Prognostic Significance of p27 and Survivin in H. pylori Gastritis and Gastric Cancer.

OBJECTIVE: to assess expression of p27 and survivin in chronic gastritis with/without H. pylori ± intestinal metaplasia (IM) and in intestinal-type gastric cancer (IGC). MATERIALS AND METHODS: Immunohistochemical staining for p27 and survivin on paraffin-embedded sections of 20 chronic gastritis, 20 H. pylori gastritis, 15 H. pylori gastritis with IM, 50 IGC, and 10 controls. Positivity (number of positive cases) and expression (mean percentage of positive gastric cells) for both proteins were evaluated. RESULTS: P27 positivity and expression decreased from control to chronic gastritis to H. pylori gastritis to H. pylori gastritis with IM. In IGC, p27 positivity and expression were lower than controls and chronic gastritis but higher than H. pylori gastritis ±IM. High grade and advanced stage IGCs have insignificantly lower p27 positivity and expression than low grade and early stage IGCs. By contrast, survivin positivity and expression increased from chronic gastritis to H. pylori gastritis to H. pylori gastritis with IM to IGCs. High grade and advanced stage IGCs have significantly higher survivin positivity and expression than low grade and early stage IGCs. Males have higher positivity and expression for p27 and survivin than females. CONCLUSION: Inverse relation between p27 and survivin in H. pylori gastritis, H. pylori gastritis with IM and IGCs lesions, suggesting that both proteins could be used as potential prognostic and/or diagnostic biomarkers in H. pylori and IM associated- gastritis as well as in IGC.

Differential Expression of HER2 and SKP2 in Benign and Malignant Colorectal Lesions.

BACKGROUND: Colorectal cancer (CRC) is the fourth most common cancer worldwide. Both HER2 and SKP2 have a carcinogenic role in CRC making them attractive targets for tailored treatment. This work aims to correlate HER2 and SKP2 protein expression as well as HER2 gene amplification with clinicopathological parameters aiming at identifying potential candidates for targeted therapy. METHODS: This Study was conducted on 127 paraffin-embedded tissue samples of different colorectal lesions [controls, chronic colitis, ulcerative colitis (UC), hyperplastic polyps (HPs), adenomas and CRCs] to investigate HER2 and SKP2 expression by immunohistochemistry (IHC), Selected CRC cases [equivocal (2+) and positive (3+) by IHC] were further evaluated by ISH (CISH and SISH ) to assess HER2 gene amplification. RESULTS: Chronic colitis, UC, HPs and adenomas were HER2-negative. HER2 positivity (scores 2+ and 3+) was found only in15% of CRCs. Both SISH and CISH showed the same results with high concordance as 66.7% of equivocal and 100% of positive cases showed amplification of HER2 gene. SKP2 positivity was detected in 26.7% and 45% of adenomas and CRCs respectively, while other studied groups were negative. A significant correlation was noted between HER2 and SKP2 expression. CONCLUSION: A small percent of CRCs exhibited HER2 gene amplification, which would be potential candidates for anti HER2 therapy whereas IHC could be a primary screening test for patient selection. A potential carcinogenic role of SKP2 was suggested by the findings that SKP2 expression was undetectable in normal colonic mucosa but significantly increases from adenoma to carcinoma, hoping adenoma patients to get benefit from targeted therapy.
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Expression of Epidermal Growth Factor Receptor and Transforming Growth Factor Alpha in Cancer Bladder: Schistosomal and Non-Schistosomal.

INTRODUCTION: Overexpression of epidermal growth factor receptor (EGFR) has been described in several solid tumors including bladder cancer. Transforming growth factor alpha (TGFα) is frequently deregulated in neoplastic cells and plays a role in the development of bladder cancer. TGFα-EGFR ligand-receptor combination constitutes an important event in multistep tumorigenesis. METHODS: This study was done on 30 bladder biopsies from patients with urothelial carcinoma, 15 with squamous cell carcinoma, 10 with cystitis and 5 normal control bladder specimens. All were immuohistochemically stained with EGFR and TGFα antibodies. RESULTS: EGFR and TGFα were over-expressed in higher grades and late stages of bladder cancer. Moreover, they show higher expression in squamous cell carcinoma compared to urothelial carcinoma and in schistosomal associated lesions than in non-schistosomal associated lesions. CONCLUSION: EGFR and TGFα could be used as prognostic predictors in early stage and grade of bladder cancer cases, especially those with schistosomal association. In addition they can help in selecting patients who can get benefit from anti-EGFR molecular targeted therapy.

Impact of epidermal growth factor receptor and transforming growth factor-α on hepatitis C virus-induced hepatocarcinogenesis.

Epidermal growth factor receptor system plays a central hepato-protective and pro-regenerative role in liver. Transforming growth factor-α (TGF-α) is an important autocrine growth regulator of hepatocytes that plays a role in development of hepatocellular carcinoma (HCC) among patients with chronic hepatitis C (CHC). This study was done on 40 core liver biopsies from patients with CHC, 20 liver specimens from HCC cases on top of CHC as well as five normal controls. All were immunohistochemically stained with epidermal growth factor receptor (EGFR) and TGF-α antibodies. Some selected HCC cases were submitted for FISH technique to detect EGFR gene alteration. By immunohistochemistry EGFR and TGF-α were overexpressed in HCC and cirrhotic cases compared to CHC cases without cirrhosis. Also, their expression was stronger in CHC cases with higher grades of activity and stages of fibrosis compared to lower ones. FISH positive results for EGFR were detected in 33.3% of the examined HCC cases. EGFR and TGF-α can be used as predictive markers for activity, fibrosis, and carcinogenesis in CHC patients. Overexpression of EGFR in HCC patients can be promising in selecting those who can get benefit from anti-EGFR target therapy.

Anti-inflammatory/anti-fibrotic effects of the hepatoprotective silymarin and the schistosomicide praziquantel against Schistosoma mansoni-induced liver fibrosis.

BACKGROUND: Praziquantel (PZQ) is an isoquinoline derivative (2-cyclohexylcarbonyl-1, 2, 3, 6, 7, 11b-hexahydro-4H-pyrazino{2,1-a}-isoquinoline-4-one), and is currently the drug of choice for all forms of schistosomiasis. Silymarin, a standardized milk thistle extract, of which silibinin is the main component, is known for its hepatoprotective, anti-inflammatory, antioxidant activities, and hepatocyte regeneration. This study investigates the anti-inflammatory/anti-fibrotic effects of silymarin and/or PZQ on schistosomal hepatic fibrosis. METHODS: Schistosoma mansoni-infected mice were divided into two large groups (I & II), each with four subgroups and were run in parallel. (i) Infected untreated; (ii) treated with silymarin, starting from the 4th (3 weeks before PZQ therapy) or 12th (5 weeks after PZQ therapy) weeks post infection (PI); (iii) treated with PZQ in the 7th week PI; and (iv) treated with silymarin, as group (ii) plus PZQ as group (iii). Comparable groups of uninfected mice run in parallel with the infected groups. Mice of groups I and II were killed 10 and 18 weeks PI, respectively. Hepatic content of hydroxyproline (HYP), serum levels and tissue expression of matrix metalloproteinase-2 (MMP-2), transforming growth factor-ß1 (TGF-ß1) and number of mast cells were determined. In addition, parasitological, biochemical and histological parameters that reflect disease severity and morbidity were examined. RESULTS: Silymarin caused a partial decrease in worm burden; hepatic tissue egg load, with an increase in percentage of dead eggs; modulation of granuloma size, with significant reduction of hepatic HYP content; tissue expression of MMP-2, TGF-ß1; number of mast cells, with conservation of hepatic reduced glutathione (GSH). PZQ produced complete eradication of worms, eggs and alleviated liver inflammation and fibrosis. The best results were obtained, in most parameters studied, in groups of mice treated with silymarin in addition to PZQ. CONCLUSIONS: Our results point to silymarin as a promising anti-inflammatory and anti-fibrotic agent; it could be introduced as a therapeutic tool with PZQ in the treatment of schistosomal liver fibrosis, but further studies on mechanisms of silymarin and PZQ in chronic liver diseases may shed light on developing therapeutic methods in clinical practice.

Potential antifibrotic effects of AT1 receptor antagonist, losartan, and/or praziquantel on acute and chronic experimental liver fibrosis induced by Schistosoma mansoni.

1. This study investigates the potential antifibrotic effect of losartan, AT-1 receptor antagonist, and/or praziquantel (PZQ) on acute and chronic hepatic fibrosis induced by Schistosoma mansoni (S. mansoni). 2. Schistosoma mansoni-infected mice were in two batches (I & II), each in four groups: (i) Infected untreated; (ii) treated with losartan, starting from the 4th or 12th weeks post-infection (PI); (iii) treated with PZQ in the 7th week PI; and (iv) treated with losartan, as group (ii) plus PZQ as group (iii). Comparable groups of uninfected mice were run in parallel with infected groups. Mice of batches I and II were killed 10 and 18 weeks PI, respectively. Hepatic content of hydroxyproline (HYP), serum levels and tissue expression of matrix metalloproteinase-2 (MMP-2), and transforming growth factor-ß1 (TGF-ß1) were determined. Parasitological, biochemical and histological parameters, which reflect disease severity and morbidity, were examined. 3. Losartan alone caused a considerable decrease in worm burden, hepatic tissue egg load with an increase in percentage of dead eggs, modulation of granuloma size and regression of inflammatory reactions, which was less obvious in the chronic stage. The best results were obtained when losartan was co-administered with PZQ, especially in the acute stage. This was revealed by a remarkable reduction in serum levels and tissue expression of MMP-2, TGF-ß1 and HYP content, accompanied by conservation of hepatic reduced glutathione (GSH) versus the PZQ-treated group. 4. In conclusion, losartan has a promising antifibrotic action and could be introduced as a therapeutic tool with PZQ especially in acute schistosomal hepatic fibrosis.

Role of human papillomavirus types 16, 18, and 52 in recurrent cystitis and urinary bladder cancer among Egyptian patients.

BACKGROUND: Bladder cancer is a common malignancy in Egypt. Human papillomavirus (HPV) could have a possible etiologic role in bladder carcinogenesis. We aimed to estimate the prevalence of HPV-16, -18, and -52 in Egyptian patients with bladder cancer or recurrent cystitis, and to study the correlation of type-specific HPV-immunoglobulin (Ig)G with polymerase chain reaction (PCR) results and different clinicopathologic parameters. METHODS: This study was conducted on 60 inpatients of the Urosurgery Department at the Theodor Bilharz Research Institute (TBRI), who were identified histopathologically and clinically as cancer bladder (group I, 20 patients), cystitis (group II, 24 patients), and cancer bladder with cystitis (group III, 16 patients), and a fourth group of 20 healthy control subjects (for serologic testing). Patients were subjected to detection of HPV-16 and -18 DNA by PCR on bladder tissue biopsies (BTB) and buffy coat cells (BCC) and serum IgG antibodies to L1 capsids of HPV-16 and -52 IgG by enzyme-linked immunosorbent assay (ELISA). RESULTS: HPV-16 and -18 DNA were detected in BTB (30% and 10%, respectively) with significantly higher rates (44.4%) in bladder cancer than cystitis cases (11.11%), with significant association with schistosomal affection (78.6% and 25%, respectively) and recurrence (48%, HPV-16). There was a significant association of transitional cell carcinoma (TCC) with HPV-16 in 69.2% and 61.1% of BCC and BTB, respectively. Multiple HPV types 16, 18, and 52 were significantly higher than single types (79.2% and 20.8%, respectively). The observed absolute association between seropositivity of HPV-52 (11.7%) and HPV-16 (26.7%) was significantly associated with TCC in patient groups only. CONCLUSION: Our study confirmed the significant association of HPV-16, -18 and -52 with bladder cancer in Egyptian patients, with the suggestion of viral synergistic action in bladder carcinogenesis. Such HPV types were significantly associated with TCC tumors of low grade and high stage, with schistosomal affection and recurrence tendency. HPV serology would pave the way for better management and follow-up of patients and for optimal design and evaluation of HPV vaccination.

SEN virus infection in Egyptian patients with chronic hepatitis C and patients undergoing hemodialysis.

The SEN virus has been tentatively linked to transfusion-associated non-A to E hepatitis. The aim of the present study was to 1) determine the prevalence of SEN virus among Egyptian patients with hepatitis C virus (HCV)-related chronic liver disease and patients undergoing hemodialysis and 2) demonstrate the clinical effect of SEN virus infection on coexistent hepatitis C in terms of severity and probability of developing hepatocellular carcinoma. Polymerase chain reaction was used to detect SEN virus-D and SEN virus-H DNA in serum samples of 74 patients with HCV-related chronic liver disease, 45 uremic patients undergoing maintenance hemodialysis, and 28 healthy controls. SEN virus-D/H DNA was detected in 13.5% of patients with chronic liver disease, 11.1% of patients undergoing hemodialysis, and 7.1% of healthy controls, with no significant differences between patients and the control group. Clinical and biochemical measures did not significantly differ between SEN virus-infected and noninfected patients in the chronic liver disease group or the hemodialysis group. The rate of SEN virus infection was significantly higher in patients with chronic liver disease and hepatocellular carcinoma (33.3%) than in those with chronic liver disease only (8.5%) (P < .05). In conclusion, SEN virus does not seem to be a common infection in Egyptian patients. It has no apparent influence on the severity of coexistent HCV-related chronic liver disease but could be a risk factor for hepatocellular carcinoma in such patients. Further studies are needed to define the etiopathogenic role of SEN virus infection in the development of hepatocellular carcinoma.

The effect of portal vein branch plus heterochronous hepatic artery branch ligation on liver regeneration (experimental study).

The proliferative capacity of non-ligated liver lobes was designned experimental study on dogs in which portal vein and hepatic artery ligation was done either simultaneously or heterochronously. Dogs were divided into four groups: G I (control G); laparotomy was performed without vascular ligation, G II; dogs were subjected to ligation of the right lateral and median branches of portal vein alone, G III, dogs were subjected to hepatic artery branches ligation 48h after portal vein branches ligation. G IV, dogs were subjected to ligation of the same branches of the portal vein and hepatic artery simultaneously. Dogs from each group were subjected to a liver biopsy before and 24, 48, 72, & 168h (one week) after surgery. Standard serum liver functions were tested before ligation, 72 hs and one week after ligation. Hepatic regeneration in the non-ligated lobe was assessed through histo-pathological study, DNA quantitation of the hepatic nuclei by the computerized image analysis system and estimation of proliferation marker in hepatic tissue. In this study, the labeling index of the nuclear factor NF Kappa B (P105), a novel monoclonal antibody specific for P105 protein, was determined immunohistochemically. Results showed induction of the NK kappa B (P105) labeling index showed maximum levels G III. Quantitative determination of serum glutamic-oxalacetate transaminase (GOT) showed peak levels in G IV at 24h after surgery. Our finding for this index that heterochronous partial portal vein and hepatic artery ligation (i.e., G III) is effective, because this procedure leads to an increase in the compensatory hypertrophy of the non-ligated liver lobes that depends on the regenerative capacity of the lobes themselves. In contrast, in G IV (i.e., synchronous ligation of portal vein and hepatic artery branches) liver regeneration did not occur due to the severe systemic damage induced by infectious necrosis in the ligated lobe. The serial changes in liver function in G III indicate that the use of this technique may minimize dysfunction in the remaining hypertrophied liver lobes, similar to findings in G II. So, the PVBL plus heterochronous HABL procedure is safer and more effective than PVBL alone, or PVBL plus simultaneous HABL. A better knowledge of the events following such heterochronous ligation should improve the clinical outcome of hepatic resection for liver diseases.