Bile detection of squamous cell carcinoma antigen (SCCA) in extrahepatic cholangiocarcinoma.

BACKGROUND: Cholangiocarcinoma (CCA) is a rare biliary tract tumor with poor prognosis that often is challenging to diagnose and the majority of patients present with advanced stage. Squamous cell carcinoma antigen 1 (SCCA1) overexpression has been found in different tumors associated with poor prognosis and chemoresistance. AIMS: To assess the presence and possible prognostic role of SCCA1/2 isoforms in bile and serum of patients with CCA. METHODS: Forty seven surgical patients (36 with CCA and 11 with benign diseases) were prospectively included in the study. Serum and bile specimens were collected at the time of surgery and free and IgM-complexed SCCA was quantified by ELISA (Xeptagen, srl). RESULTS: Free or IgM linked SCCA was rarely found in serum, while SCCA was detectable in bile samples of patients with CCA, especially in those with extrahepatic form (43% vs 17%, p = 0.008), but not in controls. Despite similar tumor stage, these positive patients presented a trend toward a higher percentage of portal invasion (27% vs 15%) and of tumor recurrence than negative cases (62% vs 40%), although the difference was not statistically significant. CONCLUSION: These preliminary results indicate that bile testing for SCCA is a specific marker of extrahepatic CCA, with potential prognostic value.

Azathioprine for prevention of clinical recurrence in Crohn's disease patients with severe endoscopic recurrence: an IG-IBD randomized double-blind trial.

OBJECTIVE: The recurrence of Crohn's Disease after ileo-colonic resection is a crucial issue. Severe endoscopic lesions increase the risk of developing early symptoms. Prevention and treatment of post-operative Endoscopic Recurrence (ER) have been studied with conflicting results. We compare effi cacy of azathioprine (AZA) vs. high-dose 5-aminosalicylic acid (5-ASA) in preventing clinical recurrence and treating severe post-operative ER. PATIENTS AND METHODS: We performed a 1-year multicenter randomized double-blind double-dummy trial. Primary end-points were endoscopic improvement and therapeutic failure (clinical recurrence or drug discontinuation due to lack of efficacy or adverse events) 12 months after randomization. We also performed a post-trial analysis on symptomatic and endoscopic outcomes 10 years after the beginning of the trial, with a median follow-up of 60 months. RESULTS: Therapeutic failure occurred in 8 patients (17.4%) within 12 months from randomization, with no significant difference between patients treated with 5-ASA (20.8%, 5 patients) and those with AZA (13.6%, 3 patients). Therapeutic failure was due to clinical recurrence in the 5-ASA group and to adverse events in the AZA group. Endoscopic improvement at 12 months was observed in 8 patients, 2 (11.8%) in the 5-ASA group and 6 (30%) in the AZA group. No serious adverse event was recorded. At the post-trial analysis (median follow-up 60 months), 47.8% (22/46) of patients experienced clinical recurrence: 54.2% (13/24) in the 5-ASA group and 40.9% (9/22) in the AZA group, p=0.546. Patients treated with AZA had lower risk of drug escalation. Clinical recurrence was associated with smoking (p=0.031) and previous surgery (p=0.003). CONCLUSIONS: Our trial indicates that there was no difference in terms of treatment failure between 5-ASA and AZA in patients with severe ER. The main limit of AZA is its less favorable safety profile.

Clinical course of severe colitis: a comparison between Crohn’s Disease and ulcerative colitis.

Few data are available about the clinical course of severe colonic Crohn’s disease (CD). The aim of this study is to describe the clinical course of severe Crohn’s colitis in a patient cohort with isolated colonic or ileocolonic CD, and to compare it with the clinical course of patients with severe ulcerative colitis (UC). Thirty-four patients with severe Crohn’s colitis were prospectively identified in our cohort of 593 consecutive hospitalized patients through evaluation of the Crohn’s Disease Activity Index score and the Harvey-Bradshaw Index. One hundred sixty-nine patients with severe ulcerative colitis were prospectively identified in our cohort of 449 consecutive hospitalized patients through evaluation of the Lichtiger score and the Truelove-Witts score. We evaluated the following data/aspects: response to steroids, response to biologics, colectomy rate in acute, colectomy rate during follow-up, megacolon and cytomegalovirus infection rate. We did not find significant differences in the response to steroids and to biologics, in the percentage of cytomegalovirus infection and of megacolon, while the rate of colectomy in acute turned out to be greater in patients with severe Crohn’s colitis compared to patients with severe UC, and this difference appeared to be the limit of statistical significance (Chi-squared 3.31, p = 0.069, OR 0.39); the difference between the colectomy rates at the end of the follow-up was also not significant. In the whole population, by univariate analysis, according to the linear regression model, a young age at diagnosis is associated with a higher overall colectomy rate (p = 0.024) and a higher elective colectomy rate (p = 0.022), but not with a higher acute colectomy rate, and an elevated ESR is correlated with a higher overall colectomy rate (p = 0.014) and a higher acute colectomy rate (p = 0.032), but not with a higher elective colectomy rate. This correlation was significant on multivariate analysis. The overall rate of colectomy in the cohort of patients with severe Crohn’s colitis was greater than that of the cohort of patients with severe UC, but this figure is not supported by a different clinical response to steroid therapy or rescue therapy with biologics. The clinical course of severe Crohn’s colitis requires to be clarified by prospective studies that include a larger number of patients in this subgroup of disease.

Liver stiffness measurement reliability and main determinants of point shear-wave elastography in patients with chronic liver disease.

BACKGROUND: Liver stiffness (LS) measured by transient elastography (TE) accurately predicts the severity of chronic liver diseases (CLD). Point quantification shear-wave elastography (pSWE) is a new technique incorporated into a conventional ultrasound system for measuring LS. We evaluated pSWE feasibility, reproducibility and diagnostic accuracy in consecutively recruited CLD patients who concomitantly underwent TE and liver biopsy. AIM: To evaluate pSWE feasibility, reproducibility and diagnostic accuracy in consecutively recruited CLD patients who concomitantly underwent TE and liver biopsy. METHODS: Over 2 years 186 CLD patients (116 males, 132 viral hepatitis) consecutively underwent pSWE (10 valid measurements by ElastPQ) blindly performed by two raters. A further operator performed TE. Inter-observer agreement for pSWE was analysed by intraclass correlation coefficient (ICC) and correlated with histological liver fibrosis (METAVIR). Main determinants of pSWE were investigated by linear regression model. RESULTS: Three hundred and seventy-two (100%) reliable measurements were obtained by pSWE and 184 by TE (99%). LS was 8.1 ± 4.5 kPa for pSWE with the first rater and 8.0 ± 4.2 kPa with the second one vs. 8.8 ± 3.6 kPa for TE. pSWE ICC was 0.89 (95% CI 0.85-0.91), not influenced by age, sex, BMI, liver enzymes, liver aetiology. ICC increased over time with year 1 at 0.86 and 95% CI 0.81-0.90 vs. year 2 at 0.92 and 95% CI 0.87-0.95. Liver fibrosis was the only independent determinant of LS on pSWE. The AUROCs for diagnosing F ≥ 2, F ≥ 3 and F = 4 were 0.77, 0.85 and 0.88 for pSWE vs. 0.81, 0.88 and 0.94 for TE. After 1-year training they were 0.86, 0.94 and 0.91. CONCLUSION: Point quantification shear-wave elastography reliably and reproducibly evaluates liver stiffness, matching transient elastography for accuracy after a 1-year learning curve or 130 examinations.

Feasibility and reproducibility of spleen transient elastography and its role in combination with liver transient elastography for predicting the severity of chronic viral hepatitis.

Liver transient elastography (L-TE) is a reliable, noninvasive predictor of disease severity in chronic liver disease of viral aetiology (CLD). Owing to the relationships among severity of CLD, portal hypertension and spleen involvement, the assessment of splenic stiffness (S-TE) may have an added value in staging CLD. Of 132 CLD patients of viral aetiology, 48 with myeloproliferative disorders (MD) and 64 healthy volunteers (HV), were concurrently investigated by both L-TE and S-TE. Liver disease severity was staged by liver biopsy (LB; Metavir) taken concurrently with TE examination and upper gastrointestinal tract endoscopy for gastro-oesophageal varices. The S-TE inter-observer agreement was analysed by an intra-class correlation coefficient (ICC); L-TE and S-TE accuracy was evaluated by receiver operating characteristic (ROC) curve analysis. Logistic regression analysis assessed the independent effect of L-TE and S-TE as predictors of hepatic fibrosis stage. S-TE failed in 22 CLD (16.6%), 12 (25%) MD and 12 (18%) HV. In the three groups, the ICC was 0.89 (0.84-0.92), 0.90 (0.85-0.94) and 0.86(0.80-0.91), respectively. In the CLD group, L-TE and S-TE independently predicted significant fibrosis (OR 5.2 and 4.6) and cirrhosis (OR 7.8 and 9.1), but at variance from L-TE, S-TE was independent from liver necroinflammation and steatosis. The NPV of S-TE for gastro-oesophageal varices was 100% using a 48 kPa cut-off. In CLD, spleen stiffness alone or in combination with hepatic stiffness can be reliably and reproducibly assessed by TE with the added value of improving the noninvasive diagnosis of severe liver disease and excluding the presence of oesophageal varices.

Estrogens need insulin-like growth factor I cooperation to exert their neuroprotective effects in post-menopausal women.

BACKGROUND: The abrupt fall in estrogens levels during the menopausal transition may connote an hormonal state predisposing to neurodegenerative disorders, e.g. Alzheimer's disease (AD). Reportedly, the neurotrophic activity of estrogen involves an interaction with IGF-I. AIM: To evaluate the leukocyte gene expression of progesterone receptor (PR-A/B) and interleukin 6 (IL-6), two parameters under the control of estrogens and involved in the pathogenesis of AD. SUBJECTS: The study was conducted in non-demented women divided into two groups according to their pre- or post-menopausal state; each group being further divided into two subgroups based on their circulating levels of IGF-I (normal or low). An additional sample of AD-affected women served as a comparison group. RESULTS: Estrogens maintained their full activity only when IGF-I levels were in the range of normalcy. On the contrary, if the concentrations of one or both hormones were reduced, estrogens were not anymore capable to control the gene expression of PR-A/B or IL-6. CONCLUSIONS: Before administering hormone-based replacement therapy, characterization of the somatotropic function should be performed in the early phase of the menopause.

Menopausal transition: a possible risk factor for brain pathologic events.

BACKGROUND AND OBJECTIVE: Incidence and prevalence of Alzheimer's disease (AD) are higher in postmenopausal women than in age-matched men. Since at menopause the endocrine system and other biological paradigms undergo substantial changes, we thought to be of interest studying whether (and how) the balance between some biological parameters allegedly neuroprotective (e.g. related to estrogen, dehydroepiandrosterone and CD36 functions) and others considered pro-neurotoxic (e.g. related to glucocorticoid and interleukin-6 activities) vary during lifespan in either sex in either normalcy or neurodegenerative disorders. SUBJECTS AND METHODS: Along with this aim, we evaluated the gene expression levels of estrogen receptors (ERs), glucocorticoid receptors (HGRs), interleukin-6 (IL-6) and CD36, a scavenger receptor of class B allegedly playing a key role in the proinflammatory events associated with AD, in a population of 209 healthy subjects (73M, 106F, 20-91-year old) and 85 AD patients (36M, 49F, 65-89-year old). Results obtained were related to plasma titers of estrogens, cortisol and dehydroepiandrosterone sulfate (DHEAS). Studies were performed in peripheral leukocytes, since these cells (1) are easily obtainable by a simple blood sampling, (2) express many molecules and multiple receptors which are under the same regulatory mechanisms as those operative in the brain and (3) some of them, e.g. monocytes, share many functions with microglial cells. RESULTS: In healthy men all the study parameters were quite stable during lifespan. In women, instead, at menopausal transition, some changes that may predispose to neurodegeneration occurred. In particular, there was (1) an up-regulation of ERs, and a concomitant increase of IL-6 gene expression, events likely due to the loss of the inhibitory control exerted by estradiol (E(2)); (2) an increase of HGR alpha:HGR beta ratio, indicative of an augmented cortisol activity on HGR alpha not sufficiently counteracted by the inhibitory HGR beta function; (3) a reduced CD36 expression, directly related to the increased cortisol activity; and (4) an augmented plasma cortisol:DHEAS ratio, widely recognized as an unfavorable prognostic index for the risk of neurodegeneration. In AD patients of both sexes, the expression of the study parameters was similar to that found in sex- and age-matched healthy subjects, thus indicating their unrelatedness to the disease, and rather a better correlation with biological events. CONCLUSIONS: Menopausal transition is a critical phase of women's life where the occurrence of an unfavorable biological milieu would predispose to an increased risk of neurodegeneration. Collectively, the higher prevalence of AD in the female population would depend, at least in part, on the presence of favoring biological risk factors, whose contribution to the development of the disease occurs only in the presence of possible age-dependent triggers, such as beta-amyloid deposition.

Primary high grade sarcoma of the specialised prostatic stroma: a case report with clinico-pathological considerations.

Malignant tumours of the prostate other than carcinomas are rare. One such malignant tumours arising from the specialised stromal tissue of the prostate is stromal prostatic sarcoma (namely low-grade and high-grade). Herein, we report the clinico-pathological features of a high grade stromal sarcoma of the prostate occurring in a 65-year-old man who presented for urinary obstructive symptoms. The clinical picture suggested a benign prostatic hyperplasia, and surgery consisting in a transcapsular adenomectomy was performed. Following a pathological diagnosis of high grade prostatic stromal sarcoma, a radical cystoprostatectomy and bilateral pelvic node dissection was performed showing residual high grade stromal sarcoma of the prostate and incidental in situ urothelial carcinoma of the bladder. No further medical treatments were planned. One year after surgery the patient is well with no evidence of local disease or distant metastases.

Biphenotypic acute leukemia with t(15;17).

Biphenotypic acute leukemias (BAL) represent 5% of all acute leukemias. The most frequent cytogenetic abnormalities described are Philadelphia chromosome and 11q23 involvement. Here we report a BAL case, with blasts showing lymphoblast morphology and positivity for myeloperoxidase (in 6% of the blast cells). Immunophenotype revealed the compromise of myeloid and B-lymphoid lineages. Cytogenetic analysis showed the t(15;17) and 8 trisomy. PML/RARa rearrangement was detected by fluorescent in situ hybridization (FISH) on interphase nuclei while PML/RARa fusion transcript was detected in the bone marrow and peripheral blood by molecular biology studies (RT-PCR). This report describes a BAL case with an unfrequent cytogenetic abnormality, and highlights the importance of correlating the results of multiple diagnostic methods in order to establish a correct diagnosis and treatment in BAL patients.

Interferon and prevention of hepatocellular carcinoma in viral cirrhosis: an evidence-based approach.

BACKGROUND/AIMS: To evaluate by meta-analysis of available literature whether interferon (IFN) reduces the incidence of hepatocellular carcinoma (HCC) in patients with hepatitis B virus (HBV) or hepatitis C virus (HCV)-related Child A cirrhosis. METHODS: Three randomized controlled trials and 15 nonrandomized controlled trials, including 4614 patients and comparing IFN to no treatment, were selected. Data on the incidence of HCC in IFN treated and untreated patients were extracted from each study. Meta-analysis by the DerSimonian and Laird risk difference (RD) method was used to pool observations. RESULTS: A different incidence of HCC between treated and untreated cirrhotic patients was observed for HCV (overall RD -12.8%; 95% CI -8.3 to -17.2%, P < 0.0001) and HBV (overall RD -6.4%; 95% CI -2.8 to -10%, P < 0.001). In HCV-related cirrhosis, the rate of HCC development was lower in sustained responders to IFN than in untreated patients (overall RD -19.1%; 95% CI -13.1 to -25.2%, P < 0.00001), with low heterogeneity among trials (P=0.053), and also in nonresponders vs. untreated patients (overall RD -11.8%; 95% CI -6.4 to -19.1%, P < 0.0001), although with significant heterogeneity. Inconsistency among the studies was a major problem, both for HCV (chi2 = 58.16 with 13 DF; P < 0.0001) and HBV (chi2 = 26.4 with 6 DF; P = 0.0001) related cirrhosis, and also when follow-up was shorter than 60 months. Consistent results were only observed when assessing data from European reports: in this subgroup no preventive effect of HCC was shown for HBV (overall RD -4.8%; 95% CI -11.1-1.5%, P, not significant), and only a weak effect for HCV (overall RD -10%; 95% CI -5.9 to -14.2%; P < 0.0001). CONCLUSIONS: Literature data pooling suggests a slight preventive effect of IFN on HCC development in patients with HCV-related cirrhosis. The magnitude of this effect is low and the observed benefit might be due to spurious associations. The preventive effect is more evident among sustained responders to IFN. IFN does not seem to affect the rate of HCC in HBV-related cirrhosis.

Impact of interferon therapy on the natural history of hepatitis C virus related cirrhosis.

BACKGROUND: The role of interferon treatment on the natural history of hepatitis C virus related cirrhosis is under debate. AIM: To evaluate the effect of interferon on the clinical course of compensated hepatitis C virus related cirrhosis. PATIENTS AND METHODS: Seventy two cirrhotic patients treated with interferon and 72 untreated controls matched treated patients with for quinquennia of age, sex, and Child-Pugh's score were enrolled in a prospective non-randomised controlled trial. Treated patients received leucocytic interferon alfa, with an escalating schedule for 12 months. The incidence and risk (Cox regression analysis) of clinical complications (hepatocellular carcinoma, ascites, jaundice, variceal bleeding, and encephalopathy) and death were calculated. RESULTS: Over median follow up periods of 55 months for treated and 58 for untreated subjects, seven and nine patients, respectively, died, and 20 and 32, respectively, developed at least one clinical complication (ns). Hepatocellular carcinoma developed in six treated and 19 untreated patients (p=0.018). Seven treated patients showed sustained aminotranferase normalisation and none died or developed complications. Clinical complications were significantly associated with low albumin, bilirubin, and prothrombin activity while hepatocellular carcinoma was significantly related to no treatment with interferon, oesophageal varices, and high alpha fetoprotein levels. By stratified analysis, the beneficial effect of interferon was statistically evident only in patients with baseline alpha fetoprotein levels > or =20 ng/ml. CONCLUSIONS: Interferon does not seem to affect overall or event free survival of patients with hepatitis C virus related cirrhosis while it seems to prevent the development of hepatocellular carcinoma. Patients who achieved sustained aminotransferase normalisation survived and did not develop any complications during follow up.

Preoperative radiotherapy for resectable rectal cancer: A meta-analysis.

CONTEXT: The benefit of adjuvant radiotherapy for resectable rectal cancer has been extensively studied, but data on survival are still equivocal despite a reduction in the rate of local recurrence. OBJECTIVE: To assess the effectiveness of preoperative radiotherapy followed by surgery in the reduction of overall and cancer-related mortality and in the prevention of local recurrence and distant metastases. DATA SOURCES: Computerized bibliographic searches of MEDLINE and CANCERLIT (1970 to December 1999), including non-English sources, were supplemented with hand searches of reference lists. The medical subject headings used were rectal cancer, radiotherapy, surgery, RCT, randomized, and clinical trial. STUDY SELECTION: Studies were included if they were randomized controlled trials (RCTs) comparing preoperative radiotherapy plus surgery with surgery alone and if they included patients with resectable histologically proven rectal adenocarcinoma, without metastatic disease. Fourteen RCTs were analyzed. DATA EXTRACTION: Data on population, intervention, and outcomes were extracted from each RCT according to the intention-to-treat method by 3 independent observers and combined using the DerSimonian and Laird method. DATA SYNTHESIS: Radiotherapy plus surgery compared with surgery alone significantly reduced the 5-year overall mortality rate (odds ratio [OR] 0.84; 95% confidence interval [CI], 0.72-0.98; P =.03), cancer-related mortality rate (OR, 0.71; 95% CI, 0.61-0.82; P<.001), and local recurrence rate (OR, 0.49; 95% CI, 0.38-0.62; P<.001). No reduction was observed in the occurrence of distant metastases (OR, 0.93; 95% CI, 0.73-1.18; P =.54). CONCLUSIONS: In patients with resectable rectal cancer, preoperative radiotherapy significantly improved overall and cancer-specific survival compared with surgery alone. The magnitude of the benefit is relatively small and criteria are needed to identify patients most likely to benefit from adjuvant radiotherapy. JAMA. 2000;284:1008-1015

Clinical aspects of bleeding complications in cirrhotic patients.

Liver disease is a frequent cause of haemostatic abnormalities, which may lead to overt or occult bleeding. Clinical manifestations of hepatic coagulopathy include upper and lower gastrointestinal haemorrhage, easy bruising and bleeding from gums, nose or the female genital tract. The most significant bleeding problem among patients with chronic liver disease is blood loss due to portal hypertension. About 30% of subjects with oesophageal or gastric varices resulting from cirrhosis have an episode of gastrointestinal bleeding in their lifetime. Risk factors for the first episode of variceal bleeding include the severity of liver dysfunction, large varices, and the presence of endoscopic red colour signs. Bacterial infection in patients with variceal haemorrhage may be critical in triggering bleeding. Nongastrointestinal bleeding events, either spontaneous or induced by minor trauma, are also a common complication of advanced cirrhosis. In women, for instance, dysfunctional uterine bleeding may become so severe that hysterectomy is required. In addition, invasive diagnostic tests (mostly solid tissue biopsies) and surgical procedures have a high risk of haemorrhage and are sometimes withheld in cirrhotic patients for fear of complications. In patients with portal hypertension, surgical procedures aggravate the injury of the hepatic parenchyma and may worsen the condition.

The long-term course of chronic hepatitis B.

The aim of this study was to assess the long-term outcome in hepatitis B virus (HBV)-infected patients according to HBV, hepatitis C virus (HCV), and hepatitis D virus (HDV) replication, focusing on survival, liver failure, and hepatocellular carcinoma (HCC). A cohort of 302 hepatitis B surface antigen (HBsAg)-positive subjects (mean age, 34 +/- 15.3 years; male/female 214/88; 39 subjects under 14 years) with biopsy-proven chronic hepatitis (86 with cirrhosis) was prospectively assessed, with a median follow-up of 94 +/- 37.6 months. One hundred nine patients received interferon alfa (IFN). At baseline, 86 subjects (28.5%) were hepatitis B e antigen (HBeAg)-positive (wild-type HBV), 80 (26.5%) were HBeAg-negative, HBV-DNA-positive, 76 (25.2%) had HDV infection, 43 (14.2%) had dual HBV/HCV infection, and 17 (5.6%) were negative for HBV-DNA, anti-HCV, and anti-HDV. During follow-up, decompensation of disease occurred in 46 subjects: 8 developed HCC, 36 developed ascites, and 2 developed jaundice. Five patients underwent transplantation. Thirty-five subjects died: 33 of hepatic and 2 of nonhepatic causes. Overall mortality was 5.2-fold that of the general population (95% CI: 3.6-7.3; 35 deaths observed, 6.7 expected; P <.0001). By Cox regression analysis, survival was independently predicted by young age, absence of cirrhosis at baseline, and sustained normalization of aminotransferases during follow-up. Survival without decompensation was independently predicted by the same factors and by IFN treatment. Chronic hepatitis B infection increases mortality in comparison with the general population in our area regardless of specific virological profiles at presentation. Presence of cirrhosis and persistent necroinflammation markedly increase the risk of death.

Natural history of chronic hepatitis C.

BACKGROUND AND AIMS: A comprehensive overview on the course of hepatitis C is not available despite the many studies published. The aim was to review the course and prognostic variables of untreated hepatitis C. METHODS: English-language articles published between January 1989 and December 1997 were identified and data extracted to answer predefined relevant questions. RESULTS: Median chronicization rate, mostly assessed in transfusion-associated hepatitis, was 67%. In retrospective studies, the interval between date of infection and diagnosis of cirrhosis or hepatocellular carcinoma was 20-40 years. Median progression rate from chronic hepatitis to cirrhosis was 27.9% after 8-12 years. Studies obtaining this figure included selected groups of patients and could reflect the worst prognostic segment of the disease. The course of hepatitis C virus infection may be more favourable: cirrhosis rarely or never occurred in young females infected by con-taminated anti-D-immunglobulins; hepatitis was histologically mild in most hepatitis C virus-RNA positive subjects with normal or near normal transminases, predicting non-progressive or very slowly progressive disease; in a population survey from Italy, among 170 infected subjects only 4% had raised transaminases, and none overt liver disease. Increasing age, histological severity, alcohol, possibly male sex and liver iron content were predictors of cirrhosis or increased fibrosis. CONCLUSIONS: Chronicization rate of hepatitis C virus infection is very high. Hepatitis C virus infection can result in a wide prognostic spectrum of liver disease, ranging from cirrhosis and hepatocellular carcinoma to subclinical, nonprogressive disease. Cofactors such as alcohol excess are important in determining the outcome of hepatitis C virus-related chronic liver disease.

[Gastric carcinoma: a histopathological study of 705 cases]. / Carcinoma gastrico: studio istopatologico di 705 casi.

We examined 705 surgical specimens of total and subtotal gastrectomy for gastric cancer, from the Surgical Pathology Department of L'Aquila, Atri and Avezzano, during the period from January 1972 to December 1991. For each case at least 15 samplings were taken, from the tumor itself and from the mucosa which appeared macroscopically normal. The cases were then classified according to the criteria proposed by Lauren and by Ming and the staging of the disease using the UICC's pTNM. Applying Ming's classification, it was evident a clear prevalence of the infiltrative (78.6%), rather than the expansive type (21.4%). Lauren's classification showed a slight prevalence of the diffuse type (56.5%), compared with the intestinal type. Intestinal metaplasia, chronic atrophic gastritis and dysplasia were found more frequently in the intestinal and expansive histotypes. These are the forms having a better prognosis and which in our results represent a minority of cases, therefore identifying the geographic area as a low risk area. With regards to the pTNM staging, T3's resulted the most numerous; T1's, or early gastric cancers (EGC), represented instead 15.7% of the total. Such a percentage is rather high in comparison with the mean percentage in western countries with low risk of disease. In reference to the macroscopic variants, a clear prevalence of the ulcerated forms (66.5%) was noted, in contrast with Ming and other Authors, that declare a slight prevalence of the fungating type. Also considering the histotypes there is a certain discrepancy between the data of Ming and ours; in fact, in our study the infiltrative type prevails, representing 78.6% against 33.6% found by Ming. Such a result can be usefully correlated to the high percentage of the ulcerated forms observed in our study and to the relative scarcity of fungating forms; these variants themselves, according to Ming, are usually related to the expansive type of gastric carcinoma. We also noted, in EGC, a remarkable age difference in regards to the diffuse type; the mean age of the 57 patients with this type classified as T1 was 52.2 years against the 63.0 years of the 341 patients with T > 1. The patients with T1 diffuse type carcinoma were not only 10.8 years younger than the patients with advanced gastric cancer of corresponding histotype, but were also 10 years younger than patients with EGC of intestinal type. Such data could support the hypothesis that EGC, diffuse type, has a peculiar biologic behavior.

Long-term course of interferon-treated chronic hepatitis C.

BACKGROUND/AIMS: To evaluate whether sustained response to a-interferon improves clinical outcome in patients with chronic hepatitis C. METHODS: A cohort of 410 consecutive patients (65% with chronic hepatitis, 35% with cirrhosis) were treated with a-interferon in two trials (mean follow-up 62.1 months, range 7-109 months). All were serum HCV RNA positive before therapy and received first 10 then 5 million units of a-2b or a-nl interferon three times weekly for 6 to 12 months. Sustained response was defined as normal aminotransferases 12 months after stopping interferon. RESULTS: Sixty-two patients (15.1%: 54 with chronic hepatitis, eight with cirrhosis) were sustained responders. At the end of follow-up, 56 out of 62 sustained responders (90.3%) were serum HCV RNA negative. No biochemical relapse after 12 months was seen in sustained responders, regardless of initial histology, HCV genotype or persistence of HCV RNA. Although three died of non-hepatic causes, no liver-related events were observed among sustained responders. Complications of liver disease occurred in 34 relapsers/non-responders: nine hepatocellular carcinomas, 21 ascites and four portal hypertensive bleedings. Eleven relapsers/nonresponders died: eight of hepatic and three of non-hepatic causes. Event-free survival was significantly longer in sustained responders than in all the remaining patients. In a regression analysis, sustained response to interferon, low age and absence of cirrhosis were independent predictors of event-free survival. CONCLUSIONS: Hepatitis C virus is probably eradicated and progression of liver disease is prevented in most patients who remain HCV RNA negative with normal transaminases for more than 1 year after stopping treatment.

Mesalamine in the maintenance treatment of Crohn's disease: a meta-analysis adjusted for confounding variables.

BACKGROUND & AIMS: The benefit of mesalamine for maintenance of remission in Crohn's disease is controversial. The aim of this study was to assess the effectiveness of mesalamine in maintaining remission of quiescent Crohn's disease. METHODS: Pertinent randomized clinical trials were selected using MEDLINE (1986-1997) database, reference lists from published articles or reviews. Fifteen randomized, controlled trials of mesalamine maintenance therapy involving a total of 2097 patients were selected. The crude rates of patients with symptomatic relapse in treated and control groups were extracted according to the intention-to-treat method. RESULTS: Therapy with mesalamine significantly reduced the risk of symptomatic relapse (pooled risk difference, -6.3%; 95% confidence interval, -10.4% to -2.1%). The pooled risk difference was significant in the postsurgical setting (-13.1%; 95% confidence interval, -21.8% to -4.5%) but not in the medical setting (-4.7%; 95% confidence interval, -9.6% to 2.8%). Multivariate model predicts that the probability of symptomatic relapse significantly decreases with mesalamine treatment, by increasing proportion of patients with ileal disease, with prolonged disease duration, and with surgically induced remission. CONCLUSIONS: Mesalamine may be recommended for maintaining remission of quiescent Crohn's disease. The benefit is mainly observed in the postsurgical setting, in patients with ileitis and with prolonged disease duration.

The effect of interferon on the liver in chronic hepatitis C: a quantitative evaluation of histology by meta-analysis.

BACKGROUND/AIMS: Several randomized clinical trials of interferon in chronic hepatitis C have examined the histological changes in paired biopsy specimens. We have attempted a quantitative evaluation by meta-analysis. METHODS: Randomized Clinical Trials found by MEDLINE search were included if: a) they compared different IFN regimens with non-active treatment or with each other, b) they obtained biopsies before starting and at the time of stopping IFN in a sizable proportion of the treated and control patients, and c) they assessed the biopsy-specimens semi-quantitatively according to Scheuer's numerical scoring system or Knodell's Histological Activity Index, with quantitation of fibrosis and of lobular, portal and periportal necroinflammation. RESULTS: Seventeen trials were identified, in which 1223 adult patients had been studied. All trials homogeneously pointed towards a favorable interferon effect. The pooled data show a statistically significant histological improvement in treated patients as compared with controls for each of the four Histological Activity Index components and for the total Histological Activity Index score (overall improvement was -0.82 in favor of interferon, p<0.0001, 95% Confidence Interval -1.25 to -0.40). In the ten trials reporting histological changes separately in biochemical responders (primary and sustained responders) and non-responders, histological improvement was confined to the subset of biochemical responders. No change or very little change occurred in non-responders. CONCLUSIONS: Interferon treatment in chronic hepatitis C significantly improves liver histology. The effect of interferon is closely related to biochemical response. Studies assessing histological outcome 1 year or more after interferon treatment in long-term responders and comparatively in non-responders or relapsers would be important to confirm the regression of the necroinflammatory process in the former, as suggested by the normal serum alanine aminotransferase levels.

A randomized controlled trial of high-dose maintenance interferon therapy in chronic hepatitis C.

In chronic hepatitis C virus (HCV) infection, the rate of sustained response to interferon is low. We evaluated, in patients responding to a 26-week course of interferon, the effect of high-dose maintenance therapy in preventing relapse. Three hundred and ten patients with chronic HCV infection (38.3% with cirrhosis, 80.6% with HCV type 1) received interferon alfa-2b for 26 weeks (10 MU tiw for 8 weeks, then 5 MU tiw for 18 weeks). One hundred and twenty-four subjects (40%) normalized aminotransferases, and were allocated randomly either to continue on 5 MU tiw for a further 26 weeks (prolonged therapy group: 60 patients) or to stop interferon (brief therapy group: 64 patients). Fifty-two weeks after stopping interferon the overall sustained biochemical response rate was 13.2% (41/310). The number of patients with normal aminotransferases was comparable between the prolonged and brief therapy groups (30% vs. 35.9%, P = n.s.), and the rate of HCV-RNA clearance was similar (48.8% vs. 42.4%, P = n.s.). The timing of posttreatment relapse was not influenced by the duration of therapy. Fifty-nine patients (19%) did not complete therapy due to adverse effects. Multivariate analysis identified four features predicting sustained biochemical response in subjects normalizing aminotransferases under therapy: negative HCV-RNA at end of therapy, normal aminotransferases at 4 weeks of therapy, high baseline aminotransferases, and high baseline platelets. Infection with HCV type 1 was not a significant predictor of response, due to its high prevalence in our population (80.6%). It is concluded that in patients with chronic hepatitis C mostly infected by HCV type 1, a prolonged high-dose interferon course (900 MU over 52 weeks) did not increase the rate of sustained biochemical response and of HCV-RNA clearance in comparison to a brief course (510 MU over 26 weeks).