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Background: The CUT score is a thyroid nodule scoring system that has become recently available as a smartphone application. It has been created on the basis of a clinical (C) and ultrasonographic ...

AimsSeveral papers have shown that programmed death-ligand 1 (PD-L1) expression is a relevant predictive biomarker in anti-PD-L1 cancer immunotherapy. While its role in several human cancers is correlated with poor prognosis and resistance to anticancer therapies, in thyroid cancers the role of PD-L1 remains questionable. Few articles have studied PD-L1 in thyroid fine-needle aspiration cytology (FNAC), demonstrating a possible correlation with papillary thyroid carcinoma. However, its role in oncocytic thyroid lesions remains controversial. We accordingly examine the performance of PD-L1 immunostaining in liquid based cytology (LBC) from oncocytic lesions.MethodsFrom January 2019 to March 2021, 114 thyroid lesions diagnosed by FNAC from lesions with a predominant oncocytic component, were enrolled for evaluation by PD-L1 immunostaining on both LBC and corresponding histology samples.ResultsThe FNAC cohort included 51 benign (B, negative controls), 4 atypia of undetermined significance/follicular lesions of undetermined significance (AUS/FLUS), 57 follicular lesions (follicular neoplasm/suspicious for FN, FN/SFN) and 2 suspicious for malignancy (SFM) cases. Fifty-four cases (11B, 2 AUS/FLUS, 39 FN/SFN and 2 SFM) had histological follow-up including: 1B case resulted as a hyperplastic oxyphilic nodule in Hashimoto thyroiditis (HT), 10B as goitre, 2 AUS/FLUS cases as oncocytic adenomas (OAs); 39 FN/SFN included 27 OAs, 4 FA and 8 oncocytic follicular carcinoma (OFC). The two SFM cases were diagnosed on histopathology as OAs. Increased plasma membrane and cytoplasmic PD-L1 expression were found in 47 cases of the LBC cases (41.2%). Among the histological series, 67.3% of OAs and 75% of OFC had PD-L1 expression, while negative PD-L1 was found in hyperplastic oncocytic cells in HT. A positivity in more than 30% of the neoplastic cells was found in 72.9% of the cases including six OFC.ConclusionsThese data suggest that PD-L1 expression is expressed in oncocytic thyroid lesions. While weak PD-L1 expression failed to discriminate benign from malignant lesions, OFC demonstrated more intense cytoplasmic and membranous expression.

The aim of this paper is to describe the direction of the link between stress, depression, increased inflammation and brain-derived neurotrophic factor (BDNF) reduction. We hypothesize that severe stress or prolonged stress can be the driving factor that promote the onset of depression. Both stress and depression, if not resolved over time, activate the production of transcription factors that will switch on pro-inflammatory genes and translate them into cytokines. This cascade fosters systemic chronic inflammation and reduced plasma BDNF levels. Since people with depression have a 60% increased risk of developing type 2 diabetes (T2D) and show high levels of inflammation and low levels of BDNF, we hypothesize possible reasons that might explain why T2D, depression and dementia are often associated in the same patient.

Aims Common Psychiatric Disorders (CPDs) are associated with the development of overweight and obesity, the strongest risk factors for the onset and maintenance of Type 2 Diabetes mellitus (T2D). To the best of our knowledge, this is the first study to assess the prevalence of CPDs in patients with T2D in Italy. Methods This is a monocentric cross-sectional study; n = 184 T2D patients were screened for CPDs using the Patient Health Questionnaire (PHQ). Primary outcome was to evaluate the prevalence of CPDs. To assess association between CPDs and risk factors, we have utilized univariable logistic regression models. Results 64.1% were men, median age was 67 (59–64) and median BMI 27 (25–30) kg/m2. The 42.9% tested positive for one or more mental disorders, 25.6% for depression. Patients with higher BMI (p = 0.04) had an increased likelihood of testing positive to the PHQ. Patients who had implemented lifestyle changes (p p = 0.07) had a reduction in the likelihood of testing positive. Conclusions Prevalence of CPDs in T2D patients is higher than in the general population. Since CPDs favor the onset and subsistence of T2D, integrated diabetic-psychiatric therapy is required for improvement or remission of T2D in patients with comorbid CPDs.

Background: The diabetic Charcot foot syndrome is a serious and potentially limbthreatening lower-extremity complication of diabetes. Introduction: The present review provides a concise account of the advances made over the last twentyfive years in understanding the pathogenesis and management of Charcot neuroarthropathy (CN). Methods: In this study, the widely known pathogenetic mechanisms underpinning CN are brought into focus, particularly the role of RANKL/RANK/OPG system and advanced glycation end production in the pathogenesis of CN. Furthermore, other potential triggering factors, namely nitric oxide, endothelial dysfunction, macro calcifications and body weight that influence CN have also been discussed. Results: The wide range of diagnostic tools available to clinicians for accurate staging of this pathology has been examined, particularly radiological and nuclear medicine imaging. Additionally, the difficult differential diagnosis between osteomyelitis and CN is also elucidated. Conclusions: The review concludes with the comprehensive summary of the major promising therapeutic strategies, including conservative treatment involving orthopedic devices, pharmacological approach, and the most common surgical techniques currently employed in the diagnosis and treatment of this acute disease.

Introduction Somatotroph pituitary tumours are often resistant to first-generation somatostatin analogues and can invade the surrounding structures, limiting the chances of curative surgery. Recent studies suggested that the immune microenvironment and pro-angiogenic factors can influence neuroendocrine tumour prognosis. In this study, we aimed to investigate the prognostic role of immune cell-specific markers and endocan, a proteoglycan involved in neoangiogenesis and cell adhesion, in a cohort of acromegaly patients who underwent pituitary surgery as first-line treatment. Subjects and methods Sixty four eligible subjects were identified. CD4+, CD8+ and CD68+ cells and endocan expression were evaluated by immunohistochemistry and results correlated with clinical and neuroradiological findings. Responsiveness to somatostatin analogues was assessed in patients with persistent disease following surgery. Results The number of CD8+ lymphocytes was significantly lower in tumours with cavernous sinus invasion (median 0.2/HPF, IQR: 2.2) compared with those without cavernous sinus invasion (median 2.4/HPF, IQR: 2.3; P = 0.04). Tumours resistant to first-generation somatostatin analogues had lower CD8+ lymphocytes (median 1/HPF, IQR: 2.4) compared with responders (median 2.4/HPF, IQR: 2.9; P = 0.005). CD4+ lymphocytes were observed sporadically. The number of CD68+ macrophages and the endothelial or tumour cell endocan expression did not differ based on tumour size, cavernous sinus invasion or treatment responsiveness. Conclusions Our study suggests that a lower number of CD8+ lymphocytes is associated with cavernous sinus invasion and resistance to treatment with first-generation somatostatin analogues in acromegaly patients. These results highlight a potential role of the tumour immune microenvironment in determining the prognosis of somatotroph pituitary tumours.

α-lipoic acid (ALA), also known as thioctic acid, is a biological thiol present in all types of prokaryotic and eukaryotic cells. It has been shown that ALA or its reduced form, DHLA, have several positive effects on human health acting as biological antioxidant, metal chelator and as a detoxifying agent. It is able to reduce oxidation of several antioxidant agents like glutathione, vitamins C and E, and to modulate insulin and NF-kB signaling pathways. ALA’s pharmacological effects are not only related to its antioxidant properties but it shows an anti-inflammatory action. In particular, ALA is able to reduce inflammasome activity, the pro-inflammatory cytokine levels, such as TNF-α, IL-1β, IL-6, IL-18 and IL-17, interferon (INF)-γ as well as the production of Vascular and Intercellular cell adhesion protein (VCAM-1 and ICAM-1). In recent papers, ALA has been indicated as a possible therapeutic approach to several endocrine or inflammatory disorders affecting female reproduction. Aim of the current review was to assess whether ALA has an evidence-based beneficial role on gynecological and obstetrical diseases such as polycystic ovary syndrome (PCOS), endometriosis, and miscarriage.

It is unequivocally recognized that thyroid nodules are frequently detected in the adult population and mostly characterized by benign lesions (up to 70% of them), with only 5%–15% malignant lesions. The evaluation of thyroid lesions with fine-needle aspiration cytology (FNAC) represents one of the first and most useful diagnostic tools in the definition of their nature. Despite the fact that the majority of thyroid lesions are correctly diagnosed as either benign (70%–75%) or malignant (5%–10%) entities, the remaining nodules (20%–25%) represent the “gray zone” of follicular lesions, which belong to indeterminate categories, according to the different classification systems. This indeterminate group of lesions includes both benign and malignant entities, which cannot be easily discriminate with morphology alone. In these last decades, the increasing role of molecular testings, feasibly performed on cytological material combined with the discoveries of specific genetic alterations in the field of thyroid pathology, has opened the pace to their more accurate and specific contribution on cytology. In fact, in 2015, in the revised management guidelines for patients with thyroid nodules and well-differentiated thyroid cancers (WDTCs), the American Thyroid Association (ATA) confirmed the performance of molecular testing in thyroid indeterminate cytology, and the same performance was addressed in recent update of the management of thyroid nodules in the second edition of the Bethesda system for reporting thyroid cytopathology (TBSRTC). In the current review, we discuss the role of molecular tests for the different thyroid diagnostic categories of the Bethesda system for reporting thyroid cytopathology, mostly focusing our attention on the follicular and indeterminate lesions.

The lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) promotes growth and progression in prostate cancer (PCa); however, little is known about its possible impact in PCa metabolism. The aim of this work has been the assessment of the metabolic reprogramming associated with MALAT1 silencing in human PCa cells and in an ex vivo model of organotypic slice cultures (OSCs). Cultured cells and OSCs derived from primary tumors were transfected with MALAT1 specific gapmers. Cell growth and survival, gene profiling, and evaluation of targeted metabolites and metabolic enzymes were assessed. Computational analysis was made considering expression changes occurring in metabolic markers following MALAT1 targeting in cultured OSCs. MALAT1 silencing reduced expression of some metabolic enzymes, including malic enzyme 3, pyruvate dehydrogenase kinases 1 and 3, and choline kinase A. Consequently, PCa metabolism switched toward a glycolytic phenotype characterized by increased lactate production paralleled by growth arrest and cell death. Conversely, the function of mitochondrial succinate dehydrogenase and the expression of oxidative phosphorylation enzymes were markedly reduced. A similar effect was observed in OSCs. Based on this, a predictive algorithm was developed aimed to predict tumor recurrence in a subset of patients. MALAT1 targeting by gapmer delivery restored normal metabolic energy pathway in PCa cells and OSCs.

Alpha-lipoic acid (ALA) is a natural compound with antioxidant and pro-oxidant properties which has effects on the regulation of insulin sensitivity and insulin secretion. ALA is widely prescribed in patients with diabetic polyneuropathy due to its positive effects on nerve conduction and alleviation of symptoms. It is, moreover, also prescribed in other insulin resistance conditions such as metabolic syndrome (SM), polycystic ovary syndrome (PCOS) and obesity. However, several cases of Insulin Autoimmune Syndrome (IAS) have been reported in subjects taking ALA. The aim of the present review is to describe the main chemical and biological functions of ALA in glucose metabolism, focusing on its antioxidant activity, its role in modulating insulin sensitivity and secretion and in symptomatic peripheral diabetic polyneuropathy. We also provide a potential explanation for increased risk for the development of IAS.

Acromegaly is a chronic disease with an increased mortality in case of persistently active disease. The treatment of acromegaly is mainly based on the surgical resection of the GH secreting pituitary tumor and, in cases with persistent disease, on the medical therapy with first generation somatostatin analogues (first gen-SSAs). Data from national registries, meta-analysis and epidemiology studies showed that 24%-65% of acromegaly patients treated with first gen-SSA did not reach the control of disease, requiring second line therapies, as the second gen-SSAs and the GH receptor antagonist. According to the high efficacy of these treatments and their molecular mechanisms of action, the choice of second line therapies should be personalized. In this review, we summarize the evidence on clinical, molecular and morphological aspects that may predict the response to second line therapies, in order to integrate and translate in the clinical practice for a patient-tailored therapeutic approach.

INTRODUCTION The use of targeted drug therapies has substantially increased in the treatment of RET-mutated thyroid and other solid cancers over the last decade. Multi-Kinase Inhibitors (MKI) have been approved by FDA, but limited efficacies and side effects make them uneasy to tolerate. Pralsetinib is an oral highly selective RET inhibitor drug that has been generated and clinically validated to have higher potency and less toxicity. AREAS COVERED The present paper offers a brief summary of RET-related thyroid cancer genetics, an overview of the preclinical development of pralsetinib and reviews its clinical validation in the treatment of thyroid cancer. EXPERT OPINION Pralsetinib is a new generation oral treatment that has been approved by the FDA for patients with RET-mutated thyroid cancer. Pralsetinib showed a safer toxicity profile compared to previously approved MKI, probably due to lower inhibition of other tyrosine kinases, especially VEGFR. The approval study ARROW trial showed that patients with RET-mutant medullary thyroid cancer had a better overall response rate to pralsetinib compared to standard-of-care treatments. Additional clinical trials or data enrichment of existing databases are desirable in order to verify and further describe the clinical benefit of pralsetinib in such patients to fully understand its pharmacological profile.

Introducion Thyroid diseases in pregnancy are common. While data on management of overt diseases are clear, there is no consensus regarding subclinical thyroid disease. Many studies have tried to clarify the impact of subclinical thyroid disease on pregnancy outcomes without reaching universal conclusions. Evidence acquisition As several studies are present in literature, but no univocal indication is present to manage each condition, the present review tries to summarize the recent indications for such disease. The most updated guidelines are 2017 American thyroid association for of thyroid disease during pregnancy, which at present represent the most accurate and reliable guide. Evidence synthesis Subclinical hyperthyroidism during pregnancy has not been associated with adverse outcomes and only needs follow up. Subclinical hypothyroidism is associated with adverse obstetric and offspring outcomes. At present thyroxine treatment is recommended in selected cases, as beneficial effects are not clear for all these patients. Data regarding the association between isolated hypothyroxinemia and adverse meternofetal outcome are controversial but treatment is not indicated. Autoimmune thyroid disease represents the main thyroid risk factor for adverse pregnancy outcomes. If patients have normal TSH values, treatment is not indicated. A possible thyroxine treatment can be evaluated on a case-by-case basis in euthyroid patients with history of abortion/infertility. Conclusions In the last years, risks of subclinical thyroid dysfunction on the outcome of gestation and newborn have been scaled back. Further prospective studies are necessary to better understand thyroid dysfunction in pregnancy to perfectly target treatment in appropriate settings.

Familial hypercholesterolemia (FH) is characterized by high low-density lipoprotein-cholesterol levels and it is primarily caused by pathogenic/likely pathogenic variants (P/LPVs) in LDLR, APOB or PCSK9 genes.Next Generation Sequencing (NGS) technology allows the evaluation of more genes simultaneously, rising the diagnostic throughput of genomics laboratories. We report a Ukrainian 37-year-old woman hypercholesterolemic since 2010. Despite a suggestive family history, FH was suspected only when the patient referred to the Endocrine and Metabolic Diseases Center of the Fondazione Policlinico Universitario A. Gemelli IRCCS in Rome. After specialist advice, genetic testing was offered to the patient at our Molecular and Genomic Diagnostics Unit.A targeted NGS-based pipeline highlighted a novel out-of-frame deletion in the LDLR gene. This variant has a clear deleterious effect on the LDLR protein and it can be classified as PV.The ideal model of care for FH is an evidence-based system aimed to provide the highest-quality health services to all FH patients. In fact, this study reports that an integrated care pathway adopted in our hospital for FH patients led successfully to the discovery of a novel LDLR PV in a Ukrainian patient. The finding of this LDLR variant allowed the clinical FH diagnosis in this patient and in her family, expanding the knowledge of FH-related genetic variants in the Ukrainian population.

(1) Background: PTTG1 sustains the EMT process and the invasiveness of several neoplasms. We previously showed the role of nuclear PTTG1 in promoting invasiveness, through its transcriptional target MMP2, in seminoma in vitro models. Here, we investigated the key players involved in PTTG1-mediated EMT in human seminoma. (2) Methods: Two seminoma cell lines and four human seminoma tumor specimens were used. E-Cadherin gene regulation was investigated using Western blot, real-time PCR, and luciferase assay. Immunoprecipitation, ChIP, RE-ChIP, and confocal microscopy analysis were performed to evaluate the interplay between PTTG1 and ZEB1. Matrigel invasion and spheroid formation assays were applied to functionally investigate PTTG1 involvement in the EMT of seminoma cell lines. RNA depletion and overexpression experiments were performed to verify the role of PTTG1/ZEB1 in E-Cadherin repression and seminoma invasiveness. E-Cadherin and ZEB1 levels were analyzed in human testicular tumors from the Atlas database. (3) Results: PTTG1 transcriptionally represses E-Cadherin in seminoma cell lines through ZEB1. The cooperation of PTTG1 with ZEB1 has a significant impact on cell growth/invasion properties involving the EMT process. Analysis of the Atlas database of testicular tumors showed significantly lower E-Cadherin levels in seminoma, where PTTG1 showed nuclear staining. Finally, PTTG1 and ZEB1 strongly localize together in the periphery of the tumors. (4) Conclusions: These results strengthen the evidence for a role of PTTG1 in the EMT process in human seminomas through its cooperation with the transcriptional repressor ZEB1 on the E-Cadherin gene. Our data enrich the molecular characterization of seminoma, suggesting that PTTG1 is a prognostic factor in seminoma clinical management.

Background Familial hypercholesterolemia (FH) is characterized by high low-density lipoprotein-cholesterol levels and it is primarily caused by pathogenic/likely pathogenic variants (P/LPVs) in LDLR, APOB or PCSK9 genes. Next generation sequencing (NGS) technology allows the evaluation of more genes simultaneously, rising the diagnostic throughput of genomics laboratories. Materials and methods We report a Ukrainian 37-year-old woman hypercholesterolemic since 2010. Despite a suggestive family history, FH was suspected only when the patient referred to the Endocrine and Metabolic Diseases Center of the Fondazione Policlinico Universitario A. Gemelli IRCCS in Rome. After specialist advice, genetic testing was offered to the patient at our Molecular and Genomic Diagnostics Unit. Results A targeted NGS-based pipeline highlighted a novel out-of-frame deletion in the LDLR gene. This variant has a clear deleterious effect on the LDLR protein and it can be classified as PV. Conclusions The ideal model of care for FH is an evidence-based system aimed to provide the highest-quality health services to all FH patients. In fact, this study reports that the integrated care pathway adopted in our hospital for FH patients led successfully to the discovery of a novel LDLR PV in an Ukrainian patient. The finding of this LDLR variant allowed the clinical FH diagnosis in this patient and in her family, expanding the knowledge of FH-related genetic variants in the Ukrainian population.

During the coronavirus disease 2019 (COVID-19) pandemic, clinicians are required to manage patient care for pre-existing conditions. Currently, there are no clear indications regarding the management of lenvatinib-treated patients for radioiodine-refractory thyroid cancer and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. A 74-year-old male patient was treated with lenvatinib since March 2019, with disease recurrence in the thyroid bed and bilateral multiple lung metastases. The patient partially responded to treatment, with reduction in lung metastases. In September 2019, the patient tested positive for SARS-CoV-2 and isolated at home. Initially asymptomatic, the patient developed mild symptoms. Lenvatinib treatment continued with daily monitoring of vital signs. After telemedicine consultation of patient's clinical condition, severity of symptoms was low. He tested negative for SARS-CoV-2 21 days after testing positive. The patient received the full course of lenvatinib treatment. This is the first reported case of a lenvatinib-treated patient who developed COVID-19 and could continue treatment. Despite concerns over COVID-19, clinicians should not overlook treatment of pre-existing diseases or discontinue treatment, particularly for cancer. Clinicians should evaluate a patient's history and clinical presentation, monitoring the patient to reduce the development of complications in high-risk settings, avoiding treatment discontinuation.

Hypophysitis is a rare and potentially life-threatening disease, characterized by an elevated risk of complications, such as occurrence of acute central hypoadrenalism, persistent hypopituitarism, or extension of the inflammatory process to the neighboring neurological structures. In recent years, a large number of patients have been described as being affected by hypophysitis, due to the increased administration of immuno-chemotherapies. At the present time, the heterogeneous nature of hypophysitis diagnostic criteria and of the treatment protocols makes the management of affected patients difficult. We review the current data and evidence on primary and secondary hypophysitis, in order to suggest a diagnostic and therapeutic protocol that should be focused on a multidisciplinary approach, for reaching a prompt diagnosis and an appropriate and safe treatment.

Background The recently introduced monoclonal V600E antibody (clone VE1) is likely to be an alternative strategy for detecting this mutation in thyroid lesions. Although VE1 immunostaining and molecular methods used to assess papillary thyroid carcinoma in surgical specimens are in good agreement, evaluation of VE1 in cytology and cell block samples is rarely performed, and its diagnostic value in cytology has not been well established. In this study, we sought to determine if VE1 is suitable for fine needle aspiration (FNA) and cell block methods. Methods A total of 86 patients who had BRAF V600E mutations were investigated with molecular and immunocytochemical (ICC) analysis in 45 FNA and 41 cell blocks. In total, 83 (96.5%) patients underwent surgical treatment. Assessment of BRAF V600E mutation status was performed in 72 (83.7%) cases. Results Among the 72 cases analysed, 54 cases agreed (ICC+/BRAF+ or ICC-/BRAF-), seven cases were false positive (ICC+/BRAF-) and 11 cases were false negative (ICC-/BRAF+). False negative cases were not detected in the cell block method. The statistical analysis showed that sensitivity and specificity of ICC for detecting the BRAF V600E mutation were 61% and 77% in FNA samples and 100% and 73% in cell block. Conclusion The use of antibody VE-1 is a reliable method and a negative result of VE1 immunostaining might help to save time and money, restricting the molecular test to antibody-positive cases only. The identification of the aggressive variants of papillary carcinoma might be enabled by the expression of the antibody in neoplastic cells with tall cell features.

Sotagliflozin is a dual sodium–glucose co-transporter-2 and 1 (SGLT2/1) inhibitor for the treatment of both type 1 (T1D) and type 2 diabetes (T2D). Sotagliflozin inhibits renal sodium–glucose co-transporter 2 (determining significant excretion of glucose in the urine, in the same way as other, already available SGLT-2 selective inhibitors) and intestinal SGLT-1, delaying glucose absorption and therefore reducing post prandial glucose. Well-designed clinical trials, have shown that sotagliflozin (as monotherapy or add-on therapy to other anti-hyperglycemic agents) improves glycated hemoglobin in adults with T2D, with beneficial effects on bodyweight and blood pressure. Similar results have been obtained in adults with T1D treated with either continuous subcutaneous insulin infusion or multiple daily insulin injections, even after insulin optimization. A still ongoing phase 3 study is currently evaluating the effect of sotagliflozin on cardiovascular outcomes (ClinicalTrials.gov NCT03315143). In this review we illustrate the advantages and disadvantages of dual SGLT 2/1 inhibition, in order to better characterize and investigate its mechanisms of action and potentialities.

Thyroid nodules are common and typically detected by palpation and/or ultrasound (US). Guidelines have defined the management of large nodules, but controversy exists regarding nodules ≤ 1 cm. We evaluated a cohort of patients with subcentimeter nodules to determine their rate of malignancy (ROM). A total of 475 thyroid FNAs of lesions ≤ 1 cm with available follow-up were identified from January 2015–December 2019. For comparative analysis, we added a control series of 606 thyroid lesions larger than 1 cm from the same reference period. All aspirates were processed with liquid-based cytology and classified according to The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC). Subcentimeter nodules were stratified as 35 category I—non-diagnostic cases (ND, 7.3%), 144 category II—benign lesions (BL, 30.3%), 12 category III—atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS, 2.5%), 12 category IV—follicular neoplasm/suspicious for follicular neoplasm (FN/SFN, 2.5%), 124 category V—suspicious for malignancy (SM, 26.1%), and 148 category VI—positive for malignancy (PM, 31.1%). A total of 307 cases (64.6%) underwent subsequent surgery. Only one ND and three BLs had a malignant outcome. ROM for indeterminate lesions (III + IV) was 3.2%, with 1.6% for category III and 3.2% for category IV. ROM for the malignant categories (V + VI) was 88.2%. The control cohort of lesions demonstrated a higher number of benign histological diagnoses (67.3%). We documented that 57.2% of suspected subcentimeter lesions were malignant, with a minor proportion that belonged in indeterminate categories. There were very few ND samples, suggesting that aspirates of subcentimeter lesions yield satisfactory results. Suspected US features in subcentimeter lesions should be evaluated and followed by an interdisciplinary team for appropriate patient management.

Background: Prolactinomas represent a unique challenge for endocrinologists and neurosurgeons. Considering recent innovations in surgical practice, the authors aimed to investigate the best management for prolactinomas. Methods: A retrospective, cross-sectional and monocentric study was designed. Consecutive patients affected by prolactinomas were enrolled if treated with a first-line treatment with a dopamine agonist (DA) or trans-sphenoidal surgery (TSS). Patients carried giant prolactinomas, and those with a follow-up &lt, 12 months were excluded. Results: Two hundred and fifty-nine patients were enrolled. The first treatment was DA for 140 patients and TS for 119 cases. One hundred and forty-six of 249 patients (58.6%) needed a second therapy. The mean follow-up was 102.2 months (12–438 months). Surgery highly impacted on the cure rate—in particular, in females (p = 0.0021) and in microprolactinomas (p = 0.0020). Considering the multivariate analysis, the female gender and surgical treatment in the course of the clinical history were the only independent positive predictors of a cure at the end of 5 years follow-up (p = 0.0016, p = 0.0005). The evaluation of serum prolactin (24 hours after TSS) revealed that 86.4% of patients with postoperative prolactin (PRL) ≤10 ng/mL were cured at the end of the follow-up (p &lt, 0.0001). Conclusions: According to our experience, surgery allows a high cure rate of prolactinomas, particularly in females with microadenoma, with a good safety profile. TSS for prolactinomas should be considered as a concrete option, during the multidisciplinary evaluation, in centers of reference for pituitary diseases.

ObjectiveThe use of once-daily dual-release HC (DR-HC) in primary adrenal insufficiency (PAI) is often associated with benefits in metabolic parameters when compared to immediate-release HC (IR-HC). In this study, we evaluated the effects on clinical, biochemical and metabolic parameters of switching from IR-HC to lower-dose DR-HC given both in once and fractionated daily doses.MethodsTwenty autoimmune-PAI subjects were included. Patients on 30 mg/day divided in three doses IR-HC regimen (group A) were switched to DR-HC 25 mg/day given in two daily doses (20 mg in the morning and 5 mg at 2.00 p.m.); patients on 25 mg/day divided in two doses IR-HC regimen (group B) were switched to DR-HC 20 mg once daily. Biochemical and metabolic parameters, BMI and quality of life (QoL) were evaluated at the baseline and six months after the switch.ResultsOur small non-randomized study with short follow up showed significant benefits in both group A and group B without any apparent side-effects. After the switch to DR-HC, a significant decrease in adrenocorticotropic hormone (ACTH), HbA1c, total cholesterol, triglycerides, LDL, cholesterol, BMI as well as a significant improvement in QoL, were observed in both groups. At 6 months, ACTH levels were lower in group A while HbA1C and total cholesterol were lower in group B.ConclusionThe DR-HC is a valid and effective therapeutic strategy to improve the metabolic control and the QoL in PAI. The reduction of ACTH levels with DR-HC regimens reflects a better biochemical control of PAI, obtained by using a lower dose and more physiological HC formulation. Both once-daily and fractionated daily doses of DR-HC showed advantages compared with IR-HC formulation.

Introduction & Backgroundthe SARS-CoV-2 infection determines the COVID19 syndrome characterized, in the worst cases, by severe respiratory distress, pulmonary and cardiac fibrosis, inflammatory cytokines release, and immunosuppression. This condition has led to the death of about 2.15% of the total infected world population so far. Among survivors, the presence of the so-called persistent post-COVID19 syndrome (PPCS) is a common finding. In patients who survived the SARS-CoV-2 infection, overt PPCS presents one or more symptoms such as fatigue, dyspnea, memory loss, sleep disorders, and difficulty concentrating. The pathophysiology of PPCS is currently poorly understood, and whether epigenetic mechanisms are involved in this process is unexplored.Methods & ResultsIn this study, a cohort of 117 COVID19 survivors (post-COVID19) and 144 non-infected volunteers (COVID19-free) were analyzed using pyrosequencing of defined CpG islands previously identified as suitable for biological age determination. Besides, telomere length (TL) and ACE2 and DPP-4 receptor expression were determined. The results show a consistent biological age increase in the post-COVID19 population (58,44 ± 14,66 ChronoAge Vs. 67,18 ± 10,86 BioAge, PConclusionIn light of these observations, we hypothesize that some epigenetic alterations are associated with the post-COVID19 condition, particularly in the youngers (

The lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) promotes growth and progression in prostate cancer (PCa), however, little is known about its possible impact in PCa metabolism. The aim of this work has been the assessment of the metabolic reprogramming associated with MALAT1 silencing in human PCa cells and in an ex vivo model of organotypic slice cultures (OSCs). Cultured cells and OSCs derived from primary tumors were transfected with MALAT1 specific gapmers. Cell growth and survival, gene profiling, and evaluation of targeted metabolites and metabolic enzymes were assessed. Computational analysis was made considering expression changes occurring in metabolic markers following MALAT1 targeting in cultured OSCs. MALAT1 silencing reduced expression of some metabolic enzymes, including malic enzyme 3, pyruvate dehydrogenase kinases 1 and 3, and choline kinase A. Consequently, PCa metabolism switched toward a glycolytic phenotype characterized by increased lactate production paralleled by growth arrest and cell death. Conversely, the function of mitochondrial succinate dehydrogenase and the expression of oxidative phosphorylation enzymes were markedly reduced. A similar effect was observed in OSCs. Based on this, a predictive algorithm was developed aimed to predict tumor recurrence in a subset of patients. MALAT1 targeting by gapmer delivery restored normal metabolic energy pathway in PCa cells and OSCs.

Aims/hypothesis Type 2 diabetes (T2D) is characterized by a progressive loss of beta-cell function, and the “disappearance” of beta-cells in T2D may also be caused by the process of beta -cell dedifferentiation. Since noradrenergic innervation inhibits insulin secretion and density of noradrenergic fibers is increased in type 2 diabetes mouse models, we aimed to study the relation between islet innervation, dedifferentiation and beta-cell function in humans. Methods Using immunohistochemistry and electron microscopy, we analyzed pancreata from organ donors and from patients undergoing pancreatic surgery. In the latter, a pre-surgical detailed metabolic characterization by oral glucose tolerance test (OGTT) and hyperglycemic clamp was performed before surgery, thus obtaining in vivo functional parameters of beta-cell function and insulin secretion. Results The islets of diabetic subjects were 3 times more innervated than controls (0.91 ± 0.21 vs 0.32 ± 0.10, n.fibers/islet; p = 0.01), and directly correlated with the dedifferentiation score (r = 0.39; p = 0.03). In vivo functional parameters of insulin secretion, assessed by hyperglycemic clamp, negatively correlated with the increase in fibers [beta-cell Glucose Sensitivity (r = −0.84; p = 0.01), incremental second-phase insulin secretion (r = −0.84, p = 0.03) and arginine-stimulated insulin secretion (r = −0.76, p = 0.04)]. Moreover, we observed a progressive increase in fibers, paralleling worsening glucose tolerance (from NGT through IGT to T2D). Conclusions/interpretation Noradrenergic fibers are significantly increased in the islets of diabetic subjects and this positively correlates with beta-cell dedifferentiation score. The correlation between in vivo insulin secretion parameters and the density of pancreatic noradrenergic fibers suggests a significant involvement of these fibers in the pathogenesis of the disease, and indirectly, in the islet dedifferentiation process.

Sappho has always been regarded as one of the greatest lyric poets of ancient Greece. Her famous poem Fragment 31 V., also known as the "Ode to Jealousy", accurately describes the profound emotional reaction triggered by the sight of her beloved. The poet's precise description of each sign and symptom triggered by this arousal makes Sappho 31 V., to the best of our knowledge, the first analytical description of the acute stress response, the so-called "fight-or-flight" response, in human history. Here, Fragment 31 V. is re-read from a medical point of view, correlating the ancient Greek lyric text, the corresponding medical terms, and the underlying catecholamine mechanism of action.

Background Mutational analysis contributes to the diagnosis and prognosis of thyroid nodules analyzed with fine-needle aspiration cytology (FNAC). Although several advanced molecular tests based on multiple molecular markers are available for clinical use and have increased their impact on clinical management of patients, they are not widely available. Among them is BRAF V600E, one of the most studied mutations. Other genetic alterations, such as TERT promoter mutations, may coexist in thyroid carcinomas. Previous studies have demonstrated that this duet might be involved in the aggressiveness of thyroid cancer, although its prognostic value related to mortality remains undefined. The detection of such genetic alterations in thyroid liquid-based cytology (LBC) thus may assist with patient management. Methods From January 2013 to June 2014, 356 thyroid FNAC samples were processed by LBC, including 174 surgical follow-up samples. BRAF V600E and TERT mutation analyses were performed on both LBC and histopathology. Results The study included 119 samples categorized as atypia of undetermined significance, 42 categorized as follicular neoplasms, 61 categorized as suspicious for malignancy, and 34 categorized as positive for malignancy. BRAF V600E mutation was detected in 10.4% of all cases, whereas TERT promoter mutations were identified in 1.1%. TERT-mutated cases belonged to the positive for malignancy category, with a histologic diagnosis of tall cell variant of papillary thyroid carcinoma. These genetic alterations correlated with lymph node metastases (P = .0349) and higher disease stage. Conclusions BRAF V600E and TERT analysis can be performed on LBC. TERT mutations are rarely identified in well differentiated thyroid carcinoma but are associated with higher stage. Although a larger molecular panel may offer more information, analyzing these few point mutations is still likely to be useful for managing potentially more aggressive thyroid carcinomas.

Introduction Disorders of glucose metabolism are a serious acromegaly comorbidity and may be differently impacted by medical treatments of acromegaly. In this retrospective longitudinal multicenter study, we investigated the outcome of glucose metabolism and its predictors in patients treated with Pasireotide LAR (PAS-LAR) alone or in combination with Pegvisomant (PAS-LAR + Peg-V). Subjects and methods Acromegaly patients treated continously with PAS-LAR or PAS-LAR + Peg-V for at least 6 months. Results Forty patients (25 females, 15 males) were enrolled. At last visit, 27/40 patients (67.5%) reached biochemical control of acromegaly. Overall, glucose metabolism improved in 3 (all in PAS-LAR + Peg-V; 7.5%), worsened in 26 (65%) and remained unchanged in 11 patients (27.5%). Glucose metabolism worsened in 25 patients (73.5%) treated with PAS-LAR and in a single patient (16.7%) treated with PAS-LAR + Peg-V (p p = 0.04) as compared to those with stable glucose status. A significantly higher reduction of HbA1c was observed in patients treated with PAS-LAR + Peg-V, as compared with those treated with PAS-LAR alone (p = 0.005). Conclusions Our data confirmed that glucose metabolism in patients treated with PAS-LAR is often worsened, and may be predicted by entity of baseline GH hypersecretion and by the dose of PAS-LAR. Moreover, our data, although limited by small numbers, may suggest that the combination treatment PAS-LAR + Peg-V can improve glucose homeostasis in selected patients.

Purpose The activity of the hypothalamus–pituitary–adrenal axis plays a crucial role as an endogenous stress-reactive system. Lifestyle and work often interfere with the endogenous circadian rhythms and can modify the physiological patterns of stress-hormones secretion, including cortisol. We evaluated the cortisol circadian rhythm in the “jet-lag syndrome” that is the most known condition associated with the desynchronization of the circadian rhythm. Methods To assess the modifications of cortisol secretion after a long-haul flight, we compared baseline and post-travel salivary cortisol rhythm in a group of 28 healthy eastward travelers (from the U.S.A. or Canada to Italy). The salivary samples were collected about 1 week before the departure at 11 p.m. on day 0 and at 8 a.m., 12 a.m. (midday) and 11 p.m. on day 1 (R0). The same samples were obtained after the landing, the day they flew back home (R1). Results Statistical analysis showed a significant difference between R0 and R1 for each sample considered (p Conclusions In eastward travelers, crossing more than five time zones, the cortisol circadian rhythm after the return to the East “remained behind,” being synchronized with the West time. This impaired cortisol secretion can contribute to the pathogenesis of the jet-lag syndrome.

Background The treatment of acromegaly resistant to first-generation somatostatin receptor ligands (SRLs) is often difficult. Pegvisomant and Pasireotide LAR are mostly used in these subset of patients, as second line therapies. Choice of the type of second line therapies is difficult, since predictors of response are still unclear, impairing personalized therapy. We aimed to investigate predictors of response to Pegvisomant and Pasireotide LAR. Methods Seventy-four acromegaly patients entered this observational, cross-sectional and retrospective study if (i) resistant to high dose first-generation SRLs and (ii) treated with Pegvisomant and Pasireotide LAR for at least 12 consecutive months. Patients treated with radiotherapy in the previous 10 years were excluded. Results Fourty-one patients were treated with Pegvisomant and 33 with Pasireotide LAR. At the end of the study, acromegaly was controlled in 35 patients treated with Pegvisomant (85.4%) and in 23 treated with Pasireotide LAR (69.7%). In this cohort, a poor Pegvisomant response and a shorter progression free time were observed in cases with tumor extension to the third ventricle (P = 0.004, HR: 1.6, 95%CI: 1.2–4.6), with a Ki67-Li >4% (P = 0.004, HR: 3.49, 95%CI: 1.4–4.0) and with pre-treatment IGF-I >3.3×ULN (P=0.03, HR: 1.3, 95%CI: 1.1–6.0). A poor Pasireotide LAR response and a shorter progression free time were observed in cases with tumor extension to the third ventricle (P=0.025, HR: 1.6 95%CI: 1.4–3.4), pre-treatment IGF-I >2.3×ULN (P=0.049, HR: 2.4, 95%CI: 1.4–8.0), absent/low SST5 membranous expression (P=0.023 HR: 4.56 95%CI: 1.3–6.4) and in patients carried the d3-delated GHR isoform (P=0.005, HR: 11.37, 95%CI: 1.3–20.0). Conclusion Molecular and clinical biomarkers can be useful in predicting the responsiveness to Pegvisomant and Pasireotide LAR.

The most known effects of endogenous Cushing’s syndrome are the phenotypic changes and metabolic consequences. However, hypercortisolism can exert important effects on other endocrine axes. The hypothalamus–pituitary–thyroid axis activity can be impaired by the inappropriate cortisol secretion, which determinates the clinical and biochemical features of the “central hypothyroidism”. These findings have been confirmed by several clinical studies, which also showed that the cure of hypercortisolism can determine the recovery of normal hypothalamus–pituitary–thyroid axis activity. During active Cushing’s syndrome, the “immunological tolerance” guaranteed by the hypercortisolism can mask, in predisposed patients, the development of autoimmune thyroid diseases, which increases in prevalence after the resolution of hypercortisolism. However, the immunological mechanism is not the only factor that contributes to this phenomenon, which probably includes also deiodinase-impaired activity. Cushing’s syndrome can also have an indirect impact on thyroid function, considering that some drugs used for the medical control of hypercortisolism are associated with alterations in the thyroid function test. These considerations suggest the utility to check the thyroid function in Cushing’s syndrome patients, both during the active disease and after its remission.

INTRODUCTION Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder whose rising incidence suggests the epidemic proportions of the disease. Impaired fasting glucose (IFG) and Impaired Glucose Tolerance (IGT) - alone or combined - represent two intermediate metabolic condition between Normal Glucose Tolerance (NGT) and overt T2DM. EVIDENCE ACQUISITION Databases were systematically screened using the following MeSH terms combination as follows: 1. prediabetes, 2. prediabetic state, 3. prevention, 4. lifestyle, 5. diet, 6. nutrition, 7. pharmacotherapy, 8. metformin, 9. thiazolidinediones, 10. sodium glucose cotransporter 2 inhibitors, 11. GLP 1 receptor agonists, 12. alpha glucosidase inhibitors, 13. insulin, 14. DPP IV inhibitors. EVIDENCE SYNTHESIS Several studies have demonstrated that insulin resistance and beta-cell impairment can be identified even in normoglycemic prediabetic individuals. Worsening of these two conditions may lead to progression of IGT and/or IFG status to overt diabetes. Starting from these assumptions, it seems logical to suppose that interventions aimed at improving metabolic conditions, even in prediabetes, could represent an effective target to halt transition from IGT/IFG to manifest T2DM. Starting from pathophysiological knowledge, in this review we evaluate two possible interventions (lifestyle modifications and pharmacological agents) eligible as prediabetes therapy since they have been demonstrated to improve insulin resistance and beta-cell impairment. CONCLUSIONS Detecting high-risk people and treating them could represent an effective strategy to slow down progression to overt diabetes, normalize glucose tolerance, and even prevent micro- and macrovascular complications.

Background: Seminoma is the most common subtype of testicular germ cell tumors (TGCTs) and its molecular patterns have not been fully clarified. The pituitary tumor-transforming gene 1 (PTTG1) is a securin, inhibitor of premature sister chromatid segregation during mitosis and is overexpressed in many cancers. PTTG1 shows the ability to sustain the invasiveness of several cancer types through its transcriptional activity. In the present study, we investigate the PTTG1 role on the invasive properties of seminoma.Methods: Three seminoma cell lines showing different proliferation rates and marker expression features were used as an in vitro model. Biochemical and immunofluorescence analyses were performed to evaluate PTTG1 levels and subcellular localization. Functional analyses, including wound healing, matrigel invasion assays and zymography were applied to study migratory and invasive capability of the cell lines. RNA interference studies and overexpression experiments were performed to address the PTTG1 role in seminoma cell lines invasiveness. Finally, the Atlas database was interrogated to study PTTG1 subcellular localization in seminoma and non-seminomas testicular tumors in order to analyze the PTTG1 and matrix metalloproteinase-2 (MMP-2) levels in these groups.Results: We found that PTTG1 was highly and differentially expressed in the seminoma cell lines. PTTG1 nuclear localization was positively correlated to the aggressive phenotype. Modulation of PTTG1 expression uncovered a direct causal link between PTTG1 and seminoma cell line invasiveness. Importantly, analysis of the human Atlas database revealed that PTTG1 was localized in the nucleus exclusively in seminoma compared with non-seminoma tumors and showed that MMP-2 levels was significant higher in seminomas.Conclusions: The results of the present research elucidate the role of nuclear PTTG1 in promoting invasiveness and metastatic process of seminoma cell lines. Analysis from the Atlas database strongly supported these results, revealing an exclusive PTTG1 nuclear localization and an increase of MMP-2 levels in seminoma versus non-seminoma tumors. Overall, these data lead to the hypothesis that nuclear PTTG1 is an eligible prognostic factor in seminomas.

BACKGROUNDThe appearance of hyperglycemia is due to insulin resistance, functional deficits in the secretion of insulin, and a reduction of β cell mass. There is a long-standing debate as to the relative contribution of these factors to clinically manifesting β cell dysfunction. The aim of this study was to verify the acute effect of one of these factors, the reduction of β cell mass, on the subsequent development of hyperglycemia.METHODSTo pursue this aim, nondiabetic patients, scheduled for identical pancreaticoduodenectomy surgery, underwent oral glucose tolerance tests (OGTT) and hyperglycemic clamp (HC) procedures, followed by arginine stimulation before and after surgery. Based on postsurgery OGTT, subjects were divided into 3 groups depending on glucose tolerance: normal glucose tolerance (post-NGT), impaired glucose tolerance (post-IGT), or having diabetes mellitus (post-DM).RESULTSAt baseline, the 3 groups showed similar fasting glucose and insulin levels; however, examining the various parameters, we found that reduced first-phase insulin secretion, reduced glucose sensitivity, and rate sensitivity were predictors of eventual postsurgery development of IGT and diabetes.CONCLUSIONDespite comparable functional mass and fasting glucose and insulin levels at baseline and the very same 50% mass reduction, only reduced first-phase insulin secretion and glucose sensitivity predicted the appearance of hyperglycemia. These functional alterations could be pivotal to the pathogenesis of type 2 diabetes (T2DM).TRIAL REGISTRATIONClinicalTrials.gov NCT02175459.FUNDINGUniversita Cattolica del Sacro Cuore; Italian Ministry of Education, University and Research; European Foundation for the Study of Diabetes.

Simple Summary Seminoma is the most common subtype of testicular germ cell tumors (TGCTs) and its molecular patterns have not been clarified. The pituitary tumor-transforming gene 1 (PTTG1) is a securin and its overexpression is reported in many cancers. We previously demonstrated that PTTG1 is mainly localized at the neoplasm periphery and infiltration area of seminoma. Therefore, we aim to investigate in vitro the role of PTTG1 on the invasive properties of seminoma. Our results elucidate the role of nuclear PTTG1 in promoting invasiveness and the metastatic process of these cells through its transcriptional target matrix-metalloproteinase-2 (MMP-2). Analysis of human testicular tumors from the Atlas database revealed an exclusive PTTG1 nuclear localization and a concomitant increase of MMP-2 levels in seminoma compared to non-seminoma tumors. Our data provide insights into the molecular characterization of seminoma, promoting PTTG1 as a prognostic marker useful in human seminoma clinical management. Abstract (1) Background: PTTG1 sustains the invasiveness of several cancer types. We previously reported that in seminomas, PTTG1 was detected in the peripheral area of the tumor and in the leading infiltrative edge. Here, we investigate the PTTG1 role on the invasive properties of seminoma. (2) Methods: three seminoma cell lines were used as in vitro model. PTTG1 levels and localization were investigated by biochemical and immunofluorescence analyses. Wound-healing, Matrigel invasion assays, and zymography were applied to study migratory and invasive capability of the cell lines. RNA interference and overexpression experiments were performed to address the PTTG1 role in seminoma invasiveness. PTTG1 and its target MMP-2 were analyzed in human testicular tumors using the Atlas database. (3) Results: PTTG1 was highly and differentially expressed in the seminoma cell lines. Nuclear PTTG1 was positively correlated to the aggressive phenotype. Its modulation confirms these results. Atlas database analysis revealed that PTTG1 was localized in the nucleus in seminoma compared with non-seminoma tumors, and that MMP-2 levels were significantly higher in seminomas. (4) Conclusions: nuclear PTTG1 promotes invasiveness of seminoma cell lines. Atlas database supported these results. These data lead to the hypothesis that nuclear PTTG1 is an eligible prognostic factor in seminomas.