Identification of potential diagnostic and prognostic biomarkers for papillary thyroid microcarcinoma (PTMC) based on TMT-labeled LC-MS/MS and machine learning.

OBJECTIVES: To explore the molecular mechanisms underlying aggressive progression of papillary thyroid microcarcinoma and identify potential biomarkers. METHODS: Samples were collected and sequenced using tandem mass tag-labeled liquid chromatography-tandem mass spectrometry. Differentially expressed proteins (DEPs) were identified and further analyzed using Mfuzz and protein-protein interaction analysis (PPI). Parallel reaction monitoring (PRM) and immunohistochemistry (IHC) were performed to validate the DEPs. RESULTS: Five thousand, two hundred and three DEPs were identified and quantified from the tumor/normal comparison group or the N1/N0 comparison group. Mfuzz analysis showed that clusters of DEPs were enriched according to progressive status, followed by normal tissue, tumors without lymphatic metastases, and tumors with lymphatic metastases. Analysis of PPI revealed that DEPs interacted with and were enriched in the following metabolic pathways: apoptosis, tricarboxylic acid cycle, PI3K-Akt pathway, cholesterol metabolism, pyruvate metabolism, and thyroid hormone synthesis. In addition, 18 of the 20 target proteins were successfully validated with PRM and IHC in another 20 paired validation samples. Based on machine learning, the five proteins that showed the best performance in discriminating between tumor and normal nodules were PDLIM4, ANXA1, PKM, NPC2, and LMNA. FN1 performed well in discriminating between patients with lymph node metastases (N1) and N0 with an AUC of 0.690. Finally, five validated DEPs showed a potential prognostic role after examining The Cancer Genome Atlas database: FN1, IDH2, VDAC1, FABP4, and TG. Accordingly, a nomogram was constructed whose concordance index was 0.685 (confidence interval: 0.645-0.726). CONCLUSIONS: PDLIM4, ANXA1, PKM, NPC2, LMNA, and FN1 are potential diagnostic biomarkers. The five-protein nomogram could be a prognostic biomarker.

Goiter in a Fresco by Giovanni Luigi Valesio (1611, Church of Saints Eusebio and Vittore, Peglio, Como).

In the Fresco, "Faith and Its Fight Against Heresy (1611, Church of Saints Eusebio and Vittore, Peglio, Como)" is depicted as an old woman with 'scattered and steep hairs', ugly and physically in poor condition, also due to the presence of a voluminous goiter.

Goiter in a fresco by simone peterzano, master of caravaggio (1578-1582, Garegnano Charterhouse, Milan).

Simone Peterzano mostly known as the master of Caravaggio executed frescoes in the presbytery of Garegnano Charterhouse. One fresco details a shepherd with a goiter.

Goiter in a fresco by i Fiammenghini, 1615 (Abbey of Santa Maria di Rovegnano, Chiaravalle, Italy).

In a large fresco, which narrates brutal episodes of torture against Cirtercian monks, in the right corner of the background an ugly aggressor with a huge goiter, symbol of evil and sin, attacks a monk with a sword.

Thyroid surgery during coronavirus-19 pandemic phases I, II and III: lessons learned in China, South Korea, Iran and Italy.

OBJECTIVE: We compared demographic and clinic-pathological variables related to the number of surgeries for thyroid conditions or for cancer, morbidity, and fine needle aspiration (FNA) practices among Covid19 pandemic phases I, II, III and the same seasonal periods in 2019. METHODS: The prospective database of the Division of Thyroid Surgery, China-Japan Union Hospital of Jilin University, Changchun, China was used for this study. Covid19 emergency levels were stratified according to the World Health Organization: phase I (January 25-February 25, 2020), phase II (February 26-March 19), phase III (March 20-April 20). RESULTS: There were fewer outpatient FNAs and surgeries in 2020 than in 2019. There were no thyroid surgeries during phase I. There were also fewer surgeries for cancer with a significant reduction of advanced stage cancer treatments, mainly stage T1b N1a in phase II and T3bN1b in phase III. Operative times and postoperative stays were significantly shorter during the pandemic compared to our institutional baseline. In phase III, vocal cord paralysis (VCP) increased to 4.3% of our baseline numbers (P = 0.001). There were no cases of Covid19-related complications during the perioperative period. No patients required re-admission to the hospital. CONCLUSION: The Covid19 outbreak reduced thyroid surgery patient volumes. The decrease of Covid19 emergency plans contributed to unexpected outcomes (reduction of early stage cancer treatment, decreased operative times and hospital stays, increased VCP rate).

Goiter drawing in Ulrich Boner's Der Edelstein Codices Palatini Germanici 794.

We provide an example of representation of thyroid swelling in the artwork of Ulrich Boner's Der Edelstein Codices Palatini Germanici 794.

Will the shepherd be able to play the alpine horn with that huge goiter (XVI century)?

PURPOSE: There are many of the representations in iconography of individuals with goiters reported in the literature. METHODS: The article describe a unique representation of goiter, as observed by the authors in a sculpture in Italy. RESULTS: In a Nativity, in the upper part of the altar of the Church of the Annunciata, Boccioleto (Val Sermenza, Piedmont, Italy), a horn player with a huge goiter, gladdens the Holy Family. Wooden work by Francesco Antonio d'Alberto, 1694. CONCLUSION: This is an appropriate example of the iconography of "real goiter," since in this case the sculptor had the aim of showing person with goiter.

Influence of body mass index on the clinicopathological features of 13,995 papillary thyroid tumors.

PURPOSE: This retrospective study aimed to assess the association between obesity, gender, and specific clinicopathological features in patients with papillary thyroid cancer (PTC) and whether diagnostic ultrasonography (US) is adversely affected by obesity in these patients. MATERIALS AND METHODS: This study retrospectively analyzed 13,995 adult patients with PTC from a single medical center in China. Data stratification was performed to assess the association of obesity with US features and aggressive clinicopathological features in different models according to the World Health Organization Body Mass Index (WHO-BMI) and Chinese BMI classification (CN-BMI). The odds ratio (OR) of malignant US features and aggressive clinicopathological features was calculated from binary logistic regression models. RESULTS: The BMI, obesity ratio, malignant US features, and aggressive pathological characteristics of males were significantly higher than those of females. After adjusting for confounding factors, the association of obesity with malignant US features and aggressive pathological characteristics was found to be sex-dependent. Next, obesity (WHO-BMI) was found to have an "interfering effect" on the US assessment of PTC (OR = 0.754, 95% CI 0.609-0.932, P = 0.009) in women. Among both sexes, obesity (WHO-BMI) increased the risk of tumor size (ORmale = 1.539 and ORfemale = 1.521) and multifocality (ORmale = 1.659 and ORfemale = 1.449). However, obesity did not increase the risk of capsular invasion or tumor staging in males. The above results are consistent with the CN-BMI. In addition, age was found to have an "interfering effect" on the US evaluation of malignant nodules in both sexes. CONCLUSION: The results of our study confirm that higher BMI is significantly associated with aggressive clinicopathological features of PTC. Gender differences were present with obesity ratios and aggressive clinicopathological features being significantly higher in men.

Experimental study of needle recording electrodes placed on the thyroid cartilage for neuromonitoring during thyroid surgery.

BACKGROUND: Needle electrodes placed on the thyroid cartilage (TC) are an alternative to endotracheal tube (ET) electrodes for assessing recurrent laryngeal nerve (RLN) function during thyroid surgery. Needle electrodes placed on the TC were evaluated in an experimental porcine model. METHODS: Continuous intraoperative neuromonitoring was used to record the electromyogram. Each TC side was delineated into nine areas to determine the optimal placement of the electrode, and needle electrode area, depth and orientation for optimal electromyographic (EMG) amplitudes were evaluated. RLN root locations were stimulated at four locations: vagus nerve distal to the neuromonitoring electrode, and most proximal, middle and laryngeal entry points of the nerve. A nerve retraction injury model was adapted to compare RLN monitoring by TC versus ET electrodes. RESULTS: An optimal site for placement of needle electrodes was identified, and electromyograms obtained from the various needle insertion depths and orientations were similar. Latencies recorded from the TC and ET electrodes were similar. The amplitude profile of TC electrodes responded earlier to RLN injury than that of ET electrodes. Amplitude and drop to loss of signal were also registered earlier. CONCLUSION: EMG amplitudes obtained using TC electrodes were higher, and identified RLN injury earlier than ET electrodes. Surgical relevance Needle electrodes placed on the thyroid cartilage (TC) are an alternative to endotracheal tube (ET) electrodes for assessing the function of the recurrent laryngeal nerve (RLN) in thyroid surgery. This study used an experimental porcine model to evaluate the use of needle electrodes inserted in the TC, compared with ET electrodes, for producing an electromyographic (EMG) profile of the RLN. Nine areas of the TC, with various needle insertion depths and orientations, were compared. Perichondral insertion into the avascular area of the TC was found to be safe. The EMG amplitude and latency features recorded via the TC and ET electrodes were compared, using both intermittent and continuous monitoring. Changes in EMG amplitudes in response to nerve traction injury were registered earlier with TC electrodes than with ET electrodes, and the amplitudes were higher and more stable. Latencies obtained via the TC and ET electrodes were similar. These results indicate that the development of a non-invasive monitoring electrode with improved function, easy placement and low cost is possible.

Classifying pain in transoral endoscopic thyroidectomy.

PURPOSES: Knowledge of visual analog scale (VAS) pain assessment for transoral endoscopic thyroidectomy vestibular approach (TOETVA) is limited. The purpose of this analysis was to classify the postoperative discomfort scores in patients undergoing TOETVA compared to open thyroidectomy. METHODS: Observational clinical study of patients who underwent thyroidectomy by VAS pain assessment from September 2016 to March 2017. Patients were stratified into two groups: patients eligible for TOETVA (Group TOETVA) and non-candidates for endoscopic intervention (open thyroidectomy approach-OTA). VAS was recorded in the recovery room, at 24 h, + 2, + 5, + 15, + 30, + 90 days, and 6 months after surgery. Pain assessment was stratified in VAS-lower lip, VAS-chin, VAS-jaw, VAS-anterior neck, VAS-cervical/back, VAS-swallowing, VAS-brushing, VAS-speaking, and VAS-shaving. Secondary outcome assessed were analgesic rescue dose, morbidity, operative notes, hospital stay, and histopathology. RESULTS: 41 TOETVA and 45 OTA constituted the analysis. There were differences between the TOETVA and OTA for age, gland volume, mean nodule diameter, coexistence thyroiditis, bilateral procedures, and use of drain. Operative time was longer in TOETVA. Results indicated that TOETVA was associated with reduced neck, cervical back, and swallowing VAS scores in the 24 h after surgery. Conversely, jaw and brushing teeth resulted in higher VAS score in TOETVA group. OTA patients never experienced lower lip or chin pain. The use of rescue analgesics did not differ between the two groups. CONCLUSIONS: VAS was used to measure treatment outcome in TOETVA. VAS scores achieved overall a minimal clinical importance difference from the two procedures. There appears to be both a short- and long-term different range of interpretations of pain between TOETVA and OTA.

Transoral thyroidectomy: advantages and limitations.

In this opinion paper of the Journal of Endocrinological Investigation, leading experts in the field report on their current clinical experience with a novel approach for thyroid gland surgery, namely, "transoral thyroidectomy" (TOT). This feasible and novel surgical procedure does not require visible incisions and is, therefore, a truly scarless surgery. Patients meeting the following criteria can be considered as candidates for TOT: (a) an ultrasonographically (US) estimated thyroid diameter ≤10 cm; (b) US-estimated gland volume ≤45 mL; (c) nodule size ≤50 mm; (d) presence of a benign tumor such as a thyroid cyst or a single- or multi-nodular goiter; (e) Bethesda 3 and/or 4 category and (f) papillary microcarcinoma without the evidence of metastasis. The procedure is conducted via a three-port technique at the oral vestibule using a 10-mm port for the 30° endoscope and two additional 5-mm ports for the dissecting and coagulating instruments. TOT is performed using conventional endoscopic instruments and is probably the best scarless approach to the thyroid because of the short distance between the thyroid and the incisions placed intra-orally that do not result in any cutaneous scar and upon following the surgical planes. Experts in TOT organized a working group of general, endocrine, head and neck ENT surgeons and endocrinologist to develop the standards for practicing this emerging technique.

Endpoints for screening thyroid cancer in the Republic of Korea: thyroid specialists' perspectives.

Cancer screening is aimed primarily at reducing deaths from the specific cancer. Thyroid-specific cancer mortality may be the most ambitious endpoint for obtaining estimates of screening effect. Numerous observations have accumulated over the years, indicating that thyroid cancer mortality endpoint has been difficult to study and is confounded by population heterogeneity, provision of randomization, and requirement of large cohorts with sufficiently long follow-up due to the excellent prognosis of the cancer. Accordingly, it may be important to reconsider how to best measure thyroid cancer screening efficacy. Recommendations against thyroid cancer screening should be based upon trials designed to evaluate its effectiveness not only in significant reduction in cancer mortality, but also of other distinct endpoints. It is desirable to evaluate derivative endpoints that can reliably predict reductions in mortality. The term "derivative" means a variable that is related to the true endpoint and is likely to be observable before the primary endpoint. Derivative endpoints may include thyroid cancer incidence, the proportion of early-stage tumors detected, more treatable stage, the identification of small tumors (to maintain in observation), decrease in the number of people who develop metastatic disease, the increased chance of lesser extent surgery, and the application of minimally invasive approaches, as well as no need for lifelong thyroid replacement therapy, a consistent follow-up, low-dose or no RAI administration and risk factor assessments where case findings should be continuous. The Korean guidelines for thyroid cancer national-level screening were published by a relevant group of multidisciplinary thyroid experts. It was concluded that the evidence is insufficient to balance the benefits and harms of thyroid cancer screening. However, the paper seems to raise the necessary investments in future research and demand a complete analysis for derivative endpoints, and offer screening participants with complete information necessary to make decisions that will provide them with the most value when a small thyroid cancer is screen-identified.

Breast cancer and thyroid diseases: analysis of 867 consecutive cases.

INTRODUCTION: The aim of this study was to evaluate the association of breast cancer with thyroid diseases. Many authors have already studied the possible relationship between these two diseases, but the results are nowadays conflicting. MATERIALS AND METHODS: Our study examining 867 patients with breast cancer (862 women and 5 men, average age = 61 years old) of whom 141 also had thyroid disease evaluated the recurrence of thyroid diseases and their association with different types of breast cancer. Statistical analyses were performed using SPSS software for Windows; we used nonparametric tests (Chi-square and Mann-Whitney), and the level of significance was set at p < 0.05. RESULTS: We found a significant association between breast cancer diagnosed after menopause and thyroid disease (p < 0.003). Moreover, we analyzed the role of thyroid autoimmunity identifying an association between chronic autoimmune thyroiditis and breast cancer diagnosed before menopause (p < 0.05). Regarding receptor profile of breast carcinoma, we have found an increased expression of estrogen receptors in patients with autoimmune thyroiditis compared to patients with any other thyroid diseases (p < 0.03). Contrariwise, we do not have found any difference between the group with every thyroid disease and the group without thyroid disease (p < 1.00). We did not find other statistically significant associations with breast cancer's parameters like family history, tumor size, lymph node metastasis, distant metastasis, cancer clinical and pathological stage, differentiation grade and expression of Ki67, p53 and Her2 in the two main groups with or without thyroid disease. Likewise, we did not found other statistically significant association between hypothyroidism or hyperthyroidism and breast cancer.

Harlequin syndrome after thyroidectomy for compressive retrosternal goiter. Case report and review of the literature.

A 74-year-old woman with known euthyroid multinodular retrosternal goiter necessitated an urgent intubation at home, due to acute respiratory distress evoked by tracheal compression. Extubation after a few days failed, and she underwent an urgent total thyroidectomy. During postoperative extubation the patient developed suddenly unilateral facial flushing and sweating at the left side, without ptosis of the left levator palpebrae superioris. These symptoms persisted during the next 24 hours. The skin at the right side of the face remained uninvolved. In the early postoperative period this appearance recurred at moments of emotions, exercise or heat. Beside this, the patient had a normal recovery. Six weeks later this reaction couldn't be provoked anymore. 'Harlequin' syndrome (unilateral facial flushing and sweating) is caused by a lesion of the controlateral sympathetic chain at the levels T2 and T3. It is unknown if the sweating and vasodilation at the "healthy" side is normal or if it is a reaction of hyperactivity.

Increased detection of non-recurrent inferior laryngeal nerve (NRLN) during thyroid surgery using systematic intraoperative neuromonitoring (IONM).

BACKGROUND: Non-recurrent inferior laryngeal nerve (NRLN) is a rare anatomical variant with a reported incidence of 0.6-1.3 %. It carries a higher risk of palsy during thyroid surgery. Its detection is mandatory in order to avoid such complication. METHODS: Systematic intraoperative neuromonitoring (IONM) was carried out for 806 consecutive nerve at risk (NAR) patients in two centers (Lille and Varese). In 402 patients surgery to the right side was performed with IONM. The IONM of the inferior laryngeal nerve (ILN) was conducted as recommended by international guidelines (V1/R1/V2/R2). RESULTS: A NRLN was detected in 11 of 402 NAR (2.7 %). In the first center (Lille) the incidence of NRLN was 6.0 % (7/117). No loss of signal (LOS) was reported in this group of patients. Postoperative laryngoscopy was normal in all patients with NRLN. CONCLUSIONS: The true incidence of NRLN may be higher than expected. Neurophysiology helps the surgeon to better understand the anatomy and function of nervous structures. Intraoperative neuromonitoring is a useful tool that should be systematically implemented in thyroid surgery to better understand the anatomy and physiology of the inferior laryngeal nerve. Its use may allow the surgeon to decrease the incidence of nerve palsy especially in case of NRLN. The IONM adjunct does not add significantly to the costs for thyroid surgery.