Abstract Disclosure: M. Mavromati: None. P. Meyer: None. F. Vermeulen: None. M. Demarchi: None. E. Saiji: None. C. De Vito: None. F. Jornayvaz: None. S. Leboulleux: None. A. Wolff: None. F. Triponez: None. Introduction:Benign thyroid nodules may increase in size over time and cause local compressive symptoms. Current guidelines suggest surgery for benign symptomatic nodules, however, complications such as hypothyroidism, bleeding, infection and recurrent laryngeal nerve injury are of concern for a growing number of patients. Minimally invasive techniques may therefore be an alternative to surgical resection. The objective of our study was to evaluate the efficacy and safety of high intensity focused ultrasound (HIFU) ablation in a single-center cohort of benign symptomatic thyroid nodules.Materials and methods:Between February 2021 and May 2022, 13 patients were treated by HIFU for a single benign solid symptomatic thyroid nodule. Benign nature of thyroid nodules was confirmed by a Bethesda II result in fine-needle aspiration, before HIFU. Treatment was performed under hypnosis, carried out by an experienced anesthesiologist. Patients were evaluated by clinical examination and ultrasound at 6 and 12 months after treatment. Results: A total of 13 patients (12 female and 1 male) were treated with HIFU for a single solid symptomatic benign thyroid nodule. Mean age was 57 years (range: 48-67 years). Thyroid nodules had an mean maximum diameter of 48 mm (range: 31-66 mm) and a meanvolume of 28.4 mL (range: 8.5-53 mL). At 12 months after HIFU, 4 patients underwent surgical ablation (31%) because of nodule growth (n=2, 15.4%) or persistent local compression (n=2, 15.4%). Those nodules were benign on final histology. Among non-operated nodules, mean decrease of volume at 6 months was 35% (range: 20-46%) and smaller nodules showed a better response to treatment. Altogether, 8 patients (61.5%) reported a clinical improvement 6 months after treatment, while 4 patients (31%) underwent surgery. Treatment was well tolerated in the majority of patients and had to be stopped because of pain in only one case (7.7%). There were no treatment-related local complications. Conclusion:High-intensity focused ultrasound (HIFU) ablation for benign symptomatic thyroid nodules is a safe minimally invasive technique but volume reduction was only 20-46% at 6 months, while 31% of patients required surgery after all. This could be attributed to the large initial volume of nodules included in our cohort. Clinical hypnosis is a useful alterative for pain management. Presentation Date: Saturday, June 17, 2023

The circadian system plays an essential role in regulating the timing of human metabolism. Indeed, circadian misalignment is strongly associated with high rates of metabolic disorders. The properties of the circadian oscillator can be measured in cells cultured in vitro and these cellular rhythms are highly informative of the physiological circadian rhythm in vivo. We aimed to discover whether molecular properties of the circadian oscillator are altered as a result of type 2 diabetes. We assessed molecular clock properties in dermal fibroblasts established from skin biopsies taken from nine obese and eight non-obese individuals with type 2 diabetes and 11 non-diabetic control individuals. Following in vitro synchronisation, primary fibroblast cultures were subjected to continuous assessment of circadian bioluminescence profiles based on lentiviral luciferase reporters. We observed a significant inverse correlation (ρ = −0.592; p < 0.05) between HbA1c values and circadian period length within cells from the type 2 diabetes group. RNA sequencing analysis conducted on samples from this group revealed that ICAM1, encoding the endothelial adhesion protein, was differentially expressed in fibroblasts from individuals with poorly controlled vs well-controlled type 2 diabetes and its levels correlated with cellular period length. Consistent with this circadian link, the ICAM1 gene also displayed rhythmic binding of the circadian locomotor output cycles kaput (CLOCK) protein that correlated with gene expression. We provide for the first time a potential molecular link between glycaemic control in individuals with type 2 diabetes and circadian clock machinery. This paves the way for further mechanistic understanding of circadian oscillator changes upon type 2 diabetes development in humans. RNA sequencing data and clinical phenotypic data have been deposited at the European Genome-phenome Archive (EGA), which is hosted by the European Bioinformatics Institute (EBI) and the Centre for Genomic Regulation (CRG), ega-box-1210, under accession no. EGAS00001003622.

BACKGROUND:Despite substantial efforts, reliable preoperative diagnostic for human thyroid malignancies in case of cytologically indeterminate nodules is still missing, resulting in high number of unnecessary thyroidectomies. In an attempt to increase precision of existing preoperative diagnostics, we aimed at validating the panel of molecular biomarkers predictive for papillary thyroid carcinoma (PTC) in preoperative fine needle aspirate (FNA) samples.METHODS:In this prospective study conducted in preoperative thyroid FNA from 44 thyroid nodules, expression levels of 11 molecular biomarkers previously validated on the postoperative samples of PTCs were measured by Cell-to-CT and QuantiGene Plex methods and correlated with final diagnosis.RESULTS:The QuantiGene Plex resulted in reliable gene expression measurements for FNA and core-needle biopsy (CNB) samples, however this method was less sensitive than pre-amplification based Cell-to-CT. Measurements conducted on the same samples by the two methods significantly correlated for most of the genes. Expression levels of TIMP1, c-MET and ARNTL were upregulated in PTC nodules as compared to benign counterparts, supporting previous post-operative studies. Strong correlation was observed between these biomarker alterations in the same samples. Within the sub-group of 15 indeterminate nodules (Bethesda II-V), TIMP1 had 100% specificity and 83% sensitivity for PTC cases.CONCLUSIONS:Assessment of TIMP1, c-MET and core-clock gene ARNTL expression levels by QuantiGene Plex assay in FNA samples holds promise as an ancillary method to the cytological preoperative diagnostics.

Background : It was recently proposed that noninvasive follicular variant of papillary thyroid carcinomas (PTCs) should be reclassified as “noninvasive follicular thyroid neoplasm with papillary-like nuclear features” (NIFTP) and treated conservatively. As this is a recent definition, limited data exist about NIFTP. The objective of this study was to report our institutional experience with NIFTP. Materials and Methods : Retrospective study from 2005 to 2015 of all patients with PTCs meeting the histological criteria to be reclassified as NIFTP. We collected information regarding patient demographics, clinical presentation, ultrasound, FNA results, nodule size, multifocality, pathological stage, type and extent of surgery, radioactive iodine treatment, lymph node and systemic metastases, and follow-up. Results : Eighty-six patients (67 women and 19 men, aged 17-83 years (median: 49.5 years)) with NIFTP (median size: 2.5 cm; range: 1.0-5.5 cm) were identified, representing 13.8% of all cases formerly diagnosed as PTC. NIFTP frequently exhibited indeterminate FNA results (71.4%, including suspicious for malignancy (42.9%), follicular neoplasm (20.6%), and AUS/FLUS (7.9%)), while benign (11.3%) and malignant (6.3%) results were less common. Treatment consisted of total thyroidectomy ( n = 42), staged total thyroidectomy ( n = 33) or lobectomy ( n = 11), combined with prophylactic cervical lymph node dissection ( n = 14; all pN0) and post-operative radioactive iodine with 30 mCi ( n = 34) or 100 mCi ( n = 28). All patients were without evidence of disease after a median follow-up of 3.1 years (range 1-11 years). Conclusions : NIFTP represents a significant fraction of cases previously diagnosed histologically as PTC. They were typically diagnosed cytologically as indeterminate and managed like PTCs. None of our patients developed metastases or recurrences. The new NIFTP terminology will have significant impact on the management of patients at our Center.

The search for preoperative biomarkers for thyroid malignancies, in particular for follicular thyroid carcinoma (FTC) diagnostics, is of utmost clinical importance. We thus aimed at screening for potential biomarker candidates for FTC. To evaluate dynamic alterations in molecular patterns as a function of thyroid malignancy progression, a comparative analysis was conducted in clinically distinct subgroups of FTC and poorly differentiated thyroid carcinoma (PDTC) nodules. NanoString analysis of FFPE samples was performed in 22 follicular adenomas, 56 FTC and 25 PDTC nodules, including oncocytic and non-oncocytic subgroups. The expression levels of CHEK1, c-KIT, SLC26A4, TG and TPO were significantly altered in all types of thyroid carcinomas. Based on collective changes of these biomarkers which correlating among each other, a predictive score has been established, allowing for discrimination between benign and FTC samples with high sensitivity and specificity. Additional transcripts related to thyroid function, cell cycle, circadian clock, and apoptosis regulation were altered in the more aggressive oncocytic subgroups only, with expression levels correlating with disease progression. Distinct molecular patterns were observed for oncocytic and non-oncocytic FTCs and PDTCs. A predictive score correlation coefficient based on collective alterations of identified here biomarkers might help to improve the preoperative diagnosis of FTC nodules.

We previously reported an upregulation of the clock transcript BMAL1, correlating with TIMP1 expression in fresh-frozen samples from papillary thyroid carcinoma (PTC). Since frozen postoperative biopsy samples are difficult to obtain, we aimed to validate the application of high-precision NanoString analysis for formalin-fixed paraffin-embedded (FFPE) thyroid nodule samples and to screen for potential biomarkers associated with PTC. No significant differences were detected between fresh-frozen and FFPE samples. NanoString analysis of 51 transcripts in 17 PTC and 17 benign nodule samples obtained from different donors and in 24 pairs of benign and PTC nodules, obtained from the same donor (multinodular goiters), confirmed significant alterations in the levels of BMAL1, c-MET, c-KIT, TIMP1, and other transcripts. Moreover, we identified for the first time alterations in CHEK1 and BCL2 levels in PTC. A predictive score was established for each sample, based on the combined expression levels of BMAL1, CHEK1, c-MET, c-KIT and TIMP1. In combination with BRAF mutation analysis, this predictive score closely correlated with the clinicopathological characteristics of the analyzed thyroid nodules. Our study identified new thyroid transcripts with altered levels in PTC using the NanoString approach. A predictive score correlation coefficient might contribute to improve the preoperative diagnosis of thyroid nodules.

CONTEXT The circadian clock represents the body's molecular time-keeping system. Recent findings revealed strong changes of clock gene expression in various types of human cancers. OBJECTIVE Due to emerging evidence on the connection between the circadian oscillator, cell cycle, and oncogenic transformation, we aimed to characterize the circadian clockwork in human benign and malignant thyroid nodules. DESIGN Clock transcript levels were assessed by quantitative RT-PCR in thyroid tissues. To provide molecular characteristics of human thyroid clockwork, primary thyrocytes established from normal or nodular thyroid tissue biopsies were subjected to in vitro synchronization with subsequent clock gene expression analysis by circadian bioluminescence reporter assay and by quantitative RT-PCR. RESULTS The expression levels of the Bmal1 were up-regulated in tissue samples of follicular thyroid carcinoma (FTC), and in papillary thyroid carcinoma (PTC), as compared with normal thyroid and benign nodules, whereas Cry2 was down-regulated in FTC and PTC. Human thyrocytes derived from normal thyroid tissue exhibited high-amplitude circadian oscillations of Bmal1-luciferase reporter expression and endogenous clock transcripts. Thyrocytes established from FTC and PTC exhibited clock transcript oscillations similar to those of normal thyroid tissue and benign nodules (except for Per2 altered in PTC), whereas cells derived from poorly differentiated thyroid carcinoma exhibited altered circadian oscillations. CONCLUSIONS This is the first study demonstrating a molecular makeup of the human thyroid circadian clock. Characterization of the thyroid clock machinery alterations upon thyroid nodule malignant transformation contributes to understanding the connections between circadian clocks and oncogenic transformation. Moreover, it might help in improving the thyroid nodule preoperative diagnostics.

Ritonavir, commonly used in combination therapy for HIV-infected patients, is an irreversible inhibitor of the cytochrome P450 (CYP) enzyme CYP3A. As most corticosteroids are metabolized by CYP3A, a pharmacokinetic interaction is expected between ritonavir and corticosteroids, and patients may be at higher risk of iatrogenic Cushing syndrome (ICS). We report a case of a 51-year-old man known for C3 HIV, admitted for inpatient workup of a nonpruritic rash that persisted for 3 months. The rash appeared 1 week after two injections of triamcinolone acetonide 40 mg in each elbow, administrated for bilateral epicondylitis. Topical clobetasol and inhaled fluticasone were introduced several weeks later for the rash and new onset dyspnea. HIV-RNA level was suppressed (<50 copies/ml) and CD4+ T-cell count was 114 per μl on a combination of booster-dose ritonavir (100 mg q.i.d.), etravirine (400 mg q.i.d.), didanosine (400 mg q.i.d.) and atazanavir (300 mg q.i.d.). His blood pressure was 119/81 mmHg and oxygen saturation was 98%. Clinical examination showed a purplish rash involving the trunk, back and upper limbs with telangiectasia and fat deposit on the face and upper trunk. Morning cortisol (0 nmol/l) and (9 nmol/l) after injection of 250 μg tetracosactid (Synacthen) suggested hypothalamic-pituitary-adrenal (HPA) axis suppression, although adrenocorticotrophic hormone was not measured. Thyroid-stimulating hormone concentration, electrolytes and renal function were all within normal range. All steroids were stopped and hydrocortisone 15 mg (morning) and 5 mg (noon) was introduced until HPA axis recovery. Six months later, partial HPA axis suppression persisted. An year after the diagnosis, hydrocortisone was discontinued spontaneously by the patient as complete symptoms resolution occurred. Further investigation revealed a pulmonary embolism of the lower right pulmonary artery (chest computed tomography scan) and a popliteal right deep venous thrombosis was visualized by ultrasound, explaining at least part of the dyspnea. No personal or other transient risks for thrombo-embolism were found. Several steroid formulations associated with ICS were consecutively used in our patient [1–3], but triamcinolone injections done a few days before symptoms appeared are the most likely cause of ICS. Ramanathan et al.[4] estimated that elimination half-life of epidural triamcinolone was 170-fold prolonged when co-administrated with ritonavir. Cushing's syndrome, either endogenous or secondary to steroids administration, increases the risk of developing a thromboembolic event, which occurs in 2.5 to 3.1 per 1000 persons-year [5–7]. The pathogenesis is not completely understood but depends on the degree of hypercortisolism and the duration of the disease. A possible underlying mechanism is cortisol-induced upregulation of transcription of various coagulation factors [8]. Apart from this, HIV has also been shown to be related with higher thrombotic risk ranging from 0.19 to 7.63% per year [9]. This is the first report of thrombosis associated with ICS secondary to ritonavir-steroid drug–drug interaction. ICS is important to recognize and may be associated with thrombotic, metabolic, bone and infectious complications. Corticosteroids, even when given in nonoral formulation have the potential for clinically relevant drug-drug interactions with inhibitor of the CYP3A (Table 1) [10], especially in HIV-infected patients receiving ritonavir as part of their combination antiretroviral regimen.Table 1: Drugs with a predominant inhibitor effect on the CYP3A.Acknowledgements Conflicts of interest There are no conflicts of interest. All authors have completed the Unified Competing Interest form and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous 3 years, no other relationships or activities that could appear to have influenced the submitted work.

ABSTRACT Thyroid hot nodules are virtually always considered benign. Rare cases of hot thyroid carcinoma exist. We briefly described a clinical case and performed a review of the literature. We performed an extensive research on medical databases, such as PubMed and compiled all published cases matching preset criteria defining true hot thyroid carcinomas as well as guidelines regarding their management. We analyzed 103 articles published over the past 50 years. We selected 16 articles, including 45 cases matching our criteria. The majority were follicular carcinomas. Papillary carcinomas were infrequently found in this setting. Recommended management and survival rates were similar to classical cold thyroid cancer. Although hot nodules should continue to be considered benign most of the time, rare cases of hot thyroid cancers exist and clinicians should not hesitate to ask for additional tests if they encounter any abnormal finding. This form of thyroid cancer can reasonably be managed the same way as the cold thyroid cancers. How to cite this article Iranmanesh P, Pusztaszeri M, Robert J, Meyer P, Schiltz B, Sadowski SM, Goumaz MO, Triponez F. Thyroid Carcinoma in Hot Nodules: Review of the Literature. World J Endoc Surg 2013;5(2):50-54.

Anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis is a rare complication of antithyroid drug use that was first described with propylthiouracil. We describe an ANCA-associated rapidly progressive glomerulonephritis in a patient treated with carbimazole during 6 months for Graves disease that resulted in end-stage renal disease. A 66-year-old man treated with carbimazole for Graves disease was admitted for macroscopic hematuria and edema of the lower extremities. Laboratory work-up showed elevated serum creatinine (435 mu mol/L), mixed hematuria, nephrotic range proteinuria, and a low positive c-ANCA titer with proteinase-3 specificity. Renal biopsy showed necrotizing, crescentic, pauci-immune glomerulonephritis. Carbimazole was discontinued and hemodialysis was initiated as well as high-dose glucocorticoids and pulses of intravenous cyclophosphamide. Despite immunosuppressive treatment, the patient remained dialysis-dependent at 6 months after diagnosis. Graves disease remained in remission after carbimazole withdrawal. ANCA-associated vasculitis manifesting as glomerulonephritis is a potential adverse effect of all antithyroid drugs. Although prognosis is usually good, end-stage renal disease may ensue in rare cases. Physicians should have a high index of suspicion in patients receiving antithyroid drugs who present with symptoms or signs suggestive of progressive renal disease.

Octreotide has an important role in the medical management of acromegaly. Its place in the management of acromegaly as an adjuvant therapy after neurosurgery is well established with a well-demonstrated efficacy. It can also be used in certain clinical conditions as a neoadjuvant treatment. Clinicians and patients should be aware of the possible side effects of octreotide treatment.

Age related male hypogonadism, or “andropause”, is increasingly recognized as of frequent occurrence in older patients. Diagnosis requires both the presence of clinical symptoms and low testosterone levels. However, diagnosing andropause in this age group may be challenging since symptoms are frequently non specific and testosterone levels are influenced by a multitude of parameters such as lifestyle factors and chronic diseases. In this article we discuss the pathophysiology, definition and diagnostic difficulties of andropause in geriatric patients. Moreover, we review the relation between testosterone levels and frequent geriatric syndromes such as falls, osteoporosis, cognitive and mood disorders, anemia and cardiovascular disease. Finally, we examine the potential benefits and risks of testosterone replacement therapy in this age group.

The prevalence of thyroid cancer is steadily rising and the fortuitous discovery of a thyroid nodule is a frequent situation for the clinician. The clinical importance is the need to exclude thyroid cancer. In this article we present the initial work up and treatment options for differentiated thyroid cancer. Initial diagnosis is done with a dosage of thyroid stimulating hormone and a fine needle aspiration guided by ultrasonography, which permits classification of the lesion and guides the choice of treatment.

Thyroid nodules are very common in the general population and most of them are benign. Fine needle aspiration (FNA) of the thyroid is routinely used because it is a rapid, simple, accurate and cost-effective technique which allows the adequate selection of patients who should be managed surgically. However, the diagnostic yield of FNA is variable and depends of multiple factors including the one who performs FNA, the aspiration and cytological slide preparation techniques, and cytopathologist's experience. On-site evaluation of thyroid FNA material and close clinico-pathological collaboration offer many advantages and optimizes the yield of FNA.

PURPOSE:To evaluate the efficacy and toxicity of stereotactic fractionated radiotherapy (SFRT) for patients with pituitary macroadenoma (PMA).METHODS AND MATERIALS:Between March 2000 and March 2009, 27 patients (male to female ratio, 1.25) with PMA underwent SFRT (median dose, 50.4 Gy). Mean age of the patients was 56.5 years (range, 20.3 - 77.4). In all but one patient, SFRT was administered for salvage treatment after surgical resection (transphenoidal resection in 23, transphenoidal resection followed by craniotomy in 2 and multiple transphenoidal resections in another patient). In 10 (37%) patients, the PMAs were functional (3 ACTH-secreting, 3 prolactinomas, 2 growth hormone-secreting and 2 multiple hormone-secretion). Three (11.1%) and 9 (33.3%) patients had PMA abutting and compressing the optic chiasm, respectively. Mean tumor volume was 2.9 ± 4.6 cm3. Eighteen (66.7%) patients had hypopituitarism prior to SFRT. The mean follow-up period after SFRT was 72.4 ± 37.2 months.RESULTS:Tumor size decreased for 6 (22.2%) patients and remained unchanged for 19 (70.4%) other patients. Two (7.4%) patients had tumor growth inside the prescribed treatment volume. The estimated 5-year tumor growth control was 95.5% after SFRT. Biochemical remission occurred in 3 (30%) patients with functional PMA. Two patients with normal anterior pituitary function before SFRT developed new deficits 25 and 65 months after treatment. The 5-year survival without new anterior pituitary deficit was thus 95.8%. Five patients with visual field defect had improved visual function and 1 patient with no visual defect prior to SFRT, but an optic chiasm abutting tumor, had a decline in visual function. The estimated 5-year vision and pituitary function preservation rates were 93.2% and 95.8%, respectively.CONCLUSIONS:SFRT is a safe and effective treatment for patients with PMA, although longer follow-up is needed to evaluate long-term outcomes. In this study, approximately 1 patient with visual field defect out of two had an improved visual function.

BACKGROUNDThe small cell variant of medullary thyroid carcinoma (SCV-MTC) is a very unusual tumor that carries a poor prognosis. This tumor type closely resembles small cell pulmonary neuroendocrine carcinoma or lymphoma.CASEA 43-year-old woman had a palpable mass on the right side of her neck. A fine needle aspiration biopsy (FNAB) revealed a hypercellular lesion composed mainly of isolated, small, round cells with salt-and-pepper chromatin interspersed with inconspicuous deposits of fluffy acellular material. A diagnosis of "malignant tumor, consistent with small cell carcinoma, metastasis not excluded" was rendered during the on-site rapid cytologic examination. Immunostaining showed a few isolated cells reactive for calcitonin, intense and diffuse immunoreactivity for carcinoembryonic antigen, dotlike positivity for chromogranin and cytokeratin, and negativity for thyroglobulin. Congo-red staining was positive in the acellular deposit, consistent with SCV-MTC. Subsequent total thyroidectomy confirmed this diagnosis.CONCLUSIONThe wide range of cytomorphologic features of MTC can be misleading on FNAB and can be a diagnostic challenge. Congo-red staining and immunoreactivity for calcitonin can be negative in this variant. Consequently, salt-and-pepper chromatin, Congo-red staining and a panel of antibodies comprising calcitonin, carcinoembryonic antigen, chromogranin, cytokeratin, leukocyte common antigen and thyroglobulin are mandatory for the correct diagnosis.

![Figure][1] [![Graphic][3] ][3][![Graphic][4] ][4] A 28-year-old man presented with paroxysmal hypertension (161/114 mm Hg) and tachycardia (131 beats/min). Urinary noradrenaline was 4,892 nmol/24 h (normal <498), and serum chromogranine A was 210 μg/l (normal 19.4 to 98.1 μg/