Hepatocellular carcinoma recurrence in patients with curative resection or ablation: impact of HCV eradication does not depend on the use of interferon.

BACKGROUND: In HCV-infected cirrhotic patients with successfully treated early hepatocellular carcinoma (HCC), the time to HCC recurrence and the effects of sustained viral eradication (SVR) by interferon (IFN)-based or IFN-free regimens on HCC recurrence remain unclear. AIM: To perform an indirect comparison of time to recurrence (TTR) in patients with successfully treated early HCC and active HCV infection with those of patients with SVR by IFN-based and by IFN-free regimens. METHODS: We evaluated 443 patients with HCV-related cirrhosis and Barcelona Clinic Liver Cancer Stage A/0 HCC who had a complete radiological response after curative resection or ablation. Active HCV infection was present in 328, selected from the Italian Liver Cancer group cohort; 58 patients had SVR achieved by IFN-free regimens after HCC cure, and 57 patients had SVR achieved by IFN-based regimens after HCC cure. Individual data of patients in the last two groups were extracted from available publications. RESULTS: TTR by Kaplan-Meier curve was significantly lower in patients with active HCV infection compared with those with SVR both by IFN-free (P = 0.02) and by IFN-based (P < 0.001) treatments. TTR was similar in patients with SVR by IFN-free or by IFN-based (P = 0.49) strategies. CONCLUSION: In HCV-infected, successfully treated patients with early HCC, SVR obtained by IFN-based or IFN-free regimens significantly reduce tumour recurrence without differences related to the anti-viral strategy used.

Years of life that could be saved from prevention of hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) causes premature death and loss of life expectancy worldwide. Its primary and secondary prevention can result in a significant number of years of life saved. AIM: To assess how many years of life are lost after HCC diagnosis. METHODS: Data from 5346 patients with first HCC diagnosis were used to estimate lifespan and number of years of life lost after tumour onset, using a semi-parametric extrapolation having as reference an age-, sex- and year-of-onset-matched population derived from national life tables. RESULTS: Between 1986 and 2014, HCC lead to an average of 11.5 years-of-life lost for each patient. The youngest age-quartile group (18-61 years) had the highest number of years-of-life lost, representing approximately 41% of the overall benefit obtainable from prevention. Advancements in HCC management have progressively reduced the number of years-of-life lost from 12.6 years in 1986-1999, to 10.7 in 2000-2006 and 7.4 years in 2007-2014. Currently, an HCC diagnosis when a single tumour <2 cm results in 3.7 years-of-life lost while the diagnosis when a single tumour ≥ 2 cm or 2/3 nodules still within the Milan criteria, results in 5.0 years-of-life lost, representing the loss of only approximately 5.5% and 7.2%, respectively, of the entire lifespan from birth. CONCLUSIONS: Hepatocellular carcinoma occurrence results in the loss of a considerable number of years-of-life, especially for younger patients. In recent years, the increased possibility of effectively treating this tumour has improved life expectancy, thus reducing years-of-life lost.

Comparison between alcohol- and hepatitis C virus-related hepatocellular carcinoma: clinical presentation, treatment and outcome.

BACKGROUND: Hepatitis C virus (HCV) and alcohol abuse are the main risk factors for hepatocellular carcinoma (HCC) in Western countries. AIM: To investigate the role of alcoholic aetiology on clinical presentation, treatment and outcome of HCC as well as on each Barcelona Clinic Liver Cancer (BCLC) stage, as compared to HCV-related HCCs. METHODS: A total of 1642 HCV and 573 alcoholic patients from the Italian Liver Cancer (ITA.LI.CA) database, diagnosed with HCC between January 2000 and December 2012 were compared for age, gender, type of diagnosis, tumour burden, portal vein thrombosis (PVT), oesophageal varices, liver function tests, alpha-fetoprotein, BCLC, treatment and survival. Aetiology was tested as predictor of survival in multivariate Cox regression models and according to HCC stages. RESULTS: Cirrhosis was present in 96% of cases in both groups. Alcoholic patients were younger, more likely male, with HCC diagnosed outside surveillance, in intermediate/terminal BCLC stage and had worse liver function. After adjustment for the lead-time, median (95% CI) overall survival (OS) was 27.4 months (21.5-33.2) in alcoholic and 33.6 months (30.7-36.5) in HCV patients (P = 0.021). The prognostic role of aetiology disappeared when survival was assessed in each BCLC stage and in the Cox regression multivariate models. CONCLUSIONS: Alcoholic aetiology affects survival of HCC patients through its negative effects on secondary prevention and cancer presentation but not through a greater cancer aggressiveness or worse treatment result. In fact, survival adjusted for confounding factors was similar in alcoholic and HCV patients.

Impact of evidence-based medicine on the treatment of patients with unresectable hepatocellular carcinoma.

BACKGROUND: A randomized controlled trial performed by the Barcelona Clinic Liver Cancer (BCLC) published in 2002 demonstrated that transcatheter arterial chemoembolisation (TACE) is an effective treatment for well-selected patients with unresectable hepatocellular carcinoma (HCC). AIM: To access whether this information has modified the use of TACE in clinical practice. METHODS: From 2042 HCC patients included in the Italian Liver Cancer database, we selected 336 cases diagnosed over two 4-year periods (1999-2002, n = 161 and 2003-2006, n = 175), fulfilling the inclusion criteria of the BCLC study. These groups were compared for TACE application rate, patient characteristics and survival. RESULTS: Patients undergoing TACE increased in the 2003-2006 period (from 62% to 73%, P = 0.035), with an increase in of Child-Pugh class A (from 64% to 77%, P = 0.048) and advanced HCC patients (from 54% to 69%, P = 0.041). In the 1999-2002 period, there was no significant difference in survival between TACE-treated and untreated patients, while in the 2003-2006 period, TACE-treated patients survived longer (P < 0.0001). CONCLUSIONS: Following the publication of studies providing evidence of a survival benefit of TACE in selected patients with unresectable HCC, significantly more patients with well-compensated cirrhosis underwent TACE within this very homogenous population, leading to an increased survival despite a more advanced tumour stage.

Contrast-enhanced Doppler ultrasonography in the diagnosis of hepatocellular carcinoma and premalignant lesions in patients with cirrhosis.

Hepatocellular carcinogenesis in cirrhosis is a multistage process that includes large regenerative nodules, dysplastic nodules, and hepatocarcinoma. The aim of this study was to establish whether contrast-enhanced Doppler ultrasonography (US) is able to distinguish between early hepatocellular carcinoma (HCC) and small nonmalignant nodules in cirrhosis. Between January 1998 and December 1999, 500 cirrhotic patients with no previous history of HCC or evidence of hepatic focal lesions were enrolled and prospectively followed-up with US every 6 months until December 2000. Sixty-one patients developed focal lesions, 12 multifocal, and 49 monofocal. Biopsy of focal lesions, contrast-enhanced Doppler US, and spiral computed tomography (CT) were performed in 41 consecutive patients with small (<3 cm) monofocal lesions. Twenty nodules were diagnosed as HCC and 21 as nonmalignant (14 large regenerative nodules, 3 low-grade, and 4 high-grade dysplastic nodules) by liver biopsy. Intratumoral arterial blood flow was detected in 19 of 20 (95%) HCC and 6 of 21 (28%) nonmalignant nodules by contrast-enhanced Doppler US (P<.0001). The mean peak resistance and pulsatility indices were 0.82 +/- 0.09 and 1.56 +/- 0.2 in HCC and 0.62 +/- 0.08 and 0.82 +/- 0.08 in dysplastic lesions (P =.002 and.0001), respectively. Spiral CT revealed arterial perfusion in 19 of 20 HCC and in 4 of 21 nonmalignant nodules (high-grade dysplastic nodules). Four of the apparently false-positive nodules at enhanced Doppler US were high-grade dysplastic nodules and 2 evolved to HCC during follow-up. In conclusion, contrast-enhanced Doppler US is a noninvasive, very sensitive technique in differentiating malignant and premalignant lesions from nonmalignant focal lesions in the liver.

[The topical therapy of ulcerative colitis. A multicenter study with beclomethasone dipropionate foam]. / Terapia topica della colite ulcerosa. Studio multicentrico con beclometasone dipropionato schiuma.

BACKGROUND AND AIMS: The use of steroids was recently extended to the various forms of ulcerative rectocolitis by the introduction of topical formulations, above all steroids with an hepatic "first pass" devoid of systemic interference. The aim of this study was to evaluate the efficacy and tolerability of Beclomethasone dipropionate (BDP) in a rectal foam formulation, in the treatment of patients suffering from ulcerative colitis. METHODS: The experimental protocol took the form of a 28-day open prospective trial using BDP rectal foam in patients suffering from ulcerative colitis. Endoscopic, histological, clinical and tolerability parameters were evaluated. The centres taking part in the trial collected data for 60 cases out of a total of 80 patients enrolled in the study, of both sexes and aged between 20 and 81 years old, suffering from proctosigmoiditis (46.7%) and ulcerative rectocolitis (53.3%). RESULTS: Endoscopic parameters showed an improvement after 28 days of treatment in 74.5% of patients; a clinical improvement was achieved in 65.2% of cases. In percentage terms of the mean value of all the improved parameters, histological parameters were altered in 56.9% of patients. With regard to tolerability 82% of patients judged the treatment to be good/excellent. CONCLUSIONS: In conclusion, in line with recent reports regarding other pharmaceutical forms of BDP, including the use of rectal foam, these data confirm the efficacy and tolerability of this molecule and emphasise the validity of its use in the treatment of ulcerative colitis and proctosigmoiditis.

[Topical beclomethasone dipropionate (BDP) in intestinal inflammatory diseases: the results of a multicentre trial]. / Beclometasone dipropionato topico nelle malattie infiammatorie intestinali: risultati di un'indagine multicentrica.

The authors assessed the efficacy and tolerability of BDP in an open protocol using rectal enemas and suppositories and in a double-blind protocol vs mesalazine using rectal enemas. A total of 47 patients suffering from ulcerous rectocolitis were enrolled in the study and treated for 42 days while undergoing endoscopic, histologic and clinical controls. In conclusion, the authors affirm that BDP may represent a useful new therapeutic instrument in the treatment of slight to moderately severe forms of inflammatory intestinal disease.

Hepatocyte proliferation rate is a powerful parameter for predicting hepatocellular carcinoma development in liver cirrhosis.

AIMS: A sound predictive test is lacking for the identification of cirrhotic patients at high risk of developing hepatocellular carcinoma. The present study evaluates the measurement of hepatocyte expression of silver stained nucleolar organiser region (AgNOR) proteins as a risk factor for the development of hepatocellular carcinoma in cirrhosis. METHODS: Liver biopsies from 176 cirrhotic patients included in a follow up surveillance programme for hepatocellular carcinoma development were evaluated prospectively for hepatocyte AgNOR protein quantity. The follow up programme consisted of clinical and biochemical assessment every three months, and ultrasound scanning and serum alpha-fetoprotein (alpha FP) assessment every six months. Histological sections from the needle biopsies performed at enrollment were stained selectively for AgNOR proteins and the percentage of hepatocytes with an AgNOR protein area > or = 7 micron 2, indicative of a proliferative state (AgNOR proliferation index (AgNOR-PI)), was measured. RESULTS: During the mean (SD) follow up time of 65.5 (36.29) months (range, 12-143; median, 67), hepatocellular carcinoma was diagnosed in 48 of 176 patients (27.3%). The AgNOR-PI of the whole series ranged from 0% to 5% (median, 0.9%), and was significantly higher in patients with liver cell dysplasia and hepatitis B surface antigen (HBsAg) positivity (p < 0.0001 and p = 0.0002, respectively). The 176 patients were divided into two groups according to their AgNOR-PI scores; a cut off value of 2.5% defined by the receiver operating characteristic curve and the Youden index was used. Forty two patients were included in the high AgNOR-PI (< 2.5%) group, and 134 patients the low AgNOR-PI (< 2.5%) group. In the high AgNOR-PI group, 25 of 42 patients developed hepatocellular carcinoma, in contrast to only 23 of 134 patients (17.2%) in the group with a low AgNOR-PI (p < 0.0001). Hepatocellular carcinoma development was also significantly more frequent in patients with liver cell dysplasia and HBsAg positivity. Multivariate analysis using AgNOR-PI, liver cell dysplasia, HBsAg positivity, and hepatitis C virus (HCV) infection as covariates demonstrated that the AgNOR-PI parameter was the only significant predictor of hepatocellular carcinoma development. CONCLUSIONS: These results demonstrate that a high hepatocyte proliferation rate is a major risk factor for hepatocellular carcinoma development in the cirrhotic liver. Therefore, the evaluation of the hepatocyte proliferation rate is very important to identify patients requiring a more strict follow up programme for early diagnosis of hepatocellular carcinoma.

Ultrasonography-detected macroregenerative nodules in cirrhosis: a prospective study.

BACKGROUND & AIMS: The preneoplastic role of macroregenerative nodules in cirrhosis is still debated. Thirty-two consecutive ultrasonography-detected macronodules were followed up to evaluate whether and which lesions are the actual precursors of hepatocellular carcinoma, if histology can identify preneoplastic macronodules, and whether additional parameters are related to neoplastic evolution. METHODS: Macroregenerative nodule classification was based on recently proposed histological criteria. Extranodular liver cell dysplasia was also evaluated. The follow-up included ultrasonography and serum alpha-fetoprotein level determination every 3 months. RESULTS: Twenty-two macronodules (78%) were classified as typical and 7 (22%) as atypical. Twenty-one were hypoechoic, and 11 were hyperechoic. Extranodular dysplasia was more frequently associated with atypical than typical macronodules (5 of 7 vs. 6 of 22). After 28 +/- 15 months, neoplastic transformation occurred in 8 macronodules (25%) and was more frequent in atypical than in typical (5 of 7 vs. 3 of 25), in hyperechoic than in hypoechoic (5 of 11 vs. 3 of 21), and in extranodular dysplasia-associated macronodules than in extranodular dysplasia-free macronodules (5 of 11 vs. 2 of 18). Five hepatocellular carcinomas appeared outside the original macronodule. CONCLUSIONS: Atypical macroregenerative nodules can be considered precursors of hepatocellular carcinoma. Histology is useful in identifying preneoplastic macronodules, and hyperechoic pattern and extranodular dysplasia are additional risk factors for neoplastic transformation.

Hepatitis C virus genotypes and risk of hepatocellular carcinoma in cirrhosis: a prospective study.

A prospective study was performed to establish whether infection with specific hepatitis C virus (HCV) genotypes was associated with an increased risk of development of hepatocellular carcinoma (HCC) in cirrhosis. A cohort of 163 consecutive hepatitis C virus antibody (anti-HCV)-positive cirrhotic patients was prospectively evaluated for the development of HCC at 6-month intervals by ultrasound (US) scan and alpha-fetoprotein (AFP) concentration. HCV genotypes were determined according to Okamoto. Risk factors associated with cancer development were analyzed by univariate and multivariate statistics. At enrollment, 101 patients (62%) were infected with type 1b, 48 (29.5%) were infected with type 2a/c, 2 (1.2%) were infected with type 3a, 1 (0.6%) was infected with type 1a, 3 (1.8%) had a mixed-type infection, and, in 8 patients (4.9%), genotype could not be assigned. After a 5- to 7-year follow-up (median, 68 months), HCC developed in 22 of the patients, 19 infected with type 1b and 3 with type 2a/c (P < .005). Moreover, HCC developed more frequently in males (P < .01), patients with excessive alcohol intake (P < .01), those over 60 years of age (P < .02), and in patients who did not receive interferon treatment (P < .02). Multivariate analysis showed that type 1b was the most important risk factor associated with tumor development (odds ratio 6.14, 1.77-21.37 95% confidence interval). Other independent risk factors were older age and male sex. Cirrhotic patients infected with HCV type 1b carry a significantly higher risk of developing HCC than patients infected by other HCV types. The latter may require a less intensive clinical surveillance for the early detection of neoplasia.

A simple method for ascites concentration and reinfusion.

A rapid and simple method for ascites concentration and reinfusion was utilized to treat 103 episodes of tense ascites in 57 patients (38 men and 19 women, mean age 63 +/- 11 years). After a bedside total paracentesis, 6.06 +/- 2.87 liters of ascites were separately ultrafiltrated using a mechanical device during a mean interval of 134 +/- 88 min, and 430 +/- 368 ml of concentrate containing 39 +/- 42 g of albumin were restituted at bedside either intravenously (44 cases) or intraperitoneally (59 cases). Ultrafiltration was successfully and easily completed in all cases. Ascites concentration and reinfusion either intravenously or intraperitoneally did not adversely modify hemodynamic or renal parameters except for a transient decrease in mean arterial pressure (P < 0.05). Transitory hyponatremia and renal failure occurred in two patients. A transient decrease in platelet count and serum fibrinogen levels (P < 0.05) and pyrexia (12%) were observed only in patients reinfused intravenously. In conclusion, this new method for ascites concentration and reinfusion was effective, safe, and, with respect to traditional methods, simpler, faster and more comfortable. Therefore it is proposed for the routine management of tense ascites.

Liver cell dysplasia is a major risk factor for hepatocellular carcinoma in cirrhosis: a prospective study.

BACKGROUND/AIMS: In humans, the role of liver cell dysplasia as a preneoplastic lesion is still debated. A prospective, long-term, multicenter study was performed to establish whether liver cell dysplasia in cirrhosis is associated with an increased risk for hepatocellular carcinoma (HCC). METHODS: A cohort of 307 consecutive patients in whom liver cirrhosis was diagnosed by histology was investigated for development of HCC at 6-month intervals by ultrasonography and determination of alpha-fetoprotein levels. RESULTS: At enrollment, liver cell dysplasia was found in 75 patients (24%) and in 53% (P < 0.01) of those positive for hepatitis B surface antigen (HBsAg). After a mean follow-up of 46 months, HCC was detected in 45 cases, and it was significantly more frequent in patients with liver cell dysplasia (P < 0.01) and HBsAg-serum positivity (P < 0.01). Multivariate analysis showed that liver cell dysplasia was the most important risk factor correlated with HCC development. HBsAg positivity and age over 60 years were also independent risk factors for HCC. CONCLUSIONS: These results indicate that liver cell dysplasia is a major risk factor for HCC, and it should be looked for carefully by pathologists in liver biopsy specimens to identify patients requiring more intensive observation.

The evaluation of fine-needle procedures for the diagnosis of focal liver lesions in cirrhosis.

To evaluate the diagnostic accuracy of fine-needle aspiration, fine-needle biopsy and extranodular fine needle biopsy in identifying focal lesions in cirrhosis, 100 consecutive ultrasound detected nodules were studied. Seventy-three were hepatocellular carcinomas (31 were well-differentiated hepatocellular carcinomas), 23 were benign lesions (one angioma and 22 large regenerative nodules) and two were metastases. The lesions were divided according to maximum diameter as follows: < 20 mm in 36, > 20 < 30 mm in 27, and > 30 mm in 33. In four cases there were multiple nodules of different sizes. Fine needle aspiration, intranodular fine needle biopsy and extranodular fine needle biopsy were obtained in each lesion. The sensitivity, specificity and diagnostic accuracy of each procedure were evaluated separately by three independent pathologists. Seven fine needle aspirations and three intranodular fine needle biopsies were considered inadequate. The highest diagnostic accuracy (96%) was obtained by the combined analysis of fine needle aspiration plus intranodular and extranodular fine needle biopsy, and this superiority was confirmed in each group of lesions. Fine needle aspiration showed a lower accuracy (48%) than intranodular fine needle biopsy (67%). When fine needle aspiration and intranodular fine needle biopsy were evaluated together, an accuracy of 91% was found. Intralesional fine needle biopsy plus extranodular fine needle biopsy analysis gave an accuracy of 78% and, particularly relevant, a specificity of 95%. These results indicate that, in patients with cirrhosis with nodular lesions < 30 mm, fine needle biopsy is superior to fine needle aspiration and that the combined evaluation of fine needle aspiration plus intranodular and extranodular fine needle biopsy is the most accurate approach.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of brodimoprim in special populations.

The pharmacokinetics of brodimoprim have been investigated after single oral dose administration in children, in healthy adults, and elderly subjects, as well as in patients with mild renal failure (creatinine clearance 40-70 mL/min) or liver insufficiency (Child-Pugh grade A or B). The plasma half-life increased moderately with age. The percent brodimoprim bound to plasma proteins, 93%, was identical in renally impaired patients and in healthy controls but decreased to 90% or less in liver insufficiency. The apparent distribution volume and clearance were much higher in children than in adults. Urinary excretion of unchanged brodimoprim amounted to 5-10% of the administered dose. The steady-state pharmacokinetics of brodimoprim has also been investigated in elderly subjects (400 mg loading dose followed by 7 days 200 mg once daily). There was no significant modification of elimination half-life and of clearance upon repeated dosing. Renal excretion of brodimoprim and hydroxy metabolite at steady-state reached 9% and 14% per 24 hours in the elderly, compared to 9% and 24% in young adults. The accumulation factor reached 3.3 +/- 0.4 and 2.7 +/- 0.3 respectively.

[A case of intestinal schistosomiasis with hepatic involvement: interdisciplinary diagnostic approach and peculiarity of the echographic and histologic findings]. / Un caso di schistosomiasi intestinale con interessamento epatico: approccio diagnostico interdisciplinare e peculiarità dei reperti ecografico e istologico.

We report a case of intestinal schistosomiasis; secondary hepatic involvement is particularly described, with a very distinctive ecographic feature of portal hypertension and a bioptic picture stressing a granulomatous periportal inflammation. In the work we emphasize the importance of a multidisciplinary approach (physicians working in the fields of internal medicine, infectious disease, gastrointestinal diseases, radiologist, pathologist) in the course of diagnostic investigation. Finally, we confirm the effectiveness of praziquantel against Schistosoma mansoni.

Thyroid function tests in chronic liver disease: evidence for multiple abnormalities despite clinical euthyroidism.

To further evaluate thyroid function in patients with liver disease, we have measured total and free T3 and T4, thyroxine binding globulin, basal and thyrotropin releasing hormone-stimulated thyrotropin and thyroglobulin antibodies in 33 patients with liver cirrhosis, in 22 with chronic hepatitis and in 30 healthy controls. All the patients but one were clinically euthyroid. T3, FT3, T3/thyroxine binding globulin and T4/thyroxine binding globulin ratios and thyrotropin after thyrotropin releasing hormone were significantly reduced, while FT4, thyroxine binding globulin and thyrotropin were significantly increased in liver cirrhosis. In chronic hepatitis group, FT3 and T3/thyroxine binding globulin ratio were significantly lower and thyroxine binding globulin and FT4 were higher than in healthy controls. The between patients comparison revealed a significantly lower T3, FT3, T3/thyroxine binding globulin and T4/thyroxine binding globulin ratios and delta thyrotropin in cirrhotics. Thyroglobulin antibodies were present at high titre only in two patients one of whom having evidence of Hashimoto's thyroiditis with subclinical hypothyroidism. The correlation coefficient between T4/thyroxine binding globulin ratio and FT4 were lower in patients than in controls. Furthermore an abnormal thyrotropin response to thyrotropin releasing hormone was shown in 10 cirrhotics and in four patients with chronic hepatitis. Serum T3 significantly correlated with serum bilirubin, albumin, and prothrombin time in both groups of patients. The present data confirm the existence of several abnormalities of thyroid function tests in patients with chronic liver disease, although showing that euthyroidism is almost always maintained, probably as a result of low-normal FT3 and high-normal FT4. Furthermore, T3 serum levels appear to parallel the severity of liver dysfunction.