Estrogen Receptor Gene Polymorphism as a Possible Genetic Risk Factor for Treatment Response in ER-Positive Breast Cancer Patients.

Estrogen receptor-α (ESR1) single nucleotide polymorphisms (SNPs) have been related to breast cancer (BC) susceptibility. In this retrospective study we investigated ESR1 SNPs in association with survival and treatment response in BC patients. Seven ESR1 SNPs were genotyped using TaqMan probe assay in 100 formalin-fixed paraffin embedded blocks of Egyptian ER+BC patients. Log-binomial regression was used to assess the association of 5 ESR1 SNPs with relative risk of non-response to adjuvant-hormonal treatment. We compared the performance of five machine learning classification models for prediction of treatment response. Predictive models were developed using rs1801132, rs2228480, and rs9322354 that were significantly associated with increased risk for non-response along with the relevant clinical features. Survival analysis was performed to detect prognostic significance of ESR1 SNPs in ESR+BC patients. rs1801132 (C), rs2228480 (A), and rs9322354 (G) minor alleles significantly increased the risk of non-response to tamoxifen by more than 81, 84, and 117%, respectively, in ER+BC patients on anthracycline/anthracycline-taxanes-based chemotherapy. Multivariate Cox regression survival analysis revealed that rs1801132 (C) and large tumor size were independent predictors for poor survival outcome in ER+BC. The best response predictive model was a combination random forest, K-nearest neighbor, and decision tree having an area under the curve of 0.94 and an accuracy of 90.8%. Our proposed predictive model based on ESR1 rs1801132, rs2228480, and rs9322354 SNPs represents a promising genetic risk stratification for selection patients who could benefit from tamoxifen therapy in such a way that might facilitate personalized medicine required to improve ER+BC patients' outcome.

Prevalence of human papilloma virus in oropharyngeal, tongue and lip squamous cell carcinoma: an experience from the Egyptian National Cancer Institute.

Human papilloma virus (HPV) is now a well-known risk factor for head and neck cancer besides smoking and alcohol. Most studies mentioned that patients affected with high-risk HPV cancers have a better outcome, and many clinical trials are trying to prove that such group of patients can receive a different and less aggressive treatment than the HPV-negative group. Although such field has received great interest within different countries and continents, African and Egyptian populations are not yet well studied within the literature. Our aim was to detect the prevalence of HPV in oropharyngeal (OP), lip and tongue squamous cell carcinoma (SSC) and correlate the viral prevalence with different clinicopathologic parameters as well as patients' outcome. HPV detection was done on 99 cases from the lip (29), tongue (38) and oropharynx (32) diagnosed at the Pathology Department of the National Cancer Institute, Cairo University. p16 immunohistochemistry was performed on all cases, followed by HPV DNA in situ hybridization (ISH) for p16-positive cases. The prevalence of HPV in OPSSC was 28% and in lip and tongue cancers lumped together was 37%. There was more than 90% concordance between p16 and HPV DNA ISH results. HPV positivity showed a statistically significant correlation with better disease-free survival (DFS), which was also maintained for OP cases. HPV is highly prevalent in OP and common oral cavity cancers in the Egyptian population. HPV positivity correlated significantly with better DFS, especially in OP cancers.

Strong association between long and heterogeneous telomere length in blood lymphocytes and bladder cancer risk in Egyptian.

Although it is widely recognized that telomere dysfunction plays an important role in cancer, the relationship between telomere function and bladder cancer risk is not well defined. In a case-control study of bladder cancer in Egypt, we examined relationships between two telomere features and bladder cancer risk. Telomere fluorescent in situ hybridization was used to measure telomere features using short-term cultured blood lymphocytes. Logistic regression was used to estimate the strength of association between telomere features and the risk of urothelial carcinoma of the bladder. High telomere length variation (TLV) across all chromosomal ends was significantly associated with an increased risk of bladder cancer [adjusted odds ratios (OR) = 2.22, 95% confidence interval (CI) = 1.48-3.35], as was long average telomere length (OR = 3.19, 95% CI = 2.07, 4.91). Further, TLV and average telomere length jointly affected bladder cancer risk: when comparing individuals with long telomere length and high TLV to those with short telomere length and low TLV, the adjusted OR was 14.68 (95% CI: 6.74-31.98). These associations were stronger among individuals who are 60 years of age or younger. In summary, long and heterogeneous telomere length in blood lymphocytes was strongly associated with an increased bladder cancer risk in Egyptian and the association was modulated by age.

Schistosomiasis and bladder cancer: similarities and differences from urothelial cancer.

Through the years, schistosoma-associated bladder cancer was believed to be a unique entity of disease, different from urothelial cancer. As carcinogenesis is a highly complex process resulting from the accumulation of many genetic and epigenetic changes leading to alterations in the cell proliferation and regulation process, confirmation of their minute differences or similarities are extremely difficult. In bladder cancer, many of these carcinogenic cascades were not fully documented in spite of the efforts undertaken. The control of schistosomiasis and the subsequent decrease in the intensity of infestation showed feature changes approaching that of urothelial tumors. However, schistosoma-associated bladder cancer still presents in more advanced stages than schistosoma-non-associated urothelial cancer. Furthermore, many data were collected proving that, upon applying the same treatment protocol and management care, stage-by-stage comparison of the treatment end results were found to be similar in bladder cancer patients with the different etiologies.

Associations differ by sex for catechol-O-methyltransferase genotypes and bladder cancer risk in South Egypt.

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. RESULTS: The 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.

Urinary bladder cancer risk factors in Egypt: a multicenter case-control study.

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.

Epidemiology and management of breast carcinoma in Egyptian males: experience of a single Cancer Institute.

OBJECTIVE: To assess the epidemiological and clinico-pathological features, surgical and reconstructive techniques, adjuvant treatments and clinical outcome of breast carcinoma in males (BCM) at the Egyptian National Cancer Institute (NCI). PATIENTS AND METHODS: Thirty-two males with breast carcinoma presented to NCI between January 2000 and December 2002. They were evaluated by complete history, physical examination, laboratory and radiological investigations. RESULTS: Median age was 59 years. Left sided and retroareolar breast lumps were the commonest presentations. Grade II tumors positive for hormone receptors were very common. Stages I, II, III and IV of the disease were encountered in 6.2%, 34.4%, 34.4% and 25.0% of patients, respectively. Curative surgery was done in 22 patients; they received adjuvant hormonal therapy, chemotherapy and radiotherapy in 22, 16 and 10 patients, respectively. Eight metastatic patients were treated with palliative measures. Surgery was done in 25 patients; the most common procedure was modified radical mastectomy (40.6%). Primary closure was feasible in 17 patients (68%), local flaps were needed in 4 cases (16%), while myocutaneous flap was done in 3 cases (12%). The commonest complication was the development of seroma (9 cases). The overall survival (OS) at 5 years was 65.4%. The disease free survival (DFS) at 5 years was 53.9%. Stage and curative surgery significantly affected OS, while type of surgery was the only variable significantly affecting DFS. CONCLUSION: Male breast carcinoma occurs at older ages than females, usually in advanced stage. This necessitates directing attention of males and awareness on the prevalence and risk factors for this disease.

Estrogen exposure and bladder cancer risk in Egyptian women.

OBJECTIVE: To examine associations between reproductive history and urinary bladder cancer in Egyptian women. METHODS: We used questionnaire data from an ongoing, multicenter case-control study in Egypt. Controls were matched on age and residence area. This analysis focused on female cases with confirmed urothelial (UC) and squamous cell (SCC) carcinoma of the bladder. RESULTS: We recruited 779 women (540 controls, 239 cases; >98.0% nonsmokers). Younger age at menopause (<45 y) and older age at first pregnancy (>18 y) were factors significantly associated with increased risk of bladder cancer, even after adjusting for schistosomiasis history and other covariates in the multivariable logistic model; adjusted odds ratio and 95% confidence intervals were 1.98 (1.41, 2.77) and 6.26 (3.46, 11.34), respectively. On the other hand, multiple pregnancies or use of oral contraceptives were associated with decreased odds of having bladder cancer. Similar associations were observed with UC and SCC when analyzed separately; however, the magnitude of association with SCC was lower than with UC. CONCLUSION: Our data suggest that early estrogen exposure, or the relative lack of it, plays a role in urinary bladder carcinoma development among Egyptian women.

Immunohistochemical detection of hepatitis C virus (genotype 4) in B-cell NHL in an Egyptian population: correlation with serum HCV-RNA.

BACKGROUND AND AIM: Retrospective evaluation of hepatitis C virus (HCV) prevalence in lymphoma tissues has important applications in clarifying the contribution of viral factors to the pathogenesis. Trials for detection of HCV at the cellular level in lymphoma tissues are, so far, minimal with unsatisfactory results. We aimed to study the detection and localization of HCV in the tissues of B-cell non-Hodgkin lymphoma (NHL) patients. DESIGN: We performed immunohistochemistry to detect the HCV nonstructural 3 protein in paraffin-embedded tissue specimens of B-cell NHL patients, in 39 serum HCV-RNA positive samples and 35 serum HCV-RNA negative samples as controls. The serum analysis was carried out for HCV antibodies using enzyme-linked immunoassay and for HCV-RNA using reverse transcription-polymerase chain reaction. Reverse transcription-polymerase chain reaction was used to detect the HCV-RNA in tissues in immunohistochemically positive cases. We correlated the results with the clinicopathologic characteristics of the patients. RESULTS: A diffuse cytoplasmic immunohistochemical staining for HCV in the lymphoid cells was detected in 8 of 39 serum positive cases (20.5%), all of which were genotype 4, which is the most prevalent HCV genotype in Egypt. Only 2 out of 35 serum negative control samples showed positive staining and in 1 of them HCV-RNA was detected in tissue. No significant correlation was detected between HCV positive cases and the clinicopathologic features of the patients. CONCLUSIONS: Immunohistochemical detection of HCV proteins in lymphoma tissues supports a potential role of viral replication in lymphomagenesis. The low number of cases showing expression of viral proteins may represent a low viral load in lymphoid tissue and/or restriction of HCV protein expression to certain subtypes of B-cell NHL. Immunohistochemistry can be used as a complementary tool for specific HCV detection in the paraffin-embedded material of lymphoma tissues not suitable for RNA analysis.

Viral and non-viral risk factors for non-Hodgkin's lymphoma in Egypt: heterogeneity by histological and immunological subtypes.

OBJECTIVE: Non-Hodgkin's lymphomas (NHL) are etiologically heterogeneous malignancies. In Egypt, we previously reported an association of increased NHL risk with chronic hepatitis C virus (HCV) infection. Our present aim is to assess the association between HCV infection and histological subtypes of NHL. METHODS: We conducted a case-control study at the National Cancer Institute of Cairo University. Cases with NHL (n = 486) were matched to controls (n = 786) who were orthopedic patients from the same referral regions. Participants provided a blood sample for HCV markers (anti-HCV, HCV RNA) and answered a questionnaire on possible risk factors. Case-control differences were assessed by odds ratios and 95% confidence intervals from logistic regression analysis. RESULTS: Cases with diffuse large B cell lymphoma (n = 146), chronic lymphocytic leukemia (n = 58), marginal zone lymphoma (n = 24), follicular lymphoma (n = 23), and mantle cell lymphoma (n = 16) were recruited. HCV RNA prevalence was 27% in controls and 26%-48% in the NHL subgroups: it was associated (p < 0.001) with diffuse large B cell, marginal zone, and follicular lymphomas with odds ratios of 3.2, 4.4, and 3.3, respectively. CONCLUSION: HCV is a risk factor for diffuse large B cell, marginal zone, and follicular lymphomas in Egypt.

Detection of hepatocellular carcinoma using glycomic analysis.

PURPOSE: Hepatocellular carcinoma (HCC) represents an increasing health problem in the United States. Serum alpha-fetoprotein, the currently used clinical marker, is elevated in only approximately 60% of HCC patients; therefore, the identification of additional markers is expected to have significant public health impact. The objective of our study was to quantitatively assess N-glycans originating from serum glycoproteins as alternative markers for the detection of HCC. EXPERIMENTAL DESIGN: We used matrix-assisted laser desorption/ionization time-of-flight mass spectrometry for quantitative comparison of 83 N-glycans in serum samples of 202 participants (73 HCC cases, 77 age- and gender-matched cancer-free controls, and 52 patients with chronic liver disease). N-glycans were enzymatically released from serum glycoproteins and permethylated before mass spectrometric quantification. RESULTS: The abundance of 57 N-glycans was significantly altered in HCC patients compared with controls. The sensitivity of six individual glycans evaluated for separation of HCC cases from population controls ranged from 73% to 90%, and the specificity ranged from 36% to 91%. A combination of three selected N-glycans was sufficient to classify HCC with 90% sensitivity and 89% specificity in an independent validation set of patients with chronic liver disease. The three N-glycans remained associated with HCC after adjustment for chronic viral infection and other known covariates, whereas the other glycans increased significantly at earlier stages of the progression of chronic viral infection to HCC. CONCLUSION: A set of three identified N-glycans is sufficient for the detection of HCC with 90% prediction accuracy in a population with high rates of hepatitis C viral infection. Further evaluation of a wider clinical utility of these candidate markers is warranted.

Candidate markers for the detection of hepatocellular carcinoma in low-molecular weight fraction of serum.

Hepatocellular carcinoma (HCC) represents an important public health problem in Egypt where up to 90% of HCC cases are attributable to hepatitis C viral (HCV) infection. Serum alpha-fetoprotein is elevated in only approximately 60% of HCC patients. The development of effective markers for the detection of HCC could have an impact on cancer mortality and significant public health implications worldwide. The objective of our study was to assess six candidate markers for detection of HCC identified by mass spectrometric analysis of enriched serum. The study examined 78 HCC cases and 72 age- and gender-matched cancer-free controls recruited from the Egyptian population. Matrix-assisted laser desorption-ionization time-of-flight mass spectrometric analysis of enriched low-molecular weight fraction of serum was used for identification of the candidate markers. Our analyses show that all six candidate markers are associated with HCC after adjustment for important covariates including HCV and hepatitis B viral infections. The marker candidates are independently predictive of HCC with areas under the receiver operating characteristic (AuROC) curve ranging from 63-93%. A combination of the six markers improves prediction accuracy to 100% sensitivity, 91% specificity and 98% AuROC curve in an independent test set of 50 patients. Two of the candidate markers were identified by sequencing as fragments of complement C3 and C4. In conclusion, a set of six peptides distinguished with high prediction accuracy HCC from controls in an Egyptian population with a high rate of chronic HCV infection. Further evaluation of these marker candidates for the diagnosis of HCC is needed.

Bilharziasis and bladder cancer: a time trend analysis of 9843 patients.

OBJECTIVE: To explore any changes in bladder carcinoma during 37 years period, in regard to: its frequency, bilharzia association, histological profile and demographic data. PATIENTS AND METHODS: This is a retrospective study on 9843 patients treated at the National Cancer Institute (NCI), Cairo University, during the years 1970-2007. Three groups were selected: series (A) included 3212 patients during 1970-1974, series (B) 3988 patients during 1985-1989 and series (C) 2643 patients during 2003-2007. For statistical analysis, data of series (A), (B) and (C) were compared to determine the significance of difference (p value 0.005). RESULTS: A significant decline of the relative frequency of bladder cancer was observed from 27.63% in the old series to 11.7% in the recent series. Bilharzia association dropped from 82.4% to 55.3%. There was a significant rise of transitional cell carcinomas from 16.0% to 65.8%, becoming at present the most common tumor type, with a significant decrease in squamous cell carcinomas from 75.9% to 28.4%. There was an increase in the median age of patients from 47.4 years to 60.5 years and a decrease of male: female (M/F) ratio from 5.4 to 3.3. CONCLUSIONS: The decline in the relative frequency of bladder cancer is associated with a decline in bilharzia egg positivity in the specimen and is probably related to better control of bilharziasis in the rural population in Egypt. This was accompanied by a change in the histological profile of tumors, with significant predominance of transitional cell carcinoma and an increase in the age of patients, a pattern rather similar to that in western reports.

Metastasis to the thyroid gland; unusual site of metastasis.

BACKGROUND: The incidence of metastasis to the thyroid gland in autopsy series varies from 1.25% to 24%. Metastasis to the thyroid gland is usually considered as a terminal event, and the effectiveness of conventional treatment has been questioned. METHODS: Seven patients with metastasis to the thyroid gland were studied retrospectively. Primary tumor origin was identified in all of them. Metastasis to the thyroid gland was confirmed by fine needle aspiration cytology or histology. Data were analyzed for the type of malignant lesions, the clinical course of the disease, and the prognosis after thyroid involvement. RESULTS: Two patients had lung as a primary tumor site. Breast, iris, kidney, parotid and soft tissue sarcoma were the involved primary sites in the other cases. The time from the diagnosis of primary tumor to metastasis to the thyroid gland was considerable (ranged from 13-135 months, median 60 months). Fine needle aspiration cytology detected metastasis in five of seven patients. Treatment was surgery alone or surgery with adjuvant therapy. One patient didn't receive any treatment. CONCLUSIONS: In any patient with a previous history of malignancy, no matter how old that history is, a new thyroid mass should be considered as recurrence until proved otherwise. Although detection of metastasis to the thyroid gland often indicates poor prognosis, aggressive surgical and medical therapy may be effective in a small percentage of patients.

Gastrointestinal stromal tumor (GIST)'s surgical treatment, NCI experience.

PURPOSE: To review the clinical presentation, surgical management, and prognostic factors for gastrointestinal stromal tumors. PATIENTS AND METHODS: A prospective study which was carried out between January 2002 and March 2004 on thirty-three patients with gastrointestinal stromal tumor (GIST) at the National Cancer Institute, Cairo University. All patients were evaluated preoperatively and underwent exploratory laparotomy with a curative intent, they were followed up for period ranging between 14-35 months. RESULTS: Among the 33 patients there were 17 males and 16 females. The mean age of patients was 52.8 years. Clinical findings included gastrointestinal bleeding (42.4%), palpable mass (33.3%) and abdominal pain (24.3%). The stomach was the most common site of origin of the disease (39.4%), followed by the colorectal region (24.2%). Tumors were high grade in 63.6% of patients and low-grade in 36.4% of patients. Complete resection of all gross disease was accomplished in 26 patients (78.7%), among whom, multiple adjacent organ resection was required in 6 patients (22.2 %) and metastatic disease was identified in the liver in 3 patients at the time of exploratory surgery of these one could be resected. Immunohistochemical staining for CD117 was positive in 88.9% of patients. The median follow-up period was 20 months (range, 14-35 months). The overall median survival in this study was 25 months, and the cumulative survival at 30 months was 46.9%. Unfavorable prognostic factors were incomplete resection and, high-grade histological features (p<0.05). None of the patients received adjuvant or palliative chemotherapy. Twenty six patients (78.8%) are alive free of disease. Of the 7 patients with incomplete resections or biopsy only; 4 patients (12.1%) are alive with disease and 3 patients died. CONCLUSION: Surgical resection, including en bloc resection of locally advanced tumors, remains the only curative treatment. Overall survival is significantly affected by high-grade tumors and positive resection margin.