Clinicopathological Impact of FOXM1 and MMP-9 Immunohistochemical Expression in Different Grades of Intracranial Meningioma.

OBJECTIVES: To find predictive biomarkers for recurrence and progression of meningioma. BACKGROUND: Despite great advances in meningioma treatment, the prognosis remained unfavorable due to the high recurrence rate. METHODS: In this study, we evaluated the immunohistochemical expression of FOXM1, MMP-9, and Ki67 in 50 cases of intracranial meningioma to detect its potential role in meningioma progression, recurrence, and patients' survival. RESULTS: Strong FOXM1 expression was detected in 20% of the cases and was significantly associated with meningioma grade (P= 0.002) and peritumoral brain edema (PTBE; P<0.001). Strong MMP-9 expression was noted in 32% of the cases and was significantly associated with meningioma grade and PTBE (P<0.001, P<0.001, respectively). High Ki67 was noted in 50% and significantly associated with tumor grade and PTBE (P<0.001, P= 0.002, respectively). The follow-up period revealed that meningiomas with strong FOXM1, strong MMP-9, and high Ki67 expression were associated with tumor recurrence, shorter OS, and recurrence-free survival. Furthermore, up-regulation of FOXM1 and MMP-9 expression had a significant relation with poor clinical response to the therapy (P= 0.010, P= 0. 001, respectively). However, high Ki67 cases were more sensitive to clinical therapy (P= 0.005). CONCLUSION: Strong FOXM1, strong MMP-9, and high Ki67 in meningiomas indicate highly aggressive tumors with a shortened survival rate, dismal outcome, and high risk of recurrence after the standard protocol of therapy.

Prognostic Value of Immunohistochemical Expression of MTAP and AKIP1 in IDH1 Mutant Astrocytoma.

BACKGROUND: Definite treatment for glioma is not exist, and with increased drug resistance, more effort should be paid to identify new prognostic biomarkers and molecular targets for therapy for glioma patients. AIM: The current study aimed to evaluate the immunohistochemical (IHC) expression of MTAP and A-Kinase Interacting Protein 1 (AKIP1) in astrocytoma and to investigate their association with the clinicopathological characters of these cases. METHODS: Totally 66 cases of astrocytoma patients involved in this study. Cases underwent tumor resection and tissue sections were stained with MTAP, AKIP1 and IDH1 by IHC and evaluated in different grades of astrocytoma and their association with survival and response to therapy was investigated. RESULTS: High AKIP1 expression was positively correlated with treatment resistance and progressive disease. Positive IDH and retained MTAP expressions had shown better treatment response rather than negative IDH and lost MTAP. High AKIP, negative IDH and loss of MTAP expressions were significantly associated with poor survival outcome. CONCLUSION: Irrespective to grade and IDH status, the loss of MTAP immunoreactivity and high AKIP1 expression are predictive factors in astrocytoma, and they may be used as a biomarker for guiding astrocytoma management and prognosis surveillance.

Prognostic Impact of FSTL3, ADAM12, and FAT4 in Patients of Colon Cancer: Clinicopathologic Study.

There is a cellular crosstalk between Wnt/ß-catenin and Hippo/Yes-related protein 1 signaling paths in colon cancer (CC) which promotes EMT processes that mediate the metastatic progression of CC. We aimed to evaluate follistatin-like 3 (FSTL3), ADAM12, and FAT4 expressions in CC. A statistical analysis was done to establish how disease-free survival, overall survival (OS), and relapse all performed a prognostic role. High FSTL3 was detected in 68% of CC and significantly related to left-sided tumors ( P = 0.002) and the advanced tumor features, such as metastasis ( P = 0.010), pT ( P = 0.006), high grade ( P = 0.005), lymph node contribution ( P = 0.013), and advanced stage ( P = 0.003). Positive ADAM12 expression was observed in 60% and significantly related to left-sided tumors ( P = 0.001) and significantly common in high grade ( P = 0.028), lymph node involvement ( P < 0.001), and advanced stage ( P = 0.004). Low FAT4 expression was recognized in 76% and linked with the right-sided tumors ( P = 0.036). FAT4 expression was contrariwise linked with CC grade ( P < 0.001). Furthermore, FAT4 expression was inversely correlated with lymph node involvement ( P = 0.002), metastasis ( P = 0.046), and advanced stage ( P = 0.002). During the follow-up, 14 cases were relapsed and positively associated with high FSTL3 expression ( P = 0.001) and ADAM12 expression ( P < 0.001), but negatively linked with FAT4 expression ( P = 0.003). Shorter disease-free survival was substantially correlated with positive ADAM12, extreme FSTL3, and low FAT4 expression ( P < 0.001, P = 0.002, P = 0.003, consecutively). Moreover, Kaplan-Meier curves demonstrated a significant correlation between shorter OS with extreme FSTL3, positive ADAM12, and low FAT4 ( P = 0.004, <0.001, 0.019, consecutively). High FSTL3, positive ADAM12, and low FAT4 expression are unfavorable prognostic influences in CC that may be accountable for relapse and therapeutic resistance in CC.

Immunohistochemical evaluation of forkhead box A1 and EphA5 markers in serous ovarian carcinomas, and their impact on the clinical outcome of patients.

Ovarian cancer is the most lethal gynaecological neoplasm in females. In ovarian cancer, forkhead box A1 (FOXA1) aids transcription of YAP-associated protein mediated by the cyclic adenosine monophosphate response element-binding protein. As a result, cellular proliferation and migration increased. The roles of erythropoietin-producing human hepatocellular carcinoma cell (Eph) receptors and ephrin ligands in cell adhesion, migration, cell proliferation regulation in various cancers, and angiogenesis are well characterized. This study included formalin-fixed, paraffin-embedded tissue specimens from 41 patients with ovarian serous cystadenocarcinoma, including both low- and high-grade tumours. For each case, a paraffin block with tumour tissue was chosen for an immunohistochemical procedure using primary antibodies against EphA5 and FOXA1. By the end of 2017, patients finished their chemotherapy and were followed for the next 3 years. Positive FOXA1 and EphA5 results were presented in 68.3% and 39% of patients, respectively. A statistically significant correlation was detected between FOXA1 expression and each of CA-125 level, tumour stage, tumour grade, and the presence of lymph node metastasis. In our work, the overall survival was positively correlated with EphA5 expression and inversely correlated to FOXA1 immunoreactivity. The estimated disease-free survival (DFS) and EphA5 immunoreactivity had a significant positive association, whereas DFS and FOXA1 protein expression had a significant inverse link. FOXA1 and EphA5 expression play a role in ovarian cancer progression and prognosis prediction.

Association between COVID-19 stress, coping mechanisms and stress-related oral conditions among Egyptian adults: a cross-sectional study.

The present study investigated the association between COVID-19 stresses and oral conditions including gingivitis, oral hygiene, oral ulcers, and dry mouth. This was a cross-sectional study that collected data from adults in community settings in Alexandria, Egypt, between October 2021, and February 2022. Gingival condition and oral hygiene were assessed using the gingival and plaque indices. Participants were asked if they experienced oral ulcers during the past week and dry mouth during the past year. COVID-19 fears and coping were assessed using the COVID Stress Scale (CSS), and the Brief Resilience Coping Scale (BRCS), respectively. Oral health behaviors were assessed using the World Health Organization questionnaire. Regression analyses were used to assess the association between the dependent variables (clinically assessed gingival and plaque indices, reported presence of oral ulcers, and dry mouth) and explanatory variables (CSS and BRCS) after adjusting for confounders (COVID-19 status, oral health behaviors, smoking, age in years, sex, and highest educational level). The response rate was 88.8% (373/420). The mean (SD) age = 39.26 (11.45) with 74.3% females and 49.3% reporting completing high school or higher education. The mean (SD) plaque and gingival indices were 1.59 (0.66) and 1.39 (0.59), respectively. Only 20.1% reported the presence of oral ulcers and 41.6% reported xerostomia. Lower plaque score was associated with higher COVID-19 contamination fears (B = - 0.03, 95% CI - 0.05, - 0.02) and higher compulsive checking and reassurance-seeking (B = - 0.02, 95% CI - 0.03, - 0.009). Lower gingival score was associated with higher COVID-19 contamination fears (B = - 0.02, 95% CI - 0.03, - 0.002). Higher odds of reporting dry mouth were associated with greater fear of COVID-19 socioeconomic consequences (AOR = 1.05, 95% CI 1.001, 1.09), and lower coping scores (AOR = 0.93, 95% CI 0.88, 0.99). The findings suggest an association between COVID-19 specific stresses and stress-related oral conditions and shed light on the possible link between mental and oral health, emphasizing the importance of integrated planning of care services.

Expression of HnRNP A1, ZEB1, and E-cadherin in Hepatocellular carcinoma and their impact on patients' prognosis and survival.

Background: Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies in Egypt. HCCs usually have a poor prognosis because of late diagnosis, aggressive metastasis, and early invasion. Heterogeneous ribonucleoproteins (HnRNPs) are nuclear proteins that play a variety of roles in telomere formation, DNA repair, cell signaling, and gene regulation. .: Zincfinger Eboxbinding homeoboxes (ZEBs) are transcription factors that have a consistent inverse correlation with Ecadherin in numerous types of cancer and associated with poor prognosis. Aim: This study aimed to verify the prognostic expression of HnRNP A1, ZEB1, and E-cadherin in HCC. Settings and Design: The retrospective study consisted of 54 formalin-fixed paraffin-embedded tissue blocks of hepatocellular carcinoma. Methods and Material: Immunohistochemical staining was performed using antibodies against HnRNP A1, ZEB1, and E-cadherin. The patients were followed at the Clinical Oncology Department from May 2018 to July 2021. Statistical Analysis: SPSS version 20 using the Chi-square test to compare data and the Kaplan-Meier plot for comparing survival. Results: HnRNP A1 high positivity was detected in 59.3% of the cases, whereas negative E-cadherin and ZEB 1 expression presented in 37% and 70.4% of the patients, respectively. A statistically significant relation was present between HnRNP A1, ZEB1, E-cadherin, and various clinicopathological variables. The mean progression-free survival and overall survival in low HnRNP A1 and negative ZEB1 expressions were longer than those exhibited in high HnRNP A1 and positive ZEB1 expressions. Conclusion: HnRNP A1 and ZEB1 expressions are poor prognostic factors of HCC. E-cadherin has an important role in the development of differentiated HCCs and favorable outcome.

Outcome of Patients With Head and Neck Squamous Cell Carcinoma Can be Predicted by Expression of eIF4E and Osteopontin in Free Surgical Margins.

Squamous cell carcinoma of the head and neck (HNSCC) is recognized as the third most common cause of death. Incomplete resection of the primary tumor is the main cause of local recurrence and poor prognosis in HNSCC. Histologic assessment in order to determine "tumor-free" margins could be inadequate because of malignant transformation occurs at the molecular level earlier than the morphologic level. The present study aimed to evaluate the prognostic significance of eukaryotic initiation factor 4E (eIF4E) and Osteopontin in the tumor cells and histologically tumor free surgical margins of HNSCC. This cohort study was performed on 60 cases of HNSCC diagnosed at the Department of Pathology and treated at the Clinical Oncology Department, Faculty of Medicine, Zagazig University. Our enrolled formalin fixed paraffin embedded biopsy specimens with their matched tumor free surgical margins from resected head and neck squamous cell carcinoma were immunostaind for eIF4E and Osteopontin markers. 65% of our HNSCC patients had eIF4 E positive cytoplasmic immunostaining and 70% of them exhibited Osteopontin staining. Two-thirds of the dead patients exhibited high Osteopontin positive staining, whereas the surviving group did not exhibit this high expression. Concerning eIF4E, 85% and 5% of the dead patients showed high and low eIF4E expression, respectively. Disease-free survival (DFS) and overall survival were significantly (P=0.000) different between high and negative expression of Osteopontin, high and negative expression of eIF4E. 84% of patients with eIF4E positive margins and 75% with Osteopontin positive margins had local recurrence. In addition, negative expression of eIF4E is associated with highly significant better DFS and overall survival (P=0.000 and 0.001), respectively, in the margin negative expression status, while negative expression of Osteopontin was significantly associated with better DFS but of no significance in overall survival outcome. Our findings suggest that tumor-free surgical margins in HNSCC may be redefined as histologically Osteopontin and eIF4E negative resection margins. However, multicenter prospective studies are required to further evaluate their clinical utility in the surgical management of primary HNSCC.

Expression of Immune Checkpoint Regulators, Cytotoxic T-Lymphocyte Antigen-4, and Programmed Death-Ligand 1 in Epstein-Barr Virus-associated Nasopharyngeal Carcinoma.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is the most common cancer arising from the nasopharynx with a poor prognosis. Targeting immune checkpoint is one of the new promising lines in cancer treatment. Cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed death-ligand 1 (PD-L1) are immune checkpoints that regulate T-cell immune function. AIM: This work aimed to assess the immunohistochemical expression of PD-L1 and CTLA-4 in NPC and their ability to predict survival and response therapy and to check their validity as immunotherapy targets. Twenty-six cases of NPC were studied by immunohistochemistry for PD-L1 and CTLA-4 and by nested polymerase chain reaction followed by DNA sequencing for the presence of EBNA-1 gene of Epstein-Barr virus (EBV). All investigated cases were diagnosed and treated in the Zagazig University Hospital in the period from August 2015 to July 2018. EBNA-1 gene was identified in 84.6% of the cases. Whereas the expression of PD-L1 was noted in 46.2% of all cases studied, 54.6% of EBV-associated NPCs were found to express PD-L1. There was a significant association between PD-L1 expression and the advanced stage of the tumor (P<0.001). CTLA-4 expression was observed in 88.4% of all NPC cases as cytoplasmic staining in both tumor cells and tumor-infiltrating lymphocytes. CTLA-4 expression in lymphocytes was associated with the presence of EBV. A significant association was detected between CTLA-4 and tumor-infiltrating lymphocyte expression on one side and the stage of the tumor on the other. High expression of CTLA-4 was significantly associated with disease progression and worse overall survival. CONCLUSION: PD-L1 and CTLA-4 are adverse prognostic markers in NPC. The authors propose that targeted therapy against PD-L1 and CTLA-4 will be a hopeful therapy for cases of NPC with resistance to concurrent chemoradiation treatment in Egypt, especially EBV-associated cases.

Clinicopathological Features and Treatment Challenges in Triple Negative Breast Cancer Patients: A Retrospective Cohort Study.

OBJECTIVE: As the genetic and molecular profiles of triple negative breast carcinoma (TNBC) are elucidated, multiple therapeutic targets have been produced. TNBC with less than 1% androgen receptor (AR) expression may respond to enzalutamide with greater response association in higher levels. A metronomic dose of capecitabine and docetaxel are effective developed drugs for angiogenic process inhibition. We aimed to demonstrate the treatment outcome of triple-negative breast cancer patients in correlation to their clinicopathological features. MATERIALS AND METHODS: A retrospective cohort study of 80 TNBC patients was conducted. The patients underwent proper observation with the reporting of their treatment and follow-up data. Patients with a metastatic disease, neoadjuvant chemotherapy, follow-up drop or data shortage were excluded from the survival analysis. RESULTS: The study results revealed a significant association between negative androgen expression and younger age ≤35 years, premenopausal status, higher grade, extracapsular extension, lymphovascular invasion, Ki 67, and CA15-3 (p=0.003, 0.02, < 0.001, 0.001, 0.027, 0.005, 0.009 respectively). The three-year overall survival (OS) in patients who received bicalutamide was better than those patients who received capecitabine or docetaxel but of no significance (p=0.46). The three-year disease free survival (DFS) was significantly better in the bicalutamide arm versus the other two groups (p=0.012). CONCLUSIONS: We concluded that extended adjuvant antiandrogen such as bicalutamide and metronomic capecitabine are well tolerated with accepted compliance and affordability compared to docetaxel and are warranted for problem-solving and better DFS and OS in some TNBC patients.

Tolerability and outcome of sunitinib by giving 4/2 schedule versus 2/1 schedule in metastatic renal cell carcinoma patients: a prospective randomized multi-centric Egyptian study.

INTRODUCTION: Sunitinib is a standard of care first line treatment for patients with metastatic renal cell carcinoma (RCC). Sunitinib standard dose is 50 mg once daily for 4 consecutive weeks followed by 2 weeks' off (4/2 schedule). Long-term and high exposure to this medication lead to severe adverse events (AEs); therefore, this trial was done to find the best schedule which gives the best outcome with minimal toxicity. MATERIALS AND METHODS: Seventy patients were randomly assigned into 2 groups, then received 50 mg/day of sunitinib. Group 1 (40 patients) received sunitinib for 4 consecutive weeks followed by 2 weeks off (4/2 schedule) while 30 patients were admitted to group 2 with 2 weeks on and 1 week off (2/1 schedule). RESULTS: All patients (100%) had significantly higher AEs on schedule 4/2 vs. 73.3% on schedule 2/1 (p = 0.001). Furthermore, the grade 3 AEs on schedule 2/1 were significantly lower than those on schedule 4/2 (26.7% vs. 82.5%) respectively (p = 0.001), such as fatigue, diarrhea, hypertension, hand foot syndrome (HFS) and mucositis. Progression-free survival (PFS) rate was significantly higher in 2/1 schedule (60.9% vs. 38.6%) than in 4/2 schedule (p < 0.008). Multivariate analysis suggested that: age > 60 years, poor International Metastatic RCC Database Consortium (IMDC) risk category, tumor size > 10 cm and treatment schedule (group 1) were poor prognostic factors of PFS. CONCLUSIONS: Our study supported the use of 2/1 schedule of sunitinib in patients with metastatic RCC because of lower toxicity profile and better efficacy with improved PFS in comparison to 4/2 schedule.

Prognostic Value of Cyclin D1 and CD44 Expression in Gastric Adenocarcinoma.

BACKGROUND: Worldwide, gastric carcinoma (GC) is the 5th most common malignancies in both sexes representing 6.8% of the total fatalities and is the 3rd leading cause of cancer death representing 8.8% of total fatalities. In Egypt, GC considers the 12th leading cause of cancer death representing 2.2% of the total cancer mortality. A growing body of evidence supports that cancer stem cells (CSCs) are resistant to chemotherapy or radiation, and the cell adhesion molecule CD44 has been identified as a cell surface marker associated with cancer stem cell in several types of tumors including gastric cancer. CD44 regulates gastric stem cell proliferation by increasing cyclin D1 expression which represents an important regulatory protein in the cell cycle transition from G1 phase to S phase. This study aimed to investigate whether cyclin D1 and CD44 can be used as prognostic indicators in gastric cancer. MATERIAL AND METHODS: Forty formalin-fixed and paraffin-embedded gastric tissues, obtained from patients who underwent endoscopic resection or surgical resection, constituted the group of our study. The immunohistochemical expression of cyclin D1 and CD44 was examined and correlated with clinical-pathological parameters and outcome of the patients. RESULTS: Overexpression of CD44 and cyclin D1 was noted (in of 55 and 50% respectively). Cyclin D1 and CD44 positive expressions in GC were positively correlated with tumor differentiation (p = 0.020, p = 0.004 respectively), TNM stage (p < 0.001 for both), poor survival (p < 0.001 for both), and with increased rate of recurrence (p = 0.020, p = 0.005 respectively). CONCLUSION: CD44 and cyclin D1 were associated with poor prognosis in gastric cancer, and so, they comprise an attractive target for anticancer drug development.

The Prognostic Value of Cancer Stem Cell Markers (Notch1, ALDH1, and CD44) in Primary Colorectal Carcinoma.

BACKGROUND: Cancer stem cells proved to have a vital role in cell migration, invasion, metastasis, and treatment resistance of colorectal cancer (CRC) that subsequently lead to poor clinical outcomes. These stem cells may be a novel therapeutic target for the management of CRC progression. Signals of the Notch-1 pathway are responsible for acquisition of stem cell characters. ALDH1 and CD44 are usually detected in stem cells in colorectal cancer. AIM: The aims of this work are to evaluate the immunohistochemical expression of cancer stem cell markers ALDH1, Notch1, and CD44 in colorectal cancer and investigate their correlation with clinicopathological characters and patient survival. METHODS: Paraffin-embedded specimens of 70 patients with primary colorectal carcinoma were analyzed for Notch 1, ALDH1, and CD44 expressions by immunohistochemistry. RESULTS: Notch1 was mainly located in the cytoplasm of CRC tissues, rarely expressed in adjacent normal tissues. A highly statistically significant relationship was found between grading, lymphovascular invasion, the degree of lymphocytic infiltration, peritumoral budding, lymph node ratio, lymph node metastasis, and Notch1 expression (p < 0.001). There was a highly statistically significant relationship found between AJCC stage and Notch1 expression (p < 0.001). CD44 was mainly located in the cell membrane of CRC tissues. A highly statistically significant relationship was found between grading (p = 0.006), lymphovascular invasion, the degree of lymphocytic infiltration, peritumoral budding, lymph node metastasis, lymph node ratio, and CD44 expression (p < 0.001). There was a highly statistically significant relationship found between AJCC stage and CD44 expression (p < 0.001). ALDH1 was detected in the cytoplasm of the CRC tissue. A highly statistically significant relationship was found between grading, lymphovascular invasion, the degree of lymphocytic infiltration, peritumoral budding, lymph node metastasis, lymph node ratio, and ALDH1 expression (p < 0.001). There was a highly statistically significant relationship found between AJCC stage and ALDH1 expression (p < 0.001). There is a highly statistically significant direct correlation between Notch1, CD44 expression, and ALDH1 expression (p < 0.001). CONCLUSIONS: There is a substantial correlation between Notch 1, ALDH1, and CD44 as cancer stem cell markers and lymph node metastasis, advanced stage and tumor recurrence in colorectal carcinoma. CONCLUSION: Expression of stem cell markers ALDH1, Notch1, and CD44 correlates with poor prognosis in a CRC and represents an independent prognostic factor. They are associated with a feature of epithelial-mesenchymal transition evidenced by their association with high tumor burden.