A randomized trial of pegylated-interferon-alpha2a plus ribavirin with or without amantadine in the re-treatment of patients with chronic hepatitis C not responding to standard interferon and ribavirin.

BACKGROUND: There is yet no established treatment for chronic hepatitis C patients non-responder to standard interferon and ribavirin. AIM: To evaluate efficacy and safety of pegylated-interferon-alpha2a plus ribavirin with or without amantadine in such patients. METHODS: 161 non-responders to standard interferon and ribavirin were randomized into two groups: 81 patients (Group 1) were given weekly Peg-IFN-alpha2a 180 microg plus ribavirin 1,000-1,200 mg/daily for 12 months, 80 patients (Group 2) received weekly Peg-IFN-alpha2a 180 microg plus ribavirin 1,000-1,200 mg/daily and amantadine 200 mg/daily for 12 months. RESULTS: At the end of follow-up, HCV-RNA was negative in 29.6% of Group 1 and in 21.2% of Group 2 patients (P = 0.22). Patients with genotypes 1 and 4 responded better to bi-therapy (21.7%) than to triple therapy (17.3%, P = 0.5) while among patients with genotypes 2 and 3 there was a trend towards a higher sustained virological response rate when retreated with triple treatment (80% vs. 75%, P = 0.82). On multivariate analysis, genotype 1 or 4, high body mass index and >20% reduction of Peg-interferon were associated with the treatment failure. CONCLUSIONS: The addition of amantadine does not improve the overall SVR rate in non-responder patients retreated with Peg-IFN and ribavirin; however, about 30% of non-responders may achieve a sustained response, in particular patients with genotypes 2 and 3 show a high SVR (75%).

Phase III randomized study of fluorouracil, epirubicin, and cyclophosphamide v fluorouracil, doxorubicin, and cyclophosphamide in advanced breast cancer: an Italian multicentre trial.

From February 1983 to January 1985, 497 patients with advanced breast cancer were randomly allocated to receive either epirubicin or doxorubicin in the following combination chemotherapy regimen: fluorouracil (5-FU) 500 mg/m2 intravenous (IV) on days 1 and 8; epirubicin or doxorubicin 50 mg/m2 IV on day 1; cyclophosphamide 500 mg/m2 IV on day 1 (FEC or FAC). Cycles were repeated every 21 days until progression or to cumulative doses of 700 mg/m2 for epirubicin and 550 mg/m2 for doxorubicin. Dose reductions were applied according to the standard criteria. Activity was evaluated in 443 patients (222 in the FEC arm and 221 in the FAC arm). The two experimental groups were comparable in age, performance status, menopausal status, histology, previous treatments, and site of the disease. The overall response rate (complete response and partial response [CR + PR]) was not significantly different: 53.6% for FEC and 56.5% for FAC. The median time to progression was 273 days for FEC and 314 days for FAC; the median survival time was 591 and 613 days, respectively. Leukopenia, anemia, nausea, and vomiting were significantly lower in patients treated with FEC. As for cardiotoxicity, four cases of congestive heart failure (CHF) were recorded among patients treated with FAC while only one was observed in the FEC group. These results indicate that epirubicin in a combination chemotherapy regimen is as active as doxorubicin and is significantly less toxic.

Comparison between single morning and bedtime doses of 40 mg famotidine for the treatment of duodenal ulcer.

The aim of this study was to compare the duodenal ulcer healing effects of morning (08.00 hours) vs. single bedtime (22.00 hours) doses of 40 mg famotidine, bearing in mind that the known efficacy of bedtime doses of H2-antagonists is regarded as evidence of the predominance of nocturnal gastric acidity in the pathogenesis of duodenal ulcer. This randomized double-blind multicentre trial was conducted in a total of 127 patients with endoscopically proven active duodenal ulcer. Nine patients dropped out and thus 118 were included in the final analysis. The duration of treatment was 4 weeks, and this was extended to 8 weeks in patients whose ulcers failed to heal by week 4. The patients in the two treatment groups were well matched for age and sex. The therapeutic efficacy parameters were endoscopic healing of the ulcer lesion and disappearance of pain. Results were compared using the chi-square method. The 4- and 8-week (cumulative) ulcer healing rates in the patients treated with the morning dose of famotidine were 77.2% and 86%, respectively, compared with 78.6% and 91.8% in those who received the bedtime dose. The differences failed to prove statistically significant either at week 4 (P = 0.85) or at week 8 (P = 0.31). The percentages of patients with ulcer pain, evaluated weekly, were similar in the two treatment groups. The equivalent efficacy of the morning and bedtime famotidine regimens raises doubts concerning the predominance of nocturnal gastric acidity in the pathogenesis of duodenal ulcer.

Effects of different proportions of carbohydrates, polysaccharides/monosaccharides, and different fibers on the metabolic control in diabetic rats.

Recent findings have suggested that diets with a high level of carbohydrates may impair the metabolic control of diabetes mellitus in humans. Moreover, other investigations have indicated that if the simple sugar content is increased in order to attain a proportion of polysaccharides/monosaccharides equal to 1, then neither the blood glucose nor the lipidic response show any change. We have studied the effect of increasing carbohydrates in the diet (59% v 82%), while maintaining cereal fiber levels constant (30%) and replacing cereal fiber in high carbohydrate diets by guar gum (30%) and lentil-derived leguminous fiber (30%) on the metabolic control of streptozotocin-induced diabetic rats. A study with different diets was performed for 3 weeks. An increase of carbohydrates in the diet produces an increase in the HbA1 concentration (1.9% v 3.9%, P less than 0.01) and in serum triglyceride levels (98.75 +/- 22.09 mg/dL v 144.50 +/- 3.52 mg/dL, P less than 0.05). Total cholesterol and HDL-cholesterol levels remained unchanged. The increase does not occur if the cereal fiber is replaced by lentil-derived leguminous fiber. In a second experiment, we substituted 50% of the complex carbohydrates in diets with 80% carbohydrates by glucose. Blood glucose, triglycerides, and HbA1 levels rose significantly in the four groups of rats that received diets containing 50% carbohydrates in glucose form. In addition, a test meal was carried out on day 19, consisting of 2.5 g of food/kg of wt. The maximum increase in blood glucose and the area below the glucose curve response was also significantly higher in the four groups of rats who received glucose in their diet.(ABSTRACT TRUNCATED AT 250 WORDS)

Interferon retreatment in chronic hepatitis C: which patients to choose, and what schedule to use.

UNLABELLED: OBJECTIVE; To evaluate the results of a large cohort of non-responder or relapsing responder patients with chronic hepatitis C retreated with various schedules of interferon (IFN). METHODS: Our study included 276 patients (158 non-responders and 118 relapsing responders) who underwent IFN retreatments. Among the non-responder group, 158 patients underwent further courses of IFN. In particular, 108 patients underwent one course of IFN retreatment, 40 patients underwent two courses, eight patients underwent three courses, and two patients underwent four courses. Regarding the relapsing responder group, the 118 patients were retreated with the same dosage for varying periods. In particular, 50 patients were treated for 6 months, 43 patients for 12 months, and 25 for 24 months. Patients in the subgroups of IFN retreatment were homogeneous as far as age and gender distribution, as well as virological and histological characteristics, are concerned. Qualitative and quantitative HCV-RNA was evaluated at baseline, at the end of treatment and at the last check-up of follow-up. HCV genotype was determined on baseline serum samples. Alanine transaminase (ALT) levels were tested monthly. RESULTS: Long-term biochemical (normal ALT levels) and virological (HCV-RNA negative) response was obtained in 2.6% of non-responder retreated patients, and in 33.9% of relapsing responder retreated patients. Evaluation of response on the basis of the duration of treatment showed that 48%, 19% and 16% of relapsing responder patients retreated for 24, 12 and 6 months, respectively, obtained long-term biochemical and virological response. CONCLUSION: Non-responder patient retreatment is inefficient especially in cirrhotic and/or genotype 1 b patients. IFN retreatment is warranted in relapsing responder patients. In particular, 24-month therapy induces significant long-term biochemical and virological response.

Bacterial infection in patients with advanced cirrhosis: a multicentre prospective study.

AIMS: To evaluate the prevalence, incidence and clinical relevance of bacterial infection in predominantly non-alcoholic cirrhotic patients hospitalised for decompensation. PATIENTS/METHODS: A total of 405 consecutive admissions in 361 patients (249 males and 112 females; 66 Child-Pugh class B and 295 class C) were analysed. Blood, urine, ascitic and pleural fluid cultures were performed within the first 24 hours, during hospitalisation whenever infection was suspected, and again before discharge. RESULTS: Over a one year period, 150 (34%) bacterial infections (89 community- and 61 hospital-acquired) involving urinary tract (41%), ascites (23%), blood (21%) and respiratory tract (17%) were diagnosed. The prevalence of bacterial peritonitis was 12%. Infections were asymptomatic in 69 cases (46%) and 130 (87%) involved a single site. Enteric flora accounted for 62% of infections, Escherichia Coli being the most frequent pathogen (25%). Community-acquired infections were associated with more advanced liver disease (Child-Pugh mean score 10.2+/-2.1 versus 9.5+/-1.9, p<0.05), renal failure (p<0.05), and high white blood cell count (p<0.01). Hospital-acquired infections occurred more frequently in patients admitted for gastrointestinal bleeding (p<0.05). The in-hospital mortality was significantly higher in infected than in non-infected patients (15% versus 7%, p<0.05), and infection emerged as an independent variable affecting survival. Moreover bacterial infection accounted for a significantly prolonged hospital stay. CONCLUSIONS: Bacterial infection, regardless of the aetiology, is a severe complication of decompensated cirrhosis, and, although frequently asymptomatic, accounts for both longer hospital stay and increased mortality.

Patients with acute myocardial infarction in northern Italy are often infected by Helicobacter pylori.

BACKGROUND: The classical risk factors for acute myocardial infarction (AMI) fail to explain all the epidemiological variations of the disease. Among the new risk factors recently reported, several infectious agents appear to increase the risk of AMI. In particular, acute and chronic respiratory diseases due to Chlamydia pneumoniae, and Helicobacter pylori (H. pylori) infection seem to be strongly involved. The aim of this work is to determine the prevalence of H. pylori infection in a group of male patients with AMI, in a case-control study, where a group of blood donors matched for sex and age served as control. We searched for the classical risk factors in all patients. METHODS: We studied 212 consecutive male patients, aged 40-65 years, admitted for AMI at the Coronary Care Units at Hospitals in three towns of Northern Italy. H. pylori infection was assessed by the highly specific and sensitive 13C-urea breath test and by presence of antibodies (IgG) against H. pylori in circulation. Volunteer blood donors attending our Hospital Blood Bank served as controls. Among the patients we investigated the presence of hypertension, cholesterol and glucose levels in serum, fibrinogen in plasma and the smoking habit. RESULTS: H. pylori infection was present in 187/212 (88%) of the patients and in 183/310 (59%) of the control population (p < 0.0001). Classical risk factors for AMI did not differ among patients with and without H. pylori infection. CONCLUSION: Patients admitted to the Coronary Care Unit for acute myocardial infarction had a notably higher prevalence of H. pylori infection than the general population. The classical risk factors for coronary disease were equally present in all patients with AMI irrespective of H. pylori status.

POEMS and Crow-Fukase syndrome: two cases giving rise to more questions about plasma cell dyscrasias.

Two cases of POEMS and Crow-Fukase syndrome are reported. We focused our attention on the problems recently debated in the literature regarding POEMS and osteosclerotic myeloma, the pathogenetic mechanisms of the clinical symptoms in these syndromes and the problems of their classification among plasma cell dyscrasias with polyneuropathy.

[Changes in acid-base equilibrium and water-electrolyte balance in hepatic cirrhosis]. / Alterazioni dell'equilibrio acido-base ed idro-elettrolitico nella cirrosi epatica.

The acid-base and hydroelectrolyte balance were evaluated in 116 patients with cirrhosis of the liver divided (a posteriori) into subjects without ascites, those with tractable ascites, and those with intractable ascites. Alterations were much earlier and more frequent in the pre-ascitic stage. A fall in arterial blood O2 tension also proved a poor prognostic factor. The water load test and 24-hr determination of natriuria best reflected the clinical picture and should thus act as pointers to the correct planning of treatment.

[Use of glucagon in the treatment of severe contractile insufficiency of the myocardium]. / L'impiego del glucagone nel trattamento della grave insufficienza contrattile del miocardio

Glucagon hydrochloride has been used to treat severe contractile insufficiency of the myocardium. The drug was administered to cardiopathic patients who had been admitted to the intensive care unit. Results in the various groups examined were satisfactory, particularly in cases of patients with valve diseases and with chronic pulmonary heart and cardiac insufficiency recalcitrant to digitalis therapy. No important side-effects were noted.

[Selective pancreatic scintiscanning in the diagnosis of pancreatic diseases]. / La scintigrafia pancreatica selettiva nella diagnostica delle pancreopatie

Pancreas scintiscanning using electronic image subtraction has proved useful in the diagnosis of pancreatic disease. Confirmation of this was found on comparison of the scintiscan picture and the surgical picture on gross inspection in 50 cases. Findings indicative of pancreatitis, cysts and tumours are illustrated, together with those given by scintiscanning of pancreas alterations occuring in the course of diseases affecting nearby organs.

[Function test of renal excretion of water and sodium after water loading in liver cirrhosis]. / Esplorazione funzionale della capacità escretoria renale di acqua e sodio dopo carico idrico nella cirrosi epatica.

Water loading was used as a diagnostic test in the study of renal excretion of water and sodium during the clinical stages of cirrhosis of the liver in 25 patients free from clinical and instrumental signs of ascites, 26 with treatable ascites, and 14 with intractable ascites. The water load consisted of 20 cc/kg water administered i.v. as a 5% glucose solution. Examination of diuresis in the ensuring 5 hr showed that: 1) clearance of free water is the most sensitive parameter for the detection of patients at short-term risk for the onset of ascites; 2) very low urinary sodium is an indicator of refractory ascites, whereas values are virtually the same and higher in subjects without ascites or with treatable forms; 3) chloruresis in only reduced significantly in cirrhosis with refractory ascites.

[The importance of thyroid hormone determination in the course of acute and chronic liver diseases]. / Importanza del dosaggio degli ormoni tiroidei in corso di epatopatie acute e croniche.

The RIA values of thyroid hormones in the course of acute and chronic liver disease were studied to see whether they were related to the severity of the picture in a series of 50 healthy subjects and 133 with various hepatopathies: 26 with acute viral hepatitis, 18 with alcoholic liver disease, 16 with alcoholic cirrhosis without ascites and 33 with ascites, 14 non-alcoholic cirrhosis without ascites and 24 with ascites. A reduction in T3 proportional to the seriousness of the clinical and laboratory findings was noted in chronic forms, whereas both T3 and T4 were high in acute viral hepatitis. There was no difference in T3 values in alcoholic and non-alcoholic cirrhosis of similar gravity, showing that the fall in serum T3 is not a specific alcohol-induced lesion. T3 less than 25 ng/100 ml proved the best index in the prediction of mortality (chi 2 = 20,5; p less than 0,0005).

[Therapy of chronic non-A, non-B hepatitis with interferon alfa-2B. A controlled clinical study and long-term follow-up]. / Terapia dell'epatite cronica non-A non-B con alfa-2b interferone. Studio clinico controllato e follow-up a lungo termine.

In order to assess the efficacy of alpha-2b interferon (r-IFN) in the treatment of non-A non-B chronic hepatitis, 30 patients were randomised to receive r-IFN (3 MU subcutaneously three times a week for 24 weeks) or no therapy. A total of 21 males and 9 females, aged between 24-66 years old and who had had increased transaminase levels for at least one year, were included in the study. Three patients were ex-drug addicts and 6 had received blood transfusions whereas the cause of the infection in the remaining 21 patients was unknown. Hepatic biopsies performed prior to the study revealed persistent chronic hepatitis in 7 patients, active chronic hepatitis (ACH) in 19 patients and ACH with hepatic cirrhosis in 4 patients. Anti-HCV antibodies were present in 21 patients (70%). Transaminase values returned to normal in 11 (73%) of the 15 patients treated and remained unchanged in controls after 6 months of therapy. During the 18-month follow-up following the suspension of r-IFN treatment, transaminase values rose again to pre-treatment levels in 4 patients. Anti-HCV antibodies did not disappear in any of the patients who responded to therapy.

[Changes in antidiuretic hormone (ADH) in liver cirrhosis with resistant ascites]. / Modificazioni dell'ormone antidiuretico (ADH) nella cirrosi epatica con ascite resistente.

The pathogenetic role of ADH in determining hyponatremia in patients with liver cirrhosis is still much debated. Osmotic stimuli are not able to inhibit secretion of ADH in refractory ascites and under such conditions the reduction in effective plasma volume has been put forward as the main cause. Twenty patients with liver cirrhosis and refractory ascites were studied before and during extraction-concentration-reinfusion (ECR) of ascitic fluid by means of Rhodiascit. ADH, renin, aldosterone, blood and urine osmolarity, plasma and urinary concentration of sodium, potassium, chlorine, and the clearance of free water were evaluated. All patients presented high renin values (15.4 +/- 11.7 ng/ml), aldosterone (341 +/- 172 ng/ml), ADH (6.3 +/- 5.2 pg/ml). During ECR, a significant drop was observed in renin (p less than 0.001), aldosterone (p less than 0.001) urinary osmolarity (p less than 0.001) and an equality significant increase in diuresis (p less than 0.001), natriuria (p less than 0.005), kaliuria (p less than 0.001) while ADH presented an irregular course: in 11 cases it remained unchanged, in 3 it fell and in 6 it presented a constant increase. To conclude, data suggest that the diminished filtrate reaching the distal tubule constitutes the greatest cause of the inability to dilute urine in many patients with cirrhosis and that ADH is a permissive rather than a primary factor.

[The renin-angiotensin-aldosterone system in liver cirrhosis]. / Il sistema renina-angiotensina-aldosterone nella cirrosi epatica.

The role of the RAA system in the genesis of ascites in liver cirrhosis patients is not yet perfectly clear. The present study was conducted on 176 cirrhosis patients in order to investigate RAA system function, to assess the changes taking place in the various stages of the disease and to correlate such changes with the various kidney function parameters. The patients were divided into 3 groups as follows: Group I: patients without ascites on admission and with no history of the condition; Group 2: patients with ascites of recent onset and/or response to diuretic treatment; Group 3: patients with ascites not responsive to diuretic treatment. In Group 1, 19 patients (38%) reveal a significant reduction in renin activity together with portal hypertension and increased hydrosaline retention. In Group 2 renin activity was reduced in 4 patients (6%), aldosterone activity in 3 (4%). Progressive deterioration in liver function parameters and progressive activation of the RAA system combined with reduced sodiuria content were found in over 50% of these patients. The presence or absence of portal hypertension in this group was not related to significant changes in diuresis or sodiuria. In Group 3 renin was activated in 54 patients (89%), aldosterone in 58 (95%) and there was also a distinct reduction in sodiuria (96% of patients) and chloruria (100%). A substantial increase was also noted in the incidence of low blood sodium (53%) while portal hypertension was found in 97% of patients. On the basis of those data it may be hypothesised that high pressure inside the liver creates the stimulus for primary sodium retention. The decrease in effective blood volume after vasodilation, accentuated by low blood albumin and splanchnic venous stagnation may the stimulate the sympathetic nervous system and RAA system. Hyperaldosteronism only becomes the dominant factor in renal imbalance when the cirrhosis reaches the resistant ascites phase.

[Intraoperative use of radiofrequency thermoablation of liver tumors: considerations on indications and related therapeutic aspects]. / L'impiego intraoperatorio della termoablazione a radiofrequenza di neoplasie epatiche: considerazioni su indicazioni ed aspetti terapeutici associati.

PURPOSE: To evaluate the usefulness of intraoperative radiofrequency thermoablation of liver tumours in association or not with hepatic resection. MATERIALS AND METHODS: 21 patients were treated between January 1998 and December 2001, there were 4 hepatocellular carcinoma and 17 metastasis. In 13 cases radiofrequency was associated to hepatectomy, in 3 cases to resection of extraepatic disease and in 5 cases were performed alone. 23 lesions were treated by radiofrequency (range 1-3); the mean dimension was 26 millimetres (range 8-70). A clamping of the liver pedicle was always done. RESULTS: There were no operative deaths, 3 (14.3%) patients developed complications related to radiofrequency (2 biliary leakages, 1 hepatic abscess). 14 (66.7%) patients were alive after a mean follow up of 14.5 months, 2 of all (9.5%) had a recurrence in the site previously treated with thermoablation. Association between hepatectomy and radiofrequency increased the number of curative liver resections from 10.1% to 16.3% (in case of colorectal metastasis). DISCUSSION: Intraoperative radiofrequency is useful to increase the number of curative hepatectomies, to treat liver masses which demonstrate unresectable or found by ultrasonography at the operating time and even to reach tumours difficult to manage by percutaneous approach. In any case the aim is to obtain the absence of macroscopic neoplastic disease (RO status). It is a safe and effective therapeutic strategy, anyway all procedures and indications are still not completely cleared. CONCLUSIONS: Intraoperative thermoablation of liver tumour is safe and effective and increases therapeutic the number of curative hepatectomies. Further progresses may improve the efficacy and extend the indications of this strategy.

Comparison of once-daily bedtime administration of famotidine and ranitidine in the short-term treatment of duodenal ulcer. A multicenter, double-blind, controlled study.

A multicenter, double-blind, randomized, controlled study was conducted in 234 duodenal ulcer patients to compare the efficacy and safety of the H2-receptor antagonists famotidine and ranitidine in the treatment of duodenal ulcer. Patients received 40 mg famotidine (119 patients) or 300 mg ranitidine (115 patients) once daily at bedtime for 4 weeks. If ulcer lesions persisted, treatment was extended to 6 weeks. Efficacy was assessed by relief of symptoms and endoscopic findings of ulcer healing. Safety was determined on the basis of reports of side effects, results of laboratory tests, and, in selected patients, changes in plasma levels of hormones. The 4- and 6-week healing rates achieved with famotidine were 76% and 91%, respectively, and with ranitidine they were 76% and 87%, respectively; the differences in healing rates for the two drugs were not statistically significant. Similarly, both drugs provided satisfactory relief of pain and dyspeptic symptoms. However, famotidine produced significantly (P less than 0.05) greater relief of postprandial fullness and heartburn. The incidence of untoward effects was low in both treatment groups, and abnormal results in laboratory tests were observed in only one patient, a chronic alcoholic receiving famotidine, who withdrew from the study because of a slight elevation in serum transaminase levels. One patient in the ranitidine treatment group dropped out of the study because of a generalized urticarial rash; however, a causal relationship between drug and effect could not be established. The authors conclude that famotidine may be regarded as the best alternative to ranitidine in the treatment of duodenal ulcer.