ABSTRACT
Vasoactive intestinal peptide (VIP) is a neuropeptide with potent immunoregulatory properties. Reduced serum VIP levels and alterations in VIP receptors/signaling on immune cells have been associated with different inflammatory/autoimmune diseases. However, its role in autoimmune thyroid diseases (AITD) remains unknown. This study examined the interrelationship between VIP system, autoimmune background and thyroid hormones in peripheral immune cells in patients with AITD. Only Graves' disease (GD) patients showed significantly lower serum VIP levels when compared to healthy subjects and to Hashimoto's thyroiditis patients. Serum VIP levels were lower at the onset of GD, showing a significant negative correlation with thyroid hormone levels. The expression of VIP receptors, VPAC1 and VPAC2, was significantly upregulated in peripheral blood mononuclear cells (PBMC) from GD patients. There was an impairment of VIP signalling in these patients, probably attributable to a dysfunction of VPAC1 with preservation of VPAC2. The correlation between VPAC1 and thyroid hormone receptor expression in PBMC from healthy subjects was lost in GD patients. In summary, the VIP system is altered in peripheral immune cells of GD patients and this finding is associated with different thyroid hormone receptor patterns, showing a dynamic inter-regulation and a prominent role of VIP in this setting.
Subject(s)
Graves Disease/metabolism , Vasoactive Intestinal Peptide/metabolism , Adult , Female , Humans , Male , Middle Aged , Receptors, Vasoactive Intestinal Peptide, Type II/metabolism , Receptors, Vasoactive Intestinal Polypeptide, Type I/metabolism , Thyroid Hormones/metabolism , Vasoactive Intestinal Peptide/bloodABSTRACT
BACKGROUND: Cancer immune therapy has shown remarkable benefit in the treatment of a range of cancer types, although it may initiate autoimmune-related disorders in some patients. We have attempted to establish whether the incidence of irAEs after the use of anti-PD-1 antibodies nivolumab or pembrolizumab in advanced malignancies is associated with anti-PD-1 treatment efficacy. PATIENTS AND METHODS: We studied patients treated with single-agent nivolumab or pembrolizumab for advanced cancer. irAEs (immune-related adverse events) were identified clinically and graded as per the Common Terminology Criteria for Adverse Events version 4.0. Efficacy was evaluated with objective response rate (ORR, immune-Response Evaluation Criteria in Solid Tumours [RECIST] criteria) progression-free survival (PFS) and overall survival (OS). Tests were performed to determine the association between irAEs and ORR, PFS or OS. RESULTS: We identified 106 patients. Primary diagnoses were lung cancer (n = 77), melanoma (n = 8), head and neck carcinoma (n = 7), renal carcinoma (n = 5), Hodgkin's lymphoma (n = 3), urothelial carcinoma (n = 3) and gallbladder adenocarcinoma, hepatocellular carcinoma and Merkel cell carcinoma (n = 1 each). IrAEs were observed in 40 patients (37.7%). The most frequent irAEs were hypothyroidism (n = 15), nephritis (n = 5) and hyperthyroidism (n = 4). Objective response was observed in 44 patients (41.5%), and median PFS was 5.5 months (0.5-31 months). Thirty-three of the 40 patients with irAEs had objective response (82.5%) in contrast with 11 of the 66 cases without irAEs (16.6%) (OR 23.5, P < 0.000001). PFS in patients with irAEs was 10 months and 3 months in those without irAEs (HR 2.2, P = 0.016). OS in patients with irAEs was 32 months and 22 in those without irAEs, without statistically significant differences. CONCLUSION: In advanced cancer treated with single-agent anti-PD-1 antibodies, patients with irAEs showed a markedly improved efficacy over patients without irAEs (ORR of 82.5% and PFS of 10 months vs ORR of 16.6% and PFS of 3 months). Future studies of anti-PD-1 immune-therapy should address this association to explore the underlying biological mechanisms of efficacy.
Subject(s)
Antibodies, Monoclonal, Humanized/adverse effects , Antineoplastic Agents, Immunological/adverse effects , Drug-Related Side Effects and Adverse Reactions/diagnosis , Immunotherapy/adverse effects , Neoplasms/drug therapy , Nivolumab/adverse effects , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Adult , Aged , Aged, 80 and over , Drug-Related Side Effects and Adverse Reactions/etiology , Female , Follow-Up Studies , Humans , Male , Middle Aged , Neoplasms/immunology , Neoplasms/pathology , Prognosis , Survival RateABSTRACT
Hyponatremia, defined as serum sodium concentrations <135 mmol/L, is the most frequent electrolyte disturbance observed in both hospitalized and ambulatory patients, and has been associated to relevant negative consequences regarding morbidity and mortality. Drug-induced hyponatremia has been widely observed. However, since it may be clinically symptomatic or asymptomatic, it is frequently an underdiagnosed condition. This review aims to highlight the main drugs involved in the pathophysiology of hyponatremia, which should be considered in the differential diagnosis when approaching a patient with hyponatremia. We discuss their impact and relative importance. In order to prevent undesirable negative consequences we also emphasize the need for awareness of this clinically-relevant adverse effect, and we suggest how clinical management of patients may be approached.
Subject(s)
Hyponatremia/chemically induced , Female , Homeostasis/drug effects , Humans , Hyponatremia/diagnosis , Hyponatremia/epidemiology , Hyponatremia/physiopathology , Hyponatremia/prevention & control , Inappropriate ADH Syndrome/chemically induced , Male , Pregnancy , Pregnancy Complications/chemically induced , Pregnancy Complications/drug therapy , Prevalence , Water-Electrolyte Balance/drug effectsABSTRACT
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