Neutrophil-to-lymphocyte ratio is a strong predictor for overall survival and disease free survival in many cancers. Our study is the first investigation aiming to determine the predictive value of neutrophil-to-lymphocyte ratio on prognosis of patients with stage III melanoma. This retrospective study utilized a cohort of 107 patients with stage III melanoma treated at Huntsman Cancer Institute, University of Utah, from May 2002 to March 2016. The optimal cutoff of neutrophil-to-lymphocyte ratio was determined by the significance of log-rank tests. A total of 97 log-rank tests were conducted to find the optimal cutoff. Disease free survival was assessed using the Kaplan-Meier method, and univariable and multivariable Cox models were applied to evaluate the predictive value of neutrophil-to-lymphocyte ratio. 2.5 was identified as the optimal cutoff. Kaplan-Meier curve showed that the disease free survival rate of the low value group was significantly higher compared to that of high value group. After adjusting for confounders and other prognostic factors, the neutrophil-to-lymphocyte ratio ≥ 2.5 remained a strong predictor for disease recurrence in patients with stage III melanoma.
Growing evidence suggests that thyroid dysfunction may contribute to progression of cardiac disease to heart failure. We investigated the effects of a therapeutic dose of thyroid hormones (TH) on cardiomyopathic (CM) hamsters from 4 to 6 mo of age. CM hamsters had subclinical hypothyroidism (normal thyroxine, elevated TSH). Left ventricular (LV) function was determined by echocardiography and hemodynamics. Whole tissue pathology and isolated myocyte size and number were assessed. TH treatment prevented the decline in heart rate and rate of LV pressure increase and improved LV ejection fraction. The percentage of fibrosis/necrosis in untreated 4-mo-old CM (4CM; 15.5 +/- 2.2%) and 6-mo-old CM (6CM; 21.5 +/- 2.4%) hamsters was pronounced and was reversed in treated CM (TCM; 11.9 +/- 0.9%) hamsters. Total ventricular myocyte number was the same between 4- and 6-mo-old controls but was reduced by 30% in 4CM and 43% in 6CM hamsters. TH treatment completely prevented further loss of myocytes in TCM hamsters. Compared with age-matched controls, resting and maximum coronary blood flow was impaired in 4CM and 6CM hamsters. Blood flow was completely normalized by TH treatment. We conclude that TH treatment of CM hamsters with subclinical hypothyroidism normalized impaired coronary blood flow, which prevented the decline in LV function and loss of myocytes.
Thyroid hormones (TH) enhance cardiac function and reverse gene changes typical of pathological hypertrophy. However, reports in humans, but not animals, indicate that excess TH can cause heart failure. Also, the effects of TH on normal and cardiomyopathic hearts are likely to be different. The goal of this study was to characterize the effects of prolonged hyperthyroidism on cardiac function, chamber and cellular remodeling, and protein expression in both normal and cardiomyopathic hearts. Hyperthyroidism was induced in 3-mo-old normal BIO F1B and dilated cardiomyopathic BIO TO2 hamsters. After TH treatment for 10 days and 2 mo, hemodynamics, echos, myocyte length, histology, and protein expression were assessed. After 10 days and 2 mo, there were no differences between TO2-treated (Tx) and TO2-untreated (Untx) hamsters in chamber diameters or left ventricular function. After 2 mo of treatment, however, F1B-Tx showed evidence of dilated heart failure vs. F1B-Untx. Chamber diameters were increased, and ejection fraction and positive and negative changes in pressure over time were reduced. In F1B-Tx and TO2-Tx hamsters, beta-myosin isoform expression was reduced, whereas alpha-myosin increased significantly in F1B-Tx only. In TO2-Tx hamsters, the percent of viable myocardium was increased, and percent fibronecrosis was reduced vs. TO2-Untx. Myocyte length increased with TH treatment in both hamster strains. We conclude that 1) excess TH can induce heart failure in normal animals as observed in humans, 2) reversal of myosin heavy chain expression does not necessarily improve heart function, and 3) excess TH altered cellular remodeling but did not adversely affect chamber function or dimensions in TO2 hamsters.
Although thyroid dysfunction has been linked to heart failure, it is not clear whether hypothyroidism alone can cause heart failure.Hypothyroidism was induced in adult rats by treatment with 0.025% propylthiouracil (PTU) for 6 weeks (PTU-S) and 1 year (PTU-L). Echocardiographic measurements, left ventricular (LV) hemodynamics, isolated myocyte length (KOH method), myocardial blood flow (fluorescent microspheres), arteriolar morphometry, and gene expression (Western blot) were determined. Heart weight, heart rate, LV systolic blood pressure, LV ejection fraction, LV fractional shortening, and systolic wall thickness were reduced in PTU-S and PTU-L rats. LV internal diameter in systole increased by 40% in PTU-S and 86% in PTU-L. LV internal dimension in diastole was increased in PTU-S and PTU-L rats, but only PTU-L rats showed a significant increase in myocyte length due to series sarcomere addition. Resting and maximum (adenosine) myocardial blood flow were reduced in both PTU-S and PTU-L rats. Impaired blood flow was due to a large reduction in arteriolar length density and small arterioles in PTU-S and PTU-L (P<0.05 or greater for all of the above comparisons). Expression of sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA)-2a and alpha-myosin heavy chain were reduced in hypothyroidism, whereas phospholamban and beta-myosin heavy chain were increased.Hypothyroidism led to severe, progressive systolic dysfunction and increased chamber diameter/wall thickness ratio despite a reduction in cardiac mass. Chamber dilatation in PTU-L rats was due to series sarcomere addition, typical of heart failure. Hypothyroidism resulted in impaired myocardial blood flow due to a dramatic loss of arterioles. Thus, we have identified 2 important new mechanisms by which low thyroid function may lead to heart failure.
Thyroid hormones (THs) have many effects on the cardiovascular system including cardiac hypertrophy. Although THs induce cardiac hypertrophy, the mechanism through which they exert this effect is unknown. We previously found that THs activate signaling related to increased protein synthesis [mammalian target of rapamycin (mTOR) and p70 S6 kinase] in the heart. It is unknown whether this activation contributes to TH-induced hypertrophy or whether it is merely incidental. In this study, we used rapamycin to inhibit mTOR function in mice and neonatal cardiomyocyte cultures treated with THs to test whether mTOR/S6 kinase signaling is involved in TH-mediated cardiac hypertrophy. C57 mice were treated with T4 for 3 d, 1 wk, 2 wk, or 1 month with either placebo, T4 (50 microg/100 g body weight.d), rapamycin (200 microg/100 g body weight.d) or T4/rapamycin by sc slow-release pellets. At the end of the treatment period, hemodynamics and physical data were collected and hearts were frozen for Western blot analysis or myocytes were isolated. The effects of T3 and rapamycin were also investigated using neonatal cardiomyocytes. THs activated specific components of the AKT signaling pathway in vivo and in vitro. THs induced cardiac hypertrophy, which was completely inhibited by rapamycin. Our results suggest that TH-induced hypertrophy is mediated by AKT/mTOR/S6 kinase signaling, which is important in the regulation of protein synthesis, a hallmark of cardiac hypertrophy.
e16087 Background: Immunotherapy with HDIL-2 results in long-term survival in some mRCC patients but has significant toxicities. Biomarkers predicting response to therapy are needed to better select patients most likely to benefit. NLR (ANC/ALC ratio) is a prognostic and predicative biomarker in various malignancies. The goal was to determine whether NLR can predict response to HDIL-2 in this setting. Methods: Patients with clear cell mRCC treated with HDIL-2 were identified from an institutional database from 2003-2012. Baseline variables for the assessment of MSKCC risk category, and neutrophil and lymphocyte count, were collected. Best response criteria were based on RECIST 1.0. Wilcoxon rank-sum test was used to evaluate the association of continuous baseline variables with disease control. NLR was stratified by ≤4 or >4. Progression free survival (PFS) and overall survival (OS) were estimated with the Kaplan-Meier method and the log rank test was used investigate associations of NLR with survival. Results: In 71 eligible patients, median NLR in those with an objective response (n=14, 20%) was 2.3 vs 3.4 in those without (n=57, 80%, p = 0.02). NLR significantly correlated with inferior responses and survival outcomes (Table). After adjustment for MSKCC risk criteria, NLR remained a significant predictor of PFS (ANC/ALC ≤4 vs >4; HR 0.52; 95% CI 0.29-0.97; p = 0.039) and OS (≤4 vs >4, HR 0.32; 95% CI 0.16-0.64; p = 0.0015). Conclusions: In this discovery set, NLR predicts response to therapy with HDIL-2 in mccRCC, and may allow better patient selection in this setting. Data needs validation in an independent cohort. Survival outcomes by NLR. NLR≤4 vs >4 HR; 95% CI; P-value PFS, months 8.0 vs 3.3 0.51; 0.28-0.95; 0.0338 OS, months 40.9 vs 12.5 0.31; 0.16-0.61; 0.0009
Diiodothyropropionic acid (DITPA) is a thyroid hormone analog that is currently in phase II clinical trials. However, there have not been any studies to comprehensively analyze its effect on myocyte morphology. In addition, long-term studies with DITPA have not been done. This study compares the effects of DITPA with L-thyroxine (T4) on chamber remodeling, cardiac function, cellular morphology, cardiac blood flow, and protein expression. Normal and cardiomyopathic hamsters were treated with T4 or DITPA for 2 months. At the end of the treatment, echos, hemodynamics, coronary blood flow, cell morphology, and protein expression data were collected. Both T4 and DITPA treatment reduced chamber diameter during diastole, suggesting attenuated chamber dilatation in cardiomyopathic hamsters. Wall thickness also tended to increase, which was supported by cell morphology data in which DITPA significantly increased cross-sectional growth of myocytes specifically in the minor dimension, which is oriented transmurally. T4 and DITPA also increased myocardial blood flow both at baseline and after maximal dilation. This suggests there was increased angiogenesis or reduced loss of arterioles. Both T4 and DITPA had beneficial effects on chamber remodeling, which was most likely due to beneficial changes in cell shape and improved vascular supply.
We examined the effects of thyroid hormones (THs) on left ventricular (LV) function and myocyte remodeling in rats with spontaneously hypertensive heart failure (SHHF). SHHF rats were treated with three different TH doses from 20-21 mo of age. In terminal experiments, LV function (as determined by echocardiography and catheterization) and isolated myocyte shape were examined in SHHF rat groups and age-matched Wistar-Furth control animals. Compared with Wistar-Furth rats, the ratio of alpha- to beta-myosin was reduced in untreated SHHF rats. The alpha-to-beta-myosin ratio increased in all TH groups, which suggests a reversal of the fetal gene program. Low-dose TH produced no changes in LV myocyte size or function, but high-dose TH produced signs of hyperthyroidism (e.g., increased heart weight, tachycardia). The chamber diameter-to-wall thickness ratio declined with increasing dose due to reduced chamber diameter and increased wall thickness. This resulted in a 38% reduction in LV systolic wall stress in the middle- and high-dose groups despite sustained hypertension. Isolated myocyte data indicated that chamber remodeling and reduced wall stress were due to a unique alteration in myocyte transverse shape (e.g., reduced major diameter and increased minor diameter). Based on our present understanding of ventricular remodeling and wall stress, we believe these changes are likely beneficial. Results suggest that TH may be an important regulator of myocyte transverse shape in heart disease.
