Search

Background: Molecular targeted drugs are the first line of treatment of advanced hepatocellular carcinoma (HCC) due to its chemo- and radioresistant nature. HCC has several well-documented etiologic factors that drive hepatocarcinogenesis through different molecular pathways. Currently, hepatitis C virus (HCV) is a leading cause of HCC. Therefore, we included a unified cohort of HCV genotype 4-related HCCs to study the expression levels of genes involved in the insulin-like growth factor 1 receptor (IGF1R) pathway, which is known to be involved in all aspects of cancer growth and progression. Aim: Determine the gene expression patterns of IGF1R pathway genes in a cohort of Egyptian HCV-related HCCs. Correlate them with different patient/tumor characteristics. Determine the activity status of involved pathways. Methods: Total ribonucleic acid (RNA) was extracted from 32 formalin-fixed paraffin-embedded tissues of human HCV-related HCCs and 6 healthy liver donors as controls. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) using RT2 Profiler PCR Array for Human Insulin Signaling Pathway was done to determine significantly up- and downregulated genes with identification of most frequently coregulated genes, followed by correlation of gene expression with different patient/tumor characteristics. Finally, canonical pathway analysis was performed using the Ingenuity Pathway Analysis software. Results: Six genes – AEBP1, AKT2, C-FOS, PIK3R1, PRKCI, SHC1 – were significantly overexpressed. Thirteen genes – ADRB3, CEBPA, DUSP14, ERCC1, FRS3, IGF2, INS, IRS1, JUN, MTOR, PIK3R2, PPP1CA, RPS6KA1 – were significantly underexpressed. Several differentially expressed genes were related to different tumor/patient characteristics. Nitric oxide and reactive oxygen species production pathway was significantly activated in the present cohort, while the growth hormone signaling pathway was inactive. Conclusions: The gene expression patterns identified in this study may serve as possible therapeutic targets in HCV-related HCCs. The most frequently coregulated genes may serve to guide combined molecular targeted therapies. The IGF1R pathway showed evidence of inactivity in the present cohort of HCV-related HCCs, so targeting this pathway in therapy may not be effective.

Colorectal carcinoma (CRC) is one of the most common cancers in the world. Preoperative radiation with concurrent chemotherapy and subsequent surgery is the standard treatment for locally advanced rectal cancer. However, the tumor response to preoperative chemoradiotherapy (pCRT) varies significantly. CSCs have been found in many human malignant tumors including rectal cancer. Several markers for CSCs have been proposed in CRC, OCT-4 and CD133 have been the most frequently researched. This study was targeted to evaluate the immunohistochemical expression of stem cell markers OCT-4 & CD133 in rectosigmoid adenocarcinomas and correlate their expressions with the grade, stage, and response of the tumor to CRT. The present study comprised 30 specimens of rectosigmoid adenocarcinoma. The primary antibodies used were: OCT-4 antibody, clone PA5-27438, and CD133 antibody, clone144305. Positive OCT-4 expression was observed in 12/30 cases. A significant relationship was found between OCT-4 expression and tumor stage and sex of the patients. No statistically significant relation was found between OCT-4 expression and age of the patients, tumor grade, lymph node stage, pathological response to CRT, OS, or the expression of CD133. 20/30 cases were positively stained for CD133, no significant correlation between CD133 expression and any of the clinicopathological parameters. OCT-4 was expressed in 40% and CD133 in 66% of rectosigmoid cancers studied, so they might be involved in the development of CRC. New therapeutic perspectives based on the selective targeting of the specific population of cells expressing one of those CSCs. OCT-4 expression might be a bad prognostic indicator in rectosigmoid cancer.

Objective: HER-2/neu status in gastric carcinomas (GCs) has not been studied before in the Egyptian population. Materials and Methods: Seventy-three GCs were evaluated for the expression of HER-2/neu and Ki-67 using immunohistochemistry (IHC). Fluorescence in situ Hybridization (FISH) was done for HER2/neu IHC score 2+ cases. Results: Out of the 73 gastric carcinomas, 23 (31.5%) were score 0, 17 (23.3%) were score 1+, 23 (31.5%) were score 2+, and 10 (13.7%) were score 3+. FISH analysis revealed that the HER-2/neu gene was amplified in 11 out of the 23 cases (47.8%) scored 2+ by IHC. Therefore, the overall HER-2/neu positivity rate was 28.8% and it was significantly associated with higher T-stage and lymphovascular invasion (LVI). The Ki-67 expression rate ranged between 10% and 100%, with 84.9% of the cases (n = 62) featuring high Ki-67 scores. High Ki-67 score was significantly associated with male sex, tumor grade, and number of positive nodes. HER-2/neu protein expression correlated significantly with Ki-67 score. Twenty tumors showed combined HER-2/neu positivity and high Ki-67 score and were significantly associated with higher T-stage and occurrence of LVI, implying a more aggressive behavior. Conclusions: The rate of HER-2/neu positive GCs in our series simulates universal rates, thereby mandating routine evaluation of HER-2/neu status in all GCs submitted to our laboratory to benefit from trastuzumab therapy. Further studies on a larger number of GCs are required to prove that the concurrent HER-2/neu positivity and high Ki-67 score are markers of worse prognosis.

In Egypt colorectal carcinoma (CRC) is the most common type of malignancy of the digestive system. Selectively inhibiting neoangiogenesis by targeting tumor-associated blood vessels is an important therapeutic strategy. Prostate specific membrane antigen (PSMA) is expressed in the tumor-associated neovasculature of most solid cancers making it an interesting therapeutic target. We thought to study the expression of PSMA in a series of CRCs in order to test for its possible use as a target for antiangiogenic cancer therapy in Egyptian patients. One hundred CRC cases were retrieved. Representative sections from each tumor were subjected to immunohistochemistry using PSMA antibodies and CD31 antibodies as reference marker. Accordingly vascular endothelial cell immunoreactivity was semiquantitatively scored. PSMA immunostaining was positive in the neovasculature of 75% of tumors. A statistically significant relation was found between PSMA immunostaining and distant metastasis as well as vascular invasion. The present findings strengthen the evidence on the potential usefulness of PSMA as a therapeutic vascular target. This study is the first to demonstrate a positive relation between PSMA expression in CRC and distant metastasis as well vascular invasion, suggesting that PSMA may play a significant role in vascular invasion and subsequent metastasis.

Fine-needle aspiration cytology (FNAC) of breast masses has been replaced by ultrasound-guided core-needle biopsy (USG-CNB) in many countries. However, in Egypt, breast FNAC continues to play the major role in diagnosing breast masses. In this prospective study, we evaluated the efficacy of USG-FNACs performed at a breast cancer screening center by comparing the FNAC results with the corresponding definitive histological examination outcome. We also investigated the role that CNB can play as a complementary diagnostic tool for FNAC in selected cases. A total of 229 consecutive nonpalpable breast masses were included in this study. Each FNAC was placed into one of four categories: 3.5% nondiagnostic, 13.5% benign, 12.3% atypical/suspicious (indeterminate), and 70.7% malignant. The overall diagnostic accuracy was 98.9%, with a specificity and sensitivity of 99.3 and 96.7%, respectively. The overall positive predictive values and negative predictive values were 99.3 and 96.7%, respectively. Only 37 masses (16%) were converted to CNB, with the indeterminate cytology being the most common cause (54%) for this conversion. Two cases demonstrating the superior benefit of FNAC over CNB are illustrated. Although we started the study by reserving CNB as a first choice to assess microcalcifications without architectural distortion, we ended the study by deciding to perform combined FNAC and CNB for this type of lesions. In conclusion, aiming to maximize the preoperative diagnosis of cancer, it would be cost efficient and time saving to use FNAC as a first-line investigation to benefit from the wealth of cytological information yielded, followed by CNB in selected cases. Diagn. Cytopathol. 2010;38:880–889. © 2010 Wiley-Liss, Inc.

Background: The first step in the evaluation of patients with pleural effusion is to determine whether the effusion is a transudate or an exudate. Osteopontin (OPN) is a pleiotropic integrin-binding protein with many functions. We assessed pleural effusion and serum concentrations of OPN and C-reactive protein (CRP) in patients with different types of pleural effusions. Methods: The current study comprised three groups: 20 patients with transudative effusion, 30 patients with malignant effusion and 30 patients with tuberculous effusion. OPN was analysed using a commercially available enzyme-linked immunosorbent assay kit. Results: OPN effusion values were significantly higher in exudates (both malignant and tuberculous effusion cases) compared with transudative effusion. Also when compared separately, patients with tuberculous effusion and those with malignant effusion had a significantly higher fluid and OPN effusion/serum ratio than those with transudative effusion. Patients with tuberculous effusion had a significantly higher serum CRP effusion and effusion/serum ratio of CRP than those with malignant or transudative effusion. Conclusion: OPN is significantly increased in exudative effusion compared with transudative ones. However, serum OPN and effusion/serum OPN ratio were not significantly different in patients with malignant from those with tuberculous effusions. The lack of difference in serum OPN and effusion/serum OPN ratio between patients with malignant and those with tuberculous effusion may be attributed to the heterogeneity of the malignant effusion group. Receiver-operating characteristic (ROC) curve analysis has shown that effusion/serum CRP ratio outperformed effusion/serum OPN ratio as a diagnostic marker for tuberculous pleural effusion.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. With the growing effectiveness and availability of first and second-generation tyrosine kinase inhibitor (TKI) drugs, the accurate diagnosis of GIST has become imperative. The problem is that some GISTs with KIT or Alpha-type platelet-derived growth factor receptor (PDGFRA) mutations may have low KIT expression by immunohistochemistry yet will still benefit from TKI drugs. Molecular analysis is a costly and laborious process. Therefore the emergence of a new sensitive immunohistochemical marker for GISTs would be ideal. Recently antibodies against "Discovered on GIST-1" (DOG1) have been generated. The aim of this study was to evaluate the monoclonal DOG1.1 antibody as a diagnostic marker for GISTs and to compare immunohistochemical staining and diagnostic efficacy of DOG1.1 with that of KIT in GISTs.Forty seven paraffinembedded GISTs were immunostained with both KIT and DOG1.1 antibodies. Immunoreactivity was graded semiquantitatively from 0 to 4. Some other mesenchymal tumors were included in the study and stained for both markers to test for their specificity.Out of the 47 GISTs, 44 were immunoreactive for both KIT and DOG1.1 antibodies (93.62%). Two cases (4.25%) were KIT-positive DOG-negative and the remaining case was DOG-positive KIT-negative (2.13%). A statistically significant concordance was found between KIT and DOG1.1 immunoreactivity (p=0.004), with moderate agreement between immunostaining scores (kappa =0.379). As regards tumor site, a statistically significant association was found between high DOG1.1 scores and gastric GIST (p=0.008). High KIT and DOG1.1 immunostaining scores were significantly associated with highrisk tumors (p=0.002 and p=0.002 respectively). DOG1.1 immunoreactivity was focal in more than half of the cases. The overall diagnostic accuracy of DOG1.1 was 96.5%, with a specificity and sensitivity of 100% and 95.7%, respectively. The overall positive predictive values and negative predictive values were 100% and 84.6%, respectively. As for KIT, The overall diagnostic accuracy was 94.8%, with a specificity and sensitivity of 81.8% and 97.8%, respectively. The overall positive predictive values and negative predictive values were 95.8% and 90%, respectively.This study has demonstrated that DOG1.1 is a more specific marker for GIST than KIT, yet its sensitivity is a little inferior to that of KIT owing possibly to the focal staining of DOG1 antibody in many cases. In conclusion, in our institution, in which cost effective health care is a priority, we recommend using DOG1 as the first choice antibody for the diagnosis of GIST as it is a more specific marker. If it is negative, then KIT is tried. If this latter is also negative, then several other antibodies should be tested. And owing to the potential therapeutic significance of GIST diagnosis, if still the results of immunohistochemistry are ambiguous, mutational analysis should be considered to confirm the diagnosis.GIST - DOG1 - KIT - Immunohistochemistry.

Angiogenesis and lymphangiogenesis are essential for breast cancer growth and progression. This study aimed at investigating lymphatic microvessel density (LVD) and microvessel density (MVD) as prognostic markers in breast carcinoma. Forty breast carcinomas were immunostained for D2-40, CD31 and VEGF. Median lymphatic and blood microvessel densities, as well as VEGF expression, were related to each other and to clinicopathologic parameters including lymph node (LN) status. The efficacy of haematoxylin and eosin (HE) in detecting lymphatic vessel invasion (LVI) compared to D2-40 immunostaining was also investigated. D2-40 stained normal lymphatic endothelium and myoepithelial cells, but with different staining patterns. D2-40 LVD related significantly to CD31 counts (r=0.470; p=0.002), and LN metastasis (Mann-Whitney U=101.500; p=0.043); however, it did not relate to age, tumor grade, tumor size or LVI. D2-40 identified LVI in 3 more cases (7.5%) than those detected by HE. VEGF was expressed in 85%of cases, and was significantly related to CD31 and D2-40 counts (p=0.033 and 0.007, respectively). In conclusion, D2-40 LVD showed a significant association with LN metastasis, and can be considered to segregate patients with positive from those with negative LNs. D2-40 enhances the detection of LVI relative to HE staining reflecting a potential for lymphatic metastatic spread and possible poor prognosis.

Background:Data from Egyptian studies provide widely varying estimates on the prevalence of preinvasive cervical lesions. The aim of this study was to estimate the rate of cervical intraepithelial neoplasia (CIN) in Egyptian women living in Alexandria to clarify the need for implementing a national organized screening program and a vaccination program in our community.Materials and Methods:The study was conducted over a 6 years period and covered the different socioeconomic levels to have a representative sample for women living in Alexandria. All women included did not have any cervical disorder related complaints. Conventional Pap smears were obtained and diagnosed using the Bethesda system. Women with abnormal Pap smears were managed according to the 2006 consensus guidelines within the available facilities. Persistent abnormal cytological results were referred for colposcopic biopsy. Histological results were grouped into: Reactive changes, CIN 1, CIN 2/CIN 3 and adenocarcinomain-situ(AIS).Results:Out of the 6173 smears included in the study 6072 (98.36%) were normal and only 101 (1.63%) were abnormal. After colposcopic biopsies, 0.08% had CIN 1, 0.03% had CIN 2, 3 and 0.01% had AIS.Conclusion:We concluded that cervical cancer screening programs, although life-saving for a number of women, are not a sufficiently high priority in our community. Money for national health screening programs should preferably be directed more towards recruiting women for breast cancer screening, since breast cancer accounts for about 33% of all female cancers in Egypt ranking number one, while cervical cancer ranks number 13.