Microsatellite Instability and Life Style Factors in Sporadic Colorectal Cancer.

BACKGROUND: Colorectal cancer (CRC) in Egypt is a relatively high young onset disease. As a form of heterogeneous cancer, there is interplay between genetic and environmental factors. We aimed at probing the association of life style factors and Microsatellite Instability (MSI) status that could provide more insights on carcinogenic process of CRC. METHODS: One hundred incident sporadic CRC patients were involved. Information on risk factors of CRC was obtained and microsatellite instability status was predicted through evaluation of MMR protein expression via immunohistochemistry (IHC). RESULTS: Median age was 47.50 years, females represented 54.0% and 36% of patients were Microsatellite Instability High (MSI-H). Most patients with right sided colon cancer (78.3%) were MSI-H while mostly stable or low MSS/MSI-L for left-sided colon and rectum (78.6%, 74.3% respectively, p<0.001). Patients with low physical activity had higher risk of MSS/MSI-L than those with moderate or high activity p =0.026. Patients with BMI greater than 30 Kg/m2 had higher MSS/MSI-L (75.5%) than those with BMI between 25-30 Kg/m2 (60.6%) and those with normal BMI.

FISH Analysis of TOP2A and HER-2 Aberrations in Female Breast Carcinoma on Archived Material: Egyptian NCI Experience.

BACKGROUND: HER-2 and TOP2A genes are considered of great importance in breast cancer. Their copy number variability has been proposed to be a marker for the degree of chromosomal instability. Owing to the close proximity of TOP2A gene to HER-2 gene chromosome 17, TOP2A status is believed to affect therapeutic plan. The percentage of TOP2A aberrations is greatly variable among different studies. AIM OF WORK: Is to investigate the relation between TOP2A and HER-2 gene amplification using fluorescence in situ hybridization technique. MATERIALS AND METHODS: Archival blocks of 112 breast cancer Egyptian female patients were retrieved from the pathology department at NCI, Cairo University were retrieved and investigated using fluorescence in situ hybridization technique for TOP2A and HER-2 gene assessment. In addition, correlation with some clinicopathologic parameters was done. RESULTS: HER-2 gene amplification was encountered in about 33% of cases. TOP2A gene amplification and deletion were detected in 23.9% and 2.8% of studied cases. Moderate agreement was obtained between results of HER-2 gene and TOP2A gene amplification. CONCLUSIONS: HER-2 and TOP2A genes amplification are 2 separate genetic yet closely related events in breast cancer. Polysomy of chromosome 17 is proposed to be an early event in occurrence of TOP2A gene amplification. Further studies regarding effect of TOP2A gene in response to anthracyclines in Egyptian population should be planned for to establish its role in therapeutic planning.

Topoisomerase II α Gene alteration in Triple Negative Breast Cancer and Its Predictive Role for Anthracycline-Based Chemotherapy (Egyptian NCI Patients)

Objective: Triple negative breast cancer is an aggressive variant of breast cancer; it forms about 15% of breast cancer cases. It lacks the responsiveness to hormonal and targeted therapies. Anthracyclines remain the treatment option for these patients. Anthracyclines are cardiotoxic, so predicting sensitivity of response by biological predictors may have a role in selecting suitable candidates for these drugs. Material and methods: This study included 50 TNBC cases, from National Cancer Institute, Cairo University(NCI-CU), Egypt, who underwent surgery and received adjuvant chemotherapy. Archived blocks were obtained and immunostaining for Ki-67 LI and Fluorescent In situ Hybridization (FISH) technique to assess TOP2A gene copy number and chromosome 17CEP status were done. Analysis of association between TOP2A alterations and CEP17 polysomy as well as Ki-67 LI with other clinicopathological parameters was done. Associations between the biological markers and event free survival (EFS) and overall survival (OS), were also performed. Results: TOP2A alteration was seen in 9/50 cases (5 amplified and 4 deleted). CEP17 Polysomy was detected in 14% of cases. Most of patients (80%) showed Ki-67 LI ≥20%. There was a significant association between TOP2A gene and CEP17 status. Outcome was better with abnormal TOP2A gene status and CEP17 polysomy, radiotherapy and combined anthracyclines and taxanes in the adjuvant setting, however P-values were not significant. Conclusion: TOP2A gene alterations and CEP17 polysomy may have prognostic and predictive role in TNBC treated with adjuvant Anthracyclines.

Neuroendocrine tumors of the lung: A five-year retrospective experience of Egyptian NCI (2010-2014).

BACKGROUND: The spectrum of lung neuroendocrine tumors (NETs) encompasses low grade typical carcinoid (TC), intermediate grade atypical carcionid (AC) and high grade, both large cell neuroendocrine carcinoma (LCNEC) and small cell lung cancer (SCLC), with extreme differences in management and survival. OBJECTIVE: To study clinicopathologic and prognostic factors affecting survival of lung NETs. PATIENTS AND METHODS: This is a retrospective study evaluating 35 patients with primary lung NETs treated at National Cancer Institute of Egypt (NCI-E) between January 2010 and December 2014. Pathological diagnosis depended on definite morphology and positivity to at least one of the neuroendocrine markers by immunohistochemistry. RESULTS: The mean age of the patients was 53 ±â€¯11.2 years with male predominance. Performance status (PS) I was encountered in 48.6%. SCLC was the prevalent histology in 68.6%, followed by LCNEC & TC in 20 & 11.4%, respectively. Curative surgery was employed in 100 & 57% of TC & LCNEC patients, respectively. Stage IV was anticipated in 87.5 & 43% of SCLC & LCNEC, respectively. For the entire cohort, the median event-free survival (EFS) and overall survival (OS) were 8.0 and 13.7 months, respectively, whereas the 3-year EFS and OS were 17.8 & 20%, respectively. SCLC patients showed significantly the worst OS compared to other NETs (p = 0.001). Patients who presented with stage IV and PS > I demonstrated significantly shorter OS than those with locoregional and PS I (p = 0.00001 &p = 0.002, respectively). CONCLUSIONS: SCLC subtype, stage IV and initial PS > I are poor prognostic factors for lung NETs associated with shorter survival. This conclusion needs to be confirmed by larger studies.

Expression of Plasma miRNA-221 in Colorectal Carcinoma Patients and its Diagnostic Significance in Comparison with p53 Expression.

BACKGROUND: Colorectal carcinoma development progresses through a sequence of normal mucosa-polyp-carcinoma. Early detection of premalignancy is crucial for improved outcomes. We evaluated the diagnostic performance of plasma miRNA-221 and its feasibility in discriminating premalignant from malignant neoplasms and correlating it with immunohistochemical p53 expression. METHODS: A total of 109 plasma samples were collected (76 carcinoma, 14 premalignant, and 19 controls). MiRNA221 was quantified by qPCR for calculation of ∆Ct using RNU6B as endogenous control. p53 immunohistochemical staining was performed on corresponding tissue. RESULTS: Plasma miRNA-221 and p53 in tissues were significantly overexpressed in the malignant group when compared with the premalignant and control groups. Plasma miRNA-221 was increased in late-stage tumors with nodal or distant metastasis. ROC curve construction for distinguishing between malignant and premalignant tumors revealed a cutoff value of 2.97 with 74% sensitivity, 79% specificity, 73.7% positive predictive value and 78.6% negative predictive value (AUC = 0.824; p = 0.001). Plasma miRNA-221 significantly correlated with p53 in cancer samples (r = 0.507). CONCLUSIONS: MiRNA-221 could have a diagnostic role in differentiating malignant from premalignant neoplasms and could also serve as a predictive marker indicating tumor progression.

Contributing factors to the outcome of primary malignant chest wall tumors.

BACKGROUND: Primary malignant chest-wall tumors (PMCWTs) are a heterogeneous group of tumors. They require a special experience in designing resection and reconstruction. They account for less than 1% of all primary malignant tumors. This study is designed to clarify different factors contributing to the outcome of patients with PMCWTs in our institution. METHODS: A retrospective study included 98 patients with pathology proven PMCWTs, treated at the National Cancer Institute (NCI), Cairo University, Egypt, during the past 10 years. Used variables were: age, sex, forced expiratory volume in the 1st second (FEV1), site, size, multiplicity, pathologic subtype, tumor grade, safety margin (SM), excised ribs, complications, estimated blood loss (EBL), neo-adjuvant and adjuvant treatments, Overall and disease free survival (DFS) were obtained using Kaplan-Meier method and compared using Log rank test. Cox regression was used to identify DFS predictors. RESULTS: PMCWTs represented 10.5% of all thoracic malignancies in our institution. There were 51 females (52%). The median age was 39 years [interquartile range (IQR) =25-52.3)] years. Chondrosarcoma was the commonest tumor histology (20.4%). The median tumor size was 8 cm (IQR =5-14). Tumor multiplicity was found in 18.4% of patients. Bone resection was performed in 76 patients (78.3%), ribs resection was performed in 59 patients and the median number of resected ribs per patient was 3 (IQR =1-3) ribs. Sternal resection was done in 7 (7.1%) cases. R0 resection was achieved in 62.2% of patients. There was one operative related mortality (1.02%) and 17.3% patients suffered procedure related complications. Local recurrence developed in 35 (35.7%) patients. The overall survival (OS) at 1, 3 and 5 years was 73.9%, 45.6% and 34.6% respectively and the median OS was 33 months (95% CI, 21.8-44.2), while median DFS was 24 months (95% CI, 19.6-28.4). Predictors of better DFS were -ve SM (P<0.001), tumors <5 cm (P=0.039), low grade (P=0.033), lower EBL (P=0.003) and absence of adjuvant therapy (P=0.007); however, on multivariate analysis, only -ve SM was the only predictor (HR =0.54; 95% CI, 0.29-0.97, P=0.041). CONCLUSIONS: In primary malignant CWTs (PMCWTs) achievement of wide resection margins is of great importance to minimize the local tumor recurrence that will have an adverse impact on long-term survival.

The prognostic role of tumor-associated macrophages and dendritic cells in classic Hodgkin's lymphoma.

Tumor-associated macrophages (TAMs) and dendritic cells (DCs) may play a role in tumor progression as a part of the tumor microenvironment in many neoplasms, including those in Hodgkin's lymphoma. The current study investigated the relationship between the presence and density of macrophages and dendritic cells in the background of classic Hodgkin's lymphoma (CHL) and different clinicopathological parameters, including survival and response to therapy. CD68 and CD1a immunohistochemical staining were used to detect and highlight macrophages and dendritic cells, respectively, in 61 cases of CHL. CD68 was expressed in all studied cases, with no significant association with the studied parameters. In total, 54.1% (33/61) of cases showed CD1a expression. High CD1a expression (>7%) was associated with localized lymphadenopathy (p=0.01), early stage (p=0.005), and good revised international prognostic index (R-IPI) (p=0.07). Hodgkin's lymphoma cases that showed high CD68 and low CD1a were associated with adverse prognostic parameters such as advanced stage (p=0.03) and generalized lymphadenopathy (p=0.05). Old age (>60 years) (P=0.005), poor R-IPI (P=0.010), and negative CD1a expression (P=0.045) were significantly associated with poor outcome. Finally, our study demonstrated the importance of the presence and density of DCs in determining progression and prognosis in CHL. A certain interaction between TAMs and DCs may affect the progression of CHL. Further investigation is required to clarify whether TAMs release certain factors that decrease the number or function of DCs.

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.

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.