Topoisomerase I protein expression in primary colorectal cancer and recurrences after 5-FU-based adjuvant chemotherapy.

PURPOSE: Our aim was to investigate whether chemotherapy with 5-FU induces an alteration in the levels of topoisomerase I (topo I) in colorectal neoplastic tissues METHODS: Twenty-five colorectal cancer patients were included in our study; these had undergone surgical resection of the primary tumor, received post-operatively 5-FU-based adjuvant chemotherapy and then suffered from recurrences. In a standard three-step immunohistochemical procedure, a monoclonal antibody to topo I was applied in both specimens from each patient (one from the primary location and a second one from the recurrence). Statistical analysis was subsequently performed. RESULTS: Malignant cells from the recurrences displayed a statistical significant increase, concerning the levels of topoisomerase I, by comparison with the primary tumors (P=0.01). The increase in topo I levels did not demonstrate significant correlations with Duke's stage (Fisher's Exact Test P value=0.496), differentiation grade (P value=0.661), localization (P value=0.072), patient sex (P value=0.434), nor with relapse free interval (P value=0.493). There was a statistically significant relationship between the age of patients and increase in topo I levels (P=0.011). CONCLUSIONS: Topo I expression may be part of the malignant cells' phenotype in recurrent colorectal carcinomas, suggesting a potential role for Topo I in the acquisition of a metastatic phenotype. The increase of topo I immunohistochemical status is likely to be attributed to 5-FU and given the fact that high levels of topo I correlate with sensitivity to camptothecin, advanced colorectal cancer patients seem to benefit from topo I targeted anticancer drug therapy.

Intraepithelial lumina in urothelial bladder neoplasms. A histochemical, immunohistochemical and electron microscopy study.

Intraepithelial lumina observed in 12 urothelial bladder neoplasms were studied histochemically, immunohistochemically and ultrastructurally. Both intercellular and intracytoplasmic lumina could be demonstrated showing an alcianophilic margin and containing non-sulphated acid mucins. The presence of secretory component (SC) was identified in neoplastic urothelial cells around or adjacent to intercellular lumina as well as in cells with intracytoplasmic lumina. The cells surrounding intercellular lumina revealed ultrastructurally tight junctions, microvilli and a prominent glycocalyx while cellular remnants were found quite often within the lumen. As similar histochemical, immunohistochemical and ultrastructural characteristics are also expressed in surface umbrella cells of normal urothelium it is suggested that a focal differentiation of neoplastic urothelial cells towards surface umbrella-like cells takes place and that this process is intimately related to the formation of lumina.

Prostatic-type epithelium in urinary bladder. Clinical, histologic, and immunohistochemical study.

Six cases of urinary bladder mucosa with prostate-type epithelium were studied clinically, morphologically, and immunohistochemically. All patients were male with an average age of fifty-three years; most presented with painless hematuria. Histologically, two types of lesions were observed, the polypoid located in various sites of the bladder wall and the flat lesion found in the bladder neck. Both lesions shared in common a prostatic-type and transitional surface epithelium while prostatic-type glands were prominent in the polypoid lesion. The prostatic-type epithelium was confirmed immunohistochemically by detection of prostatic specific antigen and prostatic acid phosphatase. Based on specific findings we considered the metaplasia as the most reliable histogenetic aspect.

Carcinosarcoma of the submandibular salivary gland.

We report a rare case of submandibular salivary gland carcinosarcoma ('true' malignant mixed tumour) which occurred in a 77-year-old man. Microscopic examination showed a neoplasm comprised of sarcomatous elements (chondrosarcoma, rhabdomyosarcoma and osteosarcoma) with tabular salivary ductal adenocarcinoma. A short review of the literature is also presented and the poor prognosis of these tumours, in spite of complete surgical removal and additional radiation therapy and chemotherapy, is discussed.

Overlap syndrome of primary sclerosing cholangitis and autoimmune hepatitis.

We report a 46-year-old patient with the typical biochemical, histological and cholangiographic findings of primary sclerosing cholangitis (PSC) whose clinical and laboratory findings would also qualify her for the diagnosis of definite autoimmune hepatitis (AIH), according to the aggregate score of the International Autoimmune Hepatitis Group. We suggest that this patient may represent an example of the overlapping syndrome of PSC and AIH.

Biochemical and virological response of chronic hepatitis C after treatment with interferon-alpha for 6 or 12 months: predictors of sustained remission.

OBJECTIVE: To evaluate the biochemical and virological response in chronic hepatitis C patients treated with interferon-alpha at the usual dosage of 3 MU thrice weekly for 6 or 12 months, and to analyse the significance of clearance of serum HCV RNA and of HCV genotype in the prediction of sustained biochemical remission. SETTING: Liver Unit, Western Attica General Hospital, Athens, Greece. PARTICIPANTS: Sixty consecutive patients with histologically confirmed chronic hepatitis C. INTERVENTIONS: All patients received interferon-alpha-2b in a dose of 3 MU thrice weekly for 6 (n = 26) or 12 (n = 34) months. Serial serum samples were retrospectively tested for the presence of HCV RNA by a polymerase chain reaction assay and pretreatment serum samples for the determination of HCV genotype. RESULTS: Sustained biochemical response rate was significantly higher in the 12-month group (62% vs. 35%, P = 0.037). Clearance of serum HCV RNA at the end of treatment was achieved in 33 (58.9%) of the 56 patients with detectable pretreatment HCV RNA. HCV RNA reappeared in serum significantly more often in patients treated for 6 than for 12 months (35.7% vs. 5.3%, P = 0.037). Serum HCV RNA after 6 months of therapy was a prognostic factor of sustained biochemical response, which was observed in 75% of the HCV RNA-negative and in only 16.7% of the HCV RNA-positive patients (OR 0.067, P < 0.001). Moreover, in patients negative for HCV RNA after 6 months of therapy, 12 months' treatment resulted in a higher sustained response rate than did 6 months' (89% vs. 57%, P = 0.05). HCV genotype 1 was associated with a significantly lower sustained response rate (30% vs. 60.7%, P = 0.035), whereas 12 months' treatment induced sustained remission significantly more often only in patients with genotype 1 (6/12 vs. 0/8, P = 0.024). CONCLUSION: In chronic hepatitis C treatment HCV genotype and serum HCV RNA after 6 months of therapy are strong predictive factors of a sustained response, and a 12-month rather than a 6-month interferon regimen may induce a more persistent clearance of HCV RNA in total and a higher sustained response rate in patients with HCV genotype 1 and in those who clear HCV RNA after 6 months of therapy.

Carcinoma arising in a duplicated colon.

One case of adenocarcinoma arising in a duplicated transverse colon is presented. Its unusual feature was the site of the carcinoma origin, which was the true colonic segment and not the duplication.

Irinotecan as salvage chemotherapy for advanced small bowel adenocarcinoma: a series of three patients.

Small bowel adenocarcinoma (SBA) is a relatively rare disease. Because of its rarity the role of chemotherapy either as adjuvant or for advanced disease has not been clearly defined. Therefore any information, including case reports, is warranted. We report on three patients with adenocarcinoma of the jejunum and ileum. Two patients with positive lymph nodes received postoperative adjuvant chemotherapy with 5-fluorouracil-folinic acid (5FU-FA) for 12 months but they developed metastatic disease 3 and 8 months later, respectively. The third patient was initially treated with the same agents but for metastatic disease. All patients were subsequently treated for tumor recurrence with irinotecan 350 mg/m2 i.v. every 3 weeks as salvage chemotherapy supported by Granulocyte Colony Stimulating Factor (GCSF) for 5 days. Two patients achieved a minor response and had a dramatic improvement of their symptoms. Their survival times after irinotecan administration were 14 and 6 months with an overall survival after primary diagnosis of 29 and 27 months, respectively. The third patient who had a tumor refractory to 5FU-FA progressed also on irinotecan and had an 8-month overall survival. Although conclusions cannot be drawn regarding the role of adjuvant chemotherapy in SBA, it seems reasonable to extrapolate from large bowel carcinoma experience. Irinotecan seems to have some degree of activity in the treatment of SBA but further studies are warranted.

Amineptine induced liver injury. Report of two cases and brief review of the literature.

Two cases of amineptine induced liver injury in patients treated with the drug for 18 and 15 days respectively, are reported. Hepatic reaction lasted 60 days in the first case and 120 days in the second one, with the latter considered unusually prolonged. The patients history, the course of the reaction and the histologic findings were compatible with the diagnosis of drug induced liver disease in both cases. Furthermore, every other possible origin of hepatobiliary injury such as disorders of bile ducts, ongoing viral hepatitis and autoimmune hepatitis were excluded. The mechanism of amineptine induced liver injury and the influence of a possible genetic predisposition to amineptine hepatotoxicity are also discussed.

Factors associated with severity and disease progression in chronic hepatitis C.

BACKGROUND/AIMS: Chronic hepatitis C appears to have a highly variable natural course with 20% of patients developing cirrhosis within 20 years, while the majority of them run a relatively mild course. We studied the relationships of epidemiological, biochemical and virological features with histological severity (grade) and liver disease progression (stage). METHODOLOGY: Liver histology, serum HCV RNA level and HCV genotype were determined in a well-defined cohort of 152 consecutive (100 males, 52 females) patients with chronic hepatitis C. RESULTS: Patients with minimal or mild chronic hepatitis were significantly younger than those with moderate or severe chronic hepatitis (mean age: 41.1 vs 49.5 years respectively, p=0.003). On the other hand, patients with no or mild fibrosis compared to those with moderate or severe fibrosis and to those with cirrhosis were significantly more frequently males (73%, 64% and 43%, p=0.01), parenteral drug users (36%, 11% and 11%, p=0.01) and infected with other than 1b genotype (86%, 52% and 33%, p<0.0001), significantly younger (mean age: 37, 48 and 58 years, p<0.0001) and had significantly lower HCV RNA levels (geometric mean: 6.9, 19.2 and 17.5 x 10(5) eq/ml, p=0.007). Multivariate analysis showed that stage was significantly related only to patient age (p<0.0001), HCV genotype (p=0.0025) and HCV RNA level (p=0.044). CONCLUSIONS: In chronic hepatitis C, histological severity seems to be associated only with patient age, while progression of the disease is mainly associated with patient age, HCV genotype and viremia level.

Hamartoma of Brunner's glands causing massive haematemesis.

BACKGROUND: Brunner's gland hamartomas are very uncommon lesions and are usually asymptomatic. METHODS: A 77-year-old man was urgently operated on for massive upper gastrointestinal bleeding, associated with haematemesis. RESULTS: A 3.5 x 3 x 3 cm mass arising from the anterior aspect of the first part of the duodenum was found. Histologic examination showed groups of Brunner-type glands without atypia; these coexisted with heterotopic pancreatic acini and ducts. CONCLUSIONS: This is a very rare cause of massive upper gastrointestinal bleeding and may easily be confused with bleeding from a peptic ulcer.

Portal tract lipogranulomas in liver biopsies.

Portal lipogranulomas in liver biopsy specimens were investigated. The incidence of biopsies containing portal lipogranulomas was 2.4%. Out of 20 biopsies with lipogranulomas 10 biopsies contained only one lipogranuloma. Portal lipogranulomas show a distinctive morphology with fat vacuoles surrounded by macrophages. They are consistently found together with parenchymal steatosis and probably originate from parenchymal fat being transported to portal tracts. Portal lipogranulomas are of importance in the differential diagnosis from other granulomas.

Significance of immune status, genotype and viral load in the severity of chronic hepatitis C in HIV infected haemophilia patients.

Chronic hepatitis C is associated with more severe liver disease in patients coinfected with HIV, but the pathogenic mechanism of this more aggressive course is still unclear. The aim of this study was to assess the relationship of HCV genotype, viral load and epidemiological factors with the histological severity of chronic hepatitis in haemophilia patients with HCV/HIV coinfection, taking into consideration the immune status of the patients. Twenty-one HIV/HCV coinfected haemophilia patients, with mean age +/- SD 35.7 +/- 8.7 years, underwent transcutaneous liver biopsy 6-15 years (median 12 years) after HIV and 6-32 (median 21.5 years) years after HCV infection. Twelve patients were stage A (CDC), six stage B and three stage C. CD4 cells were < 50 microL(-1) in three patients (14.3%), 50-200 in 11(52.4%) and > 200 in 7(33.3%). Mean +/- SD log(10) HCV-RNA was 6.87 +/- 0.7 copies mL(-1) (range 5.4-7.9), and mean +/- SD log(10) HIV-RNA was 3.75 +/- 0.98 copies mL(-1) (range 2.7-6), at the time of liver biopsy. Minimal hepatitis was diagnosed in five patients (24%), mild in 10 (48%) and moderate in six (28%). Hepatitis stage 0-2 was found in seven cases (33%) and cirrhosis in six (29%). Statistical analysis showed a significant association of CD4 count < 50 with minimal hepatitis and of CD > 200 with mild and moderate hepatitis (P = 0.033). In addition, minimal hepatitis was found only in patients with stage C, while the majority of subjects with HIV stage A showed mild and moderate hepatitis (P = 0.003). Moreover genotype 1 was independently associated with advanced hepatitis stage (P = 0.04). No relationship was found between hepatitis severity, HIV or HCV RNA levels, patient's age and duration of HIV or HCV infection. Our results suggest that HCV/HIV coinfection may aggravate the course of hepatitis in the phase of immunocompetence, most probably through an immune mediated process. Genotype 1 seems to be associated with advanced liver disease.

Cholestatic syndrome with bile duct damage and loss in renal transplant recipients with HCV infection.

BACKGROUND/AIMS: Bile duct cells are known to be susceptible to hepatitis B and C virus, while it has been recently suggested that hepatitis B virus (HBV) and hepatitis C virus (HCV) infection may have a direct role in the pathogenesis of vanishing bile duct syndrome (VBDS) after liver transplantation. We report the development of a cholestatic syndrome associated with bile duct damage and loss in four HCV-infected renal transplant recipients. METHODS: All four patients were followed up biochemically, serologically and with consecutive liver biopsies. Serum HCV RNA was quantitatively assessed and genotyping was performed. RESULTS: Three patients were anti-HCV negative and one was anti-HCV/HBsAg positive at the time of transplantation and received the combination of methylprednisolone, azathioprine and cyclosporine A. Two patients became anti-HCV positive 1 year and one patient 3 years post-transplantation. Elevation of the cholestatic enzymes appeared simultaneously with seroconversion, or 2-4 years later, and was related to lesions of the small-sized interlobular bile ducts. Early bile duct lesions were characterized by degenerative changes of the epithelium. Late and more severe bile duct damage was associated with bile duct loss. The progression of the cholestatic syndrome coincided with high HCV RNA serum levels, while HCV genotype was 1a and 1b. Two patients (one with HBV co-infection) developed progressive VBDS and died of liver failure 2 and 3 years after biochemical onset. One patient, despite developing VBDS within a 10-month period, showed marked improvement of liver function after cessation of immunosuppression because of graft loss. The fourth patient, who had mild biochemical and histological bile duct changes, almost normalized liver function tests after withdrawal of azathioprine. CONCLUSION: A progressive cholestatic syndrome due to bile duct damage and loss may develop in renal transplant patients with HCV infection. The occurrence of the lesions after the appearance of anti-HCV antibodies and the high HCV RNA levels are indicative of viral involvement in the pathogenesis. Withdrawal of immunosuppressive therapy may have a beneficial effect on the outcome of the disease.

HBcAg and HBsAg expression in ductular cells in chronic hepatitis B.

The possible involvement of bile duct epithelium (BDE) in chronic hepatitis B was examined by immunohistochemical investigation of HBcAg and HBsAg expression in biliary cells in 47 liver biopsies with both viral antigens detectable in hepatocytes. HBcAg- and HBsAg-positive cells were identified in nine and five cases, respectively, in atypical and occasionally in typical ductules in cases of acute exacerbation, chronic active hepatitis and active cirrhosis. Atypical ductules were usually located in areas of periportal fibrosis and in cirrhotic septa. Liver cell plates expressing viral markers and undergoing ductular transformation (positive reaction of hepatocytes to BDE-specific, wide-spectrum keratin) were also observed in acinar zone 1, at the periphery and within parenchymal nodules in a number of cases. The presence of both viral antigens in atypical ductules in cases of advanced chronic liver disease most probably expresses the persistence of the virus in cells deriving from biliary metaplasia of infected hepatocytes. However, the detection of the virus in a few typical ductules is indicative of a direct viral infection. According to these findings, ductular cells seem to serve as a suitable host for HBV, their genotype permitting viral replication and antigen production.

Ductular structures in acute hepatitis with panacinar necrosis.

The development of ductular structures in acute hepatitis with panacinar necrosis was studied in 15 cases of fulminant hepatitis with variable clinical duration, using immunohistochemical markers. The immunophenotype of ductular structures was assessed by the expression of two bile duct epithelium determinants, wide spectrum cytokeratin and epithelial membrane antigen (EMA), and by their glycoconjugate expression using the specific binding lectins Dolichos biflorus agglutinin (DBA) and soybean agglutinin (SBA). Ductular structures showed a predilective, but not a strictly selective location in acinar zone 1 and at the periphery of newly formed parenchymal nodules. All were positive for keratin, while EMA and the lectins were identified less frequently. Cytokeratin expression was additionally observed in hepatic cells with no other phenotypic alteration: this occurred along isolated hepatic cords, within parenchymal remnants, in the spared parenchyma in acinar zone 1 and occasionally at the periphery of parenchymal nodules. The presence of cytokeratin expression in liver cell plates in association with intermediate morphological stages of tubular remodelling speaks in favour of biliary metaplasia of hepatocytes. This process may represent a phenotypic-functional accommodation of hepatocytes to an altered microenvironment, due to loss of parenchymal integrity. During the phenotypic shift, altered cytokeratin expression appears as one of the earliest biliary features, while EMA and the expression of glycoconjugates represent maturation markers.

Fulminant hepatitis due to Epstein-Barr virus infection.

Epstein-Barr virus infection is a benign disease, which may occasionally be fatal, particularly in children. Epstein-Barr virus infection is rare in elderly subjects and appears to have a self-limited course. An unusual case of fulminant hepatitis due to primary Epstein-Barr virus infection in a 62-year-old male 18 days after a cardiosurgical operation and blood transfusions is described in the present paper. Post-mortem examination of the liver showed massive hepatic necrosis. The etiology was established by increase in IgM antibodies to Epstein-Barr virus (titer 1:3.120) in serum and by cellular expression of Epstein-Barr virus DNA in liver tissue.

Terbinafine-induced cholestatic liver disease.

Hepatobiliary disorders associated with orally administered terbinafine have rarely been reported. We describe a case of prolonged terbinafine-induced cholestatic liver disease. Extrahepatic cholestasis, viral hepatitis and autoimmune liver disorders were excluded. The histological findings of marked cholestasis without evidence of extrahepatic biliary obstruction or acute hepatitis were compatible with the diagnosis of drug-induced liver disease. Biochemical parameters of liver cell damage returned to normal levels 6 months later.