Atezolizumab plus bevacizumab versus lenvatinib or sorafenib in non-viral unresectable hepatocellular carcinoma: an international propensity score matching analysis.

BACKGROUND: A growing body of evidence suggests that non-viral hepatocellular carcinoma (HCC) might benefit less from immunotherapy. MATERIALS AND METHODS: We carried out a retrospective analysis of prospectively collected data from consecutive patients with non-viral advanced HCC, treated with atezolizumab plus bevacizumab, lenvatinib, or sorafenib, in 36 centers in 4 countries (Italy, Japan, Republic of Korea, and UK). The primary endpoint was overall survival (OS) with atezolizumab plus bevacizumab versus lenvatinib. Secondary endpoints were progression-free survival (PFS) with atezolizumab plus bevacizumab versus lenvatinib, and OS and PFS with atezolizumab plus bevacizumab versus sorafenib. For the primary and secondary endpoints, we carried out the analysis on the whole population first, and then we divided the cohort into two groups: non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) population and non-NAFLD/NASH population. RESULTS: One hundred and ninety patients received atezolizumab plus bevacizumab, 569 patients received lenvatinib, and 210 patients received sorafenib. In the whole population, multivariate analysis showed that treatment with lenvatinib was associated with a longer OS [hazard ratio (HR) 0.65; 95% confidence interval (CI) 0.44-0.95; P = 0.0268] and PFS (HR 0.67; 95% CI 0.51-0.86; P = 0.002) compared to atezolizumab plus bevacizumab. In the NAFLD/NASH population, multivariate analysis confirmed that lenvatinib treatment was associated with a longer OS (HR 0.46; 95% CI 0.26-0.84; P = 0.0110) and PFS (HR 0.55; 95% CI 0.38-0.82; P = 0.031) compared to atezolizumab plus bevacizumab. In the subgroup of non-NAFLD/NASH patients, no difference in OS or PFS was observed between patients treated with lenvatinib and those treated with atezolizumab plus bevacizumab. All these results were confirmed following propensity score matching analysis. By comparing patients receiving atezolizumab plus bevacizumab versus sorafenib, no statistically significant difference in survival was observed. CONCLUSIONS: The present analysis conducted on a large number of advanced non-viral HCC patients showed for the first time that treatment with lenvatinib is associated with a significant survival benefit compared to atezolizumab plus bevacizumab, in particular in patients with NAFLD/NASH-related HCC.

Nonalcoholic steatohepatitis in hepatocarcinoma: new insights about its prognostic role in patients treated with lenvatinib.

BACKGROUND: Hepatocellular carcinoma (HCC) treatment remains a big challenge in the field of oncology. The liver disease (viral or not viral) underlying HCC turned out to be crucial in determining the biologic behavior of the tumor, including its response to treatment. The aim of this analysis was to investigate the role of the etiology of the underlying liver disease in survival outcomes. PATIENTS AND METHODS: We conducted a multicenter retrospective study on a large cohort of patients treated with lenvatinib as first-line therapy for advanced HCC from both Eastern and Western institutions. Univariate and multivariate analyses were performed. RESULTS: Among the 1232 lenvatinib-treated HCC patients, 453 (36.8%) were hepatitis C virus positive, 268 hepatitis B virus positive (21.8%), 236 nonalcoholic steatohepatitis (NASH) correlate (19.2%) and 275 had other etiologies (22.3%). The median progression-free survival (mPFS) was 6.2 months [95% confidence interval (CI) 5.9-6.7 months] and the median overall survival (mOS) was 15.8 months (95% CI 14.9-17.2 months). In the univariate analysis for OS NASH-HCC was associated with longer mOS [22.2 versus 15.1 months; hazard ratio (HR) 0.69; 95% CI 0.56-0.85; P = 0.0006]. In the univariate analysis for PFS NASH-HCC was associated with longer mPFS (7.5 versus 6.5 months; HR 0.84; 95% CI 0.71-0.99; P = 0.0436). The multivariate analysis confirmed NASH-HCC (HR 0.64; 95% CI 0.48-0.86; P = 0.0028) as an independent prognostic factor for OS, along with albumin-bilirubin (ALBI) grade, extrahepatic spread, neutrophil-to-lymphocyte ratio, portal vein thrombosis, Eastern Cooperative Oncology Group (ECOG) performance status and alpha-fetoprotein. An interaction test was performed between sorafenib and lenvatinib cohorts and the results highlighted the positive predictive role of NASH in favor of the lenvatinib arm (P = 0.0047). CONCLUSION: NASH has been identified as an independent prognostic factor in a large cohort of patients with advanced HCC treated with lenvatinib, thereby suggesting the role of the etiology in the selection of patients for tyrosine kinase treatment. If validated, this result could provide new insights useful to improve the management of these patients.

Liver Transplantations and Brain Dead Donors With Alcohol Abuse.

BACKGROUND AND AIM: Liver grafts from donors with chronic and active history of alcohol abuse are usually immediately ruled out for use in liver transplantation (LT). The aim of our study is to evaluate the use of those grafts. METHODS: From 2011 to 2016, a study group (Group 1) composed of 5 adult LT patients transplanted with livers from donors with alcohol abuse, was compared with a control group (Group 2) of 10 randomly matched patients who received liver transplants. Preoperative, intraoperative, and postoperative data were compared. RESULTS: Among donors, serum gamma-glutamyl transferase values were significantly higher in Group 1. In recipients, post-LT laboratory exams showed significantly higher peak values of aspartate transaminase and alanine transaminase in Group 1; higher values of aspartate aminotransferase, alanine aminotransferase, and total bilirubin in Group 1 were also recorded on day 0. Early allograft dysfunction occurred at higher rates in Group 1 (80% vs 20%, P = .025), with no differences in early rejection episodes or early surgical repeat interventions. All patients from both groups were alive after 20 ± 10 (range 6-35) months from LT. CONCLUSION: Despite higher rates of early allograft dysfunction, selected liver grafts from donors with alcohol abuse can be accepted for LT with good clinical results.

Clinical features and outcomes of hepatocellular carcinoma in Caucasian cirrhotic patients on long-term analogue therapy for hepatitis B.

BACKGROUND: Long-term oral nucleos(t)ide analogue (NUC) therapy in hepatitis B virus (HBV)-related compensated cirrhotics prevents clinical decompensation but not hepatocellular carcinoma (HCC) development. AIMS: To define the clinical features and outcomes of HCC in long-term NUC-treated HBV patients. METHODS: All HCCs developing between 2005 and 2016 in NUC-treated HBV patients under surveillance were studied, excluding those that occurred within the first 6 months of therapy. Clinical features of HCC, alpha faetoprotein (AFP) patterns and patients' outcome were studied. RESULTS: Seventy-six HCC patients were included. Median age was 67 (40-83) years, 84% males, 96% Caucasian, 95% HBeAg-negative, 96% with undetectable HBV DNA, 83% with normal ALT levels, and 92% with compensated cirrhosis. Median serum AFP levels were 4 (1-3615) ng/mL (>7 ng/mL in 36%). HCC was monofocal in 78%, had a median diameter of 20 (6-57) mm and was in its early stage in 92% which allowed potentially curative treatments in 78% (39% ablation, 28% surgical resection, 11% liver transplantation). Overall, a complete response was obtained in 61 (80%) patients: in 40 after a first-line treatment, in 3 after the second-line treatment, in 2 after the third-line treatment, while 16 underwent liver transplantation (8 as second line). During 45 (7-144) months after HCC diagnosis, 19 patients died, 84% from HCC progression. The median time to recurrence was 20.2 (3-53) months, and the cumulative 5-year liver-related survival was 74%. CONCLUSIONS: HCCs developing in patients under long-term NUC treatment were single, small tumours, amenable to curative therapies able to confer excellent 5-year survival rates.

Evolution of Metastable Defects and Its Effect on the Electronic Properties of MoS2 Films.

We report on structural and electronic properties of defects in chemical vapor-deposited monolayer and few-layer MoS2 films. Scanning tunneling microscopy, Kelvin probe force microscopy, and transmission electron microscopy were used to obtain high resolution images and quantitative measurements of the local density of states, work function and nature of defects in MoS2 films. We track the evolution of defects that are formed under heating and electron beam irradiation. We observe formation of metastable domains with different work function values after annealing the material in ultra-high vacuum to moderate temperatures. We attribute these metastable values of the work function to evolution of crystal defects forming during the annealing. The experiments show that sulfur vacancies formed after exposure to elevated temperatures diffuse, coalesce, and migrate bringing the system from a metastable to equilibrium ground state. The process could be thermally or e-beam activated with estimated energy barrier for sulfur vacancy migration of 0.6 eV in single unit cell MoS2. Even at equilibrium conditions, the work function and local density of states values are strongly affected near grain boundaries and edges. The results provide initial estimates of the thermal budgets available for reliable fabrication of MoS2-based integrated electronics and indicate the importance of defect control and layer passivation.

Observation of superconducting vortex clusters in S/F hybrids.

While Abrikosov vortices repel each other and form a uniform vortex lattice in bulk type-II superconductors, strong confinement potential profoundly affects their spatial distribution eventually leading to vortex cluster formation. The confinement could be induced by the geometric boundaries in mesoscopic-size superconductors or by the spatial modulation of the magnetic field in superconductor/ferromagnet (S/F) hybrids. Here we study the vortex confinement in S/F thin film heterostructures and we observe that vortex clusters appear near magnetization inhomogeneities in the ferromagnet, called bifurcations. We use magnetic force microscopy to image magnetic bifurcations and superconducting vortices, while high resolution scanning tunneling microscopy is used to obtain detailed information of the local electronic density of states outside and inside the vortex cluster. We find an intervortex spacing at the bifurcation shorter than the one predicted for the same superconductor in a uniform magnetic field equal to the thermodynamical upper critical field Hc2. This result is due to a local enhanced stray field and a competition between vortex-vortex repulsion and Lorentz force. Our findings suggest that special magnetic topologies could result in S/F hybrids that support superconductivity even when locally the vortex density exceeds the thermodynamic critical threshold value beyond which the superconductivity is destroyed.

Emergence of coherence in the charge-density wave state of 2H-NbSe2.

A charge-density wave (CDW) state has a broken symmetry described by a complex order parameter with an amplitude and a phase. The conventional view, based on clean, weak-coupling systems, is that a finite amplitude and long-range phase coherence set in simultaneously at the CDW transition temperature T(cdw). Here we investigate, using photoemission, X-ray scattering and scanning tunnelling microscopy, the canonical CDW compound 2H-NbSe2 intercalated with Mn and Co, and show that the conventional view is untenable. We find that, either at high temperature or at large intercalation, CDW order becomes short-ranged with a well-defined amplitude, which has impacts on the electronic dispersion, giving rise to an energy gap. The phase transition at T(cdw) marks the onset of long-range order with global phase coherence, leading to sharp electronic excitations. Our observations emphasize the importance of phase fluctuations in strongly coupled CDW systems and provide insights into the significance of phase incoherence in 'pseudogap' states.

Visualizing domain wall and reverse domain superconductivity.

In magnetically coupled, planar ferromagnet-superconductor (F/S) hybrid structures, magnetic domain walls can be used to spatially confine the superconductivity. In contrast to a superconductor in a uniform applied magnetic field, the nucleation of the superconducting order parameter in F/S structures is governed by the inhomogeneous magnetic field distribution. The interplay between the superconductivity localized at the domain walls and far from the walls leads to effects such as re-entrant superconductivity and reverse domain superconductivity with the critical temperature depending upon the location. Here we use scanning tunnelling spectroscopy to directly image the nucleation of superconductivity at the domain wall in F/S structures realized with Co-Pd multilayers and Pb thin films. Our results demonstrate that such F/S structures are attractive model systems that offer the possibility to control the strength and the location of the superconducting nucleus by applying an external magnetic field, potentially useful to guide vortices for computing application.

The local effect of magnetic impurities on superconductivity in CoxNbSe2 and MnxNbSe2 single crystals.

We investigate the effect of individual atomic impurities on the superconducting state that they are embedded in. Using low temperature scanning tunneling microscopy and spectroscopy we could identify Co and Mn atoms in the Co(x)NbSe(2) and Mn(x)NbSe(2) single crystals and observe the influence on the local electronic density of states (LDOS) at 0.4 K. We find that Co is in the weak scattering limit. In this case the LDOS is quite homogeneous on the sample surface, despite the number of defects, and retains sharp coherent superconducting peaks. This is in strong contrast to the effects of Mn impurities, which locally destroy superconductivity. In this case the LDOS shows a strong enhancement of spectral weight inside the superconducting gap even far from the Mn atoms. Moreover, two impurity bound states are found within the superconducting gap at E/Δ(0) = 0.18 and 0.36 at locations close to defects.

Transarterial embolization with microspheres in the treatment of monofocal HCC.

BACKGROUND: Transarterial embolization using one permanent embolic agent alone enhances tumour ischaemia and spares patients with hepatocellular carcinoma form toxic chemotherapeutic drugs. PURPOSE: We assessed feasibility, tolerability and efficacy of transarterial embolization with microspheres in patients with a single node hepatocellular carcinoma. MATERIALS AND METHODS: Eighteen consecutive patients with compensated cirrhosis, hypervascularized single hepatocellular carcinoma, in whom liver transplantation was indicated (no.=3), or excluded from radical therapies (no.=15), received selective transarterial embolization with microspheres. Treatment was repeated every other month until complete devascularitazion was demonstrated by computed tomography, for a maximum of 3 cycles. RESULTS: Fifty transarterial embolization courses (mean: 2.8 courses, range 1-6) were administered, corresponding to a 100% applicability rates. Initial complete response was achieved in 16 (89%) patients and confirmed by histology in 2 transplanted patients. During 21-month follow-up (range 8-36), hepatocellular carcinoma recurred in 10 (62%) patients who achieved initial complete response, and de novo tumour nodes developed in 10 (56%). No patient required analgesics and none had liver function deteriorated following transarterial embolization. CONCLUSIONS: Transarterial embolization is a well-tolerated treatment for patients with early or intermediate hepatocellular carcinoma who are not suitable for radical treatment or await liver transplantation, but it allows to achieve a sustained complete response in a minority of patients.

Increased expression of vascular endothelial growth factor in small hepatocellular carcinoma.

Vascular endothelial growth factor (VEGF) is involved in both development and progression of several epithelial tumours, but its role in hepatocellular carcinoma (HCC) is unclear. Assessment of liver and blood levels of VEGF may provide further insights on angiogenesis in HCC. Tissue mRNA of VEGF-165, VEGF-189 and their receptor KDR was assessed by a semi-quantitative retro-transcriptase polymerase chain reaction, and expressed as target transcript/beta-actin ratio, in 29 patients with HCC, 26 with cirrhosis and 15 with chronic hepatitis. VEGF-165 was also measured by ELISA in plasma samples obtained from both hepatic and femoral veins in additional 58 patients, including 15 with HCC. The liver expression of mRNA of VEGF-165, VEGF-189 and KDR was higher in HCC than in chronic liver diseases (1.54 +/- 0.89 vs 0.62 +/- 0.47, P < 0.0001; 1.09 +/- 0.65 vs 0.64 +/- 0.54, P = 0.003; 1.30 +/- 1.09 vs 0.69 +/- 0.72, P = 0.014). VEGF-165 was higher in HCC tissue than in extra-tumoural tissues (1.44 +/- 0.31 vs 1.03 +/- 0.21, P = 0.0009) and in the cirrhotic tissue of HCC patients than in HCC-free cirrhosis (1.03 +/- 0.23 vs 0.45 +/- 0.45, P = 0.0002). Tissue VEGF-189 mRNA inversely correlated with tumour size and degree of tumour cell proliferation. The hepatic and femoral vein levels of VEGF-165 protein were significantly higher in HCC patients than in cirrhotic patients (66.7 +/- 57.1 vs 24.2 +/- 16.4 pg/mL, P = 0.0001 and 37.1 +/- 42.2 vs 13.5 +/- 9.6 pg/mL, P = 0.001). There was a gradient of VEGF-165 between hepatic and femoral veins in both HCC and cirrhosis. In conclusion, VEGF appears to be involved in the development of HCC and it could be a predictor of HCC development in patients with cirrhosis.

Direct observation of geometrical phase transitions in mesoscopic superconductors by scanning tunneling microscopy.

Using scanning tunneling microscopy, we mapped the distribution of the local density of states in a single crystal superconductor heterostructure with an array of submicron normal metal islands. We observe the coexistence of strongly interacting multiquanta vortex lattice with interstitial Abrikosov vortices. The newly formed composite magnetic flux structure undergoes a series of phase transitions between different topological configuration states. The vortex configuration states are strongly dependent on the number of flux quanta and the nanoscale confinement architecture of the mesoscopic superconductor. Here, we present images of vortex phase transitions due to confinement effects when the number of magnetic flux quanta in the system changes. The vortex dynamics in these systems could serve as a model for behavior of confined many-body systems when the number of particles changes.

A prospective study of blood alpha-fetoprotein messenger RNA as a predictor of hepatocellular carcinoma in patients with cirrhosis.

Blood alpha-fetoprotein messenger RNA (AFP mRNA) is thought to be a marker of hepatocellular carcinoma (HCC). Its value as a predictor of HCC in patients at risk is not known. A series of 201 patients with compensated cirrhosis (114 men, mean age 58 years) underwent surveillance with semi-annual ultrasound and serum alpha-fetoprotein measurements. Total RNA was extracted from peripheral blood mononuclear cells collected at different intervals and AFP mRNA was retrotranscribed and amplified by nested polymerase chain reaction. Ten patients with HCC and 30 blood donors were used as controls. Three patients with HCC, 39 with cirrhosis under surveillance and four blood donors circulated AFP mRNA (30, 20 and 13%, NS). During 50 months of surveillance, 27 patients with cirrhosis developed HCC: the tumour was detected more often in patients with higher than normal baseline serum AFP (> or =7 IU/L) than in those with normal AFP levels (21%vs 9%, P = 0.02). The incidence of HCC was the same in patients with and without AFP mRNA at baseline (15%vs 14%). In 53 patients, AFP mRNA was re-tested after 6-25 months of surveillance. HCC developed in two of 11 (18%) who were initially AFP mRNA positive and later became negative, in none of those who were initially negative and later became positive and in two of 39 (5%) who remained persistently negative. In conclusion, blood AFP mRNA is not a sensitive predictor of HCC in patients with compensated cirrhosis.

Two-band superconductivity in MgB2.

The study of the anisotropic superconductor MgB2 using a combination of scanning tunneling microscopy and spectroscopy reveals two distinct energy gaps at Delta(1)=2.3 meV and Delta(2)=7.1 meV at 4.2 K. Different spectral weights of the partial superconducting density of states are a reflection of different tunneling directions in this multiband system. Temperature evolution of the tunneling spectra follows the BCS scenario [Phys. Rev. Lett. 3, 552 (1959)]] with both gaps vanishing at the bulk T(c). The data confirm the importance of Fermi-surface sheet dependent superconductivity in MgB2 proposed in the multigap model by Liu et al. [Phys. Rev. Lett. 87, 087005 (2001)]].

Detection and qualitative identification of mineral fibers and particles in alveolar macrophages of BAL fluid by SEM and EDXA.

Inorganic dust inhalation diseases represent one of the most important chapters in respiratory medicine because of their diagnostic, therapeutic, legal, ecological and social implications. While, in fact, toxic substances inhalation may be easily related to particular occupations, it is more difficult to recognize the potential damage represented by occasional and fortuitous exposition due to pollution of one's living environment. The aim of this study was to suggest a useful investigative method for detecting the presence of mineral substances (dusts and fibers) in the lung in pulmonary fibrosis of uncertain origin. We used scanning electron microscopy (SEM) and semi-quantitative energy-dispersive x-ray microanalysis (EDXA) on broncholaveolar lavage (BAL) and sputum samples of 10 patients, all males, aged 41-66 years, smokers, affected by interstitial lung disease. Two subjects had a negative professional anamnesis while the other 8 declared a potential exposition to inorganic toxic dusts: 2 subjects were involved in the production of asbestos-containing building materials, 2 were miners, 1 a ceramic worker, and 3 insulating materials handlers. Data are reported on the detection of asbestos bodies, vitreous fibers and silica content of alveolar macrophages in BAL fluid.

Scanning tunneling spectroscopy in MgB2.

We present scanning tunneling microscopy measurements of the surface of superconducting MgB2 with a critical temperature of 39 K. In zero magnetic field the conductance spectra can be analyzed in terms of the standard BCS theory with a smearing parameter gamma. The value of the superconducting gap is 5 meV at 4.2 K, with no experimentally significant variation across the surface of the sample. The temperature dependence of the gap follows the BCS form, fully consistent with phonon-mediated superconductivity in this novel superconductor. The application of a magnetic field induces strong pair breaking as seen in the conductance spectra in fields up to 6 T.

Preliminary investigation of suitable bacteria strains for the detection of bacteriophages in environmental polluted surface waters.

Different host-specific bacteriophages were monitored in several water systems together with the usual faecal contamination indicator bacteria (thermotolerant coliforms). The host bacteria used for the plaque assay were E. coli K12, E. coli K12 Hfr, E. coli CHfr and S. typhimurium LT2F+. S. typhimurium LT2F+ showed significantly lower phage counts than the three E. coli strains. The phages specific for E. coli K12 (somatic phages) were in high correlation (r = 0.86, r = 0.91; P less than 0.001) with other coliphages, but not with phages specific for S. typ. LT2F+ (r = 0.33; P less than 0.05). There was an high degree of correlation among phages of E. coli K12 Hfr, E. coli C Hfr and S. typhimurium LT2F+ (pilus F-carrying bacteria) (r = 0.96, r = 0.73, r = 0.75; P less than 0.001). Good correlation was seen between faecal coliforms and male-specific phages but not among faecal coliforms and E. coli K12-specific phages (r = 0.30; P less than 0.05). The relative suitability of host strains when using phages in the evaluation of faecal and viral pollution of aquatic environments is discussed.