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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.

Objective No consistent data are present in literature about the effectiveness of Levothyroxine (L‐T4) liquid formulation in patients without malabsorption after thyroidectomy. The aim of this study is to compare the effectiveness of L‐T4 liquid formulation, with L‐T4 tablets, in thyroid cancer patients after thyroidectomy (without malabsorption or drug interference). Methods One hundred five patients were recruited; 52 patients were treated with liquid L‐T4 formulation, while 53 with L‐T4 tablets, at the same dosage (1.5 mcg/kg/day). Patients started to assume the drug the day after surgery, 30 min before breakfast. In both groups circulating levels of thyrotropic hormone (TSH), free thyroxine (FT4), and free triiodothyronine (FT3) were dosed at week 6 (first control), and then at week 12 (second control). Results We obtained significantly lower TSH values in the liquid L‐T4 group patients, compared to the tablet L‐T4 group, at the first control (P < .05), and at the second control (P < .01), while FT4 and FT3 levels were not significantly different. Hypothyroid range (TSH > 3.6 mcU/mL) was significantly more prevalent in the patients treated with L‐T4 tablet. Conclusions A better control of TSH was observed in thyroidectomized patients (without malabsorption, gastric disorders, or drug interference) with liquid L‐T4 regimen. Level of Evidence 2c–Outcomes Research

Lenvatinib is an oral, multitargeted tyrosine kinase inhibitor (TKI) of VEGFR1-VEGFR3, FGFR1-FGFR4, PDGFRα, RET and v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) signaling networks involved in tumor angiogenesis. We have evaluated the antitumor activity of lenvatinib in primary anaplastic thyroid cancer (ATC) cells, in the human cell line 8305C (undifferentiated thyroid cancer) and in an ATC-cell line (AF). The AF cell line was obtained from the primary ATC cultures and was the one that grew over 50 passages. The effect of lenvatinib (1 and 100 nM; and 1, 10, 25 and 50 µM) was investigated in primary ATC, 8305C and AF cells as well as in AF cells in CD nu/nu mice. Lenvatinib significantly reduced ATC cell proliferation (P<0.01, ANOVA) and increased the percentage of apoptotic ATC cells (P<0.001, ANOVA). Furthermore, lenvatinib inhibited migration (P<0.01) and invasion (P<0.001) in ATC. In addition, lenvatinib inhibited EGFR, AKT and ERK1/2 phosphorylation and downregulated cyclin D1 in the ATC cells. Lenvatinib also significantly inhibited 8305C and AF cell proliferation, increasing apoptosis. AF cells were subcutaneously injected into CD nu/nu mice and tumor masses were observed 20 days later. Tumor growth was significantly inhibited by lenvatinib (25 mg/kg/day), as well as the expression of VEGF-A and microvessel density in the AF tumor tissues. In conclusion, the antitumor and antiangiogenic activities of lenvatinib may be promising for the treatment of anaplastic thyroid cancer, and may consist a basis for future clinical therapeutic applications.

Medullary thyroid cancers (MTCs) are neuroendocrine tumors, which secrete calcitonin and carcinoembryonic antigen, both of which can serve as tumor markers. Extensive and accurate surgical resection is the primary treatment for MTC, whereas the use of external beam radiotherapy is limited. Moreover, since MTC is derived from thyroid parafollicular cells or C cells, it is not responsive to either radioiodine or thyroid-stimulating hormone suppression, and therefore, they cannot be considered as treatment strategies. Traditional therapies for advanced or metastatic progressive medullary thyroid cancer (pMTC) are poorly effective. Among the new approaches tested in clinical trials, targeted chemotherapies with tyrosine kinase inhibitors (TKIs) are now available and they represent effective interventions for progressive disease, with additional investigational options emerging. This paper reviews the efficacy and safety of vandetanib in patients with a pMTC, as it has been shown to improve progression-free survival (30.5 vs 19.3 months in controls). Vandetanib is approved by the FDA and EMA for symptomatic or progressive MTC in patients with unresectable locally advanced or metastatic disease in adults, adolescents, and children older than 5 years. The most common adverse events in vandetanib-treated patients are diarrhea, rash, folliculitis, nausea, QTc prolongation, hypertension, and fatigue. More data are required to deepen our knowledge on molecular biology of tumor and host defense, with the aim to achieve better prognosis and higher quality of life for affected patients. Keywords: MTC, pediatric MTC, vandetanib, RET, VEGFR, AEs

(1) Background: Autoimmune diseases, including autoimmune endocrine diseases (AIED), are thought to develop following environmental exposure in patients with genetic predisposition. The vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could represent a new environmental trigger for AIED, including Graves’ disease (GD). (2) Methods: We performed a literature search of MEDLINE/PubMed databases regarding thyroid dysfunction after SARS-CoV-2 vaccination since 1 January 2020 to 31 July 2022, considering only cases of thyrotoxicosis that meet the 2016 American Thyroid Association guidelines criteria for the diagnosis of GD and arising after administration of the anti-SARS-CoV-2 vaccine, regardless of the number of doses. (3) Results: A total of 27 articles were identified, consisting of case reports or case series, of which 24 describe the appearance of 48 new diagnoses of GD and 12 GD recurrences arising after the administration of the anti-SARS-CoV-2 vaccine, and 3 papers that instead report only 3 cases of GD relapse following vaccination. (4) Conclusions: physicians should be aware of the possibility of developing GD and other autoimmune sequelae following SARS-CoV-2 vaccination. Regardless of the underlying pathogenetic mechanisms (autoimmune/inflammatory syndrome induced by adjuvants (ASIA syndrome), cytokines induction, molecular mimicry, and cross-reactivity), an individual predisposition seems to be decisive for their development.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological culprit of COronaVIrus Disease 19 (COVID-19), can enter the cells via the angiotensin-converting enzyme 2 (ACE2) receptor, which has been found in several tissues including in endocrine organs, such as the ovaries, testes, pancreas, and thyroid. Several thyroid disorders have been associated with SARS-CoV-2 infection [subacute thyroiditis (SAT), thyrotoxicosis, and non-thyroidal illness syndrome (NTIS)] and, in part, they are believed to be secondary to the local virus replication within the gland cells. However, as documented for other viruses, SARS-CoV-2 seems to interfere with several aspects of the immune system, inducing the synthesis of autoantibodies and triggering latent or new onset autoimmune disease (AID), including autoimmune thyroid disease (AITD), such as Hashimoto Thyroiditis (HT) and Graves’ disease (GD). Several mechanisms have been hypothesized to explain this induction of autoimmunity by SARS-CoV-2 infection: the immune system hyper-stimulation, the molecular mimicry between the self-antigens of the host and the virus, neutrophils extracellular traps, and finally, the virus induced transcriptional changes in the immune genes; nonetheless, more evidence is needed especially from large, long-term cohort studies involving COVID-19 patients, to establish or reject this pathogenetic relationship.

Chemokine (C-X-C motif) ligand (CXCL)10 and other CXCR3 chemokines are involved in the pathogenesis of acute and “chronic hepatitis C virus (HCV) infection” (CHC). Here, we review the scientific literature about HCV and CXCL10. The combination of circulating CXCL10 and single nucleotide polymorphisms (SNPs) in IL-28B can identify patients with acute HCV infection most likely to undergo spontaneous HCV clearance and those in need of early antiviral therapy. In CHC, the HCV and intrahepatic interferon- (IFN-) γ drive a raised CXCL10 expression by sinusoidal endothelium and hepatocytes, thereby inducing the recruitment of CXCR3-expressing T cells into the liver; thus, CXCL10 plays an important role in the development of necroinflammation and fibrosis. Increased CXCL10 was significantly associated with the presence of active vasculitis in HCV-associated cryoglobulinemia, or with autoimmune thyroiditis in CHC. Pretreatment CXCL10 levels are predictive of early virological response and sustained virological response (SVR) to IFN-α and ribavirin and may be useful in the evaluation of candidates for therapy. The occurrence of SNPs adjacent to IL-28B (rs12979860, rs12980275, and rs8099917), and CXCL10 below 150 pg/mL, independently predicted the first phase viral decline and rapid virological response, which in turn independently predicted SVR. Directly acting antiviral agents-mediated clearance of HCV is associated with the loss of intrahepatic immune activation by IFN-α, associated by decreased levels of CXCL10. In conclusion, CXCL10 is an important marker of HCV clearance and successful therapy in CHC patients. Whether CXCL10 is a novel therapeutic target in CHC will be evaluated.

The use of radioactive iodine (RAI) after total thyroidectomy for patients at the American Thyroid Association (ATA) who are at intermediate risk of recurrence is controversial. This is due to the lack of prospective randomized trials proving a benefit to recurrence or survival of RAI therapy in this group. In the absence of such evidence, clinicians struggle to recommend for or against this therapeutic approach which frequently results in overtreatment. This review describes key elements in the decision-making process that help clinicians more comprehensively evaluate the need for RAI therapy in patients with thyroid cancer at intermediate risk of recurrence. A clear definition of the purpose of RAI therapy should be conveyed to patients. In this sense, adjuvant RAI therapy intends to decrease recurrence, and ablation therapy is used to facilitate surveillance. Better stratification of the intermediate risk category into a low–intermediate subgroup and an intermediate–high-risk subgroup results in less heterogeneity and a more precise prediction of recurrence risk. The evaluation of post-operative thyroglobulin levels may prevent the overtreatment of low–intermediate-risk patients when their thyroglobulin level is <2.5 ng/mL. the integration of tumor genomics (when available) alongside pathologic features can enhance the ability of the clinician to predict iodine concentration in thyroid cancer cells. Finally, a detailed consideration of the adverse effects of RAI, patients’ comorbidities, and patient preferences will result in a patient-centered personalized approach. Systematic examination of these variables will ultimately provide a framework for making more educated decisions on the use of RAI in patients at intermediate risk of recurrence that will prevent overtreatment and minimize harm.

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.

Natural compounds possess anti-tumor capabilities for a wide range of cancers. The present study aims to analyze and compare the antiproliferative activity of Moringa oleifera and Moringa stenopetala leaf extracts against anaplastic thyroid carcinoma and lung adenocarcinoma cells in primary cell culture. Samples were collected from Arba Minch, Ethiopia. Water-soluble tetrazolium salt-1 assay was used to assess the antiproliferative activity of these samples against anaplastic thyroid carcinoma and lung adenocarcinoma cells in primary cell culture. Cell number counting was another method used to confirm cell proliferation. The results showed that, in comparison to the control, both Moringa species significantly lowered cancer cell proliferation in a dose-responsive manner. Although Moringa oleifera showed a stronger inhibitory effect compared to Moringa stenopetala , there was no statistically significant difference ( p  > 0.05) in the proliferation of anaplastic thyroid carcinoma and lung adenocarcinoma cells between the two species. Moringa oleifera extract had a lower IC 50 value in anaplastic thyroid carcinoma cells, 84.2 µg/ml, than Moringa stenopetala leaf extract, 90.6 µg/ml. Moringa oleifera leaf extract has a lower IC 50 value in lung adenocarcinoma cells, 64.7 µg/ml, than Moringa stenopetala leaf extract, 75.3 µg/ml. In conclusion, the two species have antiproliferative activity on anaplastic thyroid carcinoma and lung adenocarcinoma cells in primary cell culture. These findings indicated that both extracts may serve as a basis for future cancer therapeutic applications.