Woung Youn Chung

A multicenter, phase II trial of everolimus in locally advanced or metastatic thyroid cancer of all histologic subtypes

BACKGROUND This phase II study investigated the efficacy and safety of everolimus, an inhibitor of mammalian target of rapamycin (mTOR), in locally advanced or metastatic thyroid cancer. PATIENTS AND METHODS Patients with thyroid cancer of any histology that was resistant or not appropriate for (131)I received everolimus 10 mg daily orally until unacceptable toxicity or disease progression. The primary end point was disease control rate [partial response (PR) + stable response ≥12 weeks]. Secondary end points included response rates, clinical benefit (PD + durable stable disease (SD)], progression-free survival (PFS), overall survival, duration of response, and safety. RESULTS Thirty-eight of 40 enrolled patients were evaluable for efficacy. The disease control rate was 81% and two (5%) patients achieved objective response; their duration of response was 21+ and 24+ weeks. Stable disease (SD) and progressive disease was reported in 76% and 17% of patients, respectively. Seventeen (45%) patients showed durable SD (≥24 weeks) and clinical benefit was reported in 19 (50%) patients. Median PFS was 47 weeks [95% confidence interval (CI) 14.9-78.5]. Calcitonin, CEA, and thyroglobulin concentrations were ≥50% lower than baseline in three (30%) and four (44%) patients with medullary thyroid cancer and five (33%) patients with PTC, respectively. The most common treatment-related adverse events were mucositis (84%), anorexia (44%), and aspartate transaminase/alanine transaminase elevation (26%). CONCLUSIONS Everolimus had a limited activity with low response rate in locally advanced or metastatic thyroid cancer. Reasonable clinical benefit rate and safety profile may warrant further investigation. CLINICALTRIALSGOV NUMBER NCT01164176.

Minimally invasive open thyroidectomy.

Abstract We recently developed a new surgical technique for carrying out thyroidectomy, to minimize tissue trauma by obviating unnecessary neck exploration. This report describes our technique of performing minimally invasive open thyroidectomy and compares the results with those of conventional thyroidectomy. Minimally invasive open thyroidectomy was performed by making a small skin incision, 3.0–4.5 cm long, and approaching the thyroid directly via a transverse divi-sion of the strap muscles without raising skin flaps. The outcomes of 466 patients who underwent a minimally invasive open thyroidectomy were retrospectively compared with those of 437 patients who underwent conventional thyroidectomy for various types of thyroid nodules. There was no significant difference in the extent of surgery between the group of patients who underwent minimally invasive thyroidectomy and the group of patients who underwent conventional thyroidectomy. However, the length of the skin incision, at 3.7 ± 0.7 vs 9.6 ± 3.3 cm, respectively, operative time, at 57.6 ± 11.7 vs 85.2 ± 32.3 min, respectively, blood loss, at 18.4 ± 15.3 vs 43.1 ± 21.8 ml, respectively, and hospital stay, at 1.6 ± 0.5 vs 4.3 ± 1.6 days, respectively, were significantly reduced in the minimally invasive open thyroidectomy group (P < 0.05). Moreover, the number of patients who required postoperative analgesia was significantly less in the minimally invasive open thyroidectomy group. These results show that minimally invasive open thyroidectomy provides surgeons with a clear operative field, and that it has proven to be simple, safe, and practical for selected patients.

The Role of Ultrasound in Thyroid Nodules with a Cytology Reading of Suspicious for Papillary Thyroid Carcinoma

BACKGROUND Irrespective of ultrasound (US) features, surgery is usually recommended for patients who have a fine-needle aspiration biopsy (FNAB) read as suspicious for papillary carcinoma (PTC). The aim of the present study was to evaluate the role of US in the management of thyroid nodules with a FNAB reading suspicious for PTC. METHODS Between August 2002 and May 2006, 303 patients who had thyroid nodules with a FNAB reading suspicious for PTC underwent surgery. The sonographic findings in the patients were classified as suspicious for malignancy or probably benign based on the US reading. The US readings and final pathological diagnoses of thyroid nodules were analyzed in these patients. RESULTS The malignancy rate was 84.2% in patients with a FNAB specimen suspicious for PTC. Sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of the US were 96.4%, 74.5%, 92.7%, 94.9%, and 80.9%, respectively, in nodules read as suspicious for PTC on FNAB. Whereas 243 (96.4%) lesions were found to be malignant at surgery, in the 252 lesions that had ultrasound findings suspicious for malignancy, only 13 (25.5%) lesions were malignant out of the 51 that had US readings of probably benign (p < 0.05). CONCLUSIONS The probability of malignancy is much lower in thyroid nodules with benign US findings even if the FNAB is read as suspicious for PTC. Therefore, US may be useful in planning the extent of surgery in patients with a FNAB reading of suspicious for PTC. As thyroid malignancy occurs in approximately 26% of patients with cytology readings suspicious for PTC and benign-appearing US, the US reading alone is not sufficient to determine the need for surgery. The US and FNAB are complementary to each other and should be useful when providing informed consent before thyroid surgery.

Expression and role of estrogen receptor α and β in medullary thyroid carcinoma: different roles in cancer growth and apoptosis

Medullary thyroid carcinoma (MTC) originates from parafollicular C cells. Estrogen receptorb (ERb) expression was detected in normal parafollicular C cells and MTC tumor tissue, but ERa expression in MTC tumors still remains undetermined. The appearance and loss of ERa or ERb expression has been known to play a role in the development and progression of many human cancers. We performed immunohistochemical studies of ERa ,E Rb, and Ki67, a mitotic index, in 11 human MTC tissue samples. ERa was detected in 10 cases (91%), and ERb expression was observed in 8 cases (72 . 7%). A majority (8/10) of ERa-positive tumors showing ERb Ki67 expression was detected in three cases (27 . 3%). Neither clinical parameters nor tumor node metastasis (TNM) tumor staging was correlated with the positivity for ERs or Ki67. To investigate the biological role of each ER, we used ER-negative MTC TT cells and adenoviral vectors carrying ERa (Ad-ERa), ERb (Ad-ERb), estrogen response element (ERE)-Luc (Ad-ERE-Luc), and activator protein 1 (AP1)-Luc (Ad-AP1-Luc). Estrogen stimulated and anti-estrogen, ICI 182 780, suppressed ERE reporter activity in TT cells expressing ERa or ERb ,s uggesting that both ERs use the same classical ERE-mediated pathway. Ad-ERa infection stimulated TT cell growth; in contrast, Ad-ERb infection suppressed their growth. Apoptosis was detected in Ad-ERb-infected TT cells. Estrogen and antiestrogen suppressed AP1 activity in Ad-ERa-infected cells, whereas upon Ad-ERb infection estrogen further stimulated AP1 activity which in turn is suppressed by anti-estrogen, suggesting that each ER acts differently through a non-EREmediated pathway. Our results suggest that ERa and ERb may play different roles in MTC tumor growth and progression.

The Combined Role of Ultrasound and Frozen Section in Surgical Management of Thyroid Nodules Read as Suspicious for Papillary Thyroid Carcinoma on Fine Needle Aspiration Biopsy: A Retrospective Study

BackgroundThe purpose of this study was to evaluate the combined role of ultrasound (US) and frozen section (FS) in the surgical management of thyroid nodules that are suspicious for papillary thyroid carcinoma (PTC) on US-guided fine-needle aspiration biopsy (US-FNAB).MethodsBetween 2006 and 2008, 217 patients with thyroid nodules classified as suspicious for PTC on US-FNAB underwent intraoperative FS and surgery. A thyroid nodule with any suspicious US findings of marked hypoechogenicity, microlobulated or irregular margins, microcalcifications, or taller than wider in shape was defined as positive and that without was defined as negative. FSs were classified as malignant, indeterminate, defer, and benign. We compared the results of US groupings, FS, and final histopathologic diagnosis.ResultsTwenty-one (52.5%) of 40 patients with a negative US revealed malignancy. In contrast, 168 (94.9%) of 177 patients with a positive US had malignancy. Fourteen (50%) of 28 patients with benign pathology on FS had malignancy, and 166 (97.6%) of 170 patients with malignancy on FS proved malignancy on histopathology. Of 40 patients with negative US, 13 (92.9%) of 14 with malignancy on FS proved malignancy.ConclusionsThe malignancy rate of thyroid nodules read as “suspicious for PTC” on US-FNAB was 87.1%. When a thyroid nodule with “suspicious for PTC” on US-FNAB has suspicious malignant US features, FS may be unnecessary due to a very high risk of malignancy (94.9%). In contrast, when a thyroid nodule read as “suspicious for PTC” on US-FNAB has no suspicious malignant US features, FS can help surgeons determine the extent of surgery.

Anaplastic Thyroid Carcinoma: A Therapeutic Dilemma

Anaplastic thyroid carcinoma (ATC) is one of the most malignant human neoplasms and has a grave prognosis. This study gives an update on our experience with this unusual neoplasm, with specific focus on the response to various treatment modalities. Forty-seven patients with histologically proven ATCs were enrolled (19 men, 28 women; mean age, 62.8 years). This number represents 1.5% among a total of 3,088 thyroid cancers treated between 1977 and 2002. The mean tumor diameter was 8.8 cm, and 22 patients had distant metastasis. Extrathyroidal extension was seen in 26 (89.7%) of the cases that underwent surgery. Treatment modalities adopted could be classified into 5 groups: Group 1, biopsy only; Group 2, biopsy and chemoradiotherapy; Group 3, debulking only; Goup 4, debulking and chemoradiotherapy; Group 5, complete excision and chemoradiotherapy. Survival was calculated from the time of diagnosis, and comparisons of survival were done by log-rank analysis. The mean survival was 4.3 months (range, 1.0-21 months). The mean survival based on treatment modalities were as follows: Group 1 (n = 10), 2.1 months, Group 2 (n = 8); 3.6 months; Group 3 (n = 7), 3.0 months; Group 4 (n = 14), 3.5 months, Group 5 (n = 8), 9.4 months. There was no significant difference in survival time between the various types of treatment modalities. Even though a small improvement in survival was observed with complete excision and aggressive multimodality therapy, nearly all ATCs remain unresponsive to ongoing treatment modalities and as such, present a therapeutic dilemma. A more effective treatment regimen should be sought in order to improve survival.

Ultrasonographic Mass Screening for Thyroid Carcinoma: A Study in Women Scheduled to Undergo a Breast Examination

Abstract This study was carried out to clarify the sensitivity of ultrasonographic mass screening for thyroid carcinoma. Between December 1997 and July 1998, a total of 1 401 subjects who were scheduled to undergo either a breast examination or a follow-up examination for breast cancer were enrolled in this study. Patients with thyroid nodules were classified into two groups according to their potential risk for malignancy based on the ultrasonographic findings. Ultrasonographic high-risk patients for thyroid cancer underwent an ultrasound guided fine-needle aspiration biopsy (FNAB) and were advised to undergo a thyroidectomy based on the FNAB results. The characteristics of the thyroid cancer patients detected by mass screening were then compared with those of 106 consecutive female patients with clinical thyroid cancer during the same period. Thyroid nodules were detected in 353 (25.2%) of the subjects, 94 (26.6%) of whom were placed in the high-risk group for thyroid cancer. Among the 94 high-risk patients, 43 underwent a thyroidectomy and 37 turned out to have thyroid carcinomas. The detection rate for thyroid cancer was 2.6% for all subjects. The tumor size was significantly smaller than that of the clinically detected cancer group (P < 0.05). Ultrasonographic mass screening for thyroid carcinoma in women who require breast examinations is thus considered to be effective for the detection of subclinical thyroid carcinoma.

Cytological Results of Ultrasound-Guided Fine-Needle Aspiration Cytology for Thyroid Nodules: Emphasis on Correlation with Sonographic Findings

Purpose To compare the cytological results of ultrasound-guided fine-needle aspiration (US-FNA) cytology of thyroid nodules to sonographic findings and determine whether US findings are helpful in the interpretation of cytological results. Materials and Methods Among the thyroid nodules that underwent US-FNA cytology, we included the 819 nodules which had a conclusive diagnosis. Final diagnosis was based on pathology from surgery, repeated FNA cytology or follow-up of more than one year. Cytological results were divided into five groups: benign, indeterminate (follicular or Hurthle cell neoplasm), suspicious for malignancy, malignant, and inadequate. US findings were categorized as benign or suspicious. Cytological results and US categories were analyzed. Results Final diagnosis was concluded upon in 819 nodules based on pathology (n=311), repeated FNA cytology (n=204) and follow-up (n=304), of which 634 were benign and 185 were malignant. There were 560 benign nodules, 141 malignant nodules, 49 nodules with inadequate results, 21 with indeterminate results, and 48 that were suspicious for malignancy. The positive and negative predictive values of the US categories were 59.1% and 97.0%, and those of the cytological results were 93.7% and 98.9%. The US categories were significantly correlated with final diagnosis in the benign (p=0.014) and suspicious for malignancy (p<0.001) cytological result groups, but not in the inadequate and indeterminate cytological results groups. The false positive and negative rates of cytological results were 1.9% and 3.2%. Conclusion Sonographic findings can be useful when used alongside cytological results, especially in nodules with cytological results that are benign or suspicious for malignancy.

Application of BRAF, NRAS, KRAS mutations as markers for the detection of papillary thyroid cancer from FNAB specimens by pyrosequencing analysis

Abstract Background: BRAFV600E, the most common BRAF gene mutation, is detected in approximately 50% of sporadic papillary thyroid carcinoma (PTC) and may be associated with triggering tumorigenesis of PTC. The aim of our study was to discover additional mutations to increase the diagnostic performance of molecular tests in screening for thyroid cancer from fine needle aspiration biopsy (FNAB) specimens. Methods: DNA was extracted from 120 freshly obtained FNAB specimens selected according to cytopathology grades of the Bethesda system. A conventional BRAF V600E test was carried out with real-time PCR, and further mutation screening for BRAF mutations in codons 464, 466, 469, NRAS and KRAS codons 12/13 and 61 was done by pyrosequencing. Histopathology reports were reviewed for those who underwent thyroidectomy (n=83). Results: The real-time PCR method detected 45 BRAF V600E- positive cases whereas pyrosequencing detected 30 cases. Additional BRAF (n=4), NRAS (n=11) and KRAS (n=3) mutations were detected in 17 cases (one overlapping BRAF and NRAS mutation). Among 11 NRAS-mutated cases, eight were confirmed as PTC and one as FVPTC on histopathology reports. Five PTC-confirmed cases with BRAF V600E mutation showed additional mutations, all of which were NRAS mutations. Discussion: Despite the higher sensitivity of real-time PCR for detecting BRAFV600E mutations, pyrosequencing easily detected additional point mutations. NRAS mutations were the most prevalently identified additional mutations and were highly associated with malignancy. In conclusion, our findings demonstrate that additional mutations identified by pyrosequencing may help in the pre-operative process in determining the possibility of malignancy and further studies on the occurrence of simultaneous mutations of BRAF, KRAS and NRAS may be warranted.

Influence of buffer composition and sample pretreatment on efficiency separation for monitoring neuropeptides in plasma using capillary electrophoresis

More efficient and faster separation conditions for qualitative as well as quantitative analysis of neuropeptides in human plasma using capillary zone electrophoresis (CZE) have been developed. The analysis method for neuropeptides has been improved specifically to study thyroid hormone related neuropetides for the regulation of thyroid disease. In this study, we investigated the pretreatment methods, composition of the running buffer and rinsing procedures between runs in order to obtain more sensitive and faster separation of trace neuropeptides in plasma by CZE. The tested neuropeptides were somatostatin (SOMA), vasopressin (VP), neurotensin (NT), and thyrotropin‐releasing hormone (TRH). Plasma samples were pretreated by deproteinization and solid‐phase extraction method. The fraction of neuropeptides was reconstituted in 40% acetonitrile followed by ultrafiltration, and then analyzed by CZE. Resolution and sensitivity was improved using the separation buffer composition with 100 mM Tris‐phosphate buffer (pH 2.0) while the sensitivity was further improved via a stacking method using the sample buffer of 40% acetonitrile. These sample pretreatment methods and buffer condition permit quantitative analysis on tested neuropeptides at the 20 ng/mL level. The rinsing procedures between runs using 90% ethanol dramatically shortened the rinsing time to 30 min.