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.

A validation study of combined resection and ablation therapy for multiple hepatocellular carcinoma.

AIM: To validate the utility of hepatic resection combined with complementary radiofrequency ablation (RFA) compared with resection alone for patients with multiple hepatocellular carcinoma (HCC), and to compare these results with those of a previous report. MATERIALS AND METHODS: A total of 78 HCC patients with multiple (≤5) tumours who were initially treated with hepatic resection only (Resection group) or with combined hepatic resection and RFA (Combination group) were included. Overall and disease-free survival were analysed. RESULTS: There were 21 women and 57 men with a median age of 72.5 (64.3-76.8) years. Fifty-three patients were treated with resection alone and 25 received combination therapy. The 3-, 5-, and 7-year cumulative overall survival rates were 81.2%, 68.2%, and 57.1%, respectively, in the Resection group, and 81.3%, 59.6%, and 42.4%%, respectively, in the Combination group (hazard ratio [HR], 1.462; 95% confidence interval [CI], 0.682-3.136; p=0.329). The 1-, 3-, and 5-year cumulative disease-free survival rates were 61.4%, 45.7%, and 39.8%, respectively, in the Resection group, and 53.1%, 18.6%, and 0%, respectively, in the Combination group (HR, 2.080; 95% CI, 1.157-3.737; p=0.014). The overall survival rate was not significantly different between the Resection and Combination groups in patients within the up-to-seven HCC criteria (n=56; HR, 2.101; 95% CI, 0.805-5.486; p=0.130) or those beyond these criteria (n=22; HR, 0.804; 95% CI, 0.197-3.286; p=0.761). CONCLUSIONS: The combination of hepatic resection and RFA therapy may be an effective strategy for HCC patients with multiple tumours.

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.

Effect of ethanol on hemorheology in patients with ischemic cerebrovascular disease and elderly healthy men.

Changes in hemorheological parameters were studied in patients with ischemic cerebrovascular disease and elderly healthy men who ingested ethanol at 0.5 and 1 g/kg body weight. Following ingestion of 1 g/kg, but not 0.5 g/kg of ethanol, there were significant changes in hemorheologic factors. Whole blood viscosity (WBV, shear rate: 18.8, 37.5, 75, 150, 350 sec(-1)) and blood viscosity corrected for hematocrit (BVC) were increased. WBV and BVC at high shear rate were increased and red blood cell deformability impaired in patients with ischemic cerebrovascular disease, while those factors were not significantly changed in healthy men. It is considered that ethanol ingestion could has bad influences for the microcirculation in patients with ischemic cerebrovascular disease.

[Crow-Fukase syndrome associated with Castleman disease showing hypertrophic cranial pachymeningitis and bilateral internal carotid artery occlusion].

A 51-year-old woman was diagnosed as Crow-Fukase syndrome on July 1997, presenting with lymph node swelling, polyneuropathy, hepatomegaly, hypothyroidism, renal dysfunction, edema and skin change. Lymph node swelling and polyneuropathy improved in some degree after chemotherapy. She was admitted to our hospital on march 6, 1998 because of consciousness disturbance, right hemiparesis and non-fluent aphasia after fever and hypotension. The next day of admission, consciousness disturbance, right hemiparesis and non-fluent aphasia disappeared. MR images of the brain revealed low intensity on a T1-weighted image and high intensity on a T2-weighted image in the left parietal lobe. Furthermore, MR images also revealed diffuse hypertrophic dura matter with enhancement by Gd-DTPA, which made the diagnosis of chronic cranial pachymeningitis. The cerebral angiographies showed bilateral internal carotid artery occlusion. The cerebrospinal fluid showed normal cell count, total protein level of 82 mg/dl, and IgG level of 18 mg/dl. Since there has been very few case reports describing intimate relationship between Crow-Fukase syndrome and pachymeningitis, and between carotid occlusion and pachymeningitis, we speculated that the pachymeningitis might be associated with Crow-Fukase syndrome. Furthermore, pachymeningitis might be a cause of her bilateral carotid occlusion. The number of cases of Crow-Fukase syndrome associated with cerebrovascular disease was very rare. This is the first case which had bilateral internal carotid artery occlusion probably caused by chronic cranial pachymeningitis. Therefore, it is necessary to pay attention to cerebrovascular disease when the patient of Crow-Fukase syndrome is associated with pachymeningitis.

Arteriovenous malformation in the buttock: treatment with a combination of selective embolization and excision.

Arteriovenous malformation (AVM) in a 22-year-old Japanese female is reported. The malformation presented as a nontender, pulsating tumor. An area of marked hypervascularity was revealed in the dermis and muscles of the right buttock by arteriography. The tumor was removed after embolizing the right superior and inferior gluteal arteries, which were the main feeding arteries. Histological examination revealed a number of artery-like vessels, encircled by proliferating capillaries. Follow-up three years after excision showed no clinically remarkable changes. Selective embolization was useful for the excision.

Isolation of Strongyloides venezuelensis from Rattus norvegicus in Kagoshima Prefecture.

On 30 August 1984, Strongyloides sp. specimens were isolated from a rat (Rattus norvegicus) trapped at a pig farm in Kiire-cho, Ibusuki-gun, Kagoshima Prefecture. Both anterior and posterior ovaries of parasitic female were spirally coiled. The means of body length and width, esophagus length, and the distances from mouth to vulva and from anus to tail end were 2,493, 34.5, 719.8, 1,682.8 and 54.4 microns respectively. Filariform larvae measured 544.2, 15.6 and 238.5 microns in the means of body length and width, and esophagus length respectively. These measurements of the present Strongyloides species agreed with those described for S. venezuelensis. Infection rate by oral administration of larvae was low, while subcutaneous inoculation and percutaneous exposure to larvae produced high infection rate to rats which discharged many egg in the feces. The present parasite has been passaged through rats (SD strain) in these 8 years. This isolate is designated as the Kagoshima strain of S. venezuelensis.

Evaluation of jejunal function in Wolman's disease.

Findings in a 1-month-old male infant with Wolman's disease, a rare autosomal defect characterized by intractable diarrhea and severe malabsorption, are described. Investigations in this case focused on the digestive and absorptive functions of the jejunum using histological, biochemical, and electrophysiological methods. The intestinal villi were found to be distorted and club-shaped as a result of the infiltration of foam cells into the lamina propria of the mucosa. The microvilli of the epithelial cells were found on electron microscopy to be markedly shortened and irregular, and had a severe impairment of disaccharidase activity. Documentation of the loss of the sugar- and amino acid-evoked potential differences in the jejunum confirmed the severity of intestinal malabsorption. These observations indicate that the intestinal damage in Wolman's disease is so severe as virtually to exclude the absorption of any form of enteral nutrition. Despite the administration of i.v. hyperalimentation, the infant died of hepatic failure at the age of 6 months.

Renal lesions in Cockayne syndrome.

Two siblings with typical features of the Cockayne syndrome were studied at autopsy. Many glomeruli revealed a paucity of capillary loops and had thickened capillary walls. Some glomeruli with advanced lesions showed collapse of the glomerular tufts or complete hyalinization. Atrophy of tubules and interstitial fibrosis were also observed. There were no significant arteriosclerotic changes in the vessels. Ultrastructural studies demonstrated thickened glomerular basement membranes with bends and folds. These histopathological findings are different to those previously reported with the exception of the 1966 report by Ohno and Hirooka.

Partial ornithine transcarbamylase deficiency in females: diagnosis by an immunohistochemical method.

Females heterozygous for the X-linked urea cycle disorder, ornithine transcarbamylase (OTC) deficiency have a significant risk of developing hyperammonaemia. Diagnosis of this genetic defect in a proband is the essential starting point for family studies. By an immunohistochemical analysis of the liver specimens fixed in 10% formalin, we confirmed heterozygous status for OTC deficiency in two female patients, a 15-year-old girl and a 2-year-old girl, who died of hyperammonaemia. Since most affected males lack cross reactive materials (CRM), an immunochemical analysis should be useful for the diagnosis of most heterozygous females.

Gigantism associated with McCune-Albright's syndrome.

The case of a 16 year-old boy with McCune-Albright's syndrome which is rarely accompanied by gigantism was studied endocrinologically. The stimulation of growth hormone (GH) release by hypoglycemia, the decline of elevated GH by hyperglycemia and a little lower somatostatin like immunoreactivity (SLI) may support abnormalities of hypothalamic function, but the existence of pituitary microadenoma cannot be ruled out because of the paradoxical suppression of GH release by oral administration of bromocriptine (CB-154) and L-DOPA and the stimulation of GH release by intravenous administration of TRH.

Chronic nephropathy in idiopathic multicentric osteolysis.

A 19-year-old girl having a sporadic form of idiopathic multicentric osteolysis with nephropathy is described. She was first diagnosed as having sporadic carpotarsal osteolysis at the age of 6. Her proteinuria was first detected at 15 years of age and renal biopsy specimens obtained at the same age were compatible with those of focal segmental glomerulosclerosis with interstitial fibrosis and tubular atrophy. Immunofluorescence microscopy revealed negative deposits of Ig G, Ig A and C3 but a trace amount of mesangial Ig M in unsclerosed segments of the glomeruli. Electronmicroscopy showed no specific changes. Renal vascular changes such as proliferation of vascular intima and medial hypertrophy were not demonstrated in the present case. It is our conclusion that focal segmental glomerulosclerosis is part of the spectrum of nephropathy in the sporadic form of idiopathic multicentric osteolysis.

Curative effects of 1alpha-hydroxycholecalciferol on calcium metabolism and bone disease in patients with chronic renal failure.

Synthetic 1alpha-hydroxycholecalciferol (1alpha-OH-D3) was given intravenously in a dose of 2.5-10 mug per day to three patients with chronic renal failure. As little as 10 mug of 1alpha-OH-D3 daily for a week improved intestinal calcium absorption to a normal level, raised serum calcium, and reduced serum alkaline phosphatase. Severe rickets which had not responded to large amounts (greater than 200 mg in total) of vitamin D2 was markedly cured with 2.5 mug of 1alpha-OH-D3 given daily for 3 weeks. These clinical data hold promise that is certainly useful in the improvement of intestinal malabsorption of calcium and bone diseases in renal failure.