Eman Abdelzaher

Recurrence of benign meningiomas: predictive value of proliferative index, BCL2, p53, hormonal receptors and HER2 expression

Introduction. The biological behaviour of meningiomas and the risk of recurrence in individual cases cannot be predicted by using conventional histological criteria alone. A number of histologically benign meningiomas may recur, even after gross complete surgical removal. Material and methods. A retrospective immunohistochemical and statistical analysis of 60 patients with benign intracranial meningiomas (that have been grossly totally resected) was undertaken to determine the correlation of clinicopathological characteristics and expression of biological markers (proliferation index (PI) assessed by Ki67, hormonal receptors, p53, BCL2 and HER2, estrogen receptors, ER and progesterone receptors, PR) with prediction of recurrence. Results. HER2 expression showed a significant inverse correlation with PR and a significant direct correlation with PI. PR-negative and HER2-positive cases showed a statistically significant higher mean PI than PR positive and HER2-negative cases. Univariate analysis showed that recurrence was significantly associated with male gender, cranial base location, the presence of bone and soft tissue invasion, some atypical histological features, higher PI, negative PR expression, and positive p53, BCL2 and HER2 expression. Multivariate analysis showed that the presence of bone and soft tissue invasion and/or the expression of p53 proved to be independent predictors of tumour recurrence. The presence of some atypical histological features and high PI were significant predictors of tumor recurrence, however, they were statistically excluded to avoid multicolinearity. Conclusions. Risk stratification based on histomorphology alone remains problematic. We conclude that soft tissue and bone invasion, some atypical histological features, p53 expression and high PI identify meningiomas with benign histological features but unfavourable clinical outcome. We suggest that those patients should be followed more closely for evidence of recurrent tumour or may be treated more aggressively at the time of diagnosis.

Stem cell markers OCT4 and nestin in laryngeal squamous cell carcinoma and their relation to survivin expression

We explored the expression of the stem cell markers OCT4 and nestin in laryngeal squamous cell carcinoma (LSCC) and investigated their relationship to survivin expression. Eighty-five LSCC, and 62 non-neoplastic laryngeal tissues were analyzed immunohistochemically for the presence of OCT4, nestin and survivin. Marker expression was correlated to clinicopathological parameters. The positive detection rates of OCT4 (42.35%) and nestin (51.76%) in LSCC were higher than those of non-neoplastic mucosa (p<0.05). OCT4 expression was positively associated with nestin expression (p=0.0001). High expression of both OCT4 and nestin was associated with higher tumor grade (p=0.0001). Also, high OCT4 expression was related to higher T stage (p=0.0001). Co-expression of OCT4 and nestin was more significantly associated with glottic location, higher T stage and nodal metastasis than high expression of either marker (p=0.015, 0.006 and 0.008, respectively). Survivin expression was not significantly related to expression of OCT4 or nestin (p=0.094 and 0.266, respectively). OCT4 and nestin are overexpressed in LSCC and may contribute to laryngeal carcinogenesis. Their co-expression may help to predict the lymph node metastatic potential of LSCC. No relationship was detected between expression of survivin and OCT4 or nestin.

Predictive value of immunohistochemical expression of claudin-1 in colonic carcinoma.

OBJECTIVE Colonic carcinoma is one of the most common cancers worldwide. Recently, the possible involvement of claudin-1, one of the major tight junction proteins, in the process of tumorigenesis has been suggested. Also, claudin-1 has emerged as a potential prognostic factor in different types of tumors. The aim of this study was to detect caludin-1 expression in colonic carcinoma and to correlate its expression with clinicopathological variables in an attempt to delineate its role as a potential new prognostic marker. MATERIAL AND METHODS Immunohistochemical expression of claudin-1 was assessed in 50 Egyptian patients with colonic adenocarcinoma. The predictive performance of claudin-1 expression was statistically evaluated. RESULTS Decreased claudin-1 expression was found in 62% of colonic adenocarcinoma cases while similar expression was found in 38% of the cases. Statistical analysis showed a statistically significant inverse correlation between claudin-1 expression and tumor grade, depth of invasion, lymph node involvement, and tumor stage. Regression analysis showed that claudin-1 decreased expression significantly predicts that the tumor is of a high grade, high stage, and is associated with lymph node involvement. ROC curve analysis showed that claudin-1 had a sensitivity of 88.24% and a specificity of 81.25% for the prediction of tumor stage and a sensitivity of 73.33% and a specificity of 82.86% for the prediction of lymph node involvement. CONCLUSIONS Claudin-1 decreased expression in colonic carcinoma contributes to tumor dedifferentiation, invasion and metastasis. Claudin-1 expression could be used as a predictor of colonic carcinoma stage and lymph node status with a high sensitivity and specificity.

Management of Glioblastoma Multiforme in a Patient Treated With Ketogenic Metabolic Therapy and Modified Standard of Care: A 24-Month Follow-Up

Few advances have been made in overall survival for glioblastoma multiforme (GBM) in more than 40 years. Here, we report the case of a 38-year-old man who presented with chronic headache, nausea, and vomiting accompanied by left partial motor seizures and upper left limb weakness. Enhanced brain magnetic resonance imaging revealed a solid cystic lesion in the right partial space suggesting GBM. Serum testing revealed vitamin D deficiency and elevated levels of insulin and triglycerides. Prior to subtotal tumor resection and standard of care (SOC), the patient conducted a 72-h water-only fast. Following the fast, the patient initiated a vitamin/mineral-supplemented ketogenic diet (KD) for 21 days that delivered 900 kcal/day. In addition to radiotherapy, temozolomide chemotherapy, and the KD (increased to 1,500 kcal/day at day 22), the patient received metformin (1,000 mg/day), methylfolate (1,000 mg/day), chloroquine phosphate (150 mg/day), epigallocatechin gallate (400 mg/day), and hyperbaric oxygen therapy (HBOT) (60 min/session, 5 sessions/week at 2.5 ATA). The patient also received levetiracetam (1,500 mg/day). No steroid medication was given at any time. Post-surgical histology confirmed the diagnosis of GBM. Reduced invasion of tumor cells and thick-walled hyalinized blood vessels were also seen suggesting a therapeutic benefit of pre-surgical metabolic therapy. After 9 months treatment with the modified SOC and complimentary ketogenic metabolic therapy (KMT), the patient’s body weight was reduced by about 19%. Seizures and left limb weakness resolved. Biomarkers showed reduced blood glucose and elevated levels of urinary ketones with evidence of reduced metabolic activity (choline/N-acetylaspartate ratio) and normalized levels of insulin, triglycerides, and vitamin D. This is the first report of confirmed GBM treated with a modified SOC together with KMT and HBOT, and other targeted metabolic therapies. As rapid regression of GBM is rare following subtotal resection and SOC alone, it is possible that the response observed in this case resulted in part from the modified SOC and other novel treatments. Additional studies are needed to validate the efficacy of KMT administered with alternative approaches that selectively increase oxidative stress in tumor cells while restricting their access to glucose and glutamine. The patient remains in excellent health (Karnofsky Score, 100%) with continued evidence of significant tumor regression.

Biological and Demographic Profile of Meningiomas in a Cohort of Egyptian Patients: Impact on Tumor Recurrence

Objective. This work was designed to study the biological and demographic characteristics of meningiomas and their impact on tumor recurrence in Egyptian patients. Material and Methods. A cohort of 265 Egyptian patients with meningioma was studied. Immunohistochemistry for VEGF, Ki67, PR, CD20, and CD3 was performed. Statistical analysis was used to detect independent predictors of recurrence. Results. Adults represented 98.9% of cases, with female preponderance (M : F ratio = 1 : 2.4). Histologically, 78.10% of cases were grade I, 19.20% were grade II, and 2.60% were grade III. Transitional variant was the most common (43.40%). VEGF expression (38.50% of cases) correlated positively with perifocal edema, tumor size, and proliferative index (PI). PR expression (64.5% of cases) correlated inversely with the PI (mean 3.75). Lymphocytic aggregates were detected in 7.20% of cases, with a mean CD20 : CD3 ratio of 1 : 10.1. In a multivariate analysis, only tumor size, PR expression and necrosis predicted recurrence independently. Using ROC curve, size was the best predictor of tumor recurrence with a cut-off point of >6 cm and an excellent negative predictive value (97.6%). Conclusions. Meningiomas in our region showed some distinctive clinicopathological and demographic criteria. Tumor size was found to be the best recurrence predictor factor of meningioma.

FGF18 as a potential biomarker in serous and mucinous ovarian tumors

Fibroblast growth factor 18 (FGF18) has been suggested to play important roles in promoting progression of ovarian high-grade serous carcinoma. Our aim was to investigate FGF18 expression in the whole spectrum of serous and mucinous ovarian tumors, highlighting differences in expression within the adenoma-carcinoma sequence and differences between type I and type II tumors. We also aimed to test the prognostic significance of this expression and its relation to microvessel density (MVD). We evaluated the immunohistochemical expression of FGF18 and CD31 in 103 ovarian tumors and statistically analyzed their association with clinicopathological variables and patients’ outcome. FGF18 score increased significantly within the adenoma-carcinoma sequence for serous and mucinous tumors. MVD increased significantly only among serous tumors. FGF18 and MVD correlated significantly (overall and among serous tumors only) and were significantly higher in type II than type I tumors. Cox regression models were built. Independent predictors could not be determined due to multicollinearity between the predictors. However, the combination of International Federation of Gynecology and Obstetrics (FIGO) stage, ovarian carcinoma type, and/or FGF18 score achieved the highest predictability of poor prognosis. FGF18 could play a role within the adenoma-carcinoma sequence in type I tumors and might modulate angiogenesis among serous tumors. Our findings further augment the differences between type I and type II tumors. The combination of FIGO stage, ovarian carcinoma type, and/or FGF18 score could predict poor prognosis among ovarian carcinoma patients. Our work identifies FGF18 in ovarian neoplasia as a promising field of research, although evaluation of the performance of the developed models is still needed.

High Coexpression of Runt-related Transcription Factor 2 (RUNX2) and p53 Independently Predicts Early Tumor Recurrence in Bladder Urothelial Carcinoma Patients.

Conventional prognostic factors for bladder cancer are inadequate to predict tumor recurrence and/or progression successfully; thus, the identification of adjunctive novel prognostic biomarkers is of paramount importance. In this study, the immunohistochemical expression patterns and clinical significance of RUNX2, WWOX, and p53 were investigated in a tissue microarray of 87 primary urothelial carcinomas and 17 control cases. We found that RUNX2, WWOX, and p53 were significantly correlated and overexpressed in urothelial carcinoma cases compared with the control group. RUNX2 and p53 were significantly upregulated in association with high-grade, nonpapillary pattern, and bilharziasis. Muscle-invasive tumors significantly overexpressed RUNX2. WWOX overexpression was significantly associated with high-grade tumors and inversely correlated with age. In a bivariate analysis, the risk of early tumor recurrence and progression was significantly associated with RUNX2 and p53 overexpression and bilharziasis. A multivariate Cox regression analysis proved that RUNX2 and p53 were independent predictors of early tumor recurrence. The ROC curve analysis showed that combined RUNX2 and p53 high expression (scores >3 and >5, respectively) had the highest accuracy (73.6%) for the prediction of early tumor recurrence. We conclude that RUNX2 and p53 might be functionally related and are likely involved in bladder tumor carcinogenesis and aggressiveness, which provides a new perspective for targeted therapy. RUNX2 and p53 independently predict early tumor recurrence in bladder carcinoma patients, with the highest prediction accuracy being achieved on their combined high expression. The role of WWOX in bladder urothelial carcinoma and its relationship with RUNX2 and p53 remains unclear and warrants further investigation.

Stromal expression of Cd10 in invasive breast carcinoma and its correlation with clinicopathological parameters

Background Breast cancer is the most common cancer in women worldwide, and it is the fifth cause of death from cancer overall. Stromal factors are now emerging as novel markers in assessing the prognosis of many neoplasms. Recent studies have highlighted the importance of noncellular stromal components, especially the extracellular matrix, during cancer progression. CD10 is considered as the prototype of extracellular matrix metalloproteinases, and has currently been associated with more aggressive behavior of many tumors. A few published studies have investigated stromal expression of CD10 in breast cancer and its impact on patient outcome. Patients and methods Immunohistochemical evaluation of stromal expression of CD10 in primary breast carcinomas in 60 Egyptian female patients was carried out. The associations between CD10 stromal expression and clinicopathological variables and patient outcome were statistically analyzed. Results Primary invasive carcinomas showed stromal CD10 expression in 81.7% of cases, which was significantly higher than the adjacent non-neoplastic breast tissue that lacked CD10 expression. CD10 stromal overexpression was significantly associated with higher tumor grade, presence of necrosis, negative estrogen receptor, and progesterone receptor status, as well as the triple-negative molecular subtype. In addition, CD10 upregulation was significantly associated with a shorter median disease-free survival time, the development of local and distant recurrence, and the occurrence of a new primary tumor in the contralateral breast. Conclusion From the present study, it can be concluded that CD10 stromal expression may be implicated in breast cancer tumorigenesis. CD10 is associated with poor prognostic indicators in breast cancer, and thus may contribute to tumor aggressiveness and progression. CD10 expression is a potential poor prognostic factor in breast cancer and might help identify a group of patients with higher propensity to tumor recurrence, which might aid in patient management.

RUNX2 and WWOX genes as molecular biomarkers and candidates for targeted therapy in Egyptian patients with primary conventional osteosarcoma

BackgroundThe conventional osteosarcoma (OS) is the commonest primary malignant, bone tumor with complex genomic profiles and poor survival. Runt-related transcription factor 2 (RUNX2) and WW domain containing oxidoreductase (WWOX) genes are implicated in normal osteogenesis as well as in the development of primary conventional OS.MethodsWe retrospectively assessed protein and RNA expression of the RUNX2 and WWOX genes by quantitative real time PCR (qPCR) and immunohistochemistry (IHC) in 80 cases of primary OS and 20 normal control (NC) subjects. Proteins and RNA expression levels of both genes were correlated to clinico-pathological features of the patients, progression free and overall survival (PFS& OS) rates.ResultsIn OS, RUNX2 protein was detected in 72/80 (90%) cases compared to 4/20 (20%) NC samples (p. < 0.001) and RUNX2-RNA was up regulated (up to 103.2 folds) in 60/80 (75%) (p = 0.01). WWOX protein and RNA (up to 7.2 folds) were detected in all NC samples but in 24/80 (30%) and 20/80 (20%) OS cases; respectively (p. < 0.001 for each). The concordance between the RNA and protein expressions for RUNX2 and WWOX was significantly high (X_trend^2 = 6.33; p = 0.012 and X_trend^2 = 19, p < 0.001; respectively). A significant inverse relation existed between RUNX2 and WWOX RNA and protein (p = 0.032, p = 0.008). There was significant correlation between RUNX2 RNA/protein, high tumor grade and stage (p = <0.001; each); RUNX2 RNA and male gender, tumor site and metastasis (p = 0.007, 0.041, 0.003; respectively). WWOX protein associated significantly with advanced stage and metastasis (p = 0.001& 0.024; respectively) and WWOX RNA associated with metastasis (p = 0.003).ConclusionsRUNX2 and WWOX play opposing roles in the development and progression of OS. They could be used as sensitive prognostic biomarkers for OS patients and RUNX2 represents a promising candidate for targeted therapy.

Immunohistochemical localization of β-catenin in medulloblastoma

Objectives The aim of this study was to explore the relationship between immunohistochemical expression of β-catenin and the relevant clinicopathological features of medulloblastoma in Egyptian patients. Background Medulloblastoma is a small round blue cell malignancy of the cerebellum and is a major cause of morbidity and mortality in pediatric oncology. Identification of the signaling pathways involved in the pathogenesis of medulloblastoma represents a key challenge for medulloblastoma management. The wingless (WNT)-signaling pathway has been reported to be responsible for 15% of sporadic medulloblastoma. β-Catenin represents the downstream effector of the WNT pathway. Activation of the WNT-signaling pathway results in stabilization of β-catenin and its translocation from the cytoplasm to the nucleus where it regulates the related genes. Patients and methods This retrospective study was conducted on 49 tissue specimens of medulloblastoma patients for evaluation of immunohistochemical expression of β-catenin. Results None of the studied medulloblastoma patients showed nuclear localization of β-catenin. However, 29 patients exhibited cytoplasmic staining and 20 patients were absolutely negative. No statistically significant difference was found when comparing patients with cytoplasmic β-catenin expression and negative patients with the studied parameters. In addition, the H-score value of patients with cytoplasmic β-catenin did not show significant relationship with the studied clinicopathologic parameters. Conclusion In view of the absence of nuclear localization of β-catenin, we could conclude that β-catenin does not play a role in the pathogenesis in all evaluated medulloblastoma patients. However, a large-scale study is recommended to elicit the exact role of the WNT-signaling pathway through dysregulation of components other than β-catenin.