The CA.ME.LI.A (CArdiovascular risks, MEtabolic syndrome, LIver and Autoimmune disease) epidemiological study was conducted in Abbiategrasso (Milan, Italy) to identify risk factors for metabolic and cardiovascular disease in an apparently healthy population of northern Italy. The population (n = 2,545, 1,251 men, 1,254 women) was stratified according to body mass index [normal body weight (NBW): <25 kg/m2; overweight-obese (OWO): ≥25 kg/m2] and according to fasting blood glucose [normal fasting glucose: <100 mg/dL; impaired fasting glucose (IFG): 100-125 mg/dL; diabetes mellitus (DM): ≥126 mg/dL]. The incidence of cardiovascular (CV) events and overall mortality were studied by the Kaplan-Meier method using the log rank test. Univariate analysis was conducted with time-dependent Cox models. During the 7-yr follow-up period, 80 deaths and 149 CV events occurred. IFG [hazard ratio (HR): 2.81; confidence interval (CI): 1.37-5.77; P = 0.005], DM (HR: 4.88; CI: 1.47-16; P = 0.010), or OWO (HR: 2.78; CI:1.68-4.59; P < 0.001) all produced significant increases in CV events and deaths. In the combination IFG/OWO (HR: 5.51; CI: 3.34-9.08; P < 0.001), there was an apparent additive effect of the two conditions, whereas in the combination DM/OWO (HR: 12.71; CI: 7.48-22; P < 0.001), there was an apparent multiplicative effect on the risk for CV events and deaths. In males, the DM/NBW group had a higher incidence of cardiovascular events and deaths than the IFG/OWO group. In contrast, in females, the IFG/OWO group had a higher incidence of cardiovascular events and deaths than the DM/NBW group. In women, there was a greater incidence of CV events in the IFG/OWO group (HR: 6.23; CI: 2.88-13; P < 0.001) than in men in the same group (HR: 4.27; CI: 2.15-8.47; P < 0.001). Consistent with these data, also all-cause mortality was progressively increased by IFG/DM and OWO, with an apparently exponential effect in the combination DM/OWO (HR: 11.78; CI: 6.11-23; P < 0.001). IFG/DM and OWO, alone or in combination, had major effects in increasing mortality for all causes and CV events. The relative contributions of hyperglycemia and overweight/obesity on cardiovascular events and deaths were apparently, to a certain extent, sex dependent. Females were more affected by overweight/obesity either alone or combined with IFG, as compared with males.NEW & NOTEWORTHY For the first time, the combined effects of glucose tolerance and BMI have been investigated in an apparently healthy large population sample of a city in the north of Italy. We found that there are synergistic effects of glucose levels with BMI to increase not only cardiovascular events and deaths but also cancer-related deaths and all-cause mortality.

In patients with cirrhosis with severe thrombocytopenia (platelet count [PC] <50 × 109/L) and undergoing invasive procedures, it is common clinical practice to increase the PC with platelet transfusions or thrombopoietin receptor agonists to reduce the risk of major periprocedural bleeding. The aim of our study was to investigate the association between native PC and perioperative bleeding in patients with cirrhosis undergoing surgical procedures for the treatment of hepatocellular carcinoma (HCC). We retrospectively evaluated 996 patients with cirrhosis between 1996 and 2018 who underwent surgical treatments of HCC by liver resection (LR) or radiofrequency ablation (RFA) without prophylactic platelet transfusions. Patients were allocated to the following three groups based on PC: high (>100 × 109/L), intermediate (51‐100 × 109/L), and low (≤50 × 109/L). PC was also analyzed as a continuous covariate on multivariable analysis. The primary endpoint was major perioperative bleeding. The overall event rate of major perioperative bleeding was 8.9% and was not found to differ significantly between the high, intermediate, and low platelet groups (8.1% vs. 10.2% vs. 10.8%, P = 0.48). On multivariable analysis, greater age, aspartate aminotransferase, lower hemoglobin, and treatment with LR (vs. RFA) were found to be significant independent predictors of major perioperative bleeding, with associations with disease etiology and year of surgery also observed. After adjusting for these factors, the association between PC and major perioperative bleeding remained nonsignificant. Conclusion: Major perioperative bleeding was not significantly associated with PC in patients with cirrhosis undergoing surgical treatment of HCC, even when their PC was <50 × 109/L. With the limit of a retrospective analysis, our data do not support the recommendation of increasing PC in patients with severe thrombocytopenia in order to decrease their perioperative bleeding risk.

Background Liver dysfunction has been widely reported in connection with anorexia nervosa (AN) but the pathogenesis of these alterations has never been fully understood despite reported theories about the presence of insulin resistance (IR) and non-alcoholic fatty liver disease (NAFLD). The aim of this study is to investigate if hypertransaminasemia in AN is linked to IR and NAFLD. Methods Anthropometric data and laboratory exams of 34 patients and 34 controls were analyzed, including alanine-aminotransferase, aspartate-aminotransferase and homeostatic model assessment of insulin resistance (HOMA-IR) index. All subjects also underwent magnetic resonance imaging (MRI), ultrasonography (US), and transient elastography (TE). Results Evidence of increased alanine aminotransferase in AN patients was confirmed in our sample together with a lower HOMA-IR index compared to controls. Positive results in US appeared in 16 patients vs none in controls (p = 0.0007); patients with liver parenchyma abnormalities in US were not different than normal-US patients in any of the studied variables. Only one patient showed non-alcoholic fatty liver disease in MRI while abnormal TE was found in four patients and never in controls. Conclusions Liver damage suggested by increased serum liver enzymes cannot be due to liver steatosis but potentially to a different liver disease (not identified by MRI) or to an early liver fibrosis not associated with an insulin-resistant status.

Hepatocellular adenoma (HCA) is a rare benign monoclonal neoplasm, recently categorized on genetic and histopathological basis into four subtypes with different biological behaviors. Since contrast-enhanced ultrasonography (CEUS) is nowadays a well-established technique for liver nodule characterization, the aim of our study was to assess CEUS features of HCAs to identify criteria that correlate with different HCA subtypes as compared to histopathologic examination and other imaging modalities.

Background & Aims: Preoperative prediction of both microinvasive hepatocellular carcinoma and histological grade of hepatocellular carcinoma is pivotal to treatment planning and prognostication. The aim of this study was to evaluate whether some intraoperative ultrasound features correlate with both the presence of same histological patterns and differentiation grade of hepatocellular carcinoma on the histological features of the primary resected tumour. Methods: All patients with single, small hepatocellular carcinoma that underwent hepatic resection were included in this prospective double-blind study: the intraoperative ultrasound patterns of nodule were registered and compared with similar histological features. Results: A total of 179 patients were enclosed in this study: 97 (54%) patients (34% in HCC = 2 cm) had a microinvasive hepatocellular carcinoma at ultrasound examination, while 82 (46%) patients (41% in HCC = 2 cm) at histological evaluation. Statistical analysis showed that diameters = 2 cm, presence of satellites and microinvasive hepatocellular carcinoma at ultrasound examination were the variables with the strongest association with the histological findings. In the multivariate analysis, the vascular microinfiltration and infiltrative hepatocellular carcinoma aspect were independent predictors for grading. Conclusions: In patients with cirrhosis and hepatocellular carcinoma, the prevalence of microinvasive hepatocellular carcinoma is high, even in cases of HCC = 2 cm. Intraoperative ultrasound findings strongly correlated with histopathological criteria in detecting microinvasive patterns and are useful to predict neoplastic differentiation. The knowledge of these features prior to treatment are highly desired (this can be obtained by an intraoperative ultrasound examination), as they could help in providing optimal management of patients with hepatocellular carcinoma.

Laparoscopic thermal ablation is a common alternative to surgical resection in treating hepatic tumors, particularly in those located in difficult-to-reach locations.The aim of this study was to compare the safety and long-term efficacy of laparoscopic radiofrequency ablation (RFA) and microwave ablation (MWA) in treating hepatocellular carcinoma (HCC).From February 2009 to May 2015, data from patients with HCC nodules who had undergone either laparoscopic MWA or laparoscopic RFA were examined. Complications, complete ablation rates, local tumor progression (LTP) rates, and disease-free and cumulative survival rates were compared between the two treatment groups.A total of 154 patients with HCC (60 MWA and 94 RFA) were treated via the laparoscopic approach. Major complication rates were identified as 1 and 2 % in the RFA and MWA groups, respectively (p = 0.747). Complete ablation rates were 95 % for both treatment groups (p = 0.931), and LTP rates were 21.2 % for RFA and 8.3 % for MWA (p = 0.034). Disease-free survival rates at 5 years were 19 % in the RFA group and 12 % in the MWA group (p = 0.434), while cumulative survival rates at 5 years were 50 % in the RFA group and 37 % in the MWA group (p = 0.185).Laparoscopic RFA and MWA appear to be safe in the treatment of early-stage HCC. The LTP rates were lower in the laparoscopic MWA group compared with the laparoscopic RFA group, but their respective overall and disease-free survival rates remained similar.

When compatible with the liver functional reserve, laparoscopic hepatic resection remains the treatment of choice for hepatocellular carcinoma while laparoscopic ablation therapies appear as a promising less invasive alternative. The aim of the study is to compare two homogeneous groups of patients submitted to either hepatic resection or thermoablation for the treatment of single hepatocellular carcinoma (≤ 3 cm).

Several staging systems for hepatocellular carcinoma (HCC) have been developed. The Barcelona Clinic Liver Cancer staging system is considered the best in predicting survival, although limitations have emerged. Recently, the Italian Liver Cancer (ITA.LI.CA) prognostic system, integrating ITA.LI.CA tumor staging (stages 0, A, B1‐3, C) with the Child‐Turcotte‐Pugh score, Eastern Cooperative Oncology Group performance status, and alpha‐fetoprotein with a strong ability to predict survival, was proposed. The aim of our study was to provide an external validation of the ITA.LI.CA system in an independent real‐life occidental cohort of HCCs. From September 2008 to April 2016, 1,508 patients with cirrhosis and incident HCC were consecutively enrolled in 27 Italian institutions. Clinical, tumor, and treatment‐related variables were collected, and patients were stratified according to scores of the Barcelona Clinic Liver Cancer system, ITA.LI.CA prognostic system, Hong Kong Liver Cancer system, Cancer of the Liver Italian Program, Japanese Integrated System, and model to estimate survival in ambulatory patients with hepatocellular carcinoma. Harrell's C‐index, Akaike information criterion, and likelihood‐ratio test were used to compare the predictive ability of the different systems. A subgroup analysis for treatment category (curative versus palliative) was performed. Median follow‐up was 44 months (interquartile range, 23‐63 months), and median overall survival was 34 months (interquartile range, 13‐82 months). Median age was 71 years, and patients were mainly male individuals and hepatitis C virus carriers. According to ITA.LI.CA tumor staging, 246 patients were in stage 0, 472 were in stage A, 657 were in stages B1/3, and 133 were in stage C. The ITA.LI.CA prognostic system showed the best discriminatory ability (C‐index = 0.77) and monotonicity of gradients compared to other systems, and its superiority was also confirmed after stratification for treatment strategy. Conclusion: This is the first study that independently validated the ITA.LI.CA prognostic system in a large cohort of Western patients with incident HCCs. The ITA.LI.CA system performed better than other multidimensional prognostic systems, even after stratification by curative or palliative treatment. This new system appears to be particularly useful for predicting individual HCC prognosis in clinical practice. (Hepatology 2018;67:2215‐2225)

Patients and Methods: Two hundred pairs of patients with cirrhosis and HCC and unrelated patients with cirrhosis alone were enrolled.Polymorphisms of TNFa -238, TNFa -308, and lymphotoxin (LT)a +252 were genotyped by the polymerase chain reaction with direct sequencing or restriction fragmented length polymorphism.TNF haplotypes were also analyzed.From routine laboratory data, the following surrogate markers associated with hepatic fibrosis were measured: platelet count, aspartate aminotransferase/alanine aminotransferase ratio, aspartate aminotransferase/platelet ratio index, Pohl score, and cirrhosis discriminant score.These fibrosis surrogate markers were analyzed with polymorphisms and haplotypes of TNF locus.Results: The frequencies of the variant genotypes and alleles of LTa +252 and TNFa -308 in patients with HCC were significantly higher than those in patients with cirrhosis alone.There was no such a difference in the TNFa -238 polymorphisms.Univariate analysis indicated that LTa +252 G/G genotype (odds ratio (OR) = 2.31) and TNFa -308 G/A genotype (OR = 2.31) were significantly associated with HCC.Multivariate analysis indicated that LTa +252 G/G (OR = 2.05, 95% confidence interval (CI), 1.20-3.51),TNFa -308 G/A (OR = 1.77, 95% CI, 1.02-3.07),and TNF haplotypes (AGA, OR = 5.69; 95% CI, 1.90-17.10;GGA, OR = 2.07; 95% CI, 1.18-3.63;and GGG, OR = 1.51, 95% CI, 1.11-2.04)were independent risk factors for HCC.Among patients with cirrhosis and HCC, significant hepatic fibrosis was found between 71.4% and 93.5% of patients with variant TNF genotypes and between 54.4% and 86.8% of patients harboring TNF haplotypes (AGA, GAG and GGG).Multivariate analysis showed that factors associated with variant genotypes included cirrhosis with Child-Pugh C (OR = 8.85; 95% CI, 3.08-35.64),serum a-fetoprotein >100 ng/ml (OR = 2.50; 95% CI, 1.23-5.06),and thrombocytopenia (OR = 3.26; 95% CI, 1.14-9.30).Conclusions: Patients with cirrhosis who carry the TNF genetic variants were correlated with advanced fibrosis and severe liver damage, which may contribute to a higher risk to HCC.

Our aim was to assess the capability of Barcelona Clinic Liver Cancer (BCLC) staging system in allocating stage A patients to hepatic resection (HR) and the effect on survival.

BACKGROUND:Aggressive treatment of intrahepatic recurrence of hepatocellular carcinoma (HCC) increases patients' survival. This study aimed to evaluate laparoscopic thermal ablation (TA) in the treatment of intrahepatic HCC recurrences.METHODS:A retrospective analysis was performed on 88 patients (REC group) who underwent laparoscopic TA after prior TA (66 patients.) or partial hepatic resection (HR) (22 patients) as initial local treatment. Another 170 patients with primary HCC tumors (PRIM group) were regarded as the control group.RESULTS:The postoperative morbidity rates were similar for the patients with prior TA (18%) and those with prior HR (21%) (nonsignificant difference [NS]). The overall survival rates were not significantly different between the two groups (3-year survival rates of 59 and 78%, respectively; P = 0.1662). Moreover, the disease-free survival (DFS) rates did not differ significantly between the patients with prior TA and those with prior HR (3-year DFS of 21 and 8%, respectively; P = 0.1911). The incidences of morbidity in the whole REC (21%) and PRIM (20%) groups were similar (P = NS), and no mortality occurred in either group (0%). The cumulative 3-year survival rate was 63% in the REC group and 59% in the PRIM group (P = 0.5739), whereas the 3-year DFS rate was 17% in the REC group and 22% in the PRIM group (P = 0.5266).CONCLUSION:Laparoscopic TA can be performed safely and may be effective for intrahepatic HCC recurrence after prior TA or HR. It leads to survival and DFS rates similar to those obtained using laparoscopic TA for primary HCC without increasing morbidity. Laparoscopic TA could be proposed as first-line treatment of intrahepatic HCC recurrence for selected patients.

Despite the high complete necrosis rate of radio-frequency ablation (RFA) or the complete removal following curative hepatic resection (HR), recurrent hepatocellular carcinoma (HCC) remains a significant problem. The aim of the study is to identify some intraoperative ultrasound (IOUS) patterns, predicting intrahepatic recurrences. From January 1997 to July 2009, 410 patients with HCC were treated (162 HR and 248 RFA through a surgical access). All patients were submitted to IOUS examination: 148 IOUS were performed during the laparotomic access while 262 IOUS were performed during the laparoscopic access. Primary HCC was classified according to diameter, HCC pattern (nodular or infiltrative), echogenicity (hyper- or hypo-echoic), echotexture (homogeneous or inhomogeneous), capsular invasion, mosaic pattern, nodule in nodule aspect and infiltration of portal vessels. Number of HCC nodules was also considered. Multivariate analysis (Cox model) was performed to determine features associated with recurrent HCC using IOUS patterns that independently predicted recurrent HCC, a IOUS score was developed. The patients were followed for 3-127 months, (median follow-up: 21.5 months). In 220 patients (54%), intrahepatic recurrences occurred. In 155 patients (38%), distant intrahepatic recurrences arose in different segments at the primary tumor site. In 65 HCC cases (16%), local recurrences were found. At multivariate analysis, multiple nodules, HCC diameter (>20 mm), HCC pattern (infiltrative), hyperechoic nodule and portal infiltration were statistically significant for risk factor of intrahepatic recurrences. Therefore, a IOUS scoring system was calculated on the basis of multivariate analysis and identified three risk categories of patients: in group 1 recurrences occurred in 37%, group 2 in 46% and group 3 in 66% (p = 0.0001). IOUS is an accurate staging tool during "surgical" procedures. This study showed an added value of IOUS: it permitted to identify ultrasound patterns, which can predict the risk of HCC recurrences. The calculated IOUS score permits to intraoperatively evaluate the actual surgical choice and to program the best treatment strategies during the follow-up period.

INTRODUCTION:Hepatocellular carcinoma (HCC) is associated with a high incidence of postoperative recurrence, despite high rates of complete necrosis with radiofrequency ablation (RFA) and curative hepatic resections (HR). The aim of this study was to identify intraoperative ultrasound patterns observed during HR or RFA that predicting intrahepatic HCC recurrence.MATERIALS AND METHODS:From January 1997 through August 2008, we treated 377 patients with HCC (158 with HR and 219 with surgical RFA). All patients underwent intraoperative ultrasound (IOUS) examination. Primary HCCs was classified according to diameter, HCC pattern (nodular or infiltrative), echogenicity (hyper- or hypo-), echotexture (homogeneous or inhomogeneous), capsular invasion, mosaic pattern, nodule-in-nodule appearance, and infiltration of portal vessels. Number of HCC nodules was also considered. Comparisons between the groups of possible factors for intrahepatic recurrence of treated tumors were performed using the Kaplan-Meier method and compared using the log-rank test.RESULTS:Patients were followed for 9-127 months (median: 18.6 months), and intrahepatic recurrence was observed in 198 (52.5%). In 138 patients (36.5%), recurrences were located in different segments with respect to the primary tumor. In 60 HCC tumors (16%), local recurrences were found in the same segment as the primary tumor. At univariate analysis, primary HCC echogenicity and mosaic pattern were the only factors not significant associated with intrahepatic recurrences.CONCLUSION:IOUS is an accurate staging tool for use during "surgical" resection or RFA. This study shows that IOUS patterns can also be used to estimate the risk of post-treatment HCC recurrence. In patients at high risk for this outcome, closer follow-up and use of adjuvant therapies could be useful.

This study compared two homogeneous groups of patients submitted to either surgical resection (HR) or laparoscopic radiofrequency ablation (LRFA) for the treatment of hepatocellular carcinoma (HCC). When compatible with the liver functional reserve, HR remains the treatment of choice for HCC, while LRFA seems to be a promising, less invasive alternative. We thus compared HR or LRFA for short- and long-term outcomes in patients with a single HCC nodule and Child-Pugh class A liver cirrhosis.

BACKGROUND The optimal treatment for hepatocellular carcinoma (HCC) is surgical resection. However, only a small percentage of patients are operative candidates. Percutaneous radiofrequency interstitial thermal ablation (RITA) has been shown to be efficacious in the treatment of unresectable HCC. Recent advances in laparoscopic ultrasound have greatly improved the accuracy in detecting intrahepatic HCC nodules, many of which were missed by computed tomography. Our objective was to introduce a novel operative combination of laparoscopic ultrasound with laparoscopic RITA in the treatment of HCC. METHODS Eighty-eight patients with HCC in liver cirrhosis were submitted to laparoscopic RITA under sonographic guide. Most patients were in Child's A class of liver function. Patients with large tumors (> 5 cm), portal vein thrombosis, or severe liver disease (Child's C class) were excluded. RESULTS The laparoscopic RITA procedure was completed in 86 of 88 patients (98% feasibility rate). Laparoscopy with laparoscopic ultrasound identified 23 new malignant lesions (27%) in comparison with the results of preoperative imaging. A total of 127 lesions were treated by RITA. There was no operative mortality. Sixty-one patients had no complication (71%). After a mean follow-up of 14.3 +/- 11.6 months, a complete response with a 100% necrosis was achieved in 70 of 83 patients examined (86%). During follow-up, 9 patients (11%) locally recurred at the RITA site and 38 patients (46%) had new malignant nodules. CONCLUSIONS Laparoscopic RITA of HCC proved to be a safe and effective technique in the short term. This technique may be indicated when the percutaneous approach to the lesion is very difficult or if the patient is too ill to undergo laparotomy.

BACKGROUND:The laparoscopic approach to radiofrequency interstitial thermal ablation (RITA) of hepatocellular carcinoma (HCC) with intraoperative ultrasound guidance has been proposed with the aim of obtaining additional information for a better neoplastic staging and a complete and effective treatment of the liver lesions in patients with a difficult percutaneous approach.METHODS:In this pilot study, 29 patients with HCC in liver cirrhosis were submitted to laparoscopic RITA under sonographic guide. Most of these patients were in Child's A class of liver function. Patients with large tumors (> 5 cm), portal vein thrombosis, or severe liver disease (Child's C class) were excluded from the study.RESULTS:The laparoscopic RITA procedure was completed in 27 of 29 patients (93% feasibility rate). The laparoscopic ultrasound examination identified new malignant liver nodules in five patients (18.5%). A total of 44 lesions were treated. The mean operative time was 75.8 +/- 20.5 min (range, 45-120 min), and the mean RITA time was 18 +/- 10 min (range, 10-56 min). There was no operative mortality, and postoperative morbidity was low (four cases) without any mortality. A complete tumor necrosis was observed in 90% of the patients via spiral computed tomography (CT) 1 month after treatment.CONCLUSIONS:Laparoscopic RITA of hepatocellular carcinoma proved to be a safe and effective technique, at least in the short term. Its role in the treatment of HCC needs to be defined in larger series.

The laparoscopic approach to radiofrequency interstitial thermal ablation (RITA) of hepatocellular carcinoma (HCC) with intraoperative ultrasound guidance has been proposed with the aim of obtainning additional information for a better neoplastic staging and a complete and effective treatment of the liver lesions in patients with a difficult percutaneous approach.