Increased international normalized ratio level in hepatocellular carcinoma patients with diabetes mellitus

AIM: To determine the association of diabetes mellitus (DM) and international normalized ratio (INR) level in hepatocellular carcinoma (HCC) patients. METHODS: Our present study included 375 HCC patients who were treated at the China-Japan Friendship Hospital, Ministry of Health (Beijing, China), in the period from January 2003 to April 2012, and with a hospital discharge diagnosis of HCC. The demographic, clinical, laboratory, metabolic and instrumental features were analyzed. χ2 test, Student’s t test and Mann-Whitney U test were used to compare the differences between HCC patients with and without DM. Unconditional multivariable logistic regression analysis was used to determine the association of DM and INR level in HCC patients. A sub-group analysis was performed to assess the effect of liver cirrhosis or hepatitis B virus (HBV) infection on the results. The Pearson correlation test was used to determine the relationship between INR level and fasting glucose. In addition, association between diabetes duration, and diabetes treatment and INR level was determined considering the potentially different effects. RESULTS: Of the total, 63 (16.8%) patients were diabetic (diabetic group) and 312 (83.2%) patients were diagnosed without diabetes (non-diabetic group). Their mean age was 56.4 ± 11.0 years and 312 (83.2%) patients were male. Compared with patients without DM, the HCC patients with diabetes were older (59.5 ± 10.3 vs 55.8 ± 11.1, P=0.015), had a lower incidence of HBV infection (79.4% vs 89.1%, P=0.033), had increased levels of systolic blood pressure (SBP) (133 ± 17 vs 129 ± 16 mmHg, P=0.048) and INR (1.31 ± 0.44 vs 1.18 ± 0.21, P=0.001), had lower values of hemoglobin (124.4 ± 23.9 vs 134.2 ± 23.4, P=0.003) and had a platelet count (median/interquartile-range: 113/64-157 vs 139/89-192, P=0.020). There was no statistically significant difference in the percentages of males, overweight or obesity, drinking, smoking, cirrhosis and Child classification. After controlling for the confounding eff     

Monitoring serum insulin-like growth factor-I (IGF-I), IGF binding protein-3 (IGFBP-3), IGF-I/IGFBP-3 molar ratio and leptin during growth hormone treatment for disordered growth

OBJECTIVE: Serum IGF-I levels are monitored during GH replacement treatment in adults with GH deficiency (GHD) to guide GH dose adjustment and to minimize occurrence of GH-related side-effects. This is not routine practice in children treated with GH. The aim of this study was to evaluate changes in (1) serum IGF-I, IGFBP-3 and IGF-I/IGFBP-3 molar ratio, and (2) serum leptin, an indirect marker of GH response, during the first year of GH treatment in children with disordered growth. DESIGN: An observational prospective longitudinal study with serial measurements at five time points during the first year of GH treatment was carried out. Each patient served as his/her own control. PATIENTS: The study included 31 patients, grouped as (1) GHD (n = 20) and (2) non-GHD (Turner syndrome n = 7; Noonan syndrome n = 4), who had not previously received GH treatment. MEASUREMENTS: Serum IGF-I, IGFBP-3 and leptin levels were measured before treatment and after 6 weeks, 3 months, 6 months and 12 months of GH treatment, with a mean dose of 0.5 IU/kg/wk in GHD and 0.7 IU/kg/wk in non-GHD groups. IGF-I, IGFBP-3 and the calculated IGF-I/IGFBP-3 molar ratio were expressed as SD scores using reference values from the local population. RESULTS: In the GHD group, IGF-I SDS before treatment was lower compared with the non-GHD (-5.4+/-2.5 vs. -1.8+/-1.0; P<0.001). IGF-I (-1.8 SDS +/- 2.2) and IGFBP-3 (-1.1 SDS +/- 0.6) levels and their molar ratios were highest at 6 weeks and remained relatively constant thereafter. In the non-GHD group, IGF-I levels increased throughout the year and were maximum at 12 months (0.3 SDS +/- 1.4) while IGFBP-3 (1.1 SDS +/- 0.9) and IGF-I/IGFBP-3 molar ratio peaked at 6 months. In both groups, IGF-I SDS and IGF-I/IGFBP-3 during treatment correlated with the dose of GH expressed as IU/m2/week (r-values 0. 77 to 0.89; P = 0.005) but not as IU/kg/week. Serum leptin levels decreased significantly during GH treatment in the GHD (median before treatment 4.0 microg/l; median after 12 months treatment 2.4 microg/l; P = 0.02) but not the non-GHD (median before treatment 3.0 microg/l; median after 12 months treatment 2.6 microg/l). In the GHD group, serum leptin before treatment correlated with 12 month change in height SDS (r = 0.70, P = 0.02). CONCLUSIONS: The pattern of IGF-I, IGFBP-3 and their molar ratio during the first year of GH treatment differed between the GHD and non-GHD groups. Calculation of GH dose by surface area may be preferable to calculating by body weight. As a GH dose-dependent increase in serum IGF-I and IGF-I/IGFBP-3 may be associated with adverse effects, serum IGF-I and IGFBP-3 should be monitored routinely during long-term GH treatment. Serum leptin was the only variable that correlated with first year growth response in GHD.     

Diagnostic efficiency of serum IGF-I, IGF-binding protein-3 (IGFBP-3), IGF-I/IGFBP-3 molar ratio and urinary GH measurements in the diagnosis of adult GH deficiency: importance of an appropriate reference population

OBJECTIVE: To analyse the diagnostic role of serum IGF-I, IGF-binding protein-3 (IGFBP-3), IGF-I/IGFBP-3 molar ratio and urinary GH (uGH) excretion in adult GH deficiency (GHD). DESIGN: Twenty-seven adults (age range: 18-71 years) with severe GHD, defined by a peak GH response to an insulin tolerance test below 3microg/l in patients with at least one additional pituitary hypofunction. Reference values were established from a selected age- and body mass index-matched population (154 healthy adults grouped in four age groups). METHODS: IGF-I and IGFBP-3 were measured by RIA (Nichols) and results expressed as standard deviation (s.d.) scores from our reference population and assay normative data (s.d. score Nichols). uGH was measured by IRMA. RESULTS: Within the control group, IGF-I, IGFBP-3, IGF-I/IGFBP-3 ratio standardisation regarding our control population and IGF-I with respect to the assay normative data resulted in disappearance of age-related differences. However, IGFBP-3 s.d. score Nichols resulted in mean values between +1.4 and +2.5 s.d. score. Greatest diagnostic efficiency was for IGF-I standardised with respect to our controls (97.2%), followed by s.d. score IGFBP-3 (92.9%). s.d. score IGF/IGFBP-3 ratio and uGH showed poor diagnostic efficiency. Any combination of at least two abnormal parameters raised specificity to 100%. IGF-I standardised with respect to assay reference (s.d. score Nichols) showed similar diagnostic value (95.0%) whereas IGFBP-3 showed low sensitivity (33. 3%). Within the GHD patients, those with three or more additional deficiencies had lower s.d. score IGF-I than those with only two or one. CONCLUSION: We underline the importance of an appropriate reference population for correct interpretation of GH secretion markers. Considering our results, specificity obtained with two simultaneous abnormal parameters when referred to an adequate reference population may add valuable information to alternative GH stimulation tests to confirm adult GHD.     

IGF-I and IGFBP-3 serum levels in patients hospitalized for complications of liver cirrhosis

Background. IGF-I and IGFBP-3 are part of IGF system and, due to their predominantly hepatic synthesis, they seem to correlate with hepatic dysfunction intensity. Aims. To investigate the significance of IGF-I and IGFBP-3 in patients with decompensated liver disease.Material and methods. Cross-sectional study that included cirrhotic patients admitted to hospital due to complications of the disease, in whom IGF-I and IGFBP-3 serum levels were measured by chemiluminescence. Results. Seventy-four subjects with a mean age of 53.1 ± 11.6 years were included in the study, 73% were males. IGF-I levels were positively correlated with IGFBP-3 and albumin, and negatively correlated with Child-Pugh, MELD, creatinine, INR and aPTT ratio. IGFBP-3 levels were positively correlated with IGF-I and albumin, and negatively correlated with Child-Pugh, MELD, creatinine, INR, total bilirubin and aPTT ratio. Significantly lower scores of IGF-I and IGFBP-3 were observed in patients with higher MELD values and higher Child-Pugh classes (P < 0.05).Conclusions. In cirrhotic patients admitted to hospital due to complications of the disease, IGF-I and IGFBP-3 serum levels were associated with variables related to liver dysfunction and to more advanced liver disease. The levels of these markers seem to undergo little influence from other clinical and laboratory variables, therefore mainly reflecting hepatic functional status.     

IGF-I but not the IGF-I variant long R(3)IGF-I increases serum IGFBP-3 in adolescent monkeys.

Previous work in rhesus monkeys has shown that both acute or chronic subcutaneous (s.c.) administration of insulin-like growth factor (IGF)-I elevates serum concentrations of IGF binding protein (IGFBP)-3. In order to determine whether an analog of IGF-I, which has a reduced affinity for the IGFBPs, has similar effects, a series of studies using adolescent female rhesus monkeys were conducted. In the first study, an s.c. injection of IGF-I (110 mg/kg;n = 6) significantly elevated serum IGFBP-3 concentrations through 7 h following treatment. In contrast, serum IGFBP-3 decreased throughout the day following an injection of Long R(3)IGF-I (110 mg/kg, s.c., n = 5). However, this decrease was not due to the analog treatment as serum IGFBP-3 also declined in a similar fashion in untreated females (n = 5) sampled on the same schedule. Serum GH levels were acutely suppressed by both IGFs but were not altered in untreated females. In the second study, serum IGFBP-3 were compared between untreated control females (n = 6) and females treated continuously by s.c. infusion with either Long R(3)IGF-I (120 mg/kg/day, s.c.;n = 5) or IGF-I (120 mg/kg/day, s.c.;n = 5) or IGF-I s.c.;n = 4). Serum IGFBP-3 was consistently elevated by IGF-I infusion, whereas levels in analog-treated monkeys were similar to those in control females. Although acute or chronic administration of Long R(3)IGF-I did not elevate serum IGFBP-3, chronic administration of the analog did not block the acute facilitating effects of IGF-I on serum IGFBP-3. The increase in serum IGFBP-3 following an acute injection of IGF-I (110 mg/kg, s.c.) was not significantly different between untreated females and females receiving a constant s.c. infusion of Long R(3)IGF-I. These data indicate either acutely or chronically administered IGF-I but not its analog Long R(3)IGF-I can elevate serum concentrations of IGFBP-3. Although the analog fails to increase serum IGFBP-3, it does not block the facilitating effects of IGF-I on concentrations of this IGFBP. Taken together, these data suggest that the increase in serum IGFBP-3 by exogenous IGF-I may not be a receptor mediated event but may be the result of IGF-I binding to IGFBP-3 and forming the binary and ternary complex, slowing IGFBP-3 degradation.     

Normal IGF-I and enhanced IGFBP-3 response to very low rhGH dose in patients with dilated cardiomyopathy

Well-nourished patients with dilated cardiomyopathy (DCM) show slight reduction of mean basal IGF-I levels which, however, display a response to a rhGH dose as low as 5.0 microg/kg/day similar to that of age-matched control subjects (CS). To further investigate peripheral GH sensitivity, we studied the IGF-I and IGFBP-3 responses to 4-day s.c. 2.5 microg/kg/day rhGH administration, the lowest effective dose able to increase IGF-I levels in normal subjects, in 10 DCM patients [age (mean+/-SE): 57.6+/-1.0 yr, body mass index (BMI): 24.0+/-1.2 kg/m2, left ventricular ejection fraction: 26.2+/-3.2%, NYHA (New York Heart Association): I/0, II/4, III/4, IV/2] and in 9 age-matched healthy CS (age: 55.3+/-1.2 yr, BMI: 23.7+/-1.8 kg/m2). Basal IGF-I levels in DCM were lower though not significantly than those in CS (147.7+/-9.8 vs 174.7+/-17.0 microg/l). Basal IGFBP-3 levels in DCM were similar to those in CS (3.1+/-0.3 vs 2.7+/-0.2 mg/l). In CS 4-day rhGH increased IGF-I levels (222.4+/-14.9 microg/l; p<0.01 vs baseline) but did not modify IGFBP-3 levels (3.0+/-0.2 mg/l). In DCM IGF-I levels were increased by 4-day rhGH administration (175.7+/-11.0 microg/l; p<0.05 vs baseline) with a similar percent extent than in CS. On the other hand, in DCM, but not in CS, 4-day rhGH significantly increased IGFBP-3 levels (3.5+/-0.3 mg/l; p<0.05 vs baseline). Therefore, in conclusion, testing with the lowest effective rhGH dose further suggest that peripheral GH sensitivity in well-nourished DCM is preserved. On the other hand, DCM patients show enhanced IGFBP-3 sensitivity to stimulation by rhGH.     

中性粒细胞与淋巴细胞比值:一项评价肝细胞癌患者预后的新指标

越来越多的证据表明中性粒细胞与淋巴细胞比值(NLR)可作为炎症反应的评价指标,与多种恶性肿瘤的预后密切相关。归纳总结了NLR与肝细胞癌总生存期、无瘤生存期、肿瘤病理特征的关系及其主要作用机制的最新研究进展,认为NLR是评价肝细胞癌患者预后的方便、经济、有效的新指标。     

Increased extrinsic apoptotic pathway activity in patients with hepatocellular carcinoma following transarterial embolization

AIM:To determine the apoptosis pathway in residualviable hepatocellular carcinoma(HCC) tissues followingtransarterial embolization(TAE) .METHODS:Ten patients with HCC who received sur-gical resection after TAE were enrolled in the study group,and 24 patients with HCC who received surgical resection only served as the control group. In thestudy group,we measured the changes in tumor sizeand α fetoprotein(AFP) levels after TAE. All tissuesamples were taken from the residual tumors. The ex-pression of various ...     

Neutrophil-to-lymphocyte ratio associated with mortality in early hepatocellular carcinoma patients after radiofrequency ablation

Background and Aim: Increasing evidence correlates the presence of systemic inflammation with poor survival in patients with hepatocellular carcinoma (HCC). We studied whether peripheral blood neutrophil‐to‐lymphocyte ratio (NLR), a marker of systemic inflammatory response, would be a useful predictor for outcome in patients with early HCC undergoing radiofrequency ablation (RFA). Methods: A total of 158 patients with early HCC underwent RFA. Potential prognostic factors such as age, gender, tumoral characteristics, Child‐Turcotte‐Pugh (CTP) class and NLR were analyzed. The study endpoints were overall survival (OS) and new recurrence. Results: We modeled NLR as a continuous explanatory variable in regression analyses. Multivariate analysis revealed that tumor size (P = 0.005) and high baseline NLR (P = 0.001) were independent explanatory variables associated with unfavorable OS. Regarding new recurrence, multivariate analysis showed that CTP class B (P = 0.002), α‐fetoprotein > 400 ng/mL (P = 0.030), tumor size (P = 0.002) and tumor multiplicity (P = 0.013) were found to be worse prognosticators, but not baseline NLR. In a subset analysis of 140 patients whose post‐RFA NLR data at first follow‐up visit were available, multivariate analysis revealed that high post‐RFA NLR was identified as an independent covariate, not only for OS (P = 0.006), but for new recurrence (P = 0.010) as well. Conclusions: High baseline NLR was associated with worse OS for patients with early HCC; post‐RFA NLR predicted not only OS, but also tumor recurrence.     

Increased survival of cirrhotic patients with a hepatocellular carcinoma detected during surveillance

BACKGROUND & AIMS: Significant improvements in management of hepatocellular carcinoma (HCC) have occurred in the last years, but their impact on surveillance outcome is unknown. To clarify this, we compared survival of HCC patients identified along 3 consecutive quinquennia of surveillance. METHODS: A cohort of 417 HCC-free outpatients with compensated cirrhosis was prospectively followed for 148 months (range, 1-213 months) with periodic ultrasound examinations. RESULTS: HCC developed in 112 patients, at a 3.4% rate per year, and was the prime cause of death (n = 54). Forty-six (41%) patients had a single tumor, with a mean size of 3.7 cm, 3.0 cm, and 2.2 cm in the 3 quinquennia (first vs. second: ns; first vs. third: P = 0.017; second vs. third: P = 0.02), and 38 (44%) underwent radical therapy. Mortality rates in HCC patients fell from 45% in the first quinquennium to 37% in the second and 10% in the third (first vs. second: ns; first vs. third: P = 0.0009; second vs. third: P = 0.018) in parallel with a reduction in yearly mortality of treated patients (34%, 28%, and 5%, respectively; first vs. second: ns; second vs. third: P = 0.036; first vs. third: P = 0.0024). After stratification for quinquennium, tumor staging, according to Cancer of the Liver Italian Program (CLIP), was the only independent predictor of survival (P = 0.015). CONCLUSIONS: Cirrhotic patients developing a HCC during the last 5 years of surveillance survived longer than previously, as a consequence of improved management of the tumor and complications of cirrhosis.     

Body mass index, waist circumference and waist-hip ratio and serum levels of IGF-I and IGFBP-3 in European women

OBJECTIVE: To examine the relationship between body mass index (BMI) and waist-hip ratio (WHR) with serum levels of insulin-like growth factor-I (IGF-I), and its binding protein (IGFBP)-3. DESIGN: Cross-sectional study on 2139 women participating in a case-control study on breast cancer and endogenous hormones. Data on lifestyle and reproductive factors were collected by means of questionnaires. Body height, weight, waist and hip circumferences were measured. Serum levels of IGF-I and insulin-like binding protein (IGFBP)-3 were measured by enzyme-linked immunosorbent assays. Adjusted mean levels of IGF-I and IGFBP-3 across quintiles of BMI, waist circumference, and WHR were calculated by linear regression. Results were adjusted for potential confounders associated with IGF-I and IGFBP-3. RESULTS: Adjusted mean serum IGF-I values were lower in women with BMI<22.5 kg/m(2) or BMI>29.2 kg/m(2) compared to women with BMI within this range (P(heterogeneity)<0.0001, P(trend)=0.35). Insulin-like growth factor-I was not related to WHR after adjustment for BMI. IGF-binding protein-3 was linearly positively related to waist and WHR after mutual adjustment. The molar ratio IGF-I/IGFBP-3 had a non-linear relation with BMI and a linear inverse relationship with WHR (P (trend)=0.005). CONCLUSIONS: Our data confirm the nonlinear relationship of circulating IGF-I to total adiposity in women. Serum IGFBP-3 was positively related to central adiposity. These suggest that bioavailable IGF-I levels could be lower in obese compared to non-obese women and inversely related to central adiposity.     

Lymphocyte-to-monocyte ratio predicts survival of patients with hepatocellular carcinoma after curative resection

AIM: To investigate the prognostic value of preoperative lymphocyte-to-monocyte ratio(LMR) in patients with hepatocellular carcinoma(HCC) undergoing curative hepatectomy.METHODS: Clinicopathological data of 210 hepatitis B virus(HBV)-associated HCC patients who were treated by radical hepatic resection between 2003 and 2010 were retrospectively analyzed. None of the patients received any preoperative anticancer therapyor intraoperative radiofrequency ablation. The diagnosis was confirmed by pathological examination after surgery. Absolute peripheral blood lymphocyte and monocyte counts were derived from serum complete blood cell count before surgery,and LMR was calculated by dividing lymphocyte count by monocyte count. The best cutoff was determined by receiver operating characteristics(ROC) curve analysis. Correlations between LMR levels and clinicopathological features were assessed using the χ2 test. Survival outcomes were estimated using the Kaplan-Meier method and compared by the log-rank test. Univariate and multivariate analyses were performed to evaluate the prognostic impact of LMR and other clinicopathological factors on overall survival(OS) and recurrence-free survival(RFS),using the Cox proportional hazards model.RESULTS: The optimal cutoff value of LMR for survival analysis was 3.23,which resulted in the most appropriate sensitivity of 55.3% and specificity of 74.7%,with the area under the curve(AUC) of 0.66(95%CI: 0.593-0.725). All patients were dichotomized into either a low(≤ 3.23) LMR group(n = 66) or a high( 3.23) LMR group(n = 144). A low preoperative LMR level was significantly correlated with the presence of cirrhosis,elevated levels of total bilirubin and larger tumor size. Patients with a low LMR level had significantly reduced 5-year OS(61.9% vs 83.2%,P 0.001) and RFS(27.8% vs 47.6%,P = 0.009) compared to those with a high LMR level. Multivariate analyses indicated that a lower LMR level was a significantly independent predictor of inferior OS(P = 0.003) and RFS(P = 0.006). Subgroup analysis indicated that survival outcome was significantly more favorable in cirrhotic patients with LMR 3.23. However,there were no differences between low and high LMR groups for OS and RFS in non-cirrhotic patients.CONCLUSION: Preoperative LMR was demonstrated for the first time to serve as an independent prognostic factor in HBV-associated HCC patients after curative resection. Prospective studies with larger cohorts for validation are warranted.     

Neutrophil-lymphocyte ratio is useful for the prognosis of patients with hepatocellular carcinoma

There is increasing evidence that neutrophil-lymphocyte ratio (NLR) may play a role in predicting recurrence in patients with hepatitis B virus-related hepatocellular carcinoma (HCC) after liver transplantation. In the original study by Yan et al, it was aimed to determine whether an elevated NLR is associated with tumor recurrence. Total tumor size (> 9 cm) and macro-vascular invasion were found to be more significant than NLR according to the multivariate logistic regression analysis. Therefore, substantive significance should be emphasized rather than NLR because total tumor size and macro-vascular invasion are easier and more expressive than NLR in assessing HCC recurrence. NLR and platelet-lymphocyte ratio (PLR) are markers which are easy to obtain and can be used as inflammation indicators. Moreover, assessment of both NLR and PLR may add some value as a good predictor of risk for post-liver transplantation HCC recurrence. However, while the study was constructed on whole blood analysis, further details about the features and performance characteristics of the whole-blood analyzer, and preanalytical/analytical variables should also be mentioned.     

Increased adiponectin associated with poor survival in hepatocellular carcinoma

Background

Alterations of adiponectin (APN), one of the adipokines, have been associated with human cancers. However, the clinical significance and impacts of APN on hepatocellular carcinoma (HCC) remain undetermined.

Methods

Using immunohistochemistry, expression patterns of APN were semiquantitatively scored and further statistically correlated with clinicopathological characteristics and patient survival. Furthermore, the bioeffects and underlying mechanisms of ectopic APN overexpression were determined in Hep3B and HepG2 cells by XTT, immunoblotting, flowcytometry, and invasion assays with or without chemical inhibitors and neutralization antibody.

Results

We found that cytoplasmic APN staining in 85 cancerous lesions was increased and associated with a poor survival rate (P = 0.007), even when using the Cox regression model (OR = 3.590; 95 % CI = 1.240–10.394; P = 0.018). Ectopic overexpression of APN in Hep3B and HepG2 cells increased proliferation and invasion as well as the levels of p-AKT (Ser473), p-STAT3 (Tyr705), and those downstream, i.e., cyclin D1 and β-catenin. Similar results were also demonstrated in a stable APN-overexpressing clone, HepG2#136. APN neutralization antibody and LY294002 blocked the APN-mediated effects via inhibition of activated AKT.

Conclusions

Our results suggest that increased APN may contribute to HCC at least in part through its activation of AKT signalling and may serve as a prognostic factor in HCC.