Abstract
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.
Background
The surgical management of papillary thyroid microcarcinoma (PTMC), especially regarding the necessity of central lymph node dissection (CLND), remains controversial. This meta-analysis ...was conducted to investigate the clinicopathologic factors predictive of central compartment lymph node metastasis (CLNM) in patients diagnosed with PTMC.
Methods
PubMed, EMBASE, Ovid, Web of Science, and the Cochrane Library were searched from their inception to September 2013. Published studies that explored the association between clinicopathologic factors and CLNM in PTMC patients were included. From the identified studies, we extracted the number of individuals with or without each risk factor to calculate the CLNM-positive proportions and used fixed/random-effects models for the meta-analyses of overall relative risk (RR). The pooling analysis on the association between CLNM or the different CLNDs and prognosis was also conducted.
Results
A total of 19 eligible studies that included 8345 patients were identified. Three studies did therapeutic CLND, while the other 16 studies performed prophylactic CLND in PTMC patients. Meta-analyses revealed that CLNM was associated with male gender (RR = 1.36; 95 % CI 1.22–1.52,
p
= 0.001), younger age (<45 years; RR = 1.15; 95 % CI 1.04–1.27,
p
= 0.006), larger tumor size (>5 mm; RR = 1.51 95 % CI 1.32–1.65,
p
= 0.001), multifocality (RR = 1.40; 95 % CI 1.27–1.54,
p
= 0.001), and extrathyroidal extension (RR = 1.81; 95 % CI 1.34–2.43,
p
= 0.001). Meta-regression analysis indicated that a disparity in the proportion of PTMC patients with CLNM in each study was the main factor resulting in heterogeneity among the 19 studies. In addition, the pooling analyses suggested that CLNM did not significantly predict neck recurrences hazard ratio (HR) = 0.95, 95 % CI 0.67–1.22,
p
= 0.054, and the prophylactic CLND group did not improve local control significantly compared to the therapeutic group (RR = 0.96, 95 % CI 0.46–2.01,
p
= 0.544).
Conclusion
Prophylactic CLND may be performed in PTMC patients with clinically uninvolved central lymph nodes but with high risk factors; multicenter studies with long-term follow-up are recommended to better understand the risk factors and surgical management for central nodes in PTMC.
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EMUNI, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UL, UM, UPUK, VKSCE, ZAGLJ
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.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Abstract
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 CD25+ 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.
Abstract
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.
Long non-coding RNAs (lncRNAs) participate in cancer cell tumorigenesis, cell cycle control, migration, proliferation, apoptosis, metastasis and drug resistance. The BRAF-activated non-coding RNA ...(BANCR) functions as both an oncogene and a tumor suppressor. Here, we investigated BANCR's role in papillary thyroid carcinoma (PTC) by assessing BANCR levels in PTC and matched normal thyroid epithelial tissues from 92 patients using qRT-PCR. We also used lentiviral vectors to establish PTC cell lines to investigate the effects of BANCR overexpression on cancer cell proliferation, apoptosis, migration and invasion. Our results indicate BANCR levels are lower in PTC tumor tissues than control tissues. Decreased BANCR levels correlate with tumor size, the presence of multifocal lesions and advanced PTC stage. BANCR overexpression reduced PTC cell proliferation and promoted apoptosis, which inhibited metastasis. It also inactivated ERK1/2 and p38, and this effect was enhanced by treatment with the MEK inhibitor U0126. Finally, BANCR overexpression dramatically inhibited tumor growth from PTC cells in xenograft mouse models. These results suggest BANCR inhibits tumorigenesis in PTC and that BANCR levels may be used as a novel prognostic marker.
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.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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.
Full text
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CMK, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Papillary thyroid cancer (PTC) often presents as multifocal. However, the association of multifocality with poor prognosis remains controversial. The aim of this retrospective study was to identify ...the characteristics of PTC with multiple foci and to evaluate the association between multifocality and prognosis.
We reviewed the medical records of 496 patients who underwent total thyroidectomy for PTC. Patients were classified as G1 (1 tumor focus), G2 (2 foci), and G3 (3 or more foci). We analyzed the clinicopathological features and clinical outcomes in each classification. A Cox regression model was used to assess the relationship between multifocality and recurrence or cancer mortality.
The G1, G2 and G3 groups included 287, 141 and 68 patients, respectively. The mean age was 47.1±16.1 yr in G1, 41.1±18.4 yr in G2, and 35.5±15.9 yr in G3 and differed significantly among the 3 groups (p=0.001). The proportion of extrathyroidal extension, central lymph node metastasis (CLNM), and lateral lymph node metastasis (LLNM) in the G1 to G3 groups increased with increasing number of tumor foci. The Kaplan-Meier curves revealed that G3 had the shortest recurrence-free survival, and differences were significant among the 3 groups (p=0.001, Log Rank test). Furthermore, cancer-specific survival rates decreased significantly with increasing number of tumor foci (p=0.041). Independent predictors of recurrence by multivariate Cox analysis included >3 tumor foci HR 2.60, 95% confidence interval (CI) 1.53-4.39, p=0.001 and extrathyroidal extension (HR 1.95, CI 1.12-3.38, p=0.018).
An increase in the number of tumors is associated with a tendency toward more aggressive features and predicts poor prognosis in PTC.
Full text
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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