ResearchPad - thyroid Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[SAT-454 A Novel Role of Thyroid Hormone Receptor in Synaptic Plasticity in Cerebellar Purkinje Cells]]> Thyroid hormone (TH) is essential for the development and the maintenance of the brain function. TH action is mediated by TH receptor (TR). TR binds to a specific DNA sequence on TH-target genes and thus functions as a ligand-dependent transcription factor. In thyroid diseases such as congenital hypothyroidism or resistance to TH (RTH), TH-TR binding is dominantly disrupted, leading to the various symptoms such as motor deficits. However, in such cases, all the cells that express TR get affected by the disrupted TR signaling; thus, the specific mechanism has not been cleared. It has been well known that proper motor coordination is deeply related to long term depression (LTD) of synaptic transmission from parallel fiber (PF) to Purkinje cell (PC) in the cerebellum (Ito, 1989). Therefore, we examined the involvement of TR in synaptic plasticity at PF-PC synapses by using transgenic mice (Mf-1 mice) which express dominant-negative TR specifically in PCs. Since Mf-1 display the impairment of motor coordination and motor learning, a decrease in TR signaling in PCs may alter synaptic plasticity and contribute to motor incoordination. A whole-cell patch clamp recording of Mf-1 PCs revealed the inhibition of LTD but instead the induction of long term potentiation (LTP) of the synaptic transmission at PF-PC synapses. This indicates that the intracellular calcium dynamics may be disrupted in Mf-1 PCs since LTD requires a higher elevation of the intracellular calcium concentration in PCs than LTP does. Indeed, single-PC qPCR showed that the mRNA levels of some important molecules for the intracellular calcium dynamics in PCs (SERCA2, IP3R, and P/Q-type calcium channel) are downregulated in Mf-1 PCs. This result suggests those genes as possible TH-target genes. Taken together, the present study suggested a novel possible role of TR in synaptic plasticity at PF-PC synapses by regulating the expression of some important genes for LTD occurrence in the cerebellum. This finding could give a new insight into the mechanism of motor deficits in thyroid diseases.

<![CDATA[MON-513 Suppressing the Growth of Human Medullary Thyroid Cancer Cells Using FDA-Approved Drug]]> Medullary thyroid carcinoma (MTC) is a solid tumor of the parafollicular cells in the thyroid gland. MTC has worse prognosis, when compared with other differentiated thyroid cancers, and MTC patients with distant metastases have a low survival rate unless thyroidectomy is performed at an early stage. Furthermore, conventional treatments have only marginal benefits. Therefore, there is a need to develop novel therapeutics for MTC. Several drugs that are developed and tested in preclinical trials fail in clinical trials. Therefore, repurposing the already US Food and Drug Administration (FDA)-approved drugs towards the treatment of cancers may have potential benefits, like saving the lives of cancer patients and lowering the investment cost of drug development. Here, we explored a novel precision treatment for thyroid cancers by repurposing the FDA-approved small molecule anti-parasitic drug Nitazoxanide (NTZ). In our study, we examined the anticancer effects of NTZ on human MTC cells using the TT cell line. We treated the TT cells with different concentrations of NTZ and assessed the cell proliferation by water-soluble tetrazolium salt (WST-1) assay and oxygen consumption rate (OCR) by Seahorse extracellular flux analysis (Seahorse XFe24 Analyzer). Additionally, we determined the effects of NTZ on the protein expression of key signaling molecules that regulate MTC cell growth by western blot analysis. Our results indicated that NTZ significantly suppressed the growth of TT cells at 24 h treatment. Very importantly, NTZ reduced the basal OCR demonstrating the inhibition of mitochondrial respiration. Moreover, protein expression studies revealed that NTZ markedly reduced the key Hippo signaling pathway effector molecule TAZ and the oncogene c-myc. Interestingly, NTZ decreased the expression of epidermal growth factor receptor (EGFR) that plays an important role for RET activation in MTC. Importantly, NTZ increased the expression of p53 upregulated modulator of apoptosis (Puma). Taken together, our findings demonstrate for the first time that NTZ inhibits the growth of MTC cells and decreases the cancer cell metabolism. The mechanisms by which NTZ targets the MTC cells involve the suppression of key oncogenic proteins and upregulation of tumor suppressor molecule. Thus, our study highlights that repurposing this FDA-approved currently used drug may have a greater advantage of being tested in preclinical models of MTC, and therefore, for the rapid consideration of NTZ as a potential therapeutic drug to treat MTC patients in the near future.

<![CDATA[MON-508 Clinicopathological Features of Papillary Thyroid Cancer After Fukushima and Chernobyl Accidents]]> The phenomenon of a sharp increase in the incidence of thyroid cancer worldwide is now under debate. Screening activity, diagnostic improvements or real rise in incidence as a result of unknown carcinogens are discussed. Studies in Belarus after Chernobyl showed that the synergistic influence of radiation and nitrates might lead to an increased thyroid cancer (TC) risk in children. For better understanding of the etiology, we compared the published clinical data of pediatric TC patients after the nuclear emergency of Fukushima with the observations we made after the Chernobyl accident.

In a large-scale survey after the Fukushima accident, 300,476 subjects were screened and by September 2018, 191 subjects were diagnosed with thyroid malignancy or suspected malignancy by fine needle aspiration. Mean age of TC patients was 17.8 years at presentation. Mean tumor size was 14.9 mm. Postoperative lymph node metastasis, extra-thyroidal invasion, and pulmonary metastasis were detected in 79%, 45%, and 2.1% of all cases, respectively. Only 4.8% TC cases were staged as low risk pT1aN0M0 (Suzuki et al. 2018). For comparison, in Belarus patients mean age was 13.0 years at presentation (1078 cases), mean tumor size 14.4 mm. Lymph node metastases were observed in 74%, pulmonary metastasis in 11% and extra-thyroidal extension in 48.5 - 64.1% (with respect to latency period). The low risk (pT1aN0M0) TC patients were diagnosed in 19.2% cases.

The most of TC cases from Japan and Belarus were clinically significant, not “overdiagnosed” and screened on time. Given that the accidental thyroid doses were very low in Japanese cases, it would be very important to evaluate and compare the exposure to endocrine disruptors as e.g. nitrates and low radiation doses from diagnostic procedures (dental X-ray examination and computed tomography).


Suzuki S, Matsumoto Y, Ookouchi C, Nakano K, Iwadate M, Suzuki S, Nakamura I, Fukushima T, Mizunuma H, Yamashita S, Takenoshita S. The clinicopathological features of childhood and adolescent thyroid cancer in Fukushima after the Fukushima Daiichi nuclear power plant accident. Thyroid. 2018; Supplement 1, (Poster 136).

<![CDATA[MON-490 Calcitonin-Based Thyroidectomy Is a Safe Approach in Patients with Germline RET Mutation and Permits to Delay Surgery in Children]]> Introduction: Medullary thyroid cancer (MTC) arises from C cells secreting calcitonin. In familial MTC cases, a germline RET mutation is discovered in 98% of cases. Nowadays, an early diagnosis and radical surgery are the only curative approach. However, thyroidectomy in children is associated with a higher rate of surgical adverse events, compared to surgery in adults. The best clinical approach in patient harboring germline RET mutation (gene carriers, GC) is still undefined. Methods and materials: since 1994 to 2018 we identified 174 GC by RET screening. 56 GC underwent total thyroidectomy and lymph node dissection for the evidence of high calcitonin levels at the first clinical evaluation, whereas 27 GC underwent surgery for high stimulated calcitonin levels during the active surveillance (median 16 months, range 13-118). 90 GC are still in follow up. Results: In the group of 27 GC patients who underwent surgery during the active surveillance, 15 GC had only C cells hyperplasia (CCH) foci and 12 were affected by MTC. These carcinomas were all confined to the thyroid, without any lymph node and distant metastasis. All these patients are still in clinical remission, after a median follow-up of 4 years (range 1-11). At time of the surgery, the patients affected by MTC were significantly older than patients harboring only CCH (median 49 vs 30 years old, respectively). Among these 27 GC, 7 were diagnosed as GC when they were younger than 18 years (median 7 years old, range 2-18) and they underwent surgery after a median period of 3 years (range 1-10 years), when they were all older than 7 years. In this group, 6 of 7 were affected by CCH and only one case by a microMTC. There were not any persistent surgical adverse events and all of them are still in clinical remission. 41 of 90 GC, who are still in active surveillance, were younger than 18 years at time of RET screening: nowadays, 10/41 are older than 18 years and 15/41 are older than 14 years, all with calcitonin still in the normal range. Conclusions: we demonstrated that the calcitonin-based thyroidectomy is a safe approach in GC. Intriguingly, this approach seems to be interesting especially in children in order to perform still an early and safe surgery but when they are older, possibly adults.

<![CDATA[MON-532 Characterization of the Angiogenic Factor SFRP2 in Papillary Thyroid Carcinoma]]> Over the last decade, there has been an average annual increase of 3.1% in thyroid cancer diagnosis in the U.S. Papillary thyroid carcinoma (PTC) accounts for 80% of all thyroid cancer diagnoses. However, few molecular markers exist to identify clinically aggressive phenotypes. The angiogenic factor, secreted frizzled-related protein 2 (SFRP2), is associated with a poor prognosis in several malignancies including breast cancer and melanoma. The role of SFRP2 in PTC has yet to be investigated. The aims of this study were to determine the differential expression of SFRP2 in PTC, benign thyroid adenomas, normal thyroid tissue (from patients without cancer), and normal adjacent tissue (NAT) (non-cancerous tissue from patients with PTC) and investigate the role of SFRP2 in tumor development in two PTC cell lines, PTC classical variant (PTC-CV) and PTC follicular variant (PTC-FV), upon treatment with a humanized anti-SFRP2 monoclonal antibody (hSFRP2 mAb). Immunohistochemistry (IHC) was performed using human tissue protein microarrays including 226 PTC, 79 benign adenomas, 112 NAT, and 30 normal thyroid tissue samples. In-vitro proliferation and apoptosis experiments were performed on MDA-T41 (PTC-CV) and MDA-T68 (PTC-FV) cell lines by treating with hSFRP2 mAb, Xolair IgG control, and a vehicle control. SFRP2 expression was significantly higher in PTC compared with benign adenomas and normal thyroid (mean expression scores 9, 6, and 1, respectively; p<0.05). SFRP2 expression was significantly higher in NAT than normal thyroid (mean expression score 4 and 0, respectively, p<0.05). Apoptotic rates were increased by 40% and 62% in the PTC-CV hSFRP2 mAb treatment group compared with the Xolair and vehicle treatment groups, respectively (p<0.05). Apoptotic rates were increased by 126% and 59% in the PTC-FV hSFRP2 mAb treatment group compared with the Xolair and vehicle treatment groups, respectively (p<0.05). Treatment with hSFRP2 mAb had no significant effect on proliferation in either cell line. In conclusion, SFRP2 expression is significantly higher in PTC than in benign adenomas and normal thyroid tissue. SFRP2 expression in NAT is significantly higher than in normal thyroid tissue and not significantly different from benign adenomas. SFRP2 expression in nonmalignant tissue adjacent to PTC could be due to expression in the tumor microenvironment. Treatment with a novel hSFPR2 mAb increases apoptotic rates in two different PTC cell lines. These data suggest that SFPR2 is involved in tumorigenesis of PTC.

<![CDATA[SUN-483 A Retrospective Diagnosis of Malignant Struma Ovarii After Discovery of Pulmonary Metastases]]> Background: Malignant struma ovarii is a rare ovarian tumor that is histologically identical to differentiated thyroid carcinoma.1 We present a case of a struma ovarii that was recognized as being malignant only after the discovery of pulmonary metastases.

Clinical Case: A 29 year old female presented to the hospital with acute right lower abdominal pain, suspicious for ovarian torsion. She underwent urgent right salpingoopherectomy and pathology demonstrated a mature cystic teratoma with benign struma ovarii. Two years later, a CT of the abdomen incidentally revealed bilateral pulmonary nodules. Review of the imaging showed that these pulmonary nodules were also present two years prior, and had since become larger. Video-assisted thoracoscopic surgery was performed and lung biopsy was positive for well-differentiated thyroid carcinoma. The patient then underwent total thyroidectomy which revealed a 0.3 x 0.3 cm infiltrative papillary thyroid cancer, follicular variant, without lymphovascular invasion. Thyroglobulin level decreased from 169 ng/mL pre-operatively to 80 ng/mL post-operatively, but then continued to be variable ranging from 56 to 252 ng/mL (1.6-50 ng/mL). Thyroglobulin antibodies remained negative.

Pathology from right ovary was re-reviewed at a second institution and found to be consistent with highly differentiated thyroid carcinoma with characteristic nuclear features of papillary thyroid carcinoma.

A diagnostic whole body I-131 scan showed uptake within the thyroid bed, bilateral lung nodules, left distal thigh and right mid thigh. These thigh lesions were not visualized on lower extremity ultrasound. After dosimetry was performed, the patient received radioactive iodine-131 200 mCI. Post-therapy scan six days later demonstrated uptake in the thyroid bed, bilateral lungs and bilateral thighs. About five months later, thyroglobulin level had decreased to 0.4 ng/mL with a suppressed TSH. A repeat CT chest demonstrated that the lung nodules had all decreased in size, largest from 0.5 cm to 0.3 cm.

Conclusion: Careful examination of struma ovarii pathology should be performed to evaluate for malignant features since benign appearing histology can present diagnostic difficulty.2 In this case, thyroglobulin level was lower than reported in previous cases; however, sites of metastases were responsive to radioactive iodine therapy indicating well differentiated disease and a favorable prognosis.

References: 1. Goffredo P, Sawka AM, Pura J, Adam MA, Roman SA, Sosa JA. Malignant Struma Ovarii: A Population-Level Analysis of a Large Series of 68 Patients. Thyroid. 2015:25(2): 211-216.

2. Roth LM, Miller AW, Talerman A. Typical Thyroid-Type Carcinoma Arising in Struma Ovarii: A Report of 4 Cases and Review of Literature. Int J Gynecol Pathol. 2008:27(4): 496-506.

<![CDATA[MON-459 Bilateral Killian-Jamieson Diverticulum Mimicking Thyroid Nodules]]> Background

In recent years, incidence and prevalence of thyroid and extrathyroid lesion is increasing in the worldwide due to increase awareness of medical check-up, and widespread use of imaging techniques. A Killian Jamieson diverticulum (KJD), a rare type of hypopharyngeal pulsion diverticulum outpouching from the lateral wall of the proximal cervical esophagus, was incidentally detected and likely to be misinterpreted as a thyroid nodule while performing thyroid sonography. Clearly differentiate between those lesions is essential to avoid unnecessary invasive procedure. Here we report a typical case of bilateral Killian Jamieson diverticulum mimicking thyroid nodules.

Clinical case

A 57-year-old Taiwanese man was referred to our endocrine outpatient department for further evaluation of thyroid nodules. The lesions were discovered while sonographic examination performed in the clinic for routine medical check-up. He denied having dysphagia, epigastric pain, odynophagia, halitosis, chronic cough or acid regurgitation, body weight loss, fever and dyspnea. He had no previous systemic disease and no prior radiation therapy. He lives in Nangang District, Taipei city. His body weight was 70 kg and BMI was 25. An examination of head and neck was unremarkable. Laboratory data revealed normal thyroid function (TSH: 0.67 uIU/ml; range 0.4~4.0, free T4: 0.83 ng/dl; range 0.9~1.8 and aTPO <1.0 IU/ml; range <5). Thyroid ultrasonography demonstrated oval, hypoechoic nodule-like lesions containing bright foci with acoustic shadow in the posterior aspect of the both lobes of thyroid gland. The rest of thyroid glands were normal appearance. An esophagography was performed and showed two contrast-filling anterior outpouching lesions at both sides of the cervical esophagus, around C7 level and both lesions were showing anterior outpouching appearance, consider Killian-Jamieson diverticulum. Taken together, he was diagnosed as KJD and clinical follow-up alone is suggested.

Clinical lessons

KJD is usually incidentally detected and misdiagnosed as a thyroid nodule containing punctuate microcalcification foci as found in papillary thyroid carcinoma. To differentiate these nodules, real time sonographic examination is important. Although rare, non-thyroid lesions originating from the esophagus should be considered in the differential diagnosis of the thyroid nodules to avoid unnecessary invasive fine needle aspiration of thyroid gland.

<![CDATA[SAT-489 The Weary Beating Heart: Complications of Severe Hypothyroidism in a Mentally Ill Patient]]> Myxedema coma is a severe form of hypothyroidism representing a endocrinologic emergency. It requires prompt identification and management, as mortality rates exceed 50%. Its rarity stems from early recognition and thyroid medication availability. Its presentation can be non-specific, making it a challenging diagnosis.

This is a 67-year-old male inmate who was brought to the ED due to hypoactivity. He had a long-standing history of bipolar disorder, and hypothyroidism receiving oral levothyroxine.

On evaluation, patient had slowed mentation, GCS 14/15, sluggish reactive pupils, macroglossia, diffuse non-pitting edema, and delayed relaxation of the deep tendon reflexes in the extremities. Vital signs were abnormal; T: 35.2 °C, RR: 10 rpm, SpO2: 84 %, BP: 137/89 mmHg and HR: 42 bpm without chronotropism. 12-lead ECG revealed a complete atrioventricular block (AV block), with non-conductive P waves and idioventricular rhythm. Patient became hemodynamically unstable, transcutaneous pacemaker was placed. Dopamine infusion was initiated for adequate mean arterial pressure. Subsequently, a femoral transvenous pacemaker was performed. However, neurological deterioration prompted mechanical ventilation.

Exploring reversible AV block etiologies, laboratory results were markedly elevated for TSH at 184.775 ng/mL and decreased T4 at 1.5 ng/mL. Lithium levels were therapeutic.

Myxedema coma was identified and timely treatment was provided with intravenous thyroid hormone replacement, intravenous hydrocortisone, and supportive care. Patient was transferred to an ICU where TSH was monitored. After 5 days of receiving IV thyroid hormone replacement therapy, TSH improved. However, patient remained dependent on transvenous pacemaker, for which permanent pacemaker had to be placed. With further therapy, patient’s neurological status improved leading to extubation, and subsequent discharge.

Thyroid hormones play a vital role in the electrical current of the heart; hence, disturbances may potentiate cardiac arrhythmias. Sinus bradycardia and QT interval prolongation are commonly seen. As the severity of hypothyroidism progresses, high-grade AV block may be encountered, being third degree AV block the most challenging and severe.

Patients with high-degree AV block in the setting of reversible etiologies, commonly, do not need a permanent pacemaker. On the contrary, our patient developed complete dependence of the pacemaker for adequate cardiac synchrony, despite adequate replacement therapy.

With this case, we illustrate the importance of a thorough evaluation in patients with AV block of unknown origin, with special attention to reversible etiologies. Thyroid function abnormalities should be promptly identified and managed for better outcomes. Furthermore, it may decrease cardiac death risk and the need for invasive procedures, such as permanent pacemaker placement.

<![CDATA[SAT-410 Long Term Evaluation of TSH Receptor Antibodies and Thyroid Stimulating Immunoglobulin After Radioiodine Therapy for Thyrotoxicosis]]> Background Radioioactive iodine therapy (RAI) is an excellent choice to treat thyrotoxicosis, particularly Graves′ disease (GD) patients. After RAI therapy, it is well known that TSH receptor antibodies (TRAb) rise in GD patients and autoimmunity can eventually surge in patients with toxic multinodular or uninodular goiter (TNG). Recently, biological assay distinguishes stimulating TRAb, called thyroid stimulating immunoglobulin (TSI) bringing a new perspective on follow-up, as TSI is involved in Graves′ pathogenesis of persistent thyrotoxicosis and ophthalmopathy after RAI therapy. Objective Analyze TRAb and TSI levels after 6 and 12 months of RAI therapy for thyrotoxicosis. Patients and Methods Patients were evaluated prospectively immediately before and 6 to 12 months after RAI therapy for thyrotoxicosis. Thyroid hormones were all measured using immunoassays (Roche Diagnostics Ltd). TRAb was analyzed by Elecsys Anti-TSHR assay (Roche Diagnostics, Germany) and was considered negative if < 1.75 IU/L (analytical range: 0.3 to 40 IU/L). TSI was measured by Immulite TSI assay (Siemens Healthcare, UK) and was considered negative if < 0.55 IU/L (analytical range: 0.1 to 40 IU/L). Clinical data and comparison of assays were analyzed by SPSS and MedCalc softwares. Results From 2017 to 2019, 54 patients (44 females) were prospectively evaluated after 6 months of RAI therapy, mostly because of GD (40 patients). A high degree correlation was observed between TRAb and TSI (Spearman correlation coefficient =0.875; p < 0.0001, 95% CI 0.784 to 0.929). After 6 months, among patients with GD, 5/40 patients had negative TRAb levels and 2/40 had negative TSI levels, whereas all TNG patients had both negative TRAb and TSI levels. In GD group, 4 patients showed subclinical hyperthyroidism and relapse occurred in 1 case. All patients with TNG showed euthyroidism status with or without thyroid medications. One year after RAI therapy, we evaluated 32 patients (23 GD) and 4/23 of GD had negative TRAb levels and only 1/23 had negative TSI level. All patients with TNG had negative TRAb and TSI levels after one year fo treatment. Subclinical hyperthyroidism was diagnosed in 5 patients with GD but none with TNG. Along follow-up, 4 patients with clinical diagnosis of GD with TRAb negative before RAI therapy became positive after RAI therapy and 3 patients became TSI positive. Conclusions Long term after RAI therapy for thyrotoxicosis treatment, TRAb and TSI are still positive in most GD patients and few cases can even turned to positive levels. Nevertheless, in TNG patients, RAI therapy is safe as TRAb and TSI maintained at negative concentrations and thyrotoxicosis is properly resolved.

<![CDATA[MON-480 Isolated Hyperthyroxinemia - Does Everyone Needs Treatment?]]> Background: Raised free thyroxine (T4) with normal thyroid stimulating hormone (TSH) levels should be identified and interpreted with caution. Some of these conditions do not need treatment. We present three cases with similar biochemical abnormalities from three different causes.

Case 1: A 62-year-old clinically asymptomatic lady was referred to us with Free T4 34.9 pmol/L (10.0 – 24.0 pmol/L), TSH 0.81 mU/L (0.2 – 5.0 mu/L) and negative TSH receptor antibodies (<0.9 IU/L). She was trialled on antithyroid drugs for 6 months. Her Free T4 stayed elevated between 29.0 – 35.0 pmol/L with normal TSH. We worked up for assay interference by running tests on two analysers, Roche Cobas e801 and Siemens ADIVA Centaur CP, both yielded similar results. Alpha1 glycoprotein subunits and SHBG were normal with clinical euthyroid status making TSHoma less likely. Serum protein electrophoresis did not detect any abnormal albumin. We were unable to perform equilibrium dialysis due to non-availability of facility at our centre. Due to strong clinical suspicion and family history of thyroid dysfunction that never needed a treatment, we tested her genetically for familial dysalbumineic hyperthyroxinemia (FDH) using mutation surveyor and fluorescent sequence analysis showed her to be heterozygous for c.725G>A ALB variant confirming diagnosis of FDH.

Case 2: A 65-year-old clinically asymptomatic lady, was referred to us with Free T4 28.8 pmol/L (10.0 – 24.0 pmol/L) and TSH 2.50 mU/L (0.2 – 5.0 mu/L). Given inappropriately normal TSH levels, we repeated her TFTs using 3 different analysers, Roche cobas e801, Siemens ADIVA centaur CP and Abbot ARCHITECT i1000SR. Roche and Siemens assays yielded similar results, however Abbot assay showed normal thyroid function tests with TSH 1.01 mu/L (0.4-5.0 mu/L) and free T4 18.7pmol/L (9.0-19.0 pmol/L), confirming assay interference. As Siemens and Roche uses streptavidin-biotin immobilizing system while Abbot uses a magnetic bead-based capture system, the abnormal results could be due to biotin interference.

Case 3: A 65-year-old lady, clinically asymptomatic was referred to us with Free T4 29.2 pmol/L (10.0 – 24.0 pmol/L) and TSH 1.59 mU/L (0.2 – 5.0 mu/L), 3 months after stopping amiodarone, which she took for 3 weeks for atrial fibrillation. This was thought to be due to amiodarone, owing to its long half-life of 58 days. We repeated thyroid function tests in 3 months from first clinical encounter i.e. 6 months after stopping amiodarone that showed Free T4 24.2pmol/L and TSH 2.30 mU/L and repeated further 3 months later that were normal, confirming amiodarone induced abnormal biochemical profile requiring no treatment.

Conclusion: Hyperthyroxinaemia with normal TSH need to be interpreted with caution as illustrated above. Some of them do not need treatment and inappropriate interpretation can potentially cause anxiety for the patient and harm due to unnecessary treatment.

<![CDATA[SAT-500 Response to Tocilizumab Retreatment in Refractory Thyroid Eye Disease]]> Background: The current standard of care for moderate to severe thyroid eye disease (TED) is intravenous methylprednisolone (IVMP), though alternative immunosuppressive options are emerging. In a recent randomized trial, Tocilizumab (TCZ), an anti-IL-6 receptor antibody, demonstrated improved efficacy for corticosteroid-resistant TED compared to placebo. Clinical response to TCZ retreatment, however, has not been previously reported.

Clinical case: A 64-year old man presented with progressive diplopia, eyelid retraction and edema and retrobulbar pain. Initial labs revealed TSH 0.221 uIU/mL, free thyroxine (FT4) 1.11 ng/dL, total T3 172 ng/dL and a thyroid stimulating immunoglobulin (TSI) index of 329 (normal < 140). The patient was a former cigarette smoker who had recently transitioned to e-cigarettes. He was treated with 12 weeks of IVMP with improvement in ocular redness and swelling. Three months following completion of treatment, he presented with worsening left sided proptosis, restrictive strabismus, and compressive optic neuropathy (CON) evidenced by deteriorating central acuity and color vision. He underwent urgent surgical decompression for CON with full restoration of visual acuity. He then received a second 12-week course of IVMP with concomitant orbital radiation. Of note, his hyperthyroidism was well controlled with methimazole. Two months after his second IVMP course, he had a third flare of ophthalmic symptoms. He was then treated with TCZ 8 mg/kg (800mg) IV monthly for six months. The patient’s Clinical Activity Score (CAS) improved from 4 to 2 and TSI index decreased from 610 to 92 (normal). He had significant improvement in periorbital edema, caruncle/plica swelling, and conjunctival injection. However, ten months following completion of the TCZ course he again complained of worsening diplopia and left proptosis. Of note, relapse of his TED symptoms was preceded by an increase in TSI from 92 to 300 two months prior. Orbital CT demonstrated progression of left orbitopathy and increased orbital apex crowding. Following these CT findings he was restarted on TCZ, of which he has now completed 5 additional infusions. His CAS has improved from 3 to 2 and TSI index has decreased from 284 to 100.

Conclusion: This is the first reported case of response to successive courses of TCZ in relapsing, severe, corticosteroid-resistant TED. TCZ can be an effective option for refractory TED though retreatment may be necessary for recurrent inflammation. Further study of TCZ is required to determine its role in relapsing TED and the optimal duration of therapy needed.


Perez-Moreiras et al., 2018. Efficacy of Tocilizumab in patients with moderate to severe corticosteroid resistant Graves’ orbitopathy: a randomized controlled trial. Am J Ophthalmol 195:181

<![CDATA[MON-103 Pattern and Predictors of Thyroid Dysfunction Among Paediatric Endocrine Referrals at Tertiary Care Centre: A Longitudinal Study]]> Background Post iodisation era has experienced gradual change in pattern of thyroid disorders among paediatric population with autoimmunity taking precedence over iodine deficiency disorders and subclinical hypothyroidism (SCH) now more frequently diagnosed but inappropriately managed. Aims This study was conducted to evaluate pattern of abnormal thyroid function among children referred to our tertiary care centre, to ascertain characteristics that influence treatment decisions and to follow them for various outcome measures. Design It was an observational longitudinal follow up study where all children less than 18 years, referred to our outpatient clinic for suspected thyroid disorder were recruited. Demographic data, personal and family history, clinical features were noted and laboratory tests including TT4, TT3, TSH, anti-thyroid peroxidase(antiTPO) and anti-thyroglobulin(antiTG) antibody were conducted in study subjects. Management was based on the clinical judgment of the attending endocrinologist. Patients were followed at 6 week, 3 months, 6 months and one year with clinical and laboratory work up at each visit. Results A total of 241 subjects aged 18 days to 17 years were included out of which 62.25% were females. Initial evaluation revealed SCH in 40% of refereed subjects, overt hypothyroidism (OH) in 33%, congenital hypothyroidism (CH) in 18% and overt thyrotoxicosis in 5%. Autoimmune thyroiditis constituted the major cause of hypothyroidism in the OH group with significantly higher prevalence of anti-TPO and antiTG antibody in comparison of SCH group (61% vs 31%; 45% vs 21.9%, p<0.05) respectively. All subjects in OH group were treated whereas 76% subjects in SCH group were treated and the mean dose of L thyroxine required to treat OH was significantly higher (2.31+1.1ug/kg/day vs 1.76+1.07ug/kg/day; p<0.001) in comparison of SCH group. A major independent predictor of treatment in SCH was initial TSH which was significantly higher in the treated group (11.65 + 3.80 uIU/ml vs 9.24 + 1.31 uIU/ml; p<0.001). Subjects with congenital hypothyroid presented at a mean age of 6 months (18 days to 2 years) with most common aetiology being thyroid hypoplasia and dyshormonogenesis

(20% each). Graves’ disease was diagnosed in 11 out of 12 subjects with thyrotoxicosis and were treated with antithyroid drugs. Overall 85.5% of refereed subjects were treated and after one-year follow up management was found to be adequate in 81% subjects. Conclusions The evolving trend of diagnosing children having nonspecific symptoms with SCH is a matter of concern as many are subjected to the burden of unwanted prolonged treatment and frequent testing as highlighted in our study. Delayed presentation of CH in our study warrants active surveillance of children at birth for thyroid disorders to avoid long term adverse effects on mental development.

<![CDATA[SUN-516 Unplanned Pregnancy Post Thyroid RAI Ablation]]> A patient’s pregnancy and fetus are at an increased risk for complications secondary to history of recent RAI ablation and maternal secondary hypothyroidism.

A 31 year old female with a recent history of miscarriage presented with abnormal thyroid function tests and was history of low dose levothyroxine use. She complained of a 3 month history of extreme fatigue, palpitations and 18 pound weight loss at the time of presentation. Her thyroid stimulating immunoglobulin was 9.21 IU/L (0-0.55), free thyroxine 6.2ng/dL (0.9-1.8), free triiodothyronine 20.04 pg/mL (1.8-4.6) with a suppressed TSH 0.01 uIU/ml (0.27 - 4.2). She was started on methimazole. Her 24 hour radioactive iodine uptake was 60% and she subsequently underwent radioactive iodine-131 ablation in capsule form. She failed the ablation after 7 months and remained on methimazole during that duration. Her second radioactive iodine uptake was 58% and she underwent a second RAI ablation. Her TSH was 50 uIU/ml and her free thyroxine was 0.1 ng/dl. She was started on levothyroxine for replacement. Patient unexpectedly became pregnant approximately six weeks after her radioactive iodine treatment.

Studies have shown that with the exception of miscarriages, there is no evidence that exposure to radioiodine affects the outcome of subsequent pregnancies and offspring. Although the number of children born of mothers exposed to radioiodine is relatively small, the present data indicates that there is no reason for patients exposed to radioiodine to avoid pregnancy. The only adverse effect observed in the study series is an increased incidence of miscarriages in women exposed to therapeutic radioiodine during the year which preceded conception. The fetus would be at risk due to maternal hypothyroidism.

Discussion: Radioactive iodine exposure does not appear to be associated with an increased risk of miscarriage or abnormal subsequent pregnancies.

Conclusion: Pregnancies achieved after exposure to radioactive iodine treatment do not appear to be at increased risk for negative outcomes. Nevertheless, it is recommended that pregnancy be avoided for 1 year following radioactive iodine therapy to allow reproductive function to normalize.

<![CDATA[MON-469 Rapidly Expanding Thyroid Goiter as the First Manifestation of Systemic Amyloidosis]]> INTRODUCTION

Amyloidosis is a condition manifesting with extracellular tissue deposition of fibrils of low molecular weight proteins. In Ig light chain amyloidosis (AL), the deposition of Ig light chains can cause organ dysfunction, and patients can have involvement of a range of organs including kidney (70%), liver (70%), heart (60%), peripheral nerves (20%), the tongue, skin, and the coagulation system (1). We describe a unique case of AL amyloidosis, which first presented with thyroid involvement.


A 78 year old female patient with hx of small lymphocytic lymphoma and normal thyroid function presented with an expanding symptomatic goiter and compressive symptoms (positive Pemberton sign) for which a total thyroidectomy was performed. Pathology showed Congo red-birefringent amyloid deposition. SPEP showed a small amount of M protein, with circulating monoclonal free lambda light chain on immunofixation. The free kappa lambda light chain ratio was low (0.04) with an elevated serum free lambda light chain (283.93). Mass spectrometry confirmed AL light chain amyloidosis - lambda type. A work up was initiated to assess other organ involvement. Echocardiogram showed mild thickening of left ventricle with a preserved EF and EKG showed low voltage in limb leads. Creatinine (1.05) was minimally elevated from baseline with minimal proteinuria (396 mg/24 hours). Alkaline phosphatase, APTT, and PT were normal. The patient described tongue enlargement and scalloping of the tongue from tooth impingement was seen. Biopsies of tongue and bone marrow also showed amyloidosis thereby securing the diagnosis of systemic amyloidosis, and chemotherapy was initiated.


This case illustrates the importance of considering amyloid goiter in the differential for a rapidly enlarging thyroid, even when there is no history of amyloidosis. Although extremely uncommon, a few case reports have described amyloid goiter. In our case, thyroid AL was the initial presentation of systemic amyloidosis. Because disease can be localized or systemic, work up should include an assessment for the presence of a monoclonal gammopathy and an assessment for amyloid mediated organ dysfunction. Tissue should be sent for amyloid typing – there are 35 different proteins known to form amyloid fibrils and prognosis and treatment depends on amyloid type (2). Typing using Liquid Chromatography-Tandem Mass Spectrometry, is the most sensitive and specific methodology, though, in experienced hands, typing by immune histochemistry is an option.


1. Rajkumar, S.V., Dispenzieri, A. Clinical presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain (AL) amyloidosis. Uptodate. 2019.

2. Winter, M., Tholey, A., Kristen, A., Röcken, C. MALDI Mass Spectrometry Imaging: A Novel Tool for the Identification and Classification of Amyloidosis. Proteomics 2017, 17, 1700236.

<![CDATA[SAT-490 A Case of Unilateral Exophthalmos Due to Thyroid Orbitopathy and Its Association with Chronic Kidney Disease]]> Graves ophthalmopathy(GO)is the most common extra-thyroidal manifestation of Graves’ disease (GD). Most cases of GO are bilateral which may be asymmetric, whereas unilateral ophthalmopathy is less common and has been observed in 9-15% cases. Association between chronic kidney disease and unilateral Grave’s ophthalmopathy in a clinically euthyroid patient is rare. We report a case of a 24-year-old male with no previous history of any chronic medical illnesses who presented with protruded right eye for the past 6 months. He did not have any other visual symptoms or symptoms related to thyroid disease. Laboratory results revealed low TSH, normal free T3 and free T4. TSH receptor antibodies were positive. He also had elevated serum creatinine at 418 umol/L (normal levels 64 - 110 umol/L). US KUB showed bilateral small sized kidneys and increased parenchymal echogenicity suggestive of chronic kidney disease. MRI Head showed features suggestive of unilateral thyroid associated orbitopathy. Patient received 1-week course of oral prednisolone 10 mg per day after which his exophthalmos improved.Case report: A 24 year old male with no previous history of any chronic medical illnesses, presented to the clinic with protruded right eye for the past 6 months that was progressively getting worse. There was no eye pain, visual changes, ophthalmoplegia, dryness or discharge from eye. Patient did not report any other symptoms, Physical examination revealed a comfortable man with protruded right eye, lid retraction, normal eye movements and no signs of orbital cellulitis. Neck examination was significant for a mild diffuse goitre. Laboratory studies were significant for haemoglobin of 12.1 g/dl (normal 13-17 g/dl). He also had elevated serum creatinine at 418 umol/L (normal 64 - 110 umol/L). Serum electrolytes, liver function tests and lipid profile were within normal range. 24 hr urine collection showed 3.08 gm/24 hr proteinuria. Serum TSH was 0.04 mIU/L (normal 0.45 - 4.5 mIU/L), free T4 was 13.8 pmol/L (normal 9 - 20 pmol/L) and free T3 was 4.56 pmol/L (normal 2.89 - 4.88 pmol/L). Thyrotropin Receptor Ab titre was 4.69 IU/L (normal 0.00 - 1.75 IU/L). ANA, ANCA, C3, C4, Anti thyroid peroxidase and Anti GBM antibodies were negative. Screening for hepatitis B, C and HIV was negative US KUB showed bilateral small sized kidneys and increased parenchymal echogenicity suggestive of CKD. MRI Head was remarkable for proptosis of the right eye with increased retro-orbital fat, thickening and T2 hyper-intensity with sparing of the tendinous insertion involving the right inferior, medial, superior and lateral rectus muscles with crowding at the orbital apex. Features were suggestive of unilateral thyroid associated orbitopathy. Patient received 1-week course of oral prednisolone 10 mg per day after which his exophthalmos improved. An association between CKD and GO in a clinically euthyroid patient is rare.

<![CDATA[SAT-420 Interaction Between Gene Polymorphisms and Urine Iodine Levels on Susceptibility to TPOAb Positivity in the Chinese Population]]> Objective: Hashimoto thyroiditis, characterized by positive thyroid peroxidase antibodies (TPOAbs), is caused by the interaction of genetic and environment factors. The aim of this study was to clarify the interaction of gene polymorphisms and iodine intake in the incidence of TPOAb positivity. Methods: 1733 subjects were included in this study. Genomic DNA was extracted from peripheral blood white cells. Seven SNPs (rs10944479, rs11675434, rs1230666, rs3094228, rs653178, rs9277555 and rs301799) were selected for genotyping. Thyroid hormones and autoimmune antibodies (TPOAb and TGAb) were determined using the electrochemiluminescence immunoassay method. Results: The mean TSH level in TPOAb-positive subjects was higher than in TPOAb-negative subjects (P<0.001). There were no significant differences in urine iodine and blood iodine between these two groups. Genotype GG of rs9277555 and genotype TT of rs11675434 were associated with an increased risk of TPOAb positivity. Logistic regression analysis showed rs9277555 was associated with TPOAb positivity in all models. Furthermore, rs9277555 was also associated with TPOAb levels in linear regression analysis. The cross-validation consistency and the testing accuracy indicated that there were no significant differences between SNPs and urine iodine interaction. Conclusion: rs9277555 was associated with an increased risk of TPOAb positivity in a Chinese Han population. Furthermore, there was no gene polymorphisms-iodine intake interactions in our cohort.

<![CDATA[SAT-498 Graves’-Associated Takotsubo Cardiomyopathy: An Uncommon Condition]]> Introduction Graves’ disease is an autoimmune disorder that causes excess thyroid hormone (T4 and T3). T4 is converted into T3 (active hormone) in the peripheral tissues by the deiodinase enzyme. T3 has an effect on the cardiac electrical system as well as myocyte contractility. Excess T3 can result in cardiac arrythmias as well as ventricular dysfunction (heart failure). Takotsubo cardiomyopathy is a subtype of nonischemic cardiomyopathy related to severe physiologic or mental stress. Excess catecholamine levels have been reported to cause this disease as well. Takotsubo cardiomyopathy has rarely been reported in Graves’-associated thyrotoxicosis.

Case report 55-year-old female who presented to the ED with palpitations and difficulty breathing. She had been seen by her PCP within the past two weeks with complaint of recent 30 lb weight. TSH was noted to be < 0.001 and a neck ultrasound revealed a diffusely enlarged, hypervascular thyroid. She was referred for outpatient endocrinology consultation for further workup. Prior to her initial endocrinology appointment, she developed palpitations and shortness of breath. She did not have any known family history of thyroid disease or other autoimmune conditions. She drinks 1-2 glasses of wine per week and quit smoking in 2017. Physical exam on admission revealed a heart rate of 133 bpm and a blood pressure of 145/93, normal temperature, and normal respirations. Thyroid was diffusely enlarged and without nodularity. No evidence of orbitopathy. Heart was tachycardic but without murmur. Lungs clear. Abdomen soft, nontender. No significant peripheral edema or pretibial rash. No neurological dysfunction. Labs revealed TSH < 0.001, Free T4 > 7.77, Free T3 12.0, TRAb 44.4%, TSI 433%, Anti-TPO 614, high-sensitivity troponin of 112. EKG showed nonspecific infero-lateral T wave changes, rate 123. Echocardiogram demonstrated left ventricular apical hypokinesis but preserved basilar contractility. Ejection fraction was estimated at 40-45%. Nuclear stress test did not reveal any indication of myocardial hypoperfusion.

Discussion/Conclusion Takotsubo cardiomyopathy can mimic acute myocardial infarction both clinically as well as on EKG/serum biomarkers. Troponin levels are typically elevated as a result of myocardial stretch and subsequent troponin “leak”. Echocardiogram demonstrates apical ballooning of the left ventricle, and by definition coronary arteries will be free of significant occlusive disease. A small number of cases have been reported in association with endocrine conditions including thyrotoxicosis due to Graves’ disease. The majority of cases associated with thyrotoxicosis will resolve spontaneously with 1-3 weeks. Treatment consists of medication to decrease cardiac preload as well as afterload (ACE inhibitor, beta blocker, diuresis as needed), similar to medical treatment of other nonischemic cardiomyopathies.

<![CDATA[SAT-418 Finding the Needles in the Haystack: Harnessing the Electronic Health Record to Find Thyroid Immune Related Adverse Events]]> Background: Immune checkpoint inhibitors (CPIs) are being used to effectively treat a growing number of cancers but can cause immune related adverse events (irAE). Thyroid dysfunction is the most common endocrine irAE. A meta-analysis of clinical trials estimated that following CPI exposure, 6.6% will become hypothyroid and 2.9% will have hyperthyroidism1. It is unclear if this reflects the real-world incidence of these irAEs. We used electronic health record (EHR) data to identify patients who developed thyroid dysfunction after CPI to estimate the real-world incidence of these irAEs.

Methods: Data were derived from the EHR of a large U.S. academic center. We identified subjects treated with CPIs between 2012 and 2018 and excluded those with thyroid cancer or pre-existing thyroid disease. Thyroid dysfunction was identified as either a TSH > 10, an abnormal free T4 or a prescription for thyroid hormone replacement or anti-thyroid medication. Those with thyroid dysfunction were then categorized as having pre-existing disease or a new-onset thyroid irAE based on the timing of CPI initiation. Logistic regression was used to evaluate the association of thyroid irAE with age, gender, CPI and type of cancer.

Results: In total, 1146 individuals without pre-existing thyroid disease that received CPIs were assessed. Pembrolizumab was the most common treatment (45%), followed by nivolumab (20%). Less than 10% of subjects received atezolizumab, durvalumab, ipilimumab monotherapy, combined ipilimumab/nivolumab, or other combinations of CPIs. Melanoma was the most common cancer treated (32%), followed by non-small cell lung cancer (13%). The prevalence of any other cancer was < 10% each. Overall, 19% developed thyroid irAEs. After adjustment for gender and age, the type of cancer was significantly associated with new onset thyroid dysfunction (p=0.01). The rates of thyroid irAEs ranged from 10% in glioblastoma to 40% in renal cell cancer. Although there was no significant association between irAEs and specific CPIs in the overall analysis, thyroid irAEs were more common in subjects who received combined ipilimumab/ nivolumab (31%) compared to pembrolizumab (18%, p=0.03), nivolumab (18%, p<0.01) and ipilimumab (15%, p=0.02).

Conclusion: Thyroid irAEs are much more common in real world practice than in clinical trials and there is emerging evidence that certain cancer types incur a higher risk of thyroid irAEs even after adjustment for CPI exposure. Clinicians and patients should be educated about these risks. Future work should focus on exploring the reasons underlying the differing rates of thyroid irAEs among different cancers including effect on cancer outcomes.

1Barroso-Sousa et al. Incidence of Endocrine Dysfunction Following the Use of Different Immune Checkpoint Inhibitor Regimens. JAMA Oncol. 2017; 02215: 1–10.

<![CDATA[MON-478 Impaired Sensitivity to Thyroid Hormone - A Diagnostic and Therapeutic Challenge]]> Background: Impaired sensitivity to thyroid hormone refers to any process that negatively affects its action, including defects in its transport, metabolism and action on the receptor. Resistance to thyroid hormone due to beta-receptor mutations (RTH-beta) is the most common form of this entity and is characterized by reduced response of peripheral tissues to the action of thyroid hormone. The genetic variability of cofactors involved in the action of thyroid hormone explains the heterogeneity of resistance among affected individuals. Generally, patients with this disorder, have increased levels of free T4 and free T3 in association with normal or high TSH. Clinical case: 11-year-old boy, with personal history of Attention-deficit/hyperactivity disorder (ADHD). A pediatric endocrinology consultation was requested to evaluate abnormalities in his thyroid function tests. A few months earlier, his father was referred to endocrinology consultation because of thyroid function tests abnormalities: TSH - 3.01 μIU / mL (N: 0.35 - 4.94); Free T4 1.7 ng / dL (N: 0.7-1.48); Free T3 4.77 pg / mL (N: 1.71-3.71). Initially, two diagnostic hypotheses were considered: central hyperthyroidism or impaired sensitivity to thyroid hormone. The adult underwent pituitary magnetic resonance, which raised the hypothesis of a pituitary microadenoma, and TRH stimulation test, whose result was strongly suggestive of the second diagnostic possibility. A genetic study was requested and the presence of the c700 G> A variant (p. Ala 324 trh) in the THRB gene was identified, which confirmed the most likely hypothesis. At the time of the pediatric endocrinology consultation, the 11-year-old boy had the results of his lab tests: TSH - 6.67 μIU / mL (N: 0.35 - 5); T4L 2.27 ng / dL (N: 0.88-1.58); T3L 7.79 pg / mL (N: 2-4.20). Given his perfect height and weight evolution and the absence of symptoms suggestive of hypo or hyperthyroidism, it was decided not to start any medication, keeping only periodic surveillance. Conclusion: This case exemplifies unusual thyroid function tests. This discordance between serum thyroid hormone and TSH concentrations should raise the possibility of impaired sensitivity to thyroid hormone. In this condition, patients may present with symptoms of hypo or hyperthyroidism and the etiology of thyroid function tests abnormalities are not easily recognized. This can lead to misdiagnosis and consequently unnecessary treatment.

<![CDATA[MON-471 The Broken Heart That Hid Behind the Goiter]]> Most goiters grow slowly over many years and are often asymptomatic. Although substernal goiters are estimated to represent between 5-24% of all mediastinal masses [1], a majority are benign. Symptoms may include neck fullness, nocturnal or positional dyspnea, or dysphagia due to tracheal and/or esophageal compression [2-3]. We present a case of a patient with new onset dyspnea that was initially attributed to a large intrathoracic goiter, but ultimately was found to be due to severe heart failure.

A 72-year-old man with a history of HTN, type 2 diabetes, and moderate aortic regurgitation presented to his primary care physician with exertional dyspnea, dry cough, and bilateral leg edema for 2 months. He was referred to pulmonology and a chest CT showed a large intrathoracic goiter, measuring 8.5 x 4.6 x 5.3 cm, extending from the left limb of the thyroid into the mediastinum with rightward tracheal and leftward aortic arch displacement. The patient had no prior history of thyroid disease, cancer, or neck radiation. He denied neck fullness, dysphagia, positional or nocturnal dyspnea, though his exertional dyspnea was progressive. Labs revealed that the patient was biochemically euthyroid. Due to concern for malignancy, the patient underwent a biopsy via EBUS/bronchoscopy, which was non-diagnostic. The case was ultimately discussed at cardiothoracic tumor board, and it was determined that since the mass had likely been present for several years and with the surgical risks being high, to continue monitoring with serial imaging.

At this point, the patient’s dyspnea and edema continued to worsen, and he was evaluated with an echocardiogram which showed a severe worsening of ejection fraction in just three months, from 53% to 5%, with global hypokinesis. He was started on diuretics and medical therapy with prominent improvement in his dyspnea. His cardiology team felt this acute decompensation was likely due to coronary artery disease and recommended left heart cardiac catheterization, however the patient declined.

Goiters tend to be asymptomatic and grow slowly over time. Given their intra-thoracic location and ability to prominently deviate the mediastinum, it can be tempting to attribute respiratory symptoms to large substernal goiters. However, when a patient develops acute symptoms, one must always rule out alternative diagnoses.


1. Priola AM, Priola SM, Cardinale L, Cataldi A, Fava C. The anterior mediastinum: diseases. Radiol Med. 2006;111(3):312

2. Katlic MR. Wang CA, Grillo HC. Substernal goiter. Ann thorac surg. 1985;39(4):391.

3. Benbakh M, Abou-elfadl M, Rouadi S, Abada RL, Roubal M, Mahtar M. Substernal goiter: experience with 50 cases. Euroepean annals of otorhinolaryngology, head and neck diseases. 2016-02-01, volume 133, issue 1, 19-22.