Synergistic effects of glucose tolerance and BMI on cardiovascular events and all-cause mortality in a healthy population. CA.ME.LI.A study 7 year follow-up.

Background The CA.ME.LI.A. study aimed to identify risk factors for metabolic and cardiovascular disease in a healthy population. Methods The population (n=2545; 1254 women) was stratified according to BMI (NBW < 25 kg/m2, OWO ≥ 25 kg/m2) and fasting glucose (NFG <100 mg/dL, IFG 100 - 125 mg/dL, DM ≥ 126 mg/dL). Incidence of cardiovascular (CV) events and all-causes mortality was studied by the Kaplan-Meier method using the log rank test. Univariate analysis was conducted with time-dependent Cox models. Results During the 7 years follow-up period, 80 deaths and 149 CV events occurred. IFG (HR: 2.81; p=0.005), DM (HR: 4.88; p=0.010) or OWO (HR: 2.78; p<0.001), all produced significant increases in CV events and deaths. IFG/OWO (HR: 5.51; p< 0.001) produced an additive effect, while DM/OWO (HR: 12.71; p<0.001), produced a multiplicative effect. In males, the DM/NBW group had higher incidence of cardiovascular events and deaths than the IFG/OWO group. On the other hand, in females, the IFG/OWO group had 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; p<0.001) than in men in the same group (HR: 4.27; p< 0.001). All-cause mortality was progressively increased by IFG/DM and OWO with an apparently exponential effect in the combination DM/OWO (HR 11.78; p<0.001). Conclusions IFG/DM and OWO, progressively increased mortality for all causes and CV events. Females were more affected by overweight/obesity as compared to males.

Impact of Platelet Count on Perioperative Bleeding in Patients With Cirrhosis Undergoing Surgical Treatments of Liver Cancer.

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.

Liver alterations in anorexia nervosa are not caused by insulin resistance.

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.

Contrast-enhanced ultrasound patterns of hepatocellular adenoma: an Italian multicenter experience.

PURPOSE: 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. METHODS: We retrospectively analyzed data of patients with histology-proven HCA who underwent CEUS, computed tomography or magnetic resonance imaging (MRI) in seven different Italian ultrasound units. RESULTS: The study enrolled 19 patients (16 females; 69% with concomitant/prior use of oral contraceptives): the mean size of all HCAs was 4.2 cm (range 1.6-7.1 cm); 14/19 had inflammatory HCAs (I-HCA), 1/19 ß-catenin-activated HCA, and the others unclassified HCAs. On CEUS, during the arterial phase, all but one HCA displayed a rapid enhancement, with 89% of these showing centripetal and 11% centrifugal filling pattern, whereas during the portal and late venous phase 58% of HCA showed washout and the remaining 42% displayed persistent enhancement. In particular, among I-HCAs 7/14 showed no washout, 3/14 and 4/14 showed washout in the portal or late phase, respectively. CONCLUSIONS: This dataset represents one of the few published experiences on HCAs and CEUS in Italy and shows that HCAs are hypervascularized in the arterial phase usually with a centripetal flow pattern and have a heterogeneous behavior in portal and late phase. In particular, occurrence of delayed washout on CEUS but not on MRI is frequently observed in the subtype of I-HCA.

External validation of the ITA.LI.CA prognostic system for patients with hepatocellular carcinoma: A multicenter cohort study.

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).

Surgical Resection vs. Ablative Therapies Through a Laparoscopic Approach for Hepatocellular Carcinoma: a Comparative Study.

BACKGROUND: 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). METHODS: We enrolled 264 cirrhotic patients out of 905 cases consecutively evaluated for hepatocellular carcinoma. We performed 59 hepatic resections and 205 thermoablations through a laparoscopic approach, and they were then followed for similar follow-up (41.7 ± 31.5 months for laparoscopic hepatic resection vs. 38.7±32.3 for laparoscopic ablation therapy). Outcomes included short- and long-term morbidities, tumoral recurrence, and overall survival. RESULTS: Short-term morbidity was significantly higher in the resection group (but the two groups had similar rates for severe complications) while, during follow-up, recurrence was more frequent in patients treated with thermoablation, with a clear disadvantage in terms of survival. At multivariate analysis, only the type of surgical treatment was an independent predictor of disease recurrence, while plasmatic alpha-fetoprotein and Hb values, model for end-stage liver disease score, time to recurrence, and the type of surgical treatment were independent predictors of overall survival. CONCLUSION: Our data ultimately support some therapeutic advantages for hepatic resection in patients with a single nodule and preserved liver function. However, thermoablation is an adequate alternative in patients with nodules that would require complex surgical resections or imply a poor prognosis that might therefore better tolerate a less invasive procedure.

Intraoperative ultrasound for prediction of hepatocellular carcinoma biological behaviour: Prospective comparison with pathology.

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.

Virtual Dissection by Ultrasound: Probe Handling in the First Year of Medical Education.

OBJECTIVES: The aim of the present study was to assess the educational plan of first-year students of medicine by analyzing their scores in ultrasound body scanning. METHODS: Since 2009, the San Paolo Medical School (Milan, Italy) has vertically integrated the study of anatomy with ultrasound-assisted virtual body dissection. Three modules were supplied: musculoskeletal system, heart and abdomen pelvis. 653 first-year students were trained. The students alternated as mutual model and operator. A skillfulness score was assigned to each student. The scores were consequently listed. Nonparametric exact multiple contrast tests were employed to determine relative group effects. RESULTS: Statistical analysis showed that: no gender-related differences were found (0:49; p=0.769); peer learners performed less well than peer tutors (0.677; p=0); between modules, scores in the musculoskeletal system (pMS=0.726) tend to be higher (p<0.001) than those obtained in the heart and abdomen pelvis (pH=0.398; pAP=0.375 p=0.270); significant differences were found compared to the beginning of the project's academic year. CONCLUSION: The students considered this didactic course an engaging and exciting approach. Acceptance of peer teaching was extraordinarily high. Autonomous exercitation allowed the students to improve self-criticism and enhance their own skills. The level of expertise obtained by peer tutors and by peer learners can be considered satisfactory. The main objective of training future physicians on personal stethoechoscope with the necessary competence seems to have been successfully started.

Management and prognosis of hepatocellular carcinoma in the elderly: Results of an in-field multicenter cohort study.

AIMS: This multicentre cohort study evaluated the role of ageing on clinical characteristics, treatment allocation and outcome of new hepatocellular carcinomas (HCCs), in clinical practice. MATERIAL & METHODS: From September 2008, 541 patients >70 years old (elderly group), and 527 ≤70 years old (non-elderly group) with newly diagnosed HCC were consecutively enrolled in 30 Italian centres. Differences in clinical characteristics and treatment allocation between groups were described by a multivariable logistic regression model measuring the inverse probability weight to meet the elderly group. Survival differences were measured by unadjusted and adjusted (by inverse probability weight) survival analysis. RESULTS: Elderly patients were mainly females, hepatitis C virus infected and with better conserved liver function (P<.001). At presentation, HCC median size was similar in both groups while, in youngers, HCC was more frequently multinodular (P=.001), and associated with neoplastic thrombosis (P=.009). Adjusted survival analysis showed that age did not predict short-mid-term survival (within 24 months), while it was a significant independent predictor of long-term survival. Moreover, age had a significant long-term survival impact mainly on early HCC stages (Barcelona Clinic for Liver Cancer [BCLC] 0-A), its impact on BCLC B stage was lower, while it was negligible for advanced-terminal stages. CONCLUSIONS: Age per se does not impact on short-mid-term prognosis (≤24 months) of HCC patients, and should not represent a limitation to its management.

Comparison of Laparoscopic Microwave to Radiofrequency Ablation of Small Hepatocellular Carcinoma (≤3 cm).

BACKGROUND: Laparoscopic thermal ablation is a common alternative to surgical resection in treating hepatic tumors, particularly in those located in difficult-to-reach locations. OBJECTIVE: 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). METHOD: 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. RESULTS: 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). CONCLUSION: 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.

Hepatic resection for "BCLC stage A" hepatocellular carcinoma. The prognostic role of alpha-fetoprotein.

BACKGROUND: 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. METHODS: We enrolled 132 patients with hepatocellular carcinoma (HCC) amenable to HR. All patients underwent ultrasound (US)-guided anatomical resection (≤2 segments) and then postoperative results were evaluated. RESULTS: Results showed 95% of patients were Child A, 49% in BCLC A1, 21% in A2, 6% in A3, and 24% in A4. No 30-day mortality occurred. Overall survival got worse from A1 to A4 (P = 0.0271), while no differences were found in Childs A patients with or without portal hypertension (P = 0.1674). Multivariate analysis (Cox model) shows that only AFP (<20 ng/ml) was an independent predictor of survival: If the AFP is incorporated in BCLC staging system (all A1 and A2 patients with abnormal AFP levels were included in A3 subgroup), 5-year survival rate including normal AFP for A1 was 57% and for A2 was 65%, whereas the survival rates impaired in the worst candidates (5-year survival rate including AFP abnormal for A3 and A4 was 36%; P = 0.002). So, introducing AFP in BCLC classification it is possible to simplify the algorithm in only 2 classes, well-separated in survival curves (class 1 [AFP-]: 60%; class 2 [AFP+]: 37%; P = 0.0001). CONCLUSION: Our experience stressed the high value of BCLC system in staging of patients with HCC, but underlined that in selected patients (normal AFP) even A2 group may benefit from HR with a good survival.

Recurrent hepatocellular carcinoma successfully treated with laparoscopic thermal ablation.

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.

Intraoperative ultrasound score to predict recurrent hepatocellular carcinoma after radical treatments.

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.

Surgical resection versus laparoscopic radiofrequency ablation in patients with hepatocellular carcinoma and Child-Pugh class a liver cirrhosis.

BACKGROUND: 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. METHODS: We enrolled 152 cirrhotic patients out of 372 cases consecutively evaluated for HCC. Enrolled patients with similar baseline characteristics underwent HR (n = 78) or LRFA (n = 74), in both cases with intraoperative ultrasonography, and they were then followed for similar durations (mean +/- standard deviation, 36.2 +/- 23.5 months for HR vs. 38.2 +/- 28.4 for LRFA). Outcomes included short- and long-term morbidity, HCC recurrence, and overall survival. RESULTS: Short-term morbidity was far higher in the HR group while, during follow-up, HCC recurrence (mainly local) was more frequent in patients treated with LRFA. More importantly, baseline alfa-fetoprotein levels and early HCC recurrence after treatment greatly influenced overall survival, while the use of HR or LRFA did not predict it. On the other hand, HCC recurrence was found to be determined by the surgical approach and ultrasound characteristics of the tumor. CONCLUSIONS: Our data were obtained from a large number of HCC cases and support similar survival rates after HR or LRFA for single HCC nodules on Child-Pugh class A liver cirrhosis, despite a marked increase in HCC recurrence rates after LRFA.