Portrait of the Inflammatory Response to Radioiodine Therapy in Female Patients with Differentiated Thyroid Cancer with/without Type 2 Diabetes Mellitus.

No clinical studies have investigated the effect of radioiodine (131I)-targeted therapy on the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) as inflammatory response markers in patients with differentiated thyroid cancer (DTC) associated with type 2 diabetes mellitus (T2DM) and obesity. This study aimed to assess the relationship between blood radioactivity, body mass index (BMI), and peripheral blood cells three days after 131I intake in 56 female patients without T2DM (DTC/-T2DM) vs. 24 female patients with T2DM (DTC/+T2DM). Blood radioactivity, measured three days after 131I intake, was significantly lower in the DTC/+T2DM than in the DTC/-T2DM patients (0.7 mCi vs. 1.5 mCi, p < 0.001). The relationship between blood radioactivity and BMI (r = 0.83, p < 0.001), blood radioactivity and NLR (r = 0.53, p = 0.008), and BMI and NLR (r = 0.58, p = 0.003) indicates a possible connection between the bloodstream 131I uptake and T2DM-specific chronic inflammation. In patients without T2DM, 131I therapy has immunosuppressive effects, leading to increased NLR (19.6%, p = 0.009) and PLR (39.1%, p = 0.002). On the contrary, in the chronic inflammation context of T2DM, 131I therapy amplifies immune metabolism, leading to a drop in NLR (10%, p = 0.032) and PLR (13.4%, p = 0.021). Our results show that, in DTC/+T2DM, the bidirectional crosstalk between neutrophils and obesity may limit 131I uptake in the bloodstream. Considering the immune response to 131I therapy, the two groups of patients can be seen as a synchronous portrait of two sides. The explanation could lie in the different radiosensitivity of T and B lymphocytes, with T lymphocytes being predominant in patients with DTC/-T2DM and, most likely, B lymphocytes being predominant in T2DM.

Cardiovascular Effects of Cumulative Doses of Radioiodine in Differentiated Thyroid Cancer Patients with Type 2 Diabetes Mellitus.

Radioiodine (131I) therapy for differentiated thyroid cancer (DTC) involves exposure of the whole body, including the heart, to ionizing radiation. This exposure to the subsequent risk of heart disease is uncertain, especially in patients with DTC associated with type 2 diabetes mellitus (DTC/+T2DM). The current study aimed to assess the relationship between left ventricular ejection fraction (LVEF), high cumulative 131I dose, and peripheral blood parameters in patients with DTC/−T2DM and DTC/+T2DM. The study enrolled 72 female patients with DTC/−T2DM and 24 with DTC/+T2DM who received cumulative 131I doses above 150 mCi (5.55 GBq). LVEF was lower in patients with concomitant T2DM than those without (p < 0.001). The cumulative 131I dosage was inversely correlated with LVEF only in DTC/−T2DM patients (r = −0.57, p < 0.001). In the DTC/+T2DM group, LVEF was negatively associated with absolute platelet count (r = −0.67, p < 0.001) and platelet-to-lymphocyte ratio (r = −0.76, p < 0.001). Our results demonstrate that exposure to high cumulative 131I doses has different cardiovascular effects in DTC/−T2DM and DTC/+T2DM.

Analysis of the Correlation between the Radioactive Iodine Activity and Neutrophil-to-Lymphocyte Ratio in Patients with Differentiated Thyroid Cancer.

Publications investigating the effect of radioactive iodine (131I) therapy on the circulating peripheral blood cells in patients with differentiated thyroid cancer (DTC) are limited to blood samples collected more than 92 h after 131I. Studies conducted on blood samples collected up to 92 h are rare due to the radioactive contamination risk. This research aimed to assess the relationship between the prescribed 131I activity, human whole blood activity, and peripheral blood cells at many time points (6, 22, 46, 69, and 92 h after 131I). The study enrolled 50 female patients with DTC who received a 131I median activity of 90.54 mCi (3.35 GBq). The neutrophil-to-lymphocyte ratio (NLR) was measured as an inflammatory marker. 131I uptake in the residual thyroid tissue peaked after 46 h. Blood activity decreased in the first 46 h and increased 69 h after the 131I intake. Blood activity was associated with the absolute lymphocyte count and the NLR at 69 h (r = −0.49 and r = 0.52, p < 0.001). Our results demonstrate that the time interval between 46 and 69 h should be associated with the release of hematological inflammatory mediators, such as neutrophils and lymphocytes, to eradicate tumor cells in response to 131I therapy.

Clinical significance of serum matrix metalloproteinase 9 and tissue inhibitor of metalloproteinase 1 in the first phase of burn trauma evolution.

No prospective study has specifically examined the serum levels of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) in the early shock phase of burn-injured patients. Thus, we aimed to detect early changes, activity dynamics, and the predictive value of MMP-9, TIMP-1, and the MMP-9/TIMP-1 ratio to better understand the early repair mechanisms for the development of future therapies for patients with thermal burns. Twenty-five patients with a total body surface area (TBSA) affected by burn <25%, and 30 healthy subjects were enrolled in the study. Serum levels of MMP-9 and TIMP-1 were determined by the ELISA method. Our results showed that MMP-9 concentrations increased immediately after injury and remained on a plateau. In contrast, TIMP-1 showed an upward trend throughout the 7-day study period, and the time course of the MMP-9/TIMP-1 ratio followed the inverse dynamics of TIMP-1. Analysis of the areas under the receiver operating characteristic (ROC) curves (AUC) showed that patients with burn wounds tended to have a MMP-9 value higher than 421.5 ng/ml (AUC=0.979), TIMP-1 value higher than 231.6 ng/ml (AUC=0.908), and MMP-9/TIMP-1 ratio higher than 2.31 (AUC=0.959) (P<0.001). Our findings suggest that although the variations in the two biomarkers were different regarding the time of the initial insult, their ratio is a specific and sensitive indicator of burn evolutivity in patients with a TBSA affected by a burn <25%.

Role and dynamics of matrix metalloproteinase 9 and tissue inhibitor of metalloproteinase 1 in burn patients.

Burn injuries can trigger tissue changes that can explain the variation in the level of different biochemical markers that can be recorded both locally or systemically. Some events observed in burn wounds such as vascular hyperpermeability have been associated with the release of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) after trauma. Because it is unknown whether the serum levels of MMP-9 and TIMP-1 are a consequence of these destructions or a local response to thermal damage, we decided to follow their dynamics. Twenty-five patients (mean age 49.40±17.55 years) with a total body surface area (TBSA) affected by a thermal burn of <25% and 30 healthy subjects (mean age 49.70±8.04 years) were enrolled in the present study. Enzyme immunoassays were used to measure the serum levels of MMP-9 and TIMP-1. Our results showed that MMP-9 was increased 6.25-fold immediately after injury compared to the controls and remained on a plateau throughout the 7-day monitoring period. TIMP-1 showed an upward trend with an increase of 49.52% on the seventh day after triggering insult. The time-course of the MMP-9/TIMP-1 ratio followed the inverse dynamics of TIMP-1 starting from a ratio value measured at admission 3.82-fold higher than the one observed in the healthy volunteers and a highly statistically significant correlation between the values measured at different time-points during the monitoring period (P<0.001). The results of this retrospective study indicate that the MMP-9/TIMP-1 ratio may provide information on local changes over time, starting from the triggering insult, and may be considered as a predictive biomarker of burn evolutivity.

TNF-α May Exert Different Antitumor Effects in Response to Radioactive Iodine Therapy in Papillary Thyroid Cancer with/without Autoimmune Thyroiditis.

Autoimmune thyroiditis (AIT) may impair radioiodine (131I) uptake in papillary thyroid cancer (PTC). Finding the mechanisms that govern immune cells during 131I therapy of PTC with concomitant AIT (PTC + AIT) could provide a rationale. Our study aimed to evaluate the effects of 131I on anti-thyroglobulin antibodies (TgAb), matrix metalloproteinase-9 (MMP-9) and its tissue inhibitor TIMP-1 and tumor necrosis factor-α (TNF-α) and its receptors TNFR1 and TNFR2, in PTC and PTC + AIT patients. Peripheral blood was collected from 56 female patients with PTC and 32 with PTC + AIT before and 4 days after 131I (3.7 GBq). The serum levels of TgAb, MMP-9, TIMP-1, TNF-α, TNFR1 and TNFR2 were measured by ELISA. The mean radioactivity of blood samples collected after 131I intake was higher in the PTC + AIT group than in PTC (p < 0.001). In the PTC + AIT group, TNF-α/TNFR1 and TNF-α/TNFR2 ratios decreased by 0.38-fold and 0.32-fold after 131I and were positively correlated with the MMP-9/TIMP-1 ratio (r = 0.48, p = 0.005, and r = 0.46, p = 0.007). In the PTC group, TNF-α/TNFR1 and TNF-α/TNFR2 ratios increased by 3.17-fold and 3.33-fold and were negatively correlated with the MMP-9/TIMP-1 ratio (r = -0.62, p < 0.001 and r = -0.58, p < 0.001). Our results demonstrate that TNF-α may exert different antitumor effects in response to 131I therapy depending on the patient's immune profile.

Serum melatonin is inversely associated with matrix metalloproteinase-9 in oral squamous cell carcinoma.

Matrix-metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) expression levels have been demonstrated to have prognostic value in oral squamous cell carcinoma (OSCC). The present study hypothesized that melatonin, a small lipophilic molecule primarily secreted by the pineal gland, may be able to regulate MMP activity in OSCC progression. This study aimed to investigate the associations between melatonin, MMPs, TIMPs and the histopathological characteristics of patients with OSCC. A total of 40 men with OSCC (mean age, 57±7 years) and 30 healthy men (mean age, 56±5 years) were enrolled in the present study. Enzyme immunoassays were used to measure the serum levels of melatonin, MMP-9, MMP-2, TIMP-1 and TIMP-2 before and after transoral surgery for OSCC. Serum melatonin level was significantly lower in patients with OSCC compared with controls, both pre-surgery and 2 days after surgery (P<0.001). In addition, melatonin level was negatively correlated with MMP-9 (r=-0.6371) and the MMP-9/TIMP-1 ratio (r=-0.4700), but not with the MMP-2 or MMP-2/TIMP-2 ratio, in patients with OSCC. These results demonstrated that low levels of melatonin and high levels of MMP-9 correlated with large tumors with invasive depth (r=-0.35 and r=0.33) and lymph node metastasis (r=-0.56 and r=0.34). The results of this retrospective clinical study suggested that melatonin may be considered as a predictive biomarker of tumor growth and metastasis and a potential therapeutic agent for patients with OSCC.

NT-proBNP and CA 125 levels are associated with increased pro-inflammatory cytokines in coronary sinus serum of patients with chronic heart failure.

PURPOSE: Heart failure (HF) is considered to be a complex syndrome associated with neurohormonal and cytokine activation, that contribute to its progression. There are evidences which showed that, carbohydrate antigen 125 (CA 125), a tumor marker widely used for ovarian cancer therapy monitoring, was significantly elevated in HF patients. We hypothesized that inflammatory stimuli may be responsible for amino-terminal fragment of the prohormone B-type natriuretic peptide (NT-proBNP) and CA-125 production and release in chronic HF (CHF). We aimed to measure the levels of NT-proBNP, CA 125, pro-anti-inflammatory cytokines (IL-6, IL-1ß, IL-8, TNF-α and IL-4), from peripheral venous (PV) and coronary sinus (CS) blood samples, in patients with CHF and to assess their correlation with echocardiographic indices. METHODS: We enrolled 32 subjects (20M/12F) with CHF (III-IV NYHA functional class) who were to undergo cardiac resynchronization therapy (CRT) device implantation and 30 healthy controls (18M/12F). Two blood samples, from PV and CS, were collected at the time of CRT for each CHF patient. Serum levels of biomarkers were measured by ELISA. Cardiac function was assessed echocardiographically. RESULTS: All investigated biomarkers were significantly higher in CHF patients than in non-CHF controls (P < 0.001). There were positive correlations between biomarkers concentrations in PV and CS (r between 0.54 and 0.98, all P < 0.003). NT-proBNP, IL-6 and IL-1ß levels were 17%, 86% and 36% higher in CS than in PV, these increases being very well correlated each other, while CA 125 levels were 86% higher in PV than in CS. Moreover, CS NT-proBNP, CS IL-6 and CS IL-1ß serum concentrations were inversely related to the echocardiographically determined left ventricular ejection fraction (LVEF) (r = -0.61, P < 0.001; r = -0.71, P < 0.001 and r = -0.48, P = 0.005, respectively). A positive relationship was found between CA 125 and IL-1ß (r = 0.51, P = 0.003) in CS serum and between CA 125 and IL-6 (r = 0.43, P = 0.015), TNF-α (r = 0.46, P = 0.008) in PV serum. CA 125 concentrations were closely related to NT-proBNP both in CS (r = 0.46, P = 0.008) and PV (r = 0.52, P = 0.002). CONCLUSIONS: CS sampling of NT-proBNP, CA 125 and pro-anti-inflammatory cytokines provides an additional insight into the possible mechanisms by which these biomarkers lead to left ventricular remodeling. Our results clearly suggest that serum NT-proBNP and CA 125 levels not only in PV, but also in CS of patients with CHF, may be dependent on inflammation as a consequence of cytokine network activation.

The role of pro-fibrotic biomarkers in paroxysmal and persistent atrial fibrillation.

PURPOSE: Signaling pathways involved in electrical, structural and contractile remodeling processes behind development and progression of atrial fibrillation (AF) have not been completely elucidated, but it seems to be related to complex interactions among neurohormonal and cellular mediators. We aimed to investigate interleukin-6 (IL-6), transforming growth factor-beta1 (TGF-ß1), matrix metalloproteinase-9 (MMP-9), tissue inhibitor of metalloproteinase-1 (TIMP-1), as biomarkers of atrial remodeling, in patients with paroxysmal and persistent AF, and their correlation with N-terminal prohormone of brain natriuretic peptide (NT-proBNP) and left atrial (LA) diameter. METHODS: Thirty-seven patients (22M/15F) with paroxysmal AF, 32 patients (22M/10F) with persistent AF and 30 healthy control subjects (18M/12F) were enrolled in the study. Serum levels of biomarkers were measured by ELISA. Cardiac function was assessed echocardiographically. RESULTS: IL-6 levels and MMP-9/TIMP-1 ratio were significantly higher in AF patients than in non-AF controls (P < .001), and in persistent than in paroxysmal AF (P < .001), in line with NT-proBNP and LA diameter. In contrast, TGF-ß1levels declined with increasing AF duration (from 51.2 pg/mL, IQR: 38.9-87.9 pg/mL in paroxysmal to 23.9 pg/mL, IQR: 16.9-43.6 pg/mL in persistent AF). TGF-ß1 was negatively correlated with NT-proBNP (r = -0.53, P = .001 in paroxysmal AF and r = -0.71, P < .001 in persistent AF) and LA diameter (r = -0.44, P = .006 in paroxysmal AF and r = -0.51, P = .003 in persistent AF). CONCLUSIONS: Our results demonstrate that AF development and progression (from paroxysmal to persistent) is associated with a gradual increase in serum levels of NT-proBNP, IL-6 and MMP-9/TIMP-1 ratio. Moreover, this study suggests that the relationship between TGF-ß1, NT-proBNP and LA diameter allows for the progression of atrial remodeling during AF, despite compensatory changes in the TGF-ß1 signaling pathway.

Effects of thyroid hormone withdrawal on natriuretic peptides during radioactive iodine therapy in female patients with differentiated thyroid cancer.

OBJECTIVE: We aimed to investigate the effects of thyroid hormone withdrawal on N-terminal prohormone forms of atrial natriuretic peptide (NT-proANP) and brain natriuretic peptide (NT-proBNP) during radioiodine therapy in female patients with differentiated thyroid cancer (DTC). METHODS: Serum concentrations of thyroid-stimulating hormone (TSH), free triiodothyronine (FT3), NT-proANP and NT-proBNP were measured in 51 female patients with DTC (48.7 ± 4.2 years) at three time-points: day of radioiodine therapy (t1 - under acute hypothyroidism), 5 days after radioiodine (t2 - under acute hypothyroidism) and 3 months after radioiodine (t3 - under TSH suppression). Thirty healthy euthyroid women served as controls (42.8 ± 5.6 years). RESULTS: At t1/t2/t3, median NT-proANP was 5.2/1.7/487 pmol/L vs. 297.7 pmol/L in control group (p < 0.001), median NT-proBNP was 50.1/36.5/79.5 pmol/L vs. 64.5 pmol/L (p < 0.001) and median NT-proANP/NT-proBNP ratios was 0.20/0.18/4.81 vs. 4.14 (p < 0.001). In acute hypothyroidism, FT3 levels were positively correlated with NT-proANP (r = 0.38, p = 0.005), NT-proANP/NT-proBNP ratios (r = 0.47, p = 0.001), heart rate (r = 0.39, p = 0.005), and negatively with mean arterial blood pressure (r = -0.58, p < 0.001). CONCLUSIONS: Our results indicate that NT-proANP reflects more accurately direct thyroid hormone effects than NT-proBNP. Thyroid hormone-dependent hemodynamic effects seem to be overlapped on the direct stimulatory effect of thyroid hormones on NT-proANP secretion by cardiac myocytes.

Cardiac resynchronization therapy in patients with chronic heart failure is associated with anti-inflammatory and anti-remodeling effects.

OBJECTIVES: Proinflammatory cytokines, matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) play a role in left ventricular (LV) structural remodeling. We aimed to investigate the effects of cardiac resynchronization therapy (CRT) on serum levels of amino-terminal prohormone B-type natriuretic peptide (NT-proBNP), some interleukins (IL-1ß, IL-6, IL-8), MMP-2 and TIMP-2 in patients with chronic heart failure (CHF). DESIGN AND METHODS: We studied 27 patients (15 M/12 F) with CHF, III-IV NYHA class, implanted with a biventricular pacemaker/defibrillator and 40 healthy subjects (23 M/17 F). Blood samples were collected at baseline and 1 week, 3, 6, and 12 months after CRT device implantation. Cardiac function was assessed echocardiographically. RESULTS: CRT induced significant improvement in the NYHA class (baseline 3.2±0.5 vs. 1.0 at 12 months, P=0.0002) and significant LV reverse remodeling, with a 41% (P=0.001) reduction in LV end-systolic volume (LVESV). This was associated with a significant reduction in serum NT-proBNP, IL-6 and IL-8. Positive extracellular matrix remodeling was illustrated by decreasing levels of MMP-2 and increasing TIMP-2. MMP-2/TIMP-2 ratio decreased with 55% (P=0.003) from baseline value at 12 months and the correlation with LVESV reduction was 0.41 (P=0.001). CONCLUSIONS: Structural response to CRT is associated with reduced immune activation and positive extracellular matrix remodeling.