Jeonghun Lee

Central Lymph Node Metastasis Is an Important Prognostic Factor in Patients with Papillary Thyroid Microcarcinoma

Papillary thyroid microcarcinoma (PTMC) has been increasing, without a consensus for the management of this condition. In the present study, we analyzed the clinicopathological features of patients with PTMC to examine the impact of initial therapy and establish appropriate treatment. A total of 2,018 patients with PTMC were enrolled at a single university hospital. Of them, 1,245 patients (61.8%) underwent total thyroidectomy, and 1,838 patients (91.3%) underwent central lymph node (LN) dissection. Five-and 10-yr recurrence rates were 3.2% and 4.6%, respectively. In univariate analysis, the prognostic factors for recurrence were N stage, the number of LN metastases, and extrathyroidal extension. However, multivariate analysis revealed LN metastases and N stage as the only significant prognostic factors after adjusting for confounding factors (P < 0.001). Additionally, multivariate analysis of a subgroup consisting of PTMC patients without N1b revealed the number of central LN metastases as the only significant factor. Therefore, intraoperative examination for central LN metastasis may discriminate high or low risk group.

VE1 Antibody Is Not Highly Specific for the BRAF V600E Mutation in Thyroid Cytology Categories With the Exception of Malignant Cases

OBJECTIVES We evaluated the utility of the VE1 antibody that can detect a mutant protein resulting from the BRAF V600E mutation as a diagnostic tool for thyroid fine-needle aspiration cytology (FNAC). METHODS We performed VE1 immunocytochemistry on 202 FNAC specimens from surgically confirmed thyroid nodules. The results were compared with the molecular analyses of the BRAF mutation in these specimens matched with their corresponding histology. RESULTS Diagnoses of FNAC specimens included benign (9.4%), atypia of undetermined significance/follicular lesion of undetermined significance (11.4%), follicular neoplasm/suspicious for follicular neoplasm (2.0%), suspicious for malignancy (9.4%), and malignancy (65.8%). VE1 immunostaining was positive in 71.3% of FNAC specimens. The overall sensitivity of the VE1 antibody was 88.8%, specificity was 71.2%, positive predictive value was 88.2%, negative predictive value was 72.4%, and diagnostic accuracy was 83.7%. CONCLUSIONS VE1 immunocytochemistry in thyroid FNAC as a screening test for BRAF mutations is highly specific for malignant category cases but can be suboptimal due to its high false-positive rate for the nonmalignant cases.

TSH signaling overcomes B-RafV600E-induced senescence in papillary thyroid carcinogenesis through regulation of DUSP6.

B-RafV600E oncogene mutation occurs most commonly in papillary thyroid carcinoma (PTC) and is associated with tumor initiation. However, a genetic modification by B-RafV600E in thyrocytes results in oncogene-induced senescence (OIS). In the present study, we explored the factors involved in the senescence overcome program in PTC. First of all, we observed down-regulation of p-extracellular signal-regulated kinases 1/2 and up-regulation of dual specific phosphatase 6 (DUSP6) in the PTC with B-RafV600E mutation. DUSP6 overexpression in vitro induced extracellular signal-regulated kinases 1/2 dephosphorylation and inhibited B-RafV600E–induced senescence in thyrocytes. Although DUSP6 protein was degraded by B-RafV600E–induced reactive oxygen species (ROS), thyroid-stimulating hormone (TSH) stabilized DUSP6 protein by increasing Mn superoxide dismutase expression and inhibited B-RafV600E–induced senescence. Although serum TSH was not increased, its receptor was markedly upregulated in PTC with B-RafV600E. Furthermore, TSH together with DUSP6 reactivated Ras signaling, resulted in activation of Ras/AKT/glycogen synthase kinase 3β, and stabilized c-Myc protein by inhibiting its degradation. These observations led us to conclude that increased TSH signaling overcomes OIS and is essential for B-RafV600E–induced papillary thyroid carcinogenesis.

Integrative analysis of congenital muscular torticollis: from gene expression to clinical significance

BackgroundCongenital muscular torticollis (CMT) is characterized by thickening and/or tightness of the unilateral sternocleidomastoid muscle (SCM), ending up with torticollis. Our aim was to identify differentially expressed genes (DEGs) and novel protein interaction network modules of CMT, and to discover the relationship between gene expressions and clinical severity of CMT.ResultsTwenty-eight sternocleidomastoid muscles (SCMs) from 23 subjects with CMT and 5 SCMs without CMT were allocated for microarray, MRI, or imunohistochemical studies. We first identified 269 genes as the DEGs in CMT. Gene ontology enrichment analysis revealed that the main function of the DEGs is for extracellular region part during developmental processes. Five CMT-related protein network modules were identified, which showed that the important pathway is fibrosis related with collagen and elastin fibrillogenesis with an evidence of DNA repair mechanism. Interestingly, the expression levels of the 8 DEGs called CMT signature genes whose mRNA expression was double-confirmed by quantitative real time PCR showed good correlation with the severity of CMT which was measured with the pre-operational MRI images (R2 ranging from 0.82 to 0.21). Moreover, the protein expressions of ELN, ASPN and CHD3 which were identified from the CMT-related protein network modules demonstrated the differential expression between the CMT and normal SCM.ConclusionsWe here provided an integrative analysis of CMT from gene expression to clinical significance, which showed good correlation with clinical severity of CMT. Furthermore, the CMT-related protein network modules were identified, which provided more in-depth understanding of pathophysiology of CMT.

B-RafV600E inhibits sodium iodide symporter expression via regulation of DNA methyltransferase 1

B-RafV600E mutant is found in 40–70% of papillary thyroid carcinoma (PTC) and has an important role in the pathogenesis of PTC. The sodium iodide symporter (NIS) is an integral plasma membrane glycoprotein that mediates active iodide transport into the thyroid follicular cells, and B-RafV600E has been known to be associated with the loss of NIS expression. In this study, we found that B-RafV600E inhibited NIS expression by the upregulation of its promoter methylation, and that specific regions of CpG islands of NIS promoter in B-RafV600E harboring PTC were highly methylated compared with surrounding normal tissue. Although DNA methyltransferase 3a and 3b (DNMT3a,3b) were not increased by B-RafV600E, DNMT1 expression was markedly upregulated in PTC and B-RafV600E expressing thyrocytes. Furthermore, DNMT1 expression was upregulated by B-RafV600E induced NF-κB activation. These results led us to conclude that NIS promoter methylation, which was induced by B-RafV600E, is one of the possible mechanisms involved in NIS downregulation in PTC.

Senescent tumor cells lead the collective invasion in thyroid cancer

Cellular senescence has been perceived as a barrier against carcinogenesis. However, the senescence-associated secretory phenotype (SASP) of senescent cells can promote tumorigenesis. Here, we show senescent tumour cells are frequently present in the front region of collective invasion of papillary thyroid carcinoma (PTC), as well as lymphatic channels and metastatic foci of lymph nodes. In in vitro invasion analysis, senescent tumour cells exhibit high invasion ability as compared with non-senescent tumour cells through SASP expression. Collective invasion in PTC is led by senescent tumour cells characterized by generation of a C-X-C-motif ligand (CXCL)12 chemokine gradient in the front region. Furthermore, senescent cells increase the survival of cancer cells via CXCL12/CXCR4 signalling. An orthotopic xenograft in vivo model also shows higher lymphatic vessels involvement in the group co-transplanted with senescent cells and cancer cells. These findings suggest that senescent cells are actively involved in the collective invasion and metastasis of PTC.

Prevention of Thyroidectomy Scars in Asian Adults With Low-Level Light Therapy.

BACKGROUND Abnormal wound-healing after thyroidectomy with a resulting scar is a common dermatologic consultation. Despite many medical and surgical approaches, prevention of postoperative scars is challenging. OBJECTIVE This study validated the efficacy and safety of low-level light therapy (LLLT) using an 830/590 nm light-emitting diode (LED)-based device for prevention of thyroidectomy scars. METHODS AND MATERIALS Thirty-five patients with linear surgical suture lines after thyroidectomy were treated with 830/590 nm LED-LLLT. Daily application of 60 J/cm2 (11 minutes) for 1 week starting on postoperative day 1 was followed by treatment 3 times per week for 3 additional weeks. The control group (n = 15) remained untreated. Scar-prevention effects were evaluated 1 and 3 months after thyroidectomy with colorimetric evaluation using a tristimulus-color analyzer. The Vancouver Scar Scale (VSS) score, global assessment, and a subjective satisfaction score (range: 1–4) were also determined. RESULTS Lightness (L*) and chrome values (a*) decreased significantly at the 3-month follow-up visit in the treatment group compared with those of controls. The average VSS and GAS scores were lower in the treatment group, whereas the subjective score was not significantly different. CONCLUSION Light-emitting diode based LLLT treatment suppressed the formation of scars after thyroidectomy and could be safely used without noticeable adverse effects.

The usefulness and accuracy of sentinel lymph node biopsy using single photon emission computed tomography/computed tomography with 99mTc phytate to detect locoregional lymph node metastases in patients with papillary thyroid carcinoma

Purpose Regional lymph node (LN) metastases are detected in 57-85% of patients with papillary thyroid carcinoma (PTC) and are associated with increased tumor recurrence. However, the management of lymphatic disease in patients with PTC has been ongoing source of debate. We have prospectively assessed the usefulness and accuracy of sentinel LN (SLN) biopsy for the detection of LN metastases in patients with PTC on preoperative imaging using single photon emission computed tomography/computed tomography (SPECT/CT) and 99mTc phytate. Methods We prospectively assessed 39 patients with PTC who had risk factors for recurrence or with the necessity of intraoperative LN sampling for suspicious LN metastases on preoperative imaging from August 2010 to March 2011. The patients underwent preoperative lymphoscintigraphy and SPETC/CT and intraoperative SLN biopsy (SLNB). Results 99mTc lymphoscintigraphy and SPECT/CT localized SLN in 38 patients (97.4%), with the gamma probe identifying 2.15 mean SLNs in the lateral neck of the 39 patients. Skip metastasis was found in one patient, and lateral compartment LN metastasis in 17 (43.5%). The sensitivity, specificity, and accuracy of SLNB for lateral compartment LN metastasis were 88.2%, 100%, and 94.8%, respectively. SLNB was more accurate and useful for lateral than for central compartment LN metastasis. Conclusion SPECT/CT improved SLN detection and anatomical localization compared with lymphoscintigraphy. SLNB in patients with risk factors for recurrence or the necessity of intraoperative LN sampling for suspected LN metastases on preoperative imaging was accurate in detecting LN metastases and may help in deciding whether to perform lateral compartment dissection in patients with PTC.

Urinary Pentosidine levels negatively associates with trabecular bone scores in patients with type 2 diabetes mellitus

SummaryPentosidine levels were higher in diabetic patients with vertebral fractures. Trabecular bone scores were negatively associated with pentosidine levels in diabetic patients only. Our results provide further evidence that AGEs are associated with the pathogenesis of bone fragility in patients with T2DM.IntroductionType 2 diabetes mellitus (T2DM) is associated with fracture risk. Pentosidine, an advanced glycation end product (AGE), is associated with prevalent vertebral fractures (VFs) in patients with T2DM. Trabecular bone score (TBS) has been proposed as an index of bone microarchitecture associated with bone quality. This study evaluated the associations of urine pentosidine and TBS in T2DM and non-T2DM groups.MethodsA total of 112 T2DM patients and 62 non-T2DM subjects were enrolled. TBS was calculated using TBS insight® software (version 2.1). Pentosidine levels were measured using high-performance liquid chromatography method. We compared the BMD, TBS, and pentosidine levels between those with and without VFs with or without adjustment for age and sex. The association with TBS, lumbar spine BMD, and pentosidine levels were also evaluated in both T2DM and non-T2DM groups.ResultsPentosidine levels were significantly higher in T2DM patients with VFs. TBSs were significantly lower in patients with T2DM and VFs. In non-diabetic patients, there were no significant differences in TBS and pentosidine levels for those with and without VFs after adjustment for age and sex. Pentosidine levels were negatively associated with TBS only in patients with T2DM. In multivariate stepwise regression analysis, pentosidine levels were significantly associated with TBS in patients with T2DM.ConclusionsTBS and pentosidine could be used as a method to assess bone quality to identify T2DM patients at risk of VFs. Our results also provide further evidence that AGEs are associated with the pathogenesis of bone fragility in patients with T2DM.

Analgesic Effects of Ultrasound-Guided Serratus-Intercostal Plane Block and Ultrasound-Guided Intermediate Cervical Plexus Block After Single-Incision Transaxillary Robotic Thyroidectomy: A Prospective, Randomized, Controlled Trial.

Background and Objectives Single-incision transaxillary robotic thyroidectomy (START) requires substantial tissue disruption, which produces moderate-to-severe pain in the axilla and neck areas during the early postoperative period. This study aimed to investigate the analgesic effects of ultrasound-guided serratus-intercostal plane blocks and intermediate cervical plexus blocks (CPBs) on the early postoperative pain after START. Methods We randomized 22 patients to undergo either ultrasound-guided serratus-intercostal plane and intermediate CPBs (the block group, n = 11) or to not undergo any block (the control group, n = 11). We compared postoperative axillary pain, postoperative neck pain, and analgesic use between the groups during the first 24 hours. The rescue analgesics were intravenous fentanyl (0.5 &mgr;g/kg) in the postanesthesia care unit, and intravenous ketorolac tromethamine (30 mg) in the general ward. Results The block group showed consistently lower pain scores than the control group in the axillary area in the first 24 hours and in the neck area only in the first 3 hours after surgery. The numbers (proportions) of patients who required analgesics were 11 (100%) in the control group and 6 (54.5%) in the block group during the first 24 hours (P = 0.035). No adverse effect was observed related to the peripheral nerve blocks. Conclusions After START, a serratus-intercostal plane block performed at the level of the third rib was an effective analgesic technique for axillary pain; however, the clinical effectiveness of intermediate CPB for neck pain may be limited.