Selective inhibition of V600E-mutant BRAF gene induces apoptosis in thyroid carcinoma cell lines

Purpose@#Papillary thyroid cancer (PTC) has a high incidence of BRAF V600E mutation. The purpose of this study was to evaluate the potential relationship between thyroiditis and BRAF V600E mutation status in patients with PTC. We investigated how a selective inhibitor of BRAF V600E PLX4032 affects the proliferation and inflammatory cytokine levels of thyroid cancer. @*Methods@#Two thyroid cancer cell lines TPC1 and 8505C were treated with PLX4032, an analysis was done on cell growth, cell cycle, the degree of apoptosis, and levels of inflammatory cytokines. To identify the functional links of BRAF, we used the STRING database. @*Results@#Docking results illustrated PLX4032 blocked the kinase activity by exclusively binding on the serine/threonine kinase domain. STRING results indicated BRAF is functionally linked to mitogen-activated protein kinase. Both cell lines showed a dose-dependent reduction in growth rate but had a different half maximal inhibitory concentration value for PLX4032. The reaction to PLX4032 was more sensitive in the 8505C cells than in the TPC1 cells. PLX4032 induced a G2/ M phase arrest in the TPC1 cells and G0/G1 in the 8505C cells. PLX4032 induced apoptosis only in the 8505C cells. With PLX4032, the TPC1 cells showed decreased levels of vascular endothelial growth factor, granulocyte-macrophage colonystimulating factor, chemokine (C-C motif) ligand 2/monocyte chemoattractant protein 1, whereas the 8505C cells showed significantly decreased levels of IL-8, serpin E1/plasminogen activator inhibitor-1, and matrix metalloproteinase (MMP)-3. @*Conclusion@#PLX4032 was cytotoxic in both TPC1 and 8505C cells and induced apoptosis. In the 8505C cells, inflammatory cytokines such as IL-8 and MMP-3 were down-regulated. These findings suggest the possibility that the BRAF V600E mutation needs to target inflammatory signaling pathways in the treatment of thyroid cancer.

Comparative study of bilateral axillo-breast approach endoscopic and robotic thyroidectomy: propensity score matching analysis of large multi-institutional data

Purpose@#The aim of this study was to compare the large multi-institutional data of surgical outcomes of bilateral axillo-breast approach (BABA) robotic (RT) and endoscopic thyroidectomy (ET) and to evaluate the merits of robotic thyroidectomy. @*Methods@#From 2004 to 2015, 1,029 patients underwent BABA ET, and from 2008 to 2015, 2003 patients underwent BABA RT in 3 large volume centers in Korea. Two groups were retrospectively compared in terms of clinicopathologic characteristics, complications, surgical completeness, and long-term outcomes using propensity score matching analysis. @*Results@#Both groups had similar demographic characteristics including age, sex, tumor size, pathologic stage, and hospital stay after matching. Each group had similar rate of transient hypoparathyroidism, however, ET showed significantly higher rate of permanent hypoparathyroidism (ET 5.2% vs. RT 2.3%, P = 0.05), and transient vocal cord palsy (ET 14.4% vs. RT 9.1%, P = 0.006). Total operation time was longer in the ET group irrespective of surgical extents, including lobectomy (P = 0.016), total thyroidectomy (P = 0.031), and total thyroidectomy with central lymph node dissection (P = 0.019). The rate of patients with off-Tg under 1.0 ng/mL after 1st ablation was significantly higher in RT than ET group (ET 64.6% vs. RT 92.7%, P < 0.001). In long-term follow-up of cancer patients, 1.4% experienced recurrence after ET (10 cases), while 0.3% cases experienced recurrence after RT (5 cases) (P < 0.001). @*Conclusion@#Both ET and RT can be safe and effective methods to treat thyroid diseases. However, the application of robotic system may help to overcome the limitations of the instruments and surgeon’s skills.

Comparative study of bilateral axillo-breast approach endoscopic and robotic thyroidectomy: propensity score matching analysis of large multi-institutional data

Purpose@#The aim of this study was to compare the large multi-institutional data of surgical outcomes of bilateral axillo-breast approach (BABA) robotic (RT) and endoscopic thyroidectomy (ET) and to evaluate the merits of robotic thyroidectomy. @*Methods@#From 2004 to 2015, 1,029 patients underwent BABA ET, and from 2008 to 2015, 2003 patients underwent BABA RT in 3 large volume centers in Korea. Two groups were retrospectively compared in terms of clinicopathologic characteristics, complications, surgical completeness, and long-term outcomes using propensity score matching analysis. @*Results@#Both groups had similar demographic characteristics including age, sex, tumor size, pathologic stage, and hospital stay after matching. Each group had similar rate of transient hypoparathyroidism, however, ET showed significantly higher rate of permanent hypoparathyroidism (ET 5.2% vs. RT 2.3%, P = 0.05), and transient vocal cord palsy (ET 14.4% vs. RT 9.1%, P = 0.006). Total operation time was longer in the ET group irrespective of surgical extents, including lobectomy (P = 0.016), total thyroidectomy (P = 0.031), and total thyroidectomy with central lymph node dissection (P = 0.019). The rate of patients with off-Tg under 1.0 ng/mL after 1st ablation was significantly higher in RT than ET group (ET 64.6% vs. RT 92.7%, P < 0.001). In long-term follow-up of cancer patients, 1.4% experienced recurrence after ET (10 cases), while 0.3% cases experienced recurrence after RT (5 cases) (P < 0.001). @*Conclusion@#Both ET and RT can be safe and effective methods to treat thyroid diseases. However, the application of robotic system may help to overcome the limitations of the instruments and surgeon’s skills.

Role of charcoal tattooing in localization of recurred papillary thyroid carcinoma: initial experiences

PURPOSE: Surgical excision is the definitive treatment for localized recurrence of papillary thyroid carcinoma. Reoperation for recurrence, however, is challenging and associated with increased operative times and complication rates. For safe and effective reoperation, ultrasound-guided charcoal tattooing localization can be used. The aim of this study was to investigate the feasibility and safety of the ultrasound-guided charcoal tattooing localization. METHODS: Between November 2012 and August 2013, ten patients underwent preoperative charcoal tattooing localization for twelve recurrent lesions. Patient demographics, pathologic features, and operation results were reviewed. RESULTS: The technical success rate of charcoal tattooing was 100%. Eight patients had one recurrent lesion, and two patients had double lesions. Among these 12 recurrent lesions, three (25%) were found in level II, four (33%) in level IV, four (33%) in level VI, and one (8%) was found in the thyroidectomy bed site. The mean size of lesions was 0.87 +/- 0.35 cm. Of these 10 patients, eight patients underwent selective lymph node dissection, one patient underwent modified radical neck dissection, and one patient underwent recurrent mass excision. Transient hypocalcemia developed in one patient, and no recurrent laryngeal nerve palsy occurred. There were no major complications related to the injection of the charcoal. The mean follow-up period after reoperation was 8.6 +/- 2.7 months; in the follow-up ultrasound, there were no remnant lesions in all patients. CONCLUSION: Preoperative ultrasound-guided charcoal tattooing localization for recurrent thyroid cancer appears to be a feasible and safe procedure for reoperation. Further evaluation is warranted in larger patients' cohorts.

Intraoperative neuromonitoring of the external branch of the superior laryngeal nerve during robotic thyroid surgery: a preliminary prospective study

PURPOSE: The aim of this study was to evaluate the feasibility of monitoring external branch of the superior laryngeal nerve (EBSLN) during robotic thyroid surgery. METHODS: A total of 10 patients undergoing bilateral axillo-breast approach (BABA) robotic thyroid surgery were enrolled. The nerve integrity monitor (NIM Response 2.0 System) was used for EBSLN monitoring. We performed voice assessments preoperatively and at 1 and 3 months postoperatively using Voice Handicap Index-10 (VHI-10), maximal phonation time (MPT), phonation efficient index (PEI), and laryngeal electromyography (EMG). RESULTS: A total of 19 EBSLNs were at risk and 14 EBSLNs (73.7%) were identified using neuromonitoring. VHI-10 showed a change of voice over time (0.1 vs. 3.6 vs. 1.3); however, this was not statistically significant. VHI-10 scores normalized at 3 months postoperatively compared to the preoperative scores. MPT (a) (16.0 vs. 15.6 vs. 15.4), and MPT (e) (20.1 vs. 15.4 vs. 18.5) showed no significant differences preoperatively compared to the values obtained 1 and 3 months postoperatively. There was a significant change of PEI over time (4.8 vs. 1.1 vs. 4.6) (P = 0.036); however, the values normalized at 3 months postoperatively. Laryngeal EMG results showed 4 cases (21.2%) of neuropathy of EBSLNs at 1 month postoperatively, and electrodiagnostic studies revealed nearly complete recovery of the function of EBSLNs in 4 patients at 3 months postoperatively CONCLUSION: It is suggested that neuromonitoring of EBSLNs during BABA robotic thyroid surgery is feasible and might be helpful to preserve voice quality.

Can Robotic Thyroidectomy Be Performed Safely in Thyroid Carcinoma Patients?

Since the adoption of the Da Vinci robotic system for remote access thyroid surgery, robotic thyroidectomy (RT) has become a popular surgical option for patients who want to avoid neck scars. Surgeons in South Korea pioneered this surgical technique and have reported successful outcomes. Although many studies have reported that RT is a feasible and safe therapeutic alternative, concerns over the surgical and oncological safety of RT remain. This article reviews the advantages and disadvantages of RT and compares the surgical safety and oncological completeness of RT with conventional open thyroidectomy.

Gene Methylation Associated with Differentiated Thyroid Cancer / 대한갑상선학회지

Epigenetic alteration changes expression of many genes, such as tumor suppressor gene and molecular specific gene, without change in DNA sequence. Cancers, including thyroid cancer, often exhibit an aberrant methylation of gene promoter regions, which is associated with loss of gene function. Aberrant methylation plays a fundamental role in tumorigenesis. Methylation of some genes tends to occur in certain types of thyroid cancer. Methylation of TIMP3, SLC5A8, p16, RARbeta2, DAPK genes is associated with papillary thyroid cancer. Some studies show that aberrant methylation is related to the BRAF V600E mutation. Methylation of PTEN and RASSF1A genes occurs commonly in follicular thyroid cancer. Methylation of thyroid-specific genes, such as sodium/iodide symporter, thyroid-stimulating hormone receptor, and SLC26A4 which encodes pendrine, also has a relation to thyroid cancer. Methylation of these genes could be utilized as markers to detect early disease, to define prognosis and to predict therapeutic targets of thyroid cancer.

Characteristics of Hypoparathyroidism after Total Thyroidectomy with or without Hashimoto Thyroiditis / 대한내분비외과학회지

PURPOSE: The characteristics of hypoparathyroidism in patients with Hashimoto thyroiditis (HT) after total thyroidectomy are not well established. The aim of this study was to investigate the relationship between hypoparathyroidism and loss of parathyroid glands in patients with or without HT who underwent total thyroidectomy. METHODS: Patients who underwent total thyroidectomy were divided into two groups; with HT (n=166) and without HT (n=526). Clinicopathologic characteristics were compared between the two groups. RESULTS: The mean numbers of parathyroid glands in specimens were significantly smaller in the with HT group than in the without HT group (0.34+/-0.51 vs. 0.42+/-0.58, P=0.003). The rate of transient hypoparathyroidism was significantly higher in the with HT group than in the without HT group (51.8% vs. 34.6%, P=0.000). Serum total calcium levels in patients who experienced transient hypoparathyroidism did not differ significantly between groups (P=0.335). The incidence of transient hypoparathyroidism of patients who preserved all four parathyroid glands or sacrificed one parathyroid gland was higher in the with HT group than in the without HT group, although that of patients who sacrificed two or more parathyroid glands was similar between groups. The incidence of permanent hypoparathyroidism in the two groups did not differ (P=0.546). CONCLUSION: Patients with HT had a higher rate of transient hypoparathyroidism after total thyroidectomy, particularly patients who preserved all four or three parathyroid glands. It is likely that the blood supply to the parathyroid gland might be vulnerable in patients with HT. Therefore, even though all parathyroid glands were preserved, careful monitoring of hypoparathyroidism is necessary after total thyroidectomy in patients with HT.

Localization of Parathyroid Adenoma and Minimally Invasive Parathyroidectomy: A Review / 대한내분비외과학회지

More than 80% of cases of patients with sporadic primary hyperparathyroidism are caused by a single parathyroid adenoma. Therefore, traditional bilateral neck exploration has been replaced by minimally invasive parathyroidectomy (MIP) in recent years. Benefits, of MIP include decreased pain and complications, a shorter length of hospital stay, and improved cosmesis. Preoperative imaging studies for localization and intraoperative PTH assay (IoPTH) play an essential role for in MIP. The standard imaging studies are cervical ultrasound and 99mTc sestamibi scanning (with SPECT/CT), while 4D CT is attracting significant interest. The half-life of PTH is less than 5 minutes and PTH rapidly drops after the resection of target lesions. These characteristics of PTH enable IoPTH. If target lesions are localized by recent imaging studies and IoPTH is adopted, MIP can be performed successfully in patients with primary hyperparathyroidism.

Antiadhesive effect and safety of oxidized regenerated cellulose after thyroidectomy: a prospective, randomized controlled study / 대한외과학회지

PURPOSE: To evaluate the antiadhesive effects and safety of an oxidized regenerated cellulose (Interceed) after thyroidectomy. METHODS: Seventy-six thyroidectomized patients were prospectively randomized into two groups with regard to the use of Interceed. We evaluated each group for their adhesive symptoms using four subjective and four objective items at the 2nd week, 3rd and 6th month after thyroidectomy. All patients were examined for vocal cord motility by indirect laryngoscope at each period. RESULTS: Total adhesion scores at each postoperative follow-up period decreased with time, but were not significantly different in each group. The median score for swallowing discomfort for liquid was significantly lower in the Interceed group than in the control group 2 weeks after surgery. In addition, the severity of skin adhesion to the trachea was reduced in the Interceed group compared with the control group 6 months after surgery. During the study, there were no adverse effects or significant differences in postoperative complications between the groups. CONCLUSION: Interceed appeared to be safe and effective in improving neck discomfort at early postoperative periods and preventing skin adhesion to the trachea 6 months after thyroidectomy.

Role of adjuvant postoperative external beam radiotherapy for well differentiated thyroid cancer

PURPOSE: To analyze the outcome of adjuvant postoperative external beam radiotherapy (EBRT) in well-differentiated thyroid cancer (WDTC). MATERIALS AND METHODS: We identified 84 patients treated with EBRT for WDTC from February 1981 to December 2010. Among them, we analyzed 39 patients who received EBRT after initial radical surgery. Twenty-four females and 15 males were included. The median age was 49 years (range, 16 to 72 years). There were 34 papillary thyroid carcinomas and 5 follicular thyroid carcinomas. Most patients showed pathologic T3/T4 stage (54%/26%). Ten patients (25.6%) had gross residual tumors. Five patients (12.8%) had tumor cells at the margin. The median EBRT dose and fraction size were 62.6 Gy and 1.8 to 2.0 Gy, respectively. RESULTS: The median follow-up was 73 months (range, 21 to 372 months). The five-year overall survival (OS) and locoregional recurrence free survival (LRFS) were 97.4% and 86.9%, respectively. Locoregional failures occurred in 5 and all failure sites were the neck node area. In univariate analysis, OS was significantly influenced by invasion of the trachea (p = 0.016) or esophagus (p = 0.006). LRFS was significantly decreased by male (p = 0.020), gross residuum after resection (p = 0.002), close or positive tumor at surgical margin involvement (p = 0.044), and tracheal invasion (p = 0.040). No significant prognostic factor was identified in the multivariate analysis. No patient experienced the Radiation Therapy Oncology Group grade 3 or more toxicity. CONCLUSION: Our locoregional control rate of 87.2% is comparable to historical controls with surgery alone, even though our study had a large proportion of advanced stage. Adjuvant EBRT may an effective and safe treatment option in patients with WDTC.

Antiadhesive effect and safety of sodium hyaluronate-carboxymethyl cellulose membrane in thyroid surgery / 대한외과학회지

PURPOSE: A number of researchers have suggested the use of sodium hyaluronate carboxymethyl cellulose (HA-CMC) membrane for preventing postoperative adhesion. This study evaluated the antiadhesive effect and safety of HA-CMC membrane in thyroidectomy for papillary thyroid cancer. METHODS: One hundred sixty-two patients who underwent thyroidectomy were prospectively randomized. In the study group of 80 patients, the 7.5 cm x 13 cm HA-CMC membrane was applied to the operative field after thyroidectomy. The subjects were asked about complications including adhesive symptoms using an 8-item questionnaire at 2 weeks, 3 months, and 6 months after surgery. In addition, items on the appearance of neck wrinkles and scars were evaluated by a physician who had no information about the patient's allocation. RESULTS: There were no significant differences in complications such as swallowing difficulty, and wrinkles between study and control groups. Both groups presented significantly decreased scores over time in swallowing difficulty, and wrinkles. There were no complications regarding the HA-CMC membrane. CONCLUSION: The antiadhesive effect of HA-CMC membrane in thyroid surgery is still uncertain, although it is biologically safe. Further investigation is needed to confirm the antiadhesive effect of HA-CMC membrane in thyroid surgery.

Analysis of patients with anaplastic thyroid cancer expected to have curative surgery / 대한외과학회지

PURPOSE: Anaplastic thyroid cancer (ATC) is rare and has a poor prognosis. The aim of this study was to analyze the clinicopathologic characteristics of patients diagnosed with ATC expected to undergo curative thyroidectomy, with the goal of finding differences between patients surviving > or =6 months and or =6 months after operation. In patients surviving > or =6 months, all lesions were 5 cm, and two of the five patients underwent less than total thyroidectomy (P = 0.287 and 0.152, respectively). All patients with lesion size <5 cm underwent total thyroidectomy and showed a shorter median operation time (P = 0.182 and 0.033, respectively). CONCLUSION: ATC showed female predominance. Patients initially presented with neck mass, and median age was 55 years. In patients with ATC who are expected to undergo curative thyroidectomy, surgery should actively be considered as primary therapy for patient survival when the size is <5 cm.

Regionalization strategy of the emergency medical service system

A regionalization strategy is a model for improving the performance of the emergency medical service (EMS) system. The regionalization strategy has goals to provide appropriate, timely, effective, and efficient EMS in a region. However, the current EMS regionalization model in Korea is insufficient to achieve these goals due to a shortage of resources in rural regions, crowded emergency departments in metropolitan regions, and non-customized and mismatched levels of emergency departments. Recently, the concept of the regionalization model has been changed from a general regionalized model to a specialty care regionalization one. For example, the trauma care system, cardiac arrest care system, stroke care system, and ST elevation myocardial infarction care system are modern regionalization strategies to improve the performance of EMS. This is a new method of customizing and matching between region-based needs and the supply of EMS. If we can implement this strategy, we can expect improved performance of regional EMS systems.

Berberine Inhibited the Growth of Thyroid Cancer Cell Lines 8505C and TPC1

PURPOSE: Thyroid cancer is the most common malignancy in Korean females and can be treated with good prognosis. However, drugs to treat aggressive types of thyroid cancer such as poorly differentiated or anaplastic thyroid cancer have not yet been established. To that end, we analyzed the effects of berberine on human thyroid cancer cell lines to determine whether this compound is useful in the treatment of aggressive thyroid cancer. MATERIALS AND METHODS: The two thyroid cancer cell lines 8505C and TPC1, under adherent culture conditions, were treated with berberine and analyzed for changes in cell growth, cell cycle duration, and degree of apoptosis. RESULTS: Following berberine treatment, both cell lines showed a dose-dependent reduction in growth rate. 8505C cells showed significantly increased levels of apoptosis following berberine treatment, whereas TPC1 cells showed cell cycle arrest at the G0/G1 phase. Immunobloting of p-27 expression following berberine treatment showed that berberine induced a little up-regulation of p-27 in 8505c cells but relatively high up-regulation of p-27 in TPC1 cells. CONCLUSION: These results suggest that berberine treatment of thyroid cancer can inhibit proliferation through apoptosis and/or cell cycle arrest. Thus, berberine may be a novel anticancer drug for the treatment of poorly differentiated or anaplastic thyroid cancer.

Vision of Thyroid Surgery: Past, Present and Future / 대한갑상선학회지

We are presenting perspectives of how thyroid surgery has evolved from the past to the future. Technological process in thyroid surgery is the history of modern surgery and the evolution of knowledge of thyroid gland led us to the fields of organ preservation, hemostasis, cancer surgery, and minimally invasive surgery. Thyroid surgery in the present time is characterized by low mortality rate, low complication rate, and considerations about the quality of life of patients. Robotic surgery has been adopted to thyroid surgery for these reasons and now has advanced significantly to perform safe and effective operations. The future of thyroid surgery will be evolved beyond our imagination; however the advances of the skills should be focused on the safety and convenience of patients.

Development of a canine model for recurrent laryngeal injury by harmonic scalpel / 한국실험동물학회지

Various energy devices had been used in thyroid surgery. Aim of study is to develop canine model for recurrent laryngeal nerve injury by harmonic scalpel and to evaluate feasibility of using this model for evaluating the safety use of harmonic scalpel during thyroid surgery. Nine dogs were divided into 3 groups according to distance between harmonic scalpel application and recurrent laryngeal nerve; group 1 (1 mm), 2 (2 mm), and 3 (3 mm). Vocal cord function was assessed pre- and postoperatively using video laryngoscopy. Harmonic scalpel was applied adjacent to left recurrent laryngeal nerve and, two weeks later, right recurrent laryngeal nerve at assigned distances. Recurrent laryngeal nerves were evaluated for subacute and acute morphologic changes. Laryngoscopy demonstrated 3 abnormal vocal cords in group 1, 1 in group 2, and no in group 3 (P=0.020). Subacute histologic changes were observed in nerves with abnormal function. Acute histologic changes were observed 5/8 (62.5%) in group 1, 1/7 (14.3%) in group 2, and not in group 3. We developed canine model for recurrent laryngeal injury. The functional outcomes matched with the histologic changes. These warrant further study to determine the safety margin for energy device in vicinity of recurrent laryngeal nerve.

An exclusively dopamine secreting paraganglioma in the retroperitoneum: a first clinical case in Korea / 대한외과학회지

Exclusively dopamine producing retroperitoneal paragangliomas are extremely rare. We have experienced the first Korean case managed successfully based on the proper evaluation. A 26-year-old female patient came to our attention after the accidental detection of an adrenal mass. She had no symptoms and denied any family history. Laboratory evaluations were normal but serum dopamine (425 ng/L) and 24-hour urine dopamine levels (1,565.3 microg/day) were elevated. She underwent laparoscopic right adrenalectomy. Histopathological diagnosis was a paraganglioma. After operation, dopamine levels in serum and 24-hour urine dropped to 0.09 ng/L and 388.4 microg/day. Dopamine producing paraganglioma elicit no clinical symptoms. Only the dopamine level is elevated in serum and 24-hour urine samples. Surgical resection without using preoperative alpha blockage is the treatment of choice. The prognosis for patients with this tumor tends to be poor because the diagnosis is usually delayed due to lack of symptoms.

Antiproliferation and Redifferentiation in Thyroid Cancer Cell Lines by Polyphenol Phytochemicals

Thyroid carcinogenesis is accompanied by loss of thyroid-specific functions and refractory to radioiodine and thyroid stimulating hormone (TSH) suppression therapy. Redifferentiating agents have been shown to inhibit tumor growth and improve the response to conventional therapy. Polyphenol phytochemicals (PPs) in fruits and vegetables have been reported to inhibit cancer initiation, promotion, progression and induce redifferentiation in selected types. In this study we examined PPs induce redifferentiation in thyroid cancer cell lines. We investigated the effects of genistein, resveratrol, quercetin, kaempferol, and resorcinol on the F9 embryonal carcinoma cell differentiation model. The thyroid cancer cell lines, TPC-1, FTC-133, NPA, FRO, and ARO, displayed growth inhibition in response to genistein, resveratrol, quercetin. We further demonstrated that genistein decreased the dedifferention marker CD97 in NPA cells and resveratrol decreased CD97 in FTC-133, NPA, FRO cells and quercetin decreased CD97 in all cell lines. We observed increased expression of differentiation marker NIS in FTC-133 cells in response to genistein, and resveratrol but no change in NPA, FRO, ARO cells. Quercetin increased or induced NIS in FTC-133, NPA, FRO cells. These findings suggest that PPs may provide a useful therapeutic intervention in thyroid cancer redifferentiation therapy.

The Author Response: Antiproliferation and Redifferentiation in Thyroid Cancer Cell Line by Polyphenol Phytochemicals

No abstract available.