Marco Zoli

Estimation of lead-time bias and its impact on the outcome of surveillance for the early diagnosis of hepatocellular carcinoma

BACKGROUND & AIMSnLead-time is the time by which diagnosis is anticipated by screening/surveillance with respect to the symptomatic detection of a disease. Any screening program, including surveillance for hepatocellular carcinoma (HCC), is subject to lead-time bias. Data regarding lead-time for HCC are lacking. Aims of the present study were to calculate lead-time and to assess its impact on the benefit obtainable from the surveillance of cirrhotic patients.nnnMETHODSnOne-thousand three-hundred and eighty Child-Pugh class A/B patients from the ITA.LI.CA database, in whom HCC was detected during semiannual surveillance (n = 850), annual surveillance (n = 234) or when patients came when symptomatic (n = 296), were selected. Lead-time was estimated by means of appropriate formulas and Monte Carlo simulation, including 1000 patients for each arm.nnnRESULTSnThe 5-year overall survival after HCC diagnosis was 32.7% in semiannually surveilled patients, 25.2% in annually surveilled patients, and 12.2% in symptomatic patients (p<0.001). In a 10-year follow-up perspective, the median lead-time calculated for all surveilled patients was 6.5 months (7.2 for semiannual and 4.1 for annual surveillance). Lead-time bias accounted for most of the surveillance benefit until the third year of follow-up after HCC diagnosis. However, even after lead-time adjustment, semiannual surveillance maintained a survival benefit over symptomatic diagnosis (number of patients needed to screen = 13), as did annual surveillance (18 patients).nnnCONCLUSIONSnLead-time bias is the main determinant of the short-term benefit provided by surveillance for HCC, but this benefit becomes factual in a long-term perspective, confirming the clinical utility of an anticipated diagnosis of HCC.

Factors That Affect Efficacy of Ultrasound Surveillance for Early Stage Hepatocellular Carcinoma in Patients With Cirrhosis

BACKGROUND & AIMSnUltrasound surveillance does not detect early stage hepatocellular carcinomas (HCCs) in some patients with cirrhosis, although the reasons for this have not been well studied. We assessed the rate at which ultrasound fails to detect early stage HCCs and factors that affect its performance.nnnMETHODSnWe collected information on 1170 consecutive patients included in the Italian Liver Cancer (ITA.LI.CA) database who had Child-Pugh A or B cirrhosis and were diagnosed with HCC during semiannual or annual ultrasound surveillance, from January 1987 through December 2008. Etiologies included hepatitis C virus infection (59.3%), alcohol abuse (11.3%), hepatitis B virus infection (9%), a combination of factors (15.6%), and other factors (4.7%). Surveillance was considered to be a failure when patients were diagnosed with HCC at a stage beyond the Milan criteria (1 nodule ≤5 cm or ≤3 nodules each ≤3 cm).nnnRESULTSnHCC was found beyond Milan criteria in 34.3% of surveilled patients (32.2% during semi-annual surveillance and 41.3% during annual surveillance; P < .01). Nearly half of surveillance failures were associated with at least one indicator of aggressive HCC (levels of AFP >1000 ng/mL, infiltrating tumors, or vascular invasion and metastases). Semiannual surveillance, female sex, Child-Pugh class A, and α-fetoprotein levels of 200 ng/mL or less were associated independently with successful ultrasound screening for HCC.nnnCONCLUSIONSnBased on our analysis of surveillance for HCC in patients with cirrhosis, the efficacy of ultrasound-based screening is acceptable. Ultrasound was least effective in identifying aggressive HCC, and at surveillance intervals of more than 6 months.

Determinants of alpha‐fetoprotein levels in patients with hepatocellular carcinoma: Implications for its clinical use

α‐Fetoprotein (AFP) is a biomarker commonly used in the management of patients with hepatocellular carcinoma (HCC), although the possible determinants of its serum levels in these patients have not been adequately explored. For this study, the authors evaluated the relevance of demographic, clinical, and oncologic factors to the presence of elevated AFP levels in large cohort of patients with HCC.

Association of Abnormal Plasma Bilirubin With Aggressive Hepatocellular Carcinoma Phenotype

Cirrhosis-related abnormal liver function is associated with predisposition to hepatocellular carcinoma (HCC). It features in several HCC classification systems and is an HCC prognostic factor. The aim of the present study was to examine the phenotypic tumor differences in HCC patients with normal or abnormal plasma bilirubin levels. A 2,416-patient HCC cohort was studied and dichotomized into normal and abnormal plasma bilirubin groups. Their HCC characteristics were compared for tumor aggressiveness features, namely, blood alpha-fetoprotein (AFP) levels, tumor size, presence of portal vein thrombosis (PVT) and tumor multifocality. In the total cohort, elevated bilirubin levels were associated with higher AFP levels, increased PVT and multifocality, and lower survival, despite similar tumor sizes. When different tumor size terciles were compared, similar results were found, even among patients with small tumors. A multiple logistic regression model for PVT or tumor multifocality showed increased odds ratios for elevated levels of gamma glutamyl transpeptidase (GGTP), bilirubin, and AFP and for larger tumor sizes. We conclude that HCC patients with abnormal bilirubin levels had worse prognosis than patients with normal bilirubin. They also had an increased incidence of PVT and tumor multifocality, and higher AFP levels, in patients with both small and larger tumors. The results show an association between bilirubin levels and indices of HCC aggressiveness.

The Senile Lung as a Possible Source of Pitfalls on Chest Ultrasonography and Computed Tomography

Background: Age-associated changes in the pulmonary system could be detected with imaging techniques. Widespread use of lung ultrasonography (US) requires characterization of a normal pattern. Objectives: To compare US and computed tomography (CT) findings in healthy subjects undergoing both techniques (with CT as the gold standard). Methods: We prospectively selected 59 subjects undergoing chest CT and US on the same day, without a history of smoking, respiratory symptoms, or known pulmonary pathologies. There were 44 patients in group 1 (age =60 years - elderly) and 15 patients in group 2 (age =50 years - young). Lung US was performed with a convex and a linear probe, and 10 chest areas per patient were analyzed. Convex and linear probe agreement was evaluated by means of the Cohen κ statistic; Fishers exact test was used to compare categorical variables between groups. Results: Isolated B-lines were frequent in both group 1 (54.5%) and group 2 (40.0%); the number of chest areas positive for B-lines increased with age (16.1% in group 1 vs. 5.3% in group 2, p = 0.0028). In group 2, we found that 37.5% of subjects with B-lines had at least 1 chest area with multiple B-lines, but only 2 subjects had 2 or more. Moreover, in group 1 the chest CT documented a reticular pattern (2.3%), areas of increased density (9.1%), ground glass (6.8%), cysts (2.3%), bronchiectasis (22.7%), and bronchial thickening (6.8%); in group 2, only cysts (6.7%) and bronchiectasis (6.7%) were found. Conclusions: The senile lung is characterized by mild changes on CT and US. Chest areas positive for B-lines increase with age, and focal multiple B-lines can be found. However, diffuse patterns, especially in symptomatic subjects, suggest a different diagnosis.

Changes of liver enzymes and bilirubin during ischemic stroke: mechanisms and possible significance

BackgroundSmall changes of bilirubin and liver enzymes are often detected during the acute phase of stroke, but their origin and significance are still poorly understood.MethodsOn days 0, 3, 7, and 14 after admission, 180 patients with ischemic stroke underwent serial determinations of bilirubin, GOT, GPT, γGT, alkaline phosphatase, C-reactive protein (CRP) and complete blood count. On days 0 and 7 common bile duct diameter was measured by ultrasound, and on day 3 cerebral infarct volume (IV) was calculated from CT scan slices.ResultsDuring the first week GOT, GPT, γGT (Pu2009<u20090.001) and CRP (Pu2009=u20090.03) increased with subsequent plateau, while significant decrements (Pu2009<u20090.001) concerned unconjugated bilirubin, erythrocytes and haemoglobin. Alkaline phosphatase, direct bilirubin and common bile duct diameter remained stable. IV correlated with CRP, leukocytes, GOT, γGT (ru2009>u20090.3, Pu2009<u20090.001 for all) and direct bilirubin (ru2009=u20090.23, Pu2009=u20090.008). In multivariate analysis only CRP and GOT remained independently associated with IV (Pu2009<u2009=0.001). The correlation of IV with GOT increased progressively from admission to day 14. GOT independently correlated with GPT which, in turn, correlated with γGT. γGT was also highly correlated with leukocytes. Unconjugated bilirubin correlated with haemoglobin, which was inversely correlated with CRP.ConclusionsThe changes of bilirubin and liver enzymes during ischemic stroke reflect two phenomena, which are both related to IV: 1) inflammation, with consequent increment of CRP, leukocytes and γGT, and decrease of haemoglobin and unconjugated bilirubin and 2) an unknown signal, independent from inflammation, leading to increasing GOT and GPT levels.

Thyroid function tests and early outcomes of acute ischemic stroke in older euthyroid patients

Blood thyroid function tests (TFT) are routinely used to screen for thyroid disorders in several clinical settings. TFT on hospital admission may also be useful prognostic predictors of acute IS: according to recent evidence, poststroke outcome is better in patients with lower thyroid function and worse in those with higher thyroid function. However, previous reports are few and mostly compared patients with thyroid disorders to euthyroid patients. Thyroid disorders are known risk factors for cerebrovascular disease. However, hyperthyroidism is related to cardioembolic IS whereas hypothyroidism is related to atherosclerotic risk factors. Therefore, findings from available studies of TFT might just reflect the worse prognosis of cardioembolic IS compared to other IS subtypes. Another limitation of previous studies is the lack of information for older persons, who represent three quarters of all IS patients. In this paper, we investigated whether serum thyroid stimulating hormone (TSH), free thyroxine (FT4) and free triiodothyronine (FT3) measured on Stroke Unit (SU) admission are associated with early outcomes of acute IS in 775 euthyroid patients aged ≥65 years (mean age 80.1±8.7 years). Two composite outcomes were investigated: poor functional outcome (death during SU stay or disability at SU discharge), and unfavorable discharge setting (death during SU stay, transfer from SU to other acute hospital unit or transfer from SU to long-term care-facilities as opposed to direct discharge home). Analyses were performed using logistic regression models. Curvilinear associations were tested including TFT as polynomial terms. Models were adjusted for demographics, prestroke, and IS-related confounders. We found that lower TSH had a complex curvilinear association with poor functional outcome and that the shape of the associations changed with age. At age 65, the curve was U-shaped: outcome risk decreased with increasing TSH, reached its minimum at TSH near 3.00mUI/L and then started to rise. Between ages 70 and 75, however, the shape of the curve straightened and, starting from age 80 took an inverted U-shape: outcome risk rose with increasing TSH, reached its maximum at TSH values that progressively shifted upward with increasing age (from 1.70mU/L at age 80 to about 2.20mUI/L at age 90), then started to decrease. A linear inverse association was found between FT3 and unfavorable discharge setting. Our study suggests that measurement of TFT on SU admission can provide independent prognostic information for early outcomes of acute IS in older euthyroid patients.

Combination of the clock drawing test with the physical phenotype of frailty for the prediction of mortality and other adverse outcomes in older community dwellers without dementia.

Background: Cognitive assessment is thought to increase the ability of the physical phenotype of frailty to identify older persons at a higher risk for adverse outcomes. Objective: Data from a cohort of dementia-free community dwellers were used to investigate whether the clock drawing test (CDT), a quick and easy cognitive screening test, is associated with adverse health outcomes independently of the physical phenotype of frailty. Methods: This was a prospective population-based cohort study of 766 dementia-free Italian community dwellers aged 65 years or older. Baseline assessment included the physical phenotype of frailty, 3 different CDT protocols [Sunderland, Shulman, and the clock drawing interpretation scale (CDIS)], and several health confounders. Hazard ratios (HR) and odds ratio (OR) along with their corresponding 95% confidence intervals (CI) from models adjusted for frailty and sociodemographic and health confounders were used to estimate the independent association of the CDT with the 7-year risk of all-cause mortality and the 3-year risk of new and worsening disability, hospitalization, and fractures. Results: After adjustment for confounders, the Sunderland CDT was significantly associated with all-cause mortality independently of the physical phenotype of frailty (HR = 1.44, 95% CI 1.03-2.01, p = 0.031). However, compared to all nonfrail participants with a normal Sunderland CDT, the HR was 1.57 (95% CI 1.09-2.26, p = 0.016) for those with impairment on the Sunderland CDT only, 2.48 (95% CI 1.46-4.20, p = 0.001) for those with frailty only, and 2.52 (95% CI 1.34-4.77, p = 0.004) for those with both frailty and impairment on the Sunderland CDT. Mortality was unrelated to the CDIS CDT (p = 0.359) and the Shulman CDT (p = 0.281). No statistically significant relationship was found between nonlethal outcomes and any CDT protocol, although trends were found for an association of both the Sunderland CDT (p = 0.118) and the CDIS CDT with worsening disability (p = 0.154). Conclusions: In older persons, depending on the scoring system, the CDT may predict the mortality risk independently of the physical phenotype of frailty. However, combining the two measurements does not improve their individual prognostic abilities.

Diastolic dysfunction and cardiovascular risk in old subjects: Possible association with NAFLD?

Non-alcoholic fatty liver disease (NAFLD) is frequently associated with metabolic syndrome (MS) and may represent a cardiovascular (CV) risk factor. Functional cardiac abnormalities have been reported in patients with NAFLD. The aim of this paper is to investigate whether these findings are present also in elderly people. We tested 171 subjects aging more than 65 years, enrolled in a prospective study on CV risk reduction, for laboratory examination, abdominal ultrasound for evaluation of hepatic steatosis and standard echocardiography for determining morphological and functional cardiac parameters. Higher BMI, serum levels of glucose, triglycerides, cholesterol, insulin and visceral adipose tissue and lower serum levels of HDL-cholesterol were significantly associated with NAFLD. Furthermore, subjects with NAFLD had higher prevalence of diabetes, pathological waist-circumference, insulin-resistance and positive ATP-III criteria. While NAFLD had only a borderline significant association with higher end-diastolic thicknesses of left-ventricle posterior wall (edPW) and right-ventricle wall, higher values of edPW and end-diastolic thickness of interventricular septum were significantly correlated with glucose levels above 100mg/dl, hypertension, MS and insulin-resistance. Moreover, subjects with MS and/or pathological waist-circumference had a lower early-diastolic mitral annular motion, whereas those with insulin-resistance had lower E/A ratio and early-diastolic filling peak velocity. Regression analyses identify hypertension and pathological waist-circumference as factors independently associated to pathological edPW, and hypertriglyceridemia to pathological left-ventricle mass. In conclusion, an ultrasonographic diagnosis of NAFLD in old subjects may be an alert on the coexistence of multiple CV risk factors and on the presence of possible alterations of cardiac morphology and diastolic function.

Adipocyte-fatty acid binding protein and non-alcoholic fatty liver disease in the elderly

BackgroundAdipocyte-fatty acid binding protein (A-FABP) is an intracellular lipid transporter that mediates metabolically triggered inflammation, and it is associated with insulin resistance, atherogenic dyslipidemia, and cardiovascular risk.AimsThe aim of this study was to evaluate A-FABP behavior in elderly people, and especially its association with liver steatosis at abdominal ultrasound.MethodCross-sectional study of two cohort of individuals with and without steatosis, with assessment of several clinical and laboratory variables. Prospective evaluation of liver steatosis remodeling after six years of follow-up. One hundred and fifty-six subjects aged over 65xa0years were enrolled.ResultsSerum A-FABP positively correlated with body fat percentage, total cholesterol, serum triglycerides and erythrocyte sedimentation rate. Unlike expected, high A-FABP levels were associated with absence of liver steatosis, while there was no evidence of association with steatosis grade changes after 6xa0years of follow-up.ConclusionAmong individuals aging more than 65xa0years included in the study, A-FABP was inversely associated with liver steatosis. It can be argued, that still uncovered mechanisms modify A-FABP behavior in elderly people, especially its association with multifactorial diseases.