Diagnostic values of thyroglobulin in lymph node fine-needle aspiration washout: a systematic review and meta-analysis diagnostic values of FNA-Tg.

Thyroglobulin measurement in the needle washout after fine-needle aspiration (FNA-Tg) served as an important measurement for suspicious recurrent or metastatic lesions. We conducted a pooled analysis to evaluate the diagnostic accuracy of FNA-Tg and searched electronic databases for original articles in English from 1993 through 2017. Finally, a total of 22 studies containing 2,670 lymph nodes (LNs) that enrolled participants with suspicious neck LNs during thyroid nodule workup or papillary thyroid cancer (PTC) follow-up were included. In our analysis, the overall pooled sensitivity for FNA-Tg was 0.91 (95%CI: 0.87-0.93), specificity was 0.94 (95% CI: 0.91-0.96). Meta regression revealed that the cutoff value and status of serum Tg were sources of heterogeneity for sensitivity, and the cutoff value was source of heterogeneity for specificity. Additionally, the cutoff value and status of serum Tg were sources of heterogeneity in the joint model. Subgroup analysis about cut-off value showed that the choice of 1 ng/mL had highest sensitivity, 40 ng/mL had highest specificity. At last, we arrived at the conclusion that FNA-Tg measurement had high specificity and sensitivity in the early detection of LNs metastases from PTC by our meta-analysis. The technique was simple and could be recommended to apply in any FNA facility, especially when LN were small-sized. Significantly, a better standardization of criteria for FNA-Tg detection and cutoff value was required to provide useful data and to improve management of PTC patients in the future.

Clinicopathological features and prognosis of familial papillary thyroid carcinoma--a large-scale, matched, case-control study.

OBJECTIVE: It remains controversial whether or not the aggressiveness of familial nonmedullary thyroid cancer (FNMTC) differs from sporadic carcinoma. The aim of this study was to determine the clinicopathological features and prognosis of FNMTC. DESIGN: A matched-case comparative study. METHODS: Three hundred and seventy-two patients with familial papillary thyroid carcinoma (FPTC) were enrolled as the study group, and another 372 patients with sporadic PTC were enrolled as controls and matched for gender, age, tumour/node/metastasis (TNM) staging and approximate duration of follow-up. We compared the differences in the clinicopathological features and prognosis between the subgroups. RESULTS: Compared with sporadic PTC, patients with FPTC were more likely to present tumour multicentricity, bilateral growth and a concomitant nodular goitre (P < 0·05). In papillary thyroid microcarcinoma (PTMC), a higher recurrence rate was noted in patients with a family history of PTC, and this remained independently predictive on multivariate analysis. The patients with FPTC in the second generation showed an earlier age of onset, more frequent Hashimoto's thyroiditis and a higher recurrence rate than the first generation, while the first-generation offspring of patients had a higher incidence of nodular goitre than the second generation. CONCLUSIONS: The presence of familial history in PTC indicates an increase in biological aggressiveness, and patients in the second generation may exhibit the 'genetic anticipation' phenomenon. At present, the available data are not sufficient to support a more aggressive approach for FPTC. However, a family history of PTC is an independent risk factor for recurrence in patients with PTMC.

miR-21 regulates tumor progression through the miR-21-PDCD4-Stat3 pathway in human salivary adenoid cystic carcinoma.

miR-21, which is a putative tumor onco-miR and frequently overexpressed microRNA in various tumors, has been linked to tumor progression through targeting of tumor-suppressor genes. In this study, we sought to determine whether miR-21 has any role on tumor progression of salivary adenoid cystic carcinoma (SACC) and the possible mechanisms. We found that the level of miR-21 expression was significantly higher in SACC than that in normal salivary tissues, and it is also higher in tumors with metastasis than that without metastasis. Using an anti-miR-21 inhibitor in an in vitro model, downregulation of miR-21 significantly decreased the capacity of invasion and migration of SACC cells, whereas a pre-miR-21 increased the capacity of invasion and migration of SACC cells. To explore the potential mechanisms by which miR-21 regulate invasion and migration, we identified one direct miR-21 target gene, programmed cell death 4 (PDCD4), which has been implicated in invasion and metastasis. The suppression of miR-21 in metastatic SACC-LM cells significantly increased the report activity of PDCD4 promoter and the expression of PDCD4 protein. This subsequently resulted in downregulation of the p-STAT3 protein. The level of miR-21 expression positively related to the expression of PDCD4 protein and negatively related to the expression of p-STAT3 protein in SACC specimens, respectively, indicating the potential role of the STAT3-miR-21-PDCD4 pathway in these tumors. Dysregulation of miR-21 has an important role in tumor growth and invasion by targeting PDCD4. Therefore, suppression of miR-21 may provide a potential approach for the treatment of advanced SACC patients.

Quantitative comparison of three thyroidectomy approaches in neck muscles, voice, and swallowing functions.

OBJECTIVE: This study compares endoscopic thyroidectomy by gasless unilateral axillary approach (ETGUA) and sternocleidomastoid leading-edge approach (SLEA) with conventional open thyroidectomy (COT) in hemithyroidectomy. The main focus is on the protection of neck muscles (sternocleidomastoid, omohyoid, sternothyroid) and the postoperative function of voice and swallowing yielded through these common approaches. METHODS: A total of 302 patients who underwent hemithyroidectomy were enrolled and divided into three groups: ETGUA (n = 101), SLEA (n = 100), and COT (n = 101). Ultrasound was used to measure the thickness of bilateral neck muscles, including the sternocleidomastoid, omohyoid, and sternothyroid. The changes in thickness on the surgical side compared to the non-surgical side. Analyzed factors included muscle thickness changes, Swallowing Impairment Score (SIS), Voice Handicap Index (VHI), Scar Cosmesis Assessment and Rating (SCAR), Neck Injury Index (NII), surgery duration, drainage volume, hospitalization, and number of lymph nodes. RESULTS: The clinical characteristics among the three groups were consistent except for differences in sex, age, and BMI. Metrics such as sternocleidomastoid muscle, NII, hypocalcemia, postoperative PTH, transient hoarseness, and number of lymph nodes showed no significant differences among the three groups. However, significant differences were found in the duration of surgery, drainage volume, hospitalization period omohyoid muscle, Sternohyoid muscle, VHI, SIS, and SCAR (all p < 0.001). CONCLUSION: In comparison to COT, ETGUA and SLEA demonstrate superiority in protecting neck muscles and preserving voice and swallowing function without compromising surgical safety or radicality.

Ruxolitinib induces apoptosis and pyroptosis of anaplastic thyroid cancer via the transcriptional inhibition of DRP1-mediated mitochondrial fission.

Anaplastic thyroid carcinoma (ATC) has a 100% disease-specific mortality rate. The JAK1/2-STAT3 pathway presents a promising target for treating hematologic and solid tumors. However, it is unknown whether the JAK1/2-STAT3 pathway is activated in ATC, and the anti-cancer effects and the mechanism of action of its inhibitor, ruxolitinib (Ruxo, a clinical JAK1/2 inhibitor), remain elusive. Our data indicated that the JAK1/2-STAT3 signaling pathway is significantly upregulated in ATC tumor tissues than in normal thyroid and papillary thyroid cancer tissues. Apoptosis and GSDME-pyroptosis were observed in ATC cells following the in vitro and in vivo administration of Ruxo. Mechanistically, Ruxo suppresses the phosphorylation of STAT3, resulting in the repression of DRP1 transactivation and causing mitochondrial fission deficiency. This deficiency is essential for activating caspase 9/3-dependent apoptosis and GSDME-mediated pyroptosis within ATC cells. In conclusion, our findings indicate DRP1 is directly regulated and transactivated by STAT3; this exhibits a novel and crucial aspect of JAK1/2-STAT3 on the regulation of mitochondrial dynamics. In ATC, the transcriptional inhibition of DRP1 by Ruxo hampered mitochondrial division and triggered apoptosis and GSDME-pyroptosis through caspase 9/3-dependent mechanisms. These results provide compelling evidence for the potential therapeutic effectiveness of Ruxo in treating ATC.

[Aberrant methylation of hMLH1 gene promoter in papillary thyroid cancer and its clinical significance].

OBJECTIVE: To investigate the aberrant promoter methylation of hMLH1 gene promoter and its clinical significance in papillary thyroid cancer (PTC). METHODS: methylation of hMLH1 gene promoter in the cancer tissue and matched tumor-adjacent normal tissue of 152 PTC patients were detected by real-time methylation specific PCR (qMSP). The relationship between the methylation of hMLH1 gene promoter and clinicopathological features was analyzed. RESULTS: The methylation rate of hMLH1 gene promoter in cancer tissues was 37.5% (57/152), of which 33 cases were totally methylated and 24 cases were partially methylated. The methylation rate of adjacent normal tissues was 5.3% (8/152)(all were partially methylated). The methylation rate of PTC tissues was significantly higher than that in the tumor-adjacent normal tissue (P < 0.01). The promoter methylation of hMLH1 gene in PTC was significantly correlated with age, size and number of the primary lesion, local invasion, T stage and lymph node metastasis (P < 0.05) , but not correlated with gender and clinical stage (P > 0.05). CONCLUSION: Promoter methylation of hMLH1 gene is a common molecular event in PTC tissue, and it is significantly correlated with the progression of PTC.

The incidence trends of oral cancers worldwide from 1988 to 2012 and the prediction up to 2030.

BACKGROUND: This paper aims to analyze the time trend of OCs incidence in 43 countries (1988-2012) and predict the incidence trend of OCs (2012-2030). METHODS: In the database for Cancer Incidence in Five Continents, the annual data on OCs incidence grouped by age and gender were obtained from 108 cancer registries in 43 countries. The age-standardized incidence rates were calculated, and the Bayesian age-period-cohort model was used to predict the incidence in 2030. RESULTS: South Asia and Oceania had the highest ASR in 1988 (9.24/100 000) and 2012 (6.74/100 000). It was predicted that India, Thailand, the United Kingdom, the Czech Republic, Austria, and Japan would be the countries with an increased incidence of OCs in 2030. CONCLUSION: Regional custom is an important factor affecting the incidence of OCs. According to our predictions., it is necessary to control risk factors according to local conditions and enhance screening and education.

Level II lateral neck dissection for papillary thyroid carcinoma: A retrospective cohort study.

BACKGROUND: For N1b papillary thyroid carcinoma (PTC) patients, lateral neck dissection encompassing levels Ⅱ-Ⅴ is generally recommended. However, routine level Ⅱ dissection is controversial given the low incidence of metastasis, and potential complications such as increased shoulder syndrome. METHODS: Retrospective analysis of consecutive patients with papillary thyroid carcinoma who underwent lateral neck dissection at a single institution from January 2019 to April 2021 was performed. Clinicopathological features such as age, gender, tumor location, tumor size, TgAb and TPOAb levels, capsular invasion, multifocality and lymph node metastases were examined to evaluate the occurrence of metastatic Level Ⅱ lymph nodes. RESULTS: Overall and occult level Ⅱ metastases were observed in 51.83% and 34.84% of cN1b PTC patients. Multivariant analysis showed that primary tumor, location of primary tumor and positive level Ⅴ can serve as independent risk factors of metastasis in level Ⅱ. For cN1b PTC patients not suspected of level Ⅱ lymph nodes preoperatively, independent risk factors for predicting occult level Ⅱ metastases may include the location of primary tumor, positive level Ⅲ and positive level Ⅴ. CONCLUSION: A significant number of patients with PTC and lateral neck disease experienced Level Ⅱ metastasis, with the location of primary tumor and multilevel lymph node involvement being the independent risk factors. If the tumor is less than 1 cm and located at lower 2/3 lobe, there is minimal possibility of level Ⅱ lymph node metastasis.

[Expression of epidermal growth factor receptor in salivary adenoid cystic carcinoma and its role in cancer invasion].

OBJECTIVE: To assess the epidermal growth factor receptor (EGFR) status in salivary adenoid cystic carcinoma and explore its role in cancer invasion. METHODS: Fifty-four patients with pathologically confirmed salivary adenoid cystic carcinoma (SACC) were divided into invasion group and non-invasion group. The EGFR expression was determined by immunohistochemstry (SP staining). The relations between the EGFR expression and the SACC clinical pathological characteristics were analyzed. RESULTS: EGFR were mainly expressed in the cell membrane and cytoplasm in the tissue of SACC. The positive rate of EGFR expression in the tumor tissue was 75.9% (41/54), and EGFR was over-expressed in the cytoplasm. The positive rate of EGFR expression in invasion group was higher than that in the non-invasion group (10.0%, P < 0.05). EGFR expression were related with the SACC T stages, histological types, distant metastasis, lymph node metastasis, and nerve invasion (P < 0.05). CONCLUSIONS: A higher expression of EGFR gene in the cytoplasm may have important effect on the progression of invasive carcinoma. Further investigations are required to develop new strategy in the treatment of salivary adenoid cystic carcinoma.

[Expression and significance of E-cadherin in adenoid cystic carcinoma of salivary glands].

OBJECTIVE: To examine the expression of E-cadherin and the methylation status of CDH1 and explore their clinical significance in salivary adenoid cystic carcinoma (SACC). METHODS: The expression of E-cadherin was detected by the immunohistochemical method. And the methylation of CDH1 gene promoter 5'-CpG island was analyzed by real-time methylation-specific polymerase chain reaction (real-time MSP) in salivary adenoid cystic carcinoma and normal salivary gland tissue respectively. RESULTS: The expression rate of E-cadherin was lower in SACC than that in normal salivary gland tissue (100.0% vs 55.6%, P < 0.05). And the expression of E-cadherin was associated with different histopathological types, T-stage, nerve invasion, lymphatic and distant metastasis (P < 0.05). However, there was no correlation between the expression of E-cadherin and gender, age and tumor location. Partial methylation of CDH1 was detected in 3 of 30 cases with a positive expression of E-cadherin and full methylation of CDH1 in 23 of 24 cases with a negative expression of E-cadherin. There was a negative correlation between the expression of E-cadherin and the methylation of CDH1 in salivary adenoid cystic carcinoma (r = -0.483, P < 0.001). CONCLUSION: The down-regulation of E-cadherin, as modulated by the methylation of CDH1, may contribute to nerve invasion, lymphatic and distant metastasis in SACC. Thus it may be used as a biological indicator of malignancy and prognosis.

Case report: Successful treatment of a rare case of combined parathyroid adenoma, cervical bronchogenic cyst, and tracheal diverticulum with gasless endoscopic resection of neck masses via an axillary approach: A case report and literature review.

Parathyroid adenoma (PA), one of the most common causes of hyperparathyroidism, generally involves a single parathyroid gland and is manifested as hyperparathyroidism. Bronchogenic cysts are rare congenital cystic lesions caused by a development malformation in bronchi during the embryonic period, which mostly occur in the lung and mediastinum, with an extremely low morbidity rate in the neck. A 27-year-old young female was found to suffer from hyperparathyroidism on routine physical examination, and further examination suggested a cystic lesion in the right inferior parathyroid area combined with a tracheal diverticulum. Therefore, she was initially diagnosed with cystic hyperplasia of the parathyroid glands complicated by a tracheal diverticulum. Gasless endoscopic resection of neck masses via an axillary approach was performed because of the high requirements for the surgical cosmetic effect of the patient. During the surgery, we observed that the preoperatively diagnosed cystic lesion was a combination of two masses, which were successfully resected under endoscopy. Based on the postoperative pathology and clinical features, the patient was eventually diagnosed with a rare case of triple diseases including PA, cervical bronchial cyst, and tracheal diverticulum. Now, the patient recovered well as per the follow-up with no signs of recurrence and was extremely satisfied with the cosmetic effect of the surgery.

Clinical application of endoscopic surgery using a gasless unilateral transaxillary approach in the treatment of primary hyperparathyroidism.

Objectives: To investigate the safety and feasibility of gasless axillary parathyroid surgery in the treatment of primary hyperparathyroidism. Methods: A total of 12 patients who received gasless axillary parathyroidectomy (endoscope group) and 14 patients who received traditional open parathyroidectomy (open group) from January 2019 to April 2022 were screened and included. The differences in baseline characteristics, surgical efficiency, incidence rate of complications, changes in biochemical indicators, and incision satisfaction between the two groups were analyzed and compared. Results: The proportion of young patients was higher in the endoscopic group than in the open group, and the difference was statistically significant [(41.33 ± 13.65) years vs. (58.00 ± 9.44) years, P < 0.01]. The differences in operation time, intra-operative blood loss, post-operative drainage volume, hospital stay, and surgical efficiency between the two groups yielded no statistical significance (P > 0.05). Patients in the open group had more significant neck pain 3 days after surgery (P = 0.046), but the degree of pain 3 months after surgery was the same in the 2 groups (P = 0.432). Evaluation of post-operative mature stage scar and incision satisfaction regarding aesthetics in the endoscope group were significantly superior to that in the open group [(1.92 ± 0.92) points vs. (0.92 ± 1.00) points, P = 0.017 and (1.57 ± 0.51) points vs. (1.00 ± 0.013) points, P = 0.013, respectively]. No statistical significance was found in terms of incidence rate of post-operative fever (P > 0.05). No temporary recurrent laryngeal nerve injury, post-operative bleeding, incision hematoma infection, or other complications were observed. Comparing the two groups, the extent of the level decrease of PTH was similar to that of serum calcium and phosphorus (P < 0.05), where most patients experienced transient hypocalcemia after operation yielding no significant difference in incidence (P = 0.225). During a follow-up period of 3 to 36 months, a total of 1 patient in the open group experienced recurrence at 10 months after surgery and was treated non-surgically. Conclusion: Gasless axillary approach to parathyroid surgery for primary hyperparathyroidism possesses good safety and patient satisfaction in terms of aesthetics.

Novel statistical framework to identify differentially expressed genes allowing transcriptomic background differences.

MOTIVATION: Tests of differentially expressed genes (DEGs) from microarray experiments are based on the null hypothesis that genes that are irrelevant to the phenotype/stimulus are expressed equally in the target and control samples. However, this strict hypothesis is not always true, as there can be several transcriptomic background differences between target and control samples, including different cell/tissue types, different cell cycle stages and different biological donors. These differences lead to increased false positives, which have little biological/medical significance. RESULT: In this article, we propose a statistical framework to identify DEGs between target and control samples from expression microarray data allowing transcriptomic background differences between these samples by introducing a modified null hypothesis that the gene expression background difference is normally distributed. We use an iterative procedure to perform robust estimation of the null hypothesis and identify DEGs as outliers. We evaluated our method using our own triplicate microarray experiment, followed by validations with reverse transcription-polymerase chain reaction (RT-PCR) and on the MicroArray Quality Control dataset. The evaluations suggest that our technique (i) results in less false positive and false negative results, as measured by the degree of agreement with RT-PCR of the same samples, (ii) can be applied to different microarray platforms and results in better reproducibility as measured by the degree of DEG identification concordance both intra- and inter-platforms and (iii) can be applied efficiently with only a few microarray replicates. Based on these evaluations, we propose that this method not only identifies more reliable and biologically/medically significant DEG, but also reduces the power-cost tradeoff problem in the microarray field. AVAILABILITY: Source code and binaries freely available for download at http://comonca.org.cn/fdca/resources/softwares/deg.zip.

Aberrant methylation of different DNA repair genes demonstrates distinct prognostic value for esophageal cancer.

BACKGROUND: DNA mismatch repair (MMR) deficiency results in a strong mutator phenotype and high-frequency microsatellite instability (MSI-H), which are the hallmarks of many tumors. AIM: The objective of this study is to investigate the promoter CpG island methylation status of mismatch repair genes human mutL homolog 1 (hMLH1), human mutS homolog 2 (hMSH2), and O(6)-methylguanine-DNA methyltransferase (MGMT) in esophageal squamous cell carcinoma (ESCC) and its roles in alkylating agents chemotherapy. METHODS: Real-time methylation-specific polymerase chain reaction (PCR) (real-time MSP) was employed to detect promoter CpG island methylation of the hMLH1, hMSH2, as well as MGMT genes in 235 surgical tumor tissue samples from ESCC patients and their corresponding normal tissue samples. RESULTS: Promoter CpG island methylation of hMLH1, hMSH2, and MGMT were detectable in 43.4, 28.9, and 40.4% of ESCC tumor DNA, respectively, and the loss rates of hMLH1, hMSH2, and MGMT protein expression were 48.6, 34.5, and 40.9% in tumor tissues, respectively. For the entire population of 235 ESCC patients who were enrolled in operating treatment combined with radiotherapy and chemotherapy with alkylating agents, there was a significant difference in the overall survival between patients with methylated MGMT promoter and those with an unmethylated MGMT promoter (P < 0.05). CONCLUSION: Promoter CpG island methylation may be a frequent event in ESCC carcinogenesis. Detection of the methylated sequences of hMLH1, hMSH2, and MGMT appears to be promising as a predictive factor in primary ESCC.

Synthesis and characterization of CD133 targeted aptamer-drug conjugates for precision therapy of anaplastic thyroid cancer.

Anaplastic thyroid cancer (ATC) is an undifferentiated and highly aggressive type of thyroid cancer and is extremely resistant to standard therapies such as surgical resection and radioactive iodine therapy. Although targeted therapeutic agents including small molecule drugs and monoclonal antibodies are rapidly developed in recent years, no ATC targeted drugs are available to date; thereby, novel targeted therapies are needed to improve the outcomes of ATC patients. Aptamers are single-stranded DNA (or RNA) molecules that can selectively bind to cancer specific antigens, and aptamer-based targeted therapy has certain advantages over that based on antibodies due to its high binding affinity and low immunogenicity. Here, we identified that CD133, a cancer stem cell marker, was specifically expressed in ATC tumor tissues and cells, implying that CD133 is a potential drug target for ATC therapy. Additionally, we successfully obtained a CD133 targeted aptamer AP-1 by paired cell-based SELEX, which can precisely recognize CD133 antigen in vitro. Furthermore, the truncated AP-1-M aptamer from its precursor AP-1 has shown higher binding affinity for CD133, and specifically accumulated in anaplastic thyroid cancer FRO cell derived tumor in vivo. Conjugation of truncated AP-1-M with doxorubicin could dramatically inhibit CD133 positive FRO cell proliferation, induce cell apoptosis in vitro, and also suppress tumor growth in FRO cell xenograft mice in vivo. Our results clearly demonstrated that the CD133 targeted aptamer AP-1-M conjugated with anticancer drugs has potential to become a promising therapeutic approach against ATC in the near future.

Role of oncogene PIM-1 in the development and progression of papillary thyroid carcinoma: Involvement of oxidative stress.

In this study, we aimed to clarify the role of PIM-1 in papillary thyroid carcinoma (PTC) in vitro and investigate the relationship between PIM-1 and redox proteins (NOX4, SOD2, and GPX2) at the tissue and cellular levels. As a PIM-1 inhibitor, SGI-1776 inhibited cell proliferation, colony formation, migration and induced an increase in apoptosis and reactive oxygen species in two PTC cell lines (BCPAP and TPC-1). The expressions of PIM-1, SOD2 and GPX2 were downregulated after siNOX4 exposure. Immunohistochemistry in 120 PTC patients showed that all four proteins exhibited higher expression levels in PTC tissues than in adjacent normal tissues. PIM-1 expression was related to NOX4, SOD2, and GPX2 expressions. The Cancer Genome Atlas database analysis showed the significant correlation between the expression of NOX4 and PIM-1. Our results demonstrated that PIM-1 played an important oncogenic role in PTC carcinogenesis that may be related to oxidative stress.

Pathological analysis and surgical modalities selection of cT1N0M0 solitary papillary thyroid carcinoma in the isthmus.

BACKGROUND: prognosis, identify clinicopathological characteristics, and determine optimal modalities for cT1N0M0 solitary papillary thyroid carcinoma in the isthmus (PTCI). METHODS: The clinical data of 124 patients with cT1N0M0 solitary PTCI from 3 medical centers were analyzed retrospectively. Of these, 32 participants had undergone total thyroidectomy plus unilateral central neck dissection, 36 had received total thyroidectomy plus bilateral central neck dissection, 24 had less-than-total thyroidectomy plus unilateral central neck dissection, and 32 had less-than-total thyroidectomy plus bilateral central neck dissection. We compared the effects of different surgical modalities and clinicopathological characteristics on the prognosis of cT1N0M0 solitary PTCI. RESULTS: There was no significant difference in postoperative recurrence-free survival between participants who received different extents of central region lymph node dissection and thyroidectomies (P>0.05). Temporary hypocalcemia occurred in participants who underwent total thyroidectomy plus bilateral central neck dissection [chi-square (χ2) =7.87, P=0.005]. Tumors with primary lesions ≥0.55 cm were prone to have central lymph node metastasis [95% confidence interval (CI): 0.51 to 0.71, P=0.047]. Multiple logistic analysis suggested that age over 55 years [odds ratio (OR) =11.90, 95% CI: 1.36 to 104.03, P=0.025], tumor size greater than 0.55 cm (OR =4.16, 95% CI: 1.28 to 13.52, P=0.018), and absence of nodular goiter (OR =2.57, 95% CI: 1.05 to 6.32, P=0.04) were risk factors for central lymph node metastasis of patients with cT1N0M0 solitary PTCI. CONCLUSIONS: Less-than-total thyroidectomy is recommended for patients with cT1N0M0 solitary PTCI. Central lymph node dissection is recommended for patients who are prone to have central occult lymph node metastases with tumor size ≥55 cm, older than 55 years, and without nodular goiter.

Comparison of Proteomics Profiles Between Xenografts Derived from Cell Lines and Primary Tumors of Thyroid Carcinoma.

Patient-consistent xenograft model is a challenge for all cancers but particularly for thyroid cancer, which shows some of the greatest genetic divergence between human tumors and cell lines. In this study, proteomic profiles of tumor tissues from patients, included anaplastic thyroid carcinoma (ATC) and papillary thyroid carcinoma, and xenografts (8305C, 8505C, FRO, BAPAP and IHH4) were obtained using HPLC-tandem mass spectrometry and compared based on all proteins detected (3,961), cancer-related proteins and druggable proteins using pairwise Pearson's correlation analysis. The human tissue showed low proteomic similarity to the ATC cell lines (8305C, r = 0.344-0.416; 8505C, 0.47-0.579; FRO, 0.267-0.307) and to PTC cell lines (BCPAP, 0.303-0.468; IHH4, 0.262-0.509). Human tissue showed the following similarity to cell lines at the level of 135 cancer-related pathways. The ATC cell lines contained 47.4% of the cancer-related pathways (19.26%-33.33%), while the PTC cell lines contained 40% (BCPAP, 25.93%; IHH4, 28.89%). In patient tumor tissues, 44-60 of 76 and 52-53 of 93 druggable proteins were identified in ATC and PTC tumors, respectively. Ten and 29 druggable proteins were not identified in any of the ATC and PTC xenografts, respectively. We provide a reference for CDX selecting in in vivo studies of thyroid cancer.

Hyperthermia Selectively Destabilizes Oncogenic Fusion Proteins.

The PML/RARα fusion protein is the oncogenic driver in acute promyelocytic leukemia (APL). Although most APL cases are cured by PML/RARα-targeting therapy, relapse and resistance can occur due to drug-resistant mutations. Here we report that thermal stress destabilizes the PML/RARα protein, including clinically identified drug-resistant mutants. AML1/ETO and TEL/AML1 oncofusions show similar heat shock susceptibility. Mechanistically, mild hyperthermia stimulates aggregation of PML/RARα in complex with nuclear receptor corepressors leading to ubiquitin-mediated degradation via the SIAH2 E3 ligase. Hyperthermia and arsenic therapy destabilize PML/RARα via distinct mechanisms and are synergistic in primary patient samples and in vivo, including three refractory APL cases. Collectively, our results suggest that by taking advantage of a biophysical vulnerability of PML/RARα, thermal therapy may improve prognosis in drug-resistant or otherwise refractory APL. These findings serve as a paradigm for therapeutic targeting of fusion oncoprotein-associated cancers by hyperthermia. SIGNIFICANCE: Hyperthermia destabilizes oncofusion proteins including PML/RARα and acts synergistically with standard arsenic therapy in relapsed and refractory APL. The results open up the possibility that heat shock sensitivity may be an easily targetable vulnerability of oncofusion-driven cancers.See related commentary by Wu et al., p. 300.

[Evolution pattern of the Runx3 gene 5'-CpG island methylation in human salivary gland adenoid cystic carcinoma].

OBJECTIVE: To investigate the evolution pattern of the Runx3 gene 5'-CpG island ~3478 bp region methylation in human salivary gland adenoid cystic carcinoma (SGACC). METHODS: Quantitative MSP method was used to detect the methylation status of CpG island in various regions (No.1-10) of Runx3 promoter region, and Western blot was used for detection of the expression of Runx3 protein in 41 salivary gland SGACC samples and corresponding non-neoplastic salivary gland tissues. A Logistic model was used to analyze the risk ratio between the methylation status of CpG island in Runx3 gene and development of salivary SGACC, meanwhile, the possible association among the methylation of Runx3 gene, the clinicopathological parameters of SGACCs, and Runx3 protein expression was compared. RESULTS: The results of qMSP showed that the hypermethylation initially occurred at the most 5' region of the Runx3 CpG island and spread to the transcription start site. The methylation rate was highest in region No. 1 and No. 2 among the successive ten regions ranging from the 5' region to the transcription start site within the Runx3 CpG island, and lowest in the transcription start site both in SGACCs and normal salivary glands. Furthermore, there was no methylation in the transcription start site in nomal salivary glands tissues. Together with the results of Logistic model analysis, those results indicate that the transcription start site within the Runx3 promoter CpG island is critical for gene silencing. Western blot results revealed that the Runx3 protein level in SGACC was significantly lower than that in normal salivary glands (P < 0.01). In combination of the results of qMSP, it is presumed that the Runx3 gene methylation is one of the reason inducing the down-regulation of Runx3 in SGACCs. CONCLUSIONS: Methylation of the Runx3 CpG island spreads from the most 5'-region to the transcription start site in human salivary gland adenoid cystic carcinoma, and the transcription start site may be a critical region for the methylation of Runx3. The evolution pattern of Runx3 gene methylation is related to the tumorigenesis of SGACCs.