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.

Identification of lenvatinib prognostic index via recursive partitioning analysis in advanced hepatocellular carcinoma.

BACKGROUND: After the advent of new treatment options for advanced hepatocellular carcinoma (HCC), the identification of prognostic factors is crucial for the selection of the most appropriate therapy for each patient. PATIENTS AND METHODS: With the aim to fill this gap, we applied recursive partitioning analysis (RPA) to a cohort of 404 patients treated with lenvatinib. RESULTS: The application of RPA resulted in a classification based on five variables that originated a new prognostic score, the lenvatinib prognostic index (LEP) index, identifying three groups: low risk [patients with prognostic nutritional index (PNI) >43.3 and previous trans-arterial chemoembolization (TACE)]; medium risk [patients with PNI >43.3 but without previous TACE and patients with PNI <43.3, albumin-bilirubin (ALBI) grade 1 and Barcelona Clinic Liver Cancer stage B (BCLC-B)]; high risk [patients with PNI <43.3 and ALBI grade 2 and patients with PNI <43.3, albumin-bilirubin (ALBI) grade 1 and Barcelona Clinic Liver Cancer stage C (BCLC-C)]. Median overall survival was 29.8 months [95% confidence interval (CI) 22.8-29.8 months] in low risk patients (n = 128), 17.0 months (95% CI 15.0-24.0 months) in medium risk (n = 162) and 8.9 months (95% CI 8.0-10.7 months) in high risk (n = 114); low risk hazard ratio (HR) 1 (reference group), medium risk HR 1.95 (95% CI 1.38-2.74), high risk HR 4.84 (95% CI 3.16-7.43); P < 0.0001. The LEP index was validated in a cohort of 127 Italian patients treated with lenvatinib. While the same classification did not show a prognostic value in a cohort of 311 patients treated with sorafenib, we also show a possible predictive role in favor of lenvatinib in the low risk group. CONCLUSIONS: LEP index is a promising, easy-to-use tool that may be used to stratify patients undergoing systemic treatment of advanced HCC.

Correction to: Bilateral atypical ulnar fractures occurring after long-term treatment with bisphosphonate for 7 years and with teriparatide for 2 years: a case report.

The original version of this article, published on 10 September 2020 contained a mistake.

Bilateral atypical ulnar fractures occurring after long-term treatment with bisphosphonate for 7 years and with teriparatide for 2 years: a case report.

Most atypical fractures associated with the long-term treatment with bisphosphonates (BP) commonly develop in the femoral shaft or subtrochanteric region. We report a rare case of bilateral atypical ulnar fractures in an 86-year-old woman with osteoporosis who finished the treatment with teriparatide for 2 years after long-term treatment with BP. She slid down from an approximately 30-cm-tall seat and slightly contused her left elbow. Plain radiography revealed that both ulnae had a noncomminuted short oblique fracture with cortical thickening and sclerosis at the fracture site. Based on the clinical and radiological findings, she was diagnosed with bilateral atypical ulnar fractures. The fracture of the left ulna was completely displaced and treated surgically. On the other hand, since the right ulna was an incomplete fracture, it was treated conservatively. During surgery, drilling with Kirschner wire and curettage were performed in the osteosclerotic lesion, and an autologous cancellous bone graft was inserted from the ipsilateral olecranon. Bone union was achieved in both fractures at 1 year after surgery. There have been no reports regarding the development of atypical ulnar fractures occurring after the long-term treatment with BP and 2-year use of teriparatide, and the treatment strategies of such fractures have not been established. If teriparatide cannot be used after occurring atypical fractures, the use of low-intensity pulsed ultrasound (LIPUS) and subsequent treatment for osteoporosis are recommended for the bone union. In addition, the treatment of the osteosclerotic lesion and rigid internal fixation are required in surgery.

The glucagon-like peptide-1 receptor agonist liraglutide improves hypoxia-induced pulmonary hypertension in mice partly via normalization of reduced ET(B) receptor expression.

The glucagon-like peptide-1 receptor (GLP-1R) agonist liraglutide is an incretin hormone mimetic used in the treatment of diabetes. However, the effects of liraglutide on pulmonary hypertension (PH) and pulmonary endothelin (ET) system are unknown. Eight-week-old C57BL6/J mice were injected liraglutide or vehicle for 5 weeks. One week after injection, the mice were exposed to either room air (normoxia) or chronic hypoxia (10 % O(2)) for 4 weeks. The right ventricular systolic pressure (RVSP) was significantly higher in hypoxia + vehicle group than in normoxia + vehicle group. ET-1 mRNA expression in the lungs was comparable among all the groups. ET(B) mRNA and protein expression in the lungs was significantly lower in hypoxia + vehicle group than in normoxia + vehicle group. The above changes were normalized by liraglutide treatment. The expression of phospho-eNOS and phospho-AMPK proteins in the lungs was significantly higher in hypoxia + liraglutide group than in normoxia + vehicle group. We demonstrated for the first time that liraglutide effectively improved RVSP and RV hypertrophy in hypoxia-induced PH mice by activating eNOS through normalization of impaired ET(B) pathway and augmentation of AMPK pathway. Therefore, GLP-1R agonists can be promising therapeutic agents for PH.

Structural evolution in the neutron-rich nuclei ¹°6Zr and ¹°8Zr.

The low-lying states in ¹°6Zr and ¹°8Zr have been investigated by means of ß-γ and isomer spectroscopy at the radioactive isotope beam factory (RIBF), respectively. A new isomer with a half-life of 620 ± 150 ns has been identified in ¹°8Zr. For the sequence of even-even Zr isotopes, the excitation energies of the first 2⁺ states reach a minimum at N = 64 and gradually increase as the neutron number increases up to N = 68, suggesting a deformed subshell closure at N = 64. The deformed ground state of ¹°8Zr indicates that a spherical subshell gap predicted at N = 70 is not large enough to change the ground state of ¹°8Zr to the spherical shape. The possibility of a tetrahedral shape isomer in ¹°8Zr is also discussed.

ß-decay half-lives of very neutron-rich Kr to Tc isotopes on the boundary of the r-process path: an indication of fast r-matter flow.

The ß-decay half-lives of 38 neutron-rich isotopes from (36)Kr to (43)Tc have been measured; the half-lives of (100)Kr, (103-105)Sr, (106-108)Y, (108-110)Zr, (111,112)Nb, (112-115)Mo, and (116,117)Tc are reported here. The results when compared with previous standard models indicate an overestimation in the predicted half-lives by a factor of 2 or more in the A≈110 region. A revised model based on the second generation gross theory of ß decay better predicts the measured half-lives and suggests a more rapid flow of the rapid neutron-capture process (r-matter flow) through this region than previously predicted.

MAC-CCD system: a novel lymphocyte microwell-array chip system equipped with CCD scanner to generate human monoclonal antibodies against influenza virus.

We previously developed a lymphocyte microwell-array system, which effectively detects antigen-specific B-cells by monitoring intracellular Ca(2+) mobilization at the single-cell level with a fluorescent Ca(2+) indicator, fluo-4. However, it is difficult for the system to perform time-lapse monitoring. Here, we developed a novel method, a lymphocyte microwell-array chip system equipped with a charge-coupled device (CCD) time-lapse scanner (MAC-CCD system), for monitoring intracellular Ca(2+) mobilization. The MAC-CCD system is able to monitor intracellular Ca(2+) mobilization of more than 15,000-20,000 individual live B-cells every 10 s. In addition, we adopted a correlation method in a MAC-CCD system, which enabled us to detect B-cells with a frequency of as few as 0.046%. Furthermore, we succeeded in obtaining six influenza nucleoprotein-specific human monoclonal antibodies from the peripheral blood of influenza-vaccinated volunteers. These results demonstrate that the MAC-CCD system with a correlation method could detect very rare antigen-specific B-cells.

Intracerebroventricular administration of NMDA-R1 antisense oligodeoxynucleotide significantly alters the activity of ventral tegmental area dopamine neurons: an electrophysiological study.

In this study, we determined the activity of midbrain dopamine (DA) neurons in male albino rats following the intracerebroventricular (i.c.v.) administration of antisense oligodeoxynucleotide (aODN) against the mRNA for the NR1 subunit of the NMDA receptor. In addition, the effect of aODN on the specific binding of the NMDA receptor ligand [(3)H]MK-801 was also examined in various brain areas, including the midbrain. Antisense ODN against the NR1 mRNA, the corresponding sense ODN (sODN) or saline was continuously administered into the right ventricle of rats by osmotic minipumps for 7 days (20 nmol/day). Autoradiographic binding studies indicated that aODN significantly reduced the density of [(3)H]MK-801 binding by an average of 20-30% in several forebrain regions, including the anterior cingulate cortex, caudate putamen, and nucleus accumbens. However, [(3)H]MK-801 binding was not significantly altered in the ventral tegmental area (VTA) or substantia nigra pars compacta (SNC). Subsequently, using the technique of extracellular single-unit recording, the number, as well as the firing pattern, of spontaneously active DA neurons was determined in the VTA and SNC. The administration of aODN did not significantly alter the number of spontaneously active VTA and SNC DA neurons compared to saline- of sODN-treated animals. Furthermore, the firing pattern of spontaneously active SNC DA neurons was not significantly altered. However, for spontaneously active VTA DA neurons, the administration of aODN significantly decreased the percent events in bursts, number of bursts, and percentage of DA neurons exhibiting a bursting pattern compared to saline- and sODN-treated animals, i.e., neurons show less bursting activity. The present results suggest that subchronic aODN treatment against the mRNA for the NR1 subunit of the NMDA receptors can reduce NMDA receptor number and can result in an altered activity of spontaneously active VTA DA neurons in anesthetized rats.

Role of medullasin in nifedipine-induced gingival overgrowth in rats.

To clarify the possible pathophysiological role of medullasin, a neutrophil elastase-like proteinase, in nifedipine (NF)-induced gingival overgrowth, a rat model of gingival overgrowth was first established using a diet containing NF. The relation between histopathological changes and the distribution of the proteinase was then investigated. Thirty-two, specific pathogen-free 20 day-old, male, Fisher 344 rats were fed a diet containing NF and killed at 2, 8, 16 and 32 weeks. Control rats (n = 32) were fed the same diet but without the drug. The mandible of each rat was resected and sectioned at 4-microm thickness buccolingually between the first and second molars. Computer image analysis was used to evaluate the extent of overgrowth in the approximal gingiva of each sample. To examine medullasin activity, the mean percentage of medullasin-positive cells per total cells counted in the pocket epithelium and the connective tissue adjacent to the epithelium of approximal gingiva was determined immunohistochemically. The height of the mid-portion and the area in NF-treated group increased significantly with time (with the exception of area at 2 weeks) compared with the corresponding regions in the control group. A marked inflammatory-cell infiltration and elongated rete pegs, especially in the mid-portion of approximal gingiva, were seen in the NF-treated group. The mean percentages of medullasin-positive cells in the NF-treated group at 8, 16 and 32 weeks were significantly higher than those of the control. Although medullasin-positive cells were mainly neutrophils, in several samples of the NF-treated group they were recognized as macrophage-like. These findings suggest that medullasin may be involved in host defence and immunoregulation in a NF-induced rat model of gingival overgrowth.

Clinical significance of arterial ketone body ratio in chronic liver disease.

BACKGROUND: Arterial ketone body ratio (acetoacetate/3-hydroxybutyrate, AKBR) has been reported to be a useful tool for the estimation of liver functional reserve, but a more recent report has cast doubt on the clinical significance of this redox theory. Furthermore, the effect of a diminution of liver functional reserve on AKBR has not been documented in chronic liver disease. METHODS: AKBR was measured in normal control subjects (n = 10), heavy alcohol drinkers (n = 19), patients with chronic hepatitis (n = 18) and patients with liver cirrhosis (n = 25). RESULTS: Though AKBR was lower in heavy alcohol drinkers (1.66 +/- 0. 82) than in the other noncirrhotic groups (1.97 +/- 0.93 in normal control subjects, 2.25 +/- 1.11 in patients with chronic hepatitis), this discrepancy did not reach a level of significance. AKBR in patients with liver cirrhosis (1.18 +/- 0.52) was significantly lower than that in normal controls (p < 0.01). AKBR in Child's class A, Child's class B, and Child's class C was 1.20 +/- 0.60, 1.07 +/- 0.56, and 1.27 +/- 0.45, respectively, and there were no significant differences among them. CONCLUSION: AKBR may be parallel to liver mitochondrial redox potential and hepatic functional reserve to some extent, but it does not appear to be an accurate parameter for their estimation.

Common peroneal nerve block for sciatica.

The effectiveness of common peroneal nerve block for lumbar disc herniation was evaluated in a double blind study. Common peroneal nerve block was performed near the fibular head in nine patients using 2% lidocaine and in 10 patients using saline. The average pain scale score decreased from 3.1 to 0.6 in the lidocaine group, whereas it decreased from 3.0 to 2.6 in the placebo group. The average result in the straight leg raising test increased from 61 degrees to 84 degrees in the lidocaine group, but from 44 degrees to 50 degrees in the placebo group. Lower leg pain lessened more in the lidocaine group than in the placebo group. The finding that lower leg pain disappeared or decreased with a lidocaine block at a site far distal to the lumbar lesion suggests that impulses that are transmitted distal to the lesion may be important for the generation of sciatic radicular pain.

Nonalcoholic steatohepatitis masquerading as autoimmune hepatitis.

Nonalcoholic steatohepatitis is an increasingly recognized clinicopathologic condition. We report two cases of nonalcoholic steatohepatitis in middle-aged Japanese women whose clinical and laboratory data mimicked autoimmune hepatitis. Histologic findings of both cases were definite steatohepatitis with portal and pericellular fibrosis. Both patients' HLA-DR haplotypes were DR4 and DR2, which are frequently observed in Japanese patients with autoimmune hepatitis. Our cases suggest a diversity in the pathogenesis of nonalcoholic steatohepatitis.

Enhanced renal susceptibility to ischemia-reperfusion injury in the rat with obstructive jaundice.

BACKGROUND/AIMS: To investigate the susceptibility of kidneys to ischemia-reperfusion injury under obstructive jaundice. MATERIALS AND METHODS: Bile ducts of male rats were ligated for five days, right kidneys were removed, and vascular clamps were placed across left renal arteries for 30 minutes. RESULTS: Twenty-four hours later, ischemia-reperfusion produced renal injury in jaundiced rats as shown by increased serum creatinine and urea nitrogen levels. Histological observation showed tubular damages. These changes were minimal after ischemia-reperfusion in control rats. Renal thiobarbituric acid reactive substance contents were increased after bile duct ligation, which did not change after ischemia-reperfusion. On the other hand, ischemia-reperfusion produced a significant increase in renal thiobarbituric acid reactive substance contents in control rats. Renal glutathione contents were increased two fold after bile duct ligation and they were significantly decreased by ischemia-reperfusion. CONCLUSIONS: Kidneys in obstructive jaundice appear to be susceptible to ischemia-reperfusion injury. Although protective roles of GSH is suggested, the role of oxygen radicals in this type of renal injury remains to be further elucidated.

Choledochal cyst with adenocarcinoma in the cystically dilated intrahepatic bile duct.

A rare case of choledochal cyst complicated by papillary adenocarcinoma in the cystically dilated intrahepatic bile duct is reported. The tumor was located in the neck of the cystic lesion, and imaging modalities failed to show communication between the cystic lesion and the bile ducts.

Ischemic hepatitis in cirrhosis. clinical features and prognostic implications.

To characterize liver dysfunction in patients with cirrhosis after variceal bleeding, we analyzed 50 cirrhotic patients who had bleeding esophageal varices with or without shock. Increases in serum total bilirubin levels by 1.5 times were observed within 24 h in 11 of 12 patients with shock who died > 4 days after hemorrhage but in only one of eight patients with shock who survived (p < 0.01). Increases in serum aspartate aminotransferase and alanine aminotransferase by 2.5 times were observed in six patients in the former group but in none of the latter (p < 0.05). In postmortem livers, hepatocellular degeneration with minimal inflammatory cell infiltration was observed. Ischemic hepatitis is frequently noted in cirrhotic patients with ruptured esophageal varices. Patients with increases in the serum level of total bilirubin and/or aminotransferases within 24 h from onset of hemorrhage should be carefully treated even if hemorrhage is controlled.

Systemic hypotension and diuresis by L-arginine in cirrhotic patients with ascites: role of nitric oxide.

To investigate the role of nitric oxide in renal function and hemodynamics in cirrhotic patients with ascites, L-arginine (30 g in 300 mL of distilled water), a substrate for nitric oxide synthase, was infused into six cirrhotic patients with ascites, and the effects were compared with those of saline infusion. Healthy controls (n = 5) were also studied under the same conditions. In the patients, L-arginine infusion significantly decreased systolic and diastolic blood pressures while markedly increasing urinary flow and urinary sodium excretion; no significant changes were seen with saline infusion. In controls, only diastolic blood pressure was decreased by L-arginine infusion, whereas urinary flow and urinary sodium excretion were increased by both L-arginine and saline infusion. In both groups, a similar increase of plasma atrial natriuretic factor (ANF) was seen with L-arginine and saline infusions; endothelin and catecholamines were not affected by either infusion. In both groups, plasma levels of vasopressin were increased by L-arginine infusion. In the cirrhotic patients, urinary excretions of cyclic guanosine monophosphate (cGMP) and nitrates/nitrites (NOx) were significantly increased by L-arginine infusion, whereas no significant changes were seen with saline infusion. In controls, only the excretion of cGMP was increased by L-arginine infusion. In summary, L-arginine infusion induces diuresis and natriuresis accompanied by increased excretions of cGMP and NOx in cirrhotic patients with ascites. This differs from the response in controls, where the increase in urinary sodium excretion is not accompanied by an increase in markers of increased nitric oxide synthesis.

Increased renal susceptibility to gentamicin in the rat with obstructive jaundice. Role of lipid peroxidation.

To study whether renal susceptibility to nephrotoxic stimuli is increased in obstructive jaundice, the effect of gentamicin on the renal function in bile duct-ligated rats was investigated. Gentamicin (50 mg/kg/day, subcutaneously) or saline was given to bile duct-ligated rats or sham-operated rats for six days. Mortality in the bile duct-ligated group that received gentamicin was 64% whereas that in the other groups was 0%. In the bile duct-ligated group, although serum creatinine and blood urea nitrogen were minimally affected, focal granulo-vacuolar degeneration in the proximal tubule was observed, which was accompanied by an increase in renal malondialdehyde. Gentamicin significantly increased serum creatinine and blood urea nitrogen levels and caused marked degeneration in the proximal tubule in the bile duct-ligated group, which was accompanied by a further increase in renal malondialdehyde, while these changes were not observed in the sham group. The kidney in obstructive jaundice appears to be susceptible to gentamicin. Enhanced production of oxygen radicals may be responsible for this effect.