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2000
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, vol. 36, no. SUPPL. 2, pp. S34-S37, 2000. AbstractWebsite

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/m2) on days 1, 8 and 15 and cisplatin (70 mg/m2) 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. Copyright (C) 2000.

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, vol. 36, no. SUPPL. 2, pp. S34-S37, 2000. AbstractWebsite

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/m2) on days 1, 8 and 15 and cisplatin (70 mg/m2) 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. Copyright (C) 2000.

d Zaghloul, M. S. a, M. a El Naggar, A. b El Deeb, H. c Khaled, and N. b Mokhtar, "Prognostic implication of apoptosis and angiogenesis in cervical uteri cancer", International Journal of Radiation Oncology Biology Physics, vol. 48, no. 5, pp. 1409-1415, 2000. AbstractWebsite

Purpose: A retrospective study was performed to investigate the relationship between spontaneous apoptosis and angiogenesis uterine cervix squamous cell carcinoma patients. The prognostic value of each (and both) of these biologic parameters was also tested.Methods and Materials: The pathologic materials of 40 cervical uteri squamous cell carcinoma patients were examined and immunohistochemically stained to determine the tumor angiogenesis (tumor microvascular score), using factor VIII-related antigen, and their tumor apoptotic index (AI), using the TdT-mediated dUTP nick end-labeling (TUNEL) method. Three patients were Stage I, 18 were Stage II, 15 were Stage III, and 4 were Stage IV (FIGO classification). All patients were treated with radical radiotherapy and all had follow-up for more than 2 years.Results: The mean AI was 15.1 ± 12.8, with a median of 8.3. The mean tumor microvascular score was 3 9.7 ± 14.4, with a median of 3 8. The patients' age and tumor grade did not seem to significantly affect the prognosis. On the other hand, AI and angiogenesis (tumor microvascular score) were of high prognostic significance. The 3-year disease-free survival (DFS) rate for the patients having AI above the median was 78% (confidence interval [CI] 69-87%), compared to 32% (CI 22-42%) for those having AI below the median. The DFS was 18% (CI 9-27%) for patients having an angiogenesis score above the median, while it was 86% (CI 78-94%) for those patients having a score below the median.Conclusion: Determination of both tumor microvascular score and AI can identify patients with the best prognosis of 100% DFS (with low angiogenesis score and high AI). Women with a high score and low AI had the worst prognosis (DFS = 3%, CI 1-5%). Moreover, high AI can compensate partially for the aggressive behavior of tumors showing a high rate of angiogenesis. Copyright (C) 2000 Elsevier Science Inc.

d Zaghloul, M. S. a, M. a El Naggar, A. b El Deeb, H. c Khaled, and N. b Mokhtar, "Prognostic implication of apoptosis and angiogenesis in cervical uteri cancer", International Journal of Radiation Oncology Biology Physics, vol. 48, no. 5, pp. 1409-1415, 2000. AbstractWebsite

Purpose: A retrospective study was performed to investigate the relationship between spontaneous apoptosis and angiogenesis uterine cervix squamous cell carcinoma patients. The prognostic value of each (and both) of these biologic parameters was also tested.Methods and Materials: The pathologic materials of 40 cervical uteri squamous cell carcinoma patients were examined and immunohistochemically stained to determine the tumor angiogenesis (tumor microvascular score), using factor VIII-related antigen, and their tumor apoptotic index (AI), using the TdT-mediated dUTP nick end-labeling (TUNEL) method. Three patients were Stage I, 18 were Stage II, 15 were Stage III, and 4 were Stage IV (FIGO classification). All patients were treated with radical radiotherapy and all had follow-up for more than 2 years.Results: The mean AI was 15.1 ± 12.8, with a median of 8.3. The mean tumor microvascular score was 3 9.7 ± 14.4, with a median of 3 8. The patients' age and tumor grade did not seem to significantly affect the prognosis. On the other hand, AI and angiogenesis (tumor microvascular score) were of high prognostic significance. The 3-year disease-free survival (DFS) rate for the patients having AI above the median was 78% (confidence interval [CI] 69-87%), compared to 32% (CI 22-42%) for those having AI below the median. The DFS was 18% (CI 9-27%) for patients having an angiogenesis score above the median, while it was 86% (CI 78-94%) for those patients having a score below the median.Conclusion: Determination of both tumor microvascular score and AI can identify patients with the best prognosis of 100% DFS (with low angiogenesis score and high AI). Women with a high score and low AI had the worst prognosis (DFS = 3%, CI 1-5%). Moreover, high AI can compensate partially for the aggressive behavior of tumors showing a high rate of angiogenesis. Copyright (C) 2000 Elsevier Science Inc.

1999
Aly, M. S., and H. M. Khaled, "Chromosomal aberrations in Bilharzial bladder cancer as detected by fluorescence in situ hybridization.", Cancer genetics and cytogenetics, vol. 114, issue 1, pp. 62-7, 1999 Oct 1. Abstract

Cancer of the bladder is a frequent malignancy in Egypt and other developing countries in which bladder infection with the parasite Schistosoma haematobium is common. Several epidemiological, histopathological, and clinical characteristics of cancer of the Bilharzial bladder suggest that it is distinct from bladder cancer seen in other places in the world. No numerical aberrations of chromosomes that might be specific for Bilharzial bladder carcinoma have been established. In this study, we used fluorescence in situ hybridization (FISH) with centromere-specific probes for chromosomes 3, 4, 7, 8, 9, 10, 11, 16, and 17 to detect numerical aberrations of these chromosomes in frozen-stored samples of 31 Egyptian patients affected with Bilharzial carcinoma. Among 5 types of chromosomes examined, imbalance was observed; the most common imbalance was a loss of chromosome 9 (48.4%), with numerical aberration of chromosome 17 being the second most-frequent anomaly (19.4%). The presence of such anomalies, especially losses of chromosome 9, are associated with a younger age group of patients, as well as with a lower grade tumor and negative pelvic node involvement by the disease. Fluorescence in situ hybridization analysis thus proved to be a useful method for detecting numerical aberrations of individual chromosomes, with application to touch preparations of frozen-stored tissue having the advantage of exact sampling of cancer foci. This result also suggests that the mechanism of genetic progression of bladder cancer is independent of its etiology.

Zekri, A. R., A. A. Bahnassi, B. Bove, Y. Huang, I. H. Russo, A. Rogatko, S. Shaarawy, O. A. Shawki, M. R. Hamza, S. Omer, et al., "Allelic instability as a predictor of survival in Egyptian breast cancer patients.", International journal of oncology, vol. 15, issue 4, pp. 757-67, 1999 Oct. Abstract

This work was designed with the purpose of determining whether the presence of allelic imbalances (AI) such as microsatellite instability (MSI) and loss of heterozygosity (LOH) in chromosomes 2, 11, 13, and 17 in primary breast cancer could be used as prognostic indicators of patient survival. The DNA from breast cancers removed from 29 patients who were followed-up for up to five years was analyzed for MSI and LOH using a panel of 24 markers located at chromosome 2 (TPO, D2S131, D2S144, D2S171, D2S177, D2S119, D2S123, D2S147 and D2S136), chromosome 11 (C-RAS, Int-2, D11S940, D11S912), chromosome 13 (D13S289, D13S260, D13S267, D13S218, D13S263, D13S155, and D13S162), and chromosome 17 (D17S513, TP53, D17S855, and D17S785). The frequency of AI in the markers studied ranged from 30-55%, being highest for D11S912, D2S171, TP53 and D17S855. Univariate analysis showed association between overall survival rate and AI in 9 out of the 24 markers tested. Five of them were located at the area of the mismatch repair gene (MMR)-2 gene, two at 11p, one at 13q and one at 17p. Using multivariate analysis, it was observed that only pathological and clinical stage (defined as stage II or not) and AI at D2S171, D11S912, or D17STP53 generated significant predictive models for survival.

Khaled, H. M., Z. K. Zekri, N. Mokhtar, N. M. Ali, T. Darwish, I. Elattar, R. Gaafar, and M. S. Moawad, "A randomized EPOCH vs. CHOP front-line therapy for aggressive non-Hodgkin's lymphoma patients: long-term results.", Annals of oncology : official journal of the European Society for Medical Oncology / ESMO, vol. 10, issue 12, pp. 1489-92, 1999 Dec. Abstract

BACKGROUND: The value of continuous-infusion chemotherapy (EPOCH) vs. the standard CHOP combination was evaluated in 78 patients with previously untreated aggressive non-Hodgkin's lymphoma in a randomized phase III clinical trial.

PATIENTS AND METHODS: The EPOCH regimen given to 38 patients consisted of the drugs etoposide (50 mg/m2), vincristine (0.4 mg/m2), and doxorubicin (10 mg/m2), all given in a continuous infusion on days 1-4. Cyclophosphamide (750 mg/m2) was administered on day 6 as i.v. bolus, while prednisone was given orally 60 mg/m2 on days 1-6. Courses were repeated every three weeks. CHOP was given to 40 patients as routinely prescribed.

RESULTS: Forty-eight patients were males and thirty were females. Their ages ranged from 19-75 years (median 45 years). Forty-three (55%) had grade 2 and thirty-five (45%) had grade 3 pathologic subtype. Nine patients (12%) presented with stage I, fourteen (18%) with stage II, forty (51%) with stage III, and fifteen (19%) with stage IV disease. The different clinico-pathologic characteristics, including international index categories, were comparable in the two groups. The number of courses given ranged between 3 and 9 (median 6) for both the EPOCH and CHOP regimens. Complete remission (CR) was achieved in 19 (50%), and 27 (67%) of the 38 and 40 patients for both the EPOCH and CHOP combinations, respectively. After a median observation time of 27 months, the four-year overall and failure-free survival rates were 42% and 30% for the EPOCH and 71% and 54% for the CHOP regimen (P = 0.006 and 0.1 for the overall and FFS rates, respectively). Toxicities were comparable and were mostly of grades 1 and 2, except for hair loss, hematologic toxicities, and infectious episodes which were more common in the EPOCH group. In the EPOCH group, overall survival rates were 55% vs. 22% (P < 0.04) at four years for the low-risk (2 prognostic factors) and high-risk (> 2 factors) groups, respectively.

CONCLUSIONS: Thus, it may be concluded that continuous-infusion (EPOCH) chemotherapy did not improve treatment outcome over that of the CHOP regimen for aggressive non-Hodgkin's lymphoma patients.

Zekri, A. R., A. A. Bahnassi, B. Bove, Y. Huang, I. H. Russo, A. Rogatko, S. Shaarawy, O. A. Shawki, M. R. Hamza, S. Omer, et al., "Allelic instability as a predictor of survival in Egyptian breast cancer patients.", International journal of oncology, vol. 15, no. 4, pp. 757-767, 1999. AbstractWebsite

This work was designed with the purpose of determining whether the presence of allelic imbalances (AI) such as microsatellite instability (MSI) and loss of heterozygosity (LOH) in chromosomes 2, 11, 13, and 17 in primary breast cancer could be used as prognostic indicators of patient survival. The DNA from breast cancers removed from 29 patients who were followed-up for up to five years was analyzed for MSI and LOH using a panel of 24 markers located at chromosome 2 (TPO, D2S131, D2S144, D2S171, D2S177, D2S119, D2S123, D2S147 and D2S136), chromosome 11 (C-RAS, Int-2, D11S940, D11S912), chromosome 13 (D13S289, D13S260, D13S267, D13S218, D13S263, D13S155, and D13S162), and chromosome 17 (D17S513, TP53, D17S855, and D17S785). The frequency of AI in the markers studied ranged from 30-55%, being highest for D11S912, D2S171, TP53 and D17S855. Univariate analysis showed association between overall survival rate and AI in 9 out of the 24 markers tested. Five of them were located at the area of the mismatch repair gene (MMR)-2 gene, two at 11p, one at 13q and one at 17p. Using multivariate analysis, it was observed that only pathological and clinical stage (defined as stage II or not) and AI at D2S171, D11S912, or D17STP53 generated significant predictive models for survival.

Moneer, M. a, M. b El-Didi, and H. c Khaled, "Breast conservative surgery: Is it appropriate for locally advanced breast cancer following downstaging by neoadjuvant chemotherapy? A pathological assessment", Breast, vol. 8, no. 6, pp. 315-319, 1999. AbstractWebsite

The application of breast conserving surgery to down-staged cases with locally advanced breast cancer (LABC) after neoadjuvant chemotherapy (NACT) is still a controversial issue with a variable incidence of locoregional failures. In this study, the response of LABC to NACT was assessed pathologically and the elegible candidates for breast conserving surgery were identified retrospectively. The efficacy of preoperative clinical examination and mammography in detecting these pathological changes were also evaluated. The study included 41 LABC cases. They received NACT (FAC) and were then subjected to a mastectomy. The cases were examined clinically and by mammography before starting treatment and immediately before surgery. Residual tumours in the mastectomy specimens were correlated with the pretreatment and preoperative clinical and mammographic findings inorder to assess the efficacy of these tools for detection of NACT-induced changes. After 3 cycles of NACT, 78% of women showed an objective response. However, only 25% of them would have been eligible for breast conserving surgery. The remaining responders had an increased incidence of either multifocality and or peritumoural in situ carcinoma. Both clinical examination and mammography were inadequate for detection of these chemotherapy-induced changes and hence for selecting suitable candidates for breast conservation. This study has shown that tumour regression by NACT is probably induced by a process of tumour segmentation and is associated with an increased incidence of ductal in situ lesions in the original tumour bearing area. (C) 1999 Harcourt Publishers Ltd.

Moneer, M. a, M. b El-Didi, and H. c Khaled, "Breast conservative surgery: Is it appropriate for locally advanced breast cancer following downstaging by neoadjuvant chemotherapy? A pathological assessment", Breast, vol. 8, no. 6, pp. 315-319, 1999. AbstractWebsite

The application of breast conserving surgery to down-staged cases with locally advanced breast cancer (LABC) after neoadjuvant chemotherapy (NACT) is still a controversial issue with a variable incidence of locoregional failures. In this study, the response of LABC to NACT was assessed pathologically and the elegible candidates for breast conserving surgery were identified retrospectively. The efficacy of preoperative clinical examination and mammography in detecting these pathological changes were also evaluated. The study included 41 LABC cases. They received NACT (FAC) and were then subjected to a mastectomy. The cases were examined clinically and by mammography before starting treatment and immediately before surgery. Residual tumours in the mastectomy specimens were correlated with the pretreatment and preoperative clinical and mammographic findings inorder to assess the efficacy of these tools for detection of NACT-induced changes. After 3 cycles of NACT, 78% of women showed an objective response. However, only 25% of them would have been eligible for breast conserving surgery. The remaining responders had an increased incidence of either multifocality and or peritumoural in situ carcinoma. Both clinical examination and mammography were inadequate for detection of these chemotherapy-induced changes and hence for selecting suitable candidates for breast conservation. This study has shown that tumour regression by NACT is probably induced by a process of tumour segmentation and is associated with an increased incidence of ductal in situ lesions in the original tumour bearing area. (C) 1999 Harcourt Publishers Ltd.

Aly, M. S. a, and H. M. b Khaled, "Chromosomal aberrations in Bilharzial bladder cancer as detected by fluorescence in situ hybridization", Cancer Genetics and Cytogenetics, vol. 114, no. 1, pp. 62-67, 1999. AbstractWebsite

Cancer of the bladder is a frequent malignancy in Egypt and other developing countries in which bladder infection with the parasite Schistosoma haematobium is common. Several epidemiological, histopathological, and clinical characteristics of cancer of the Bilharzial bladder suggest that it is distinct from bladder cancer seen in other places in the world. No numerical aberrations of chromosomes that might be specific for Bilharzial bladder carcinoma have been established. In this study, we used fluorescence in situ hybridization (FISH) with centromere-specific probes for chromosomes 3, 4, 7, 8, 9, 10, 11, 16, and 17 to detect numerical aberrations of these chromosomes in frozen-stored samples of 31 Egyptian patients affected with Bilharzial carcinoma. Among 5 types of chromosomes examined, imbalance was observed; the most common imbalance was a loss of chromosome 9 (48.4%), with numerical aberration of chromosome 17 being the second most-frequent anomaly (19.4%). The presence of such anomalies, especially losses of chromosome 9, are associated with a younger age group of patients, as well as with a lower grade tumor and negative pelvic node involvement by the disease. Fluorescence in situ hybridization analysis thus proved to be a useful method for detecting numerical aberrations of individual chromosomes, with application to touch preparations of frozen-stored tissue having the advantage of exact sampling of cancer foci. This result also suggests that the mechanism of genetic progression of bladder cancer is independent of its etiology.

e Yates, S. C. a, M. b Hafez, M. a Beld, V. V. a Lukashov, Z. b Hassan, G. b c Carboni, H. b Khaled, M. d McMorrow, M. b Attia, and J. a Goudsmit, "Hepatocellular carcinoma in Egyptians with and without a history of hepatitis B virus infection: Association with hepatitis C virus (HCV) infection but not with HCV RNA level", American Journal of Tropical Medicine and Hygiene, vol. 60, no. 4, pp. 714-720, 1999. AbstractWebsite

The aim of this study was to analyze the association of hepatocellular carcinoma (HCC) with hepatitis C virus (HCV) in Egypt, using hepatitis B virus (HBV) and hepatitis E virus (HEV) as virus controls. In addition, the association of HCC with HCV RNA levels among persons seropositive for HCV was analyzed. We compared 131 patients with proven HCC, 247 with bladder cancer, and 466 healthy hospital employees. Age, sex, and place of residence were recorded to study confounding factors. Among the healthy controls, 16% were seropositive for HCV, 21% for HBV, and 31% for HEV. When healthy controls were age-matched with HCC patients, the latter were significantly (P < 0.001) more often HCV seropositive (67%) than were the controls (30%). The seropositivity for HBV and HEV did not differ significantly in frequency between the two groups. The seropositivity for HCV was also significantly (P < 0.001) more often found in HCC patients (76%) than in BC patients (47%), with seroprevalences for HBV and HEV not differing significantly in these age-matched groups. In HBV-negative HCC and bladder cancer patients, seroprevalence for HCV was significantly (P = 0.002) higher in HCC patients (68%) than in bladder cancer patients (36%). This difference was even more pronounced (P < 0.001) in HBV-positive HCC and bladder cancer patients (78% versus 52%, respectively). Of HCV-seropositive individuals, 49% were HCV RNA positive by branched DNA assay, and of these, 96% were infected by HCV genotype 4. No correlation between HCV RNA load and seropositivity of HBV or age or disease state was found. Infection with HCV and HCV-HBV double infection, but not HBV or HEV infection alone, is strongly correlated with HCC in Egypt.

d Khaled, H. M. a, Z. K. a Zekri, N. b Mokhtar, N. M. a Ali, T. a Darwish, I. c Elattar, R. a Gaafar, and M. S. a Moawad, "A randomized EPOCH vs. CHOP front-line therapy for aggressive non- Hodgkin's lymphoma patients: Long-term results", Annals of Oncology, vol. 10, no. 12, pp. 1489-1492, 1999. AbstractWebsite

Background: The value of continuous-infusion chemotherapy (EPOCH) vs. the standard CHOP combination was evaluated in 78 patients with previously untreated aggressive non-Hodgkin's lymphoma in a randomized phase III clinical trial. Patients and methods: The EPOCH regimen given to 38 patients consisted of the drugs etoposide (50 mg/m2), vincristine (0.4 mg/m2), and doxorubicin (10 mg/m2), all given in a continuous infusion on days 1-4. Cyclophosphamide (750 mg/m2) was administered on day 6 as i.v. bolus, while prednisone was given orally 60 mg/m2 on days 1-6. Courses were repeated every three weeks. CHOP was given to 40 patients as routinely prescribed. Results: Forty-eight patients were males and thirty were females. Their ages ranged from 19-75 years (median 45 years). Forty-three (55%) had grade 2 and thirty-five (45%) had grade 3 pathologic subtype. Nine patients (12%) presented with stage I, fourteen (18%) with stage II, forty (51%) with stage III, and fifteen (19%) with stage IV disease. The different clinico- pathologic characteristics, including international index categories, were comparable in the two groups. The number of courses given ranged between 3 and 9 (median 6) for both the EPOCH and CHOP regimens. Complete remission (CR) was achieved in 19 (50%), and 27 (67%) of the 38 and 40 patients for both the EPOCH and CHOP combinations, respectively. After a median observation time of 27 months, the four-year overall and failure-free survival rates were 42%, and 30% for the EPOCH and 71% and 54% for the CHOP regimen (P = 0.006 and 0.1 for the overall and FFS rates, respectively). Toxicities were comparable and were mostly of grades 1 and 2, except for hair loss, hematologic toxicities, and infectious episodes which were more common in the EPOCH group. In the EPOCH group, overall survival rates were 55% vs. 22% (P < 0.04) at four years for the low-risk (2 prognostic factors) and high-risk (> 2 factors) groups, respectively. Conclusions: Thus, it may be concluded that continuous-infusion (EPOCH) chemotherapy did not improve treatment outcome over that of the CHOP regimen for aggressive non-Hodgkin's lymphoma patients.

d Khaled, H. M. a, Z. K. a Zekri, N. b Mokhtar, N. M. a Ali, T. a Darwish, I. c Elattar, R. a Gaafar, and M. S. a Moawad, "A randomized EPOCH vs. CHOP front-line therapy for aggressive non- Hodgkin's lymphoma patients: Long-term results", Annals of Oncology, vol. 10, no. 12, pp. 1489-1492, 1999. AbstractWebsite

Background: The value of continuous-infusion chemotherapy (EPOCH) vs. the standard CHOP combination was evaluated in 78 patients with previously untreated aggressive non-Hodgkin's lymphoma in a randomized phase III clinical trial. Patients and methods: The EPOCH regimen given to 38 patients consisted of the drugs etoposide (50 mg/m2), vincristine (0.4 mg/m2), and doxorubicin (10 mg/m2), all given in a continuous infusion on days 1-4. Cyclophosphamide (750 mg/m2) was administered on day 6 as i.v. bolus, while prednisone was given orally 60 mg/m2 on days 1-6. Courses were repeated every three weeks. CHOP was given to 40 patients as routinely prescribed. Results: Forty-eight patients were males and thirty were females. Their ages ranged from 19-75 years (median 45 years). Forty-three (55%) had grade 2 and thirty-five (45%) had grade 3 pathologic subtype. Nine patients (12%) presented with stage I, fourteen (18%) with stage II, forty (51%) with stage III, and fifteen (19%) with stage IV disease. The different clinico- pathologic characteristics, including international index categories, were comparable in the two groups. The number of courses given ranged between 3 and 9 (median 6) for both the EPOCH and CHOP regimens. Complete remission (CR) was achieved in 19 (50%), and 27 (67%) of the 38 and 40 patients for both the EPOCH and CHOP combinations, respectively. After a median observation time of 27 months, the four-year overall and failure-free survival rates were 42%, and 30% for the EPOCH and 71% and 54% for the CHOP regimen (P = 0.006 and 0.1 for the overall and FFS rates, respectively). Toxicities were comparable and were mostly of grades 1 and 2, except for hair loss, hematologic toxicities, and infectious episodes which were more common in the EPOCH group. In the EPOCH group, overall survival rates were 55% vs. 22% (P < 0.04) at four years for the low-risk (2 prognostic factors) and high-risk (> 2 factors) groups, respectively. Conclusions: Thus, it may be concluded that continuous-infusion (EPOCH) chemotherapy did not improve treatment outcome over that of the CHOP regimen for aggressive non-Hodgkin's lymphoma patients.

1998
b i Soliman, A. S. a, M. L. b Bondy, B. c Levin, S. d El-Badawy, H. d Khaled, A. e Hablas, S. f Ismail, M. f Adly, K. G. g Mahgoub, R. S. h McPherson, et al., "Familial aggregation of colorectal cancer in Egypt", International Journal of Cancer, vol. 77, no. 6, pp. 811-816, 1998. AbstractWebsite

We have investigated the familial aggregation of colorectal cancer and hereditary nonpolyposis colorectal cancer (HNPCC) in Egypt because of the high incidence of colorectal cancer in Egyptian children and young adults and the prevalence of consanguinity there. In a pilot study, we conducted detailed interviews with 111 Egyptian colorectal cancer patients and 111 healthy Egyptian controls about their family histories of colorectal cancer, and other cancers, consanguinity, age at diagnosis, symptoms and recurrence. Eight patients (7.2%) had one or more first- or second-degree relatives under age 40 with colorectal cancer, suggestive of HNPCC by the Amsterdam criteria. One of these families had a typical history of HNPCC, with 4 relatives having colorectal cancer in 3 generations; 3 of these relatives were younger than age 45 at colon cancer diagnosis, and other relatives had extracolonic tumors. Another 14 patients (12.6%) had a first- or second-degree relative with a family history of other neoplasms such as endometrial, urinary and hepatobiliary cancers that could also be related to HNPCC. Four patients with early-onset colon cancer and a family history of other HNPCC-related cancers reported that their parents were first-degree cousins.

1997
Osman, I. A., H. I. a Scher, Z. - F. a Zhang, I. a Pellicer, R. b Hamza, S. b Eissa, H. b Khaled, and C. a c Cordon-Cardo, "Alterations affecting the p53 control pathway in bilharzial-related bladder cancer", Clinical Cancer Research, vol. 3, no. 4, pp. 531-536, 1997. AbstractWebsite

Bilharzial-related bladder carcinoma (BBC) is the most common malignant neoplasm in Egypt, also occurring with a high incidence in other regions of the Middle East and East Africa. The clinical and pathological features of BBC are different than those described for the conventional transitional cell carcinoma of the bladder, including the high incidence of squamous cell carcinoma reported in BBC and the fact that over 90% of BBC cases at presentation are advanced-stage tumors (P3 and P4). This study was conducted to better define the phenotypic alterations associated with BBC affecting the p53 cell cycle control pathway, including altered patterns of expression of downstream effect or proteins such as mdm2 and p21/WAF1. A well-characterized cohort of 125 patients affected with bilharzial-related bladder tumors was studied. Tumors were classified as squamous carcinomas (n = 68), transitional cell carcinomas (n = 55), or adenocarcinomas (n = 2). The products encoded by TP53, mdm2, and p21/WAF1 genes were analyzed by immunohistochemistry. Furthermore, the patterns of expression of these molecules were correlated with the Ki67 proliferative index. In addition, the microanatomical distribution of programmed cell death was assessed in a subset of tumors, using the so-called terminal deoxynucleotidyl transferase-mediated nick end labeling method. p53 nuclear overexpression was identified in 25 (20%) of 125 cases. Nuclear overexpression of mdm2 was detected in 74 (59.2%) of 125 cases. There was a statistically significant association between coexpression of both p53 and mdm2 and detection of lymph node metastases (P = 0.04). p21/WAF1 expression was detected in 87 (72%) of 121 evaluable cases. A high Ki67 proliferative index was observed in 99 (86%) of 115 evaluable cases. There was a statistically significant association between high Ki67 proliferative index and mdm2-positive phenotype (P = 0.005) and deep muscle invasion (P3b; P = 0.026) as well as lymph node metastases (P = 0.039). Apoptosis was observed in terminally differentiated tumor cells identified in the superficial layers of well-differentiated squamous carcinoma or exfoliating cells in transitional lesions. However, only rare apoptotic tumor cells were found in basal or suprabasal layers as well as in the invasive elements of the neoplasms studied. These results suggest that the frequency of p53 nuclear overexpression in BBC is lower than that reported for conventional transitional cell carcinoma. Nevertheless, tumors with p53 alterations have a greater propensity to progress. The prominent number of cases displaying an mdm2-positive phenotype suggests that this may be an early incident in BBC and should be regarded as a potential oncogenic phenomenon. This is supported by the significant correlation between high Ki67 proliferative index and mdm2 overexpression. The association of an aggressive clinical course with the coexpression of both p53 and mdm2 products might be viewed as a cooperative effect that develops in tumor progression.

Osman, I. A., H. a Scher, Z. - F. a Zhang, T. J. a Soos, R. b Hamza, S. b Eissa, H. b Khaled, A. a Koff, and C. a c Cordon-Cardo, "Expression of cyclin D1, but not cyclins E and A, is related to progression in bilharzial bladder cancer", Clinical Cancer Research, vol. 3, no. 12 I, pp. 2247-2251, 1997. AbstractWebsite

The present study was conducted to analyze the alterations affecting cyclins D1, E, and A in bilharzial bladder cancer and to assess their potential clinical significance. A total of 125 cases were examined. Histopathological subtypes included 68 squamous cell carcinomas, 55 transitional cell carcinomas, and 2 adenocarcinomas. Immunohistochemical analyses were performed using a panel of well-characterized antibodies. The results were correlated with proliferative index, as assessed by Ki67 antigen expression. The cyclin D1-positive phenotype, defined as the identification of positive immunoreactivity in the nuclei of ≤20% of tumor cells, was found in 33 of 107 (31%) evaluable cases. A significant association was observed between the cyclin D1-positive phenotype and deep muscle invasion (P = 0.02), high tumor grade (P = 0.02), and Ki67 high proliferative index (P = 0.03). The cyclin E-positive phenotype, defined as per cyclin D1, was found in 79 of 106 (75%) evaluable cases. The cyclin A-positive phenotype, defined using the above criteria, was identified in 60 of 108 (56%) evaluable cases. No statistically significant association was found between cyclins E or A and clinicopathological parameters or proliferative index. However, there was a strong association between the expression of cyclin D1 and the coexpression of cyclins A and/or E (P = 0.05), Ki67 proliferative index was considered high when ≤20% of tumor cells displayed positive nuclear staining, a phenotype that was observed in 99 of 115 (86%) cases. These data support the hypothesis that cyclin D1 activation deter- mines the evolution of a particular subset of aggressive bladder tumors. In addition, cyclins E and A seem to follow an unscheduled pattern of expression, based on the high frequency of identifying a positive phenotype for these cyclins and the lack of correlation between their expression and Ki67 high proliferative index. It may be postulated that the expression of G1 cyclin genes is deregulated in bilharzial bladder cancer, and that cyclin D1 acts as an oncogenic event in these neoplasms. Moreover, the moderate number of tumors displaying the cyclin D1-positive phenotype (31%) versus the high frequency observed for both cyclins E (75%) and A (56%), suggests a short G1 disbalanced by a long S phase and a rapid transversal of the cell cycle, as evidenced by a high Ki67 index observed in 86% of these cases. This imbalance in the cell cycle, together with alterations reported on the p53 pathway, might underline the accumulation of DNA damage and the aggressive clinical course of bilharzial bladder cancer.

b g Soliman, A. S. a, M. A. c Smith, S. P. c Cooper, K. d Ismail, H. e Khaled, S. f Ismail, R. S. c Mcpherson, I. A. d Seifeldin, and M. L. b Bondy, "Serum organochlorine pesticide levels in patients with colorectal cancer in Egypt", Archives of Environmental Health, vol. 52, no. 6, pp. 409-415, 1997. AbstractWebsite

The widespread use of pesticides in Egypt, the high incidence of colorectal cancer in Egyptian children and young adults, and the published U.S. case reports in which pesticides have been connected with colorectal cancer led the authors to investigate the possible association between organochlorines and colorectal cancer. The authors conducted a pilot study to describe serum organochlorine levels among 31 Egyptian colorectal patients and 17 controls. High levels and large interindividual variability of p,p'- dichloro-diphenyl-dicholoroethylene (DDE), dichloro-diphenyl-trichloroanthane (DDT), β-hexachlorocyclohexane (β-HCH), and hexachlorobenzene (HCB) levels were found among most subjects, especially those from rural areas. Farming and aging were each associated positively with high serum organochlorines. Colorectal cancer patients had higher serum organochlorines levels than controls. The high levels of organochlorines reported and their relation to age, residence, occupation, and disease status justify further study of the possible association between organochlorine pesticides and colorectal cancer in a larger population in Egypt.

1996
Khaled, H. M., N. Gad el-Mawla, A. el-Said, M. R. Hamza, R. Gaafar, I. el-Attar, A. Abu Rabia, and I. Magrath, "Combination chemotherapy for advanced bilharzial bladder carcinoma.", Annals of oncology : official journal of the European Society for Medical Oncology / ESMO, vol. 7, issue 7, pp. 751-4, 1996 Sep. Abstract

BACKGROUND: Carcinoma of the bilharzial bladder, the most common cancer in Egyptian patients has been, until recently, largely treated by surgery. We have studied the activity of a series of single agents in phase II trials and identified a number of active agents. Here we report the results of a trial in which therapeutic combinations of the most active agents were administered in alternating cycles to patients who had never received chemotherapy.

PATIENTS AND METHODS: The study included 30 patients with histologically proven inoperable (20), recurrent (5, 2 of whom subsequently developed metastases), or metastatic disease (5). There were 27 males and 3 females, with a median age of 48.5 years (range 29-65 years). Fourteen patients had squamous cell carcinoma, 12 had transitional cell carcinoma, 2 had adenocarcinoma, and the remaining 2 had undifferentiated carcinoma. Chemotherapy consisted of epidoxorubicin (120 mg/sqm i.v. d1) and vincristine (1.4 mg/sqm i.v., days 1 and 8) alternating with etoposide (100 mg/sqm i.v. infusion over 1 hour, days 1 to 5) and ifosfamide (1800 mg/sqm i.v. infusion over 2 hours, days 1 to 5). Mesna was given as a uroprotector at 40% of the ifosfamide dose at 0, 4, and 8 hours after the ifosfamide infusion. Courses were repeated every 3-4 weeks.

RESULTS: Among the 22 evaluable patients, 8 (36.5%) had a partial and one (4.5%), a complete response, giving a response rate of 46%. Three more patients had responses that were less than a partial remission, and 6 patients showed disease stabilisation on chemotherapy. Toxicities were tolerable and consisted mainly of myelosuppression. Results were further analysed in relation to pathologic subtype, disease status at the start of chemotherapy, and the delivered dose intensity. No relationship was found between any of these parameters and response to therapy.

CONCLUSION: Advanced bilharzial bladder cancer is relatively sensitive to combination chemotherapy, but complete remission and prolonged survival is rare in this subgroup of patients with advanced disease. Further studies will be needed to determine the relative efficacy of single agents and drug combinations.

Attia, M. A., A. R. Zekri, J. Goudsmit, R. Boom, H. M. Khaled, M. T. Mansour, F. de Wolf, H. M. el-Din, and C. J. Sol, "Diverse patterns of recognition of hepatitis C virus core and nonstructural antigens by antibodies present in Egyptian cancer patients and blood donors.", Journal of clinical microbiology, vol. 34, issue 11, pp. 2665-9, 1996 Nov. Abstract

Serum samples from 429 cancer patients, 82 unpaid blood donors, and 74 paid blood donors were tested for hepatitis C virus (HCV) markers in two commercially available enzyme immunoassays (EIAs). A total of 229 of 429 (53.4%) cancer patients were positive by the two EIAs. A total of 34 of 156 (21.8%) of the blood donors were positive by the EIAs, with a higher prevalence among paid blood donors (20/74; 27%) compared with that among the unpaid blood donors (14 of 82; 17%). EIA-positive sera were tested for confirmation of the results in an immunoblot assay (LiaTek) in which reactivities to four synthetic peptides representing the HCV core protein and two synthetic peptides representing nonstructural proteins 4 and 5 were measured. Of 243 first and/or second EIA-positive samples from cancer patients, 188 (77.2%) were confirmed to be positive in the synthetic peptide immunoblot. A total of 33 of 35 (94.3%) blood donor samples were confirmed to be positive. A great diversity in reactivity patterns was seen. However, all sera from the group of paid blood donors were exclusively reactive to core peptides 1 and 2. A subset of LiaTek assay-positive samples were tested by the four-antigen RIBA-2 assay. The sera from the paid blood donors were all nonreactive. A subset of the LiaTek-positive sera was analyzed for the presence of the HCV genome by reverse transcriptase-PCR. Eleven of the 20 serum samples with reactivity to LiaTek core peptides 1 and 2 only were HCV reverse transcriptase-PCR positive, as were the majority of the sera with other reactivity patterns by the LiaTek assay. The results confirm the very high prevalence of HCV infection in Egypt. Furthermore, the results indicate that there is circulating in Egypt, particularly in the group of blood donors paid for their donation, an HCV variant which elicits an immune response that is not detected by the RIBA-2 assay.

f Khaled, H. M. a, N. a Gad El-Mawla, A. b El-Said, M. - R. a Hamza, R. a Gaafar, I. c El-Attar, A. d Abu Rabia, and I. e Magrath, "Combination chemotherapy for advanced bilharzial bladder carcinoma", Annals of Oncology, vol. 7, no. 7, pp. 751-754, 1996. AbstractWebsite

Background: Carcinoma of the bilharzial bladder, the most common cancer in Egyptian patients has been, until recently, largely treated by surgery. We have studied the activity of a series of single agents in phase II trials and identified a number of active agents. Here we report the results of a trial in which therapeutic combinations of the most active agents were administered in alternating cycles to patients who had never received chemotherapy. Patients and methods: The study included 30 patients with histologically proven inoperable (20), recurrent (5, 2 of whom subsequently developed metastases), or metastatic disease (5). There were 27 males and 3 females, with a median age of 48.5 years (range 29-65 years). Fourteen patients had squamous cell carcinoma, 12 had transitional cell carcinoma, 2 had adenocarcinoma, and the remaining 2 had undifferentiated carcinoma. Chemotherapy consisted of epidoxorubicin (120 mg/sqm i.v. d 1) and vincristine (1.4 mg/sqm i.v., days 1 and 8) alternating with etoposide (100 mg/sqm i.v. infusion over 1 hour, days 1 to 5) and ifosfamide (1800 mg/sqm i.v. infusion over 2 hours, days 1 to 5). Mesna was given as a uroprotector at 40% of the ifosfamide dose at 0, 4, and 8 hours after the ifosfamide infusion. Courses were repeated every 3-4 weeks. Results: Among the 22 evaluable patients, 8 (36.5%) had a partial and one (4.5%), a complete response, giving a response rate of 46%. Three more patients had responses that were less than a partial remission, and 6 patients showed disease stabilisation on chemotherapy. Toxicities were tolerable and consisted mainly of myelosuppression. Results were further analysed in relation to pathologic subtype, disease status at the start of chemotherapy, and the delivered dose intensity. No relationship was found between any of these parameters and response to therapy. Conclusion: Advanced bilharzial bladder cancer is relatively sensitive to combination chemotherapy, but complete remission and prolonged survival is rare in this subgroup of patients with advanced disease. Further studies will be needed to determine the relative efficacy of single agents and drug combinations.

Attia, M. A. M. a, A. - R. N. a Zekri, J. b d Goudsmit, R. b Boom, H. M. c Khaled, M. T. a Mansour, F. b De Wolf, H. M. a Alam El-Din, and C. J. A. b Sol, "Diverse patterns of recognition of hepatitis C virus core and nonstructural antigens by antibodies present in Egyptian cancer patients and blood donors", Journal of Clinical Microbiology, vol. 34, no. 11, pp. 2665-2669, 1996. AbstractWebsite

Serum samples from 429 cancer patients, 82 unpaid blood donors, and 74 paid blood donors were tested for hepatitis C virus (HCV) markers in two commercially available enzyme immunoassays (EIAs). A total of 229 of 429 (53.4%) cancer patients were positive by the two EIAs. A total of 34 of 156 (21.8%) of the blood donors were positive by the EIAs, with a higher prevalence among paid blood donors (20/74; 27%) compared with that among the unpaid blood donors (14 of 82; 17%). EIA-positive sera were tested for confirmation of the results in an immunoblot assay (LiaTek) in which reactivities to four synthetic peptides representing the HCV cure protein and two synthetic peptides representing nonstructural proteins 4 and 5 were measured. Of 243 first and/or second EIA-positive samples from cancer patients, 188 (77.2%) were confirmed to be positive in the synthetic peptide immunoblot. A total of 33 of 35 (94.3%) blood donor samples were confirmed to be positive. A great diversity in reactivity patterns was seen. However, all sera from the group of paid blood donors were exclusively reactive to core peptides 1 and 2. A subset of LiaTek assay-positive samples were tested by the four-antigen RIBA-2 assay. The sera from the paid blood donors were all nonreactive. A subset of the LiaTek-positive sera was analyzed for the presence of the HCV genome by reverse transcriptase-PCR. Eleven of the 20 serum samples with reactivity to LiaTek core peptides 1 and 2 only were HCV reverse transcriptase. PCR positive, as were the majority of the sera with other reactivity patterns by the LiaTek assay. The results confirm the very high prevalence of HCV infection in Egypt. Furthermore, the results indicate that there is circulating in Egypt, particularly in the group of blood donors paid for their donation, an HCV variant which elicits an immune response that is not detected by the RIBA-2 assay.

1995
Zekri, A. - R. N., A. A. Bahnassy, H. M. Khaled, O. Mansour, and M. A. Attia, "Comparative analysis of different PCR techniques for detection of HCV in hepatocellular carcinoma patients", Cancer Journal, vol. 8, no. 6, pp. 331-335, 1995. AbstractWebsite

Background - The detection of HCV-RNA genome is at present the only direct marker for diagnosis of HCV infection in serum, liver, peripheral blood mononuclear cells, saliva, urine and spleen, through the use of PCR techniques. However, many factors can affect the final interpretation of the PCR results including heterogeneity of the HCV genome, the procedure used for isolation of the viral genome, the performance of amplification steps as well as sample contamination. Methods - In this study three different isolation procedures and a primer set from the 5-UTR were compared using three variable PCR techniques (direct PCR, single-tube RT-PCR and semi-nested PCR). This was applied for detection of HCV-RNA in sera from 30 hepatocellular carcinoma patients positive for HCV antibodies by both EIA (ORTHO HCV 2.0 ELISA) and immunoblotting (RIBA-2)technique. Results - It was found that RNA extraction with silica and semi-nested PCR technique were the most sensitive procedures. HCV genome was detected in 70%, 86.6%, and 86.6% of the samples using the 3 different PCR techniques after silica extraction, while the denaturation method gave the lowest yield (50%, 53.3%, and 60% respectively). The Guth method showed moderate sensitivity. By this combined method we were able to detect 20 copies of the in-vitro transcribed RNA compared to 50 copies and 100 copies using one tube RT-PCR and direct PCR techniques respectively. Conclusions - The detection of HCV-RNA in the clinical samples is critically dependent on the quality of the RNA and efficiency of the c-DNA synthesis. The combination of one tube-extraction (silica method) and one-tube RT-PCR or even semi-nested RT-PCR minimizes the risk of false positive results through contamination. This, together with minimal time required to individual assay as well as the ability for detect 20-50 copies of HCV-RNA in the clinical specimens make our combination ideal for monitoring patients undergoing antiviral therapy and for proper diagnosis of HCV infection.

Zekri, A. - R. N., M. El-Kabany, and H. M. Khaled, "Concordance between PCR amplifiable HPV DNA and the presence of inclusion bodies in bilharzial bladder cancer among Egyptians", Cancer Molecular Biology, vol. 2, no. 1, pp. 441-447, 1995. AbstractWebsite

Bladder cancer is a major health problem among Egyptians especially in relation to bilharziasis. The physical proximity of the urinary bladder to the genital area has led to the suggestion that Human Papilloma Virus (HPV) may play a role in the development of at least some bladder tumours. Moreover, some clinical characteristics of bladder neoplasms such as papillary morphology, multicentricity and high recurrence rate support this notion. There have been previous reports suggesting the presence of HPV in non bilharzial bladder carcinoma. In this report, we have assessed the presence of HPV in bladder cancer among Egyptian patients. We investigated 30 cases which included, 15 cases of squamous cell carcinoma (SCC), 6 cases of transitional cell carcinoma (TCC), 4 cases of adenocarcinoma and 5 cases of other uncommon variants. The presence of HPV-DNA as detected by PCR amplification was found in 7 cases (6 SCC and 1 TCC) (23.3%). Two of them had the viral subtype 6, 3 had subtype 16 and 2 had subtype 18. Six out of the 7 cases showed bilharziasis (85.7%) and revealed rather similar histological appearance indicating tumor aggressiveness in form of high grading, central necrosis, abundant mitosis and late pathological staging. Ultrastructural examination of the positive cases revealed the presence of intranuclear inclusion bodies 150-250 nm, particularly in cells of SCC with bilharzial association. These results reflected the incidence of HPV in Egyptian bladder cancer in general (23.3%) and viral-bilharzial association (33.3%) in particular.

Weintraub, M., H. M. Khaled, A. - R. Zekri, A. Bahnasi, S. Eissa, D. J. Venzon, I. T. Magrath, and K. G. Bhatia, "p53 mutations in Egyptian bladder cancer", International Journal of Oncology, vol. 7, no. 6, pp. 1269-1274, 1995. AbstractWebsite

Cancer of the bladder is a frequent malignancy in Egypt and other developing countries in which bladder infection with the parasite Schistosoma haematobium is common. Several epidemiological, histopathological and clinical characteristics of cancer of the Bilharzial bladder suggest that it is distinct from bladder cancer seen in industrialized countries. Little is known, however, about molecular aberrations in Egyptian bladder cancer. We studied the status of p53 in a series of 25 cases of Egyptian bladder cancer using immunohistochemistry to detect the p53 protein and SSCP/sequencing to identify mutations in the p53 gene. Ten of 25 (40%) tumor samples showed a mutation by SSCP/sequencing. Mutations were seen in both the squamous and transitional cell variants. The presence of mutations was associated with advanced stage of disease. Immunohistochemistry had a sensitivity of 70%, and a specificity of 85% for detecting p53 mutations. Our data show that p53 mutations are a common event in Egyptian bladder cancer, and may be an indicator of advanced disease. Immunohistochemistry is both sensitive and specific for detecting p53 mutations in this tumor, and may be used to assess the prognostic value of p53 mutations in this disease.

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