SARS-Cov-2 Infection: A New Risk Factor for Pituitary Apoplexy?

BACKGROUND: Pituitary apoplexy (PA) can arise from haemorrhage or ischaemia of pituitary tissue and is characterized by abrupt onset of headache, visual impairment and hypopituitarism. COVID-19 may be associated with various degrees of vascular complications and, recently, its relationship with PA has been suggested. Cases Presentation Case 1: A 64-year-old male with type 2 diabetes, hypertension and coronary heart disease was admitted to the ER, after several days of asymptomatic COVID-19 infection, with symptoms of PA of a known non-functioning pituitary macroadenoma. The hormonal panel was consistent with anterior panhypopituitarism and the sellar MRI showed haemorrhagic changes of macroadenoma tissue. Transsphenoidal resection of the pituitary lesion was carried out seven days after admission. Although a volumetric reduction of the lesion was apparent during follow-up, some degree of visual symptoms endured. Case 2: An 18-year-old, otherwise healthy, female presented to the ER with symptoms of PA of a recently-diagnosed non-functioning pituitary macroadenoma, after ten days of asymptomatic COVID-19 infection. Central hypocortisolism and hypothyroidism were diagnosed and, after six days, the lesion was surgically resected. At two months follow-up, clinical symptoms had completely resolved, and the hormonal panel was normal. CONCLUSION: Alongside known risk factors (hypertension, anticoagulation, pregnancy, surgery, etc.), COVID-19 infection might represent an emerging predisposing factor for PA onset. The two cases hereby presented are both significant: the first confirms the role of "classic" vascular predisposing factors for PA, while the second demonstrates that PA might arise also in young patients without known risk factors.

Endocrine-metabolic assessment checklist for cancer patients treated with immunotherapy: A proposal by the Italian Association of Medical Oncology (AIOM), Italian Association of Medical Diabetologists (AMD), Italian Society of Diabetology (SID), Italian Society of Endocrinology (SIE) and Italian Society of Pharmacology (SIF) multidisciplinary group.

Immunotherapy with immune checkpoint inhibitors (ICI) is increasingly employed in oncology. National and international endocrine and oncologic scientific societies have provided guidelines for the management of endocrine immune-related adverse events. However, guidelines recommendations differ according to the specific filed, particularly pertaining to recommendations for the timing of endocrine testing. In this position paper, a panel of experts of the Italian Association of Medical Oncology (AIOM), Italian Association of Medical Diabetologists (AMD), Italian Society of Diabetology (SID), Italian Society of Endocrinology (SIE), and Italian Society of Pharmacology (SIF) offers a critical multidisciplinary consensus for a clear, simple, useful, and easily applicable endocrine-metabolic assessment checklist for cancer patients on immunotherapy.

Glucagon-like peptide-1 receptor agonists and risk of thyroid cancer: A systematic review and meta-analysis of randomized controlled trials.

AIM: To conduct a meta-analysis of randomized clinical trials (RCTs) to investigate whether there is an association between glucagon-like peptide-1 receptor agonist (GLP-1RA) treatment and thyroid cancer. MATERIALS AND METHODS: In this meta-analysis of RCTs, we included studies comparing a GLP-1RA with any comparator, lasting at least 52 weeks, and reporting the incidence of adverse events independently of the principal endpoint and population. All cases of thyroid cancer were collected. RESULTS: We retrieved 64 trials, 26 of which reported at least one incident case of thyroid cancer. GLP-1RA treatment was associated with a significant increase in the risk of overall thyroid cancer (Mantel-Haenzel odds ratio [MH-OR] 1.52 [95% confidence interval {CI} 1.01, 2.29]; P = 0.04, I2 = 0%), with a fragility index of 1, and a 5-year number needed to harm of 1349. The association remained significant when including only trials lasting at least 104 weeks (MH-OR 1.76 [95% CI 1.00, 3.12]; P = 0.05). No significant association was found for papillary thyroid cancer (MH-OR 1.54 [95% CI 0.77, 3.06]; P = 0.22) or medullary thyroid cancer (MH-OR 1.44 [95% CI 0.23, 9.16]; P = 0.55). CONCLUSIONS: Our meta-analysis showed that GLP-1RA treatment could be associated with a moderate increase in relative risk for thyroid cancer in clinical trials, with a small increase in absolute risk. Studies of longer duration are required to assess the clinical implications of this finding.

Polybrominated Diphenyl Ethers (PBDEs) and Human Health: Effects on Metabolism, Diabetes and Cancer.

There is increasing evidence of the role of endocrine disruptors (EDs) derived from commonly employed compounds for manufacturing and processing in altering hormonal signaling and function. Due to their prolonged half-life and persistence, EDs can usually be found not only in industrial products but also in households and in the environment, creating the premises for long-lasting exposure. Polybrominated diphenyl ethers (PBDEs) are common EDs used in industrial products such as flame retardants, and recent studies are increasingly showing that they may interfere with both metabolic and oncogenic pathways. In this article, a multidisciplinary panel of experts of the Italian Association of Medical Diabetologists (AMD), the Italian Society of Diabetology (SID), the Italian Association of Medical Oncology (AIOM), the Italian Society of Endocrinology (SIE) and the Italian Society of Pharmacology (SIF) provides a review on the potential role of PBDEs in human health and disease, exploring both molecular and clinical aspects and focusing on metabolic and oncogenic pathways.

Gastric Neuroendocrine Tumors (g-NETs): A Systematic Review of the Management and Outcomes of Type 3 g-NETs.

PURPOSE: to collect data from real-life experiences of the management of type 3 g-NETs and identify possible prognostic factors that may impact the decision-making process. METHODS: We performed a systematic review of the literature on type 3 g-NET management using the PubMed, MEDLINE, and Embase databases. We included cohort studies, case series, and case reports written in the English language. RESULTS: We selected 31 out of 556 articles from between 2001 and 2022. In 2 out of the 31 studies, a 10 mm and 20 mm cut-off size were respectively associated with a higher risk of gastric wall infiltration and/or lymph node and distant metastasis at diagnosis. The selected studies reported a higher risk of lymph node or distant metastasis at diagnosis in the case of muscularis propria infiltration or beyond, irrespective of the dimensions or grading. From these findings, size, grading, and gastric wall infiltration seem to be the most relevant factors in management staff making choices and prognoses of type 3 g-NET patients. We produced a hypothetical flowchart for a standardized approach to these rare diseases. CONCLUSION: Further prospective analyses are needed to validate the prognostic impact of the use of size, grading, and gastric wall infiltration as prognostic factors in the management of type 3 g-NETs.

Management of Progressive Radioiodine-Refractory Thyroid Carcinoma: Current Perspective.

Patients with thyroid cancer (TC) usually have an excellent prognosis; however, 5-10% of them develop an advanced disease. The prognosis of this subgroup is still favourable if the lesions respond to radioactive iodine (RAI) treatment. Nearly two-thirds of advanced TC patients become RAI-refractory (RAI-R), and their management is challenging. A multidisciplinary approach in the context of a tumour board is essential to define a personalized strategy. Systemic therapy is not always the best option. In case of slow neoplastic growth and low tumour burden, active surveillance may represent a valuable choice. Local approaches might be considered if the disease progression is limited to a single or few lesions, also in combination and during systemic therapy. Antiresorptive treatment may be started in presence of bone metastases. In case of rapid and/or symptomatic progression involving multiple lesions and/or organs, systemic therapy has to be considered, in absence of contraindications. The multi-kinase inhibitors (MKIs) lenvatinib and sorafenib are currently available as first-line treatment for advanced progressive RAI-R TC. Among second-line options, cabozantinib has been recently approved in RAI-R TC who progressed during MKIs targeting the vascular endothelial growth factor receptor (VEGFR). In the last few years, next-generation sequencing (NGS) assays have been increasingly employed, permitting identification of the genetic alterations harboured by TC, with a significant impact on patients' management. Novel selective targeted therapies have been introduced for the treatment of RAI-R TC in selected cases: REarranged during Transfection (RET) inhibitors (selpercatinib and pralsetinib) and Tropomyosin Receptor Kinase (TRK) inhibitors (larotrectinib and entrectinib) have recently expanded the panorama of the therapeutic options. Moreover, immune checkpoint inhibitors (ICIs) have shown promising results, and they are still under investigation.

Corticosteroids in oncology: Use, overuse, indications, contraindications. An Italian Association of Medical Oncology (AIOM)/ Italian Association of Medical Diabetologists (AMD)/ Italian Society of Endocrinology (SIE)/ Italian Society of Pharmacology (SIF) multidisciplinary consensus position paper.

Corticosteroids (CSs) are widely used in oncology, presenting several different indications. They are useful for induction of apoptosis in hematological neoplasms, for management of anaphylaxis and cytokine release/hypersensitivity reaction and for the symptomatic treatment of many tumour- and treatment-related complications. If the employment of CSs in the oncological setting results in several benefits for patients and satisfaction for clinicians, on the other hand, many potential adverse events (AEs), both during treatment and after withdrawal of CSs, as well as the duality of the effects of these compounds in oncology, recommend being cautious in clinical practice. To date, several gray zones remain about indications, contraindications, dose, and duration of treatment. In this article, a panel of experts provides a critical review on CSs therapy in oncology, focusing on mechanisms of action and pharmacological characteristics, current and emerging therapeutic indications/contraindications, AEs related to CSs treatment, and the impact on patient outcome.

What Lies behind Paraneoplastic Hypercalcemia Secondary to Well-Differentiated Neuroendocrine Neoplasms? A Systematic Review of the Literature.

BACKGROUND: Neuroendocrine neoplasms (NEN) originate from neuroendocrine cells ubiquitously spread throughout the body. Hypercalcemia associated with cancer is the most common life-threatening metabolic disorder in patients with advanced stage cancer. Paraneoplastic hypercalcemia is more commonly associated with hematological malignancies, renal and breast carcinomas, and squamous cell carcinomas, but it has also been described in patients with well-differentiated NEN, where it often remains undiagnosed. Among its causes, systemic secretion of parathyroid hormone-related protein (PTHrP) and ectopic production of 1,25-dihydroxyvitamin D and parathyroid hormone (PTH) may be considered paraneoplastic causes of hypercalcemia. In order to clarify the diagnostic work up of paraneoplastic hypercalcemia in patients with NEN, we perform a systematic review, which is lacking in the literature. METHODS: We performed a data search using MEDLINE and SCOPUS including papers from 1961 to 2021. We selected articles on paraneoplastic hypercalcemia associated with well-differentiated NEN. RESULTS: The search led to the selection of 78 publications for a total of 114 patients. Pooled data showed that the most frequent primary tumor site associated with paraneoplastic hypercalcemia was pancreatic NEN, followed by Pheochromocytoma. In most cases, paraneoplastic hypercalcemia was caused by PTHrP production and secretion. In more than two thirds of cases, paraneoplastic hypercalcemia was present at the time of NEN diagnosis and, in metachronous cases, was related to local recurrence, distant metastasis development, or tumor progression. In most patients, a combination of therapeutic approaches was employed, and reduction of the tumor burden was essential to control the paraneoplastic syndrome. DISCUSSION: The onset of hypercalcemia associated with cancer in patients with well-differentiated NEN represents a major clinical challenge. The complex clinical and therapeutical management of paraneoplastic hypercalcemia implies the need for a multidisciplinary approach, aimed at controlling the clinical syndrome and tumor growth.

Nephrotoxicity in advanced thyroid cancer treated with tyrosine kinase inhibitors: An update.

Over the past decade, the prognosis of advanced thyroid cancer (TC) patients has dramatically improved thanks to the introduction of tyrosine kinase inhibitors (TKIs). Despite their effectiveness, these drugs are burdened with several side effects that can negatively affect quality of life and compromise therapy continuation. Among renal adverse events (RAEs), proteinuria is the most frequently reported in clinical trials and real-life experiences, especially during treatment with lenvatinib or cabozantinib. This peculiar toxicity is commonly associated with targeted therapies with anti-angiogenic activity, even if the mechanisms underlying its onset and progression are not entirely clear. RAEs should be early recognized and properly managed to avoid renal function worsening and life-threatening consequences. Aiming at providing a comprehensive summary that can help clinicians to identify and manage TKIs-related RAEs in TC patients, we reviewed the current evidence about this topic, from pathogenesis and potential risk factors to diagnosis and treatment.

Minimal Extrathyroidal Extension in Predicting 1-Year Outcomes: A Longitudinal Multicenter Study of Low-to-Intermediate-Risk Papillary Thyroid Carcinoma (ITCO#4).

Background: The role of minimal extrathyroidal extension (mETE) as a risk factor for persistent papillary thyroid carcinoma (PTC) is still debated. The aims of this study were to assess the clinical impact of mETE as a predictor of worse initial treatment response in PTC patients and to verify the impact of radioiodine therapy after surgery in patients with mETE. Methods: We reviewed all records in the Italian Thyroid Cancer Observatory database and selected 2237 consecutive patients with PTC who satisfied the inclusion criteria (PTC with no lymph node metastases and at least 1 year of follow-up). For each case, we considered initial surgery, histological variant of PTC, tumor diameter, recurrence risk class according to the American Thyroid Association (ATA) risk stratification system, use of radioiodine therapy, and initial therapy response, as suggested by ATA guidelines. Results: At 1-year follow-up, 1831 patients (81.8%) had an excellent response, 296 (13.2%) had an indeterminate response, 55 (2.5%) had a biochemical incomplete response, and 55 (2.5%) had a structural incomplete response. Statistical analysis suggested that mETE (odds ratio [OR] 1.16, p = 0.65), tumor size >2 cm (OR 1.45, p = 0.34), aggressive PTC histology (OR 0.55, p = 0.15), and age at diagnosis (OR 0.90, p = 0.32) were not significant risk factors for a worse initial therapy response. When evaluating the combination of mETE, tumor size, and aggressive PTC histology, the presence of mETE with a >2 cm tumor was significantly associated with a worse outcome (OR 5.27 [95% confidence interval], p = 0.014). The role of radioiodine ablation in patients with mETE was also evaluated. When considering radioiodine treatment, propensity score-based matching was performed, and no significant differences were found between treated and nontreated patients (p = 0.24). Conclusions: This study failed to show the prognostic value of mETE in predicting initial therapy response in a large cohort of PTC patients without lymph node metastases. The study suggests that the combination of tumor diameter and mETE can be used as a reliable prognostic factor for persistence and could be easily applied in clinical practice to manage PTC patients with low-to-intermediate risk of recurrent/persistent disease.

Pituitary metastases from neuroendocrine neoplasms: case report and narrative review.

PURPOSE: Pituitary metastases (PM) are uncommon findings and are mainly derived from breast and lung cancers. No extensive review of PM from neuroendocrine neoplasms (NENs) is on record. Here we describe a clinical case of PM from pancreatic NEN and review the clinical features of PM from NENs reported in the literature. METHODS: A case of PM from a pancreatic NEN followed at our institution is described. We also reviewed the 43 cases of PM from NENs reported in the literature. RESULTS: A 59-year old female patient, previously submitted to duodeno-cephalo-pancreasectomy for a well-differentiated pancreatic NEN, with known hepatic metastases, underwent a 68 Ga-DOTATOC PET/CT that revealed an uptake in the pituitary gland. A subsequent MRI displayed a pituitary lesion, with suprasellar extension. After a hormonal and genetic diagnostic workup that excluded the diagnosis of MEN 1, the worsening of headache and visual impairment and the growth of the lesion lead to its surgical removal. A pituitary localization of the pancreatic NEN was identified. Regarding the published cases of PM from NENs, the most common tumour type was small cell lung cancer (SCLC), accounting for nearly half of the cases, followed by bronchial and pancreatic well differentiated NENs. The most frequent symptom was a variable degree of visual impairment, while headache was reported in half of the cases. Partial or total anterior hypopituitarism was present in approximately three quarters of the cases, while diabetes insipidus was less common. The most frequent treatment for PM was surgical resection, followed by radiotherapy and chemotherapy. The clinical outcome was in line with previous reports of PM from solid tumours, with a median survival of 14 months. Surgery of PM was associated with prolonged survival. CONCLUSIONS: PM from NENs have clinical features similar to metastases derived from other solid tumours, albeit the involvement of the anterior pituitary seems more frequent; a thorough pituitary hormonal evaluation is mandatory, after focused radiological studies, particularly if a surgical approach is considered. The optimal management of PM remains disputed and seems mainly driven by the aggressiveness of the primary tumour and the presence of symptoms. In well-differentiated NENs, particularly in the case of symptomatic PM, surgical removal may be a reasonable approach.

Case Report: Unmasking Hypercalcemia in Patients With Neuroendocrine Neoplasms. Experience From Six Italian Referral Centers.

Background: Hypercalcemia is a common paraneoplastic syndrome which can occur in up to 10% of patients with advanced neoplasms. Paraneoplastic parathyroid hormone-related protein (PTHrP) represents the most frequent cause of this syndrome. In neuroendocrine neoplasms (NENs) paraneoplastic hypercalcemia is rare. Case Series: The present series includes all patients with NENs and paraneoplastic hypercalcemia from four Italian centres: (I) A 40-year-old man was hospitalized for repeated episodes of falls, hyposthenia and drowsiness. Severe hypercalcemia was found. Metastatic pancreatic G2 NEN and PTHrP-related hypercalcemia were diagnosed. The patient started therapy with somatostatin analogs (SSA) and Denosumab. After disease progression peptide receptor radionuclide therapy (PRRT) was started with an objective response associated with PTHrP reduction and normocalcemia. (II) A 45-year-old man was referred for pancreatic G2 NEN. SSA and subsequently everolimus were administered for metastases occurrence. Hypercalcemia occurred and PRRT and Denosumab were started for disease progression with the onset of bone metastases. Despite disease stability after four cycles of PRRT the patient's performance status worsened until death. (III) A 49-year-old woman was hospitalized for psychic slowdown, confusional state, sensory dullness. A severe hypercalcemia, associated with a pancreatic G1 NEN was diagnosed and treated with haemodialysis, bisphosphonates injections and continuous infusion of calcitonin. 1,25-dihydroxyvitamin D was high, PTHrP was undetectable. After surgery serum calcium levels and 1,25-dihydroxyvitamin D were normalized. (IV) A 69-year-old man was hospitalized after the onset of shortness of breath and dyspnea, asthenia and weight loss. Computed Tomography (CT) and 68Ga DOTATOC Positron Emission Tomography (PET)-CT revealed a left pulmonary nodule. Hypercalcemia and markedly elevated PTHrP levels were detected. The histological examination revealed an atypical carcinoid. After surgery, calcium levels were normalized, PTHrP was significantly reduced with an improvement of general conditions. Conclusion: In our series, paraneoplastic PTHrP-related hypercalcemia occurred in pancreatic NEN and in one bronchial carcinoid representing the third case in the literature. Our case associated with 1,25-dihydroxyvitamin D secretion represents the fourth case in the literature. PTHrP secretion should be considered in NENs' patients with hypercalcemia. Acute treatment should be focused on lowering calcium levels, and long-term control can be achieved by tumor cytoreduction inhibiting PTHrP release.

Interventional Radiology Approaches for Liver Metastases from Thyroid Cancer: A Case Series and Overview of the Literature.

BACKGROUND: Liver metastases (LMs) from thyroid cancer (TC) are relatively uncommon in clinical practice and their management is challenging. Interventional radiology loco-regional treatments (LRTs), including radiofrequency ablation (RFA) and trans-arterial chemoembolization (TACE), have been successfully employed to treat LMs from various types of cancer. METHODS: We analyzed the role of LRTs in the management of unresectable LMs from differentiated and medullary TCs performed at our institution from 2015 to 2020. A review of the available English literature regarding this topic was also performed. RESULTS: Six hepatic LRTs were performed in 4 TC patients with LMs, in 2 cases after the start of treatment with a tyrosine kinase inhibitor (TKI). A partial response was obtained in 2 patients; the diameter of the largest targeted lesion was 18 mm in both of them. The remaining procedures were performed on larger lesions and a stable disease was achieved in all but one case. Acute LRT-related complications were transient and mild. In literature, the largest studies were focused on TACE in LMs from MTC, showing good tolerance and remarkable disease control, especially in case of limited liver tumour involvement. CONCLUSION: LRTs for LMs represent a valuable option for the treatment of metastatic TC in case of isolated hepatic progression or for symptoms relief, also after the start of TKI treatment as part of a multimodal approach. The best disease control is obtained when hepatic metastatic burden is limited. These procedures are generally well tolerated; however, a cautious multidisciplinary selection of the candidates is mandatory.

Radiofrequency Thermal Ablation for a Small Papillary Thyroid Carcinoma in a Patient Unfit for Surgery: A Case Report.

Ultrasound-guided radiofrequency thermal ablation has been proposed as an effective and safe procedure for treating patients who have low-risk papillary thyroid microcarcinomas and/or are unfit for surgery. We present the case of a 72-year old male patient with a small thyroid nodule diagnosed as papillary carcinoma after fine needle aspiration. Since the patient had other serious comorbidities, priority was given to other therapies and the malignant thyroid nodule was submitted to active surveillance. After detecting at a follow-up examination a slight dimensional increase of the nodule, the possibility of a radiofrequency thermal ablation was proposed to our patient, who accepted. The procedure was safely and effectively carried out. Follow-up examinations with ultrasonography (or contrast enhanced ultrasound), conducted after 1, 3, 6, and 12 months, demonstrated a progressive reduction of size and loss of vascularization in the treated area. The fine needle aspiration was repeated after 6 months: the sample revealed a very poor cellularity composed of inflammatory cells and thick colloid; no residual neoplastic cells were observed. Our experience confirmed what already demonstrated by previous reports: radiofrequency ablation can effectively eliminate small papillary carcinomas, with a very low complication rate. It may be an alternative strategy for the treatment of low-risk, indolent papillary thyroid microcarcinomas, thus avoiding the potential side-effects of surgery in patients at risk for relevant comorbidities.

Quality of Life during Treatment with Lenvatinib for Thyroid Cancer: The Patients' Perspective beyond the Medical Evaluation.

BACKGROUND: Lenvatinib (LEN) has shown great efficacy but important toxicity in patients with advanced radioactive iodine-refractory (RAI-R) thyroid cancer (TC); a focused evaluation of its impact on patients' quality of life (QoL) is still lacking. Our prospective study investigated the impact of this drug on QoL in a group of RAI-R TC patients treated at our centre. METHODS: All patients filled in two questionnaires before and during treatment: (1) the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events adapted questionnaire, assessing prevalence, severity, and/or interference on daily activities of the most frequent symptomatic adverse events (AEs) reported in previous clinical trials during therapy with LEN, and (2) the European Quality of Life 5 Dimensions 3 Levels (EQ-5D-3L) questionnaire, providing the EQ-5D index and the EQ visual analogue scale (EQ-VAS). Data from baseline questionnaires were compared with those obtained 3, 6, and 12 months after the start of treatment. RESULTS: In our population (n = 20), an overall increased perception of symptomatic AEs emerged during treatment (statistically significant for abdominal pain, asthenia/fatigue, decreased appetite, and xerostomia). The median EQ-5D index and EQ-VAS scores after 3 months of treatment were lower than at baseline, almost returning to initial values after 12 months. CONCLUSION: RAI-R TC patients reported a general increase in prevalence and interference on daily activities of symptomatic AEs during therapy with LEN. Self-perceived QoL initially decreased during therapy. However, our data suggest that QoL could be restored after 12 months; this trend might partly reflect the impact of therapy optimisation.

Diabetes in Cancer Patients: Risks, Goals and Management.

Diabetes mellitus (DM) is commonly found in cancer patients. The relationship between DM and cancer appears to be bidirectional: DM has been associated with an increased risk of developing several types of cancer while also cancer treatments, through the induction of metabolic derangements, can facilitate the onset of DM, or worsen glucose control. In particular, novel antineoplastic treatments such as immunotherapy and targeted therapies have been associated with both acute and long-term metabolic consequences. An adequate management of DM in cancer patients is pivotal, since DM can negatively affect the clinical outcomes of these subjects, being associated with worse survival. However, DM management in cancer patients may be challenging given the peculiarities of these conditions. Lower reliability of HbA1c, a thorough evaluation of the safety profile of antidiabetic drugs, and the need to adapt glycemic targets to patients' prognosis should be taken into consideration. Moreover, DM is commonly encountered also in the ever-growing population of cancer survivors, contributing to their increased cardiovascular risk. In conclusion, taking in consideration the lack of specific guidelines, the particular features of the condition, and the potential impact on prognosis, a multidisciplinary management of DM in cancer patients and survivors is warranted.

Vitamin D Deficiency and the Risk of Cerebrovascular Disease.

Vitamin D deficiency has been clearly linked to major chronic diseases associated with oxidative stress, inflammation, and aging, including cardiovascular and neurodegenerative diseases, diabetes, and cancer. In particular, the cardiovascular system appears to be highly sensitive to vitamin D deficiency, as this may result in endothelial dysfunction and vascular defects via multiple mechanisms. Accordingly, recent research developments have led to the proposal that pharmacological interventions targeting either vitamin D deficiency or its key downstream effects, including defective autophagy and abnormal pro-oxidant and pro-inflammatory responses, may be able to limit the onset and severity of major cerebrovascular diseases, such as stroke and cerebrovascular malformations. Here we review the available evidence supporting the role of vitamin D in preventing or limiting the development of these cerebrovascular diseases, which are leading causes of disability and death all over the world.

Symptomatic Biliary Disorders During Lenvatinib Treatment for Thyroid Cancer: An Underestimated Problem.

Background: The prognosis of several human malignancies has dramatically improved after the introduction of tyrosine kinase inhibitors (TKIs); however, their use has been associated with a large spectrum of adverse events, including symptomatic biliary disorders. In the phase III trial of lenvatinib in radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC) patients, gallbladder (GB) and biliary duct (BD) diseases and complications were reported. We evaluated symptomatic biliary disorders during treatment with lenvatinib in real-life practice to provide a more exhaustive understanding of its toxicity. Methods: We retrospectively evaluated all consecutive patients treated with lenvatinib in our center for progressive RAI-refractory DTC, excluding those who underwent cholecystectomy before the start of therapy. We report all radiologically confirmed symptomatic GB/BD disorders, which were subsequently treated with cholecystectomy, and we describe their management along with relevant biochemical and histological findings. All available GB/BD imaging of patients who developed biliary toxicity during lenvatinib was reviewed by a single experienced radiologist, including computed tomography scans performed for tumor assessment at baseline and during TKI therapy. Results: Five patients (14.7%) developed symptomatic radiologically confirmed biliary disease after a median time of 4.4 months of lenvatinib treatment [interquartile range 3.4-14.4 months] and thus underwent cholecystectomy. A scheduled surgical approach was possible only in two cases; in the remaining patients, presurgical TKI interruption was shorter than one week. After wound healing, treatment was resumed by all subjects. Three patients showed mild biochemical alterations in the two previous monthly follow-up visits. Before the start of treatment, GB/BD abnormalities were radiologically detected only in one case. Conclusions: In our cohort, an unexpectedly high proportion of RAI-refractory DTC patients treated with lenvatinib developed a symptomatic biliary disorder with the need of surgical intervention. Further studies are required to optimize the diagnosis and treatment of patients at higher risk of developing a symptomatic GB/BD disease during assumption of lenvatinib.

GENDER INFLUENCES THE CLINICAL PRESENTATION AND LONG-TERM OUTCOME OF GRAVES DISEASE.

OBJECTIVE: The outcome of antithyroid drug (ATD) treatment for Graves disease (GD) is difficult to predict. In this study, we investigated whether male gender, besides other factors usually associated with a poor outcome of ATD treatment, may affect disease presentation and predict the response to medical treatment in subjects with GD. METHODS: We studied 294 patients with a first diagnosis of GD. In all patients, ATD treatment was started. Clinical features, thyroid volume, and eye involvement were recorded at baseline. Serum levels of free thyroxine (FT4), free triiodothyronine (FT3), thyroid-stimulating hormone (TSH), and TSH-receptor antibodies (TRAb) were measured at baseline and during the follow-up. Treatment outcome (FT4, FT3, and TSH serum levels and further treatments for GD after ATD withdrawal) was evaluated. RESULTS: When compared to women, men showed a significantly larger thyroid volume and a higher family positivity for autoimmune diseases. During ATD, the mean serum levels of TSH, FT4, FT3, and TRAb did not differ between groups. Within 1 year after ATD discontinuation, relapse of hyperthyroidism was significantly more frequent in men than in women. Within the 5-year follow-up period, the prevalence of men suffering a late relapse was higher compared with that of women. The outcome at the end of the 5-year follow-up period was significantly associated with gender and TRAb levels at disease onset. CONCLUSION: Male patients with GD have a poorer prognosis when submitted to medical treatment with ATDs. A larger goiter at presentation and a stronger genetic autoimmune background might explain this gender difference in patients with GD. ABBREVIATIONS: ATD = antithyroid drug FT3 = free triiodothyronine FT4 = free thyroxine GD = Graves disease GO = Graves orbitopathy RAI = radioiodine TRAb = thyroid-stimulating hormone-receptor antibody TSH = thyroid-stimulating hormone.