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Amr, S. a, R. a Dawson, D. A. c Saleh, L. S. a Magder, N. N. e Mikhail, D. M. S. a George, K. b Squibb, H. d Khaled, and C. A. f Loffredo, "Agricultural workers and urinary bladder cancer risk in egypt", Archives of Environmental and Occupational Health, vol. 69, no. 1: Taylor and Francis Inc., pp. 3-10, 2014. AbstractWebsite

The authors examined the associations between farming and the risk for squamous cell (SCC) or urothelial cell (UC) carcinoma of the urinary bladder among Egyptians. The authors used data from a multicenter case-control study (1,525 male and 315 female cases, and 2,069 male and 547 female age- and residence-matched, population-based controls) to calculate adjusted odds ratios (AORs) and 95% confidence intervals (CIs). Men in farming and who never smoked had increased risk for either SCC or UC (AOR [95% CI]: 4.65 [2.59-8.36] and 6.22 [3.82-10.15], respectively). If they ever smoked, their risks were 2.27 (1.75-2.95) and 1.93 (1.58-2.35), respectively. Women in farmer households were at increased risk for SCC (1.40 [0.93-2.09] and UC [1.25 (0.82-1.89]), although not statistically significant. Occupational and environmental exposures to farming increased the risk for bladder cancer among Egyptians. © 2014 Taylor & Francis Group, LLC.

El-Sharkawi, F. a, M. b El Sabah, Z. A. Hassan, and H. c Khaled, "The biochemical value of urinary metalloproteinases 3 and 9 in diagnosis and prognosis of bladder cancer in Egypt", Journal of Biomedical Science, vol. 21, no. 1: BioMed Central Ltd., 2014. AbstractWebsite

Background: Matrix metalloproteinases (MMPs) have long been associated with cancer-cell invasion and metastasis. Few studies are available that describe this association with bladder cancer either related or unrelated to schistosoma infection. Evaluating the urinary levels of MMP3 and MMP9 as diagnostic and prognostic biomarkers in different stages of schistosomal and non schistosomal bladder cancer was the aim of the present study. Urine samples were collected from 70 patients with schistosomal and non schistosomal bladder cancer at early and advanced stages and also from12 healthy volunteers as controls. Urinary levels of MMP-3 and MMP-9 was measured by ELISA technique. Sensitivity and specificity of both markers were determined. Results: Urinary levels of both MMP-3 and MMP-9 were significantly elevated in all bladder cancer patients compared with controls. MMP-3 started to elevate in early stages of schistosomal bladder cancer (0.173 ng/ml) and non-schistosomal bladder cancer patients (0.308 ng/ml) compared to control (0.016 ng/ml) and remained elevated in advanced stages (0.166, 0.235 ng/ml) of both types of bladder cancer patients. In contrast, MMP-9 showed a significant elevation in advanced stages only of both schistosomal and non schistosomal bladder cancer patients (10.33, 21.22 ng/ml) compared to control (0.409 ng/ml) and this elevation of both markers was much higher in non schistosomal bladder cancer. Both Metalloproteinases were specific for the diagnosis of the disease but MMP-3 was more sensitive and this sensitivity was evident in the early stage (84.85% for MMP3, 27.28% for MMP9). Conclusions: MMP3 may be the recommended urinary metalloproteinases as early diagnostic biomarker in the early stages of both types of bladder cancer although both MMP9 and MMP3 can be used in the diagnosis of advanced stages. Further studies are required on large number of urine samples to confirm these results.

Khaled, H. M. a, H. E. a Shafik, M. S. a Zabhloul, M. b Ghoneim, R. A. c Saber, M. a Manie, H. A. b Enein, H. A. a Megeed, O. a Mansur, M. E. b Sherbini, et al., "Gemcitabine and Cisplatin as Neoadjuvant Chemotherapy for Invasive Transitional and Squamous Cell Carcinoma of the Bladder: Effect on Survival and Bladder Preservation", Clinical Genitourinary Cancer, 2014. AbstractWebsite

Background: Despite aggressive local therapy, patients with locally advanced bladder cancer have a significant risk of distant metastases. This study evaluated the role of neoadjuvant combination chemotherapy with gemcitabine/cisplatin (GC) in improving the outcome of this group of patients over radical cystectomy alone. Patients and Methods: A total of 114 patients with newly diagnosed bladder cancer (T3-4, N0-2, M0) were randomized to radical cystectomy alone or initial 3 cycles of GC, then managed according to response. Patients who achieved complete response completed 6 cycles of GC followed by local radiation therapy (RT) only. If tumors were downstaged to T1, complete transurethral resection was done, followed by 3 cycles of GC and then RT. Patients with partial response underwent radical cystectomy followed by 3 cycles of GC. Patients with stable disease or disease progression underwent radical cystectomy. Results: The overall response rate to GC was 55.1%, and complete response was achieved in 28.6%. The 3-year overall survival (OS) was 51.9% versus 51.2% in the chemotherapy and surgery arms, respectively (P = .399). The 3-year disease-free survival was 31.8% in the chemotherapy arm and 45.1% in the surgery arm (P = .06). Bladder preservation was achieved in 22.5% of patients in the neoadjuvant arm. OS was 78% in responding patients and 100% in patients with complete response. Conclusion: Neoadjuvant GC did not improve survival in locally advanced bladder cancer over radical cystectomy alone. However, bladder preservation was feasible, and OS in responding patients was impressive. Therefore, predictive models to select patients are needed. This is the largest prospective study of squamous cell carcinoma and transitional cell carcinoma using neoadjuvant GC. © 2014 Elsevier Inc. All rights reserved.

Goerlitz, D. a, S. b Amr, C. a Dash, D. A. c Saleh, M. d g El Daly, M. d e Abdel-Hamid, S. d g j El Kafrawy, T. f Hifnawy, S. g Ezzat, M. A. h Abdel-Aziz, et al., "Genetic polymorphisms in NQO1 and SOD2: Interactions with smoking, schistosoma infection, and bladder cancer risk in Egypt", Urologic Oncology: Seminars and Original Investigations, vol. 32, no. 1, pp. 47.e15-47.e20, 2014. AbstractWebsite

Background: Bladder cancer is the most prevalent form of cancer in men among Egyptians, for whom tobacco smoke exposure and Schistosoma haematobium (SH) infection are the major risk factors. We hypothesized that functional polymorphisms in NAD(P)H:quinone oxidoreductase 1 (NQO1) and superoxide dismutase 2 (SOD2), modulators of the effects of reactive oxidative species, can influence an individual's susceptibility to these carcinogenic exposures and hence the risk of bladder cancer. Methods: We assessed the effects of potential interactions between functional polymorphisms in the NQO1 and SOD2 genes and exposure to smoking and SH infection on bladder cancer risk among 902 cases and 804 population-based controls in Egypt. We used unconditional logistic regression to estimate the odds ratios (OR) and confidence intervals (CI) 95%. Results: Water pipe and cigarette smoking were more strongly associated with cancer risk among individuals with the TT genotype for SOD2 (OR [CI 95%] = 4.41 [1.86-10.42]) as compared with those with the CC genotype (OR [CI 95%] = 2.26 [0.97-6.74]). Conversely, the risk associated with SH infection was higher among the latter (OR [CI 95%] = 3.59 [2.21-5.84]) than among the former (OR [CI 95%] = 1.86 [1.33-2.60]). Polymorphisms in NQO1 genotype showed a similar pattern, but to a much lesser extent. The highest odds for having bladder cancer following SH infection were observed among individuals with the CC genotypes for both NQO1 and SOD2 (OR [CI 95%] = 4.41 [2.32-8.38]). Conclusion: Our findings suggest that genetic polymorphisms in NQO1 and SOD2 play important roles in the etiology of bladder cancer by modulating the effects of known contributing factors such as smoking and SH infection. © 2014 Elsevier Inc.

Haggag, R. a, K. b Farag, F. a Abu-Taleb, S. b Shamaa, A. - R. c Zekri, T. d Elbolkainy, and H. e Khaled, "Low-dose versus standard-dose gemcitabine infusion and cisplatin for patients with advanced bladder cancer: A randomized phase II trial - An update", Medical Oncology, vol. 31, no. 1, 2014. AbstractWebsite

{Prolonged infusion of low-dose gemcitabine and cisplatin (GC) proved to be an effective treatment for patients with advanced bladder cancer. One hundred and twenty untreated patients with stage III/IV bladder cancer were randomized to receive either gemcitabine (250 mg/m2) 6-h infusion on days 1 and 8, and cisplatin (70 mg/m2) on day 2 every 21-day cycle (arm 1) or gemcitabine (1,250 mg/m2) 30-min infusion on days 1 and 8, with the same dose of cisplatin (arm 2). The 92 males and 28 females included in the study had a median age of 62 years (range 40-85 years). Among the 120 patient, complete response was achieved in 11.7 % (7/60 patients of arm 1) and 5 % (3/60 patients of arm 2). Eighteen patients in arm 1 (30 %) and 17 patients (28.3 %) in arm 2 had partial response on therapy. Thus, the overall response rate of patients in arm 1 and arm 2 was 41.7 % (25/60 patients) and 33.3 % (20/60 patients), respectively (p = 0.37). No significant difference in median time to disease progression (26 vs. 24 months

El Sharkawi, F. Z. a, H. A. b El Shemy, and H. M. c Khaled, "Possible anticancer activity of rosuvastatine, doxazosin, repaglinide and oxcarbazepin", Asian Pacific Journal of Cancer Prevention, vol. 15, no. 1: Asian Pacific Organization for Cancer Prevention, pp. 199-203, 2014. AbstractWebsite

Background: Rosuvastatine, doxazosin, repaglinide and oxcarbazepin are therapeutic drugs available in the market for the treatment of different diseases. Potential to display antitumor activities has also been suggested. The aim of the current study was to evaluate their in vitro effects on some human transformed cell lines. Materials and Methods: Cytotoxicity of the four drugs was tested in MCF-7, HeLa and HepG2 cells by the neutral red assay method and also the effect of rosuvastatine and doxazosin against Ehrlich Ascities Carcinoma Cells (EACC) by trypan blue assay. Results: Rosuvastatine exerted the greatest cytotoxic effect against HepG2 cells with an IC50 value of 58.7±69.3; in contrast doxazosin showed least activity with IC50=104.4 ±115.7. Repaglinide inhibited the growth of both HepG2 and HeLa cells with IC50 values of 87.6±117.5 and 89.3±119.5, respectively. Oxcarbazepine showed a potent cytotoxicity against both HeLa (IC50=19.4±43.9) and MCF7 cancer cells ((IC50=22±35.7).On the other hand the growth of EACC was completely inhibited by doxazosine (100% inhibition) while rosuvastatine had weak inhibitory activity (11.6%) . Conclusions: The four tested drugs may have cytotoxic effects against hepatic, breast and cervical carcinoma cells; also doxazosine may inhibit the growth of endometrial cancer cells. Further investigations in animals are needed to confirm these results.

Ahmed, O. S. a, M. B. b Mohamed, A. - R. N. a Zekri, H. b Imam, H. M. a Khaled, and M. H. b c Abdel-Kader, "Synthesis of the newly developed core-shell Au/Fe3O4 magnato-plasmonic nanocomposite in cancer cells", Life Science Journal, vol. 11, no. 10: Zhengzhou University, pp. 182-187, 2014. AbstractWebsite

Background: Fe3O4-gold-Polyethyleneimine core-shell nanostructure can be used in biotechnological and biomedical applications.This research was conducted to assess the biocompatibility of the core-shell Fe3O4@Au nanocomposite, which have potential application in biomedical imaging. Results: Magnetite nanoparticles with an average size of 14 nm in diameter were synthesized using the chemical co-precipitation method. A gold-coated Fe3O4 monotonous core-shell nanostructure was produced with an average size of 21 nm in diameter by PEI reduction of Au3+. The results of analyses with electron diffraction, particle size, zeta potential,Transmission Electron Microscopy (TEM),) and vibrating sample magnetometer (VSM) indicated that the nanoparticles were regularly shaped, and agglomerate-free, with a narrow size distribution. We use the Laser Induced Breakdown Spectroscopy (LIBS) as a promising non-destructive technique for the spectral analysis of Gold - coated magnetic nanoparticles (Fe3O4). The biocompatibility of the obtained NPs, at concentration, was evaluated via MTT(3-(4,5- dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide) assay and the results showed that the NPs were non-toxic at concentrations 50μg /mL. Conclusions: A rapid, mild method for synthesizing Fe3O4-gold nanoparticles using Polyethyleneimine was investigated. A magnetic gold core-shell- Polyethyleneimine nanocomposite, including both the supermagnetic properties of iron oxide and the optical characteristics of colloidal gold nanoparticles, was synthesized.

El Sharkawi, F. Z. a, H. A. b El Shemy, and H. c Khaled, "Anticancer activity of some commercial antihypertensive drugs by Neutral Red assay", Life Science Journal, vol. 10, no. 1, pp. 609-613, 2013. AbstractWebsite

Lisinopril, propranolol and nifedipine are three commercial drugs used clinically for the management of hypertension, angina pectoris, and cardiac arrhythmias. It has been reported that these drugs have inhibitory effects on some cancer cells. In the current study the cytotoxicity of these drugs was evaluated against HeLa, HepG2, MCF- 7 and EACC transformed cell lines using Neutral Red and Trypan Blue assay methods. The three drugs showed a cytotoxicity against HeLa, HepG2 and MCF-7 cells with different potentiality. Lisinopril was the most potent cytotoxic drug against HepG2 cells with IC50 = 33.8±88.4 μg/ml at the concentration of 300ug/ml; while Nifedipine was the most active one against HeLa cells with IC50 =130±58.4ug/ml at a concentration of 300ug/ml. Propranolol was the most active against MCF7 cells IC50 of 78.0± 121.4 μg/ml at a concentration of 3000ug/ml. The three used drugs inhibited the growth of EACC cells and propranolol showed highest inhibitory activity; it inhibited 97.7% of cell growth at a concentration of 300 ug/ml and 100% inhibition at a concentration of 3000 ug/ml. Lisinopril and nifedipine showed a lower rate of growth inhibition of 18.28% and 11.40% respectively at a concentration of 3000ug/ml. In conclusion: At these high concentrations, the three tested drugs are lethal in vitro to cancer cells of endometrial, cervical, hepatic, and breast origin. Further animal studies are required to confirm this conclusion.

Stefan, D. C. a, A. M. b Elzawawy, H. M. c Khaled, F. d Ntaganda, A. e Asiimwe, B. W. f Addai, S. f Wiafe, and I. F. g h Adewole, "Developing cancer control plans in Africa: Examples from five countries", The Lancet Oncology, vol. 14, no. 4, pp. e189-e195, 2013. AbstractWebsite

The creation and implementation of national cancer control plans is becoming increasingly necessary for countries in Africa, with the number of new cancer cases per year in the continent expected to reach up to 1·5 million by 2020. Examples from South Africa, Egypt, Nigeria, Ghana, and Rwanda describe the state of national cancer control plans and their implementation. Whereas in Rwanda the emphasis is on development of basic facilities needed for cancer care, in those countries with more developed economies, such as South Africa and Nigeria, the political will to fund national cancer control plans is limited, even though the plans exist and are otherwise well conceived. Improved awareness of the increasing burden of cancer and increased advocacy are needed to put pressure on governments to develop, fund, and implement national cancer control plans across the continent. © 2013 Elsevier Ltd.

Abdel Aziz, M. T. a, H. M. b Khaled, A. c El Hindawi, N. K. a Roshdy, L. A. a Rashed, D. A. Sabry, A. A. a Hassouna, F. a Taha, and W. I. a Ali, "Effect of mesenchymal stem cells and a novel curcumin derivative on notch1 signaling in hepatoma cell line", BioMed Research International, vol. 2013, 2013. AbstractWebsite

This study was conducted to evaluate the effect of mesenchymal stem cells (MSCs) and a novel curcumin derivative (NCD) on HepG2 cells (hepatoma cell line) and to investigate their effect on Notch1 signaling pathway target genes. HepG2 cells were divided into HepG2 control group, HepG2 cells treated with MSC conditioned medium (MSCs CM), HepG2 cells treated with a NCD, HepG2 cells treated with MSCs CM and NCD, and HepG2 cells treated with MSCs CM (CM of MSCs pretreated with a NCD). Expression of Notch1, Hes1, VEGF, and cyclin D1 was assessed by real-time, reverse transcription-polymerase chain reaction (RT-PCR) in HepG2 cells. In addition, HepG2 proliferation assay was performed in all groups. Notch1 and its target genes (Hes1 and cyclin D1) were downregulated in all treated groups with more suppressive effect in the groups treated with both MSCs and NCD. Also, treated HepG2 cells showed significant decrease in cell proliferation rate. These data suggest that modulation of Notch1 signaling pathway by MSCs and/or NCD can be considered as a therapeutic target in HCC. © 2013 Mohamed Talaat Abdel Aziz et al.

Davies, C. a, H. a Pan, J. b Godwin, R. a Gray, R. c Arriagada, V. d Raina, M. e Abraham, V. H. f Medeiros Alencar, A. g Badran, X. h Bonfill, et al., "Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial", The Lancet, vol. 381, no. 9869, pp. 805-816, 2013. AbstractWebsite

{Background For women with oestrogen receptor (ER)-positive early breast cancer, treatment with tamoxifen for 5 years substantially reduces the breast cancer mortality rate throughout the first 15 years after diagnosis. We aimed to assess the further effects of continuing tamoxifen to 10 years instead of stopping at 5 years. Methods In the worldwide Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) trial, 12 894 women with early breast cancer who had completed 5 years of treatment with tamoxifen were randomly allocated to continue tamoxifen to 10 years or stop at 5 years (open control). Allocation (1:1) was by central computer, using minimisation. After entry (between 1996 and 2005), yearly follow-up forms recorded any recurrence, second cancer, hospital admission, or death. We report effects on breast cancer outcomes among the 6846 women with ER-positive disease, and side-effects among all women (with positive, negative, or unknown ER status). Long-term follow-up still continues. This study is registered, number ISRCTN19652633. Findings Among women with ER-positive disease, allocation to continue tamoxifen reduced the risk of breast cancer recurrence (617 recurrences in 3428 women allocated to continue vs 711 in 3418 controls

Högfeldt, T. a, A. A. b Bahnassy, A. c Kwiecinska, A. a d Österborg, K. P. a Tamm, A. e Porwit, A. - R. N. f Zekri, J. g Lundahl, H. M. h Khaled, H. a Mellstedt, et al., "Patients with activated B-cell like diffuse large B-cell lymphoma in high and low infectious disease areas have different inflammatory gene signatures", Leukemia and Lymphoma, vol. 54, no. 5, pp. 996-1003, 2013. AbstractWebsite

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease with an association with inflammation and viral infections. We hypothesize that environmental factors may be involved in the pathogenesis of DLBCL. In this study, we compared gene expression profiles of lymph node tissues from patients with DLBCL from two different geographical areas with diverse environmental exposures. Specimens from Egyptian and Swedish patients with DLBCL as well as controls were studied. Gene expression analysis using microarray and quantitative polymerase chain reaction demonstrated significantly higher expression of signal transducer and activator of transcription 3 (STAT3) in Swedish as compared to Egyptian patients and control materials from both countries. This was confirmed at protein level using confocal microscopy. The receptor tyrosine kinase ROR1, a "survival factor" for malignant cells, was overexpressed and significantly related to the STAT3 expression pattern. The difference in the expression of genes involved in inflammatory responses and in the tumorigenic process of DLBCL might relate to infectious agents and/or other environmental exposures. © 2013 Informa UK, Ltd.

Metwally, A. M. a, L. A. b c Refaat, H. d Shaaban, S. e Megm, M. f Emara, A. A. g Tohamy, E. A. d Sinna, and H. f Khaled, "Role of cyclins A and E in endometrial carcinogenesis in breast cancer patients under tamoxifen treatment", Journal of the Egyptian National Cancer Institute, vol. 25, no. 4, pp. 193-198, 2013. AbstractWebsite

Purpose: The objective of our study was to determine the relevance of cyclins A and E overexpression in endometrial carcinogenesis in hormone receptor-positive breast cancer patients under tamoxifen therapy. Experimental design: We assessed expression of cyclins A and E in Endometrial cytology samples collected from 36 ER and PR positive breast cancer patients; under tamoxifen treatment by using the Tao-brush non-invasive brushing cytology technique. Cyclins were detected in the collected samples by means of immuno-cytochemistry. The patients included in this study are a cohort of 36 breast cancer patients who were operated upon at the National Cancer Institute - Cairo University in the period from February 2006 to May 2008 and received tamoxifen (TAM) as part of their adjuvant treatment. Results: Cyclins A and E were expressed in 17 and 15 of the 36 collected endometrial cytology samples (47.2% and 41.6% respectively).Expression of cyclins A and E was highly correlated to Tamoxifen exposure duration (32 and 43. months respectively) p< 0.001. Tamoxifen median exposure duration was shortened to 21. months in cases showing positivity for either markers, while in cases showing positivity for both cyclins, the median exposure duration was longer (44.5. months) (p< 0.001). Neither cyclin A nor E was detected before median tamoxifen exposure duration of 11. months. Endometrial carcinoma cases had the longest Tamoxifen exposure duration (60. months). Conclusion: Cyclins A and E expression is involved in the carcinogenesis of endometrium in women with breast cancer and under tamoxifen-treatment. Follow up of the patients using these 2 markers is highly recommended starting from the 12th month. © 2013.

Khaled, H., "Schistosomiasis and Cancer in Egypt: Review", Journal of Advanced Research, vol. 4, no. 5, pp. 461-466, 2013. AbstractWebsite

Schistosomiasis is not known to be associated with any malignant disease other than bladder cancer. Bladder cancer is still the most common malignant tumor among males in Egypt and some African and Middle East countries. However, the frequency rate of bladder cancer has declined significantly during the last 25. years. This drop is mainly related to the control of Schistosomiasis. Many studies have elucidated the pathogenic events of Schistosomal-related bladder cancer with a suggested theory of pathogenesis. Furthermore, the disease presents with a distinct clinicopathologic profile that is quite different from bladder cancer elsewhere with younger age at presentation, more male predominance, more invasive stages, and occurrence of squamous cell carcinoma pathologic subtype. However, recent data suggest that this profile has been dramatically changed over the past 25. years leading to minimization of the differences between its features in Egypt and that in Western countries. Management of muscle-invasive localized disease is mainly surgery with 5-year survival rates of 30-50%. Although still a debatable issue, adjuvant and neoadjuvant chemotherapy and radiotherapy have improved treatment outcomes including survival and bladder preservation rates in most studies. This controversy emphasizes the need of individualized treatment options based on a prognostic index or other factors that can define the higher risk groups where more aggressive therapy is needed. The treatment for locally advanced and/or metastatic disease has passed through a series of clinical trials since 1970s. These phase II and III trials have included the use of single agent and combination of chemotherapy and radiotherapy regimens. The current standard of systemic chemotherapy of generally fit patients is now the gemcitabine-cisplatin combination. In conclusion, a changing pattern of bladder cancer in Egypt is clearly observed. This is mainly due to the success in the control of Schistosomiasis. It may also be due to increased exposure to other etiologic factors that include smoking, pesticides, and/or other causative agents. This change will ultimately affect disease management. © 2013.

Aly, M. S., H. M. Khaled, M. Emara, and T. D. Hussein, "Cytogenetic profile of locally advanced and metastatic Schistosoma-related bladder cancer and response to chemotherapy.", Cancer genetics, vol. 205, issue 4, pp. 156-62, 2012 Apr. Abstract

Bladder cancer is a common malignancy in developing countries in which bladder infection with the parasite Schistosoma haematobium is prevalent. Several epidemiological, histopathological, and clinical characteristics of schistosoma-associated bladder cancer suggest that it is distinct from bladder cancer seen in other places in the world. The aim of this study was to extend establishing the cytogenetic profile of this type of malignancy in advanced and metastatic cases, and to demonstrate its relation to the end results of systemic therapy. Fluorescence in situ hybridization was applied to interphase nuclei to detect numerical chromosome changes in 41 patients with bladder cancer. Numerical chromosome aberrations were detected in 27 of 41 cases (66%). In 17 (41%) cases, a gain of chromosome 7 was observed, while losses in chromosomes 9 and 17 were detected in 20 (49%) and 18 (44%) cases, respectively. Loss of chromosome Y was detected in 7 of the 32 male patients included in this study (22%). There was a statistically significant association between stage of the disease and overall survival; Bajorin score and time to disease progression and overall survival; and between response to systemic therapy and time to disease progression and overall survival. The only chromosomal abnormality that had a significant relationship with overall survival was the gain of chromosome 4. When the genetic basis of schistosoma-associated bladder cancer is fully understood, new diagnostic and therapeutic strategies could be developed, which in turn may promote better clinical management and survival.

Wolpert, B. J. a, S. a Amr, D. A. b Saleh, S. c Ezzat, I. d Gouda, I. d Loay, T. e Hifnawy, M. f Abdel-Hamid, N. N. g Mikhail, M. a Zhan, et al., "Associations differ by sex for catechol-O-methyltransferase genotypes and bladder cancer risk in South Egypt", Urologic Oncology: Seminars and Original Investigations, vol. 30, no. 6, pp. 841-847, 2012. AbstractWebsite

Objectives:To examine associations between urinary bladder cancer risk and polymorphisms of the gene encoding the catechol estrogen-metabolizing enzyme, catechol-O-methyltransferase (COMT), among Egyptian women and men. Materials and methods:We used questionnaire and genotype data from a case-control study in Egypt. This analysis focused on South Egypt cases with confirmed urothelial (UC) or squamous cell (SCC) carcinoma of the bladder, and controls frequency-matched on sex, 5-year age-group, and residence governorate. Real-time PCR on blood specimen DNA was used to determine COMT genotypes encoding for Val/Val, Val/Met, and Met/Met, the enzyme forms associated with high, intermediate, or low activity, respectively. ResultsThe study sample, which included 255 women and 666 men, consisted of 394 cases with histologically confirmed UC (225) or SCC (n = 169), and 527 controls. The odds of having either type of bladder cancer were lower among men with genotypes encoding Val/Met or Met/Met than among those with the genotype encoding Val/Val, even after adjustment for other factors, such as smoking and schistosomiasis history [adjusted odds ratio (AOR): 0.64; 95% confidence interval (CI): 0.43, 0.96]; however, the association was statistically significant for SCC (AOR 0.57; 95% CI: 0.34, 0.96) but marginal for UC (AOR: 0.64; 95% CI: 0.39, 1.02). No significant associations were detected between bladder cancer risk and COMT genotypes among postmenopausal women.: Conclusions:These findings suggest that even after controlling for established risk factors, the involvement of COMT genotypes in bladder cancer risk differs among men compared with women in South Egypt. © 2012.

b Aly, M. S. a, H. M. c Khaled, M. c Emara, and T. D. d Hussein, "Cytogenetic profile of locally advanced and metastatic schistosoma-related bladder cancer and response to chemotherapy", Cancer Genetics, vol. 205, no. 4, pp. 156-162, 2012. AbstractWebsite

Bladder cancer is a common malignancy in developing countries in which bladder infection with the parasite Schistosoma haematobium is prevalent. Several epidemiological, histopathological, and clinical characteristics of schistosoma-associated bladder cancer suggest that it is distinct from bladder cancer seen in other places in the world. The aim of this study was to extend establishing the cytogenetic profile of this type of malignancy in advanced and metastatic cases, and to demonstrate its relation to the end results of systemic therapy. Fluorescence in situ hybridization was applied to interphase nuclei to detect numerical chromosome changes in 41 patients with bladder cancer. Numerical chromosome aberrations were detected in 27 of 41 cases (66%). In 17 (41%) cases, a gain of chromosome 7 was observed, while losses in chromosomes 9 and 17 were detected in 20 (49%) and 18 (44%) cases, respectively. Loss of chromosome Y was detected in 7 of the 32 male patients included in this study (22%). There was a statistically significant association between stage of the disease and overall survival; Bajorin score and time to disease progression and overall survival; and between response to systemic therapy and time to disease progression and overall survival. The only chromosomal abnormality that had a significant relationship with overall survival was the gain of chromosome 4. When the genetic basis of schistosoma-associated bladder cancer is fully understood, new diagnostic and therapeutic strategies could be developed, which in turn may promote better clinical management and survival. © 2012 Elsevier Inc.

Herzog, C. M. a, S. b Dey, A. c Hablas, H. M. d Khaled, I. A. c Seifeldin, M. c Ramadan, H. c El-Hamzawy, M. L. a Wilson, and A. S. a Soliman, "Geographic distribution of hematopoietic cancers in the nile delta of Egypt", Annals of Oncology, vol. 23, no. 10, pp. 2748-2755, 2012. AbstractWebsite

Background: Previous evidence indicated that incidence rates of non-Hodgkin's lymphoma (NHL) are high in Egypt although little is known about risk factors. Materials and methods: Using data from the population-based cancer registry of Gharbiah governorate in Egypt, we assessed the 1999-2005 incidence of hematopoietic cancers (HCs) based on the ICD-O3 by age- and sex-specific urban-rural distribution. Results: NHL showed the highest incidence among all HCs (11.7 per 100 000). Urban incidence of HCs was higher than rural incidence. Incidence rates of Hodgkin's lymphoma (HL) and NHL were high especially among urban males up to the 64-year age category. Rural incidence of HL and NHL was high below age 20. Among the districts of the governorate, we observed NHL incidence pattern similar to that observed for hepatocellular carcinoma because of the possible link to hepatitis C virus for both cancers. Comparison to the published HCs data from Algeria, Cyprus, and Jordan showed the highest NHL rate in Egypt than the other countries in the region. Conclusions: Future studies should define the role of environmental exposures in hematopoietic carcinogenesis in this population. In-depth studies should also investigate the role of access to health care in the urban-rural variation of HC distribution in this population. © The Author 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

Zheng, Y. - L. a, S. b Amr, D. A. c Saleh, C. a Dash, S. f Ezzat, N. N. g Mikhail, I. d Gouda, I. d Loay, T. h Hifnawy, M. e Abdel-Hamid, et al., "Urinary bladder cancer risk factors in Egypt: A multicenter case-control study", Cancer Epidemiology Biomarkers and Prevention, vol. 21, no. 3, pp. 537-546, 2012. AbstractWebsite

Background: We investigated associations between tobacco exposure, history of schistosomiasis, and bladder cancer risk in Egypt. Methods: We analyzed data from a case-control study (1,886 newly diagnosed and histologically confirmed cases and 2,716 age-, gender-, and residence-matched, population-based controls). Using logistic regression, we estimated the covariate-adjusted ORs and 95% confidence interval (CI) of the associations. Results: Among men, cigarette smoking was associated with an increased risk of urothelial carcinoma (OR = 1.8; 95% CI, 1.4-2.2) but not squamous cell carcinoma (SCC); smoking both water pipes and cigarettes was associated with an even greater risk for urothelial carcinoma (OR = 2.9; 95% CI, 2.1-3.9) and a statistically significant risk for SCC (OR = 1.8; 95% CI, 1.2-2.6). Among nonsmoking men and women, environmental tobacco smoke exposure was associated with an increased risk of urothelial carcinoma. History of schistosomiasis was associated with increased risk of both urothelial carcinoma (OR = 1.9; 95% CI, 1.2-2.9) and SCC (OR = 1.9; 95% CI, 1.2-3.0) in women and to a lesser extent (OR = 1.4; 95% CI, 1.2-1.7 and OR = 1.4; 95% CI, 1.1-1.7, for urothelial carcinoma and SCC, respectively) in men. Conclusions: The results suggest that schistosomiasis and tobacco smoking increase the risk of both SCC and urothelial carcinoma. Impact: This study provides new evidence for associations between bladder cancer subtypes and schistosomiasis and suggests that smoking both cigarettes and water pipes increases the risk for SCC and urothelial carcinoma in Egyptian men. ©2011 AACR.

Soliman, A. S., C. G. Kleer, K. Mrad, M. Karkouri, S. Omar, H. M. Khaled, A. - L. Benider, F. B. Ayed, S. S. Eissa, M. S. Eissa, et al., "Inflammatory breast cancer in north Africa: comparison of clinical and molecular epidemiologic characteristics of patients from Egypt, Tunisia, and Morocco.", Breast disease, vol. 33, issue 4, pp. 159-69, 2011-2012. Abstract

Understanding molecular characteristics that distinguish inflammatory breast cancer (IBC) from non-IBC is crucial for elucidating breast cancer etiology and management. We included 3 sets of patients from Egypt (48 IBC and 64 non-IBC), Tunisia (24 IBC and 40 non-IBC), and Morocco (42 IBC and 41 non-IBC). Egyptian IBC patients had the highest combined erythema, edema, peau d'orange, and metastasis among the 3 IBC groups. Egyptian IBC tumors had the highest RhoC expression than Tunisians and Moroccan IBCs (87% vs. 50%, vs. 38.1, for the 3 countries, respectively). Tumor emboli were more frequent in Egyptian IBC than non-IBC (Mean ± SD: 14.1 ± 14.0 vs. 7.0 ± 12.9, respectively) (P < 0.001) and Tunisians (Mean ± SD: 3.4 ± 2.5 vs. 1.9 ± 2.0, respectively) (P < 0.01). There was no difference of emboli in Moroccan tumors (1.7 ± 1.2 vs. 1.8 ± 1.2 for IBC and non-IBC, respectively (P=0.66). This study illustrates that RhoC overexpression and tumor emboli are more frequent in IBC relative to non-IBC from Egypt and Tunisia. Tumors of Moroccans were significantly different from Egyptian and Tunisian tumors for RhoC expression and emboli. Future studies should focus on relating epidemiologic factors and clinical pictures to molecular features of IBC in these and other populations.

Hamed, M. A. A., S. A. A. Ahmed, and H. M. Khaled, "Efficiency of diagnostic biomarkers among colonic schistosomiasis Egyptian patients.", Memórias do Instituto Oswaldo Cruz, vol. 106, issue 3, pp. 322-9, 2011 May. Abstract

The schistosomal parasite plays a critical role in the development of malignant lesions in different organs. The pathogenesis of cancer is currently under intense investigation to identify reliable prognostic indices for disease detection. The objective of this paper is to evaluate certain biochemical parameters as diagnostic tools to efficiently differentiate between colonic carcinoma and colonic carcinoma associated with schistosomal infection among Egyptian patients. The parameters under investigation are interleukin 2 (IL-2), tumour necrosis factor alpha (TNF-α), carcinoembryonic antigen (CEA) levels, tissue telomerase, pyruvate kinase (PK), glucose-6-phosphate dehydrogenase (G-6-PD) and lactate dehydrogenase (LDH) enzyme activities. The results revealed a significant elevation in the level of the tumour markers IL-2, TNF-α and CEA as well as the activities of LDH, telomerase and G-6-PD among non-bilharzial and bilharzial colonic cancer groups, with a more potent effect in bilharzial infection-associated colonic cancer. A significant inhibition in PK activity was recorded in the same manner as compared to normal tissues. The efficacy of this biomarker was also evaluated through detecting sensitivity, specificity, negative and positive predictive values. In conclusion, schistosomal colonic carcinoma patients displayed more drastic changes in all parameters under investigation. The combination of the selected parameters succeeded in serving as biomarkers to differentiate between the two malignant types.

Aurer, I., H. Eghbali, J. Raemaekers, H. M. Khaled, C. Fortpied, L. Baila, and R. W. M. van der Maazen, "Gem-(R)CHOP versus (R)CHOP: a randomized phase II study of gemcitabine combined with (R)CHOP in untreated aggressive non-Hodgkin's lymphoma--EORTC lymphoma group protocol 20021 (EudraCT number 2004-004635-54).", European journal of haematology, vol. 86, issue 2, pp. 111-6, 2011 Feb. Abstract

BACKGROUND:   Despite recent improvements, many patients with aggressive non-Hodgkin's lymphoma (NHL) ultimately succumb to their disease. Therefore, improvements in front-line chemotherapy of aggressive NHL are needed. Gemcitabine is active in lymphoma.

METHODS: We performed a randomized phase II trial of the addition of gemcitabine to standard CHOP chemotherapy with or without rituximab [(R)CHOP]. The trial was also designed to determine the maximal tolerated dose (MTD) of gemcitabine in this combination. Patients with previously untreated aggressive NHL were randomized to receive either eight cycles of (R)CHOP given every 3 wk or (R)CHOP combined with gemcitabine [Gem-(R)CHOP].

RESULTS: Twenty-five patients were enrolled in the trial before early closure. Twelve were randomized to Gem-(R)CHOP and 13 to (R)CHOP. MTD of gemcitabine was 800 mg/m(2) given on days 1 and 8; dose-limiting toxicity was hematologic. Five patients (42%) treated with Gem-(R)CHOP achieved complete response in comparison with 10 (77%) treated with (R)CHOP. Median time to treatment failure was 1.5 yr for Gem-(R)CHOP and 3.1 yr for (R)CHOP. Three patients receiving Gem-(R)CHOP had serious pulmonary toxicity, when compared to none receiving (R)CHOP. One patient died of pneumonitis.

CONCLUSIONS: In this group of patients, addition of gemcitabine did not seem to improve outcomes. Gem-(R)CHOP in previously untreated patients with aggressive NHL occasionally results in severe, potentially fatal, pulmonary toxicity.

Anderson, B. O., E. Cazap, N. S. El Saghir, C. - H. Yip, H. M. Khaled, I. V. Otero, C. A. Adebamowo, R. A. Badwe, and J. B. Harford, "Optimisation of breast cancer management in low-resource and middle-resource countries: executive summary of the Breast Health Global Initiative consensus, 2010.", The lancet oncology, vol. 12, issue 4, pp. 387-98, 2011 Apr. Abstract

The purpose of the Breast Health Global Initiative (BHGI) 2010 summit was to provide a consensus analysis of breast cancer control issues and implementation strategies for low-income and middle-income countries (LMCs), where advanced stages at presentation and poor diagnostic and treatment capacities contribute to lower breast cancer survival rates than in high-income countries. Health system and patient-related barriers were identified that create common clinical scenarios in which women do not present for diagnosis until their cancer has progressed to locally advanced or metastatic stages. As countries progress to higher economic status, the rate of late presentation is expected to decrease, and diagnostic and treatment resources are expected to improve. Health-care systems in LMCs share many challenges including national or regional data collection, programme infrastructure and capacity (including appropriate equipment and drug acquisitions, and professional training and accreditation), the need for qualitative and quantitative research to support decision making, and strategies to improve patient access and compliance as well as public, health-care professional, and policy-maker awareness that breast cancer is a cost-effective, treatable disease. The biggest challenges identified for low-income countries were little community awareness that breast cancer is treatable, inadequate advanced pathology services for diagnosis and staging, and fragmented treatment options, especially for the administration of radiotherapy and the full range of systemic treatments. The biggest challenges identified for middle-resource countries were the establishment and maintenance of data registries, the coordination of multidisciplinary centres of excellence with broad outreach programmes to provide community access to cancer diagnosis and treatment, and the resource-appropriate prioritisation of breast cancer control programmes within the framework of existing, functional health-care systems.

Metwally, N. S., S. A. Ali, A. M. Mohamed, H. M. Khaled, and S. A. Ahmed, "Levels of certain tumor markers as differential factors between bilharzial and non-biharzial bladder cancer among Egyptian patients.", Cancer cell international, vol. 11, issue 1, pp. 8, 2011. Abstract

BACKGROUND/OBJECTIVE: Bladder cancer is the commonest type of malignant tumors as a result of schistosomaisis which is a major healthy problem in many subtropical developing countries. The aim of this study is to comparatively elucidate the underlying biochemical tumor markers in schistosomal bladder cancer versus non-schistosomal bladder cancer when compared to normal healthy ones.

METHODS: This work was performed on tissue specimens from total 25 patients and serum samples from total 30 patients versus ten healthy individuals served as control. The investigated parameters in serum are: xanthine oxidase (XO), fructosamine, lactate dehydrogense (LDH), aspartate aminotransferase (AST), alanine aminotransferase (ALT), total proteins, essential and non- essential amino acids profile, hydroxyproline, total immunoglobulin E (IgE) and tumor necrosis factor alpha (TNF-α). In addition, the current investigation also extended to study some markers in tumor bladder tissues including, pyruvate kinase enzyme (PK), lactate dehydrogenase (LDH), aspartate aminotransferase (AST) and alanine aminotransferase (ALT).

RESULTS: Results showed that biharzial bladder cancer patients recored more significant elevation in serum XO, fructosamine, LDH, AST, ALT, hydroxyproline, IgE and TNF-α than in bladder cancer patients when compared to control ones. While, in tissues there were significant increase in PK, LDH, AST & ALT activities of schistosomal bladder cancer than in bladder cancer as compared to control healthy patients.

CONCLUSIONS: It could be concluded that, bilharzial and non-bilharzial bladder cancer showed distinct biochemical profile of tumor development and progression which can be taken into consideration in diagnosis of bladder cancer.

Yip, C. - H. a, E. b Cazap, B. O. c d Anderson, K. L. e Bright, M. f Caleffi, F. g h Cardoso, A. M. i Elzawawy, J. B. j Harford, G. D. k l Krygier, S. m Masood, et al., "Breast cancer management in middle-resource countries (MRCs): Consensus statement from the Breast Health Global Initiative", Breast, vol. 20, no. SUPPL. 2, pp. S12-S19, 2011. AbstractWebsite

In middle resource countries (MRCs), cancer control programs are becoming a priority as the pattern of disease shifts from infectious diseases to non-communicable diseases such as breast cancer, the most common cancer among women in MRCs. The Middle Resource Scenarios Working Group of the BHGI 2010 Global Summit met to identify common issues and obstacles to breast cancer detection, diagnosis and treatment in MRCs. They concluded that breast cancer early detection programs continue to be important, should include clinical breast examination (CBE) with or without mammography, and should be coupled with active awareness programs. Mammographic screening is usually opportunistic and early detection programs are often hampered by logistical and financial problems, as well as socio-cultural barriers, despite improved public educational efforts. Although multidisciplinary services for treatment are available, geographical and economic limitations to these services can lead to an inequity in health care access. Without adequate health insurance coverage, limited personal finances can be a significant barrier to care for many patients. Despite the improved availability of services (surgery, pathology, radiology and radiotherapy), quality assurance programs remain a challenge. Better access to anticancer drugs is needed to improve outcomes, as are rehabilitation programs for survivors. Focused and sustained government health care financing in MRCs is needed to improve early detection and treatment of breast cancer. © 2011 Elsevier Ltd.