Journal of the Egyptian National Cancer Institute最新文献

Background: The huge number of detected somatic KIT mutations highlights the necessity of in silico analyses that are almost absent in the relevant medical literature. The aim of this study is to report the mutation spectrum analysis of exon 11 encoding the juxtamembrane (JM) domain of the KIT gene in a group of Syrian GIST patients.

Methods: Forty-eight formalin-fixed paraffin-embedded GIST tissue samples, collected between 2006 and 2016, were retrieved from the pathological archives and analyzed for KIT exon 11 mutations by DNA sequencing. Structural/functional impact of detected variants was predicted using several bioinformatic tools.

Results: Twenty-one different variants have been detected in intron 10, exon 11, and intron 11 of the KIT gene, eight of which were novel changes. Mutations in exon 11 of the KIT gene were detected in 28 of 48 (58.3%) GIST patients and predicted to be pathogenic and cancer promoting. Specifically, age above 60 was very significantly associated with the negative selection of deletion mutations (p = .007), a phenomenon that points to deletion severity.

Conclusions: Six bioinformatic tools have proved efficient in predicting the impact of detected KIT variations in view of published structural, experimental, and clinical findings.

Background: Breast cancer is the most common tumor among females globally. Its prevalence is growing around the world, and it is alleged to be the leading cause of cancer death. Approved anti-breast cancer drugs display several side effects and resistance during the early treatment stage. Hence, there is a need for the development of more effective and safer drugs. This research was aimed at designing more potent quinazolin-4(3H)-one molecules as breast cancer inhibitors using a ligand-based design approach, studying their modes of interaction with the target enzyme using molecular docking simulation, and predicting their pharmacological properties.

Methods: The QSAR model was developed using a series of quinazoline-4(3H)-one derivatives by utilizing Material Studio v8.0 software and validated both internally and externally. Applicability domain virtual screening was utilized in selecting the template molecule, which was structurally modified to design more potent molecules. The inhibitive capacities of the design molecules were predicted using the developed model. Furthermore, molecular docking was performed with the EGFR target active site residues, which were obtained from the protein data bank online server (PDB ID: 2ITO) using Molegro Virtual Docker (MVD) software. SwissADME and pkCSM online sites were utilized in predicting the pharmacological properties of the designed molecules.

Results: Four QSAR models were generated, and the first model was selected due to its excellent internal and external statistical parameters as follows: R² = 0.919, R²_adj = 0.898, Q²_cv = 0.819, and R²_pred = 0.7907. The robustness of the model was also confirmed by the result of the Y-scrambling test performed with cR²p = 0.7049. The selected model was employed to design seven molecules, with compound 4 (pIC₅₀ = 5.18) adopted as the template. All the designed compounds exhibit better activities ranging from pIC₅₀ = 5.43 to 5.91 compared to the template and Doruxybucin (pIC₅₀ = 5.35). The results of molecular docking revealed better binding with the EGFR target compared with the template and Doruxybucin. The designed compounds exhibit encouraging therapeutic applicability, as evidenced by the findings of pharmacological property prediction.

Conclusions: The designed derivatives could be utilized as novel anti-breast cancer agents.

Objective: Immunohistochemical expression of P53 protein is so closely related to status of mutation of P53 gene which is tightly linked with pathogenesis of nephroblastoma or Wilms tumor. This study aims to determine the immunohistochemical expression of P53 protein and its predictors in formalin-fixed paraffin-embedded tissue blocks of patients with nephroblastoma.

Materials and methods: A series of 83 histologically diagnosed cases of nephroblastoma from formalin-fixed paraffin-embedded tissue blocks archived at the Department of Pathology, Makerere University, in Kampala, Uganda, were analyzed. Monoclonal anti-p53 antibody (DO-7, DAKO) was used to assess the expression of P53 protein expression. Multivariable logistic regression analysis was performed to determine the predictors of P53 protein immunohistochemical expression, and statistical significance was considered when p-value was less than 0.05.

Results: Most (42.2%, n = 35) of the cases were in advanced tumor stages (III-V), and almost one-quarter (21.7%, n = 18) of the cases were in high-risk group. The immunohistochemical expression of P53 protein was (8.4%, n = 7), and there were more (83.3%, n = 5) positive anaplastic cases for P53 protein compared with (2.6%, n = 2) of P53 expression for non-anaplastic cases. High risk (AOR = 3.42, 95% CI = 7.91-12.55, p = 0.037) and anaplasia (AOR = 1.41, 95% CI = 13.85-4.46, p = 0.001) were potential predictors of immunohistochemical expression of P53 protein.

Conclusion: Most of patients with nephroblastoma in resources-limited settings are diagnosed with advanced clinical stages. Association of P53 protein with anaplasia found in this study indicates the possibility of having novel target therapy for treatment of patients with anaplastic form of nephroblastoma with a focus of identifying molecules that lead to its suppression in such subpopulations of patients with nephroblastoma.

Background: Glioblastoma multiforme (GBM) is one of the most malignant types of central nervous system tumors. GBM patients usually have a poor prognosis. Identification of genes associated with the progression of the disease is essential to explain the mechanisms or improve the prognosis of GBM by catering to targeted therapy. It is crucial to develop a methodology for constructing a biological network and analyze it to identify potential biomarkers associated with disease progression.

Methods: Gene expression datasets are obtained from TCGA data repository to carry out this study. A survival analysis is performed to identify survival associated genes of GBM patient. A gene co-expression network is constructed based on Pearson correlation between the gene's expressions. Various topological measures along with set operations from graph theory are applied to identify most influential genes linked with the progression of the GBM.

Results: Ten key genes are identified as a potential biomarkers associated with GBM based on centrality measures applied to the disease network. These genes are SEMA3B, APS, SLC44A2, MARK2, PITPNM2, SFRP1, PRLH, DIP2C, CTSZ, and KRTAP4.2. Higher expression values of two genes, SLC44A2 and KRTAP4.2 are found to be associated with progression and lower expression values of seven gens SEMA3B, APS, MARK2, PITPNM2, SFRP1, PRLH, DIP2C, and CTSZ are linked with the progression of the GBM.

Conclusions: The proposed methodology employing a network topological approach to identify genetic biomarkers associated with cancer.

Background: The purpose of this study was to assess the usefulness of fluorodeoxyglucose positron emission tomography (¹⁸F-FDG PET)-computed tomography (CT) scan for staging urinary bladder cancer. The study also sought to determine the effect of ¹⁸F-FDG PET/CT on management decisions and its implications for patient care.

Methods: A total of 133 patients with bladder cancer who had both conventional imaging and ¹⁸F-FDG PET/CT for initial staging were identified. All ¹⁸F-FDG-PET/CT findings were classified as true positive, true negative, false positive, or false negative based on their potential to impact the intent of treatment. The sensitivity, specificity, positive predictive value, and negative predictive value were calculated using the standard definition. Furthermore, the rate of change in therapy intent was determined for the entire sample and for subgroups with non-muscle-invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC) patients.

Results: The overall concordance rate between PET/CT and conventional imaging was around 54%. On conventional images, 18% of patients had localized disease, which was upstaged in 6.8% of cases using ¹⁸F-FDG PET/CT. Pelvic lymph node involvement was detected in 18.8% of cases using conventional imaging, which was downstaged to localized disease in 4.5% of cases using ¹⁸F-FDG PET/CT. While 63.2% of patients had systemic disease on a CT scan, 24.7% of cases were downstaged using PET/CT. Overall, the rate of change in therapy intent was 26.3% for the entire sample, 24.5% for NMIBC subgroup, and 27.3% for MIBC patients.

Conclusions: The study found that ¹⁸F-FDG PET/CT is an effective and accurate tool for staging bladder cancer in newly diagnosed patients. Approximately one quarter of patients had a change in management intent based on ¹⁸F-FDG PET/CT results. The study suggests that PET/CT should be used as a standard for newly diagnosed patients, but more research is needed to confirm this.

Background: In the Ugandan setting, investigation for PHNM with CT uses a protocol with both unenhanced and contrast enhanced procedures hence doubling the ionizing radiation exposure. The purpose of this study was to determine the feasibility of single CT procedures in diagnosing PHNM.

Methods: This was a cross-sectional study using CT images from patients, aged fifteen years and below, investigated for head and neck malignancies at the Uganda Cancer Institute. Three radiologists, observers A, B and C, with 12, 5 and 2 years of experience, respectively, participated in the study. They independently reported contrast enhanced images (protocol A), unenhanced images (protocol B), then both unenhanced and contrast enhanced images (protocol C) in 2 months intervals. Inter- and intra- observer agreement was determined using Gwen's Agreement coefficient.

Results: Seventy-three CT scans of 36 boys and 37 girls, with a median age of 9 (3-13) years, were used. Intra-and inter-observer agreement on primary tumour location ranged from substantial to almost perfect with the highest intra-observer agreement observed when protocols A and C were compared. Inter-observer agreement for tumour calcifications was substantial for protocol A. Observers A and C demonstrated an almost perfect intra-observer agreement when protocols A and C were compared. There was a substantial inter-observer agreement on diagnosis for all protocols.

Conclusions: In our setting and examining a limited number of CT images, we demonstrated that contrast-enhanced CT scans provide sufficient information with no evidence of additional value of unenhanced images. Using contrast-enhanced images alone reduced the radiation exposure significantly.

Background: Gene selection from gene expression profiles is the appropriate tool for diagnosing and predicting cancers. The aim of this study is to perform a Precision Lasso regression model on gene expression of diffuse large B cell lymphoma patients and to find marker genes related to DLBCL.

Methods: In the present case-control study, the dataset included 180 gene expressions from 14 healthy individuals and 17 DLBCL patients. The marker genes were selected by fitting Ridge, Lasso, Elastic Net, and Precision Lasso regression models.

Results: Based on our findings, the Precision Lasso, the Ridge, the Elastic Net, and the Lasso models choose the most marker genes, respectively. In addition, the top 20 genes are based on models compared with the results of clinical studies. The Precision Lasso and the Ridge models selected the most common genes with the clinical results, respectively.

Conclusions: The performance of the Precision Lasso model in selecting related genes could be considered more acceptable rather than other models.

Background: Acute lymphoblastic leukemia (ALL) is a malignancy that leads to altered blast cell proliferation, survival, and maturation and eventually to the lethal accumulation of leukemic cells. Recently, dysregulated expression of various micro-RNAs (miRNAs) has been reported in hematologic malignancies, especially ALL. Cytomegalovirus infection can induce ALL in otherwise healthy individuals, so a more detailed evaluation of its role in ALL-endemic areas like Iran is required.

Methods: In this cross-sectional study, 70 newly diagnosed adults with ALL were recruited. The expression level of microRNA-155(miR-155) and microRNA-92(miR-92) was evaluated by real-time SYBR Green PCR. The correlations between the miRNAs mentioned above and the severity of disease, CMV infection, and acute graft vs. host disease after hematopoietic stem cell transplantation (HSCT) were assessed. B cell and T cell ALL distinction in the level of miRNAs was provided.

Results: After the statistical analysis, our results indicated a marked increase in the expression of miR-155 and miR-92 in ALL patients vs. healthy controls (*P = 0.002-*P = 0.03, respectively). Also, it was shown that the expression of miR-155 and miR-92 was higher in T cell ALL compared to B cell ALL (P = 0.01-P = 0.004, respectively), CMV seropositivity, and aGVHD.

Conclusion: Our study suggests that the plasma signature of microRNA expression may act as a powerful marker for diagnosis and prognosis, providing knowledge outside cytogenetics. Elevation of miR-155 in plasma can be a beneficial therapeutic target for ALL patients, with consideration of higher plasma levels of miR-92 and miR-155 in CMV + and post-HSCT aGVHD patients.

Background: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy with few accepted prognostic factors that limit the efficiency of therapy. The aim of the current study was to assess the clinical and laboratory features of T-cell receptor (TCR) aberrations and early T-cell precursor (ETP) subtype as well as their outcome to therapy.

Methods: Sixty-three newly diagnosed pediatric T-ALL patients were assessed for the ETP status using immunophenotyping. Screening of TCRA/D aberrations was done by fluorescent in situ hybridization (FISH). The data were correlated to the patients' clinical features, response to treatment, and survival rates.

Results: Seven patients (11%) had ETP-ALL. The ETP-ALL patients were older (P = 0.013), presented with lower white blood cell (WBC) count (P = 0.001) and lower percentage of peripheral blood (PB) blast cells (P = 0.037), more likely to have hyperdiploid karyotype (P = 0.009), and had been associated with TCRA/D gene amplification (P = 0.014) compared to other T-ALL patients. Of note, the same associations had been significantly observed in patients with TCRA/D gene amplification. Patients with TCRA/D amplification frequently coincided with TCRβ aberrations (P = 0.025). TCR-β aberrations were significantly associated with negative MRD at the end of induction compared to TCR-β-negative patients. There was a nonsignificant trend of ETP-positive cases to have lower overall survival (OS) (P = 0.06). Patients with TCR aberrations had no significant differences regarding disease-free survival (DFS) or OS rates compared to those with normal TCR.

Conclusion: ETP-ALL patients tend to have increased mortalities. There was no significant impact of TCR aberrations on the survival rates of the patients.

Background: Metaplastic breast cancer (MetBC) still represents a conundrum owing to its peculiar histogenesis and molecular drivers that render it extremely resistant to standard chemotherapy with ultimate dismal survival.

Aim: Describe the Egyptian National Cancer Institute's (NCI-E) experience with MetBC regarding its clinicopathologic features, treatment, and survival outcomes.

Patients and methods: Between 2011 and 2020, all MetBC patients presented to NCI-E were retrospectively evaluated. Original clinicopathologic data, therapeutic modalities, pathologic response to neoadjuvant chemotherapy (NACT), recurrence, and date of last follow-up/death were obtained from archived charts.

Results: A cohort of 135 females, the median age was 52 years, and median follow-up period was 40 months (range: 2.6-130.8). Two-thirds were triple negative (TN). Squamous carcinoma was prevalent in 74.8% followed by carcinoma with osseous/chondroid differentiation, spindle cell, and low-grade adenosquamous carcinoma encountered in 13.3, 7.4, and 4.5%, respectively. Modified radical mastectomy was done in 59.3%, and positive nodes (pN+) were depicted in 37.7%. Median Ki-67 was 45% (range: 10-88); grade III and lymphovascular invasion (LVI) were observed in 83.7 and 43.7%, respectively. Stage II was the most common (49%), whereas initial stage IV was encountered in 8.1%. Anthracyclines/taxane combinations were rampant in adjuvant/neoadjuvant settings. The latter was employed in 41 patients, with only 3 cases (7.3%) achieving pathologic complete response (pCR), while moderate/significant residual tumor burden was found in 83%. The 5-year DFS and OS were 56.4 and 57.6%, respectively. Spindle cell carcinoma showed the worst survival parameters in univariate analysis. On the multivariate level, higher tumor stage (pT3 & 4), Ki-67 ≥ 45%, and TN subtype were independent variables for worse DFS and OS; age ≥ 52 years and the presence of LVI were independent features for worse DFS, whereas pN+ was an independent parameter for worse OS.

Conclusions: This study further solidifies the dreadful response of MetBC to conventional chemotherapy regimens employed in common non-metaplastic pathologies. A radical shift in treatment standards tailored to combat the molecular landscape of this distinctive tumor is urgently needed. Immunotherapy and molecularly targeted agents demonstrated promising results in phase I and II trials with hopeful sooner implementation in phase III studies.