CD20 + T lymphocytes in isolated Hashimoto's thyroiditis and type 3 autoimmune polyendocrine syndrome: a pilot study.

BACKGROUND: CD20+ T cells represent up to 5% of circulating T lymphocytes. These cells have been shown to produce higher levels of IL-17A and IFN-γ than those of CD20- T lymphocytes. Some reports described the role of CD20+ T cells in autoimmune disorders such as multiple sclerosis and rheumatoid arthritis possibly due to their ability to produce these inflammatory cytokines. This study is aimed at describing the behavior of CD20+ T lymphocytes in the most frequent autoimmune disorder, i.e., Hashimoto's thyroiditis (HT), presenting isolated or associated to further autoaggressive disorders in a frame of poly-autoimmunity. METHODS: The study group encompasses 65 HT patients: 23 presenting in isolated form (IT) and 42 with an associated non-endocrine autoimmune disorder [16 with chronic atrophic gastritis (CAG), 15 with nonsegmental vitiligo (VIT), and 11 with celiac disease (CD)]. Twenty healthy donors act as control group (HD). Chronic use of interfering drugs, severe or chronic disorders, and pregnancy and lactation were used as exclusion criteria. Whole blood samples (100 µl) were stained with fluorescent-labeled antibodies (anti-CD45, anti-CD3, anti-CD19, anti-CD16, anti-CD56, anti-CD4, anti-CD8, anti-CD20). Red blood cells were then lysed by adding 1 ml of hypotonic buffer, and samples were acquired on a Flow Cytometer. RESULTS: CD3+CD8+CD20+ T lymphocytes' percentages, were significantly higher in the whole group of autoimmune patients compared to healthy donors (p = 0.0145). Dividing HT patients based on the type of presentation of autoimmune thyroiditis, CAG group showed the highest percentage of these cells as compared to HD and CD (p = 0.0058). IT patients showed higher percentages of CD3+ CD8+CD20+ cells than those of HD patients although not reaching statistical significance. However, dividing IT group based on thyroid function, hypothyroid patients showed higher CD8+CD20+ cell percentages than those of HD and euthyroid patients (p = 0.0111). Moreover, in IT patients, these cells were negatively correlated with FT4 levels (p = 0.0171; r = -0.4921). CONCLUSIONS: These preliminary findings indicate that CD8+CD20+ T cells are activated in patients with autoimmune thyroiditis and may behave differently according to the presence of poly-autoimmunity and hypothyroidism.

Does thyroglossal duct arborization play a role in the post-surgical outcome of Sistrunk procedure in children?

PURPOSE: The purpose of the present study is to analyze thyroglossal duct cyst (TGDC) histopathological features, with focus on "arborization", in a cohort of pediatric patients who underwent surgical removal, and evaluate a possible correlation with clinical recurrences. METHODS: A retrospective analysis of all patients who underwent surgical resection for TGDC at the division of Pediatric Surgery of the University of Pisa from 2015 to 2020 was performed; for each patient, the following data were recorded: age, sex, clinical presentation, localization, size of the lesion, diagnostic tools, histopathological features, perioperative complications, recurrence and follow-up. RESULTS: With respect to arborization, following histopathological analysis 25/30 patients (83.3%) presented thyroglossal duct branching. After a median follow-up of 3.5 years, only 2 out of 30 patients (6.7%), one male and one female, respectively aged 4 y.o. and 6 y.o., presented recurrence within one year from first surgery. CONCLUSION: Surgery for TGDC remains a challenge for pediatric surgeons, while arborization was present in most of our cases which underwent surgery. With respect to the role of arborization, our study did not highlight sufficient conclusive data regarding their role in recurrence: instead, it showed wide resection as satisfactory, being the arborization present in most of the cases at histopathology.

Antineoplastic Effect of ALK Inhibitor Crizotinib in Primary Human Anaplastic Thyroid Cancer Cells with STRN-ALK Fusion In Vitro.

Anaplastic thyroid cancer (ATC) is one of the deadliest human cancers and represents <2% of thyroid carcinomas. A therapeutic target for ATC is represented by anaplastic lymphoma kinase (ALK) rearrangements, involved in tumor growth. Crizotinib is an oral small-molecule tyrosine kinase inhibitor of the ALK, MET, and ROS1 kinases, approved in ALK-positive non-small cell lung cancer. Until now, the effect of crizotinib in "primary human ATC cells" (pATCs) with transforming striatin (STRN)-ALK fusion has not been reported in the literature. In this study, we aimed to obtain pATCs with STRN-ALK in vitro and evaluate the in vitro antineoplastic action of crizotinib. Thyroid surgical samples were obtained from 12 ATC patients and 6 controls (who had undergone parathyroidectomy). A total of 10/12 pATC cultures were obtained, 2 of which with transforming STRN-ALK fusion (17%). Crizotinib inhibited proliferation, migration, and invasion and increased apoptosis in 3/10 pATC cultures (2 of which with/1 without STRN-ALK), particularly in those with STRN-ALK. Moreover, crizotinib significantly inhibited the proliferation of AF cells (a continuous cell line obtained from primary ATC cells). In conclusion, the antineoplastic activity of crizotinib has been shown in human pATCs (with STRN-ALK) in preclinical studies in vitro, opening the way to future clinical evaluation in these patients.

Evaluation of the Therapeutic Effects of Harmine on Anaplastic Thyroid Cancer Cells.

Anaplastic thyroid carcinoma (ATC) is an extremely difficult disease to tackle, with an overall patient survival of only a few months. The currently used therapeutic drugs, such as kinase inhibitors or immune checkpoint inhibitors, can prolong patient survival but fail to eradicate the tumor. In addition, the onset of drug resistance and adverse side-effects over time drastically reduce the chances of treatment. We recently showed that Twist1, a transcription factor involved in the epithelial mesenchymal transition (EMT), was strongly upregulated in ATC, and we wondered whether it might represent a therapeutic target in ATC patients. To investigate this hypothesis, the effects of harmine, a ß-carboline alkaloid shown to induce degradation of the Twist1 protein and to possess antitumoral activity in different cancer types, were evaluated on two ATC-derived cell lines, BHT-101 and CAL-62. The results obtained demonstrated that, in both cell lines, harmine reduced the level of Twist1 protein and reverted the EMT, as suggested by the augmentation of E-cadherin and decrease in fibronectin expression. The drug also inhibited cell proliferation and migration in a dose-dependent manner and significantly reduced the anchorage-independent growth of both ATC cell lines. Harmine was also capable of inducing apoptosis in BHT-101 cells, but not in CAL-62 ones. Finally, the activation of PI3K/Akt signaling, but not that of the MAPK, was drastically reduced in treated cells. Overall, these in vitro data suggest that harmine could represent a new therapeutic option for ATC treatment.

Molecular targets of tyrosine kinase inhibitors in thyroid cancer.

Thyroid cancer (TC) is the eighth most frequently diagnosed cancer worldwide with a rising incidence in the past 20 years. Surgery is the primary strategy of therapy for patients with medullary TC (MTC) and differentiated TC (DTC). In DTC patients, radioactive iodine (RAI) is administered after thyroidectomy. Neck ultrasound, basal and thyroid-stimulating hormone-stimulated thyroglobulin are generally performed every three to six months for the first year, with subsequent intervals depending on initial risk assessment, for the detection of possible persistent/recurrent disease during the follow up. Distant metastases are present at the diagnosis in ∼5 % of DTC patients; up to 15 % of patients have recurrences during the follow up, with a survival reduction (70 %-50 %) at 10-year. During tumor progression, the iodide uptake capability of DTC cancer cells can be lost, making them refractory to RAI, with a negative impact on the prognosis. Significant advances have been done recently in our understanding of the molecular pathways implicated in the progression of TCs. Several drugs have been developed, which inhibit signaling kinases or oncogenic kinases (BRAFV600E, RET/PTC), such as those associated with Platelet-Derived Growth Factor Receptor and Vascular Endothelial Growth Factor Receptor. Tyrosine kinase receptors are involved in cancer cell proliferation, angiogenesis, and lymphangiogenesis. Several tyrosine kinase inhibitors (TKIs) are emerging as new treatments for DTC, MTC and anaplastic TC (ATC), and can induce a clinical response and stabilize the disease. Lenvatinib and sorafenib reached the approval for RAI-refractory DTC, whereas cabozantinib and vandetanib for MTC. These TKIs extend median progression-free survival, but do not increase the overall survival. Severe side effects and drug resistance can develop in TC patients treated with TKIs. Additional studies are needed to identify a potential effective targeted therapy for aggressive TCs, according to their molecular characterization.

Primary cell cultures for the personalized therapy in aggressive thyroid cancer of follicular origin.

Thyroid cancer (TC) is the most prevalent endocrine malignancy. More than 90 % of TC is represented by differentiated TC (DTC) arising from the follicular thyroid cells. DTC includes papillary TC (PTC), follicular TC (FTC), and Hürthle cell TC. Anaplastic TC (ATC) accounts for 1% of TC, and it represents 15-40 % of TC death. Current treatment strategies are not completely effective against aggressive DTC or ATC, and mortality is one of the most important challenges. Recently, progresses have been obtained in the understanding of the molecular/genetic basis of TC progression, and new drugs have been introduced [i.e. tyrosine kinase inhibitors (TKIs)], able to block the oncogenic or signaling kinases, associated with cellular growth. Thyroid cell lines, obtained from tumoral cells and chosen for high proliferation in vitro, have been used as preclinical models. Actually, these cells lose the characteristic features of the primary tumor, because they adapt to in vitro growth conditions. For these reasons, the use of these cell lines has important limitations, and more recently human primary cell cultures have been established as monolayer cultures, and investigated for their biological behavior. Moreover, in the past, primary TC cells could be collected only through surgical biopsies, while recently human primary cell cultures can be established also from samples of fine-needle aspiration citology from aggressive dedifferentiated DTC or ATC. Testing in vitro different TKIs in each patient can help to develop new personalized treatments, without using ineffective drugs. In conclusion, personalized medicine and precise oncology, which consider both patients and their disease features, represent the future of the treatment approach, and further progress is needed in this direction.

COVID-19 and Mixed Cryoglobulinemia Syndrome: Long-Term Survey Study on the Prevalence and Outcome, Vaccine Safety, and Immunogenicity.

PURPOSE: Mixed cryoglobulinemia syndrome (MCs) is a rare immunoproliferative systemic disorder with cutaneous and multiple organ involvement. Our multicenter survey study aimed to investigate the prevalence and outcome of COVID-19 and the safety and immunogenicity of COVID-19 vaccines in a large MCs series. METHODS: The survey included 430 unselected MCs patients (130 M, 300 F; mean age 70 ± 10.96 years) consecutively collected at 11 Italian referral centers. Disease classification, clinico-serological assessment, COVID-19 tests, and vaccination immunogenicity were carried out according to current methodologies. RESULTS: A significantly higher prevalence of COVID-19 was found in MCs patients compared to Italian general population (11.9% vs 8.0%, p < 0.005), and the use of immunomodulators was associated to a higher risk to get infected (p = 0.0166). Moreover, higher mortality rate was recorded in MCs with COVID-19 compared to those without (p < 0.01). Patients' older age (≥ 60 years) correlated with worse COVID-19 outcomes. The 87% of patients underwent vaccination and 50% a booster dose. Of note, vaccine-related disease flares/worsening were significantly less frequent than those associated to COVID-19 (p = 0.0012). Impaired vaccination immunogenicity was observed in MCs patients compared to controls either after the first vaccination (p = 0.0039) and also after the booster dose (p = 0.05). Finally, some immunomodulators, namely, rituximab and glucocorticoids, hampered the vaccine-induced immunogenicity (p = 0.029). CONCLUSIONS: The present survey revealed an increased prevalence and morbidity of COVID-19 in MCs patients, as well an impaired immunogenicity even after booster vaccination with high rate of no response. Therefore, MCs can be included among frail populations at high risk of infection and severe COVID-19 manifestations, suggesting the need of a close monitoring and specific preventive/therapeutical measures during the ongoing pandemic.

Increased neutrophil derived chemokines (CXCL10 and CCL2) in human trichinellosis as possible serological markers of the polarization of the immune response against the parasite.

Trichinella britovi is a widely distributed parasitic nematode, transmitted through ingestion of raw or poorly cooked meat containing muscle larvae. This helminth can regulate the host immune system during the early phase of infection. The immune mechanism mainly involves the interaction of Th1 and Th2 responses and related cytokines. Chemokines (C-X-C or C-C) and matrix metalloproteinases (MMPs) have also shown to be implicated in a number of parasitic infections, mainly malaria, neurocysticercosis, angiostronyloidosis, and schistosomiasis, but poor is known about their role in human Trichinella infection. We previously found that serum MMP-9 levels were significantly increased in T. britovi infected patients with relevant symptoms such as diarrhea, myalgia, and facial oedema, which makes these enzymes a potential reliable indicator of inflammation in trichinellosis patients. These changes were also observed in T. spiralis/T. pseudospiralis experimentally infected mice. No data are available about circulating levels of two pro-inflammatory chemokines, CXCL10 and CCL2, in trichinellosis patients with or w/o clinical signs of the infection. In this study, the association of serum level of CXCL10 and CCL2 with clinical outcome of T. britovi infection and their relation to MMP-9 were investigated. Patients (median age 49 ± 0.33 years) acquired infection by consuming raw sausages prepared with wild boar and pork meat. Sera were collected during the acute and the convalescent phases of the infection. A positive significant association (r = 0.61, p = 0.0004) was observed between MMP-9 and CXCL10 levels. The CXCL10 level significantly correlated with the severity of symptoms in patients being particularly higher in patients suffering diarrhea, myalgia, and facial oedema, thus suggesting a positive association of this chemokine with symptomatologic traits, especially myalgia (and increased LDH and CPK levels) (p < 0.005). No correlation was found between levels of CCL2 and the clinical symptoms.

Antineoplastic Activity of Pazopanib in Anaplastic Thyroid Cancer in Primary Culture.

Anaplastic thyroid cancer (ATC) is a rare and rapidly fatal human cancer. Its usual treatment includes the combination of surgery, external hyperfractionated radiation therapy, and chemotherapy. These treatments permit achieving about 6-10 months of median survival. For this reason, it is challenging to predict the ATC patient clinical therapy responsiveness. Pazopanib is a multitarget tyrosine kinase inhibitor of VEGF receptors, PDGF, and c-Kit. Until now, the effect of pazopanib in primary human ATC cells (pATC) has not been reported in the literature. The aim of our study was to evaluate in vitro the antineoplastic effect of pazopanib in pATC. Surgical thyroidal tissues were collected from five patients with ATC, from thyroid biopsy at the moment of first surgical operation. An inhibition of proliferation, migration, and invasion, and an increase in apoptosis were demonstrated upon treating pATC cells with pazopanib (p < 0.05). Moreover, pazopanib was able to significantly decrease the VEGF expression in pATC cells (p < 0.05). To conclude, in this study, we demonstrate the antineoplastic activity of the antiangiogenic inhibitor, pazopanib, in human pATC in vitro.

Absent or suboptimal response to booster dose of COVID-19 vaccine in patients with autoimmune systemic diseases.

Autoimmune systemic diseases (ASD) show impaired immunogenicity to COVID-19 vaccines. Our prospective observational multicenter study aimed at evaluating the seroconversion elicited by COVID-19 vaccine over the entire vaccination cycle including the booster dose. Among 478 unselected ASD patients originally evaluated at the end of the first vaccination cycle (time 1), 344 individuals were re-evaluated after a 6-month period (time 2), and 244 after the booster vaccine dose (time 3). The immunogenicity of mRNA COVID-19 vaccines (BNT162b2 and mRNA-1273) was assessed by measuring serum IgG-neutralizing antibody (NAb) on samples obtained at the three time points in both patients and 502 age-matched controls. In the 244 ASD group that received booster vaccine and monitored over the entire follow-up, the mean serum NAb levels (time 1, 2, and 3: 696.8 ± 52.68, 370.8 ± 41.92, and 1527 ± 74.16SD BAU/mL, respectively; p < 0.0001) were constantly lower compared to controls (p < 0.0001), but they significantly increased after the booster dose compared to the first two measurements (p < 0.0001). The percentage of patients with absent/suboptimal response to vaccine significantly decreased after the booster dose compared to the first and second evaluations (time 1, 2, and 3: from 28.2% to 46.3%, and to 7.8%, respectively; p < 0.0001). Of note, the percentage of patients with absent/suboptimal response after the booster dose was significantly higher compared to controls (19/244, 7.8% vs 1/502, 0.2%; p < 0.0001). Similarly, treatment with immune-modifiers increased the percentage of patients exhibiting absent/suboptimal response (16/122, 13.1% vs 3/122, 2.46%; p = 0.0031). Overall, the above findings indicate the usefulness of booster vaccine administration in ASD patients. Moreover, the persistence of a significantly higher percentage of individuals without effective seroconversion (7.8%), even after the booster dose, warrants for careful monitoring of NAb levels in all ASD patients to identify those with increased risk of infection. In this particularly frail patients' setting, tailored vaccination and/or therapeutic strategy are highly advisable.

Combination Strategies Involving Immune Checkpoint Inhibitors and Tyrosine Kinase or BRAF Inhibitors in Aggressive Thyroid Cancer.

Thyroid cancer is the most common (~90%) type of endocrine-system tumor, accounting for 70% of the deaths from endocrine cancers. In the last years, the high-throughput genomics has been able to identify pathways/molecular targets involved in survival and tumor progression. Targeted therapy and immunotherapy individually have many limitations. Regarding the first one, although it greatly reduces the size of the cancer, clinical responses are generally transient and often lead to cancer relapse after initial treatment. For the second one, although it induces longer-lasting responses in cancer patients than targeted therapy, its response rate is lower. The individual limitations of these two different types of therapies can be overcome by combining them. Here, we discuss MAPK pathway inhibitors, i.e., BRAF and MEK inhibitors, combined with checkpoint inhibitors targeting PD-1, PD-L1, and CTLA-4. Several mutations make tumors resistant to treatments. Therefore, more studies are needed to investigate the patient's individual tumor mutation burden in order to overcome the problem of resistance to therapy and to develop new combination therapies.

Thyroid autoimmune disorders and cancer.

In the last decades, many studies conducted in vitro, and in vivo, have shown that thyroid autoimmunity and thyroid cancer (TC) (mainly papillary TC) can be concomitant, even if the exact mechanisms at the basis of this association are still not clear. Growing incidence of TC coincides with increased registration of autoimmune thyroid disorders (AITD) suggesting an association between those pathologies. Elevated TSH levels and thyroid autoimmunity were defined as independent risk factors for TC. However a lot of evidence suggests that autoimmunity and inflammation, per se, are risk factors for TC. The link between inflammation and TC involves multiple components of the immune system, extracellular matrix, stroma, and adipose tissue, with pro-tumoral activity of inflammation being opposed to anti-inflammatory effects, favoring protection against cancer progression. Within the tumor microenvironment, inflammatory cells, belonging both to innate (macrophages) and adaptive (lymphocytes) immune responses, are interconnected with fibroblasts, endothelial cells, adipocytes, and extracellular matrix through cytokines, chemokines and adipocytokines. Under the influence of transcriptional regulators (such as Nuclear Factor-kappa B, mitogen-activated protein kinases, or Phosphoinositide-3 kinase/protein kinase-B), oncogenes connected to the different subtypes of TC promote their farthermost proliferative effect on the tumor microenvironment. Future studies will be necessary to understand the connections between thyroid autoimmunity and cancer, also in order to design a tailored therapy for TC patients with AITD.

A case of Graves' disease and type 1 diabetes mellitus following SARS-CoV-2 vaccination.

Autoimmune diseases, including autoimmune endocrine diseases (AIED), are thought to develop following environmental exposure in patients with genetic predisposition. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and vaccines against it could represent new environmental triggers for AIED. We report a patient, with history of vitiligo vulgaris and 8 years of type 2 diabetes, who came to our institution because of fever, weight loss, asthenia and thyrotoxicosis occurred 4 weeks later the administration of BNT162B2 (Pfizer-BioNTech) SARS-CoV-2 vaccine. Clinical, biochemical and instrumental work-up demonstrated Graves' disease and autoimmune diabetes mellitus. The occurrence of these disorders could be explained through different mechanism such as autoimmune/inflammatory syndrome induced by adjuvants (ASIA syndrome), mRNA "self-adjuvant" effect, molecular mimicry between human and viral proteins and immune disruption from external stimuli. However further studies are needed to better understand the underlying pathogenesis of AIED following SARS-CoV-2 vaccine.

Impaired immunogenicity to COVID-19 vaccines in autoimmune systemic diseases. High prevalence of non-response in different patients' subgroups.

Autoimmune systemic diseases (ASD) may show impaired immunogenicity to COVID-19 vaccines. Our prospective observational multicenter study aimed to evaluate the seroconversion after the vaccination cycle and at 6-12-month follow-up, as well the safety and efficacy of vaccines in preventing COVID-19. The study included 478 unselected ASD patients (mean age 59 ± 15 years), namely 101 rheumatoid arthritis (RA), 38 systemic lupus erythematosus (SLE), 265 systemic sclerosis (SSc), 61 cryoglobulinemic vasculitis (CV), and a miscellanea of 13 systemic vasculitis. The control group included 502 individuals from the general population (mean age 59 ± 14SD years). The immunogenicity of mRNA COVID-19 vaccines (BNT162b2 and mRNA-1273) was evaluated by measuring serum IgG-neutralizing antibody (NAb) (SARS-CoV-2 IgG II Quant antibody test kit; Abbott Laboratories, Chicago, IL) on samples obtained within 3 weeks after vaccination cycle. The short-term results of our prospective study revealed significantly lower NAb levels in ASD series compared to controls [286 (53-1203) vs 825 (451-1542) BAU/mL, p < 0.0001], as well as between single ASD subgroups and controls. More interestingly, higher percentage of non-responders to vaccine was recorded in ASD patients compared to controls [13.2% (63/478), vs 2.8% (14/502); p < 0.0001]. Increased prevalence of non-response to vaccine was also observed in different ASD subgroups, in patients with ASD-related interstitial lung disease (p = 0.009), and in those treated with glucocorticoids (p = 0.002), mycophenolate-mofetil (p < 0.0001), or rituximab (p < 0.0001). Comparable percentages of vaccine-related adverse effects were recorded among responder and non-responder ASD patients. Patients with weak/absent seroconversion, believed to be immune to SARS-CoV-2 infection, are at high risk to develop COVID-19. Early determination of serum NAb after vaccination cycle may allow to identify three main groups of ASD patients: responders, subjects with suboptimal response, non-responders. Patients with suboptimal response should be prioritized for a booster-dose of vaccine, while a different type of vaccine could be administered to non-responder individuals.

Association of glomerular hyperfiltration with serum chemokine levels and metabolic features in prepubertal children with overweight/obesity.

BACKGROUND AND AIMS: Glomerular hyperfiltration (GH) is proposed as one of the earliest events in obesity (OB)-associated renal disease. Children with GH and type-1 diabetes showed increased chemokine levels. Chemokine associations with glomerular filtration rate (GFR) and metabolic features in prepubertal children with overweight (OW)/OB are unknown. METHODS AND RESULTS: Cross-sectional study. 75 prepubertal children (aged: 9.0 ± 1.7 years) with OW/OB were studied. Clinical and metabolic characteristics (including non-esterified fatty acids, NEFA) and GFR (combined Zappitelli equation) were assessed. GH was defined as GFR >135 ml/min.1.73 m2. Serum levels of regulated on activation, normal T cell expressed and secreted (RANTES)/CCL5, interleukin-8 (IL-8)/CXCL8 and monokine-induced by interferon-γ (MIG)/CXCL9 were measured by ELISA. Age- and sex-adjusted correlations and differences were tested. 48% of the cohort was female and 13% were OW, 54% OB and 33% severe OB. Prepubertal children with GH showed lower z-BMI (-12%), NEFA (-26%) and uric acid (-22%) than those without GH (all p < 0.05). Similarly to high sensitivity C-reactive protein (hsCRP), there were no differences in serum chemokines between children with GH or not (all p > 0.05). Adjusted correlations were significant for RANTES and z-BMI (r = 0.26; p < 0.05) and for MIG with z-BMI (r = -0.26; p < 0.05) and with NEFA (r = 0.27; p < 0.05). CONCLUSION: GH was not associated with higher chemokine levels in prepubertal children with OW/OB. Decreased rather than elevated GFR values were correlated with obesity and worse metabolic profiles. Chemokines levels in children with severe OB suggest a regulation of the immune response. Follow-up studies are needed to address the clinical implications of these findings.

Analysis of survival at cardiac arrest in events occurred in work environments in the territory served by an operations center of the 118 of Tuscany.

BACKGROUND: Every year in Italy and all around the world, cardiac arrest hits almost 1 person every 1000 people; a great deal of these events is likely to strike people outside their private houses. OBJECTIVES: Analyzing a cohort of cardiac arrest events occurred in various public- and work-places across a territorial area concerning an Emergency Unit related to the national emergency number (118) and assessing the efficacy of a first-aid intervention and the usage of a defibrillator while handling an acute cardiac event. METHODS: We analyzed data of 32 sanitary interventions on cardiac arrest events occurred from January 2015 to June 2018 across USL Toscana Centro - Pistoia and Empoli's territory. RESULTS: The acute cardiac event occurred in a "strictly speaking workplace" in 28.2% of cases, and in 18.7% during work activity. An AED was present for immediate cardiac arrest treatment in 15.6% of cases with a survival rate of 100% (n=5/5) (p=0.04); in 84.4% of cases the AED was available only after the arrival of national emergency rescuers and the relative survival rate was 40.74% (n=11/27). Regarding cardiopulmonary resuscitation, the survival rate appears to be higher (55.5% Vs 42.8%) when it was started by witnesses. CONCLUSIONS: The results of this study suggest that early defibrillation provided by work-related First Aid Emergency Procedure, may be a primary aid and a desirable standard to improve both workers' and private citizens' survival rate after cardiac arrest.

The Immune Landscape of Thyroid Cancer in the Context of Immune Checkpoint Inhibition.

Immune cells play critical roles in tumor prevention as well as initiation and progression. However, immune-resistant cancer cells can evade the immune system and proceed to form tumors. The normal microenvironment (immune cells, fibroblasts, blood and lymphatic vessels, and interstitial extracellular matrix (ECM)) maintains tissue homeostasis and prevents tumor initiation. Inflammatory mediators, reactive oxygen species, cytokines, and chemokines from an altered microenvironment promote tumor growth. During the last decade, thyroid cancer, the most frequent cancer of the endocrine system, has emerged as the fifth most incident cancer in the United States (USA), and its incidence is steadily growing. Inflammation has long been associated with thyroid cancer, raising critical questions about the role of immune cells in its pathogenesis. A plethora of immune cells and their mediators are present in the thyroid cancer ecosystem. Monoclonal antibodies (mAbs) targeting immune checkpoints, such as mAbs anti-cytotoxic T lymphocyte antigen 4 (anti-CTLA-4) and anti-programmed cell death protein-1/programmed cell death ligand-1 (anti-PD-1/PD-L1), have revolutionized the treatment of many malignancies, but they induce thyroid dysfunction in up to 10% of patients, presumably by enhancing autoimmunity. Combination strategies involving immune checkpoint inhibitors (ICIs) with tyrosine kinase (TK) or serine/threonine protein kinase B-raf (BRAF) inhibitors are showing considerable promise in the treatment of advanced thyroid cancer. This review illustrates how different immune cells contribute to thyroid cancer development and the rationale for the antitumor effects of ICIs in combination with BRAF/TK inhibitors.

Immune and Inflammatory Cells in Thyroid Cancer Microenvironment.

A hallmark of cancer is the ability of tumor cells to avoid immune destruction. Activated immune cells in tumor microenvironment (TME) secrete proinflammatory cytokines and chemokines which foster the proliferation of tumor cells. Specific antigens expressed by cancer cells are recognized by the main actors of immune response that are involved in their elimination (immunosurveillance). By the recruitment of immunosuppressive cells, decreasing the tumor immunogenicity, or through other immunosuppressive mechanisms, tumors can impair the host immune cells within the TME and escape their surveillance. Within the TME, cells of the innate (e.g., macrophages, mast cells, neutrophils) and the adaptive (e.g., lymphocytes) immune responses are interconnected with epithelial cancer cells, fibroblasts, and endothelial cells via cytokines, chemokines, and adipocytokines. The molecular pattern of cytokines and chemokines has a key role and could explain the involvement of the immune system in tumor initiation and progression. Thyroid cancer-related inflammation is an important target for diagnostic procedures and novel therapeutic strategies. Anticancer immunotherapy, especially immune checkpoint inhibitors, unleashes the immune system and activates cytotoxic lymphocytes to kill cancer cells. A better knowledge of the molecular and immunological characteristics of TME will allow novel and more effective immunotherapeutic strategies in advanced thyroid cancer.

Autoimmune Endocrine Dysfunctions Associated with Cancer Immunotherapies.

Immune checkpoint inhibitors block the checkpoint molecules. Different types of cancer immune checkpoint inhibitors have been approved recently: CTLA-4 monoclonal antibodies (as ipilimumab); anti-PD-1 monoclonal antibodies (as pembrolizumab and nivolumab); and anti-PD-L1 monoclonal antibodies (as atezolizumab, avelumab, and durmalumab). We collect recent published results about autoimmune endocrine dysfunctions associated with cancer antibody immunotherapies. These agents cause a raised immune response leading to immune-related adverse events (irAEs), varying from mild to fatal, based on the organ system and severity. Immune-related endocrine toxicities are usually irreversible in 50% of cases, and include hypophysitis, thyroid dysfunctions, type 1 diabetes mellitus, and adrenal insufficiency. Anti-PD-1-antibodies are more frequently associated with thyroid dysfunctions (including painless thyroiditis, hypothyroidism, thyrotoxicosis, or thyroid storm), while the most frequent irAE related to anti-CTLA-4-antibodies is hypophysitis. The combination of anti-CTLA-4 and anti-PD-1 antibodies is associated with a 30% chance of irAEs. Symptoms and clinical signs vary depending on the target organ. IrAEs are usually managed by an oncological therapist, but in more challenging circumstances (i.e., for new onset insulin-dependent diabetes, hypoadrenalism, gonadal hormones dysfunctions, or durable hypophysitis) an endocrinologist is needed.

PD-1 Ligand Expression in Epithelial Thyroid Cancers: Potential Clinical Implications.

The new immunotherapy targeting the programmed cell death 1 (PD-1) receptor and its cognate ligand PD-L1 has renewed hopes of eradicating the most difficult human cancers to treat. Among these, there are the poorly differentiated and anaplastic thyroid cancers, unresponsive to all the therapies currently in use. In the present review we will summarize information regarding the expression of PD-L1 in the different thyroid cancer histotypes, its correlation with clinicopathological features, and its potential prognostic value. Then, we will evaluate the available data indicating the PD-1/PD-L1 axis as a promising target for thyroid cancer therapy.