G.L. Rapaccini

Semiannual and annual surveillance of cirrhotic patients for hepatocellular carcinoma: effects on cancer stage and patient survival (Italian experience).

OBJECTIVES:Surveillance of cirrhotic patients for early detection of hepatocellular carcinoma, based on ultrasonography and α1-fetoprotein determination, is a recommended practice. However, it has not been proved that this procedure can improve patient survival.METHODS:We conducted a multicenter retrospective study on 1051 consecutive patients with hepatocellular carcinoma. The criteria for eligibility were presence of underlying cirrhosis, and description of cancer stage and modalities of its diagnosis. Among 821 patients fulfilling these criteria, the tumor was detected during semiannual surveillance in 215 individuals (group 1), during annual surveillance in 155 (group 2), and as a result of symptoms or incidentally in 451 (group 3). Survival of patients under surveillance was corrected for lead time.RESULTS:Cancer stage was similar in groups 1 and 2 and was less advanced than in group 3 (p < 0.001). The frequency of ablative treatments or chemoembolization was similar in groups 1 and 2 and was greater than in group 3 (p < 0.001). Both surveillance programs doubled the prevalence of potential candidates for liver transplantation (68.5% and 62.5%) with respect to group 3 (32.3%, p < 0.001). However, only 15 patients underwent transplantation. In groups 1 and 2, the 5-yr survival was equivalent and was greater than in group 3 (p < 0.001). By segregating patients according to severity of cirrhosis, the benefit was confined to compensated cirrhosis (adjusted relative risk of death for patients under surveillance: 0.59 [95% CI = 0.45–0.78]).CONCLUSIONS:Semiannual and annual surveillance equally improve the survival of cirrhotic patients with hepatocellular carcinoma and greatly increase the amenability rate to liver transplantation. When access to liver transplantation is limited, this benefit is restricted to patients with a good cirrhosis-related prognosis.

Diagnostic and prognostic role of alpha-fetoprotein in hepatocellular carcinoma: both or neither?

BACKGROUND:The clinical usefulness of α-fetoprotein (AFP) in hepatocellular carcinoma (HCC) management is debatable.OBJECTIVES:To assess, in a large multi-centric survey, diagnostic and prognostic reliability of AFP, predictive factors, and any correlation with the tumor immunophenotype.METHODS:A total of 1,158 patients with HCC were analyzed with reference to serum AFP levels at diagnosis. We evaluated: HCC grading, histotype, and size; Okuda, tumor–nodes–metastases (TNM), and Child-Pugh scores; liver function, symptoms, presence of metastases or portal thrombosis, etiology, survival, and treatment. In 66 patients with histological diagnosis, the pathologists evaluated p53 overexpression, MIB 1 labeling index, BCL-2 positive cells (index of apoptosis), and CD44 (adhesion molecule) positivity.RESULTS:Patients were divided into three AFP groups: normal (<20 ng/mL) [46%], elevated (21–400 ng/mL) [36%], and diagnostic (>400 ng/mL) [18%]. Statistical correlations were significant for: weight loss (P = 0.0056), pain (P = 0.0025), Child-Pugh score (P = 0.001), tumor size, Okudas and TNM stages, metastases, thrombosis, type of treatment (all p < 0.0001), and female sex (p < 0.004). AFP correlated with survival overall, in patients untreated, transplanted, or undergoing locoregional treatments; but not in those surgically treated. In the discriminant analysis, the related variables were size, female sex, Child-Pugh score, TNM staging (steps 1–4). When using the receiver operating characteristic curve, the prognostic reliability of AFP was limited with area under the curve of 0.59. Finally, patients with low expression of BCL2 had high AFP levels (p < 0.05). AFP positively correlated with Edmonson score (p < 0.0001).CONCLUSION:The evaluation of this large series of HCC patients allowed us to: confirm the low sensitivity (54%) of AFP in the diagnosis of HCC and its prognostic value, albeit limited, being tumor size, female sex (intriguingly enough), Child-Pugh score, and TNM staging independent predictors.

Prevalence, characteristics and severity of non-alcoholic fatty liver disease in patients with chronic plaque psoriasis

BACKGROUND/AIMS The association between NAFLD and psoriasis has never been explored in prospective epidemiological studies. The aim of this 2-phase study was to study the clinical features of NAFLD in patients with psoriasis. METHODS Phase 1: Investigation of prevalence and characteristics of NAFLD in an unselected cohort of 142 adult Italian outpatients with psoriasis vulgaris. Phase 2: Comparison of the psoriasis cohort subgroup with NAFLD and an age- and body mass index-matched retrospective cohort of 125 non-psoriasis patients with biopsy proven NAFLD. RESULTS Based on histories, laboratory tests, and ultrasound studies, 84 (59.2%) received clinical diagnosis of NAFLD; 30 had factors potentially associated with liver disease other than NAFLD (e.g., viral hepatitis, significant ethanol, methotrexate use); and 28 (19.7%) had normal livers. Comparison of the normal-liver and NAFLD subgroups revealed that NAFLD in psoriasis patients (Ps-NAFLD) was significantly correlated with metabolic syndrome (p<0.05); obesity (p=0.043); hypercholesterolemia (p=0.029); hypertriglyceridemia (p<0.001); AST/ALT ratio >1 (p=0.019), and psoriatic arthritis (PsA) (p=0.036). The association with PsA remained significant after logistic regression analysis (OR=3.94 [CI, 1.07-14.46]). Compared with the retrospective non-psoriatic NAFLD cohort (controls), Ps-NAFLD patients (cases) were likely to have severe NAFLD reflected by non-invasive NAFLD Fibrosis Scores and AST/ALT >1. CONCLUSIONS NAFLD is highly prevalent among psoriasis patients, where it is closely associated with obesity (overall and abdominal), metabolic syndrome, and PsA, and more likely to cause severe liver fibrosis (compared with nonPs-NAFLD). Routine work-up for NAFLD may be warranted in patients with psoriasis, especially when potentially hepatotoxic drug therapy is being considered.

Surveillance for hepatocellular carcinoma in elderly italian patients with cirrhosis: Effects on cancer staging and patient survival

OBJECTIVES:Surveillance of cirrhotic individuals for early detection of HCC, based on ultrasonography (US) and α1-fetoprotein (AFP) determination, is a recommended practice currently applied also to elderly patients. However, several age-related factors may jeopardize the results of surveillance in these patients. Aim of the study was to evaluate the benefit of surveillance for HCC in elderly individuals.METHODS:Multicenter retrospective study on 1,277 consecutive patients with HCC. The inclusion criteria were: underlying chronic liver disease, description of cancer stage, and modalities of its diagnosis. Among the 1,037 patients fulfilling these criteria, 363 aged ≥70 yr were considered.RESULTS:The tumor was detected during surveillance, based on US and AFP performed every 6–12 months, in 158 individuals (group 1), incidentally in 138 (group 2) and because of symptoms in 67 (group 3). Surveillance reduced the risk of dealing with an advanced cancer (odds ratio (95% Confidence Interval): 0.18 (0.09–0.37) vs group 3, and 0.29 (0.17–0.49) vs group 2). The frequency of effective treatments decreased from group 1 to group 3 (73%, 57%, and 31%, respectively). The main cause of death was HCC progression. The survival corrected for the lead time of group 1 (median: 24 months) was significantly better than the crude survival of group 3 (7 months; p= 0.003) and barely better than that of group 2 (21 months). The latter also showed a better prognosis with respect to group 3 (p= 0.018).CONCLUSIONS:Surveillance for HCC improves the survival of elderly cirrhotic patients by expanding the percentage of cancers amenable to effective treatments.

Barcelona Clinic Liver Cancer staging and transplant survival benefit for patients with hepatocellular carcinoma: a multicentre, cohort study

BACKGROUND Allocation of deceased-donor livers to patients with chronic liver failure is improved by prioritising patients by 5-year liver transplantation survival benefit. The Barcelona Clinic Liver Cancer (BCLC) staging has been proposed as the standard means to assess for prognosis of patients with hepatocellular carcinoma. We aimed to create a prediction model linking the BCLC stage of patients with hepatocellular carcinoma to their 5-year liver transplant benefit. METHODS A large cohort of consecutive patients with hepatocellular carcinoma (n=1328) from the ITA.LI.CA database (n=2951) were judged as potentially eligible for liver transplantation according to the following criteria: absence of macroscopic vascular invasion or metastases, age 70 years or younger, and absence of relevant extra-hepatic comorbidities. To assess the correlation between BCLC staging and non-liver transplantation survival, we did Cox univariate and multivariate analyses including the following covariates: BCLC stage, year of diagnosis, age, sex, cause of cirrhosis, model for end-stage liver disease score, α-fetoprotein concentrations, and treatment. Liver-transplantation survival benefit for patients was calculated, using Monte Carlo simulation analysis, as the patients 5-year life expectancy with liver transplantation (estimated by the Metroticket model) minus the 5-year life expectancy without liver transplantation according to BCLC stage. FINDINGS 83 (6%) of 1328 patients had BCLC 0 stage disease, 614 (46%) had BCLC A, 500 (38%) had BCLC B-C, and 131 (10%) had BCLC D. In the Cox non-liver transplantation survival multivariate model, hazard ratios associated with increasing BCLC stages were 1.530 (95% CI 1.107-2.116) for BCLC A versus BCLC 0, 1.572 (1.350-1.830) for BCLC B-C versus BCLC A, and 1.470 (1.164-1.856) for BCLC D versus BCLC B-C. Results of the Monte Carlo simulation analysis confirmed the significant effect of BCLC classification on transplant benefit; in the adjusted model, a median 5-year transplant benefit of 11.19 months (IQR 10.73-11.67) for BCLC 0, 13.49 months (11.51-15.57) for BCLC A, 17.36 months (15.06-19.28) for BCLC B-C, and 28.46 months (26.38-30.34) for BCLC D. INTERPRETATION Liver transplantation could result in survival benefit for patients with hepatocellular carcinoma and advanced liver cirrhosis (BCLC stage D) and in those with intermediate tumours (BCLC stages B-C), regardless of the nodule number-size criteria (ie, Milan criteria), provided that macroscopic vascular invasion and extra-hepatic disease are absent. FUNDING None.

Treatments for hepatocellular carcinoma in elderly patients are as effective as in younger patients: a 20-year multicentre experience

Objectives The number of elderly patients diagnosed with hepatocellular carcinoma (HCC) is expected to increase. We compared the presenting features and outcome of HCC in elderly (≥70 years) and younger patients (<70 years). Design Multicentre retrospective cohort study and nested case–control study. Patients 614 elderly and 1104 younger patients from the ITA.LI.CA database, including 1834 HCC cases consecutively diagnosed from January 1987 to December 2004. Both groups were stratified according to treatment: hepatic resection, percutaneous procedures, transarterial chemoembolisation (TACE). Survival was assessed in the whole population and in each treatment subgroup. Age, sex, aetiology, cirrhosis, comorbidities and cancer stage (CLIP score) were tested as predictors of survival. In each subgroup, differences in patient survival were also assessed after adjustment and matching by propensity score. Results Ageing was associated with a higher prevalence of comorbidities, better liver function and CLIP score. Regardless of age, two-thirds of patients underwent radical treatments or TACE. Elderly patients underwent more ablative procedures and fewer resections or TACE sessions. The survival of elderly and younger patients was comparable in each treatment subset, and was predicted by CLIP score. This result was confirmed by the propensity analysis. Conclusions The overall applicability of radical or effective HCC treatments was unaffected by old age. However, treatment distribution differed, elderly individuals being more frequently treated with percutaneous procedures and less frequently with resection or TACE. Survival was unaffected by age and primarily predicted by cancer stage, assessed by the CLIP system, both in the overall population and in treatment subgroups.

Effect of the Etiology of Viral Cirrhosis on the Survival of Patients with Hepatocellular Carcinoma

OBJECTIVES:The aim of this study was to assess whether hepatocellular carcinoma occurring in the setting of hepatitis B or C virus infection has different prognosis.METHODS:We performed a multicentric case-control study comparing 102 pairs of patients affected by hepatitis B virus- or hepatitis C virus-related hepatocellular carcinoma. Patients were matched for sex (male/female: 84/18 pairs), age, center, and period of enrollment, underlying chronic liver disease (cirrhosis/chronic hepatitis: 97/5 pairs), Child-Pugh class (A/B/C: 70/25/7 pairs), hepatocellular carcinoma stage (nonadvanced/advanced: 50/52 pairs) and, when possible, modality of cancer diagnosis (75 pairs: 47 during and 28 outside surveillance).RESULTS:In the whole population, patients with hepatitis B tended to have a poor prognosis than those with hepatitis C (P = 0.160), and this difference became statistically significant among the patients with an advanced hepatocellular carcinoma (P = 0.025). Etiology, Child-Pugh class, gross pathology, and alpha-fetoprotein were the significant independent prognostic factors in the whole population. The distribution of these prognostic factors did not differ between patients with hepatitis B or hepatitis C, both in the whole population and in the subgroup of advanced hepatocellular carcinomas.CONCLUSION:Hepatitis B virus-related hepatocellular carcinomas have a greater aggressiveness than hepatitis C virus-related tumors, which becomes clinically manifest once they have reached an advanced stage.

Surveillance for Early Diagnosis of Hepatocellular Carcinoma: Is It Effective in Intermediate/Advanced Cirrhosis?

OBJECTIVES:Surveillance of cirrhotic patients for early diagnosis of hepatocellular carcinoma (HCC), based on ultrasonography and alpha-fetoprotein (AFP) measurement, is widely used. Its effectiveness depends on liver function, which affects the feasibility of treatments and cirrhosis-related mortality. We assessed whether patients with intermediate/advanced cirrhosis benefit from surveillance.METHODS:We selected 468 Child-Pugh class B and 140 class C patients from the ITA.LI.CA database, including 1,834 HCC patients diagnosed from January 1987 to December 2004. HCC was detected in 252 patients during surveillance (semiannual 172, annual 80 patients; group 1) and in 356 patients outside surveillance (group 2). Survival of surveyed patients was corrected for the estimated lead time.RESULTS:Child-Pugh class B: cancer stage (P < 0.001) and treatment distribution (P < 0.001) were better in group 1 than in group 2. The median (95% CI) survivals were 17.1 (13.5–20.6) versus 12.0 (9.4–14.6) months and the survival rates at 1, 3, and 5 yr were 60.4% versus 49.2%, 26.1% versus 16.1%, and 10.7% versus 4.3%, respectively (P = 0.022). AFP, gross pathology, and treatment of HCC were independent prognostic factors. Child-Pugh class C: cancer stage (P = 0.001) and treatment distribution (P = 0.021) were better in group 1 than in group 2. Nonetheless, median survival did not differ: 7.1 (2.1–12.1) versus 6.0 (4.1–7.9) months (P = 0.740).CONCLUSIONS:These results suggest surveillance be offered to class B patients and maintained for class A patients who migrate to the subsequent class. Surveillance becomes pointless in class C patients probably because the poor liver function adversely affects the overall mortality and HCC treatments.

Rectal epithelial cell proliferation patterns as predictors of adenomatous colorectal polyp recurrence.

To determine whether proliferative patterns in flat rectal mucosal samples can predict the recurrence of adenomatous colorectal polyps, after polypectomy, biopsy specimens from normal looking rectal mucosa were obtained at endoscopy from 55 patients diagnosed for the first time as having adenomatous colorectal polyps. Epithelial cell proliferation was assessed in biopsy specimens through 3H-thymidine autoradiography. After polypectomy, patients were followed for 24 months and underwent complete colonoscopy every 6 months to detect and remove any metachronous lesions. In 40 patients second biopsy specimens were taken during one of the follow up colonoscopies to evaluate the stability of proliferative indices over time. The ratio of labelled (S phase) to total cells (labelling index) for the entire crypt, as well as ratios for each of the five equal compartments into which the crypt had been divided longitudinally, was calculated for each patient. Mean labelling indices for upper crypt compartments 3 and 4 + 5 in the 22 patients in whom polyps recurred were significantly higher (respectively p < 0.05 and p < 0.01) than those of the 33 without recurrence suggesting that an upward shift of the crypts replicative compartment is associated with polyp recurrence. Labelling indices remained essentially unchanged in those patients who underwent biopsy twice. Reproducible kinetic parameters such as these might be useful in planning follow up of patients with adenomatous polyps after polypectomy.

A controlled study comparing cimetidine treatment to an intensive antacid regimen in the therapy of uncomplicated duodenal ulcer.

The authors report the results of a randomized study in which comparison was made between two different kinds of treatment in patients affected by uncomplicated duodenal ulcer endoscopically diagnosed. The first group was treated with 1 g of cimetidine per day, during a period of four weeks (200 mg three times a day and 400 mg at bedtime); the second with a liquid Al−Mg antacid compound, 210 ml/day (30 ml, 1 and 3 hr after meals and 30 ml before bedtime) for four weeks. Fifty-one patients were studied, 27 treated with cimetidine, 24 with antacids. At the end of the four-week period, 21 patients (77.7%) in the cimetidine group and 18 patients (75%) in the antacid group were completely healed. Benign side effects were remarked in both types of treatment, none of which made it necessary to suspend treatment. No significant variation of the basal and peak acid output before and after each kind of treatment was observed, while a slight but significant increase in fasting serum gastrin concentration was noted after treatment in the antacid group.