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.

Clinical significance of altered nm23-H1, EGFR, RB and p53 expression in bilharzial bladder cancer.

BACKGROUND: Clinical characterization of bladder carcinomas is still inadequate using the standard clinico-pathological prognostic markers. We assessed the correlation between nm23-H1, Rb, EGFR and p53 in relation to the clinical outcome of patients with muscle invasive bilharzial bladder cancer (MI-BBC). METHODS: nm23-H1, Rb, EGFR and p53 expression was assessed in 59 MI-BBC patients using immunohistochemistry and reverse transcription (RT-PCR) and was correlated to the standard clinico-pathological prognostic factors, patient's outcome and the overall survival (OS) rate. RESULTS: Overexpression of EGFR and p53 proteins was detected in 66.1% and 35.6%; respectively. Loss of nm23-H1and Rb proteins was detected in 42.4% and 57.6%; respectively. Increased EGFR and loss of nm23-H1 RNA were detected in 61.5% and 36.5%; respectively. There was a statistically significant correlation between p53 and EGFR overexpression (p < 0.0001), nm23 loss (protein and RNA), lymph node status (p < 0.0001); between the incidence of local recurrence and EGFR RNA overexpression (p= 0.003) as well as between the incidence of metastasis and altered Rb expression (p = 0.026), p53 overexpression (p < 0.0001) and mutation (p = 0.04). Advanced disease stage correlated significantly with increased EGFR (protein and RNA) (p = 0.003 & 0.01), reduced nm23-H1 RNA (p = 0.02), altered Rb (p = 0.023), and p53 overexpression (p = 0.004). OS rates correlated significantly, in univariate analysis, with p53 overexpression (p = 0.011), increased EGFR (protein and RNA, p = 0.034&0.031), nm23-H1 RNA loss (p = 0.021) and aberrations of > or = 2 genes. However, multivariate analysis showed that only high EGFR overexpression, metastatic recurrence, high tumor grade and the combination of > or = 2 affected markers were independent prognostic factors. CONCLUSION: nm23-H1, EGFR and p53 could be used as prognostic biomarkers in MI-BBC patients. In addition to the standard pathological prognostic factors, a combination of these markers (> or = 2) has synergistic effects in stratifying patients into variable risk groups. The higher is the number of altered biomarkers, the higher will be the risk of disease progression and death.

The impact of contrast-enhanced spectral mammogram (CESM) and three-dimensional breast ultrasound (3DUS) on the characterization of the disease extend in cancer patients.

OBJECTIVE: The main importance of imaging breast cancer is to guide conservative surgeries. In this study, we evaluated the role of contrast-enhanced spectral mammogram (CESM) in correlation with three-dimensional (3D) breast ultrasound in characterizing the extension of the intramammary cancer in view of the: (i) the size of the main tumor, (ii) the multiplicity of the breast cancer, and (iii) the peri-tumoral stromal involvement (i.e. free or intraductal extension of the cancer). METHODS: The study is a prospective analysis that included 300 breast masses proved to be malignant. The masses were evaluated for their size, multiplicity and surrounding stromal involvement. Contrast-based mammography performed with low (22-33 kVp) and high (44-49 kVp) energy exposures that were taken after i.v. injection of contrast agent and followed by bilateral 3D breast ultrasound. Operative data were the gold standard reference. RESULTS: There was no significant difference between the sizes of the included cancers as measured by CESM and 3D ultrasound and that measured at the pathological analysis. CESM showed higher accuracy (32.7%, n = 98) than 3D ultrasound (24.7%, n = 74) in the size agreement within 5% range. CESM was the most accurate modality (94%, n = 282) in detecting tumor multiplicity, followed by traditional sonomammogram (88%, n = 264), then 3D breast ultrasound (84%, n = 252). Intraductal extension of the breast cancer was best evaluated by the 3D ultrasound with an accuracy value of 98% (n = 294) compared to only 60% (n = 180) by CESM. CONCLUSION: CESM is a recommended investigation in breast cancer to increase the accuracy of size measurement and the detection of multiple tumors. The addition of 3D ultrasound can enhance the detection of intraductal extension. Advances in knowledge: Choice of conservative breast surgery vs mastectomy is still a debate. We used an advanced, contrast-based, application of the mammogram: CESM and a non-invasive 3D breast ultrasound in the assessment of the local extension of the breast cancer regarding size, perifocal stromal infiltration and multiplicity to guide the selection of proper management in proved cases of breast cancer.

RAS mutation prevalence among patients with metastatic colorectal cancer: a meta-analysis of real-world data.

AIM: A confirmed wild-type RAS tumor status is commonly required for prescribing anti-EGFR treatment for metastatic colorectal cancer. This noninterventional, observational research project estimated RAS mutation prevalence from real-world sources. MATERIALS & METHODS: Aggregate RAS mutation data were collected from 12 sources in three regions. Each source was analyzed separately; pooled prevalence estimates were then derived from meta-analyses. RESULTS: The pooled RAS mutation prevalence from 4431 tumor samples tested for RAS mutation status was estimated to be 43.6% (95% CI: 38.8-48.5%); ranging from 33.7% (95% CI: 28.4-39.3%) to 54.1% (95% CI: 51.7-56.5%) between sources. CONCLUSION: The RAS mutation prevalence estimates varied among sources. The reasons for this are not clear and highlight the need for further research.

Differing DNA methylation patterns and gene mutation frequencies in colorectal carcinomas from Middle Eastern countries.

PURPOSE: The epidemiology of colorectal carcinoma is well known to differ among countries but the molecular characteristics are usually assumed to be similar. International differences in molecular pathology have not been studied extensively but have implications for the management of patients in different countries and of immigrant patients. EXPERIMENTAL DESIGN: We evaluated the CpG island methylator phenotype pathway characterized by concordant methylation of gene promoters that often silences transcription of the genes, the microsatellite instability pathway, and K-ras and p53 gene status in 247 colorectal carcinomas from the three selected Middle Eastern countries of Egypt, Jordan, and Turkey. RESULTS: Colorectal carcinoma from Egypt had the lowest frequencies of methylation. In multinomial logistic regression analysis, Jordanian colorectal carcinoma more frequently had methylation involving the p16 tumor suppressor gene (odds ratio, 3.5; 95% confidence interval, 1.2-10.6; P = 0.023) and MINT31 locus (odds ratio, 2.3; 95% confidence interval, 1.0-5.1; P = 0.041). The K-ras proto-oncogene was more frequently mutated in colorectal carcinoma from Turkey (odds ratio, 2.9; 95% confidence interval, 1.2-6.7; P = 0.016), but p53 overexpression was more common in both Jordanian and Turkish colorectal carcinoma than in Egyptian cases (odds ratio, 2.5; 95% confidence interval, 1.2-5.5; P = 0.019; and odds ratio, 3.6; 95% confidence interval, 1.8-7.1; P = 0.0003, respectively). The findings in Turkish colorectal carcinoma were most similar to those reported for Western cases. CONCLUSIONS: Colorectal carcinoma from Middle Eastern countries have differing gene methylation patterns and mutation frequencies that indicate dissimilar molecular pathogenesis, probably reflecting different environmental exposures. These molecular differences could affect prevention strategies, therapeutic efficacy, and transferability of clinical trial results.

Association of Viral Infections with Risk of Human Lymphomas, Egypt.

BACKGROUND: The aim of this study was to determine and evaluate the association of different viral infections, with hepatitis B and C viruses, Epstein-Barr virus, cytomegalovirus and human herpes virus-8 (HBV, HCV, EBV, CMV, HHV-8) with the risk of lymphomas (Hodgkin and non-Hodgkin) among Egyptian patients, and correlate with the histopathological staging and typing as well as the prevalence of combined infections. MATERIALS AND METHODS: A total of 100 newly diagnosed lymphoma patients with 100 healthy age and sex matched normal controls were assayed for viral infection using enzyme linked immunosorbant assay (ELISA) followed by real time polymerase chain reaction (RT-PCR). RESULTS: Our results showed a high statistical significant difference between cases and controls as regards clinical and laboratory findings (<0.001 and=0.003). A high statistical difference was seen for the association of most viruses and lymphoma cases (<0.001) except for positive HBs Ag, positive CMV IgG and HHV-8 (p=0.37, 0.70 and 1.0 respectively). No statistical significant difference was found between Hodgkin (HL) and non-Hodgkin (NHL) as regards viral prevalence except HCV antigen, 57.1% for HL and 26.5% for NHL (p = 0.03). Only, HBV DNA showed a high significant value among infiltrated bone marrow cases (p=0.003) and finally, a high significant association of 2 combined viral infections with infiltrated bone marrow lymphoma cases (p=0.04). CONCLUSIONS: Our results showed that infection with HBV, HCV, CMV and EBV were associated with increased risk of lymphoma among the Egyptian population. Detection of new associations between infectious agents and risk of cancer development will facilitate progress in elaboration of prophylactic measures, early diagnostic methods and, hopefully, novel therapy of malignant tumours.

Associations of pesticides, HCV, HBV, and hepatocellular carcinoma in Egypt.

The rate of hepatocellular carcinoma (HCC) is increasing in Egypt where the major risk factors are chronic infections with hepatitis B and C viruses (HBV and HCV). A major segment of the population is employed in agriculture, raising the possibility that exposure to pesticides is an additional risk factor for HCC. The objective of this study is to investigate pesticides as environmental risk factors for HCC while taking into account viral risk factors. We conducted a case-control study of 236 subjects with confirmed HCC recruited from the National Cancer Institute, Cairo University, Egypt, and 236 controls matched on sex, age group and urban-rural status recruited from orthopedic department, Cairo University Hospital, Egypt. Patients who agreed to participate signed a consent form, answered a questionnaire and gave a blood sample for hepatitis virus testing. The manuals of the Ministry of Agriculture for approved use and type of pesticides since 1965 were linked to the questionnaire data for types of crops and pests that the subject had to combat, to attribute specific pesticides that were used by each subject. Subjects also reported duration of the exposure (years). Case-control comparisons in these data were stratified by sex, age group, and urban vs. rural residence. Data were analyzed using unconditional logistic regression models adjusting for age, HCV RNA, and current hepatitis B infection. Among rural males, the adjusted odds ratio (OR) for organophosphorus compounds was 2.7 (95% CI = 1.3-5.3) and for carbamates it was 2.9 (95% CI = 1.4-5.8). No statistically significant associations between HCC and pesticides were observed for urban males or for females. As expected, the strongest risk factors for HCC in this study were HCV RNA (OR = 16-17) and current HBV infection (OR = 27-28). This study therefore suggests that exposures to organophophorus and carbamate pesticides are additive risk factors to current HCV and HBV infection among rural males. Future investigation should address the possible hepatocarcinogenicity of pesticides using biomarkers of exposure and other techniques to better estimate dose-response relationships.

Case-control study of non-Hodgkin's lymphoma and hepatitis C virus infection in Egypt.

BACKGROUND: Chronic infection with hepatitis C virus (HCV) has been associated in some studies with increased risk for B-cell non-Hodgkin's lymphoma (NHL). To assess this further, we conducted a case-control study in Egypt, where HCV prevalence is extremely high. METHODS: Cases with B-cell NHL (N = 227) were recruited from the National Cancer Institute of Cairo University, a major referral centre. Controls (N = 227) were patients with fractures being treated at the Kasr El-Aini Orthopaedic Hospital, from the same referral base as the cases, and were frequency-matched by gender, rural versus urban birthplace, and age. Subjects were interviewed about their medical history and possible risk factors, and blood samples were collected for HCV diagnostic tests. Anti-HCV and HCV RNA were determined by enzyme-linked immunoassay and reverse transcription-polymerase chain reaction, respectively. Odds ratios (OR) and 95% CI were calculated from logistic regression models. RESULTS: Overall, 42% of subjects were anti-HCV positive and 33% had HCV RNA. There was a statistically significant unadjusted association of HCV RNA with NHL (OR = 2.3, 95% CI: 1.5, 3.5), which differed slightly by gender (males: OR = 2.1, 95% CI: 1.2, 3.7 versus females: OR = 2.5, 95% CI: 1.3, 4.8). Anti-HCV without HCV RNA was not associated with case status (OR = 0.9, 95% CI: 0.5, 1.6). After adjustment for age, gender, rural versus urban birthplace, and rural versus urban current residence, the association of HCV RNA with the risk of NHL remained statistically significant (OR = 2.9, 95% CI: 1.9, 4.5). CONCLUSIONS: These data support the hypothesis that NHL is a malignant outcome of chronic HCV infection.

Chromosomal aberrations in Cis and Ta bilharzial bladder cancer: a theory of pathogenesis.

BACKGROUND: Bladder cancer manifests many different forms ranging from superficial to aggressive muscle invasive stages, which suggests that various genetic alterations are involved. Several attempts have been made to establish correlations between specific genetic alterations and various stages of the disease. At the National Cancer Institute (NCI), Cairo, bladder cancer constitutes 30.3% of all cancers. Bladder cancer observed among Egyptians has a clinico-pathological profile that differs from transitional cell carcinoma (TCC) seen in the western world. PATIENTS AND METHODS: We used fluorescence in situ hybridization to detect numerical chromosome changes in 25 patients presenting with carcinoma in situ and Ta lesions. Twenty-four cases had transitional cell carcinoma and one case had squamous cell carcinoma. RESULTS: Five out of 24 TCC cases had diploid chromosome count with all the probes. Numerical chromosome aberrations were detected in 19 cases (79%). In eight cases, a loss of chromosome 9 was observed. In one case, an additional loss of chromosome 17 was detected. One case demonstrated a loss of chromosome 17, whereas another three cases showed a gain of chromosome 7. Loss of chromosome Y was observed in nine of the 22 male cases studied (40.9%). The only case with SCC had normal diploid chromosome count with all the probes used. CONCLUSION: When the genetic basis of bilharzial related bladder cancer is fully understood, new diagnostic and therapeutic strategies will be developed, which in turn may promote better clinical management by pathologists and urologists. A theory of bilharzial related bladder cancer pathogenesis is suggested.

Correlation between p53 mutations and HPV in bilharzial bladder cancer.

Alterations of the p53 tumor suppressor gene are the most common genetic changes detected in human cancers as well as in papillary and invasive bladder cancer. Several studies have demonstrated an association between HPV infection and urological malignancies. In the present work, the p53 gene status was studied together with the frequency of HPV in 99 cases of Bilharzial bladder cancer [BBC] in Egypt and both were correlated to the clinicopathological features of the patients. SSCP and sequencing were used to screen the p53 gene for mutations at exons 4-10 and IHC was performed to detect protein overexpression. PCR was used for detection and typing of HPV-DNA in tumor samples. p53 mutations were detected in 33.3% of the studied cases whereas protein overexpression was detected in 35.6% of the cases. The highest concordance rate was observed in cases harboring mutations at exon 4 [87.5%]. Bilharzial infestation was obvious in 72.2% of the cases that showed mutations. Exon 8 showed the highest rate of mutation [32%] followed by exons 4 and 5 [22% each]. The commonest mutational event was G:C transversion [15/50] especially at CpG dinucleotides. A mutational hot spot was detected at exon 4, codons 72-73. HPV-DNA was detected in 48.97% of the cases the majority of which [64.6%] were of type 16. Significant correlation was found between p53 mutation and the pathological stage as well as p53 overexpression and tumor grade. Our results demonstrate that the mutational spectrum in BBC is different from that of bladder cancer in Western countries in many aspects and suggest an etiological role of HPV in this type of neoplasm. However, both HPV infection and p53 gene abnormalities may contribute to Bilharzial bladder carcinogenesis in an independent way.

Ki-67 is a powerful tool for grading neuroendocrine tumors among Egyptian patients: a 10-year experience.

BACKGROUND: Neuroendocrine tumors (NETs) arise in most organs of the body and share many common pathologic features. However, a variety of organ-specific systems have been developed for nomenclature, grading and staging of NETs, causing much confusion. In collaboration with WHO, the European Neuroendocrine Tumor Society (ENETS) recommended the use of either mitotic rate or Ki-67 labeling index (LI) for grading and classification. We aim to explore the profile of NETs in Egyptian patients and apply the ENETS system. MATERIALS AND METHODS: This retrospective study was carried out on all cases of NETs diagnosed at the Pathology Department, National Cancer Institute, Cairo University, during the period from January 2000 to December 2009. Data about age, sex, anatomic site of tumor, tumor size, tumor stage and presence of nodal metastasis were retrieved. Ki-67 immunostaining and grading according to ENETS were done. RESULTS: There was a trend toward increased mean age and tumor size and grade according to Ki-67, with significant statistical difference (p < 0.001 and 0.036, respectively). Estimation of mitotic count and Ki-67 LI was strongly associated with NET histopathologic types, but this association was stronger regarding Ki-67 LI than mitotic count (p = 0.002 and 0.035, respectively). On the other hand, there was discordance between grading according to mitotic count and grading according to Ki-67 LI in relation to NET histopathologic subtypes. Concordance between mitotic rate and Ki-67 LI was reported in 18.89% of cases, while discordance occurred in 81.11% of cases and was more prevalent in G3. CONCLUSION: Ki-67 is a reliable and reproducible marker for grading of NETs and more superior than mitotic rate.

Pelvic exenteration and composite sacral resection in the surgical treatment of locally recurrent rectal cancer.

BACKGROUND: The incidence of rectal cancer recurrence after surgery is 5-45%. Extended pelvic resection which entails En-bloc resection of the tumor and adjacent involved organs provides the only true possible curative option for patients with locally recurrent rectal cancer. AIM: To evaluate the surgical and oncological outcome of such treatment. PATIENTS AND METHODS: Between 2006 and 2012 a consecutive series of 40 patients with locally recurrent rectal cancer underwent abdominosacral resection (ASR) in 18 patients, total pelvic exenteration with sacral resection in 10 patients and extended pelvic exenteration in 12 patients. Patients with sacral resection were 28, with the level of sacral division at S2-3 interface in 10 patients, at S3-4 in 15 patients and S4-5 in 3 patients. RESULTS: Forty patients, male to female ratio 1.7:1, median age 45 years (range 25-65 years) underwent extended pelvic resection in the form of pelvic exenteration and abdominosacral resection. Morbidity, re-admission and mortality rates were 55%, 37.5%, and 5%, respectively. Mortality occurred in 2 patients due to perineal flap sepsis and massive myocardial infarction. A R0 and R1 sacral resection were achieved in 62.5% and 37.5%, respectively. The 5-year overall survival rate was 22.6% and the 4-year recurrence free survival was 31.8%. CONCLUSION: Extended pelvic resection as pelvic exenteration and sacral resection for locally recurrent rectal cancer are effective procedures with tolerable mortality rate and acceptable outcome. The associated morbidity remains high and deserves vigilant follow up.

FHIT, EGFR, and MSH2: possible etiopathologic, prognostic, and predictive role in non-small cell lung carcinoma in Egyptian patients.

The high incidence and mortality of lung carcinoma in Egypt necessitates studying the factors that may be implicated in non-small cell lung carcinoma (NSCLC) pathogenesis and could affect patient management. The aim was to study FHIT, epidermal growth factor receptor (EGFR), and MSH2 protein expression in Egyptian patients with NSCLC. Immunohistochemical staining for FHIT, EGFR, and MSH2 was performed on 64 specimens from NSCLC patients and correlated with prognostic parameters, response to therapy, and overall survival. FHIT loss was observed in 64% of NSCLC patients and was significantly associated with SCC (P=0.003) and poor tumor grade (P=0.043). EGFR overexpression was observed in 47% of NSCLC patients and was significantly associated with SCC (P=0.002). MSH2 was reduced in 23.4% of NSCLC patients and was significantly associated with adenocarcinoma (P=0.024). In a univariate analysis, a significant relationship was seen between the poor overall survival in NSCLC patients and high T-stage (P=0.029), presence of metastasis (P=0.014), advanced-stage grouping (P=0.004), and FHIT loss (P=0.033). Further, FHIT loss was significantly related to disease progression in patients treated with chemotherapy (P=0.038). We conclude that all 3 markers play a role in the development of NSCLC in Egyptian patients. We suggest that FHIT loss be used as a predictor for progression in chemotherapy-treated NSCLC patients.

Role of Ki67 in predicting resistance to adjuvant tamoxifen in postmenopausal breast cancer patients.

INTRODUCTION: Breast cancer (BC) is a major health problem in Egypt and worldwide. Its prognosis depends not only on tumor stage but also on tumor biology. AIM: To correlate the expression of Ki67 with the clinical outcomes of early hormone-receptor positive postmenopausal BC patients who are receiving tamoxifen. METHODS: This cohort study included 70 patients. They were followed up for a minimum of 2 years. Ki67 was assessed on paraffin-embedded blocks using immunohistochemistry methods. RESULTS: The median Ki67 value was 22.5% (IQR, 10%-50%). Ki67 was significantly higher in patients with HER2 positive tumors compared to HER2 negative tumors. After a median follow up period of 53 months, 22 patients (31%) developed disease recurrence either loco-regional or distant in 5.7% and 30%, respectively. Recurrent patients had significantly higher tumor stage, nodal stage and Ki67 values compared to non-recurrent cases. The 2-, 3- and 5-year overall survival (OS) and disease-free survival (DFS) rates were 100% & 91%, 98% & 84% and 77% & 59%, respectively. DFS was significantly worse with higher TNM stage, lower ER expression and higher Ki67 values. OS was significantly worse in patients with Ki67 values ≥ 30%. Ki67 ≥ 30% was an independent predictor of recurrence, poor DFS and OS. CONCLUSION: High Ki67 expression is predictive of poor prognosis and of resistance to adjuvant tamoxifen therapy in postmenopausal BC. We recommend considering Ki67 as one of the risk factors that guide adjuvant treatment decisions.

Clinical prognostic factors of diffuse large B cell non-Hodgkin lymphoma: a retrospective study.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of NHL in Egypt. It represents about 49% of NHL presenting to the National Cancer Institute (NCI), Cairo University. CHOP regimen is the standard treatment used for NHL since the 1970s with only 30-40% overall survival. Recently, integration of Rituximab became a standard of care for patients with DLBCL. However, its widespread use in developing countries is still limited by the lack of financial coverage. Clinical prognostic factors, as well as the pathological markers, are mandatory to individualize treatment. AIM: The aim of the study was to evaluate the clinical risk stratification models including the age adjusted International prognostic index (aaIPI), patients profile and dose intensity (DI) of Cyclophosphamide and Doxorubicin as effective tools for predicting the outcome and prognosis of our DLBCL patients treated with first line CHOP regimen. PATIENTS AND METHODS: This retrospective study included 224 patients with diffuse large B cell lymphoma who were treated with 3-8 cycles of CHOP regimen at the Medical Oncology Department, NCI, Cairo University during the time period from 1999 to 2006. RESULTS: One hundred and seventy-eight patients (79.5%) achieved CR after the CHOP regimen with an observation period of 51 months. The median survival time was 12 months. The OS and DFS at 2 years were 82% and 68.8%, respectively. The univariate analysis of predictive factors for response to treatment showed that the CR rate was significantly affected by aa-IPI and its elements (performance status, stage & LDH), extranodal lesions and DI of Cyclophosphamide and Doxorubicin. The CR rate was 96.9%, 91.2%, 73.9% and 55.6% in cases with aa-IPI 0, 1, 2 and 3, respectively (p<0.001) and it was 82.4%, 81.9% versus 50% in cases with no extranodal site, one extranodal site and two extranodal sites, respectively (p=0.01). As regard DI of Cyclophosphamide, with DI below or equal to the median (249 mg/m(2)/week) the CR rate was 69%, while with DI above the median the CR rate was 87.7% (p=0.001). For Doxorubicin, the CR rate was 72.3% with DI below or equal to the median (16.5 mg/m(2)/week), however, it was 86.6% with DI above the median (p=0.008). The OS rate was significantly affected by aa-IPI as it was 89.8% in cases of aa-IPI 0+1 versus 75.8% in those of aa-IPI 2+3 (p=0.03). DI of Cyclophosphamide and Doxorubicin significantly influenced the OS. The OS rate was 74% with DI of Doxorubicin below or equal to the median versus 96% in cases with DI above the median (p=0.02). For Cyclophosphamide the OS rate was 72.7% with DI below or equal to the median versus 96.3% in cases with DI above the median (p=0.01). The tumor bulk (with a median tumor size of 5 cm) affected the OS, which was 91.23% versus 86.8% in the tumor bulk less than and more than or equal to the median, respectively (p=0.05). By multivariate analysis of predictive factors for response to treatment, the CR rate was significantly affected by the number of extranodal sites and the clinical staging of diffuse large B cell lymphoma. However, OS rate was strongly associated with the bulk of the tumor and the clinical staging of diffuse large B cell lymphoma. CONCLUSION: DI of Cyclophosphamide and Doxorubicin is important in the future treatment regimen plan for DLBCL especially in high risk cases. In addition to aa-IPI and its elements, extra nodal sites and bulk of the tumor proved to be significant predictors and prognostic factors for DLBCL treatment outcome.

Clinicopathologic significance of molecular classification of breast cancer: relation to nottingham prognosis index.

PURPOSE: The aim of this work is to determine the possible relationship between the different profiles of molecular expression of hormone receptors and Her-2÷neu receptors to clinical and histopathological known prognostic variables for breast cancer. MATERIALS AND METHODS: A total of 110 breast carcinoma tumor samples were included. In this study 4 groups or immunohistochemical profiles were defined, based on expression of hormone receptors (estrogen and÷or progesterone) and÷or Her2÷neu (Luminal A, Luminal B, HER2 overexpressing profile, and triple-negative profile). We studied whether there were differences between them regarding clinical and histopathological variables with a known prognostic significance in addition to Nottingham Prognosis Index (NPI). RESULTS: In this series, 65 cases corresponded to Luminal A (59.1%), 18 cases (16.4%) were Luminal B, in 14 cases (12.7%) HER2 was over-expressed, while 13 cases (11.8%) were of the triple negative subtype. It is worth noting the relationship between the triple negative and HER2 over-expressing immunophenotypes and the high NPI (>3.4) in comparison with the Luminal A and Luminal B immunophenotypes (p=.029). The association of the former two types with higher tumor grade was also observed, but such association did not reach statistical significance. CONCLUSION: The subgroups without hormone receptor expression, with Her2÷neu overexpression or without (triple-negative group), have characteristics associated with variables of a poorer prognosis. KEY WORDS: Breast cancer- Hormone receptors- Her2neu- Classification- Nottingham prognosis index.

Tissue and serum EGFR as prognostic factors in malignant pleural mesothelioma.

BACKGROUND: Malignant pleural mesothelioma (MPM) is an asbestos related aggressive tumor. Asbestos causes genetic modifications and cell signaling events that favor resistance to chemotherapy. A variety of receptor tyrosine kinases have been identified to play a central role in various aspects of tumorigenesis. Epidermal growth factor receptor (EGFR) is overexpressed in a variety of epithelial malignancies including lung cancer in which EGFR aberrations not only predict response to EGFR tyrosine kinase inhibitors but also indicate tumor progression. However in MPM, the role of EGFR is less clear. This study was designed to identify serum and tissue EGFR levels in patients with MPM and to evaluate the relationship between serum and tissue EGFR levels and clinicao-pathological prognostic factors and survival. METHODS: We investigated 71 cases of MPM for EGFR expression in tissue. Serum EGFR was assessed in 40 out of those 71 cases and 20 healthy subjects as a control. Pre-treatment serum EGFR levels were measured using quantitative enzyme-linked immunosorbent assay. Tissue EGFR protein overexpression was assessed by immunohistochemistry and gene amplification was assessed by the chromogen in situ hybridization (CISH) technique. Results were correlated with the clinical-pathological factors of the patients and overall survival (OS). RESULTS: Out of the 71 patients included in the study, 19 had undergone extrapleural pneumonectomy. As for the rest of the patients, 46 received chemotherapy while 6 had only best supportive care. EGFR immuno-reactivity was detected in 74.6% of the cases, 37 (52.1%) cases were positive for EGFR gene amplification by CISH, 31 of them revealed moderate to high (++, +++) EGFR immuno-reactivity. Elevated serum EGFR >2.5 ng/ml (the median concentration of EGFR in MPM) was reported in 45% of the cases. The overall response rate (RR) for the 46 treated patients who received chemotherapy was 24.1%. After a median follow up of 29 months, the median overall survival (OS) was 10 months. Elevated serum and tissue EGFR is significantly associated with advanced disease stage. However neither EGFR overexpression in tissues nor high serum levels were associated with survival rates. CONCLUSIONS: EGFR expression is a common feature in MPM patients. High pre-treatment levels of serum EGFR are associated with advanced stage but not with reduced OS. Detailed mutational analysis of EGFR on a larger number of patients is still needed to clarify the exact role of EGFR in MPM patients.

Evaluation of bone marrow in 143 lymphomas: the relative frequency and pattern of involvement, secondary myelopathies, pitfalls and diagnostic validity.

UNLABELLED: The aim of the present study is to assess the frequency of bone marrow (BM) involvement by both bone marrow aspirate and biopsy (BMA and BMB, respectively) procedures in established cases of lymphomas at initial presentation, and to study the relative frequency of marrow disease in relation to lymphoma types, patterns of infiltration and the 2ry associated changes, as well as the diagnostic challenges. Moreover, the diagnostic validity of BMA is tested taking the results of the BMB as the true test results, in order to determine the role of each procedure in the diagnostic approach of marrow infiltration. PATIENTS AND METHOD: This is a retrospective study carried out on 143 nonconsecutive Egyptian patients with lymphomas obtained from a private series during the years 2005 to 2008. Criteria of inclusion included the availability of full medical records and material (medical and pathological), patient consent, nodal disease with no therapy prior to BM sampling, except in 7 patients who had another 2nd BMB following therapy. BMA and BMB were performed as part of the routine workup for diagnosis and staging of lymphoma. The patients had a male to female sex ratio of 2.6:1 and a wide age range from 4 to 74 years. RESULTS: In the present series, 64 cases out of the 143 lymphoma patients studied (44.8%) had a BM disease. Involvement was mostly bilateral (80%). Patients older than 40 years showed higher incidence of bone marrow involvement. There was complete concordance (100%) between both diagnostic procedures in the detection of 76 marrow disease-free lymphoma patients. BMA showed no false positive results and a low rate of deference that makes of it an ideal screening test. Three deferred smears of CLL for BMB diagnosis were all positive for involvement. However, in a total number of 64 BMB positive patients, aspirates could only identify lymphoma involvement in 42 lymphoma patients and missed 22 patients with a BM disease, with an overall sensitivity rate of 65.6%. BMB had a high diagnostic viability and is an easily applied reproducible procedure for diagnosis of BM involvement based on a more detailed informative analysis of both architectural and individual cytomorphologic changes. CONCLUSION: The relatively high level of BM involvement in Egyptian lymphoma patients was directly proportional to high-risk factors. The diagnostic validity of BMB is higher than that of BMA. However, BMA serves as a good positive test in screening lymphomas for marrow disease. A negative BMA does not exclude involvement. Thus, smears should be taken as a complimentary procedure.

Review article composite lymphoma.

Background : Composite lymphoma (CL) is a rare disease that has been identified in recent literature. The term composite lymphoma was first proposed to denote the occurrence of more than one lymphoma in a single patient; however, the present accepted definition is the occurrence of 2 or more distinct lymphoma types in a single anatomic site. The condition could be concurrent or sequential. Unlike disease progression or transformation in lymphoma, CL should include two distinct clones proven by morphological and laboratory tests. Pathogenesis : No single definite mechanism has been suggested to explain the pathogenesis of the different types of CL. The etiology is variable, complex and differs according to the types of lymphomas involved. Several theories were proposed including clonal selection with additional mutational accumulation, genomic instability with genetic predisposition, common precursor cell and the aid of a viral factor, mostly EBV. Diagnosis : The morphologic criteria must be confirmed by one or more tests including immunohistochemistry, flow cytometry, gene rearrangement by PCR, cytogenetics, FISH, in-situ hybridization, DNA sequencing and cDNA microarray . Results are more accurate using the laser capture microdissection method. Many combinations of CL are reported, including : Multiple B-cell lymphomas; B-cell and T-cell lymphomas; NHL and HL; or complex B-cell, T-cell and HL cases. Conclusion : Due to the great advancement in molecular characterization of lymphoma, CL is being increasingly identified. It must be carefully diagnosed, because the multiple disease entities may have entirely different natural histories, prognosis and treatment modalities. Also, careful study of such cases may clarify the possible pathogenic mechanisms of the interrelationship of clonal evolution in lymphoma. Key Words : Composite lymphoma -EBV.

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.