.875., Conclusions: The researchers built a CT-based 12-score scale to evaluate the resectability of locally advanced thyroid cancer. Validation with a larger sample size is required to confirm the efficacy of the scale., Clinical Relevance Statement: This 12-score CT scale would help clinicians evaluate the resectability of locally advanced thyroid cancer., Key Points: • The researchers built a 12-score CT scale (including recurrent laryngeal nerve, trachea, oesophagus, artery, vein, and soft tissue) to evaluate the resectability of locally advanced thyroid cancer. • This scale has the potential to help clinicians make treatment plans for locally advanced thyroid cancer., (© 2023. The Author(s), under exclusive licence to European Society of Radiology.)

Background: Despite the high incidence of lateral neck lymph node (LN) metastasis in papillary thyroid cancer (PTC), the management of the lateral neck remains controversial. We aimed to map the draining LNs in the lateral neck using carbon nanoparticles and explore its potential in neck evaluation., Methods: We conducted a multicenter, prospective study in PTC patients who had non-palpable yet suspicious metastatic lateral LNs on ultrasound and/or computed tomography (CT) but could not be confirmed by fine needle aspiration. Carbon nanoparticle suspension was injected peritumorally into the thyroid and modified lateral neck dissection was subsequently performed., Results: A total of 154 patients were enrolled for analysis. And 5,070 lateral LNs were removed, of which 1,079 (21.3%) were dyed. The median of dyed LNs was 6 per case (range, 1-33). The distribution of dyed LNs in neck compartments was IV > III > IIA > IIB/V, independent of tumor size, location, multifocality or microscopic extra-thyroidal extension (ETE). Compared with undyed LNs, the probabilities of metastasis in dyed LNs were significantly increased in compartment III, IV, V, and II-V (III: 29.3% vs. 15.4%, P<0.001; IV: 26.3% vs. 14.5%, P<0.001; V: 16.7% vs. 3.3%, P=0.005; II-V: 26.3% vs. 10.0%, P<0.001). The relative risks of metastasis in dyed LNs compared with undyed LNs were 1.90, 1.82, 5.04 and 2.62 in compartment III, IV, V, and II-V, respectively., Conclusions: It was the first prospective multicenter study to map the lateral neck LNs with carbon nanoparticles, which could help surgeons visualize the suspicious LNs during surgery. Instead of unguided LN biopsy, this method has a potential role in lateral neck assessment for indeterminate lateral LNs in PTC., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gs.amegroups.com/article/view/10.21037/gs-23-222/coif). The authors have no conflicts of interest to declare., (2023 Gland Surgery. All rights reserved.)

Background: Surgery is the primary treatment for locally advanced differentiated thyroid cancer (DTC). However, some locally advanced patients are not candidates for R0/1 resection. There is limited evidence of neoadjuvant treatment in locally advanced DTC. Surufatinib targets multiple kinases, which is efficient, tolerable, and safe in patients with radioiodine-refractory DTC. In addition, surufatinib plus toripalimab (an anti-PD-1 antibody) showed encouraging antitumor activity in advanced solid tumors. This study was designed to evaluate the efficacy and safety of surufatinib plus toripalimab in locally advanced DTC in the neoadjuvant setting., Methods: In this single-arm, phase II study, patients with pathologically confirmed unresectable or borderline resectable DTC were eligible and received a combination of 250 mg of surufatinib (orally daily) with 240 mg of toripalimab (intravenous, every 3 weeks). Treatment continued until satisfied for curative surgery, disease progression, withdrawal of consent, unacceptable toxicity, or investigator decision. Primary endpoint was objective response rate (ORR). Secondary endpoints included R0/1 resection rate, adverse events (AEs), etc. RESULTS: Ten patients were enrolled and received at least 4 cycles of treatment. The ORR was 60%. Nine patients received R0/1 resections after neoadjuvant treatment. The median best percentage change in the sum of the target lesion diameter was 32%. Most adverse events (AEs) were grade 1 or 2., Conclusions: Surufatinib in combination with toripalimab as neoadjuvant therapy for locally advanced DTC was feasible, and the majority of patients achieved R0/1 resection. It represents a new option for locally advanced DTC and needs further investigation., (© 2023. Society of Surgical Oncology.)

Sufficient evidence has linked many different types of cancers and T2D through shared risk factors; however, the underlying mechanisms are not fully understood. α-Hydroxybutyrate (α-HB), a byproduct metabolite increased in diabetes and cancer, including colorectal cancer (CRC), triggers lactate dehydrogenase A (LDHA) nuclear translocation. Nuclear LDHA markedly extends NF-κB nuclear retention by interacting with phosphorylated p65, leading to an increase in TNF-α production, impaired insulin secretion and the exacerbation of azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced CRC and high-fat diet (HFD)-induced type 2 diabetes. Furthermore, metformin interrupted this process by inhibiting the transcription of FOXM1 and c-MYC, the resultant downregulation of LDHA expression and α-HB-induced LDHA nuclear translocation. Thus, the results reveal the elevated α-HB level could be a novel shared risk factor of linking CRC, diabetes and the use of metformin treatment, as well as highlight the importance of preventing NF-κB activation for protecting against cancer and diabetes., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflicts of interest., (Copyright © 2023 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

In addition to the classical role as a serum effector system of innate immunity, accumulating evidence suggests that intracellular complement components have indispensable functions in immune defense, T cell homeostasis, and tumor cell proliferation and metastasis. Here, we revealed that complement component 3 (C3) is remarkably upregulated in paclitaxel (PTX)-resistant non-small cell lung cancer (NSCLC) cells and that knockdown of C3 promoted PTX-induced cell apoptosis, sensitizing resistant cells to PTX therapy. Ectopic C3 decreased PTX-induced apoptosis and induced resistance to PTX treatment in original NSCLC cells. Interestingly, C3b, the activated fragment of C3, was found to translocate into the nucleus and physically associate with the HDAC1/2-containing SIN3A complex to repress the expression of GADD45A, which plays an important role in cell growth inhibition and apoptosis induction. Importantly, C3 downregulated GADD45A by enhancing the binding of the SIN3A complex with the promoter of GADD45A, thus decreasing the H3Ac level to compress chromatin around the GADD45A locus. Subsequently, ectopic GADD45A promoted PTX-induced cell apoptosis, sensitizing resistant cells to PTX therapy, and insufficiency of GADD45A in original cancer cells induced resistance to PTX treatment. These findings identify a previously unknown nucleus location and oncogenic property for C3 in chemotherapy and provide a potential therapeutic opportunity to overcome PTX resistance., (© 2023. The Author(s).)

Purpose: Prolactinoma is the most common type of pituitary adenoma. Most prolactinoma need medical treatment, but some of them are aggressive and require surgery. In previous decades, some miRNAs have been manifested as oncogenes or tumor suppressors. Consequently, miRNAs' abnormal expression involves tumorigenesis, invasion, and metastasis of different types of tumors, including pituitary tumors. The current study aim to explore the aggressiveness-associated miRNAs in prolactinoma and underlying molecular mechanisms based on the bioinformatic analysis and fundamental experiment studies., Methods: GSE46294 miRNA expression profile from the Gene Expression Omnibus (GEO) database was downloaded. Differentially expressed miRNAs (DEMs) were filtered from this data. Subsequently, the target genes of downregulated miRNAs were analyzed by Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. RT-qPCR, western blot, and CCK-8 assays were used to validate the effect of miR-137 on the proliferation of MMQ cells through AKT2. Finally, the binding site of rat miR-137 to AKT2 were predicted by Targetscan and Bibiserv database, and verified by double luciferase reporter assay., Results: Twenty-four changed DEMs (fourteen upregulated and ten downregulated) were identified. Target genes of downregulated DEMs were classified into three groups by GO terms. KEGG pathway enrichment analysis revealed these target genes enriched in the PI3K-Akt pathway. We also confirmed that miR-137 can target AKT2 and inhibit the proliferation of MMQ cells induced by AKT2., Conclusion: MiR-137 suppressed prolactinomas' aggressive behavior by targeting AKT2., (© 2022. The Author(s), under exclusive licence to Italian Society of Endocrinology (SIE).)

Background: Lymph node metastasis can independently predict oral squamous cell carcinoma patients' survival. This study would investigate the genetic and cellular differences between oral squamous cell carcinoma with positive and negative lymph node metastases., Methods: We gathered single-cell RNA sequencing and bulk gene expression data from the Cancer Genome Atlas and Gene Expression Omnibus databases. Sixty lymph node-metastasis-related genes were discovered with refined single-cell RNA sequencing data analysis, and consensus clustering provided three molecular subtypes of oral squamous cell carcinoma. Least absolute shrinkage and selection operator analyses were then utilized to establish a five-gene risk model. CIBERSORT analysis revealed the immune infiltration profile of different risk subgroups., Results: Oral squamous cell carcinoma patients were classified into three subtypes based on the 60 lymph node-metastasis-related key genes identified by single-cell RNA sequencing data. Patients in Subtype 3 showed a tendency for lymph node metastasis and poorer prognosis. Moreover, five biomarkers were selected from the 60 genes to construct a five-gene risk model evaluating the risk of lymph node metastasis. A lower probability of lymph node metastasis and a better prognosis was observed in the low-risk group. The immune infiltration of three different risk groups was explored with CIBERSORT. Besides, further analysis implied different sensitivities of anticancer drugs, including immunotherapy drugs and targeted compounds, in the three risk groups., Conclusion: In view of intratumoral heterogeneity, we found 60 genes associated with lymph node metastasis of oral squamous cell carcinoma. Subsequently, we constructed a five-gene signature that could improve the prediction of lymph node metastasis, clinical outcome, and promote individualized treatment strategies for oral squamous cell carcinoma., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

DL-3-n-butylphthalide (NBP)-a compound isolated from Apium graveolens seeds-is protective against brain ischemia via various mechanisms in humans and has been approved for treatment of acute ischemic stroke. NBP has shown recent potential as a treatment for Parkinson's disease. However, the underlying mechanism of action of NBP remains poorly understood. In this study, we established a rat model of Parkinson's disease by intraperitoneal injection of rotenone for 28 successive days, followed by intragastric injection of NBP for 14-28 days. We found that NBP greatly alleviated rotenone-induced motor disturbance in the rat model of Parkinson's disease, inhibited loss of dopaminergic neurons and aggregation of α-synuclein, and reduced iron deposition in the substantia nigra and iron content in serum. These changes were achieved by alterations in the expression of the iron metabolism-related proteins transferrin receptor, ferritin light chain, and transferrin 1. NBP also inhibited oxidative stress in the substantia nigra and protected mitochondria in the rat model of Parkinson's disease. Our findings suggest that NBP alleviates motor disturbance by inhibition of iron deposition, oxidative stress, and ferroptosis in the substantia nigra.

Background: To review our long-term clinical experience, analyze the failure patterns, and give suggestions for target volume delineation of carcinoma showing thymus-like differentiation (CASTLE) treated with intensity-modulated radiotherapy (IMRT)., Methods: From April 2008 to May 2019, 30 patients with CASTLE treated by postoperative or radical IMRT in our center were retrospectively reviewed. A total dose of 56-60 Gy in 28-30 fractions was prescribed to patients without residual disease and 66 Gy in 33 fractions for patients with residual or unresectable disease. Survival rates were calculated using the Kaplan-Meier method. Treatment-related toxicities were graded by National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 4.0., Results: Among the 30 patients, 12 (40%) received partial resection or biopsy. Lateral lymph node metastasis was observed in 7 (23.3%) patients. During follow-up, regional lymph node recurrence occurred in 2 patients and distant metastasis in 5 patients. With a median follow-up time of 63.5 months, the 5-year local recurrence-free survival (LRFS), regional recurrence-free survival (RRFS), distant metastasis-free survival (DMFS), overall survival (OS) and progression-free survival (PFS) rates were 100, 88.9, 78.9, 93.1 and 78.9%, respectively. For patients with no lateral neck node metastasis, prophylactic radiotherapy for lateral neck nodal regions failed to improve RRFS (p = 0.381) and OS (p = 0.153)., Conclusion: Distant metastasis was the major failure pattern for CASTLE after surgery and IMRT. For patients with no lateral neck node metastasis, the omission of irradiation for lateral neck nodal regions seems to be safe and feasible., (© 2022. The Author(s).)

Complement is operative in not only the extracellular but also the intracellular milieu. However, little is known about the role of complement activation inside tumor cells. Here, we report that intracellular C5 is cleaved by cathepsin D (CTSD) to produce C5a in lysosomes and endosomes of colonic cancer cells. After stimulation by C5a, intracellular C5aR1 assembles a complex with KCTD5/cullin3/Roc-1 and β-catenin to promote the switch of polyubiquitination of β-catenin from K48 to K63, which enhances β-catenin stability. Genetic loss or pharmacological blockade of C5aR1 dramatically impedes colorectal tumorigenesis at least by destabilizing β-catenin. In human colorectal cancer specimens, high levels of C5aR1, C5a, and CTSD are closely correlated with elevated β-catenin levels and a poor prognosis. Importantly, intracellular C5a/C5aR1-mediated β-catenin stabilization is also observed ubiquitously in other cell types. Collectively, we identify a machinery for β-catenin activation and provide a potential target for tumor prevention and treatment., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Limited studies have focused on the associated clinicopathologic features and short-term prognostic impacts of metastatic patterns at initial diagnosis in differentiated thyroid cancer (DTC)., Methods: Overall, 530 individuals with distant DTC diagnosed between 2010 and 2014 were identified from Surveillance, Epidemiology, and End Results (SEER) database. Multinomial logistic regression model was used to assess the clinicopathologic factors influencing the pattern of distant metastasis. Kaplan-Meier method and multivariable Cox regression were used to estimate the short-term effects of metastatic patterns on overall (OS) and thyroid cancer-specific survival (TCSS)., Results: Fifty, 111, 263, 59 and 47 patients presented with distant lymph node (LN)-only, bone-only, lung-only, bone plus lung, and liver and/or brain metastases (Mets), respectively. Regional lymph node metastasis (LNM) and follicular histotype were the only confirmed risk factors for distant LN-only Mets and bone-only Mets, respectively. Larger tumour size, extrathyroidal extension (ETE) and papillary histotype were associated with lung-only Mets. Synchronous bone and lung Mets were more likely to occur in older patients. In addition, patients with distant LN-only Mets had hardly any negative effect on OS and TCSS, whereas those with synchronous bone and lung or liver/brain Mets predicted unfavourable short-term outcomes, regardless of whether they received total thyroidectomy and radioisotopes., Conclusions: Different clinicopathologic factors predispose to different patterns of metastases with profound short-term survival differences among DTC patients. Our findings may help to determine effective pretreatment screening for aggressive metastatic patterns at initial diagnosis, and thus to provide additional treatment or access of clinical trials for these patients., (© 2021 John Wiley & Sons Ltd.)

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., (© 2021 Wiley Periodicals LLC.)

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 option. Anlotinib is a multitarget tyrosine kinase inhibitor, which demonstrated antitumor activity in radioiodine-refractory differentiated thyroid cancer and medullary thyroid cancer. We aimed to evaluate the efficacy and safety of anlotinib in locally advanced thyroid cancer in the neoadjuvant setting. Methods: This single-arm phase II study investigated the efficacy and safety of anlotinib (12 mg orally daily, 2 weeks on/1 week off) for 2-6 cycles in patients with locally advanced thyroid cancer in the neoadjuvant setting. The key eligibility criteria included age 14-80 years old; locally advanced thyroid cancer that would benefit from surgery, and at least one measurable lesion. Operable patients received surgery after neoadjuvant treatment. The primary endpoint was objective response rate (ORR). Results: A total of 13 patients were enrolled and received an average of 3.5 cycles of anlotinib treatment. The ORR of anlotinib was 76.9% (95% confidence interval: 46.2-95.0%). The R0/R1 resection rate in the intent-to-treat population was 61.5% and in the per-protocol population was 72.7%. The median time to response was 61.5 days, and the disease control rate at 18 weeks was 92.3%. No patients had blood transfusion or tracheotomy. Most adverse events (AEs) were grade 1 or 2 and tended to discontinue when neoadjuvant treatment ceased. Common AEs of all grades were hypertension (76.9%), hypertriglyceridemia (69.2%), proteinuria (53.8%), thyrotropin increase (53.8%), cholesterol elevation (53.8%), and hand-foot syndrome (38.5%). Conclusions: Anlotinib demonstrated antitumor activity in the neoadjuvant treatment and the majority of patients achieved R0/R1 resection. AEs were consistent with the known anlotinib AE profile. These results suggest that anlotinib neoadjuvant treatment represents a new option for locally advanced thyroid cancer. Clinical Trial Registration Number: NCT04309136.

PRDM16 (known as MEL1), a member of the PR domain zinc finger family, has been implicated in multiple biological processes, including cancers. It is not clear yet whether PRDM16 is involved in tumor progress of papillary thyroid cancer (PTC). We identified the PRDM16 expression level in PTC tissues by qRT-PCR and analyzed its relationship with clinical characteristics in both Fudan University Shanghai Cancer Center (FUSCC) and TCGA cohorts. We tested the function of PRDM16 in PTC cells both in vivo and in vitro . We found a direct downstream target of PRDM16, pyruvate carboxylase (PC), by RNA-sequencing, rescue experiments, luciferase assay, and chromatin immunoprecipitation assay. PRDM16 was downregulated in papillary thyroid cancer tissues and was significantly related with lymph node metastases and extrathyroidal extension in both FUSCC and TCGA cohorts. Overexpression of PRDM16 could attenuate proliferation and migration of PTC cells via inhibiting the epithelial-to-mesenchymal transition process. PC was upregulated in papillary thyroid cancer tissues. Knockdown of PC could inhibit proliferation and migration in TPC-1 and K1 cells. The repression effect on cell proliferation and migration from PRDM16 was PC dependent. PRDM16 could directly bind to the PC promoter and inhibit its expression at the transcription level. Moreover, the mRNA expression level of PRDM16 and PC was negatively related in human PTC tissues. In conclusion, PRDM16 exhibited an antitumor effect and EMT inhibition function in PTC by directly binding with the PC promoter. PRDM16 may be a novel therapeutic target in papillary thyroid cancer., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Liu, Guan, Wen, Ma, Xu, Hu, Wei, Li, Wang, Xiang, Liao and Ji.)

Context: The role of immune-related genes (IRGs) in thyroid cancer dedifferentiation and accompanying immune exhaustion remains largely unexplored., Objective: To construct a significant IRG-based signature indicative of dedifferentiation and immune exhaustion in thyroid cancer., Design and Settings: One exploratory cohort and 2 validation cohorts were used to identify stably dysregulated IRGs in dedifferentiated thyroid cancer (DDTC) and to obtain independent risk factors for dedifferentiation. The IRGs formed a gene signature, whose predictive value was tested by the receiver operating characteristic curve. Correlations between the signature and differentiation-related genes, immune checkpoints, and prognosis were analyzed. Gene set enrichment analyses were performed to identify related signaling pathways., Results: Four IRGs (PRKCQ, PLAUR, PSMD2, and BMP7) were found to be repeatedly dysregulated in DDTC, and they formed an IRG-based signature with a satisfactory predictive value for thyroid cancer dedifferentiation. Correlation analyses revealed that immune checkpoints were closely related to the 4 IRGs and the IRG-based signature, which was significantly associated with the histological subtype (P = 0.026), lymph node metastasis (P = 0.001), and BRAFV600E mutation (P < 0.001). The downregulated expression of PRKCQ shortened the disease-free survival for patients with thyroid cancer. Furthermore, we identified several signaling pathways inherently associated with the IRG-based signature., Conclusions: This study suggests that IRGs participate in the dedifferentiation and immune exhaustion process of thyroid cancer and are potential biomarkers for DDTC., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Though fine-needle aspiration (FNA) improved the diagnostic methods of thyroid nodules, there are still parts of nodules that cannot be determined according to cytology. In the Bethesda system for reporting thyroid cytopathology, there are two uncertain cytology results. Thanks to the development of next-generation sequencing technology, it is possible to gain the genetic background of pathological tissue efficiently. Therefore, a combination of the cytology and genetic background may enhance the accuracy of diagnosis in thyroid nodules., Methods: DNA from 73 FNA samples of thyroid nodules belonging to different cytology types was extracted and exome sequencing was performed by the ThyroLead panel. Test for BRAF mutation was also performed by ARMS-qPCR. Information including age, sex, preoperative cytology, BRAF mutation status tested by ARMS-qPCR, and surgical pathology was collected in electronic medical record system., Results: A total of 71 single nucleotide variants, three fusion gene, and two microsatellite instability-high status were detected in 73 FNA samples. BRAF V600E mutation is the most common mutation in these malignant thyroid nodules. After combining the cytology and genetic background detected by next-generation sequencing, the diagnosis sensitivity was increased from 0.582 (95% CI: 0.441-0.711) to 0.855 (95% CI: 0.728-0.930) ( P < 0.001) in our group, while the specificity, 1,000 (95% CI: 0.732-1.000) compared to 0.857 (95% CI: 0.562-0.975) ( P = 0.25), did not get affected., Conclusions: Next-generation sequencing in thyroid nodules can enhance the preoperative diagnosis sensitivity by fine-needle aspiration alone. It can also provide genetic background for direction of medication. It is possible for clinicians to combine cytology with genetic alterations for a more precise diagnosis strategy of thyroid nodules., Competing Interests: Author L-YL was employed by Zhejiang Topgen Clinical Laboratory Co, Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Tan, Liu, Zhu, Yu, Shi, Han, Zhang, Lin, Semenov, Wang, Ji, Ji, Wang and Qu.)

Objective: The coexistence of BRAF V600E and the telomerase reverse transcriptase (TERT) promoter mutation C228T/C250T is extensively associated with thyroid cancer prognosis. Our study aimed to establish a sensitive method for mutation detection and explore the correlation in detail., Methods: The BRAF and TERT promoter mutation status of 250 papillary thyroid cancers was determined using amplification-refractory mutation system quantitative polymerase chain reaction (ARMS-qPCR) and Sanger sequencing to compare the sensitivity of the 2 methods. Associations between the mutation status and clinicopathological features were then analyzed., Results: ARMS-qPCR was more sensitive than Sanger sequencing (BRAF V600E: 75.2% [188 of 250] vs 52.4% [131 of 250], P < .001; TERT promoter C228T/C250T mutation: 12.0% [30 of 250] vs 3.6% [9 of 250], P = .001; comutation: 9.6% [24 of 250] vs 3.2% [8 of 250], P = .005). Both ARMS-qPCR and Sanger sequencing indicated that patients with coexisting BRAF V600E and TERT promoter mutations had an older diagnosis age, higher recurrence rate, and were associated with a more advanced TNM stage and higher metastasis, age, completeness of resection, invasion, and size score. Moreover, ARMS-qPCR helped identify an earlier group stage, which was younger and had smaller tumors and a lower recurrence rate, compared with the group with coexisting BRAF V600E and TERT promoter mutations identified by Sanger sequencing. The newly identified group had a lower metastasis, age, completeness of resection, invasion, and size score and TNM stage., Conclusion: Patients with coexisting BRAF V600E and TERT promoter mutations had a worse prognosis. ARMS-qPCR, the more sensitive method, can be used to identify patients who have a potentially worse prognosis earlier., (Copyright © 2021 AACE. Published by Elsevier Inc. All rights reserved.)

Cerebral ischemia is one of the most common diseases in China, and the drug pair of Chuanxiong Rhizoma and Paeoniae Radix Rubra can intervene in cerebral ischemia to reduce the inflammatory response of cerebral ischemia and apoptosis. To reveal the intervention mechanism of Chuanxiong Rhizoma-Paeoniae Radix Rubra drug pair on cerebral ischemia systematically, computer network pharmacology technology was used in this paper to predict the target and signaling pathway of the drug pair on the intervention of cerebral ischemia, and then the molecular docking technology was used to further analyze the mechanism of the intervention. The target results were then verified by the rat cerebral ischemia model. The target network results showed that the active compounds of Chuanxiong Rhizoma-Paeoniae Radix Rubra for cerebral ischemic disease contained 30 compounds, 38 targets and 9 pathways. The main compounds included phenolic acids in Chuanxiong Rhizoma and monoterpene glycosides in Paeoniae Radix Rubra. The key targets involved mitogen-activated protein kinase 1(MAPK1), steroid receptor coactivator(SRC), epidermal growth factor receptor(EGFR), mitogen-activated protein kinase 14(MAPK14), caspase-3(CASP3), caspase-7(CASP7), estrogen receptor 1(ESR1), and mitogen-activated protein kinase 8(MAPK8), etc. The target gene functions were biased towards protein kinase activity, protein autophosphorylation, peptidyl-serine phosphorylation and protein serine/threonine kinase activity, etc. The important KEGG pathways involved Ras signaling pathway, ErbB signaling pathway and VEGF signaling pathway. Molecular docking results showed that catechin, oxypaeoniflorin, albiflorin, paeoniflorin and benzoylpaeoniflorin had strong binding ability with MAPK1, SRC, EGFR, MAPK14 and CASP7. MCAO rat experimental results showed that Chuanxiong Rhizoma-Paeoniae Radix Rubra significantly improved the cerebral ischemia injury and interstitial edema, and significantly reduced the activation of caspase-7 and the phosphorylation of ERK1/2. The Chuanxiong Rhizoma-Paeoniae Radix Rubra drug pair alleviated cerebral ischemia injury through a network model of multi-phenotype intervention by promoting cell proliferation and differentiation, reducing inflammatory factor expression, protecting nerve cells from death and figh-ting against neuronal cell apoptosis, with its action signaling pathway most related to Ras signaling pathway, ErbB signaling pathway and VEGF signaling pathway. This study provides the basis for clinical intervention of Chuanxiong Rhizoma-Paeoniae Radix Rubra drug pair on cerebral ischemia, and also provides ideas for the modernization of drug pairs.

Abstract: This study explored the effect of percutaneous intervertebral foraminoscopic discectomy (PIFD) in the treatment of lumbar disc herniation (LDH).This retrospective study collected a total of 88 patient cases for inclusion. Epidemiological and clinical data of patients with LDH at the First Affiliated Hospital of Jiamusi University between May 2017 and January 2020 were retrospectively analyzed. Of those, 44 patients received PIFD and were allocated to an intervention group. The other 44 patients administrated fenestration discectomy (FD), and were assigned to a control group. We compared surgery time (minute), incision length (cm), duration of hospital stay after surgery (day), pain intensity (as checked by Visual Analogue Scale (VAS), health-related quality of life (as examined by Oswestry Disability Index, ODI), and complications between 2 groups.There were not significant differences in surgery time (minute) (P = .56), VAS (P = .33) and ODI (P = .46) after surgery between 2 groups. However, there were significant differences in incision size (cm) (P < .01) and length of hospital stay (day) (P < .01) after surgery between 2 groups. When compared before the surgery, patients in both groups had significant improvements in VAS (P < .01) and ODI (P < .01) after the surgery. Moreover, both groups had similar safety profiles (P > .05).The findings of this study showed that both PIFD and FD benefit patients with LDH. However, PIFD can benefit patients more than FD in the incision size and duration of hospital stay after surgery., Competing Interests: The authors have no conflicts of interests to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Thyroid cancer is the most common type of endocrine malignancy. Although the general prognosis is good, the treatment of advanced disease is still challenging. Exosomes are vesicle units containing specific components that transmit information between cells. In order to explore its role in papillary thyroid cancer (PTC), our study screened exosome enriched lncRNA SNHG9 by lncRNA chip and explored its biological function. We used lncRNA chips combined with bioinformatics analysis to screen lncRNA SNHG9 enriched in exosomes. GO analysis suggested its relationship with autophagy and apoptosis. Quantitative PCR showed SNHG9 was highly expressed in PTC cells and exosomes and its correlation with PTC tumor size was analyzed by clinical characteristics. SNHG9 could inhibit the protective cell autophagy induced by starvation of human normal thyroid epithelial cell line Nthy-ori-3 and promote its apoptosis through PTC cell exosomes. RNA-pull down combined with protein spectrum showed that SNHG9 could interact with YBOX3. Western blot and RNA immunoprecipitation further confirmed their interaction. Western blot showed that SNHG9 could induce degradation of YBOX3, thus interfering with the stability of P21 mRNA and inducing cell apoptosis. In conclusion, our study identified SNHG9 as a PTC cell exosome-enriched lncRNA. SNHG9 could inhibit cell autophagy and promote apoptosis of Nthy-ori-3 cell through YBOX3/P21 pathway., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Wen, Liu, Lu, Cao, Ji and Wei.)

Background: An unmet need for more effective and affordable kinase inhibitors remains in patients with progressive radioactive iodine-refractory differentiated thyroid cancer (RAIR-DTC) in China, where only sorafenib is approved for this indication. This study evaluated the 24-week objective response rate (ORR) to donafenib-a new, domestic multikinase inhibitor-in the treatment of locally advanced or metastatic RAIR-DTC in patients with measurable lesions. Two dose regimens (300 mg twice daily vs. 200 mg twice daily) were used to determine its optimal dosage and safety for further phase III studies. Methods: This study was a randomized, open-label, multicenter phase II trial. Thirty-five adult RAIR-DTC patients with at least one measurable targeted lesion according to RECIST 1.1 were enrolled from 12 centers in China and randomized to receive either 200 mg (17 patients) or 300 mg (18 patients) of donafenib orally twice daily for 24 weeks. The primary endpoint was ORR, and the secondary endpoints included progression-free survival (PFS) among others. Additionally, biochemical (serum thyroglobulin) and structural (total tumor diameter [TTD]) responses were assessed, change (ΔTTD) rates were calculated, and safety was evaluated. Results: The ORRs for the 200- and 300-mg arms were 12.5% and 13.33% ( p  = 1.000), respectively. The 300-mg arm had a nonsignificant, longer median PFS than the 200-mg arm (14.98 months vs. 9.44 months) ( p  = 0.351). There was a trend toward more tumor shrinkage in the 300-mg arm compared with the 200-mg arm (average ΔTTD rate -0.52 ± 0.71 vs. -0.04 ± 1.55 mm/month, p  = 0.103). Most treatment-related adverse events (AEs) in both arms were grades 1-2. The most common grade 3 treatment-related AEs in both arms were palmar-plantar erythrodysesthesia and hypertension; the sum occurrence rates of these two AEs in the 200-mg and 300-mg arms were 11.43% and 22.86%, respectively. Conclusions: Donafenib was generally well tolerated. Both donafenib regimens demonstrated similar efficacy in terms of the ORR in locally advanced or metastatic RAIR-DTC. The results warrant further studies on donafenib as a new, feasible treatment option for RAIR-DTC patients. Clinical Trials.gov IDs: NCT02870569; CTR20160220.

Context: Programmed cell death protein-1 (PD-1), cytotoxic T-lymphocyte antigen 4 (CTLA-4), T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), lymphocyte activation gene-3 (LAG-3), and T-cell immunoglobulin and ITIM domain (TIGIT) are considered major immune co-inhibitory receptors (CIRs) and the most promising immunotherapeutic targets in cancer treatment, but they are largely unexplored in medullary thyroid carcinoma (MTC)., Objective: We aimed to provide the first evidence regarding the expression profiles and clinical significance of CIRs in a large cohort of MTC patients., Design and Patients: In total, 200 MTC patients who received initial surgery in our hospital were included. Immunohistochemistry was performed to evaluate CIR expressions in tissue microarrays (TMAs). Combined with the results of our previous programmed cell death ligand-1 (PD-L1) study, clinicopathologic and prognostic correlations of these proteins were retrospectively analyzed., Results: TIM-3, PD-1, CTLA-4, LAG-3, and TIGIT positivity was detected in 96 (48.0%), 27 (13.5%), 25 (12.5%), 6 (3.0%), and 6 (3.0%) patients, respectively, in whom TIM-3, PD-1, and CTLA-4 expressions were positively correlated. Log-rank tests and multivariate Cox analyses both indicated that TIM-3, CTLA-4 expression, and PD-1/PD-L1 coexpression were associated with worse structural recurrence-free survival. In addition, among 20 patients who developed advanced disease during follow-up, 12 (60%) showed TIM-3 positivity, among whom 6 cases also had concurrent moderate to strong PD-1, PD-L1, or CTLA-4 expression., Conclusions: Using the currently largest TMA cohort of this rare cancer, we delineated the CIR expression profiles in MTC, and identified TIM-3, CTLA-4 expression, and PD-1/PD-L1 coexpression as promising biomarkers for tumor recurrence. Furthermore, a subset of advanced MTCs are probably immunogenic, for which single or combined immunotherapy including TIM-3, PD-1, PD-L1, or CTLA-4 blockade may be potential therapeutic approaches in the future., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: To compare the efficacy and safety of Changsulin ® with Lantus ® in treating patients with type 2 diabetes mellitus (T2DM). Methods: This was a phase Ⅲ, multicenter, randomized, open-label, parallel-group, active-controlled clinical trial. A total of 578 participants with T2DM inadequately controlled on oral hypoglycemic agents were randomized 3∶1 to Changsulin ® or Lantus ® treatment for 24 weeks. The efficacy measures included changes in glycosylated hemoglobin (HbA1c), fasting plasma glucose (FPG), 2h postprandial plasma glucose (2hPG), 8-point self-monitoring of blood glucose (SMBG) profiles from baseline, and proportions of subjects achieving targets of HbA1c and FPG. The safety outcomes included rates of hypoglycemia, adverse events (AEs) and anti-insulin glargine antibody. Results: After 24 weeks of treatment, mean HbAlc decreased 1.16% and 1.25%, FPG decreased 3.05 mmol/L and 2.90 mmol/L, 2hPG decreased 2.49 mmol/L and 2.38 mmol/L in Changsulin ® and in Lantus ® , respectively. No significant differences could be viewed in above parameters between the two groups (all P> 0.05). There were also no significant differences between Changsulin ® and Lantus ® in 8-point SMBG profiles from baseline and proportions of subjects achieving the targets of HbA1c and FPG (all P> 0.05). The rates of total hypoglycemia (38.00% and 39.01% for Changsulin ® and Lantus ® , respectively) and nocturnal hypoglycemia (17.25% and 16.31% for Changsulin ® and Lantus ® , respectively) were similar between the two groups (all P> 0.05). Most of the hypoglycemia events were asymptomatic, and no severe hypoglycemia were found in both groups. No differences were observed in rates of AEs (61.77% vs.52.48%) and anti-insulin glargine antibody (after 24 weeks of treatment, 6.91% vs.3.65%) between the two groups (all P> 0.05). Conclusions: Changsulin ® shows similar efficacy and safety profiles compared with Lantus ® and Changsulin ® treatment was well tolerated in patients with T2DM.

Background: Patients with anaplastic thyroid cancer (ATC), which is among the deadliest of all cancers, often have a poor response to traditional therapies. Currently, the role of long non-coding RNAs (lncRNAs) in ATC carcinogenesis is unclear. In this study, we analyzed the lncRNA expression profile of ATC with the aim of identifying potential molecular targets for treatment of the disease., Methods: Whole transcriptome sequencing of three ATC and two normal thyroid (NT) samples was performed, and the lncRNA expression profile of ATC was analyzed. Original data as well as datasets deposited in the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) were used for clinical validation. Cell proliferation, Transwell, and apoptosis assays were performed using ATC cell lines. Gene Ontology (GO) and gene set enrichment analyses (GSEA) were performed to determine the dysregulated pathways., Results: Whole transcriptome sequencing revealed 182 lncRNAs to be differentially expressed in ATC. One of the lncRNAs, mitotically associated long non-coding RNA ( MANCR ; LINC00704), was significantly overexpressed in ATC cell lines and patient samples compared with NT and papillary thyroid cancer (PTC). MANCR depletion in ATC cells significantly inhibited cancer cell proliferation and invasion, and induced apoptosis. By further analyzing the transcriptome data, we identified 451 genes co-expressed with MANCR . GO and GSEA showed that the top dysregulated pathways were related to mitosis and cell cycle., Conclusions: MANCR is a tumor promoter in ATC, and its role in carcinogenesis is possibly associated with cell cycle regulation. Because MANCR expression is minimal in most normal tissues, it may serve as a potential target in the future treatment of ATC., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-20-4530). The authors have no conflicts of interest to declare., (2020 Annals of Translational Medicine. All rights reserved.)

The incidence of papillary thyroid cancer (PTC) with concomitant Hashimoto thyroiditis (HT) is increasing. Interleukin (IL)-10 is a cytokine previously reported to be elevated in this condition. Evidence from multiple human malignancies showed IL-10 participated in tumor immunity and exhibited therapeutic potential. The aim of this study is to investigate whether IL-10 interferes with tumor immunity in PTC with concomitant HT. Expression of IL-10 and major histocompatibility complex (MHC) class Ⅰ were compared with PTC tissues with or without concomitant HT. PTC cell lines K1 and TPC-1 were stimulated with IL-10 and analyzed for MHC class Ⅰ expression afterward. T-cell activation, production of IL-2 and interferon (IFN)-γ and programmed death-1 (PD-1) expression were assessed by coculture of donor peripheral blood lymphocytes (PBLs) with IL-10-pretreated PTC cells. Programmed death-ligand 1 (PD-L1) expression was measured in PTC tissues and IL-10-pretreated cells of K1 and TPC-1. Increased levels of IL-10 and MHC class Ⅰ were observed in PTC with concomitant HT. IL-10 stimulation increased MHC class Ⅰ expression of PTC cells in vitro. Coculture of PBLs with IL-10-pretreated PTC cells enhanced T-cell activation (% cluster of differentiation [CD]25+ of CD3+T cells) and increased IL-2 production along with decreased IFN-γ secretion and PD-1 expression. Reduced PD-L1 expression was seen in PTC + HT tissue samples and IL-10-stimulated PTC cell lines. Elevated IL-10 expression in PTC with concomitant HT restores MHC class Ⅰ expression and interferes with tumor immunity. The potential mechanism of IL-10 in tumor immunity needs further investigation., (© Endocrine Society 2020.)

Background: The objective of this study is to investigate the effects of humanistic care and psychological counseling (HCPC) on psychological disorders (PD) in medical students after coronavirus disease 2019 (COVID-19) outbreak., Methods: We will search randomized controlled trials or case-controlled studies of HCPC on PD in medical students after COVID-19 outbreak in the following electronic databases: PUBMED/MEDLINE, EMBASE, Cochrane Library, CINAHL, AMED, WANGFANG, and CNKI. The time is restricted from the construction of each database to the present. All process of study selection, data collection, and study quality evaluation will be carried out by two independent authors. Any different opinions will be solved by a third author through discussion. We will employ RevMan 5.3 software to conduct statistical analysis., Results: This study will provide a better understanding of HCPC on PD in medical students after COVID-19 outbreak., Conclusions: This study may offer strong evidence for clinical practice to treat PD in medical students after COVID-19 outbreak., Study Registration: CRD42020193199.

Background: Published trials reported that high-energy extracorporeal shock wave therapy (HEEPSWT) can effectively treat early stage femoral head osteonecrosis (ESFHO). However, their results are still inconsistent. Thus, this study will systematically and comprehensively explore the effectiveness and safety of HEEPSWT for ESFHO., Methods: We will retrieve the electronic databases of Cochrane Library, EMBASE, PubMed, Web of Science, Cumulative Index to Nursing and Allied Health Literature, VIP database, and China National Knowledge Infrastructure from inception to the present. All randomized controlled trials that focusing on the effectiveness and safety of HEEPSWT for ESFHO will be considered. Two researchers will undertake literature selection, information collection, and risk of bias evaluation separately. If disagreements occur, we will invite a third researcher for consultation and a final decision will be made. Cochrane risk of bias tool, and Grades of Recommendation, Assessment, Development and Evaluation will be utilized to assess the risk of bias and quality of evidence, respectively. We will perform statistical analysis using RevMan 5.3 software., Results: This study will provide a detailed summary of exist evidence related to the effectiveness and safety of HEEPSWT for ESFHO., Conclusion: The results of this study synthesize the evidence regarding the HEEPSWT for ESFHO, which may help to guide clinical management in the future., Systematic Review Registration: INPLASY202060055.

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.

Background: Previous studies have reported that extracorporeal shock wave (EPSW) combined spinal core decompression (SCD) has been used for the treatment of patients with femoral head necrosis (FHN) effectively. However, their results are still inconsistent. Therefore, this study will systematically assess the efficacy and safety of EPSW and SCD for the treatment of patients with FHN., Methods: This study will systematically search the following databases from inception through March 1, 2020: MEDLINE, Web of Science, Scopus, EMBASE, Cochrane Library, Cumulative Index to Nursing and Allied Health Literature, and China National Knowledge Infrastructure. All searches will be performed without language and publication date restrictions. This study will only include randomized controlled trials investigating the efficacy and safety of EPSW and SCD for the treatment of patients with FHN. Two authors will independently assess all literatures, extract data, and appraise risk of bias. Any confusion between 2 authors will be cleared up by a third author through discussion. RevMan 5.3 software will be utilized to analyze the data and to perform a meta-analysis if necessary., Results: This study will summarize up-to-date evidence and provide a detailed summary related to the efficacy and safety of EPSW and SCD for the treatment of patients with FHN., Conclusion: This study may provide helpful evidence to determine whether or not EPSW combined SCD is effective and safety for the treatment of patients with FHN., Systematic Review Registration: INPLASY202040092.

Background: Femoral head avascular necrosis (FHAN) is a very common condition among elderly population. Previous studies have reported that total hip arthroplasty (THAP) can benefit patients with such condition. However, no study systematically addressed this topic. Thus, this study will systematically explore the efficacy and safety of THAP for the treatment of patients with FHAN., Methods: We will search the following electronic bibliographic databases from inception to the February 29, 2020: MEDLINE, EMBASE, Cochrane Library, Cumulative Index to Nursing and Allied Health Literature, China National Knowledge Infrastructure, and Chinese Scientific Journal Database. Randomized controlled trials of THAP for the treatment of patients with FHAN will be included, which were reported in any language. All process of study selection, data collection, and study quality assessment will be performed independently by 2 authors independently. Any divergences will be solved by discussion with another author. RevMan 5.3 software will be carried out for data synthesis and analysis., Results: This study will provide a detailed summary of current evidence related to the efficacy and safety of THAP for the treatment of patients with FHAN through assessing pain intensity of hip or knee joints, function and limitation of attacked femoral head, health-related quality of life, and complications., Conclusion: The findings of this study may provide helpful guidance of THAP for the treatment of patients with FHAN., Systematic Review Registration: INPLASY202040067.

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., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Endeavors towards identifying key molecular markers for early diagnosis and treatment are driving the clinical study of papillary thyroid carcinoma (PTC). Recent studies have indicated that protein phosphatase, Mg2+/Mn2+ dependent, 1D (PPM1D) exerts an oncogenic function by increasing cell proliferation, migration and invasion in various cancer types. In addition, PPM1D has a high frequency of genetic alterations and has been proposed as a tumor driver in thyroid cancer, making PPM1D an attractive potential oncotarget for cancer treatment. The aims of the present study were to investigate the downstream targets of PPM1D and the potential molecular mechanisms of its oncogenic activities, as well as its clinical significance in PTC. As anticipated, PPM1D overexpression was confirmed in PTC clinical specimens. Furthermore, knockdown of PPM1D in thyroid cancer cell lines significantly suppressed the proliferation, migration and invasion but facilitated cell apoptosis. The protein levels of phosphorylated p38 mitogen‑activated protein kinase (MAPK), p53 and Bax were increased in PPM1D‑knockdown cells, while inhibition of p38 phosphorylation restored cell migration, proliferation and cell apoptosis. In addition, silencing of PPM1D expression induced nuclear translocation of p53 in K‑1 and TPC‑1 cells. The present results demonstrated that PPM1D regulated p38 MAPK and p53 signaling pathways to promote thyroid cancer progression. Collectively with the clinical results, these data qualified PPM1D as a potential diagnostic biomarker and therapeutic target in human thyroid cancer.

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 < .001). Other independent factors included extranodal extension (ETE), tumor size, and concurrent Hashimoto's thyroiditis. The inconsistency distribution of LNY in bilateral CND was associated with preoperative and intraoperative assessment. Patients with significant difference between major and minor LNY suffered from poorer prognosis (10y-RFS: 58.3% vs 92.0%; HR = 6.719, 95%, P < .0001)., Conclusions: CND surgical procedure, ETE, and Hashimoto's thyroiditis were independent factors of LNY. Inconsistent distribution of LNY was associated with prognosis of bilateral PTC patients. The impact of preoperative and intraoperative assessment on the actual extent of CND can be used to explain the relationship between LNY and PTC prognosis., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)