Encephalopathy After a High-Dose Dexamethasone Suppression Test in a Woman With X-Linked Ornithine Transcarbamylase Deficiency.

Background/Objective: The high-dose dexamethasone suppression test is a common and usually benign endocrine procedure. We report a patient with ornithine transcarbamylase deficiency (OTCD) who developed hyperammonemic encephalopathy after a high-dose dexamethasone suppression test. Case Report: A 46-year-old woman with a 1.3-cm right adrenal incidentaloma causing mild autonomous cortisol secretion underwent a high-dose dexamethasone suppression test for confirming adrenocorticotropic hormone independency. On the next day, she presented to the emergency room with confusion and somnolence. Her Glasgow Coma Scale score was 10 on arrival. The initial laboratory results showed ammonia, alanine transaminase, creatinine, and blood urea nitrogen levels of 289.51 (18.73-54.5) µg/dL, 21 (≤33) IU/L, 0.6 (0.6-1.1) mg/dL, and 13 (7-20) mg/dL, respectively. Electroencephalography showed triphasic morphology with no pathologies on brain imaging. Her husband told us that her brother and son had died in the neonatal period. On further review of medical records, we found that she was diagnosed as an OTCD carrier. We administered L-arginine, L-carnitine, rifaximin, and continuous renal replacement therapy. After 3 days, the serum ammonia level was 78.34 µg/dL with an increased Glasgow Coma Scale score of 15, and electroencephalography abnormalities disappeared. Discussion: Liver diseases and urea cycle disorders are the leading causes of hyperammonemia. This causes encephalopathy and death if the ammonia levels are too high. X-linked OTCD urea cycle disorder affects men more severely as they have only the carrier X chromosome. Glucocorticoids can exacerbate this disorder because they increase protein substrates converted to ammonia. Conclusion: This case reminds that it may be particularly important to have a complete medical history when administering glucocorticoids.

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.

Therapeutic effects of bee venom and its major component, melittin, on atopic dermatitis in vivo and in vitro.

BACKGROUND AND PURPOSE: Atopic dermatitis (AD) is a multifactorial skin condition with complex interactions of innate and adaptive immune responses. There are several existing therapies for AD, including topical glucocorticosteroids, emollients, phototherapies, calcineurin inhibitors and immunosuppressants, such as cyclosporine A. Although these therapies reduce inflammation, they also cause serious side effects. Therefore, it is necessary to develop new therapeutic approaches for AD treatment without side effects. There are several studies on natural materials or toxins, such as herbs, ginseng extract and snake venom, for AD treatment. However, treatment of AD with bee venom and its major component, melittin has rarely been studied. EXPERIMENTAL APPROACH: Effects of bee venom and melittin were studied in a model of AD in vivo induced by 1-chloro-2,4-dinitrobenzene (DNCB) in female Balb/c mice and in cultures of human keratinocytes, stimulated by TNF-α/IFN-γ. The potential pharmacological effects of bee venom and melittin on these in vivo and in vitro AD-like skin disease models were studied. KEY RESULTS: Bee venom and melittin exhibited potent anti-atopic activities, shown by decreased AD-like skin lesions, induced by DNCB in mice. In vitro studies using TNF-α/IFN-γ-stimulated human keratinocytes showed that bee venom and melittin inhibited the increased expression of chemokines, such as CCL17 and CCL22, and pro-inflammatory cytokines, including IL-1ß, IL-6 and IFN-γ, through the blockade of the NF-κB and STAT signalling pathways. CONCLUSIONS AND IMPLICATIONS: Our results suggest that bee venom and melittin would be suitable for epicutaneous application, as topical administration is often appropriate for the treatment of AD.

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.

Dynamic Risk Stratification in Stage I Papillary Thyroid Cancer Patients Younger Than 45 Years of Age.

BACKGROUND: This study validated the dynamic risk stratification (DRS) system with regard to its association with structural recurrence and risk factors associated with non-excellent responses in patients <45 years with stage I classical papillary thyroid cancer (PTC). METHODS: This historical cohort study included 598 patients with stage I classical PTC <45 years of age treated with total thyroidectomy followed by radioactive iodine remnant ablation (n = 440), total thyroidectomy without radioactive iodine remnant ablation (n = 23), and thyroid lobectomy alone (n = 135). RESULTS: The median follow-up period was 123 months. Structural recurrence occurred in 4.2% (n = 18/432) of the patients with an excellent response, 17.1% (18/105) of patients with an indeterminate response, 44.7% (17/38) of patients with a biochemically incomplete response, and 82.6% (19/23) of patients with a structurally incomplete response (p < 0.001) during the follow-up. The disease-free survival curves of each response showed significant differences (p < 0.001). Extensive extrathyroidal extension and extranodal extension were the independent risk factors associated with non-excellent response (p < 0.05). CONCLUSIONS: DRS may reduce unnecessary additional treatments by reclassifying initial risk estimates of structural recurrence. Furthermore, applying the risk factors associated with non-excellent response to initial therapy may be a more useful and viable surrogate of the risk for structural recurrence in stage I PTC patients <45 years of age.

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.