The changing scenario of hepatocellular carcinoma over the last two decades in Italy.

BACKGROUND & AIMS: This study investigates whether the aetiologic changes in liver disease and the improved management of hepatocellular carcinoma (HCC) have modified the clinical scenario of this tumour over the last 20 years in Italy. METHODS: Retrospective study based on the analysis of the ITA.LI.CA (Italian Liver Cancer) database including 3027 HCC patients managed in 11 centres. Patients were divided into 3 groups according to the period of HCC diagnosis: 1987-1996 (year of the "Milano criteria" publication), 1997-2001 (year of release of the EASL guidelines for HCC), and 2002-2008. RESULTS: The significant changes were: (1) progressive patient ageing; (2) increasing prevalence of HCV infection until 2001, with a subsequent decrease, when the alcoholic aetiology increased; (3) liver function improvement, until 2001; (4) increasing "incidental" at the expense of "symptomatic" diagnoses, until 2001; (5) unchanged prevalence of tumours diagnosed during surveillance (around 50%), with an increasing use of the 6-month schedule; (6) favourable HCC "stage migration", until 2001; (7) increasing use of percutaneous ablation; (8) improving survival, until 2001. CONCLUSIONS: Over the last 20 years, several aetiologic and clinical features regarding HCC have changed. The survival improvement observed until 2001 was due to an increasing number of tumours diagnosed in early stages and in a background of compensated cirrhosis, and a growing and better use of locoregional treatments. However, the prevalence of early cancers and survival did not increase further in the last years, a result inciting national policies aimed at implementing surveillance programmes for at risk patients.

Treatments for hepatocellular carcinoma in elderly patients are as effective as in younger patients: a 20-year multicentre experience.

OBJECTIVES: The number of elderly patients diagnosed with hepatocellular carcinoma (HCC) is expected to increase. We compared the presenting features and outcome of HCC in elderly (>or=70 years) and younger patients (<70 years). DESIGN: Multicentre retrospective cohort study and nested case-control study. Patients 614 elderly and 1104 younger patients from the ITA.LI.CA database, including 1834 HCC cases consecutively diagnosed from January 1987 to December 2004. Both groups were stratified according to treatment: hepatic resection, percutaneous procedures, transarterial chemoembolisation (TACE). Survival was assessed in the whole population and in each treatment subgroup. Age, sex, aetiology, cirrhosis, comorbidities and cancer stage (CLIP score) were tested as predictors of survival. In each subgroup, differences in patient survival were also assessed after adjustment and matching by propensity score. RESULTS: Ageing was associated with a higher prevalence of comorbidities, better liver function and CLIP score. Regardless of age, two-thirds of patients underwent radical treatments or TACE. Elderly patients underwent more ablative procedures and fewer resections or TACE sessions. The survival of elderly and younger patients was comparable in each treatment subset, and was predicted by CLIP score. This result was confirmed by the propensity analysis. CONCLUSIONS: The overall applicability of radical or effective HCC treatments was unaffected by old age. However, treatment distribution differed, elderly individuals being more frequently treated with percutaneous procedures and less frequently with resection or TACE. Survival was unaffected by age and primarily predicted by cancer stage, assessed by the CLIP system, both in the overall population and in treatment subgroups.

Shear-Induced Encapsulation into Red Blood Cells: A New Microfluidic Approach to Drug Delivery.

Encapsulating molecules into red blood cells (RBCs) is a challenging topic for drug delivery in clinical practice, allowing to prolong the residence time in the body and to avoid toxic residuals. Fluidic shear stress is able to temporary open the membrane pores of RBCs, thus allowing for the diffusion of a drug in solution with the cells. In this paper, both a computational and an experimental approach were used to investigate the mechanism of shear-induced encapsulation in a microchannel. By means of a computational fluid dynamic model of a cell suspension, it was possible to calculate an encapsulation index that accounts for the effective shear acting on the cells, their distribution in the cross section of the microchannel and their velocity. The computational model was then validated with micro-PIV measurements on a RBCs suspension. Finally, experimental tests with a microfluidic channel showed that, by choosing the proper concentration and fluid flow rate, it is possible to successfully encapsulate a test molecule (FITC-Dextran, 40 kDa) into human RBCs. Cytofluorimetric analysis and confocal microscopy were used to assess the RBCs physiological shape preservation and confirm the presence of fluorescent molecules inside the cells.

'See Me, Feel Me': Prismatic Adaptation of an Alien Limb Ameliorates Spatial Neglect in a Patient Affected by Pathological Embodiment.

Pathological embodiment (E+) is a specific contralesional delusion of body ownership, observed following brain damage, in which patients embody someone else's arm and its movements within their own body schema whenever the contralesional 'alien' arm is presented in a body-congruent position (i.e., 1st person perspective and aligned with the patient's shoulder). This disorder is often associated with spatial neglect, a neurological syndrome in which patients are unaware of stimuli presented in the contralesional (often the left) space. Capitalizing on previous evidence demonstrating that prismatic adaptation of the ipsilesional arm to right-deviating prisms is effective in ameliorating neglect symptoms, here we investigated whether such amelioration also occurs in E+ patients with neglect when prismatic training is performed by the 'alien' embodied arm. Four left neglect patients (one with and three without pathological embodiment) underwent visuomotor prismatic training performed by an 'alien' arm. Specifically, while patients were wearing prismatic goggles shifting the visual field rightward, a co-experimenter's left arm presented in a body-congruent perspective was repeatedly moved toward visual targets by another examiner. In a control condition, the co-experimenter's arm was moved toward the targets from a body-incongruent position (i.e., 3rd person perspective). Neglect symptoms were assessed before and after training through paper-and-pencil tasks. In the E+ patient, neglect improved significantly more in 1st than in 3rd person perspective training, suggesting that prismatic adaptation of the 'alien' embodied arm is effective in modulating spatial representation. Conversely, for control E- patients (not embodying the 'alien' arm), we observed more limited improvements following training. These findings indicate that the 'alien' embodied arm is so deeply embedded in the patient body and motor schema that adaptation to prismatic lenses can affect multiple processing stages, from low level sensory-motor correspondences, to higher level body, motor and spatial maps, similarly as it occurs in normal subjects and neglect patients without pathological embodiment.

Increased prothrombotic state lasting as long as one month after on-pump and off-pump coronary surgery.

OBJECTIVE: This study investigated whether the activation of coagulation, fibrinolysis, and endothelium occurring during the first postoperative month after on-pump coronary artery bypass surgery differs from that after off-pump coronary artery bypass grafting. METHODS: Thirty-five patients candidates to coronary surgery were randomized to undergo on-pump (n = 18) or off-pump (n = 17) coronary artery bypass grafting. Blood samples were collected before the intervention and to 1 month after surgery. RESULTS: Prothrombin fragment F1.2, thrombin-antithrombin complex, and D-dimer increased after surgery and were persistently higher than preoperative values as late as 30 postoperative days in both on- and off-pump groups; higher levels of these variables were detected after on-pump surgery relative to off-pump surgery only at the time point after termination of cardiopulmonary bypass (fragment F1.2 and thrombin-antithrombin complex) or from bypass end to 8 postoperative days (D-dimer). Fibrinogen levels decreased after surgery and then increased in parallel in both groups to 8 days after surgery. The von Willebrand factor level increased postoperatively in both groups and returned to baseline 30 days after surgery; it was higher after on-pump surgery from bypass end to 8 postoperative days. Soluble vascular cell adhesion molecule 1 was increased significantly from baseline in both groups 30 days after surgery, with no difference between groups. CONCLUSION: Patients undergoing off-pump surgery showed protection against activation of coagulation and fibrinolysis and against endothelial injury only during the intraoperative period; this was followed by the development of a prothrombotic pattern comparable to that of patients undergoing on-pump surgery lasting at least as late as 30 days after surgery.

Platelet activation induces cell-surface immunoreactive tissue factor expression, which is modulated differently by antiplatelet drugs.

OBJECTIVE: Tissue factor (TF) is the main activator of the coagulation cascade occurring in physiologic and pathologic conditions. Recent data suggest that human platelets might contain TF that is possibly derived from leukocytes. In this study, we investigated whether intraplatelet TF can be exposed on the membrane by platelet agonists. The modulation of this process by antiplatelet drugs has been evaluated as well. METHODS AND RESULTS: Flow cytometric analysis of unstimulated platelets showed a small amount of membrane-associated immunoreactive TF (irTF) in whole blood, platelet-rich plasma, and washed platelets isolated from healthy subjects. ADP, thrombin receptor-activating peptide, and epinephrine significantly increased functionally active, membrane-associated irTF. ADP induced irTF exposure in a concentration- and time-dependent fashion. Agonist-induced irTF expression was completely inhibited by iloprost but not by aspirin. Interestingly, glycoprotein IIb/IIIa antagonists did not inhibit but rather potentiated the stimulatory effect of ADP on platelet irTF expression. Real-time polymerase chain reaction experiments showed detectable amounts of TF mRNA in unstimulated platelets. CONCLUSIONS: These findings indicate that platelet agonists and antiplatelet drugs might modulate platelet-associated irTF expression. Regulated TF expression establishes the potential for a previously unrecognized role for platelets in sustaining thrombus formation and growth via coagulation-mediated mechanisms.

Changing aetiological factors of hepatocellular carcinoma and their potential impact on the effectiveness of surveillance.

BACKGROUND: The aetiological factors of hepatocellular carcinoma may vary over time. AIMS: The study assessed the potential impact of the aetiological factors on the effectiveness of surveillance in real-world patients. METHODS: Multicentre, cross-sectional study enrolling consecutive hepatocellular carcinoma cases during a six month period. RESULTS: 1733 cases (1311 prevalent and 422 incident) were recruited (mean age 68.6 years; 46.1% cases over 70 years; 73.9% males; 95.3% with cirrhosis); 63.0% were hepatitis C virus positive and 23.7% were virus negative. Amongst incident HCCs, 34.5% were single ≤3cm and 54.4% met the Milan criteria; 61.6% were diagnosed during surveillance; virus negative patients showed the lowest rate of surveillance (51.0%). Surveillance was an independent predictor of detecting single HCCs ≤2cm (O.R.=5.4; 95% C.I.=2.4-12.4) or HCCs meeting the Milan criteria (O.R.=3.1; 95% C.I.=1.9-5.2). Compared with an earlier Italian survey, there was a higher proportion of elderly subjects (P<0.01), Child-Pugh class A cases (P<0.01), of virus-negative patients (P<0.01) and with single tumours ≤3cm (P<0.01) and a lower prevalence of hepatitis C virus positive individuals (P<0.01). CONCLUSION: HCC is characterised by a growing prevalence of elderly patients and cases unrelated to hepatitis virus infections. The application of surveillance must be implemented, particularly amongst non-viral patients.

Hepatocellular carcinoma in non-cirrhotic liver: a reappraisal.

Although not frequently, hepatocellular carcinoma (HCC) can ensue in a non-cirrhotic liver. As compared to cirrhotic HCC, this kind of tumour has some peculiarities, such as: (a) a lower male preponderance and a bimodal age distribution; (b) a lower prevalence of the three main risk factors (hepatitis B and C virus infections and alcohol abuse), with an increased prevalence of other etiologic factors, such as exposure to genotoxic substances and sex hormones, inherited diseases, genetic mutations; (c) a more advanced tumour stage at the time of diagnosis, as it is usually detected due to the occurrence of cancer-related symptoms, outside any scheduled surveillance program; (d) a much higher amenability to hepatic resection, due to the low risk of liver failure even after extended parenchymal mutilation; (e) overall and disease-free survivals after resection of non-advanced tumours (meeting the Milano criteria) comparable to that obtained with liver transplantation in cirrhotic patients carrying an early tumour; (f) overall survival strictly dependent on tumour burden (and its recurrence) and barely influenced by liver function.

Art in the hospital: its impact on the feelings and emotional state of patients admitted to an internal medicine unit.

OBJECTIVE: This descriptive pilot study aimed at assessing the impact of art contemplation on patients' adaptation to hospital confinement and the factors influencing this effect. STUDY DESIGN: Artistic photographs were hung on the walls of the ward. Two hundred and thirty-nine (239) consecutive non-bed-constrained patients who stayed in the ward for at least 3 days (original number enrolled in study were males/females: 148/96, age 19-89 years; 5 patients declined to fill out questionnaires) participated in the study. METHODS: Patients compiled two questionnaires exploring physical, psychologic, and social/family well-being, relative/friend support, and ward functioning. The self-perceived effect of photographs on the hospitalization distress was assessed. Clinical conditions were evaluated with the Eastern Cooperative Oncology Group (ECOG) performance status. RESULTS: Ninety-seven (97) (40.6%) patients belonged to ECOG stage 0, 101 (42.3%) to stage 1, 37 (15.5%) to stage 2, and 4 (1.7%) to stage 3. Two hundred and thirty-nine patients (239) (92%) looked at and 232 (85.5%) repeatedly contemplated the photographs. For most patients (72%), photographs made their stay in the hospital more pleasant. The ECOG performance status and self-perceived anxiety were the only independent modulators of the probability to obtain a restorative effect from the photographs. CONCLUSIONS: Embellishing clinical spaces with photographs has a positive effect on the adaptation to hospitalization in most patients. This effect is influenced by the patients' clinical status and self-perceived anxiety.

Liver Cirrhosis in a Patient with Sickle Cell Trait (Hb Sß Thalassemia) without Other Known Causes of Hepatic Disease.

Liver involvement in patients with sickle cell anemia/trait includes a wide range of alterations, from mild liver function test abnormalities to cirrhosis and acute liver failure. Approximately 15-30% of patients with sickle cell anemia present cirrhosis at autopsy. The pathogenesis of cirrhosis is usually related to chronic hepatitis B or C infection or to iron overload resulting from the many transfusions received by these patients in their lifetime. Thus, cirrhosis has been described almost exclusively in patients with sickle cell anemia, while only mild liver abnormalities have been associated with the sickle cell trait. In the present case study, we describe a young Mediterranean man carrying a sickle cell trait (Hb Sß(+) thalassemia) who developed liver cirrhosis being negative for hepatitis C and B viruses or for other causes of cirrhosis and not receiving chronic blood transfusions.

C-11 acetate does not enhance usefulness of F-18 FDG PET/CT in differentiating between focal nodular hyperplasia and hepatic adenoma.

PURPOSE OF THE REPORT: We assessed the usefulness of F-18 fluorodeoxyglucose positron emission tomography (FDG PET) and C-11 acetate PET (AC PET) in distinguishing hepatic lesions due to consequential disease (hepatocellular adenoma and malignant lesions) from focal nodular hyperplasia (FNH) in patients at low risk of malignancy. MATERIALS AND METHODS: Thirty-one patients with 43 lesions were prospectively enrolled. The diagnostic work-up included Doppler and contrast-enhanced ultrasonography, contrast-enhanced computed tomography, and/or magnetic resonance imaging. Fine needle biopsy was performed if the imaging study was inconclusive. The work-up revealed 36 FNH and 7 consequential lesions (5 hepatocellular adenoma, 1 hepatoma, and 1 metastasis). All patients underwent FDG and AC PET. FDG PET with target/background ratio (T/Br) greater than 1.2 and AC PET with T/Br of less than 1.2 were considered positive test for consequential disease. RESULTS: On FDG PET, we had 6 true-positive out of 7 lesions due to consequential diseases, with a sensitivity of 85.7%, and 33 true-negative out of 36 lesions with FNH, with a specificity of 91.7%. Using AC PET, there were 2 true-positive lesions out of 7 caused by neoplasms, with a sensitivity of 28.6%, and 34 true-negative lesions out of 36 FNH, with a specificity of 94.4%. CONCLUSIONS: When the goal is differentiating FNH from liver neoplasms, AC PET offered no additional diagnostic advantage over what is achieved with FDG PET.

The role of tissue factor and P-selectin in the procoagulant response that occurs in the first month after on-pump and off-pump coronary artery bypass grafting.

BACKGROUND: It has been previously shown that a persistent (up to 1 month) prothrombotic status occurs after coronary bypass surgery performed both on pump and off pump. To assess the pathways involved in the occurrence of postoperative prothrombotic state, in this study we evaluated plasma, monocyte-bound, and platelet-bound tissue factor expression, as well as platelet and soluble P-selectin expression, up to 1 month after off-pump and on-pump coronary artery bypass grafting. METHODS: Thirty patient candidates for coronary surgery were randomized to undergo off-pump coronary artery bypass grafting (n = 15) or on-pump coronary artery bypass grafting (n = 15). Blood samples were collected before the intervention, after protamine administration, and 4, 8, and 30 days after surgical intervention. RESULTS: Plasma tissue factor levels were significantly higher than baseline both in the on-pump coronary artery bypass grafting group (from protamine administration up to 4 postoperative days) and in the off-pump coronary artery bypass grafting group (at 4 postoperative days), with no differences between groups. Basal and lipopolysaccharide-stimulated monocyte tissue factor expression, as well as basal and adenosine diphosphate-stimulated platelet tissue factor expression, did not show significant variations over time and were similar in the on-pump and off-pump coronary artery bypass grafting groups throughout the course of the study. Platelet expression of P-selectin, both basal and after adenosine diphosphate stimulation, did not significantly change over time and was not different in the on-pump and off-pump coronary artery bypass grafting groups. Soluble P-selectin levels in plasma were significantly higher in patients receiving on-pump coronary artery bypass grafting only at the time point after protamine administration, whereas this variable behaved similarly in the on-pump and off-pump coronary artery bypass grafting groups for the whole postoperative period. CONCLUSIONS: The postoperative tissue factor and P-selectin expression did not differ between the on-pump and off-pump coronary artery bypass grafting groups. The distinct increase of plasma tissue factor occurring after both surgical procedures might represent a mechanism that might explain, in part, the early postoperative prothrombotic state occurring after on-pump and off-pump coronary artery bypass grafting.