The Clinical Significance of Promoter Methylation of Fluoropyrimidine Metabolizing and Cyclooxygenase Genes in Colorectal Cancer.

AIMS: This study investigated the impact of promoter methylation of flouropyrimidine (FP) metabolizing and cyclooxygenase 2 (COX2) genes on their mRNA expression and on the clinical outcome of colorectal cancer (CRC) patients. METHODS: Methylation specific-PCR and real time-PCR of thymidylate synthase (TS), thymidine phosphorylase (TP), dihydropyrimidine dehydrogenase (DPD) and COX2 were performed at baseline and after 3 and 6 months of FP therapy. Pairwise comparisons were conducted between the subgroups of CRC patients. The event free survival (EFS) and the hazard of progression were estimated by univariate and multivariate analyses. RESULTS: At baseline CRC patients, both TS and TP were overexpressed, in spite of the unmethylation of TS and the full methylation of TP genes. Significant downexpression of DPD and COX2 were associated their promoter's methylation. At the end of FP therapy, TS, DPD and COX2 were overexpressed by 7.52, 2.88 and 3.45 folds, respectively, while TP was downexpressed by 0.54 fold. However, no change was observed in the methylation status of genes with FP therapy. Pairwise comparisons revealed significant difference in the expression and the methylation status of genes according to the clinicopathological characters of CRC patients either at baseline or after FP therapy. The overexpression of DPD and COX2 genes were indicators for a poor EFS of CRC patients. Also, the high level of COX2 expression was found to be significantly correlated with the hazard of progression (HR = 1.73, 95% CI = 1.02-3.03). CONCLUSION: The promoter methylation of FP metabolizing and COX2 genes has significant impact on the expression and the treatment outcome of CRC patients.

Prognostic Impact of WT-1 and Survivin Gene Expression in Acute Myeloid Leukemia Patients.

BACKGROUND: Wilms Tumor 1 (WT1) and Survivin genes are important leukemia-associated antigens (LAAs) in AML with potential prognostic impact. METHODS: We investigated WT1 and Survivin expression levels by RT-PCR in 61 AML patients in correlation with clinical characteristics and outcomes. RESULTS: WT1 was overexpressed in 45 patients (73.8%), associated with higher BM blasts (p = 0.017), lower incidence of favorable-prognosis cytogenetics (p = 0.035), and higher incidence of Flt3-ITD mutations (p = 0.026). Survivin was overexpressed in 17 patients (27.9%) with higher mean WBC count (p = 0.049). Patients with overexpression of either gene showed inferior complete remission (CR) rates and survival rates, patients with overexpression of both genes showed higher mean WBCs (p = 0.035) and higher BM blasts (p = 0.029) while the double negative group showed higher incidence of favorable cytogenetic events (p = 0.021), better CR rates and survival rates. CONCLUSIONS: Our findings support the introduced prognostic impact of WT1 and Survivin genes in AML patients and its potential use in MRD monitoring and immunotherapy.

Efficacy and Toxicity of Metronomic Chemotherapy in Metastatic Breast Cancer: Egyptian Experience.

BACKGROUND: Metronomic chemotherapy (MC) has shown efficacy in patients with metastatic breast cancer (MBC). We therefore tested the efficacy and toxicity of MC in pretreated MBC. PATIENTS AND METHODS: This prospective phase II study included 50 patients with heavily pretreated MBC who received MC in the form of continuous oral cyclophosphamide 50 mg/day and oral methotrexate 2.5 mg twice per day on days 1 and 2 every week. The primary end point was progression-free survival (PFS), whereas the secondary end points were response rate, overall survival (OS), and safety. RESULTS: Forty-eight patients were assessed. One patient achieved complete response and 10 patients had partial response, whereas 19 patients had stable disease. The median PFS was 5 months, whereas the median OS was 7 months. Patients with negative progesterone receptors, Eastern Cooperative Oncology Group performance status (PS) 1, achieving response, and those who developed leucopenia, neutropenia, and anemia had significant prolonged PFS, whereas patients with early stage at presentation, receiving < 5 previous treatment lines, achieving response, and experiencing anemia with MC had significant superior OS. In multivariate analysis, achieving response, PS 1, a longer time interval from initial diagnosis until starting MC, and anemia were independent prognostic factors for longer PFS. Initial stage at presentation, number of previous treatment lines, and response were independent prognostic factors for OS. CONCLUSIONS: MC is an attractive treatment approach that is effective and less toxic. There are certain groups of patients who seem to benefit more, especially those who experienced toxicity with treatment. Larger trials are warranted to assess this approach early in the course of the disease and with other more active agents.

ERCC1 and ERCC2 as predictive biomarkers to oxaliplatin-based chemotherapy in colorectal cancer patients from Egypt.

BACKGROUND: The impact of Excision repair cross-complementation group 1 (ERCC1) and group 2 (ERCC2) expression levels on the efficacy of oxaliplatin-based chemotherapy is still controversial. The present study was conducted to determine the predictive value of these molecular biomarkers in stage III and IV colorectal cancer (CRC) patients receiving oxaliplatin (OX)-based chemotherapy as first-line treatment. METHODS: The study included 80 CRC patients who received first line oxaliplatin based chemotherapy The expression levels of ERCC1 and ERCC2-mRNA and proteins were determined in the primary tumors by quantitative real time reverse transcription polymerase chain reaction(RT-qPCR) and immunohistochemistry (IHC); respectively. The results of mRNA expression were correlated with patients' characteristics, response to treatment, overall- and event free survival (OS & EFS). RESULTS: Sixty four out of the 80 patients were legible for assessment of ERCC1 and ERCC2 expression. The cut-off levels of ERCC1and ERCC2-RNA were 3.8×10-3& 4.6×10-3; respectively. Reduced ERCC1 and ERCC2 RNA expressions were detected in 50 (78.1%) and 48 (75%) cases, respectively whereas reduced proteins were detected in 48 cases (75%) for ERCC1 and ERCC2. After The median follow up period was 30.5months (range: 7-104months), Patients with low mRNAERCC1levels showed significantly longer OS (p=0.011) and EFS (p˂0.001). However, no significant relation was found between ERCC2 levels and OS or EFS. In multivariate analysis performance status (PS), stage of the disease and ERCC1-mRNA expression were independent prognostic factors for EFS whereas tumor histology and stage of the disease were independent factors for OS. CONCLUSIONS: ERCC1 expression levels may help in selecting patients who benefit from oxaliplatin chemotherapy in stage III & IV CRC. Further large trials are needed to validate these data.

Untreated hepatocellular carcinoma in Egypt: outcome and prognostic factors.

BACKGROUND: Hepatocellular carcinoma (HCC) is a common cancer worldwide as well as in Egypt with hepatitis C and B, alcohol and aflatoxins being the commonest risk factors. AIM: The objective of this study was to assess the prognostic factors affecting overall survival (OS) of untreated HCC in Egypt. METHODS: This retrospective study was conducted at Tanta Cancer Center, Egypt where 288 HCC cases who received no specific therapy and were followed-up until death were identified. The impact of possible prognostic factors on OS was assessed using the log-rank test (univariate analyses) and Cox regression method (multivariate analysis). RESULTS: The median OS of untreated HCC was 2.3 months (95% confidence interval: 1.9-2.6). The 1, 3, 6, 12, 24 months OS rates were 84%, 42%, 21%, 9%, and 3%, respectively. All cases had died by 46 months. Male sex, advanced Child-Pugh class, the clinical presentation of ascites, cough, fatigue, and the presence of metastases were associated with poor survival (P<0.05 for all). In multivariate analysis; cough, presence of ascites, and Child-Pugh class were independent predictors of poor survival. CONCLUSION: OS in untreated HCC in Egypt is very short. Many factors interact to produce this dismal survival.

Age at diagnosis in women with non-metastatic breast cancer: Is it related to prognosis?

OBJECTIVE: Primary objective was to verify whether breast cancer patients aged less than 40 years at diagnosis have poorer prognosis than older patients. Secondary to assess prognostic factors influencing disease free survival. METHODS: 941 women were diagnosed with non-metastatic breast cancer at NCI, Cairo in 2003. Epidemiologic, clinico-pathological characteristics, treatment modalities and disease free survival were compared among the two age groups. Prognostic factors were evaluated for association with disease-free survival. RESULTS: One hundred-eighty-one patients (19.2%) were younger than 40 years and 760 (80.8%) were older. Older women presented with higher rates of comorbidities and younger women presented with more hormone non-responsive tumors. Young women presented with larger tumors pT4=13.8% compared to 8.6% in older women, yet not significant. Young women were treated with more conservative surgery, more adjuvant chemotherapy and radiotherapy while older women with more radical mastectomies and more hormonal treatment. Recurrence rates were significantly higher among young women 44.2% compared to 34.5% in older women. Five year disease free survival in young women was 38.9% ± 4.6% compared to 48.6% ± 2.5% with adjusted hazard ratio of 1.22 95% CI (0.91-1.64), p=0.19. Multivariate analyses identified positive axillary lymph nodes (pN2-pN3), larger tumor size (pT3-pT4), hypertension, lobular carcinoma type and lack of adjuvant systemic treatment as independent factors associated with poor DFS. CONCLUSION: Young women were not found to have poorer prognosis, yet they presented with more ER negative tumors. Most of women presented with advanced stage and young women had higher recurrence rates.

Transarterial chemoembolization for the treatment of hepatocellular carcinoma: a single center experience including 221 patients.

BACKGROUND: Hepatocelluar carcinoma (HCC) is a major health problem in Egypt as well as in many countries. Transarterial chemoemoblization (TACE) is a treatment modality applicable to locally advanced HCC beyond surgery or ablative therapies and is associated with survival improvements. The aim of this study was to assess the outcomes of TACE in our center over the past four years. METHODS: This is a retrospective cohort study that included 221 patients with locally advanced HCC treated with TACE in a single center between the years 2007 and 2010. The median age was 57 years with male predominance. Liver cirrhosis, viral hepatitis and Bilharziasis were encountered in 64%, 31% and 8% of patients, respectively. Abdominal pain was the most common presenting symptom (67%). Most cases were diagnosed based on radiology (57%) with a TNM stage I or II (73%) and a median AFP value of 150 ng/mL. RESULTS: 221 patients received 440 cycles of TACE with a median of 2 cycles per patient. Cisplatin and doxorubicin (50mg per cycle, each) were the most commonly used drugs. Impaired liver function was the most common toxicity. Liver cell failure occurred in 17% of patients. An objective tumor response was achieved in 44% of cases. The median overall survival (OS) was 16 months (95% CI, 13-19 months) and the median progression free survival (PFS) was 6 months (95% CI, 4.3-7.8 months). Responding patients, Child-Pugh class A and patients receiving standard doses of chemotherapy had a significantly better OS than their counterparts. Only Child-Pugh class A was associated with significantly longer PFS (p < 0.001). CONCLUSION: TACE produces reasonable responses and fair survival rates in locally advanced HCC but with noticeable toxicities. Proper patients' selection and prompt liver support are mandates for improving TACE outcomes.

A case of synchronous double primary breast carcinoma and osteosarcoma: Mismatch repair genes mutations as a possible cause for multiple early onset malignant tumors.

BACKGROUND: Simultaneous or consequent development of multiple solid tumors might be faced in some patients, especially the young. These tumors might be related to certain hereditary cancer syndromes or certain genetic predispositions. CASE REPORT: We present the case of a 19-year-old woman with metastatic breast cancer to the contralateral axillary lymph node, associated with simultaneous osteosarcoma of the left lower femur. As she did not fit into any of the familial cancer syndromes, genetic predisposition was suspected. We detected MLH1 and MSH2 promotor methylation (PM), microsatellite instability (MSI), and different mutational events in both tumors. BRCA1 gene mutations were detected in the breast tumor, with reduced mRNA expression of BRCA1&2. ERCC1, MLH1 and MSH2, especially in OS, and RRM1 was overexpressed in both tumors. CONCLUSIONS: Aberrations in MMR genes could explain simultaneous or consequent development of multiple solid tumors, especially in a young patient. We recommend detecting these defects, close follow-up for those patients, and genetic counseling for their family members. Further studies in a larger population are essential to support our results.