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.

Evidence for involvement of p59fyn in fasting-induced thymic involution.

p59fyn, a member of the src-family protein tyrosine kinase, is expressed abundantly in thymus. We examined the possible involvement of p59fyn in thymic involution induced by a fasting stress in Fyn-/- mice. An acute 48 h fast resulted in severe atrophy of the thymus and a marked decrease of the total thymocyte number with depletion of the CD4+CD8+[double positive (DP)] population in Fyn+/+ (control) mice. A remarkable increase in terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labelling-positive signals was detected in the fasted group of control mice. However, these findings were not observed in Fyn-/- mice. Interestingly, MRL/MPJ-lpr/lpr, a Fas-deficient model animal, also showed no significant decrease of DP cell numbers in the fasted group. p59fyn is known to interact with Fas signalling, and these findings suggest that p59fyn is involved in fasting-induced thymic involution, raising the possibility that Fas/p59fyn-mediated signalling may, at least partially, be associated with the phenomenon.

Delivery of a normal newborn after intensive medical treatment for an acute exacerbation of ulcerative colitis during pregnancy: a case report.

A 28-year-old woman developed an acute exacerbation of chronic ulcerative colitis in the second trimester of pregnancy. She was treated by intensive medical treatment with intravenous prednisolone, betamethasone enema, oral salazosulfapyridine, intravenous ceftazitim, and total parenteral nutrition. The acute relapse subsided after 73 days of the treatment and a normal female newborn weighing 2,208 g was delivered vaginally after 40 weeks' gestation. Our experience showed that the intensive medical therapy did not impair either the course of the pregnancy or the fetal outcome.

Can scores on alexithymia distinguish patients with peptic ulcer and erosive gastritis?

This study examined alexithymic characteristics of 57 patients with peptic ulcer and 198 with erosive gastritis. The prevalence rate of alexithymia, as measured on the 20-item Toronto Alexithymia Scale, was significantly higher for the peptic ulcer group (51%) than for the erosive gastritis group (21%). Scores of the Profile of Mood States were significantly higher for the peptic ulcer group than for the erosive gastritis group. The alexithymia scores were significantly correlated with the scores on the Profile of Mood States. However, discriminant analysis indicated that the alexithymia scores could account for significant additional variance beyond mood states as measured by the Profile of Mood States.

[The bone-implant-interface: an experimental study on the effects of micro-motion].

Aseptic loosening of a prosthesis is a hazardous problem after total joint replacement. In revision surgery, fibrous granulation tissue is always seen between the prosthesis and the bone or between the bone cement and the bone. We refer to this granulation tissue as the "bone-implant-interface" and it invades into the bone, resulting in osteolysis around the prosthesis. In order to investigate the histology of this granulation tissue and the mechanism of bone resorption, we produced an experimental model of the loosening of implants (alumina ceramic, PMMA, HDP) in the distal femoral condyles of rabbit. Each implant was inserted into the distal femoral condyle and connected with a Kirschner wire which was wired down to the tibia and fixed tightly to the tibial cortex. The implants could then be mobilized when the rabbits moved their knees. We called this a "micro-motion model". Besides doing this, we also developed a similar model in rabbit with ferritin-induced arthritis to investigate whether or not arthritis exacerbated the loosening of a prosthesis. The histological examinations of the bone-implant-interface in the micro-motion model in normal rabbit revealed three layers: a surface layer containing small round cells such as synovial lining cells, a middle layer containing many fibroblasts, macrophages and giant cells which phagocytize wear debris, and a deep layer adjacent to the bone containing many osteoclasts. In the models with ferritin-induced arthritis, more synovial lining cells were seen in the surface layer and more osteoclasts were seen in the deep layer. Also more osteolysis occurred around the implant in the arthritis model. In summary, the results suggested that the mechanical stress of motion stimulated the growth of synovial lining cells and macrophages in the bone-implant-interface, resulting in increased numbers of osteoclasts and in subsequent osteolysis.

Clinical experience of ceramic cementless total knee arthroplasty in RA and a histological study of the bone-ceramic interface in revision cases.

The Kyoto total knee cementless prosthesis (KC-1) was used in 23 patients with rheumatoid arthritis. Its femoral component is made of alumina ceramics which articulated with a HDP plate supported by a ceramic plate. Although the followup period is short, the postoperative result is not satisfactory, because remarkable sinking of the tibial component was noticed in those patients who have bone atrophy. We had 6 cases of revision so far. Since 1986, we have been using bone cement in all cases of RA in doing TKA.

Waveguiding properties of (Se,S)-based chalcogenide glass films and some applications to optical waveguide devices.

Fundamental waveguiding properties of As-Se-S-Ge chalcogenide glass films and some applications to passive waveguide components are presented. The refractive index of the chalcogenide glass film annealed just below the glass transition temperature (200 degrees C) increases by light irradiation near the absorption edge. The refractive-index change amounted to 0.03 at 1.06 microm. The propagation loss of 0.4 dB/cm has been achieved at 1-microm thickness for As(40)Se(10)S(40)Ge(10) glass film. The photoinduced refractive-index change in the chalcogenide glass film was large enough to be applied to making passive waveguide components. The curved waveguide and optical directional coupler were designed as passive components.

Strip-loaded waveguide formed in a graded-index LiNbO(3) planar waveguide.

An As(40)Se(50-x)S(x)Ge(10) film strip loaded waveguide, formed in the graded-index LiNbO(3) planar waveguide, has been demonstrated. Analytical results show that the optical field confinement in the waveguide loaded by the high refractive index film becomes large near the film cutoff thickness for the fundamental mode. Photostructural effect of the chalcogenide glass overcomes difficulty in precisely controlling film thickness. A 3-D waveguide has been achieved by loading As(40) Se(10)S(40)Ge(10) film 10 microm wide on a Ti diffused LiNbO(3) planar waveguide. Optical confinement in the waveguide has been improved intensively with the aid of the photostructural effect of the film.

[The effect of intravenous prostaglandin F 2 alpha on the motility of the gastrointestinal tracts after major abdominal surgery (author's transl)].

TThe effect of prostaglandin F 2 alpha was studied clinically and electromyographically on the motility of the gastric antrum, duodenum, jejunum, ileum and transverse colon in 20 patients by giving 2 hours intravenous drip infusion at 0.3 approximately 0.5 microgram/kg/min for 2 hours after major abdominal surgery. Folling results were obtained. 1. The motility of stomach and colon was least active than any other site of alimentary tract during 48 hours after surgery. This seems to be one of the most important causes of so called postoperative ileus. 2. Recovery from reflex inhibition of motility of the alimentary tract after surgery was seen in duodenum at first, and then in jejunum and ileum in order. It was proved that intravenous drip infusion of PGF 2 alpha at 0.3 approximately 0.5 microgram/kg/min for 2 hours had produced the increase of electrical activity in any site of gastrointestinal tract and subsequently brought about increasing of propulsive movement. The effect of PGF 2 alpha is proportional to its concentration. 4. tit was concluded that PGF 2 alpha could be administered most effectively by intravvenous drip infusion at 0.5 microgram/kg/min 3 times daily for 3 days after surgery for the satisfactory recovery from the postoperative ileus, and no appreciable side effect was observed.