Lenvatinib Compared with Sorafenib as a First-Line Treatment for Radioactive Iodine-Refractory, Progressive, Differentiated Thyroid Carcinoma: Real-World Outcomes in a Multicenter Retrospective Cohort Study.

Background: Sorafenib and lenvatinib have been widely adopted to treat radioactive iodine (RAI)-refractory differentiated thyroid carcinoma (DTC). However, limited data exist regarding a direct comparison of these tyrosine kinase inhibitors (TKIs). We aimed to evaluate the clinical efficacy and safety of two TKIs as first-line therapy in patients with distant metastatic or locally advanced, progressive, RAI-refractory DTC in real-world practice. Methods: In this multicenter, retrospective cohort study, we evaluated 136 patients with progressive distant metastatic or locally advanced, progressive, RAI-refractory DTC or poorly differentiated thyroid carcinoma (PDTC) who received first-line sorafenib or lenvatinib treatment. The primary outcome was progression-free survival (PFS). We also evaluated the objective response rate, disease-control rate, clinical benefit rate, and safety. Results: The median age of the patients was 68 years, and 35% (47/136) were male. Eighty and fifty-six patients were included in the sorafenib and lenvatinib groups, respectively. The median PFS was 13.3 months [95% confidence interval, CI, 9.9-18.1 months] in the sorafenib group and 35.3 months [CI, 18.2 months to upper limit not reported as the median was not reached] in the lenvatinib group (p = 0.001). A significantly prolonged PFS was observed in the lenvatinib group (compared with the sorafenib group) after adjusting for age, sex, pathology, disease-related symptom, lung-only metastasis, cumulative RAI dose, time from diagnosis, treatment duration, and longest diameter of the target lesion (hazard ratio = 0.34, CI, 0.19-0.60, p < 0.001). The partial response rate was 24% and 59% in the sorafenib and lenvatinib groups, respectively (p < 0.001). More common grade 3-4 adverse events were hypertension (16%, 9/56 vs. 1%, 1/80, p = 0.002) and proteinuria (32%, 18/56 vs. 0%, p < 0.001) in the lenvatinib group, and hand-foot skin reaction (24%, 19/80 vs. 4%, 2/56, p = 0.001) in the sorafenib group. Conclusion: In our study of Asian patients, first-line lenvatinib treatment of metastatic or locally advanced, progressive, RAI-refractory DTC or PDTC was associated with a longer PFS compared with sorafenib. However, severe hypertension and proteinuria were observed more frequently after lenvatinib treatment than after sorafenib treatment.

Estimating the Growth Rate of Lung Metastases in Differentiated Thyroid Carcinoma: Response Evaluation Criteria in Solid Tumors or Doubling Time?

Background: Estimating the growth rate of lung metastases for the treatment of patients with metastases of differentiated thyroid carcinoma (DTC) is important. This study aimed to evaluate survival outcomes according to different criteria for estimating the growth rate of lung metastases. Methods: Patients with macronodular (≥1 cm) lung metastases of DTC who underwent total thyroidectomy and high-dose radioactive iodine therapy between 1995 and 2013 were enrolled. The time to progressive disease (PD) by the Response Evaluation Criteria in Solid Tumors (RECIST), average tumor volume doubling time of the two dominant target lung lesions (midDT), and thyroglobulin doubling time (TgDT) were measured in each patient, and their association with disease-specific survival (DSS) was evaluated. Results: Forty-four patients with target lung metastatic nodules with an initial maximal diameter of 1.3 cm (median) were followed-up for a median of 6.8 years after the diagnosis of lung metastases. Based on RECIST, 12 patients (27.3%) showed fast tumor progression, with time to PD <1 year. When assessed by midDT, nine patients (20.5%) had midDT ≤1 year, showing rapid tumor progression. Seven of 33 patients (21.2%) who were negative for thyroglobulin antibody had midDT <1 year. Growth rates assessed by all three criteria were significantly associated with DSS. However, midDT had the highest predictive value for DSS, with a proportion of variation explained of 33.6%. Five-year DSS was 29.6% in patients with midDT ≤1 year, 50.0% in patients with time to PD <1 year, and 42.9% in patients with TgDT <1 year. Conclusions: Among the different criteria for estimating the growth rate of metastases in patients with lung metastases of DTC, midDT was the most powerful for predicting DSS, in comparison with RECIST and TgDT. Performing at least three serial chest computed tomography scans during the first year from the diagnosis of lung metastases can facilitate early detection of patients with rapid tumor progression and provide objective guidance for initiation of systemic therapy.

Extended Real-World Observation of Patients Treated with Sorafenib for Radioactive Iodine-Refractory Differentiated Thyroid Carcinoma and Impact of Lenvatinib Salvage Treatment: A Korean Multicenter Study.

Background: Treatment for patients with radioactive iodine (RAI)-refractory differentiated thyroid carcinoma (DTC) is challenging. Recently, two tyrosine kinase inhibitors (sorafenib and lenvatinib) have been approved and showed benefits for progression-free survival with tolerable adverse events. Methods: This is an extension study of a previous multicenter, retrospective cohort study of real-world experience in treating 98 patients with progressive RAI-refractory DTC with sorafenib. The primary endpoint was overall survival (OS). The efficacy of lenvatinib as salvage therapy after disease progression on first-line sorafenib was evaluated by comparing outcomes in 32 patients who were treated with lenvatinib with 41 patients who were not and therefore served as a no salvage treatment group. Results: The median OS of all 98 patients treated with sorafenib was 41.5 months, and the median progression-free survival was 13.5 months. Patients without disease-related symptoms before sorafenib treatment had better OS than those with symptoms (hazard ratio [HR] = 0.56 [95% confidence interval, CI 0.31-0.99], p = 0.048). Larger tumor size was associated with a minimally increased risk of death (HR = 1.02 [CI 1.00-1.03], p = 0.049). Best tumor response was not associated with OS (p = 0.490). Lenvatinib salvage treatment significantly improved OS in patients receiving it compared with those who did not (HR = 0.28 [CI 0.15-0.53], p < 0.001). The median OS from the time of disease progression after first-line sorafenib treatment was 4.9 months in no salvage treatment group, whereas it was not reached in the lenvatinib salvage group. Conclusions: The absence of disease-related symptoms and smaller tumor burden was associated with survival benefits of first-line sorafenib treatment in patients with progressive RAI-refractory DTC. Lenvatinib salvage therapy was effective in improving OS in patients with disease progression after first-line sorafenib.

Tertiary Care Experience of Sorafenib in the Treatment of Progressive Radioiodine-Refractory Differentiated Thyroid Carcinoma: A Korean Multicenter Study.

BACKGROUND: Sorafenib, a multi-kinase inhibitor, is approved for the treatment of patients with radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC). This study evaluated the efficacy and safety of sorafenib in real-world clinical practice and compared the results to those of the DECISION trial. The clinical features associated with better clinical outcomes after sorafenib treatment were also evaluated. METHODS: This multicenter, retrospective cohort study evaluated 98 patients with progressive RAI-refractory DTC who were treated with sorafenib in six tertiary hospitals in Korea. The primary objective was the progression-free survival (PFS) according to Response Evaluation Criteria In Solid Tumors v1.1. Overall survival, response rate (defined as the best objective response according to Response Evaluation Criteria In Solid Tumors v1.1), and safety were also evaluated. RESULTS: The median PFS was 9.7 months; median overall survival was not reached during follow-up. Partial responses and stable disease were achieved in 25 (25%) and 64 (65%) patients, respectively. Stable disease of >6 months was achieved in 41 (42%) patients. Subgroup analyses identified several prognostic indicators of a better PFS: absence of disease-related symptoms (hazard ratio [HR] = 0.5; p = 0.041), lung-only metastasis (HR = 0.4; p = 0.048), a daily maintenance dose ≥600 mg (HR = 0.3; p = 0.005), and a thyroglobulin reduction ≥60% (HR = 0.4; p = 0.012). The mean daily dose of sorafenib was 666 ± 114 mg, and drug withdrawals due to adverse events (AEs) occurred in 13% of patients. AEs and serious AEs were reported in 93 (95%) and 40 (41%) patients, respectively. The most frequent AE was hand-foot skin reaction (76%). CONCLUSIONS: The PFS of progressive RAI-refractory DTC patients treated with sorafenib was consistent with the findings of the DECISION trial. Disease-related symptoms, lung-only metastasis, a daily maintenance dose, and thyroglobulin reduction were significantly associated with PFS. These results suggest that sorafenib is an effective treatment option for patients with progressive RAI-refractory DTC.

Vitamin D deficiency affects thyroid autoimmunity and dysfunction in iodine-replete area: Korea national health and nutrition examination survey.

PURPOSE: We evaluated the effects of vitamin D levels and iodine intake on thyroid autoimmunity and dysfunction in the Korean population. METHODS: In this nationwide population-based study, data were obtained from the Korea National Health and Nutrition Examination Survey VI-1 and 2 (2013 and 2014), which was the first nationwide survey that measured both serum 25-hydroxy vitamin D [25(OH)D] levels and urinary iodine concentrations (UICs) in Korea. A total of 4181 participants who underwent laboratory tests for thyroid function, serum 25(OH)D levels, and UICs were included. RESULTS: Anti-thyroid peroxidase antibody (TPOAb) positivity was more prevalent in the vitamin D deficient group (9.1%) than the vitamin D insufficient and sufficient groups (5.3% each; P = 0.016). The rate of TPOAb positivity was significantly higher in the iodine deficient group (P = 0.032). Thyroid dysfunction was significantly more prevalent in the iodine excessive group than in the other groups in total (P = 0.016) and TPOAb negative participants (P = 0.007). In the vitamin D deficient group, excessive iodine intake was significantly associated with high prevalence of thyroid dysfunction in total and TPOAb negative participants (P = 0.021 and P = 0.033, respectively). In the vitamin D insufficient and sufficient groups, association between thyroid dysfunction and iodine intake disappeared in total and TPOAb negative participants. CONCLUSIONS: This nationwide survey revealed a significant association between vitamin D deficiency and high prevalence of thyroid autoimmunity and dysfunction in participants with excessive iodine intake. Our findings might be helpful for elucidating the potential benefit of vitamin D supplements in TPOAb negative patients with excessive iodine intake.

Lack of Efficacy of Radioiodine Remnant Ablation for Papillary Thyroid Microcarcinoma: Verification Using Inverse Probability of Treatment Weighting.

BACKGROUND: Most of the increase in thyroid cancer in recent decades has been due to papillary thyroid microcarcinoma (PTMC). We evaluated the efficacy of radioiodine remnant ablation (RRA) in patients with PTMC. METHODS: This historical cohort study included 1932 PTMC patients without lateral cervical lymph node (LN) or distant metastasis who underwent total thyroidectomy (TT) during the median 8.3 years of follow-up. The clinical outcomes of patients with or without RRA were compared using weighted logistic regression models with the inverse probability of treatment weighting (IPTW) method and considering risk factors, including age, sex, primary tumor size, extrathyroidal extension, multifocality, and central cervical LN metastasis. RESULTS: The median primary tumor size of the RRA group was significantly larger than that of the no-RRA group (0.7 vs. 0.5 cm, P < 0.001). There were significantly more patients with multifocality, extrathyroidal extension, and cervical LN metastasis in the RRA group compared with the no-RRA group. There was no significant difference in recurrence-free survival between the two groups (P = 0.11). Cox proportional-hazard analysis with IPTW by adjusting for clinicopathological risk factors demonstrated no significant difference in recurrence of PTMC according to RRA treatment (hazard ratio [HR] 2.02; 95% confidence interval [CI] 0.65-6.25; P = 0.2). CONCLUSIONS: RRA had no therapeutic effect on the clinical outcomes of patients with PTMC who underwent TT. Surgical treatment without RRA could be applicable for patients with PTMC if there is no evidence of lateral cervical LN metastasis or distant metastasis.

Alpha lipoic acid inhibits proliferation and epithelial mesenchymal transition of thyroid cancer cells.

The naturally occurring short-chain fatty acid, α-lipoic acid (ALA) is a powerful antioxidant which is clinically used for treatment of diabetic neuropathy. Recent studies suggested the possibility of ALA as a potential anti-cancer agent, because it could activate adenosine monophosphate activated protein kinase (AMPK) and inhibit transforming growth factor-ß (TGFß) pathway. In this study, we evaluate the effects of ALA on thyroid cancer cell proliferation, migration and invasion. We performed in vitro cell proliferation analysis using BCPAP, HTH-83, CAL-62 and FTC-133 cells. ALA suppressed thyroid cancer cell proliferation through activation of AMPK and subsequent down-regulation of mammalian target of rapamycin (mTOR)-S6 signaling pathway. Low-dose ALA, which had minimal effects on cell proliferation, also decreased cell migration and invasion of BCPAP, CAL-62 and HTH-83 cells. ALA inhibited epithelial mesenchymal transition (EMT) evidently by increase of E-cadherin and decreases of activated ß-catenin, vimentin, snail, and twist in these cells. ALA suppressed TGFß production and inhibited induction of p-Smad2 and twist by TGFß1 or TGFß2. These findings indicate that ALA reduces cancer cell migration and invasion through suppression of TGFß production and inhibition of TGFß signaling pathways in thyroid cancer cells. ALA also significantly suppressed tumor growth in mouse xenograft model using BCPAP and FTC-133 cells. This is the first study to show anti-cancer effect of ALA on thyroid cancer cells. ALA could be a potential therapeutic agent for treatment of advanced thyroid cancer, possibly as an adjuvant therapy with other systemic therapeutic agents.

Changes in the pulmonary function test after radioactive iodine treatment in patients with pulmonary metastases of differentiated thyroid cancer.

OBJECTIVE: Pulmonary function test (PFT) is a useful tool for an objective assessment of respiratory function. Impaired pulmonary function is critical for the survival and quality of life in patients with pulmonary metastases of solid cancers including thyroid cancer. This study aimed to evaluate clinical factors associated with severely impaired pulmonary function by serial assessment with PFT in patients with pulmonary metastasis of differentiated thyroid cancer (DTC) who received radioactive iodine treatment (RAIT). PATIENTS: This retrospective study enrolled 31 patients who underwent serial PFTs before and after RAIT for pulmonary metastasis of DTC. We evaluated the risk factors for severe impairment of pulmonary function. RESULTS: The median age of the patients was 44.1 years and 18 of them were female patients. Severe impairment of pulmonary function was observed in five patients (16%) after a median of three RAITs (cumulative I-131 activity = 20.4 GBq). These patients were older and more frequently had mild impairment of baseline pulmonary function, respiratory symptoms, or progressive disease compared with patients with stable pulmonary function. Neither cumulative dose nor number of RAIT was associated with decreased pulmonary function. Coexisting pulmonary diseases, presence of respiratory symptoms, and metastatic disease progression were significantly associated with severe decrease in forced vital capacity during follow-up (p =.047, p =.011, and p =.021, respectively). CONCLUSIONS: Pulmonary function was severely impaired during follow-up in some patients with pulmonary metastasis of DTC after a high-dose RAITs. Neither the number of RAIT nor the cumulative I-131 activity was associated with decreased pulmonary function. Serial PFT might be considered for some high-risk patients during follow-up.

Effects of low-dose and high-dose postoperative radioiodine therapy on the clinical outcome in patients with small differentiated thyroid cancer having microscopic extrathyroidal extension.

BACKGROUND: It is unclear whether differentiated thyroid cancer (DTC) patients classified as intermediate risk based on the presence of microscopic extrathyroidal extension (ETE) should be treated with low or high doses of radioiodine (RAI) after surgery. We evaluated success rates and long-term clinical outcomes of patients with DTC of small tumor size, microscopic ETE, and no cervical lymph node (LN) metastasis treated either with a low (1.1 GBq) or high RAI dose (5.5 GBq). METHODS: This is a retrospective analysis of a historical cohort from 2000 to 2010 in a tertiary referral hospital. A total of 176 patients with small (≤2 cm) DTC, microscopic ETE, and no cervical LN metastasis were included. Ninety-six patients were treated with 1.1 GBq (LO group) and 80 patients with 5.5 GBq (HI group). Successful RAI therapy was defined as (i) negative stimulated thyroglobulin (Tg) in the absence of Tg antibodies, and (ii) absence of remnant thyroid tissue and of abnormal cervical LNs on ultrasonography. Clinical recurrence was defined as the reappearance of disease after ablation, which was confirmed by cytologically or pathologically proven malignant tissue or of distant metastatic lesions. RESULTS: There was no significant difference in the rate of successful RAI therapy between the LO and HI groups (p=0.75). In a subgroup analysis based on tumor size, success rates were not different between the LO group (34/35, 97%) and the HI group (50/56, 89%) in patients with a tumor size of 1-2 cm (p=0.24). In patients with smaller tumor size (≤1 cm), there was no significant difference in success rates between the LO (59/61, 97%) and HI groups (22/24, 92%; p=0.30). No patient had clinical recurrences in either group during the median 7.2 years of follow-up. CONCLUSIONS: Low-dose RAI therapy is sufficient to treat DTC patients classified as intermediate risk just by the presence of microscopic ETE.

Modified dynamic risk stratification for predicting recurrence using the response to initial therapy in patients with differentiated thyroid carcinoma.

OBJECTIVE: A new risk stratification system was proposed to estimate the risk of recurrence in patients with differentiated thyroid carcinoma (DTC) using the response to initial therapy. Here, we describe the modified dynamic risk stratification system, which takes into consideration the status of serum anti-Tg antibody (TgAb), and validate this system for assessing the risk of recurrence in patients with DTC. PATIENTS AND METHODS: Patients who underwent total thyroidectomy with radioiodine remnant ablation due to DTC between 2000 and 2005 were included. We classified patients into four groups based on the response to the initial therapy ('excellent', 'acceptable', 'biochemical incomplete', and 'structural incomplete' response). RESULTS: The median follow-up period of 715 patients with DTC was 8 years. The response to initial therapy was an important risk predictor for recurrent/persistent DTC. The relative risks (95% CI) of recurrence were 16.5 (6.3-43.0) in the 'acceptable response' group, 41.3 (15.4-110.8) in the 'biochemical incomplete response' group, and 281.2 (112.9-700.5) in the 'structural incomplete response' group compared with the 'excellent response' group (P<0.001, P<0.001, and P<0.001 respectively). The disease-free survival rate of the 'excellent response' group to initial therapy was 98.3% whereas that of the 'structural incomplete response' group was only 6.8%. CONCLUSIONS: Our study validates the usefulness of the modified dynamic risk stratification system including the status of serum TgAb for predicting recurrent/persistent disease in patients with DTC. Personalized risk assessment using the response to initial therapy could be useful for the follow-up and management of patients with DTC.

Papillary thyroid carcinoma arising from a thyroglossal duct cyst: a single institution experience.

Thyroid cancers arising from a thyroglossal duct cyst (TGDC) are rarely reported. No clear consensus exists regarding optimal management. In this light, TGDC carcinomas recently treated at Asan Medical Center, as well as previously reported cases in the literature, were reviewed. There were ten patients who were diagnosed with TGDC carcinoma at our institution. All patients underwent pre-operative fine-needle aspiration biopsy (FNAB). Nine patients were suspected of having papillary carcinoma following cytology. The Sistrunk operation (SO) was performed in four patients, SO with total thyroidectomy (SO/TT) was performed in three patients, and SO/TT with neck dissection was performed in three patients. Six patients who received total thyroidectomy underwent radioactive iodine (RAI) therapy and T4 suppression. With a median follow-up period of 28.5 months, two patients showed recurrence and one of them died of the disease. We analyzed 163 cases from 1990 to 2012 with three or more cases TGDC carcinoma, including the present study. Among 48 patients who underwent FNAB, 75% had papillary thyroid carcinoma (PTC). SO, SO/TT, or SO/TT with neck dissection was performed in 27%, 41%, and 32% of patients, respectively. Among 119 patients who received total thyroidectomy, 36% had concomitant PTC in the thyroid. Among 52 patients who received neck dissection, 69% had cervical nodal involvement. The results of our review suggest that when TGDC carcinoma is suspected, ultrasonography and, if necessary, FNAB should be performed. If these tests reveal a suspected lesion in the thyroid or lymph node, SO/TT and lymph node dissection should be performed.

Adjuvant radioactive therapy after reoperation for locoregionally recurrent papillary thyroid cancer in patients who initially underwent total thyroidectomy and high-dose remnant ablation.

CONTEXT: Some patients have elevated stimulated thyroglobulin (sTg) concentrations after reoperation for locoregionally recurrent/persistent papillary thyroid cancer (PTC). Little is known, however, about the efficacy of adjuvant radioactive iodine (RAI) therapy in these patients. OBJECTIVE: The objective of the study was to evaluate the efficacy of adjuvant RAI therapy in patients with elevated sTg after reoperation for locally recurrent/persistent PTC. DESIGN AND SETTINGS: This was a retrospective observational cohort study in a tertiary referral hospital. PATIENTS: We evaluated 45 consecutive patients with sTg greater than 2 ng/ml after reoperation for locoregionally recurrent PTC, all of whom had previously undergone initial total thyroidectomy followed by high-dose RAI remnant ablation. Of these 45 patients, 23 received adjuvant RAI therapy (adjuvant group) and 22 did not (control group). MAIN OUTCOME MEASURES: Main outcome measures included changes in sTg concentration after reoperation and disease-free survival. RESULTS: Over time, there were no significant differences in mean sTg concentration in the adjuvant (P = 0.35) and control (P = 0.74) groups. Only 15% of patients in the adjuvant group and 33% in the control group showed a greater than 50% decrease in sTg level from baseline. There were no between-group differences in changes (P = 0.83) or percent decrease (P = 0.97) in sTg concentration and no difference in clinical recurrence-free survival (P = 0.20). CONCLUSION: In patients who still have elevated sTg after reoperation for locally recurrent/persistent PTC, adjuvant RAI therapy compared with no additional RAI therapy resulted in no significant differences in the subsequent sTg changes or the recurrence-free survival.

Printing of sub-100-nm metal nanodot arrays by carbon nanopost stamps.

This work reports an efficient method to fabricate hexagonally patterned metal nanodot arrays at the sub-100-nm scale, which is based on contact printing via novel nanometer-scaled stamps. Vertically aligned carbon nanoposts, supported by hexagonally ordered nanochannels of anodic aluminum oxide templates, are employed as the stamping platform to directly transfer controlled metal nanodot arrays. Using the fabrication platform, a number of patterned metal nanodot arrays made of Au, Cu, Ni, Ag, Pt, Al, and Ti can be contact-printed over large substrate areas in ambient conditions. The size, density, and interdistance of the printed nanodots are controllable with a tight correspondence to the mother stamp geometries, which can be precisely tuned by modifying the pore dimensions of the alumina matrixes. An advanced example of contact printing of metal nanoparticles is successfully demonstrated by the controlled formation of nanodot arrays in a specific area.

Anti-ulcerogenic effect and HPLC analysis of the caffeoylquinic acid-rich extract from Ligularia stenocephala.

The leaves of three Ligularia species belonging to the family Compositae, Ligularia stenocephala, L. fischeri, and L. fischeri var. spiciformis, were qualitatively and quantitatively analyzed on the caffeoylquinic acids by HPLC and subjected to peroxynitrite-scavenging assay. The IC(50) of the MeOH extract of L. stenocephala was 1.62+/-0.03 mug/ml and the major caffeoylquinic acids of L. stenocephala were 5-O-caffeoylquinic acid, 3,5-di-O-caffeoyl-muco-quinic acid, and 3,5-di-O-caffeoylquinic acid. The compositions of caffeoylquinic acids were different for the three plants. Since percentage of total caffeoylquinic acids of the extract was highest (42.20% of the MeOH extract and 94.52% of the BuOH extract) in L. stenocephala and potent in peroxynitrite-scavenging assay, the extracts of L. stenocephala were chosen to perform in vivo anti-ulcerogenic activity. Treatment of mice with the MeOH- and BuOH extracts decreased the diameter of gastric lesions caused by HCl/ethanol- and indomethacin/bethanechol and decreased the volume of gastric juice, suggesting that caffeoylquinic acids have anti-ulcerogenic activity. These results suggest that the leaves of Ligularia species may help prevent or treat gastric ulcers.

Clinical outcomes of persistent radioiodine uptake in the neck shown by diagnostic whole body scan in patients with differentiated thyroid carcinoma after initial surgery and remnant ablation.

OBJECTIVES: To evaluate the clinical outcomes of persistent radioiodine uptake (RAIU) in the neck by diagnostic whole body scan (DxWBS) after initial therapy and the efficacy of the second ablation in patients with differentiated thyroid carcinoma (DTC). DESIGN: Patients with DTC who underwent bilateral surgery and high-dose remnant ablation between 2000 and 2004 were included. Patients with elevated serum stimulated thyroglobulin (sTg) or extensive lateral neck lymph node involvement at initial surgery underwent a second ablation, and patients with undetectable sTg or in very low-risk groups were observed. RESULTS: Among 572 patients, 25 had persistent RAIU in the neck at first DxWBS. After a median 65.7 months of follow-up, five of these patients (20%) had persistent disease, whereas another 20 patients had no abnormal findings by ultrasonography (US) or other imaging modalities. Seven of 20 patients underwent second ablation and 13 were observed. RAIU disappeared spontaneously in about half of the patients in the observation group. There were no significant between-group differences in change of RAIU at follow-up DxWBS (P = 0.62). Serum sTg decreased and eventually disappeared over a few years in both groups. Ablation failure was not an independent risk factor for recurrence (P = 0.169). CONCLUSIONS: Neck US and serum sTg, but not DxWBS, were useful diagnostic tools during follow-up of patients with persistent uptake in the neck at DxWBS. A second ablation was not necessary when neck US showed no evidence of disease, especially in patients with very low sTg concentration.

Empiric high-dose 131-iodine therapy lacks efficacy for treated papillary thyroid cancer patients with detectable serum thyroglobulin, but negative cervical sonography and 18F-fluorodeoxyglucose positron emission tomography scan.

CONTEXT: Some patients with elevated serum thyroglobulin (Tg) but a negative diagnostic whole body scan (WBS) after initial therapy for differentiated thyroid carcinoma may benefit from empirical radioactive iodine (RAI) therapy. However, previous studies enrolled patients with negative diagnostic WBS, regardless of neck ultrasonography (USG) and/or (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET), which have become the preferred diagnostic procedures in such patients. OBJECTIVE: The aim of this study was to evaluate the usefulness of empirical RAI therapy in patients with elevated stimulated Tg level and negative USG/FDG-PET findings after initial therapy for papillary thyroid carcinoma (PTC). DESIGN: This comparative study enrolled 39 patients with elevated stimulated Tg, negative diagnostic WBS, and negative USG/FDG-PET 1 yr after initial treatment. Empirical RAI therapy was performed in 14 patients (treatment group), whereas 25 patients were followed up without therapy (control group). RESULTS: There was no significant between-group difference in basal clinicopathological parameters. None of the 14 patients in the treatment group showed iodine uptake on posttreatment WBS. Five of 14 patients (36%) in the treatment group and eight of 25 (32%) in the control group had recurrence during the median 37 months of follow-up (P = 0.99). Changes in serum stimulated Tg concentrations did not differ between the two groups. CONCLUSION: Empirical RAI therapy and posttreatment WBS were not useful diagnostically or therapeutically in patients with positive serum stimulated Tg if such patients had negative USG and negative FDG-PET findings after initial treatment of PTC.

Qualitative and quantitative determination of the caffeoylquinic acids on the Korean mountainous vegetables used for chwinamul and their peroxynitrite-scavenging effect.

Mountainous vegetables called chwinamul are used in Korea to promote health. Chwinamul was obtained from several plants belonging to the Compositae - e.g., Kalimeris yomena, Aster scaber, Solidago virga var. gigantea, Solidago viragaurea var. asiatica, Saussurea grandifolia, Ainsliaea acerifolia - were used for our experiments. Analytical methods for simultaneous determination of the caffeoylquinic acids (3,4-di-O-caffeoylquinic acid, 3,5-di-O-dicaffeoyl-epi-quinic acid, 3,5-di-O-caffeoylquinic acid, 4,5-di-O-caffeoylquinic acid, 5-O-caffeoylquinic acid, 3-O-caffeoylquinic acid, 3-O-p-coumaroyl-caffeoylquinic acids) were established for chwinamul. The kinds of constituents were identified from HPLC chromatograms and it was possible to calculate the percentage (w/w) of seven of these compounds in the dried plants and in the extracts. The proportion of caffeoylquinic acids in the extracts ranged from 20.25 to 38.35%. Since it is known that peroxynitrite (ONOO(-))-scavenging is beneficial for amelioration of obesity, diabetes mellitus, atherosclerosis and even Alzheimer's disease, assays for peroxynitrite-scavenging activity were performed on the seven chwinamul plants. Of the tested extracts, the MeOH extract of A. acerifolia had the most potent effect (IC(50) 1.49 +/- 0.68 microg/mL). These results suggest that chwinamul vegetables can be used for treatment or prevention of peroxynitrite-related diseases.

Redifferentiation therapy with 13-cis retinoic acids in radioiodine-resistant thyroid cancer.

Radioiodine (I-131) therapy is of proven efficacy for treatment of differentiated thyroid carcinoma (DTC). However, loss of differentiation in recurrent or metastatic DTC which decrease I-131 uptake may decrease the efficacy of I-131 therapy. Therefore, strategies to improve I-131 uptake are mandatory. This study is an open label clinical study to evaluate the effectiveness of 13-cis retinoic acid (13-cis RA) for improving I-131 uptake in recurrent or metastatic of DTC with defective I-131 uptake. Eleven patients (Age 27-66 years, M : F=4 : 7) were given 13-cis RA (1.5 mg/kg daily for 5 weeks), followed by 200 mCi (7.4 GBq) I-131 treatment. The differences of serum thyroglobulin (Tg) level and I-131 uptake on the post-treatment whole body scan (RxWBS) were compared before and after 13-cis RA therapy. Six out of 11 patients showed significantly increased (above 50%) Tg levels just after RA therapy. However, Tg levels a year after I-131 therapy were increased, stable and decreased in 7, 2 and 1 patients, respectively. Iodine uptake on RxWBS showed marginal improvement in only 2 patients and their Tg levels after one year follow-up increased. Most frequent adverse events were dry skin and lips. 13-cis RA partially restores I-131 uptake in few patients with recurrent or metastatic DTC. The use of 13-cis RA in current protocol has only limited usefulness and is not routinely recommended as currently used protocol.

The MeOH extract of Pleurospermum kamtschaticum and its active component buddlejasaponin (IV) inhibits intrinsic and extrinsic hyperlipidemia and hypercholesterolemia in the rat.

The inhibitory effect of the MeOH extract of Pleurospermum kamtschaticum (Umbelliferase) and its fractions were tested in hyperlipidemic and hypercholesterolemic rats using four animal models induced using poloxamer-407 or using Triton WR-1339 as intrinsic inducers and by 30% corn oil or high cholesterol diet as extrinsic inducers. We measured serum triglyceride, total cholesterol, HDL-cholesterol and LDL-cholesterol levels as measures of its hypocholesterolemic or hypolipidemic effects. Since the MeOH extract and the BuOH fraction of Pleurospermum kamtschaticum were found to be active using these four hypolipidemic assays, its major saponin buddlejasaponin IV {BS(IV)} isolated from the BuOH fraction were also tested to demonstrate the active components. BS(IV) was found to significantly inhibit hypercholesterolemia and hyperlipidemia by extrinsic and intrinsic inducers. In particular, BS(IV) reduced the blood thiobarbituric acid reactive substance (TBARS) and hydroxy radical levels, and increased superoxide dismutase activity in high cholesterol diet-induced rats, thus suggesting that BS(IV) reduces oxidative stress caused by a high cholesterol diet. Moreover, these effects of BS(IV) were comparable to probucol, which was used as a positive control. These results suggested that Pleurospermum kamtschaticum which is traditionally used to treat atherosclerosis and its active major saponin BS(IV) could be used to treat hypercholesterolemia or hyperlipidemia.

Clinical features and prognostic factors for survival in patients with poorly differentiated thyroid carcinoma and comparison to the patients with the aggressive variants of papillary thyroid carcinoma.

We performed this study to compare the clinicopathologic features and outcomes between the patients with poorly differentiated thyroid carcinoma (PDTC) and the patients with the aggressive variants of papillary thyroid carcinoma (PTC). To evaluate the prognostic factors for survival of the patients with PDTC, we selected 49 patients with PDTC and 23 patients with the aggressive variants of PTC from three hospitals during the recent 15 years. The five-year survival rate and clinicopathologic features of the patients with PDTC were not different from those of the patients with the aggressive variants of PTC. Univariate analysis revealed the significant poor prognostic factors for survival of the patients with PDTC and the aggressive variants of PTC as follows: 1) an age more than 45 years, 2) a tumor size larger than 4 cm, 3) the presence of tumor invasion to extrathyroidal tissue or the trachea, 4) the presence of cervical lymph node invasion, 5) the presence of distant metastasis, 6) the absence of high-dose radioactive iodine (RAI) therapy, and 7) TNM stage II, III and IV. Distant metastasis and high-dose RAI therapy were independent significant predictors for survival of the patients with PDTC and the aggressive variants of PTC on multivariate analysis. However, distant metastasis was the only independent significant predictors for survival of the patients with PDTC excluding patients with the aggressive variants of PTC.