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2001
b El Mawla, N. G. a, M. N. a El Bolkainy, and H. M. a Khaled, "Bladder cancer in Africa: Update", Seminars in Oncology, vol. 28, no. 2, pp. 174-178, 2001. AbstractWebsite

Carcinoma of the bladder is the most prevalent cancer in Egypt and in most African countries. At the National Cancer Institute (NCl), Cairo, it constitutes 30.3% of all cancers. The median age at diagnosis is 46 years, with a male preponderance of 5:1. Whether in Egypt or other African countries such as Sudan, Kenya, Uganda, Gold Coast, and Senegal, it is mostly of the squamous cell type, and arises in a background of schistosomiasis or bilharziasis. Tumors are usually advanced at the time of presentation. Bladder carcinogenesis is probably related to bacterial and human papilloma virus (HPV) infections, usually associated with bilharzial infestation. Management is mainly surgery, with 5-year survival rates after radical cystectomy increasing from 35% in the 1970s to 48% in the 1990s. The addition of adjuvant and neoadjuvant radiotherapy and chemotherapy to surgery since 1976 significantly improved both disease-free and overall survival rates. Molecular genetic studies concerning potential prognostic markers, tumorigenesis, and tumor progression in bilharzial bladder cancer are limited. However, a comprehensive detailed analysis of these factors is underway. Bilharzial bladder cancer is a preventable malignant disease. Primary prevention could be possible if the parasite is eliminated nationwide. Chemoprevention using retinoids or cyclooxygenase 2 (COX-2) inhibitors is a possible alternative. Copyright © 2001 by W.B. Saunders Company.

Zekri, A. - R. N., A. A. Bahnassi, A. Raafat, N. Mokhtar, Z. S. El-Din, and H. M. Khaled, "Correlation between P53 mutation and HPV in Bilharzial bladder cancer", Cancer Molecular Biology, vol. 8, no. 3, pp. 1671-1686, 2001. AbstractWebsite

Alterations of the p53 tumor suppressor gene are the most common genetic change detected in human cancers as well as in papillary and invasive bladder cancer. Several studies have demonstrated an association between HPV infection and urological malignancies. In the present work, the p53 gene status was studied together with the frequency of HPV in 101 cases of Bilharzial bladder cancer (BBC) in Egypt and both were correlated to the clinicopathological features of the patients. SSCP and sequencing were used to screen the p53 gene for mutations at exons 4-10 and IHC was performed to detect the protein overexpression. PCR was used for detection and typing of HPV-DNA in tumor samples. P53 mutations were detected in 32.7% of the studied cases whereas protein overexpression was detected in 36.6% of the cases. The highest concordance rate was observed in cases harboring mutations at exon 4 (87.5%). Bilharzial infestation was obvious in 72.2% of the cases that showed mutations. Exon 8 showed the highest rate of mutation (32%) followed by exons 4 and 5 (22% each). The commonest mutational event was G:C transversion (15/50) especially at CpG dinucleotides. A mutational hot spot was detected at exon 4, codons 72-73. HPV-DNA was detected in 48.97% of the cases the majority of which (64.6%) were of type 16. Significant correlation was found between p53 mutation and the pathological stage as well as p53 overexpression and tumor grade. Our results demonstrate that the mutational spectrum in BBC is different than that of bladder cancer in Western countries in many aspects and suggest an etiological role of HPV in this type of neoplasm. However, both HPV infection and p53 gene abnormalities may contribute to Bilharzial bladder carcinogenesis in an independent way.

c Khaled, H. M. a, I. a Abdel-salam, M. a Abdel-gawad, A. A. Metwally, S. a El-demerdash, M. a El-didi, A. a Morsi, and L. b Ishak, "Evaluation of the BTA tests for the detection of bilharzial related bladder cancer: The Cairo experience", European Urology, vol. 39, no. 1, pp. 91-94, 2001. AbstractWebsite

Objective: To evaluate the clinical performance of the BTA stat test and the BTA TRAK assay in the diagnosis of bilharzia-related bladder cancer and to calculate a new 'Egyptian' cut-off value for the BTA TRAK (quantitative) assay. Methods: Urine samples of 149 individuals were tested for the presence of the human complement factor H-related protein, the antigen detected by the BTA stat and BTA TRAK tests. The group consisted of 53 healthy volunteers, 20 patients with active bilharziasis, 11 patients with other urologic disorders including prostate cancer, and 65 patients with histologically proven bladder cancer. All samples were obtained prior to surgery or therapy. Results: The BTA stat test was positive in 64 of 65 samples from patients with bladder cancer, for an overall sensitivity of 99%. With a BTA TRAK assay cut-off of 60 U/ml (set at 97% specificity in the healthy population), the sensitivity of the TRAK assay was 94%. There was no statistically significant difference between the sensitivities of the two BTA tests in patients diagnosed with squamous cell carcinoma and those with transitional cell carcinoma. The overall specificity of the BTA stat test was 67% ranging from 15% in patients with bilharziasis to 94% in healthy volunteers. The overall specificity of the TRAK assay was 66%, again with negative results in 15% of the patients with bilharziasis. Conclusions: The BTA stat test and TRAK tests are extremely sensitive in the detection of bladder cancer in the Egyptian population. Positive results (85%) are also observed in patients with active bilharziasis, which often leads to bladder cancer. Longitudinal follow-up of these positive cases is needed to determine whether these positive results are false or predictive of bladder cancer. Copyright © 2001 S. Karger AG, Basel.

Khaled, H. M., A. Raafat, N. Mokhtar, A. R. N. Zekri, and H. Gaballah, "Human papilloma virus infection and overexpression of p53 protein in bilharzial bladder cancer", Tumori, vol. 87, no. 4, pp. 256-261, 2001. AbstractWebsite

Aims and background: An association between human papilloma virus (HPV) and bladder cancer has been reported. However, the role of HPV in bilharzial bladder cancer and its prevalence have not yet been clarified. Study design: We investigated 50 cases for HPV types 16/18 by in situ hybridization. Also, p53 protein expression by immunohistochemistry was evaluated in 41 of the 50 cases, with correlation of these factors to clinicopathologic parameters and tumor relapse after primary treatment. Results: HPV was detected in 46% of Egyptian bladder carcinomas (23/50 cases). Positivity was 47.8% for squamous cell carcinoma and 36.4% for transitional cell carcinoma. There was a possible viral-bilharzial association as 52.8% of Bilharzial cases, whereas only 12.5% of non-Bilharzial cases were HPV positive (P < 0.05). P53 protein was found in 19/41 (46.3%) cases. There was a concordance between HPV and p53 in 58.5% of cases. Neither factor was related to tumor recurrence after primary treatment. Conclusions: HPV may thus be implicated in the etiology of bilharzial bladder cancer, but a definite causal relationship remains to be demonstrated. HPV together with p53 alterations work in synergy to accelerate the carcinogenic process, as there was concordance in the results of both parameters in 24/41 (58.5%) cases.

Soliman, A. S., B. Levin, S. El-Badawy, S. S. Nasser, A. A. Raouf, H. Khaled, O. H. El-Hattab, and R. M. Chamberlain, "Planning cancer prevention strategies based on epidemiologic characteristics: An Egyptian example", Public Health Reviews, vol. 29, no. 1, pp. 1-11, 2001. AbstractWebsite

Background and Methods: We describe the epidemiology, cancer prevention strategies, and educational messages to be learned from four characteristic cancers in Egypt: urinary bladder, liver, lung, and early-onset colorectal cancers. Results: For bladder cancer, effective and convenient treatment of schistosomiasis, using social marketing and mass media in public and medical education has contributed dramatically to primary prevention of bladder cancer in Egypt. For liver cancer, educating hospital administrators to remove structural barriers to good practice may help the control of hepatitis transmission and related liver cancer. For lung cancer, the 50-year American experience for controlling tobacco smoking, beginning with physicians, could be very effective in Egypt and other countries with increasing smoking rates in the young so as to avert the expected epidemics of lung cancer. For colorectal cancer, more attention to physician and public education about the importance of interviewing colorectal cancer patients about a family history of cancer and the screening of at -risk families could be very effective in early detection of colorectal cancer. Conclusion: Countries with similar cancer epidemiology experience should make use of successful cancer prevention and education strategies that could be translated from the Egyptian experience.

Abdel-Salam, I. M. a, H. M. a Khaled, H. E. b Gaballah, O. M. b Mansour, H. A. A. c Kassem, and A. M. a Metwaly, "Telomerase activity in bilharzial bladder cancer: Prognostic implications", Urologic Oncology, vol. 6, no. 4, pp. 149-153, 2001. AbstractWebsite

{Background: Bladder cancer is a common malignancy in Egypt and other developing countries in which infection with Schistosoma haematobium is prevalent. Bladder cancer caused by bilharziasis has different clinical and biological characters than that observed in the western world. In this study, we used the TRAP technique to estimate telomerase activity in bilharzial bladder cancer specimens and we correlated the findings with other clinical and pathological findings. Patients and methods: Bladder cancer specimens were obtained from 57 patients who underwent radical cystectomy and pathological diagnosis was obtained in all patients. Tissue samples were frozen in liquid nitrogen and stored at -80°C. Telomerase activity by PCR-ELISA technique was measured using TRAP technique. Results: Our patient group included 45 males and 12 females with a median age of 49 years. The majority of our patients (35/57) have squamous histology and they have proven bilharzial history shown in the pathology specimens. Stage P3b was encountered in 29/57 patients whereas thirty-five patients have grade II tumors. The majority of our patients (41/57) were negative for pelvic nodes metastases. Telomerase activity was detected in 27/57 patients (47.4%). The mean level of telomerase was 0.85±0.77 in positive patients and 0.029±0.025 in negative patients. The expression of telomerase and its mean level in patients above age of 60, in males and in those with squamous pathology, higher grade of tumors or positive node was higher than those without but the difference did not reach statistical significance (P>0.05). Alternatively, expression was significantly higher in those with stages (P1-P3a) compared with P3b-P4a disease stages (66.6% vs. 37.1

2000
Abdel-Rahman, S. Z., A. S. Soliman, M. L. Bondy, S. Omar, S. A. El-Badawy, H. M. Khaled, I. A. Seifeldin, and B. Levin, "Inheritance of the 194Trp and the 399Gln variant alleles of the DNA repair gene XRCC1 are associated with increased risk of early-onset colorectal carcinoma in Egypt.", Cancer letters, vol. 159, issue 1, pp. 79-86, 2000 Oct 16. Abstract

Patients under age 40 constitute 35.6% of all colorectal cancer cases in Egypt, an unusual disease pattern to which both environmental exposures and inefficient DNA repair may contribute. While a number of polymorphisms in DNA repair genes have been recently identified, their role as cancer risk modifiers is yet to be determined. In a pilot case-control study, we tested the hypothesis that polymorphisms in the gene for the DNA repair enzyme XRCC1 are associated with increased risk of colorectal cancer among Egyptians. Using a multiplex polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methodology, allelic variants of the XRCC1 gene at codons 194 (Arg-->Trp) (194Trp) and 399 (Arg-->Gln) (399Gln), were analyzed in DNA from lymphocytes of 48 newly-diagnosed colorectal cancer cases and 48 age- and sex-matched controls. Overall, the inheritance of 194Trp allele (Arg/Trp genotype) and 399Gln allele (combined Arg/Gln and Gln/Gln genotypes) was associated with increased colorectal cancer risk (odds ratio (OR)=2.56, 95% confidence limits (CL) 0.73-9.40, and P=0. 08 for 194Trp allele and OR=3.98, 95% CL 1.50-10.6, and P<0.001 for 399Gln allele). Interestingly, the frequencies of 194Trp and 399Gln genotypes were higher in colorectal cancer cases under age 40 than in corresponding controls, and an association between both polymorphisms and early age of disease onset was observed (OR=3.33, 95% CL 0.48-35.90, and P=0.16 for 194Trp and OR=11.90, 95% CL 2.30-51.50, and P=0.0003 for 399Gln). Analysis of the data after adjustment for place of residence indicated that the frequencies of the genotypes with the 194Trp and the 399Gln alleles were higher among urban residents (OR=3.33, 95% CL 0.48-35.90, and P=0.16 for 194Trp and OR=9.97, 95% CL 1.98-43.76, and P<0.001 for 399Gln) than among rural residents (OR=2.00, 95% CL 0.36-26.00, and P=0.30 for 194Trp and OR=1.90, 95% CL 0.50-7.53, and P=0.20 for 399Gln). These findings support our hypothesis and suggest that polymorphisms in the XRCC1 gene, in conjunction with place of residence, may modify disease risk. This first demonstration that polymorphisms in DNA repair genes may contribute to colorectal cancer susceptibility and may increase the risk of early onset of the disease opens the door for future studies in that direction.

Abdel-Rahman, S. Z., A. S. Soliman, M. L. Bondy, S. Omar, S. A. El-Badawy, H. M. Khaled, I. A. Seifeldin, and B. Levin, "Inheritance of the 194Trp and the 399Gln variant alleles of the DNA repair gene XRCC1 are associated with increased risk of early-onset colorectal carcinoma in Egypt.", Cancer letters, vol. 159, issue 1, pp. 79-86, 2000 Oct 16. Abstract

Patients under age 40 constitute 35.6% of all colorectal cancer cases in Egypt, an unusual disease pattern to which both environmental exposures and inefficient DNA repair may contribute. While a number of polymorphisms in DNA repair genes have been recently identified, their role as cancer risk modifiers is yet to be determined. In a pilot case-control study, we tested the hypothesis that polymorphisms in the gene for the DNA repair enzyme XRCC1 are associated with increased risk of colorectal cancer among Egyptians. Using a multiplex polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methodology, allelic variants of the XRCC1 gene at codons 194 (Arg-->Trp) (194Trp) and 399 (Arg-->Gln) (399Gln), were analyzed in DNA from lymphocytes of 48 newly-diagnosed colorectal cancer cases and 48 age- and sex-matched controls. Overall, the inheritance of 194Trp allele (Arg/Trp genotype) and 399Gln allele (combined Arg/Gln and Gln/Gln genotypes) was associated with increased colorectal cancer risk (odds ratio (OR)=2.56, 95% confidence limits (CL) 0.73-9.40, and P=0. 08 for 194Trp allele and OR=3.98, 95% CL 1.50-10.6, and P<0.001 for 399Gln allele). Interestingly, the frequencies of 194Trp and 399Gln genotypes were higher in colorectal cancer cases under age 40 than in corresponding controls, and an association between both polymorphisms and early age of disease onset was observed (OR=3.33, 95% CL 0.48-35.90, and P=0.16 for 194Trp and OR=11.90, 95% CL 2.30-51.50, and P=0.0003 for 399Gln). Analysis of the data after adjustment for place of residence indicated that the frequencies of the genotypes with the 194Trp and the 399Gln alleles were higher among urban residents (OR=3.33, 95% CL 0.48-35.90, and P=0.16 for 194Trp and OR=9.97, 95% CL 1.98-43.76, and P<0.001 for 399Gln) than among rural residents (OR=2.00, 95% CL 0.36-26.00, and P=0.30 for 194Trp and OR=1.90, 95% CL 0.50-7.53, and P=0.20 for 399Gln). These findings support our hypothesis and suggest that polymorphisms in the XRCC1 gene, in conjunction with place of residence, may modify disease risk. This first demonstration that polymorphisms in DNA repair genes may contribute to colorectal cancer susceptibility and may increase the risk of early onset of the disease opens the door for future studies in that direction.

Khaled, H. M., M. R. Hamza, O. Mansour, R. Gaafar, and M. S. Zaghloul, "A phase II study of gemcitabine plus cisplatin chemotherapy in advanced bilharzial bladder carcinoma.", European journal of cancer (Oxford, England : 1990), vol. 36 Suppl 2, pp. 34-7, 2000 Jul. Abstract

Bilharzial bladder cancer represents a distinct clinicopathological entity. To investigate whether gemcitabine-cisplatin is also active against bladder cancer of bilharzial origin, we performed a phase II study of previously untreated patients with stage III/IV disease. Standard eligibility criteria were used. Patients received gemcitabine (1000 mg/m(2)) on days 1, 8 and 15 and cisplatin (70 mg/m(2)) on day 2 of every 28-day cycle. The 32 males and 5 females had a median age of 59 years (range: 29-81 years). Of 33 evaluable patients, 8 (24%) achieved complete responses, and 10 (30%) partial responses, for an overall response rate of 55%. 3 patients had minor responses. Responses were observed at all disease sites including lung and liver lesions. Myelosuppression was significant but manageable. Non-haematological toxicity was limited mainly to nausea and vomiting and raised liver enzymes. Thus, these data suggest that gemcitabine plus cisplatin induces high response rates in patients with bilharzial bladder cancer with a moderate toxicity profile.

Zekri, A. R., A. A. Bahnassy, S. M. Shaarawy, O. A. Mansour, M. A. Maduar, H. M. Khaled, and O. El-Ahmadi, "Hepatitis C virus genotyping in relation to neu-oncoprotein overexpression and the development of hepatocellular carcinoma.", Journal of medical microbiology, vol. 49, issue 1, pp. 89-95, 2000 Jan. Abstract

The distribution of hepatitis C virus (HCV) genotypes among Egyptian patients positive for anti-HCV was determined and their influence, when combined with neu-oncoprotein overexpression, on the development of hepatocellular carcinoma (HCC) was examined. The study groups included asymptomatic carriers (ASC) and patients with chronic active hepatitis (CAH) and HCC. HCV genomes were detected in the sera of 27 ASC, 29 CAH and 33 HCC patients known to have HCV infection defined by EIA and recombinant immunoblotting techniques (Inno-LiA) as well as by reverse transcriptase (RT)-PCR. The HCV genotype was determined by a reverse hybridisation technique (Inno-LiPA I and II), whereas neu-overexpression was detected by the Oncogene Science EIA Kit. Eighty-nine patients were eligible for HCV genotyping; 75 patients (84.3%) were infected with a single genotype, including 1a in 11 patients (12.4%), 1b in 2 patients (2.2%) and 2a in 10 patients (11.2%). Genotype 4 (a or c+d) was detected in 51 patients (57.3%) and only one patient had genotype 10a (1.2%). Fourteen patients (15.7%) showed mixed infection; eight of them had 1a+4 (a or c+d) and four had 2a+4 (a or c+d); the remaining two cases had 1a+2a and 1b+2a. The results revealed an increased incidence of genotype 4 in CAH and HCC patients in comparison with ASC. There was also a significant overexpression of neu-oncoprotein in CAH and HCC patients compared with ASC, which was significantly associated with subtype 4 infection. The results suggest that infection with subtype 1a and 4 HCV may be considered a risk factor for the induction of neu-overexpression and subsequent development of HCC.

Khaled, H. M., M. S. Aly, and I. T. Magrath, "Loss of Y chromosome in bilharzial bladder cancer.", Cancer genetics and cytogenetics, vol. 117, issue 1, pp. 32-6, 2000 Feb. Abstract

Bilharzial bladder cancer is the most common malignant neoplasm in Egypt, also occurring with a high incidence in other regions of the Middle East and East Africa. In a previous study, using centromere probes specific for chromosomes 3, 4, 7-11, 16, and 17, we demonstrated that monosomy of chromosome 9 (48.4%), and numerical aberrations of chromosome 17 (19.4%) were the most common observed imbalances. The present study extends the establishment of the baseline cytogenetic profile of this type of malignancy. Interphase cytogenetics by fluorescence in situ hybridization with the use of a panel of centromere-associated DNA probes for chromosomes 1, 2, 5, 6, 12, 13/21, 14, 15, 18, 19, 20, X, and Y was performed on paraffin-embedded bladder specimens from 25 Egyptian patients affected with bilharzial bladder cancer. No numerical aberrations were detected in the 25 cases for chromosomes 1, 2, 5, 6, 12, 13/21, 14, 15, 18, 19, 20, and X. However, loss of chromosome Y was observed in 7 of the 17 male cases studied (41.2%). No significant correlation was observed between loss of the Y chromosome and any of the different clinicopathologic characteristics of these cases. These data suggest that loss of the Y chromosome is the second frequent event that can occur in bilharzial bladder cancer. A molecular genetic model of bilharzial bladder cancer is evolving.

El-Didi, M. H., M. M. Moneer, H. M. Khaled, and S. Makarem, "Pathological assessment of the response of locally advanced breast cancer to neoadjuvant chemotherapy and its implications for surgical management.", Surgery today, vol. 30, issue 3, pp. 249-54, 2000. Abstract

The effectiveness of breast-conserving surgery for patients with locally advanced breast cancer (LABC) after neoadjuvant chemotherapy (NACT) is still a controversial issue, and variable incidences of locoregional failures have been reported. The present study was conducted to pathologically assess the response of LABC to NACT, and also to evaluate the efficacy of preoperative clinical examination and mammography in detecting these pathological changes. A total of 38 patients with LABC received NACT in the form of three cycles of fluorouracil/adriamycin/cyclophosphamide and were then subjected to a mastectomy. The residual tumors in the mastectomy specimens were measured, mapped, and compared to the pretreatment and preoperative clinical and mammographic findings for evaluation. An objective response to NACT was observed in 70.4% of the patients; however, only 26.7% of them were suitable candidates for conservative surgery. The rest of the responders showed an increased incidence of multifocality and in situ lesions localized within the original tumor-bearing area. Both clinical examinations and mammography were inadequate for the selection of candidates for breast conservation. Tumor regression by NACT is probably induced by a process of tumor segmentation. It is also associated with an increased incidence of multifocality and in situ lesions.

El-Didi, M. H., M. M. Moneer, H. M. Khaled, and S. Makarem, "Pathological assessment of the response of locally advanced breast cancer to neoadjuvant chemotherapy and its implications for surgical management.", Surgery today, vol. 30, issue 3, pp. 249-54, 2000. Abstract

The effectiveness of breast-conserving surgery for patients with locally advanced breast cancer (LABC) after neoadjuvant chemotherapy (NACT) is still a controversial issue, and variable incidences of locoregional failures have been reported. The present study was conducted to pathologically assess the response of LABC to NACT, and also to evaluate the efficacy of preoperative clinical examination and mammography in detecting these pathological changes. A total of 38 patients with LABC received NACT in the form of three cycles of fluorouracil/adriamycin/cyclophosphamide and were then subjected to a mastectomy. The residual tumors in the mastectomy specimens were measured, mapped, and compared to the pretreatment and preoperative clinical and mammographic findings for evaluation. An objective response to NACT was observed in 70.4% of the patients; however, only 26.7% of them were suitable candidates for conservative surgery. The rest of the responders showed an increased incidence of multifocality and in situ lesions localized within the original tumor-bearing area. Both clinical examinations and mammography were inadequate for the selection of candidates for breast conservation. Tumor regression by NACT is probably induced by a process of tumor segmentation. It is also associated with an increased incidence of multifocality and in situ lesions.

b El-Rifai, W. a, D. c Kamel, M. L. a e Larramendy, S. d Shoman, Y. b Gad, S. c Baithun, M. b El-Awady, S. d Eissa, H. d Khaled, S. a e Soloneski, et al., "DNA copy number changes in schistosoma-associated and non-schistosoma-associated bladder cancer", American Journal of Pathology, vol. 156, no. 3, pp. 871-878, 2000. AbstractWebsite

DNA copy number changes were investigated in 69 samples of schistosoma-associated (SA) and non-schistosoma-associated (NSA) squamous cell carcinoma (SCC) and transitional cell carcinoma (TCC) of the bladder by comparative genomic hybridization (CGH). DNA copy number changes were detected in 47 tumors. SA tumors had more changes than NSA tumors (mean, 7 vs. 4), whereas the number of changes in SCC and TCC tumors was similar. SA tumors displayed more gains than losses (1.7:1), whereas NSA tumors showed an equal number of gains and losses. Changes that were observed at similar frequencies in SCC and TCC, irrespective of the schistosomal status, included gains and high-level amplifications at 1q, 8q, and 20q and losses in 9p and 13q. These changes may be involved in a commom pathway for bladder tumor development and progression independent of schistosomal status or histological subtype. Losses in 3p and gains at 5p were seen only in SCC (P < 0.01) and losses in 5q were more frequent in SA-SCC than in other tumors (P < 0.05). However, changes that were more frequent in TCC than those in SCC included gains at 17q (P < 0.01) and losses in 4q (P < 0.05) and 6q (P < 0.01). Gains and high-level amplifications at 5p were seen only in SA-SCC (P < 0.01), whereas gains and high-level amplifications with minimal common overlapping regions at 11q13 were more frequently seen both in SA-SCC and SA-TCC tumors (P < 0.01). In addition to the above mentioned alterations, several other changes were also seen at lower frequencies. The variations in the DNA copy number changes observed in TCC, SCC, SA, and NSA bladder carcinomas suggest that these tumors have different genetic pathways.

b El-Rifai, W. a, D. c Kamel, M. L. a e Larramendy, S. d Shoman, Y. b Gad, S. c Baithun, M. b El-Awady, S. d Eissa, H. d Khaled, S. a e Soloneski, et al., "DNA copy number changes in schistosoma-associated and non-schistosoma-associated bladder cancer", American Journal of Pathology, vol. 156, no. 3, pp. 871-878, 2000. AbstractWebsite

DNA copy number changes were investigated in 69 samples of schistosoma-associated (SA) and non-schistosoma-associated (NSA) squamous cell carcinoma (SCC) and transitional cell carcinoma (TCC) of the bladder by comparative genomic hybridization (CGH). DNA copy number changes were detected in 47 tumors. SA tumors had more changes than NSA tumors (mean, 7 vs. 4), whereas the number of changes in SCC and TCC tumors was similar. SA tumors displayed more gains than losses (1.7:1), whereas NSA tumors showed an equal number of gains and losses. Changes that were observed at similar frequencies in SCC and TCC, irrespective of the schistosomal status, included gains and high-level amplifications at 1q, 8q, and 20q and losses in 9p and 13q. These changes may be involved in a commom pathway for bladder tumor development and progression independent of schistosomal status or histological subtype. Losses in 3p and gains at 5p were seen only in SCC (P < 0.01) and losses in 5q were more frequent in SA-SCC than in other tumors (P < 0.05). However, changes that were more frequent in TCC than those in SCC included gains at 17q (P < 0.01) and losses in 4q (P < 0.05) and 6q (P < 0.01). Gains and high-level amplifications at 5p were seen only in SA-SCC (P < 0.01), whereas gains and high-level amplifications with minimal common overlapping regions at 11q13 were more frequently seen both in SA-SCC and SA-TCC tumors (P < 0.01). In addition to the above mentioned alterations, several other changes were also seen at lower frequencies. The variations in the DNA copy number changes observed in TCC, SCC, SA, and NSA bladder carcinomas suggest that these tumors have different genetic pathways.

Zekri, A. - R. N. a, A. A. b Bahnassy, S. M. c Shaarawy, O. A. f Mansour, M. A. d Maduar, H. M. e Khaled, and O. f El-Ahmadi, "Hepatitis C virus genotyping in relation to neu-oncoprotein overexpression and the development of hepatocellular carcinoma", Journal of Medical Microbiology, vol. 49, no. 1, pp. 89-95, 2000. AbstractWebsite

The distribution of hepatitis C virus (HCV) genotypes among Egyptian patients positive for anti-HCV was determined and their influence, when combined with neu-oncoprotein overexpression, on the development of hepatocellular carcinoma (HCC) was examined. The study groups included asymptomatic carriers (ASC) and patients with chronic active hepatitis (CAH) and HCC. HCV genomes were detected in the sera of 27 ASC, 29 CAH and 33 HCC patients known to have HCV infection defined by EIA and recombinant immunoblotting techniques (Inno-LiA) as well as by reverse transcriptase (RT)-PCR. The HCV genotype was determined by a reverse hybridisation technique (Inno-LiPA I and II), whereas neu-overexpression was detected by the Oncogene Science EIA Kit. Eighty-nine patients were eligible for HCV genotyping; 75 patients (84.3%) were infected with a single genotype, including 1a in 11 patients (12.4%), 1b in 2 patients (2.2%) and 2a in 10 patients (11.2%). Genotype 4 (a or c + d) was detected in 51 patients (57.3%) and only one patient had genotype 10a (1.2%). Fourteen patients (15.7%) showed mixed infection; eight of them had 1a + 4 (a or c + d) and four had 2a + 4 (a or c + d); the remaining two cases had 1a + 2a and 1b + 2a. The results revealed an increased incidence of genotype 4 in CAH and HCC patients in comparison with ASC. There was also a significant overexpression of neu-oncoprotein in CAH and HCC patients compared with ASC, which was significantly associated with subtype 4 infection. The results suggest that infection with subtype 1a and 4 HCV may be considered a risk factor for the induction of neu-overexpression and subsequent development of HCC.

Zekri, A. - R. N. a, A. A. b Bahnassy, S. M. c Shaarawy, O. A. f Mansour, M. A. d Maduar, H. M. e Khaled, and O. f El-Ahmadi, "Hepatitis C virus genotyping in relation to neu-oncoprotein overexpression and the development of hepatocellular carcinoma", Journal of Medical Microbiology, vol. 49, no. 1, pp. 89-95, 2000. AbstractWebsite

The distribution of hepatitis C virus (HCV) genotypes among Egyptian patients positive for anti-HCV was determined and their influence, when combined with neu-oncoprotein overexpression, on the development of hepatocellular carcinoma (HCC) was examined. The study groups included asymptomatic carriers (ASC) and patients with chronic active hepatitis (CAH) and HCC. HCV genomes were detected in the sera of 27 ASC, 29 CAH and 33 HCC patients known to have HCV infection defined by EIA and recombinant immunoblotting techniques (Inno-LiA) as well as by reverse transcriptase (RT)-PCR. The HCV genotype was determined by a reverse hybridisation technique (Inno-LiPA I and II), whereas neu-overexpression was detected by the Oncogene Science EIA Kit. Eighty-nine patients were eligible for HCV genotyping; 75 patients (84.3%) were infected with a single genotype, including 1a in 11 patients (12.4%), 1b in 2 patients (2.2%) and 2a in 10 patients (11.2%). Genotype 4 (a or c + d) was detected in 51 patients (57.3%) and only one patient had genotype 10a (1.2%). Fourteen patients (15.7%) showed mixed infection; eight of them had 1a + 4 (a or c + d) and four had 2a + 4 (a or c + d); the remaining two cases had 1a + 2a and 1b + 2a. The results revealed an increased incidence of genotype 4 in CAH and HCC patients in comparison with ASC. There was also a significant overexpression of neu-oncoprotein in CAH and HCC patients compared with ASC, which was significantly associated with subtype 4 infection. The results suggest that infection with subtype 1a and 4 HCV may be considered a risk factor for the induction of neu-overexpression and subsequent development of HCC.

Raafat, A., H. Khaled, N. Mokhtar, A. R. Zekri, and H. Gaballah, "Human papilloma virus infection and overexpression of p53 protein in bilharzial bladder cancer", Cancer Molecular Biology, vol. 7, no. 3, pp. 1481-1492, 2000. AbstractWebsite

An association between human papilloma virus (HPV) and bladder cancer has been reported. However, the role of HPV in bilharzial bladder cancer and its prevalence are not yet clarified. We investigated 50 cases for HPV types 16/18 by in situ hybridization (ISH). Also, p53 protein expression by immunohistochemistry was evaluated in 41 of these 50 cases, with correlation of these factors to clinicopathologic parameters and tumor relapse after primary treatment. HPV was detected in 46% of Egyptian bladder carcinomas (23/50 cases). Positivity was 47.8% for squamous cell carcinoma (SCC) and 36.4% for transitional cell carcinoma (TCC). There was a possible viral- bilharzial association as 52.8% of bilharzial cases, while only 12.5% of non bilharzial cases were HPV positive (p<0.05). P53 protein was found in 19/41cases (46.3%). Concordance between HPV and p53 was present in 58.5% of cases. Both factors studied were not related to tumor recurrence after primary treatment. So, HPV may be implicated in the aetiology of bilharzial bladder cancer, however a definite causal relationship remains unsolved. HPV together with p53 alterations might work in synergy to accelerate the carcinogenic process, as there was concordance in the results of both parameters in 24/41 cases (58.5%).

Raafat, A., H. Khaled, N. Mokhtar, A. R. Zekri, and H. Gaballah, "Human papilloma virus infection and overexpression of p53 protein in bilharzial bladder cancer", Cancer Molecular Biology, vol. 7, no. 3, pp. 1481-1492, 2000. AbstractWebsite

An association between human papilloma virus (HPV) and bladder cancer has been reported. However, the role of HPV in bilharzial bladder cancer and its prevalence are not yet clarified. We investigated 50 cases for HPV types 16/18 by in situ hybridization (ISH). Also, p53 protein expression by immunohistochemistry was evaluated in 41 of these 50 cases, with correlation of these factors to clinicopathologic parameters and tumor relapse after primary treatment. HPV was detected in 46% of Egyptian bladder carcinomas (23/50 cases). Positivity was 47.8% for squamous cell carcinoma (SCC) and 36.4% for transitional cell carcinoma (TCC). There was a possible viral- bilharzial association as 52.8% of bilharzial cases, while only 12.5% of non bilharzial cases were HPV positive (p<0.05). P53 protein was found in 19/41cases (46.3%). Concordance between HPV and p53 was present in 58.5% of cases. Both factors studied were not related to tumor recurrence after primary treatment. So, HPV may be implicated in the aetiology of bilharzial bladder cancer, however a definite causal relationship remains unsolved. HPV together with p53 alterations might work in synergy to accelerate the carcinogenic process, as there was concordance in the results of both parameters in 24/41 cases (58.5%).

Abdel-Rahman, S. Z. a, A. S. b Soliman, M. L. b Bondy, S. c Omar, S. A. c El-Badawy, H. M. c Khaled, I. A. d Seifeldin, and B. b Levin, "Inheritance of the 194Trp and the 399Gln variant alleles of the DNA repair gene XRCC1 are associated with increased risk of early-onset colorectal carcinoma in Egypt", Cancer Letters, vol. 159, no. 1, pp. 79-86, 2000. AbstractWebsite

Patients under age 40 constitute 35.6% of all colorectal cancer cases in Egypt, an unusual disease pattern to which both environmental exposures and inefficient DNA repair may contribute. While a number of polymorphisms in DNA repair genes have been recently identified, their role as cancer risk modifiers is yet to be determined. In a pilot case-control study, we tested the hypothesis that polymorphisms in the gene for the DNA repair enzyme XRCC1 are associated with increased risk of colorectal cancer among Egyptians. Using a multiplex polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methodology, allelic variants of the XRCC1 gene at codons 194 (Arg → Trp) (194Trp) and 399 (Arg → Gln) (399Gln), were analyzed in DNA from lymphocytes of 48 newly-diagnosed colorectal cancer cases and 48 age- and sex-matched controls. Overall, the inheritance of 194Trp allele (Arg/Trp genotype) and 399Gln allele (combined Arg/Gln and Gln/Gln genotypes) was associated with increased colorectal cancer risk (odds ratio (OR) = 2.56, 95% confidence limits (CL) 0.73-9.40, and P = 0.08 for 194Trp allele and OR = 3.98, 95% CL 1.50-10.6, and P < 0.001 for 399Gln allele). Interestingly, the frequencies of 194Trp and 399Gln genotypes were higher in colorectal cancer cases under age 40 than in corresponding controls, and an association between both polymorphisms and early age of disease onset was observed (OR = 3.33, 95% CL 0.48-35.90, and P = 0.16 for 194Trp and OR = 11.90, 95% CL 2.30-51.50, and P = 0.0003 for 399Gln). Analysis of the data after adjustment for place of residence indicated that the frequencies of the genotypes with the 194Trp and the 399Gln alleles were higher among urban residents (OR = 3.33, 95% CL 0.48-35.90, and P = 0.16 for 194Trp and OR = 9.97, 95% CL 1.98-43.76, and P < 0.001 for 399Gln) than among rural residents (OR = 2.00, 95% CL 0.36-26.00, and P = 0.30 for 194Trp and OR = 1.90, 95% CL 0.50-7.53, and P = 0.20 for 399Gln). These findings support our hypothesis and suggest that polymorphisms in the XRCC1 gene, in conjunction with place of residence, may modify disease risk. This first demonstration that polymorphisms in DNA repair genes may contribute to colorectal cancer susceptibility and may increase the risk of early onset of the disease opens the door for future studies in that direction. (C) 2000 Published by Elsevier Science Ireland Ltd.

Abdel-Rahman, S. Z. a, A. S. b Soliman, M. L. b Bondy, S. c Omar, S. A. c El-Badawy, H. M. c Khaled, I. A. d Seifeldin, and B. b Levin, "Inheritance of the 194Trp and the 399Gln variant alleles of the DNA repair gene XRCC1 are associated with increased risk of early-onset colorectal carcinoma in Egypt", Cancer Letters, vol. 159, no. 1, pp. 79-86, 2000. AbstractWebsite

Patients under age 40 constitute 35.6% of all colorectal cancer cases in Egypt, an unusual disease pattern to which both environmental exposures and inefficient DNA repair may contribute. While a number of polymorphisms in DNA repair genes have been recently identified, their role as cancer risk modifiers is yet to be determined. In a pilot case-control study, we tested the hypothesis that polymorphisms in the gene for the DNA repair enzyme XRCC1 are associated with increased risk of colorectal cancer among Egyptians. Using a multiplex polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methodology, allelic variants of the XRCC1 gene at codons 194 (Arg → Trp) (194Trp) and 399 (Arg → Gln) (399Gln), were analyzed in DNA from lymphocytes of 48 newly-diagnosed colorectal cancer cases and 48 age- and sex-matched controls. Overall, the inheritance of 194Trp allele (Arg/Trp genotype) and 399Gln allele (combined Arg/Gln and Gln/Gln genotypes) was associated with increased colorectal cancer risk (odds ratio (OR) = 2.56, 95% confidence limits (CL) 0.73-9.40, and P = 0.08 for 194Trp allele and OR = 3.98, 95% CL 1.50-10.6, and P < 0.001 for 399Gln allele). Interestingly, the frequencies of 194Trp and 399Gln genotypes were higher in colorectal cancer cases under age 40 than in corresponding controls, and an association between both polymorphisms and early age of disease onset was observed (OR = 3.33, 95% CL 0.48-35.90, and P = 0.16 for 194Trp and OR = 11.90, 95% CL 2.30-51.50, and P = 0.0003 for 399Gln). Analysis of the data after adjustment for place of residence indicated that the frequencies of the genotypes with the 194Trp and the 399Gln alleles were higher among urban residents (OR = 3.33, 95% CL 0.48-35.90, and P = 0.16 for 194Trp and OR = 9.97, 95% CL 1.98-43.76, and P < 0.001 for 399Gln) than among rural residents (OR = 2.00, 95% CL 0.36-26.00, and P = 0.30 for 194Trp and OR = 1.90, 95% CL 0.50-7.53, and P = 0.20 for 399Gln). These findings support our hypothesis and suggest that polymorphisms in the XRCC1 gene, in conjunction with place of residence, may modify disease risk. This first demonstration that polymorphisms in DNA repair genes may contribute to colorectal cancer susceptibility and may increase the risk of early onset of the disease opens the door for future studies in that direction. (C) 2000 Published by Elsevier Science Ireland Ltd.

Khaled, H. M. a, M. S. b Aly, and I. T. c Magrath, "Loss of Y chromosome in Bilharzial bladder cancer", Cancer Genetics and Cytogenetics, vol. 117, no. 1, pp. 32-36, 2000. AbstractWebsite

Bilharzial bladder cancer is the most common malignant neoplasm in Egypt, also occurring with a high incidence in other regions of the Middle East and East Africa. In a previous study, using centromere probes specific for chromosomes 3, 4, 7-11, 16, and 17, we demonstrated that monosomy of chromosome 9 (48.4%), and numerical aberrations of chromosome 17 (19.4%) were the most common observed imbalances. The present study extends the establishment of the baseline cytogenetic profile of this type of malignancy. Interphase cytogenetics by fluorescence in situ hybridization with the use of a panel of centromere-associated DNA probes for chromosomes 1, 2, 5, 6, 12, 13/21, 14, 15, 18, 19, 20, X, and Y was performed on paraffin-embedded bladder specimens from 25 Egyptian patients affected with bilharzial bladder cancer. No numerical aberrations were detected in the 25 cases for chromosomes 1, 2, 5, 6, 12, 13/21, 14, 15, 18, 19, 20, and X. However, loss of chromosome Y was observed in 7 of the 17 male cases studied (41.2%). No significant correlation was observed between loss of the Y chromosome and any of the different clinicopathologic characteristics of these cases. These data suggest that loss of the Y chromosome is the second frequent event that can occur in bilharzial bladder cancer. A molecular genetic model of bilharzial bladder cancer is evolving. Copyright (C) 1999 Elsevier Science Inc.

Khaled, H. M. a, M. S. b Aly, and I. T. c Magrath, "Loss of Y chromosome in Bilharzial bladder cancer", Cancer Genetics and Cytogenetics, vol. 117, no. 1, pp. 32-36, 2000. AbstractWebsite

Bilharzial bladder cancer is the most common malignant neoplasm in Egypt, also occurring with a high incidence in other regions of the Middle East and East Africa. In a previous study, using centromere probes specific for chromosomes 3, 4, 7-11, 16, and 17, we demonstrated that monosomy of chromosome 9 (48.4%), and numerical aberrations of chromosome 17 (19.4%) were the most common observed imbalances. The present study extends the establishment of the baseline cytogenetic profile of this type of malignancy. Interphase cytogenetics by fluorescence in situ hybridization with the use of a panel of centromere-associated DNA probes for chromosomes 1, 2, 5, 6, 12, 13/21, 14, 15, 18, 19, 20, X, and Y was performed on paraffin-embedded bladder specimens from 25 Egyptian patients affected with bilharzial bladder cancer. No numerical aberrations were detected in the 25 cases for chromosomes 1, 2, 5, 6, 12, 13/21, 14, 15, 18, 19, 20, and X. However, loss of chromosome Y was observed in 7 of the 17 male cases studied (41.2%). No significant correlation was observed between loss of the Y chromosome and any of the different clinicopathologic characteristics of these cases. These data suggest that loss of the Y chromosome is the second frequent event that can occur in bilharzial bladder cancer. A molecular genetic model of bilharzial bladder cancer is evolving. Copyright (C) 1999 Elsevier Science Inc.

El-Didi, M. H. a, M. M. b e Moneer, H. M. c Khaled, and S. d Makarem, "Pathological assessment of the response of locally advanced breast cancer to neoadjuvant chemotherapy and its implications for surgical management", Surgery Today, vol. 30, no. 3, pp. 249-254, 2000. AbstractWebsite

The effectiveness of breast-conserving surgery for patients with locally advanced breast cancer (LABC) after neoadjuvant chemotherapy (NACT) is still a controversial issue, and variable incidences of locoregional failures have been reported. The present study was conducted to pathologically assess the response of LABC to NACT, and also to evaluate the efficacy of preoperative clinical examination and mammography in detecting these pathological changes. A total of 38 patients with LABC received NACT in the form of three cycles of fluorouracil/adriamycin/cyclophosphamide and were then subjected to a mastectomy. The residual tumors in the mastectomy specimens were measured, mapped, and compared to the pretreatment and preoperative clinical and mammographic findings for evaluation. An objective response to NACT was observed in 70.4% of the patients; however, only 26.7% of them were suitable candidates for conservative surgery. The rest of the responders showed an increased incidence of multifocality and in situ lesions localized within the original tumor-bearing area. Both clinical examinations and mammography were inadequate for the selection of candidates for breast conservation. Tumor regression by NACT is probably induced by a process of tumor segmentation. It is also associated with an increased incidence of multifocality and in situ lesions.

El-Didi, M. H. a, M. M. b e Moneer, H. M. c Khaled, and S. d Makarem, "Pathological assessment of the response of locally advanced breast cancer to neoadjuvant chemotherapy and its implications for surgical management", Surgery Today, vol. 30, no. 3, pp. 249-254, 2000. AbstractWebsite

The effectiveness of breast-conserving surgery for patients with locally advanced breast cancer (LABC) after neoadjuvant chemotherapy (NACT) is still a controversial issue, and variable incidences of locoregional failures have been reported. The present study was conducted to pathologically assess the response of LABC to NACT, and also to evaluate the efficacy of preoperative clinical examination and mammography in detecting these pathological changes. A total of 38 patients with LABC received NACT in the form of three cycles of fluorouracil/adriamycin/cyclophosphamide and were then subjected to a mastectomy. The residual tumors in the mastectomy specimens were measured, mapped, and compared to the pretreatment and preoperative clinical and mammographic findings for evaluation. An objective response to NACT was observed in 70.4% of the patients; however, only 26.7% of them were suitable candidates for conservative surgery. The rest of the responders showed an increased incidence of multifocality and in situ lesions localized within the original tumor-bearing area. Both clinical examinations and mammography were inadequate for the selection of candidates for breast conservation. Tumor regression by NACT is probably induced by a process of tumor segmentation. It is also associated with an increased incidence of multifocality and in situ lesions.

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