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In the setting of cancer pathology, molecular characterization of tumors providing diagnostic and predictive information is acquiring more and more relevance. Moreover, the advent of innovative technologies continuously improves the knowledge of the molecular landscape of tumors and strengthens the links between clinics, tumor pathology and molecular features. In the clinical management of patients with thyroid nodules and thyroid tumors, the aid of molecular testing is encouraged but still not strongly recommended by current guidelines. Also for this reason this field of study is attracting much interest. The nCounter system is a relatively new technology based on a direct hybridization of fluorescent probes to specific nucleic acid targets, followed by digital measurement of signals; the reaction is highly multiplexable and results are robust and reproducible. This review reports and discusses the available data related to the application of this specific technique to thyroid nodules and thyroid tumors samples. The available data indicate that nCounter system represents a solid approach for the research of relevant diagnostic and prognostic biomarkers in thyroid pathology.

Background The hepatokine fibroblast growth factor 21 (FGF21) influences eating behavior and sugar consumption in rodent models. However, whether circulating FGF21 concentration is associated with food and soda intake in humans is still unclear. Objective We investigated whether fasting plasma FGF21 concentration is associated with objective measures of ad libitum food intake and soda consumption. Methods Healthy individuals [n = 109; 69 men, aged 34 ± 10 y; BMI (kg/m2): 30.4 ± 7.7; body fat by DXA: 30.5% ± 8.9%] with available plasma for hormonal measurements participated in an inpatient cohort study to objectively quantify ad libitum food and soda intake for 3 d using an automated and reproducible vending machine paradigm. Fasting plasma FGF21 concentration was measured by ELISA prior to ad libitum feeding. Results Fasting FGF21 concentration was inversely associated with daily soda intake (R = -0.22, P = 0.02 adjusted for demographics and anthropometrics), such that an interindividual difference of 200 pg/mL was associated with an average lower soda consumption by 68 kcal/d. Conversely, no associations were observed with total daily energy intake or macronutrient intake (all P > 0.17). Conclusions Higher plasma fasting FGF21 concentration is associated with lower ad libitum soda intake. Although this inverse correlation does not imply causation, the present results support the putative role of FGF21 in the reward pathways regulating sugar consumption in humans. This trial was registered at www.clinicaltrials.gov as NCT00342732.

Background Successful long-term weight loss maintenance after caloric restriction (CR) is rarely achieved. Besides known metabolic, behavioural, and cognitive factors, 24-hour energy expenditure (24hEE) relative to body size (i.e., metabolic efficiency) might influence subsequent weight loss maintenance. Methods Eleven participants with obesity (BMI = 39.0 ± 8.7 kg/m2, body fat = 36.1 ± 6.4%) had 24hEE measured in a whole-room indirect calorimeter during eucaloric conditions and weight stability prior to starting a 6-week inpatient CR study (50% of daily energy needs). Twenty-four-hour energy expenditure was adjusted via regression analysis for fat free mass (FFM) and fat mass (FM) by DXA. Body composition was reassessed at the end of CR and after 1-year follow-up. Free-living weight was assessed by monthly weight measurements during 12 months. Results After 6-week CR, participants lost 8.5 ± 2.7% weight (FFM: -6.3 ± 3.6 kg, FM: -3.4 ± 1.2 kg) but regained 5.1 ± 8.0% 1 year following CR, which was mostly due to FFM regain (+5.7 ± 5.5 kg) and unchanged FM. A relatively higher 24hEE by 100 kcal/day prior to CR was associated with an average greater rate of weight regain by +0.3 kg/month during follow-up and a greater final weight regain by +5.1 kg after 1 year of follow-up. Conclusion These results suggest that reduced metabolic efficiency in 24hEE during eucaloric, sedentary conditions may predict greater weight regain after CR-induced weight loss.

Subjects with obesity may exhibit an increase in serum TSH concentrations. Several mechanisms have been proposed to explain this association, including the presence of a compensatory mechanism to counterbalance an accelerated turnover of thyroid hormones in subjects with obesity. This study aimed at evaluating whether the thyroids of subjects with obesity differs from those of normal-weight individuals regarding histology and gene expression profiling. Ninety-eight patients were selected among those scheduled for thyroidectomy. At histology, thyroid tissue samples were investigated for the presence of adipocytes and/or lymphocyte infiltration. In a subset of patients, the expression at mRNA level of several genes involved in metabolic pathways and immune cell-related mechanisms was quantified by NanoString Technology. The presence of adipose cells was documented in thyroid specimens from 40% normal weight, 52.9% overweight and 73.5% patients with obesity. The number of infiltrating adipocytes was greater in specimens of patients with overweight or obesity compared to normal weight. The lymphocytes common antigen (CD45) and mast cell (MC) scores, and the number of CD3+ and CD8+ lymphocytes were higher in patients with overweight and obesity than in normal-weight subjects. Several genes involved in metabolic pathways were differently expressed in patients with overweight or obesity compared to normal weight, with upregulation of Leptin receptor and downregulation of Fatty Acid-Binding Protein 5. Increased BMI is associated with adipocyte and lymphocyte infiltration of the thyroid, not related to an autoimmune process, which might affect thyroid function in subjects with obesity. A differential gene expression profiling of metabolic and immune pathways in thyroid tissues of patients with obesity was also observed.

Papillary thyroid carcinoma (PTC) presents distinct clinico-pathological and molecular differences in children compared with adult patients. Whether the presence of rearrangements or point mutations is associated with aggressive PTC clinical presentation is still controversial. In this study, PTCs diagnosed in patients aged less than 18 years were retrospectively searched from the institutional archive and tumor tissue was tested for point mutations in BRAF and RAS genes and for rearrangements in RET, NTRK1, NTRK3, ALK, PPARG, BRAF and THADA. A total of 163 PTCs were analyzed. Point mutations were found in 83 (51%) and gene fusions in 48 cases (30%). The most frequent alteration was the BRAFV600E mutation (36.8%), followed by NTRK3 fusion (11%), NRAS mutation (10.4%) and RET fusion (10.4%). Fusion-driven PTCs showed more frequently infiltrative growth, larger tumors, extrathyroidal extension and N1b disease. PTCs showing solid growth pattern were significantly enriched in gene fusions. This is one of the largest cohorts of pediatric PTCs. Fusion-driven tumors most frequently show aggressive pathological features, the search for rearrangements, especially in tumors with solid areas, could improve the characterization of pediatric PTCs and offer possible therapeutic options.

Classification schemes for reporting thyroid cytology of fine needle aspiration (FNA) of thyroid nodules are largely used in clinical practice, but the level of inter-observer agreement among cytopathologists is poorly acknowledged. The present study aimed to explore the inter-observer agreement among the experienced authors of the 2014 Italian Consensus for Classification and Reporting of Thyroid Cytology (ICCRTC). A stratified randomization was performed in order to obtain a sample homogeneously distributed and representative of all ICCRTC classes. Four high-experience raters were randomly selected among the extensors of the Italian consensus. They independently reviewed 60 FNA samples blindly of the initial cytological report and clinical features. Their overall agreement was evaluated according to Fleiss' kappa. The overall inter-observer agreement was moderate (κ 0.46). Specifically, a good agreement was found when the samples were consistent for malignancy (TIR5) or were not adequate for diagnosis (TIR1) (κ 0.67 and κ 0.73, respectively). A moderate agreement was present for suspicious-for-malignant category (TIR4), and a fair agreement was recorded in the two intermediate ones (TIR3A and TIR3B) (κ 0.36 and κ 0.35, respectively). For clinical purposes, the agreement was good (κ 0.74) in differentiating cases with surgical indication (TIR4/TIR5) from those in which surgery is not essential or requires limited extension (TIR3B/TIR3A/TIR2). In conclusion, the present study confirms the reliability of ICCRTC. These data represent a reference for cytopathologists using this system and are useful for the practice of clinicians and surgeons.

To assess the reliability of a simple, accessible, cost-effective rule-out tool, for use in triaging patients with Bethesda IV nodules to appropriate surgery. The diagnostic tool was assembled by combining the negativity for suspicious ultrasound features (irregular margins, microcalcification, and a taller-than-wide orientation), and mutational marker negativity (BRAF and NRAS). The tool, (US−/mutation−), was tested on 167 patients with solitary Bethesda IV nodules. The primary outcome was its negative predictive value (NPV) for lesions requiring total thyroidectomy (TT). The impact of mutational marker negativity, as part of the tool, was evaluated by comparing the NPV of (US−/mutation−) to that of (US−/mutation+). 10 out of 167 lesions were positive for a mutational marker. These underwent TT, and only 2/10 (20%) were benign, on final histology. In 6/8 malignant lesions, TT was concordant with current clinical guidelines. 157 patients comprised the negative study cohort, for both mutational markers and suspicious US features. These underwent thyroid lobectomy, and 17 cases resulted in malignancy, only 8 of which required completion thyroidectomy. Accordingly, the NPV of (US−/mutation−) for malignancy was 89% (140/157), and 95% (149/157) for malignancy requiring TT. However, the NPV of (US−/mutation+) was 20% for malignancy, and 40% for malignancy requiring TT. These differences were statistically significant (89% vs. 20%; p

OBJECTIVE: We aimed to assess the relationship between dopamine, a neurotransmitter involved in feeding behavior, and ad libitum energy intake in humans. METHODS: Healthy individuals (n=158, 72 Native Americans/50 Whites/18 Blacks/18 Hispanics, BMI: 33±9 kg/m(2), body fat: 33±9%) were admitted for two inpatient studies investigating the determinants of ad libitum energy intake assessed for 3 days using a highly reproducible, computerized vending machine paradigm. Urine was collected for 24 hours during eucaloric conditions prior to the ad libitum feeding period and urinary dopamine excretion rate was quantified by high-performance liquid chromatography. RESULTS: Urinary dopamine excretion rate was on average 346±106 mcg/24h and positively correlated with BMI (r=0.28, p0.3). CONCLUSIONS: Higher urinary dopamine concentrations are associated with greater ad libitum energy intake, indicating a role for dopamine in the reward pathway regulating human feeding behavior.

The extent to which mononuclear cells and TSH-receptor autoantibodies (TRAb) contribute to Graves’ orbitopathy (GO) is not completely defined. Here we investigated the relationship between the immunohistochemical phenotype of orbital infiltrating cells and GO features in a large number of patients. We conducted an observational cohort study in 76 consecutive patients with GO (16 men and 60 women) who underwent orbital decompression over a period of 18 consecutive months. An ophthalmological evaluation was performed in all patients, as well as immunohistochemistry for CD3, CD4, CD8, CD56 (T-cell markers), CD25 (T and B-cell marker), CD20, CD19 (B-cell markers), and CD138 (plasmacell marker) in specimens collected at decompressive surgery. Having established cutoff values for each marker, cell infiltrates were found in 60 patients (78.9%; CD3: 39.4%, CD4 55.2%, CD8 50%, CD56: 0%, CD25: 28.9%, CD20: 51.3%, CD19: 25%, CD138: 26.3%). Eleven (14.4%) stained exclusively for CD138 (plasmacells). Patients with CD4-positive mononuclear cells had a significantly greater GO clinical activity score (CAS) (mean difference 1.07, 95% CI − 0.33 to − 1.82, P = 0.004 by univariate, P = 0.05 by multivariate analysis). CAS as well as the remaining GO features were not affected significantly by the mononuclear cell subpopulations in multivariate analyses. Mononuclear cell infiltrates are present in the majority of GO patients, with a small percentage represented exclusively by plasmacells. CD4 cells exert a major role on GO activity. These findings may represent a further advancement in the comprehension of GO pathogenesis.

Contains fulltext : 238976.pdf (Publisher’s version ) (Open Access) On January 2020, the WHO Director General declared that the outbreak constitutes a Public Health Emergency of International Concern. The world has faced a worldwide spread crisis and is still dealing with it. The present paper represents a white paper concerning the tough lessons we have learned from the COVID-19 pandemic. Thus, an international and heterogenous multidisciplinary panel of very differentiated people would like to share global experiences and lessons with all interested and especially those responsible for future healthcare decision making. With the present paper, international and heterogenous multidisciplinary panel of very differentiated people would like to share global experiences and lessons with all interested and especially those responsible for future healthcare decision making.

Purpose The SARS-CoV-2 genome has been detected in a variety of human samples including blood, urine, semen, and faeces. However, evidence of virus presence in tissues other than lung are limited. Methods We investigated whether SARS-CoV-2 could be detected in 50 autoptic specimens of endocrine organs from 29 patients who died of COVID-19. Results The virus was detected in 25 specimens including ten abdominal subcutaneous adipose tissue samples (62%), six testes (67%), and nine thyroid (36%) samples. The analysis of multiple endocrine organ samples obtained from the same patients showed that, in virus-positive cases, the viral genome was consistently detected in all but two matched specimens. Conclusion Our findings show that the virus spread into endocrine organs is a common event in severe cases. Further studies should assess the rate of the phenomenon in clinically mild cases. The potential long-term effects of COVID-19 on endocrine functions should be taken into consideration.

Background Thyroid dysfunctions have been reported after SARS-CoV-2 infection. However, the biological mechanisms behind these conditions remain unexplored. Herein, we report on changes of the immune transcriptome in autoptic thyroid tissues of people who have died from COVID-19. Methods Twenty-five autoptic thyroid specimens of subjects dying from COVID-19 were investigated. Eleven autoptic thyroid specimens of subjects dying from causes other than infectious conditions served as controls. RNA transcripts of 770 immune-related genes together with RNA genomes of multiple coronavirus types were measured by the nCounter system. RT-PCR for two SARS-CoV-2 genes was used to assess virus positivity. Results were validated by immunohistochemistry. Results The SARS-CoV-2 genome and antigens were detected in nine out of 25 (36%) thyroid specimens from the COVID-19 cohort. Virus-negative thyroid tissues from COVID-19 subject did not show changes of gene transcription nor significant numbers of infiltrating immune cells. Conversely, SARS-CoV-2-positive thyroid specimens showed marked up-regulation of immune genes, especially those proper of the type I and type II interferon (IFN) pathways. In infected tissues, infiltrates of innate immune cells (macrophages and polymorphonuclear neutrophils) were prevalent. Conclusions The thyroid gland can be directly infected by the SARS-CoV-2. Infection strongly activates IFN pathways. The direct viral insult combined with an intense immune response may trigger or worsen thyroid conditions in predisposed individuals.

Multiple Endocrine Neoplasia 2 (MEN2) is a hereditary cancer syndrome for developing medullary thyroid cancer (MTC) due to germline mutations of RET gene. Subjects harboring a germline RET mutation without any clinical signs of MTC are defined as gene carriers (GCs), for whom guidelines propose a prophylactic thyroid surgery. We evaluate if active surveillance of GCs, pursuing early thyroid surgery, can be safely proposed and if it allows safely delaying thyroid surgery in children until adolescence/adulthood. We prospectively followed 189 GCs with moderate or high risk germline RET mutation. Surgery was planned in case of: elevated basal calcitonin (bCT) and/or stimulated CT (sCT), surgery preference of subjects (or parents, if subject less than 18 years old), other reasons for thyroid surgery. Accordingly, at RET screening, we sub-grouped GCs in subjects who promptly were submitted to thyroid surgery (Group A, n = 67) and who were not (Group B, n = 122). Group B was further sub-grouped in subjects who were submitted to surgery during their active surveillance (Group B1, n = 22) and who are still in follow-up (Group B2, n = 100). Group A subjects presented significantly more advanced age, bCT and sCT compared to Group B. Mutation RETV804M was the most common variant in both groups but it was significantly less frequent in Group A than B. Analyzing age, bCT, sCT and genetic landscape, Group B1 subjects differed from Group B2 only for sCT at last evaluation. Group A subjects presented more frequently MTC foci than Group B1. Moreover, Group A MTCs presented more aggressive features (size, T and N) than Group B1. Accordingly, at the end of follow-up, all Group B1 subjects presented clinical remission, while 6 and 12 Group A MTC patients had structural and biochemical persistent disease, respectively. Thank to active surveillance, only 13/63 subjects younger than 18 years at RET screening have been operated on during childhood and/or adolescence. In Group B1, three patients, while actively surveilled, had the possibility to reach the age of 18 (or older) and two patients the age of 15, before being submitted to thyroid surgery. In Group B2, 12 patients become older than 18 years and 17 older than 15 years. In conclusion, we demonstrated that an active surveillance pursuing an early thyroid surgery could be safely recommended in GCs. This patient-centered approach permits postponing thyroid surgery in children until their adolescence/adulthood. At the same time, we confirmed that genetic screening allows finding hidden MTC cases that otherwise would be diagnosed much later.

Objectives This study is aimed to report a case of SV-related gastritis and the results of a systematic review of SV infections in the literature. Methods Following a case presentation, we systematically searched different databases (MEDLINE, PubMed, Scopus, Web of Science, EMBASE) for the items “sarcina,” “ventriculi,” “clostridium” with AND/OR. Results A total of 55 articles reporting 65 cases of Sarcina Ventriculi were found. Thus, 66 patients, including our case, were reviewed. Median age was 51 years (IQR: 0-87 years). Females accounted for 51% of cases. 68% of patients had one or more comorbidities. SV was isolated in the gastrointestinal tract (88%), respiratory (5%), urine (4%), and bloodstream (3%) systems. Upper endoscopy was performed in 52 patients (79%). Biopsies were obtained in all 52 cases, and resulted normal in 23%. Surgery was warranted in 15 patients (23%), and specific antimicrobial therapy was delivered in 34 (52%) patients. Mortality was 14%. At follow-up, 88% of patients showed complete eradication of the SV infection. Conclusions Upper gastrointestinal biopsy positive for SV should prompt an evaluation of the clinical conditions, being the risk of gastric perforation not negligible. Antibiotic therapy may eradicate the infection and prevent complications. Emergency surgery is required in case of source control.

Introduction: Serum thyrotropin (TSH) receptor antibodies (TRAbs) are occasionally found in patients with amiodarone-induced thyrotoxicosis (AIT), and usually point to a diagnosis of type 1 AIT (AI...

Context The dramatic rise in the incidence of thyroid cancer over the last 30 years is largely attributable to the increasing diagnosis of papillary microcarcinomas (mPTCs). Current guidelines endorse an observational management approach in properly selected cases. Objective To evaluate the feasibility of active surveillance in mPTC in Italy, its impact on real life, and to identify risk factors of progression. Design and setting In 2014 we started a prospective–observational study of active surveillance in mPTC patients. Patients Included patients demonstrated a single Thy4 or Thy5 thyroid nodule, with largest diameter ≤1.3 cm, and no suspicious laterocervical lymph nodes by neck ultrasonography. Of 185 eligible subjects, 50.3% (93/185) enrolled in the observational management protocol while the others opted for surgery and were excluded from this analysis. Intervention Enrolled patients were followed with neck ultrasound at 6- to 12-month intervals. Disease progression was defined as the appearance of abnormal lymph nodes or nodule enlargement during follow-up. In these cases, patients were directed to surgery. Results Three patients (3/93, 3%) showed clinical progression and required surgery. Another 19 patients (19/93, 20%) decided to transition to surgical intervention even though there was no evidence of disease progression. All operated patients had excellent response to initial treatment despite the delayed surgery. Conclusions Within an Italian medical context, active surveillance appears to be a feasible and safe alternative to immediate surgery in healthy mPTC patients. Only 3% of mPTC demonstrated disease progression during a median follow-up of 19 months (range 6–54) and importantly demonstrated excellent outcomes after surgical intervention in a short-term follow-up.

Background: A greater decrease in 24-hour energy expenditure (EE) during fasting and a smaller increase in 24-hour EE during low-protein overfeeding (metabolic “thrifty” phenotype) predict weight gain. As thyroid hormones (TH) are implicated in energy intake and metabolism, we assessed whether: (i) TH concentrations are altered by 24-hour fasting or overfeeding diets with varying protein content and (ii) diet-related changes in TH correlate with concomitant changes in EE. Methods: Fifty-eight euthyroid healthy subjects with normal glucose regulation underwent 24-hour dietary interventions including fasting, eucaloric feeding, and five overfeeding diets in a crossover design within a whole-room indirect calorimeter to measure the 24-hour EE. Overfeeding diets (200% of energy requirements) included three diets with 20% protein, one diet with 3% protein (low-protein overfeeding diet [LPF]: 46% fat), and one diet with 30% protein (high-protein overfeeding diet [HPF]: 44% fat, n = 51). Plasma free thyroxine (fT4), free triiodothyronine (fT3), and fibroblast growth factor 21 (FGF21) concentrations were measured after overnight fast the morning of and after each diet. Results: On average, fT4 increased by 8% (+0.10 ng/dL, 95% confidence interval [CI 0.07–0.13], p 0.1). No associations were observed between TH concentrations and diet-related changes in 24-hour EE during any diet (all p > 0.07). Conclusions: Acute (200%) short-term (24 hours) changes in food intake induce small changes in TH concentrations only after diets with low (0% fasting and 3% protein overfeeding) or high (30% protein overfeeding) protein content. The fT3-FGF21 association after high-protein overfeeding suggests a role for TH in inhibiting FGF21 secretion by the liver during protein excess. These results indicate that TH are involved in protein metabolism; however, they do not mediate the short-term EE response to diets that characterize the metabolic phenotypes and determine the individual susceptibility to weight gain.

Background/Objective Evidence from non-human species indicate that hydration and arginine vasopressin (AVP) influence fuel selection, energy expenditure (EE), and food intake, but these relationships are unclear in humans. We sought to assess whether hydration biomarkers [24-h urine volume (UVol) and urine urea nitrogen concentration (UUN)] and copeptin (a surrogate for AVP) are associated with 24-h EE, respiratory quotient (RQ), and daily energy intake (DEI). Subjects/Methods In a secondary analysis of collected data, we selected healthy adults (Group 1, n = 177) who had 24-h whole-room indirect calorimetry measurements in energy balance with 24-h urine collection and fasting copeptin measurements (n=117), followed by 3 days ad libitum food intake. A separate group (Group 2, n=284) with hydration markers and calorimetry measurements was also studied. The main outcome measures were 24-h RQ, 24-h EE, DEI, substrate oxidation. Results In Group 1, lower 24-h UVol and higher 24-h UUN, indicating lower hydration, were correlated with lower 24-h RQ (r = 0.35, p

Context Recent diagnostic criteria updates of the tall cell variant of papillary thyroid carcinoma (TCPTC) by the World Health Organization (WHO) have determined the inclusion of tumors with 30% to 49% of tall cells. However, the impact of tall cell percentage on papillary thyroid carcinoma (PTC) patients’ prognosis is still debated. Objective We aimed to evaluate whether tall cell percentage affects patient outcome in the absence of aggressive features. Methods Rates of aggressive features, recurrence-free survival (RFS), and distant RFS (5-year median follow-up) were compared among tumors with less than 30%, 30% to 49% and at least 50% tall cells. We also evaluated the impact of the new tall cell cutoff on patient management. Results Overall, 3092 tumors (15.7% of all PTCs) were collected: A total of 792 PTCs had less than 30%, 503 had 30% to 49%, and 1797 had 50% or more tall cell areas. With the new WHO definition, the number of TCPTCs increased by 28%. There were no differences in recurrence rates according to tall cell percentage. The coexistence of BRAF and TERT promoter mutations predicted a worse RFS. Considering the new definition of TCPTC, the level of risk according to the American Thyroid Association increased from low to intermediate in 4.2% of cases. However, the recurrence rate within this subgroup was comparable to low risk. Conclusion TCPTC and PTC with tall cell areas can be considered as a unique group with similar recurrence risk. However, whenever aggressive features are absent, tumors have a low risk of recurrence independently of tall cell percentage.

Sporadic medullary thyroid carcinoma (MTC) is a rare malignancy with a heterogeneous clinical course. Several potential prognostic factors have been investigated, but the impact of some of these is controversial, such as age at diagnosis. We evaluated the data of 432 sporadic MTC patients followed-up for a median of 7.4 years. Patients were divided and compared according to their age at diagnosis in group A (&lt, 65 years&mdash, n = 338, 78.2%) and group B (&ge, n = 94, 21.8%). No differences were detected between the two groups. Median follow-up time was significantly longer in patients &lt, 65 than &ge, 65 years. We observed 41 (9.5%) cancer-related death events. The death rate was similar between the two age groups. However, the Kaplan Meier curve showed a longer survival time for younger patients compared to older patients [HR 2.5 (CI 95%: 1.27&ndash, 4.94), p &lt, 0.01]. Nevertheless, no differences in the aggressiveness of the disease at presentation and in the number and type of treatments performed were found in the two subgroups of dead patients. In patients with sporadic MTC, age at diagnosis did not correlate with any clinical and pathological features. Cancer-related death events are similar in older and younger patients, but survival time is longer in the younger.

Context Tumor capsule integrity is becoming a relevant issue to predict the biological behavior of human tumors, including thyroid cancer. Objective This work aims to verify whether a whole tumor capsule in the classical variant of papillary thyroid carcinoma (CVPTC) could have as a predictive role of a good outcome as for follicular variant (FVPTC). Methods FVPTC (n = 600) and CVPTC (n = 554) cases were analyzed. We distinguished between encapsulated-FVPTC (E-FVPTC) and encapsulated-CVPTC (E-CVPTC) and, thereafter, invasive (Ei-FVPTC and Ei-CVPTC) and noninvasive (En-FVPTC and En-CVPTC) tumors, according to the invasion or integrity of the tumor capsule, respectively. Cases without a tumor capsule were indicated as invasive-FVPTC (I-FVPTC) and invasive-CVPTC (I-CVPTC). The subgroup of each variant was evaluated for BRAF mutations. Results E-FVPTC was more frequent than E-CVPTC (P Conclusion En-CVPTC is less prevalent than En-FVPTC. However, it has good clinical/ pathological behavior comparable to En-FVPTC. This finding confirms the good prognostic role of a whole tumor capsule in CVPTC as well. New nomenclature for En-CVPTC, similar to that introduced for En-FVPTC (ie, noninvasive follicular thyroid neoplasm with papillary-like nuclear features; NIFTP) could be envisaged.

A statistically significant higher prevalence of the RET p.Met918Thr somatic mutation, identified by direct sequencing, was previously reported in MTC > 2 cm than in smaller tumors. Aim of this study was to correlate the full RET and RAS mutation profile, identified by a Next Generation Sequencing approach, with the growth rate, proliferation and tumor size of MTC. Data of 149 sporadic MTC patients were correlated with RET mutations and Ki67 positivity. Eighty-one cases had a somatic RET mutation, 40 had a RAS mutation and 28 were negative. A statistically significant higher prevalence of RET mutations was found in MTC > 2 cm. A higher prevalence of RET more aggressive mutations, higher allelic frequencies and, higher percentage of Ki67 positive cells were found in larger tumors which had also a worse outcome. Our study highlights the predominant role of RET somatic mutations in MTC tumorigenesis. We demonstrate that RET mutation prevalence and allelic frequency (AF) are significantly higher in larger tumors. Based on these results, we can conclude that RET mutated C-cells’s growth and proliferation are more rapid than those of non-mutated cells and give origin to bigger and more aggressive MTC.

Background: Dopamine, a key neurotransmitter in the autonomic nervous system participating in the homeostatic balance between sympathetic and parasympathetic divisions, is involved in food intake regulation. Objective: We investigated whether dopamine is altered by acute fasting or overfeeding diets with varying macronutrient content. Design: Ninety-nine healthy subjects underwent 24-h dietary interventions including eucaloric feeding, fasting, and five different overfeeding diets in a crossover design. Overfeeding diets (200% of eucaloric requirements) included one diet with 3%-protein (low-protein high-fat overfeeding—LPF: 46%-fat), three diets with 20%-protein, and a diet with 30%-protein (44%-fat). Urine was collected for 24 h and urinary dopamine concentration was quantified by high-performance liquid chromatography. Plasma pancreatic polypeptide (PP) concentration, an indirect marker of parasympathetic activity, was measured prior to and after each diet after an overnight fast. Results: During 24-h of fasting, dopamine decreased on average by ~14% compared to eucaloric conditions, whereas PP increased by two-fold (both p &lt, 0.001). Lower dopamine during 24-h fasting correlated with increased PP (r = −0.40, p &lt, 0.001). Similarly, on average urinary dopamine decreased during LPF by 14% (p &lt, 0.001) and lower dopamine correlated with increased PP (r = −0.31, p = 0.01). No changes in dopamine and PP concentrations were observed during other overfeeding diets (all p &gt, 0.05). Conclusions: Dopamine concentrations decrease during short-term fasting and overfeeding with a low-protein diet. As both dietary conditions have in common protein deficit, the correlation between dopamine and PP suggests a compensatory mechanism underlying the shift from sympathetic to parasympathetic drive during dietary protein deprivation.

ContextAtypical parathyroid adenomas (APAs) are neoplasms with uncertain malignant potential but lack unequivocal histological signs of malignancy.ObjectiveThis work aims to retrospectively evaluate the clinical and biochemical profiles of patients with APA, the outcome after parathyroidectomy (PTX), and the presence of CDC73 germline and somatic mutations.MethodsThis monocentric study was conducted on consecutive patients undergoing PTX for primary hyperparathyroidism (PHPT) between June 2000 and December 2020. Fifty-eight patients with a confirmed histopathological diagnosis of APA, and age- and sex-matched controls with parathyroid adenoma (PA) were also included.ResultsFifty-four patients had sporadic PHPT and 4 had familial isolated hyperparathyroidism (FIHP). Thirty-four patients (59%) had symptomatic disease. Serum calcium and parathyroid hormone (PTH) levels were significantly higher in symptomatic compared to asymptomatic patients (P = .048 and .008, respectively). FIHP patients were younger than their sporadic counterparts (30 ± 17 years vs 55 ± 13 years). APA patients had significantly higher serum calcium and PTH levels and lower 25-hydroxyvitamin D concentration, bone mineral density, and T score at one-third distal radius compared to those with PA. Four of 56 APA patients displayed a CDC73 germline mutation. No somatic CDC73 mutation was identified in 24 tumor specimens. The mean follow-up after surgery was 60 ± 56.4 months. All but 6 patients (90%), 5 with apparently sporadic PHPT and 1 with FIHP, were cured after surgery.ConclusionThe large majority of patients with APA, despite a moderate/severe phenotype, have a good prognosis. Germline CDC73 mutation–positive patients had a higher rate of persistent/recurrent disease. CDC73 gene alterations do not seem to have a relevant role in the tumorigenesis of sporadic APA.

Background We recently demonstrated that thrifty subjects, characterized by a greater decrease in 24 h energy expenditure (24hEE) during short-term fasting, have less capacity for cold-induced thermogenesis (CIT) during 24 h of mild cold exposure. Objective As cold-induced brown adipose tissue activation (CIBA) is a determinant of CIT, we sought to investigate whether thrifty individuals also have reduced CIBA. Methods Twenty-four healthy subjects (age: 29.8 ± 9.5y, body fat: 27.3 ± 12.4%, 63% male) were admitted to our clinical research unit and underwent two 24hEE assessments in a whole-room indirect calorimeter during energy balance and fasting conditions at thermoneutrality to quantify their degree of thriftiness. Positron emission tomography/computed tomography scans were performed after exposure to 16 °C for 2 h to quantify peak CIBA. Results A greater decrease in 24hEE during fasting was associated with lower peak CIBA (r = 0.50, p = 0.01), such that a 100 kcal/day greater reduction in 24hEE related to an average 3.2 g/mL lower peak CIBA. Conclusion Our results indicate that reduced CIBA is a metabolic trait of the thrifty phenotype which might explain reduced CIT capacity and greater predisposition towards weight gain in individuals with a thrifty metabolism.

Background. Multiple endocrine neoplasia type 2 (MEN2) is a hereditary cancer syndrome caused by RET proto-oncogene mutation. Two different clinical variants of MEN2 are known (MEN2A and MEN2B): medullary thyroid carcinoma (MTC) almost always present and associated with pheochromocytoma (Pheo), and primary hyperparathyroidism (HPTH) in MEN2A and with Pheo and other nonendocrine diseases in MEN2B. Case Report. A 7-year-old girl, previously treated for a pelvic plexiform neurofibroma, arrived at our observation with a peculiar MEN2B syndrome and with HPTH. The neck ultrasound showed bilateral thyroid nodules, local lymph node lesions, and a suspicious left hyperplastic parathyroid. The CT scan showed a megacolon and described the persistence of the pelvic tumor. A new RET germline deletion in exon 11 (c.1892_1899delCGAGCT; p.Glu632_Leu633del) was found. She underwent total thyroidectomy, central compartment and latero-cervical lymph node dissection, and neck exploration for primary HPTH. The histology confirmed bilateral MTC, multiple lymph node metastases, a hyperplastic parathyroid, and a parathyroid adenoma. Conclusions. This is the first case of a complex syndrome characterized by peculiar features of MEN2B, without Pheo but with a pelvic plexiform neurofibroma and with HPTH, which is typical of MEN2A. A “de novo” new germline RET deletion located in exon 11 was found.

Background: Our previous retrospective study demonstrated that the absence of tumor capsule or, if present, its invasion were independent risk factors for the persistence of the disease (OR 6.75, CI 1.97-23.08 and OR 7.89, CI 1.78-34.94, respectively) in papillary thyroid cancer (PTC). This data was confirmed also analyzing separately the most frequent PTC variants [follicular variant (FVPTC) and classical variant (CVPTC)]. Moreover, we demonstrated that the absence of tumor capsule was significantly more frequent in FVPTC BRAF V600E mutated than FVPTC wild-type for BRAF gene or with rare-BRAF mutations (e.g., BRAF K601E, BRAF V600_K601delinsE). These data confirmed the importance of the integrity of the tumor capsule in FVPTC which led in 2016 to the definition of a new thyroid neoplasm entity named NIFTP. According to these retrospective data, we have assumed that the integrity of the tumor capsule in CVPTC could have a prognostic role similar to that confirmed in the NIFTP group. Methods: we have prospectively collected data of patients (pts) underwent total thyroidectomy or lobectomy for encapsulated-CVPTC (E-CVPTC) or NIFTP. In both cases the tumor was accurately analyzed by the pathologists according to the criteria used for the NIFTP (in particular with one capsule sample every 1 mm). All pts performed at least one clinical control and neck US within 6 months from surgery. Results: From January 2018 to June 2019, 144 E-CVPTC and 177 NIFTP were prospectively collected. 83/144 (57.6%) E-CVPTC and 106/177 (59.8%) NIFTP cases were included. The others were excluded due to the presence of other thyroid tumors associated in the same gland. No differences in epidemiological and pathological features were found between E-CVPTC and NIFTP except for the tumor size, significantly bigger in NIFTP than E-CVPTC [22±16mm (2-68) vs 8±11mm (1-80), p Conclusions: These prospective data demonstrated that NIFTP and E-CVPTC have a similar clinical behavior in a short-term follow-up, thus suggesting that the presence of an intact tumor capsule is predictive of a good outcome. A longer follow up is needed to confirm these initial interesting findings.

Background Adaptive thermogenesis during prolonged energy deficit refers to the greater than expected reduction in energy expenditure (EE) independent of concomitant loss of metabolically active body mass. Objective As inter-individual variability in the magnitude of adaptive thermogenesis may influence the extent of energy deficit thereby predicting the amount of weight reduction, we investigated whether early adaptive thermogenesis is a determinant of weight loss after 6 weeks of daily 50% caloric restriction in an inpatient setting. Design and methods The current study reports the results of an exploratory, secondary analysis in overweight but otherwise healthy subjects (n = 11, 7 men, 35 ± 9y, BMI = 40 ± 7 kg/m2, body fat = 63.3 ± 5.3%). Body composition and 24-h EE (24hEE) measurement in a whole-room indirect calorimeter were used to calculate the magnitude of adaptive thermogenesis while on caloric restriction after 1, 3 and 6 weeks. Energy deficit during caloric restriction was quantified via food, stool, and urine bomb calorimetry. Fasting hormonal concentrations (FT4, FT3, FGF21, leptin) were obtained at baseline and at weeks 3 and 6 during caloric restriction. Results The magnitude of adaptive thermogenesis in 24hEE after 1 week of caloric restriction was −178 ± 137 kcal/day (mean ± SD), was overall stable during and following caloric restriction, and demonstrated remarkable intra-individual consistency. A relatively greater decrease in 24hEE of 100 kcal/d after 1 week of caloric restriction was associated on average with reduced energy deficit by 8195 kcal over 6 weeks and predicted 2.0 kg less weight loss, of which 0.5 kg was fat mass, after 6 weeks. No correlations were found between hormonal concentrations and weight loss. Conclusions The extent of weight loss is influenced by the magnitude of adaptive thermogenesis in the early stage of caloric restriction. Although these results need replication in larger study groups with adequate statistical power, targeting adaptive thermogenesis may help to optimize long-term interventions in obesity therapy.

Background Peritoneal carcinomatosis (PC) is a common manifestation of many gastrointestinal (GI) malignancies and is an advanced stage that is often associated with disseminated disease. Considerable progress has been made to achieve safe elimination of macroscopic disease using cytoreductive surgery (CRS) and more recently in combination with hyperthermic intraperitoneal chemotherapy (HIPEC) for the treatment of microscopic disease or disease with minimal volume. The aim of this study was to assess the effects of such procedures on the quality of life (QoL), the long-term benefit and the functional status of the treated patients. Patients and methods Data from patients who underwent CRS-HIPEC for peritoneal metastasis (PM) at our center from November 2016 to November 2018 were analyzed retrospectively. The drugs administered were mitomycin and cisplatin. Quality of life (QoL) was assessed using the Euroquol-5D-5L and National Comprehensive Cancer Network Functional Assessment of Cancer Therapy-Breast Cancer Symptom Index v2 questionnaires before CRS-HIPEC, and 1, 3 and 6 months after were administered. Results In our series, the survival efficacy of CRS plus HIPEC was confirmed in the treatment of primary and secondary peritoneal pathologies, particularly in ovarian cancer, although larger studies are needed to investigate its role in the pathology of gastric, colonic and rectal cancer. The QoL data were promising, with essentially stable values between the preoperative and the 1-month follow-up, but with incremental benefits from the second to the third month.

A greater decrease in 24-h energy expenditure (24 EE) during 24-h fasting defines a “thriftier” metabolic phenotype prone to weight gain during overfeeding and resistant to weight loss during caloric restriction. As the thermogenic response to mild cold exposure (COLD) may similarly characterize this human phenotype identified by acute fasting conditions, we analyzed changes in 24 EE and sleeping metabolic rate (SLEEP) in a whole-room indirect calorimeter during 24-h fasting at thermoneutrality (24°C) and during energy balance both at thermoneutrality (24°C) and mild cold (19°C) in 20 healthy volunteers (80% male; aged 36.6 ± 11.4 years; percentage body fat 34.8 ± 10.5%). Greater decrease in 24 EE during fasting (thriftier phenotype) was associated with less increase in 24 EE during COLD (i.e., less cold-induced thermogenesis). Greater decreases in plasma fibroblast growth factor 21 (FGF21) after 24-h fasting and after COLD were highly correlated and associated with greater decreases in SLEEP in both conditions. We conclude that the metabolic responses to short-term fasting and COLD are associated with and mediated by the liver-derived hormone FGF21. Thus, the 24 EE response to COLD further identifies the “thrifty” versus “spendthrift” phenotype, providing an additional setting to investigate the physiological mechanisms underlying the human metabolic phenotype and characterizing the individual susceptibility to weight change.

To compare the epidemiological, clinical, and pathological features of follicular (FVPTC) and classical (CVPTC) variants of papillary thyroid cancer and to correlate their outcomes according to different features. Retrospective analysis of FVPTC and CVPTC patients selected at the moment of surgical treatment from 1999 to 2004, with a median follow-up of 15 years. Several significant differences were found between FVPTC and CVPTC such as the mean age at diagnosis, the presence of tumor capsule, the presence of thyroid capsule invasion, the presence of perithyroid soft tissue invasion, the lymph node metastases, the multifocality and bilaterality. At the end of follow-up only 9% (77/879) patients were not cured. However, a statistically significant lower percentage of persistent disease was found in the FVPTC than in the CVPTC group (3% vs. 14.5%, respectively, p

Since its first official definition in 2016, the new histo-pathological entity of noninvasive follicular neoplasm with papillary-like nuclear features (NIFTP) has attracted much interest among “thyroidologists” worldwide. This is a subset of encapsulated and noninvasive follicular variant papillary thyroid cancer, whose introduction had the intent of de-escalating treatment given its very low malignant potential, approaching to that of follicular adenomas. Many researchers focused on the possibility of preoperatively identifying NIFTP, and investigated their cyto-morphological and molecular characteristics; other ones explored histological and clinical-pathological NIFTP features. Although the majority of published studies confirmed that NIFTP are indolent lesions, some papers did question their low-risk nature. In this brief review, the main aspects of histology, cytology and molecular pathology of NIFTP are discussed based on the current literature.

OBJECTIVE With the upsurge in interest in the gut microbiome, complete and accurate measurement of ingested calories and calories lost through excreted stool is crucial for assessing the effect of the microbiota on nutrient absorption. METHODS Measurement of ingested and excreted calories was conducted over 3 days. Meals were made in duplicate: one was given to the participant, and one was used for the measurement of calories. Stool was marked by nonabsorbable dye ingested prior to and at the end of each 3-day diet period and was collected for caloric assessment from the appearance of the first dye marker until the appearance of the second dye marker. RESULTS Stool calories per gram for pellets were 4.91 ± 0.06 kcal/g. The mean stool calorie loss as a percentage of ingested calories was 7.3% ± 1.6% (range, 6.6%-8.5%). The stool measurement of kilocalories per gram was not associated with the total measured stool calories or with stool weight (P = 0.2 and P = 0.2, respectively) over the 3-day period. However, the weight of stool samples during each dietary intervention was positively associated with the calorie loss in stool (r = 0.58, P

OBJECTIVE The relationship between adipocyte size and ad libitum energy intake has not been previously examined. This study hypothesized an inverse relationship between adipocyte size and daily energy intake (DEI). METHODS Seventy healthy adults (39 men and 31 women; BMI 30.0 [SD 6.3]) underwent dual-energy x-ray absorptiometry and subcutaneous fat biopsies from the abdomen and thigh. Osmium-fixed adipocytes were sized with a Coulter counter. Volunteers self-selected food from a vending machine paradigm as the only source of energy intake over 3 days as inpatients. Volunteers also had 24-hour respiratory quotient (RQ) measured in a whole-room indirect calorimeter. RESULTS In women, the large cell peak diameter of the thigh depot was greater than that of the abdominal depot (Δ = +15.8 μm; P

Background Obesity is a risk factor for several cancers, including differentiated thyroid cancer (DTC). Moreover, it has also been investigated as a potential risk factor for aggressiveness of DTC, but the data gathered so far are conflicting. The aim of our study was to evaluate the relationship between body mass index (BMI), aggressiveness of DTC at diagnosis, and clinical outcome. Methods We evaluated 1058 consecutive DTC patients treated with total thyroidectomy and enrolled at the time of first radioactive iodine (131I) treatment. Patients were divided into 4 groups based on their BMI: underweight (< 18.5 kg/m2), normal weight (18.5-24.9 kg/m2), overweight (25-29.9 kg/m2), and obese (≥ 30 kg/m2). Histological aggressiveness of DTC at the time of diagnosis and clinical outcome according to 2015 American Thyroid Association (ATA) guidelines were evaluated. Results No differences in histological features, ATA risk of recurrence, activity of 131I administered and prevalence of 131I avid metastatic disease after first131I treatment, have been demonstrated among the groups. Furthermore, at the end of follow up (median = 5.7 years), no differences were evident in the number of further treatments performed as well as in the clinical response. Conclusions In our study group of Caucasian subjects, we could not demonstrate any association between BMI and aggressiveness of DTC, neither at the time of diagnosis nor during follow-up. These data indicate that postsurgical assessment and therapeutic attitude for treatment and follow-up of DTC should be based on the class of risk applied to the general population, with no concern for BMI.

Author(s): Sanders, BF; Schubert, JE; Goodrich, KA; Houston, D; Feldman, DL; Basolo, V; Luke, A; Boudreau, D; Karlin, B; Cheung, W; Contreras, S; Reyes, A; Eguiarte, A; Serrano, K; Allaire, M; Moftakhari, H; AghaKouchak, A; Matthew, RA | Abstract: ©2019. The Authors. Existing needs to manage flood risk in the United States are underserved by available flood hazard information. This contributes to an alarming escalation of flood impacts amounting to hundreds of billions of dollars per year and countless disrupted lives and affected communities. Making information about flood hazards useful for the range of decisions that dictate the consequences of flooding poses many challenges. Here, we describe collaborative flood modeling, whereby researchers and end-users at two coastal sites co-develop fine-resolution flood hazard models and maps responsive to decision-making needs. We find, first of all, that resident perception and awareness of flooding are enhanced more by fine-resolution depth contour maps than Federal Emergency Management Agency (FEMA) flood hazard classification maps and that viewing fine-resolution depth contour maps helps to minimize differences in flood perception across subgroups within the community, generating a shared understanding. We also find that collaborative flood modeling supports the engagement of a wide range of end-users in contemplating the risks of flooding and provides strong evidence that the co-produced knowledge can be readily adopted and applied for Flood Risk Management (FRM). Overall, collaborative flood modeling advances FRM by providing multiple points of entry for diverse groups of end-users to contemplate the spatial extent, intensity, timing, chance, and consequences of flooding, thus enabling the web of decision-making related to flooding to be better informed with the best available science. This transdisciplinary approach emphasizes vulnerability reduction and is complementary to FEMA Flood Insurance Rate Maps used for flood insurance administration.

Objective: In intermediate risk (IR) differentiated thyroid cancer (DTC) patients, selective use of radioiodine (131-I) for remnant ablation and/or as adjuvant therapy (RRA) is advocated. The recently suggested postoperative evaluation could delay the use of RRA. The aim of this study was to evaluate if a delayed RRA can worsen the clinical outcome of IR-DTC patients. Methods: Four hundred and fourteen consecutive IR-DTC patients were divided according to the time elapsed from surgery to RRA

Prophylactic central compartment lymph node dissection (pCCND) results in a higher percentage of surgical-related complications. To date, no evidence of the impact of pCCND on the clinical outcome of papillary thyroid carcinoma (PTC) patients with synchronous ipsilateral cervical lymph node metastases has been reported.We evaluated all consecutive patients affected by PTC and synchronous ipsilateral cervical, but without evidence of central compartment, lymph node metastases. We selected 54 consecutive patients (group A) treated by total thyroidectomy, ipsilateral cervical lymph node dissection, and pCCND and 115 patients (group B) matched for sex, age at diagnosis, number and dimension of the metastatic lateral cervical lymph nodes, without pCCND. Clinical outcome after a median of 5 years and surgical-related complications were assessed.The two groups were completely similar in terms of clinical features. Clinical outcomes showed a higher percentage of biochemical and indeterminate but not structural response in group B. Group B required significantly more radioiodine treatments, but no difference was shown in the need to repeat surgery for recurrences. Conversely, the prevalence of permanent hypoparathyroidism was significantly higher in group A (14.8%) than in group B (4.3%).In PTC patients with synchronous ipsilateral cervical lymph node metastases, in absence of clinically evident lymph node metastases of the central compartment, performing pCCND does not improve the 5-year outcome in terms of structural disease, despite a greater number ofIQR = interquartile range; pCCND = prophylactic central compartment lymph node dissection; PTC = papillary thyroid carcinoma; Tg = thyroglobulin; US = ultrasound.

Simple Summary Thyroid tumors that derive from follicular cells are not a homogeneous entity, showing variable morphological appearance and different degrees of differentiation. Molecular markers are useful for both diagnostic purposes and prognostic stratification of patients. In presurgical setting, molecular testing of indeterminate thyroid nodules on aspirates provides useful diagnostic information; the molecular analysis on tumor tissues can also reveal the presence of genetic alterations related to patients’ prognosis. In recent years, the molecular characterization of these tumors has acquired even more importance thanks to the introduction of targeted drugs. This review summarizes the current literature on the molecular landscape of follicular-derived thyroid tumors. Abstract Thyroid cancer is the most common type of endocrine-related malignancy, whose incidence rates have increased dramatically in the last few decades. Neoplasms of follicular origin generally have excellent prognosis, with the exception of less differentiated tumors. Follicular-derived thyroid cancer can manifest as a variety of morphologically distinct entities, characterized by various degrees of differentiation and invasiveness. Histological evaluation is thus crucial for the definition of patients’ prognosis. However, within each histological subtype, tumor behavior can be highly variable, and, in this respect, molecular characterization can provide insightful information to refine the risk stratification of tumors. In addition to the importance of its prognostic role, molecular testing can be used to support the differential diagnosis of thyroid nodules in the absence of marked cyto-morphological aberrations. Finally, with the advent of targeted drugs, the presence of molecular alterations will guide the therapeutic strategies for patients with advanced tumors who do not respond to standard treatment. This review aims to describe the genetic landscape of follicular-derived thyroid tumors also highlighting differences across histological subtypes.

Several molecular tests have been developed for thyroid cytology with the main purpose to define the nature of indeterminate nodules in presurgical phase thus overcoming the limitations of cytological analysis. Molecular tests currently available for thyroid nodules are based on a variety of methodologies and display peculiar strengths and limitations: in this review of the literature they are summarized and critically discussed. The use of molecular diagnostics for thyroid cytology is increasingly widespread and accepted, however large, prospective validation studies are still needed to ultimately demonstrate the clinical efficacy of a wide incorporation of molecular tests into clinical practice.

Background: Thyroglobulin (Tg) antibodies (TgAb) can interfere with Tg measurement and can be used as “Tg surrogate” in patients with differentiated thyroid cancer (DTC) treated with total thyroide...

The disruption of the Hippo pathway occurs in many cancer types and is associated with cancer progression. Herein, we investigated the impact of 32 Hippo genes on overall survival (OS) of cancer patients, by both analysing data from The Cancer Genome Atlas (TCGA) and reviewing the related literature. mRNA and protein expression data of all solid tumors except pure sarcomas were downloaded from TCGA database. Thirty-two Hippo genes were considered; for each gene, patients were dichotomized based on median expression value. Survival analyses were performed to identify independent predictors, taking into account the main clinical-pathological features affecting OS. Finally, independent predictors were correlated with YAP1 oncoprotein expression. At least one of the Hippo genes is an independent prognostic factor in 12 out of 13 considered tumor datasets. mRNA levels of the independent predictors coherently correlate with YAP1 in glioma, kidney renal clear cell, head and neck, and bladder cancer. Moreover, literature data revealed the association between YAP1 levels and OS in gastric, colorectal, hepatocellular, pancreatic, and lung cancer. Herein, we identified cancers in which Hippo pathway affects OS; these cancers should be candidates for YAP1 inhibitors development and testing.

Fine-needle aspiration (FNA) cytology is a mainstay in the evaluation of thyroid nodules, but fails to reach reliable results in 25–30% of cases. The role of molecular markers in helping clinical decisions has been investigated for the last years, but their clinical usefulness is still unsettled. Mutation analysis of BRAF, RAS genes and TERT promoter was performed in a series of 617 consecutive cytological specimens undergoing FNA. The 617 nodules had the following cytological diagnosis: non diagnostic 22 (3.6%), benign 425 (68.9%), indeterminate 114 (18.5%), suspicious 11 (1.8%) and malignant 45 (7.3%). BRAF mutations were found in 31 cases (5.0%), all but two in suspicious and malignant nodules. RAS mutations were detected in 47 samples (7.6%): 25 benign (5.9%) and 19 indeterminate nodules (16.7%). TERT promoter mutation alone was detected in three samples. Histological outcome was available for 167 nodules, 81 of which proved malignant: all the 48 with suspicious or malignant cytology; 25 out of 56 (44.6%) with indeterminate and 8 out of 57 (14%) with benign cytology. BRAF mutations were associated with worse tumors pathological features. The presence of RAS mutations was indicative of follicular-patterned malignancies in 5 out of 8 benign nodules and 9 out of 11 indeterminate nodules. Our study established mutational rates for BRAF and RAS genes in a large series of FNA specimens. BRAF mutations were confirmed as highly specific but not able to improve cytological diagnosis, while RAS testing proved effective in assessing malignancy in nodules with indeterminate and benign cytology.

// Cristina Romei 1 , Raffaele Ciampi 1 , Francesca Casella 1 , Alessia Tacito 1 , Liborio Torregrossa 2 , Clara Ugolini 2 , Fulvio Basolo 2 , Gabriele Materazzi 2 , Paolo Vitti 1 and Rossella Elisei 1 1 Endocrine Unit, Department of Clinical and Experimental Medicine, University Hospital of Pisa, Pisa, Italy 2 Department of Surgical, Medical and Molecular Pathology, University Hospital of Pisa, Pisa, Italy Correspondence to: Rossella Elisei, email: rossella.elisei@med.unipi.it Keywords: medullary thyroid carcinoma; RET; genetic instability; tumor clonality Received: August 09, 2017 Accepted: November 16, 2017 Published: January 04, 2018 ABSTRACT Purpose : Medullary Thyroid Cancer (MTC) whose pathogenesis is strictly related to RET proto-oncogene alterations, has been shown to have a heterogenic RET mutation profile in subpopulations of MTC. The aim of our study was to investigate the RET somatic mutation profile in primary MTC and in the corresponding metastatic tissues in a series of advanced metastatic cases. Results : This study demonstrated that in about 20% of cases a different RET mutation profile can be found when comparing primary tumor and its corresponding metastases. Furthermore in 8% of tumors, RET intratumor heterogeneity was observed We also showed that in some cases an imbalance of RET copy number was present. We confirmed a high prevalence (90%) of RET somatic mutations in advanced tumors. Materials and Methods : Fifty-six MTC patients (50 somatic and 6 hereditary cases) have been included in the study and a total of 209 specimens have been analysed by direct sequencing. Multiplex ligation-dependent probe amplification (MLPA) has been used to investigate amplification/deletion of RET alleles. Conclusions : In conclusion, this study showed a genetic intra- and intertumor heterogeneity in MTC, But in only 20% of CASES These results could justify the relatively moderate level of aggressiveness of the disease with respect to more aggressive human tumors that are characterized by a high rate of mutation and heterogeneity.

Purpose The human thrifty phenotype hypothesis presupposes that lower 24-hour (24h) energy expenditure (24EE) during famine preserves body mass and promotes survival. The prevailing view defines thrifty individuals as having a lower 24EE during fasting. However, it is also plausible that the greater decline in 24EE during fasting in thrifty individuals is due to higher 24EE during energy balance conditions (ENBAL). Herein, we provide evidence that this is indeed the case. Methods In 108 healthy subjects, 24EE was measured in a whole-room indirect calorimeter both during ENBAL and 24h fasting conditions. Subjects were categorized as thrifty or spendthrift based on the median value (−162 kcal/day) of the difference in 24EE (adjusted for body composition) between fasting and ENBAL conditions. Concomitant 24h urinary catecholamines were assessed by liquid chromatography–mass spectrometry. Results Compared to ENBAL, 24EE decreased during 24h fasting by 172 kcal/day (standard deviation = 93; range, −470 to 122). A greater-than-median decrease in 24EE (“thriftier” phenotype) was due to higher 24EE during ENBAL (+124 kcal/day; P < 0.0001) but not to lower 24EE during fasting (P = 0.35). Greater fasting-induced increase in epinephrine was associated with concomitant lower decrease in 24EE (r = 0.27; P = 0.006). Main Conclusion The greater decrease in 24EE during acute fasting (which characterizes the thrifty phenotype) is not due to reduced metabolic rate during fasting but to a relatively higher 24EE during feeding conditions, and this decrease in 24EE during fasting is accompanied by a smaller increase in epinephrine. These results recharacterize the prevailing view of the short-term 24EE responses that define the human metabolic phenotypes. Clinical Trials: NCT00523627, NCT00687115, NCT02939404

Herein we report an unusual case of sudden death occurring in a 65 year old woman during a minor oral surgery. The subject, who had a medically treated anxiety, had a history of two reversible left ventricle dysfunction episodes consistent with recurrent Takotsubo Syndrome that had occurred seven and six years before, respectively. She also suffered from moderate, well treated post-menopausal systemic hypertension. Post-mortem examination showed apical biventricular ballooning of the heart with no cardiac rupture, coronary artery lesion or other cardiac/extra-cardiac disease. Toxicological tests and forensic investigations excluded unnatural causes of death, including pharmacological or iatrogenic causes related to medical malpractice. Only non-specific contraction bands and mild hypertrophy were observed by histology in the left ventricle myocytes. Takotsubo syndrome is usually an acute and reversible heart failure syndrome with acute left ventricle apex ballooning, no coronary artery disease or other macroscopic or microscopic cardiac changes; physical or emotional stress are well known triggering factors. Nevertheless, recurrent forms, major cardiac adverse events and even sudden death may occur in a minority of cases, meaning that a diagnosis of Takotsubo syndrome must be considered in cases of sudden death and in forensic investigations.