Potential functions and mechanisms of lysine crotonylation modification (Kcr) in tumorigenesis and lymphatic metastasis of papillary thyroid cancer (PTC).

OBJECTIVES: To examine the putative functions and mechanisms of lysine crotonylation (Kcr) during the development and progression of papillary thyroid cancer (PTC). METHODS: Samples of thyroid cancer tissues were collected and subjected to liquid chromatography-tandem mass spectrometry. Crotonylated differentially expressed proteins (DEPs) and differentially expressed Kcr sites (DEKSs) were analyzed by Motif, dynamic expression model analysis (Mfuzz), subcellular localization, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway annotation, Go Ontology (GO) annotation, and protein-protein interaction analysis (PPI). Validation was performed by immunohistochemistry (IHC). RESULTS: A total of 262 crotonylated DEPs and 702 DEKSs were quantitated. First, for the tumor/normal comparison, a dynamic expression model analysis (Mfuzz) of the DEKSs revealed that clusters 1, 3, and 4 increased with the progression of thyroid cancer; however, cluster 6 showed a dramatic increase during the transition from N0-tumor to N1-tumor. Furthermore, based on GO annotation, KEGG, and PPI, the crotonylated DEPs were primarily enriched in the PI3K-Akt signaling pathway, Cell cycle, and Hippo signaling pathway. Of note, crosstalk between the proteome and Kcr proteome suggested a differential changing trend, which was enriched in Thyroid hormone synthesis, Pyruvate metabolism, TCA cycle, Cell cycle, and Apoptosis pathways. Similarly, for the LNM comparison group, the DEKSs and related DEPs were primarily enriched in Hydrogen peroxide catabolic process and Tight junction pathway. Finally, according to The Cancer Genome Atlas Program (TCGA) database, the differential expression of Kcr DEPs were associated with the prognosis of thyroid cancer, indicating the prognostic significance of these proteins. Moreover, based on the clinical validation of 47 additional samples, Kcr was highly expressed in thyroid tumor tissues compared with normal tissue (t = 9.792, P < 0.001). In addition, a positive correlation was observed between Kcr and N-cadherin (r = 0.5710, P = 0.0015). Moreover, N-cadherin expression was higher in the relatively high Kcr expression group (χ2 = 18.966, P < 0.001). CONCLUSIONS: Higher Kcr expression was correlated with thyroid tumorigenesis and lymphatic metastasis, which may regulate thyroid cancer progression by Pyruvate metabolism, TCA cycle, Cell cycle, and other pathways.

Critically evaluated key points on hereditary medullary thyroid carcinoma.

Medullary thyroid carcinoma (MTC) accounts for only 3% of all thyroid carcinomas: 75% as sporadic MTC (sMTC) and 25% as hereditary MTC (hMTC) in the context of multiple endocrine neoplasia type 2 (MEN2). Early diagnosis is possible by determining the tumour marker calcitonin (Ctn) when clarifying nodular goitre and by detecting the mutation in the proto-oncogene RET in the MEN2 families. If the Ctn level is only slightly elevated, up to 30 pg/ml in women and up to 60 pg/ml in men, follow-up checks are advisable. At higher levels, surgery should be considered; at a level of > 100 pg/ml, surgery is always advisable. The treatment of choice is total thyroidectomy, possibly with central lymphadenectomy. In the early stage, cure is possible with adequate surgery; in the late stage, treatment with tyrosine kinase inhibitors is an option. RET A mutation analysis should be performed on all patients with MTC. During follow-up, a biochemical distinction is made between: healed (Ctn not measurably low), biochemically incomplete (Ctn increased without tumour detection) and structural tumour detection (metastases on imaging). After MTC surgery, the following results should be available for classification in follow-up care: (i) histology, Ctn immunohistology if necessary, (ii) classification according to the pTNM scheme, (iii) the result of the RET analysis for categorisation into the hereditary or sporadic variant and (iiii) the postoperative Ctn value. Tumour progression is determined by assessing the Ctn doubling time and the RECIST criteria on imaging. In most cases, "active surveillance" is possible. In the case of progression and symptoms, the following applies: local (palliative surgery, radiotherapy) before systemic (tyrosine kinase inhibitors).

Surgical resection of recurrent differentiated thyroid cancer: patterns, detection, staging, and treatment of 683 patients.

Background: Despite improvements in overall survival, the recurrence of differentiated thyroid cancer (DTC) is becoming more common and remains a challenge necessitating accurate reappraisal of the patient. This study aimed to describe the characteristics, reasons, morbidity, and strategies of second operations for DTC. Methods: This was a retrospective observational study of patients with DTC who underwent a second surgery between June 2008 and June 2021 in the Department of Thyroid Surgery at China-Japanese Union Hospital, Jilin University, P.R. China. All clinical characteristics were recorded, and the analysis was estimated using SPSS. Results: Second surgeries were detected in 683 patients. The proportion of second operations changed with the update of international guidelines from 2015 (P < 0.001). The true recurrence rate progressively increased from 21.3% to 61.5%. The rate of an "absence of preoperative FNA" or an "absence of intraoperative pathology at first surgery" decreased from 49.8% to 12.7%, while that of a "misdiagnosis of preoperative FNA at second surgery" decreased from 10% to 1.8%. The most common tumor location during the second surgery was the lateral lymph nodes (n = 104, 36.5%), with a median time to relapse of 36 months. Completion of thyroidectomy and lymph node dissection correlated with the second operation. Conclusion: After 2015, second surgeries were more standardized, the incidence of complications decreased, and real recurrence became the most common reason for a second DTC surgery.

Thirty synchronous medullary and papillary thyroid carcinomas.

Synopsis for table of contents: An exceptional number of synchronous MTC/PTC in the same thyroid gland is presented. This may be the most numerous case series reported in the literature. Synchronous PTC/MTC in the same thyroid gland were classified into 4 subtypes and the clinical and pathological aspects as well as the results are presented. Background and objectives: The synchronous occurrence of multiple neoplastic processes in the thyroid gland is unusual. We investigated the clinicopathological features of 30 medullary thyroid carcinomas (MTC) in association with papillary (PTC). Method: Retrospective analysis of operated patients for thyroid tumors. Synchronous PTC/MTC in the same thyroid gland were classified into 4 subtypes: (type I) True mixed MTC/PTC, MTC and PTC closely intermingled. (Type II) Collision MTC/PTC, i.e. tumors that meet at the same site, invade each other and appear as a single mass in the thyroid gland, i.e. MTC and PTC merge. (Type III) Synchronous anatomically separate tumors in the same thyroid lobe, i.e. separated from each other by non-tumorous thyroid parenchyma. (Type IV) Synchronous tumors occurring in separate anatomical lobes or in the isthmus. Clinical and pathological data were reviewed. Location: Department of thyroid surgery, China-Japan Union Hospital, Jilin University. Time frame: 14 years (June 2008-November 2022). Results: Thirty patients were identified with an overall prevalence of 28621 (0.1%). 17 (56.7%) were male, 13 (43.3%) female, mean age 51.3 ± 11.0 years, mean BMI 23.6 ± 3.6kg/m2. Mean duration of symptoms was 11.2 ± 18.4 months. Mean calcitonin level was 133.7 ± 196.4 pg/ml. Fine needle aspiration (FNA) was offered in 21 cases: 9 (42.9%) were suspected carcinoma, 9 (42.9%) PTC, 1 (4.8%) MTC, 2 (9.4%) MTC/PTC. Pathology revealed type I 4 (13.3%), type II 2 (6.7%), type III 14 (46.7%), type IV 10 (33.3%). The mean diameter of MTC was 1.6 ± 2.0cm, 18 (60%) were micro-MTC. The mean diameter of PTC was 0.9 ± 1.9 cm, 26 (86.7%) were micro-PTC. In 16 (53.3%) micro-PTC/-MTC occurred in synchronous sequence. Four patients had a recurrence: 2 had to be re-operated due to MTC recurrence, 2 died due to distant metastases (bone, liver). Conclusion: We report an exceptional number of MTC/PTC in the same thyroid gland. This may be the most numerous case series reported in the literature. The clinical and pathological aspects as well as the results are presented.

Measuring discrepancies between simple medullary and synchronous medullary/papillary thyroid carcinomas: a comparative cross-sectional study.

Objective: To study the clinicopathological characteristics of patients with synchronous medullary and papillary thyroid carcinomas. Methods: The clinical data of patients with medullary thyroid carcinoma (MTC) operated in our hospital (Department of Thyroid Surgery, China-Japan Union Hospital, Jilin University) from February 2009 to February 2023 were evaluated using an analytical review approach. They were divided into an observation group (patients with synchronous MTC and papillary thyroid carcinoma PTC) and a control group (simple MTC) according to whether the clinical data were associated with MTC, in order to compare the clinical features, pathological types, stage characteristics and molecular biology characteristics of the two groups and to investigate the follow-up of the two groups. Results: The study included 122 MTC, 30 with synchronous MTC/PTC and 92 simple MTC. When the data were compared, the sex ratio, preoperative calcitonin level, preoperative CEA level, presence of calcifications in the MTC lesions, surgical methods, number of MTC lesions, presence of nodular goitre and presence of thyroiditis were higher in the observation group than in the control group. There was a significant difference between the groups when the MTC lesion diameter was ≤1cm in terms of preoperative CEA value (P<0.05); when the MTC lesion diameter was >1cm, there was a statistical difference between the two groups in terms of preoperative Ctn value (P<0.05). Type III was significantly different from the simple group, while type IV was more similar to the simple group. The preoperative serum Ctn value was positively correlated with maximum tumour diameter in both groups, although the correlation was stronger in the easy group. Preoperative CEA was positively correlated with maximum tumour diameter in both groups, with a stronger correlation in the combination group. Preoperative Ctn and CEA were positively correlated with lymph node metastasis in the simple group, whereas there was no apparent correlation with lymph node metastasis in the combination group. The cut-off value of preoperative serum Ctn for cervical lymph node metastases in the simple group was 39.2pg/ml and for lateral cervical lymph node metastases 195.5pg/ml. The cut-off value of preoperative serum Ctn for cervical lymph node metastases in the combination group was 60.79pg/ml and for lateral cervical lymph node metastases 152.6pg/ml. In the simple group, prognosis was significantly worse in the progression group (P<0.001), with no statistical difference between the remission and stable groups. In the combination group, the prognosis of the progression and stable groups was significantly worse than that of the remission group (P<0.001), with no statistical difference between the progression and stable groups. Conclusion: In patients with synchronous medullary and papillary thyroid carcinomas, preoperative Ctn and CEA levels, calcifications, solitary lesions, combined goitre or thyroiditis differ significantly from simple MTC. Therefore, clinical management should pay attention to the above factors and early risk screening should be performed to improve prognosis as much as possible.

A novel risk stratification model based on tumor size and multifocality to predict recurrence in pediatric PTC: comparison with adult PTC.

Background: Pediatric papillary thyroid cancer presents with a more advanced stage of disease than adult PTC; and it is more likely to be aggresive and distant metastases, although the survival rate is high. Methods: A retrospective observational study was performed in children and adults with PTC. Fisher's exact, chi-square, and rank-sum tests were used to examine the differences. Univariate and multivariate Cox regression analyses were applied to determine the possible risk factors for prognosis. A Kaplan-Meier curve analysis was performed to investigate the relationship between the clinicopathological characteristics and recurrence rate. Results: The study involved 156 children and 1,244 adults with PTC. Compared to the group without recurrence, proportions of tumors measuring > 1 cm (48.3% vs. 90.9%) and multifocality (30.3% vs. 63.6%) were higher, N1b stage occurred more frequently (33.8% vs. 100%). However, among adult PTC patients, those with recurrence were older (76.1% vs. 59.4%) than those without recurrence. Risk factors for pediatric PTC recurrence included tumor size and multifocality. However, in adult PTC, the risk factor was LLNM. The newly constructed Stratification.N showed better performance, as illustrated by the fact that patients who were classified into Stratification.N 3 showed an obviously poorer prognosis (P=0.01 and P=0.00062), especially in those aged >14 years (P=0.0052). Conclusion: Compared with adult PTC, pediatric PTC showed unique characteristics in terms of clinical pathology and recurrence. Tumor size and multifocality were strong risk factors for pediatric PTC. Accordingly, the novel proposed risk stratification method could effectively predict the recurrence of pediatric PTC.

Does pretreatment elevated calcitonin level cause the poor prognosis in patients with medullary thyroid cancer?

Background: Medullary thyroid carcinoma (MTC) patients have poor survival, tumor/node/metastasis (TNM) stage and biochemical prognosis are the most important factors. We investigated the clinical significance of calcitonin (Ctn) to assess the biochemical prognosis of MTC. Methods: This retrospective observational study enrolled 77 MTC patients with complete information and primary surgery at the Department of Thyroid Surgery, China-Japan Union Hospital of Jilin University between 2009 and 2020. Patient and MTC characteristics were recorded. All patients were divided into remission, stable, and progression according to biochemical prognosis. We analyzed the correlation between preoperative serum Ctn, TNM stage and biochemical prognosis. Results: Elevated preoperative serum Ctn was positively correlated with TNM stage. Patients with higher Ctn, multifocality, and bilateral tumors were associated with a higher TNM stage. Multivariate logistic regression analysis showed that preoperative serum Ctn level was an independent risk factor for TNM stage. Receiver operating characteristic (ROC) analysis found the best Ctn cut-off value for predicting TNM III was 45.88 pg/mL, which had a sensitivity of 87.2% and a specificity of 65.8%. The best Ctn cut-off value for predicting TNM IV was 167.00 pg/mL, with a sensitivity of 92.9% and a specificity of 77.6%. In univariate analysis, patients with higher preoperative serum Ctn, multifocality, bilateral tumors, and higher TNM stage were more likely to progress. The optimal cut-off value for progression was 195.5 pg/mL, which had a sensitivity of 80.0% and a specificity of 70.2%. For every 1-unit increase in preoperative serum Ctn levels, the risk of progression increased by 1.004 times (P=0.008), and patients with TNM stage III [hazard ratio (HR) =9.663; 95% confidence interval (CI): 1.411, 66.156] were nearly 9.7-fold more likely to progress than those in TNM stage I/II. Conclusions: Elevated preoperative serum Ctn predicted poor clinical outcomes in MTC.

Robotic bilateral axillo-breast versus endoscopic bilateral areola thyroidectomy outcomes of 757 patients.

Background: Remote endoscopic thyroidectomy (ET) and robotic thyroidectomy (RT) seem to be beneficial in selected situations to avoid anterior neck scars. There are limited data in the literature to determine whether RT via a bilateral axillo-breast approach (RT-BABA) is superior to ET via a bilateral areolar approach (ET-BAA). Therefore, the aim of this study was to evaluate the surgical outcomes of RT-BABA versus ET-BAA. Methods: Between May 2013 and May 2022, 757 patients who underwent RT-BABA or ET-BAA at a high-volume Chinese thyroid center were included. Intraoperative and postoperative outcome parameters were collected and retrospectively analyzed. The moving average method was used to evaluate the learning curve. Results: The proportion of patients older than 45 years was greater in the RT group than in the ET group (14.8% vs. 7.4%, p < 0.001). The percentage of overweight patients was greater in the RT group (28.8% vs. 9.5%, p < 0.001). The number of patients treated for malignant lesions was higher in the RT group (86.8% vs. 75%, p < 0.001). The rate of thyroiditis was higher in the RT group (10.9% vs. 6.6%, p < 0.001). Surgical time was significantly shorter in the RT group (140 vs. 165min, p < 0.001). Drainage volume was higher in the RT group (100 vs. 85ml, p < 0.001). Postoperative hospital stay was shorter in the RT group (3.04 ± 0.44 vs. 3.67 ± 0.89 days, p < 0.001). The cost in the RT group was higher (49627 ± 2795 vs. 25094 ± 3368 yuan, p < 0.001). Transient vocal cord dysfunction was lower in the RT group (2.9% vs. 8.0%, p = 0.003). There was no significant difference between the two groups in the number of central lymph nodes sampled, positive lymph nodes, neural monitoring (EMG) results, and rate of transient hypoparathyroidism. The learning curve for RT was 26 cases, and the operative time for ET was constant throughout the study. Conclusions: RT-BABA is as safe and feasible as ET-BAA. RT-BABA performed better in some surgical outcomes. Further prospective studies are needed to confirm the safety of RT-BABA.

Time trend analysis of thyroid cancer surgery in China: single institutional database analysis of 15,000 patients.

PURPOSE: The institutional database of the Thyroid Surgery Division in China-Japan Union Hospital of Jilin University was queried to audit time trend patterns in thyroid cancer (TC) management between 2008 and 2017. METHODS: Retrospective longitudinal analysis. Clinicopathological features and treatment strategies were analyzed. Frequencies and multivariate tests were used to detect correlations. RESULTS: Clinical data were obtained from 15,000 TC patients (i.e., 71.3% of 21,044 operations). Papillary was the most common histological subtype (n = 14,916, 99%), and 76% were microcarcinomas. Stage I (95%) and low-risk patients (58%) were prevalent throughout the 10-year period. The trend for total thyroidectomy increased from 29.1% (2008-2012) to 67.9% (2013-2015), and then dropped to 48.6% (2016-2017). A total of 8827 (52%) patients received central lymph node dissection (CLND). The tendency for CLND increased from 15.7 to 86.4% during the 10-year period. While the trend of lateral lymph node dissection decreased from 71.3 to 13.3%. Radioactive iodine therapy was offered to 10% of patients (2008-2012), except for a low value (5.4%) in 2009, and then increased from 12.3% (2012) to 41.3% (2015), while decreased to 32.4% (2017). CONCLUSION: The surgical management of TC patients has undergone continuous changes over the past 10 years. The evolution from aggressive treatment to a more conservative approach has been constant. Our results suggest that the current surgical management approach for TC is adequate and in support of the published guidelines. Our findings warrant further investigation to determine the clinical implications of decision making for TC.

Lymph node characteristics of 6279 N1 differentiated thyroid cancer patients.

PURPOSE: This study examined the clinicopathological characteristics of 6279 N1 differentiated thyroid cancer (DTC) patients who underwent operations in our center. METHODS: This was a retrospective longitudinal analysis. We categorized the DTC on the basis of various lymph node (LN) characteristics. Logistic regression models and multiple linear regression models were used for the correlation analysis. RESULTS: A total of 3693 (58.8%) N1a patients and 2586 (41.1%) N1b patients were included. Patients with N1b disease had larger metastatic foci (0.5 vs. 0.15 cm), a greater number of metastatic LNs (5 vs. 2), a greater number of dissected LNs (25 vs. 7), and a smaller lymph node ratio (NR, number of positive LNs / number of sampled LNs) (23.1% vs. 28.6%) than patients in stage N1a. Comparing the clinicopathological features, we found that male, increased tumor size, multifocality, and thyroiditis increased the risk of stage N1b disease (P<0.05). Sex, multifocality, capsular infiltration, and tumor size were associated with the size of the metastatic LNs (P<0.05). Sex, capsular infiltration, and nodular goiter were associated with the NR (P<0.05). Male sex, tumor located in inferior lobe, maximal tumor diameter (MTD) <1cm, and nodular goiter were independent predictors for skip metastases (P<0.05). MTD <1cm, central neck metastasis and advanced age were independent predictors for bilateral lateral neck metastasis (BLNM) (P<0.05). CONCLUSION: The LN characteristics of stage N1a and N1b disease were associated with significantly different features, such as sex, tumor size, multifocality, capsular infiltration, and nodular goiter.