Exposure to obinutuzumab does not affect outcomes of SARS-CoV-2 infection in vaccinated patients with newly diagnosed advanced-stage follicular lymphoma.

URBAN is a multicentric, ambispective study evaluating the effectiveness and safety of obinutuzumab-based immuno-chemotherapy and maintenance in patients with untreated advanced follicular lymphoma (FL). The study began before the COVID-19 emergency declaration in Italy. It is currently ongoing for follow-up, and the enrolment timeline encompassed different stages of the pandemic, various vaccination roll-out phases and prevalence of SARS-CoV-2 variants. Outcomes of interest of the present sub-analysis included SARS-CoV-2 infection rates and COVID-19-related hospitalizations/deaths. At data cut-off, 86 (28.8%) and 213 patients (71.2%) were treated before and during/after the COVID-19 outbreak respectively; 294 (98.3%) completed the induction, 31 (10.4%) completed maintenance and 170 (56.9%) were still on maintenance. Overall, 245 patients (81.9%) received at least one SARS-CoV-2 vaccine dose: 13.5%, 31.4% and 55.1% received one, two and three doses respectively. We observed a substantial decrease in COVID-19-related mortality rates in pre- versus post-vaccination phases, along with a reduction in COVID-19-related outcomes due to the shift from alpha/delta to omicron variant predominance. No differences emerged between patients given maintenance or not, although the schedule was modified in 65% of cases. To our knowledge, URBAN represents the largest dataset of COVID-19-related outcomes in FL patients extensively exposed to obinutuzumab. ClinicalTrials.gov identifier: NCT04034056.

Competing risks and prognostic stages of cirrhosis: a 25-year inception cohort study of 494 patients.

BACKGROUND: Morphological, haemodynamic and clinical stages of cirrhosis have been proposed, although no definite staging system is yet accepted for clinical practice. AIM: To investigate whether clinical complications of cirrhosis may define different prognostic disease stages. METHODS: Analysis of the database from a prospective inception cohort of 494 patients. Decompensation was defined by ascites, bleeding, jaundice or encephalopathy. Explored potential prognostic stages: 1, compensated cirrhosis without oesophago-gastric varices; 2, compensated cirrhosis with varices; 3, bleeding without other complications; 4, first nonbleeding decompensation; 5, any second decompensating event. Patient flow across stages was assessed by a competing risks analysis. RESULTS: Major patient characteristics were: 199 females, 295 males, 404 HCV+, 377 compensated, 117 decompensated cirrhosis. The mean follow-up was 145 ± 109 months without dropouts. Major events: 380 deaths, 326 oesophago-gastric varices, 283 ascites, 158 bleeding, 146 encephalopathy, 113 jaundice, 126 hepatocellular carcinoma and 19 liver transplantation. Patients entering each prognostic stage along the disease course were: 202, stage 1; 216, stage 2; 75 stage 3; 206 stage 4; 213 stage 5. Five-year transition rate towards a different stage, for stages 1-4 was 34.5%, 42%, 65% and 78%, respectively (P < 0.0001); 5-year mortality for stages 1-5 was 1.5%, 10%, 20%, 30% and 88% respectively (P < 0.0001). An exploratory analysis showed that this patient stratification may configure a prognostic system independent of the Child-Pugh score, Model for End Stage Liver Disease and comorbidity. CONCLUSION: The development of oesophago-gastric varices and decompensating events in cirrhosis identify five prognostic stages with significantly increasing mortality risks.

Treatment of small hepatocellular carcinoma associated with cirrhosis by percutaneous ethanol injection. A trial with a comparison group.

BACKGROUND: Ethanol injection has been reported to be effective in the treatment of hepatocellular carcinoma, but no controlled randomized trials have been performed. We therefore performed a trial comparing ethanol injection with an untreated, matched historical comparison group in the treatment of hepatocellular carcinoma. METHODS: From 1992 to 1993, 35 patients (14 Child's A and 21 Child's B cirrhosis) with small (< 4 cm) hepatocellular carcinoma associated with cirrhosis were treated by ethanol injection. Each patient was matched with an untreated case (followed up during the period 1984-89) for variables known to have independent prognostic value (age, Child's classification, number of lesions, alpha-fetoprotein, and modality of diagnosis). RESULTS: The 1-, 2-, and 3-year survival rates of ethanol-treated patients were 86% (95% confidence interval (CI), 69-94), 53% (95% CI, 34-68), and 33% (95% CI, 15-52), whereas the survival rates of the comparison group were 75% (95% CI, 56-85), 26% (95% CI, 13-41), and 14% (95% CI, 5-27) (P = 0.01). The 1-, 2-, and 3-year survival rates of Child's A were 100%. 87% (95% CI, 30-97), 71% (95 CI, 33-90), 71% (95% CI, 33-90) in the ethanol-treated patients and 92 (95% CI, 59-99), 43% (95% CI, 23-73), and 21% (95% CI, 23-72) in untreated patients. The 1-, 2-, and 3-year survival of Child's B patients were 76% (95% CI, 59-97), 32% (95% CI, 13-53), and 9% (95% CI, 0.8-33) in the treated group and 61% (95% CI, 40-83), 14% (95% CI, 3-32), and 9% (95% CI, 1-26) in the treated group. CONCLUSIONS: These data suggest that ethanol injection prolongs the life of patients with hepatocellular carcinoma associated with Child's A cirrhosis but seems not to influence the survival of Child's B patients.

Screening for hepatocellular carcinoma in patients with Child's A cirrhosis: an 8-year prospective study by ultrasound and alphafetoprotein.

One hundred and forty-seven patients with Child's A cirrhosis and no evidence of hepatocellular carcinoma were followed up in an 8-year prospective surveillance program with testing by ultrasound and alphafetoprotein every 6 months. Eighteen of 147 patients were HBsAg positive. Anti-hepatitis C virus antibodies were found in 103 out of 133 cases tested. Sixteen patients had a history of heavy drinking. Thirty hepatocellular carcinomas were detected during follow up. At the time of diagnosis, ultrasound detected focal lesions in all the patients whereas alphafetoprotein was below diagnostic levels. The hepatocellular carcinoma was single in 26 patients and multiple in four. The overall 8-year cumulative tumor-free rate was 69% (95% confidence interval = 58-73). The yearly hepatocellular carcinoma incidence from 1985 to 1992 was respectively 2%, 1.5%, 2%, 3%, 5%, 4.8%, 7% and 10%. The initial value of AFP > 50 ng/ml and < 400 ng/ml was significantly related to the development of hepatocellular carcinoma. This series shows that the cumulative incidence of hepatocellular carcinoma in cirrhosis in Italy is higher than previously reported, but lower than that observed in Asiatic areas. A 6-month interval for ultrasound is reasonable to detect treatable tumors. Alphafetoprotein has no value for early diagnosis, although its intermediate values (> 50 and < 400 ng/ml) may indicate the presence of undetectable cancer which will appear during the follow up, and suggests that ultrasound should be employed more frequently in patients with these values.

Expression of leukocyte adhesion molecules in the liver of patients with chronic hepatitis B virus infection.

Virus-specific T-cell responses are believed to be involved in the pathogenesis of liver cell injury secondary to hepatitis B virus infection. In this study, liver biopsy specimens from patients with chronic hepatitis B virus infection were analyzed for expression of two major pathways of adhesion used by cytotoxic T cells to interact with target cells. The lymphocyte function-associated antigen 3 was found preferentially expressed on hepatocytes of patients with active hepatitis B virus replication, whereas the expression of the intercellular adhesion molecule 1 on hepatocytes seemed more closely related with inflammatory activity. Adhesion molecules were also highly expressed on T lymphocytes found in areas of piecemeal and spotty necrosis, indicating the presence of antigen-specific "memory" T cells at the site of hepatocellular injury. This study suggests that the expression of the lymphocyte function-associated antigen 3 on hepatocytes may be important for viral elimination. The coordinate expression of the intercellular adhesion molecule 1 may regulate inflammatory response and enhance viral antigen presentation to T cells. Conversely, the absence of hepatocyte adhesion molecules might be a favorable factor for viral persistence.

Asymptomatic hepatocellular carcinoma in Child's A cirrhosis. A comparison of natural history and surgical treatment.

The present study deals with the natural history of 37 asymptomatic patients with cirrhosis and hepatocellular carcinoma, 25 with 2-9-cm tumors who were not surgically treated (first group) and 12 with tumors smaller than 4 cm who underwent resection (second group). All patients were in Child's A class. Two-year survival (according to life-table analysis by the Kaplan-Meier method) was 50% in the first group and 39% in the second group. This difference was not significant. In the first group no relation was found between survival and initial tumor size or alpha-fetoprotein levels. Ultrasound examinations at 3-mo intervals revealed the following patterns of tumor growth: (a) no significant growth during the follow-up (9 patients); (b) significant growth (tumor size at least doubling) only in the final stage of the disease (11 patients); (c) initial significant growth followed by a period of no increase in size (5 patients). These findings show that in our geographical area (a) 2-yr survival of untreated asymptomatic patients with hepatocellular carcinoma associated with cirrhosis does not differ from that of similar patients undergoing resection and (b) the tumor can exhibit long periods of no growth alternating with periods of exponential growth.

[Evolution of the echographic picture in primary liver tumor associated with cirrhosis]. / Evoluzione del quadro ecografico nel tumore primitivo del fegato associato a cirrosi.

To study the sonographic (US) evolution of hepatocellular carcinoma, 53 tumors in 45 untreated patients were observed regularly with real-time US for a period of 6 to 56 months. At the beginning, 25 tumors were hypoechoic, 18 isoechoic, 4 hyperechoic, and 6 had mixed hypo/hyper echo patterns. At the follow-up, 7 initially hypoechoic tumors had changed to hyperechoic or to mixed echo patterns; 8 hypoechoic tumors had become isoechoic; 9 of the 25 initially hypoechoic neoplastic lesions had maintained the same echo density. Ten of the 15 initially isoechoic tumors had changed to mixed echo patterns, and 5 had remained unchanged. Three initially isoechoic lesions and a hypoechoic one had turned into diffuse patterns; 2 initially hyperechoic neoplastic lesions had remained unchanged; 1 had switched into hypoechoic, and 1 changed to mixed echo pattern; 4 out of 6 tumors with echo pattern had remained unchanged, 1 had become hyperechoic and 1 hypoechoic. The current study has proven various tumors less than or equal to 3 cm phi to be isoechoic, and most tumors greater than 3 cm phi to have mixed hypo/hyper echo patterns. The echogenicity of small hepatocellular carcinomas increases with the tumor growth, and remains unchanged when they do not increase in size.

Early detection of hepatocellular carcinoma associated with cirrhosis by ultrasound and alfafetoprotein: a prospective study.

A prospective surveillance of hepatocellular carcinoma (HCC) associated with cirrhosis, using alfafetoprotein (AFP) and real-time ultrasonography (US) was carried out in 157 patients with histologically proven cirrhosis. During a two-year follow-up, 15 asymptomatic HCCs were identified. HCCs detected by these methods were at a relatively early stage, as most tumors were small (13 out of 15 less than 5 cm). US was more sensitive than AFP in the diagnosis of HCC when values greater than 400 ng/ml were considered. Patients with initial AFP values greater than 20 ng/ml developed HCC within two years more frequently than patients with values less than 20 ng/ml. A combined approach using US and AFP is suggested in our geographical area.

Procollagen type I production by hepatocytes: a marker of progressive liver disease?

The presence of collagen-producing cells and its relation to disease activity were determined in cryostat liver tissue sections from subjects with active cirrhosis (n = 15), inactive cirrhosis (n = 5), chronic persistent hepatitis (n = 8), or normal histology (n = 3) by means of an immunofluorescence technique using a monoclonal antibody to the carboxy-terminal domain of procollagen type I (anti-Pc). In all patients with active cirrhosis hepatocytes showed a strong intracellular staining with anti-Pc; in 4 of them bileducts also showed a membrane-like reaction. By contrast, tissue sections from chronic inactive liver disease and normal liver were essentially negative. These findings suggest that in chronic liver disease hepatocytes and sometimes biliary epithelium produce collagen and that production is related to disease activity. The detection of active production of procollagen type I by hepatocytes could become a useful marker of progressive liver disease.

Delta agent infection in acute hepatitis and chronic HBsAg carriers with and without liver disease.

Hepatitis B virus (HBV) is a major cause of chronic liver disease in southern Italy. In the same area superinfection with the delta agent is endemic. To assess the prevalence of delta infection in a large population of patients with acute and chronic HBV related liver disease and to look for differential features among delta infected and uninfected subjects sera from 592 consecutive HBsAg positive patients were tested for the delta/anti-delta system by RIA. In no case was delta Ag found in serum. The prevalence of anti-delta was low in acute hepatitis (6.6%) and in asymptomatic carriers (6.4%) but raised in chronic active hepatitis with or without cirrhosis (52.3%). A decrease in frequency of anti-delta was seen in inactive cirrhosis (38.8%) and in hepatocellular carcinoma (11.9%). A younger mean age of delta-infected subjects was observed in each type of chronic liver disease. Our data confirm that delta agent superinfection is definitely associated with severe chronic active liver disease. The difference in age between anti-delta positive and negative patients suggests that delta infection accelerates the natural history of HBV related liver disease.