Clinicopathologic Impact of NANOG, ZEB1, and EpCAM Biomarkers on Prognosis of Serous Ovarian Carcinoma.

OBJECTIVES: Serous ovarian carcinoma (SOC) is a biologically heterogeneous with different genomic and molecular profiles, beside clinical response to the chemotherapy with subsequent in obstacles in starting unified, acceptable treatments and so we assess immunoexpression of Nanog, ZEB1, and EpCAM in SOC. METHODS: In this study, the immunoexpression of Nanog, ZEB1, and EpCAM was studied in 60 cases of SOC. Overall survival (OS), disease-free survival (DFS) data and response to chemotherapy were  analyzed. RESULTS: NANOG was immunostained in 65% of the cases with a significant association with tumor grade, lymph node metastasis, and FIGO stage (p < 0.001 for each). ZEB1 showed moderate- high expression in 58.3% of the cases with significant up-regulation of ZEB1 expression with SOC grade, nodal metastasis, and SOC FIGO stage (p<0.001). EpCAM revealed high expression in 60% of the cases with significant association with higher grade, nodal metastasis, and advanced stage (p < 0.001 for each). Up-regulation of Nanog was significantly associated with response to chemotherapy, relapse, shorter OS and DFS (p < 0.001 for each). ZEB1 overexpression exhibited a significant association with response to chemotherapy (p= 0.012), relapse, shorter OS and DFS (p<0.001 for each). Moreover, the high EpCAM had a significant association with response to chemotherapy (p= 0.043), relapse (p < 0.001) shorter OS (p=0.006) and DFS (p< 0.001). CONCLUSIONS: Up-regulation of Nanog and ZEB-1 and EpCAM perhaps promote an aggressive SOC with a high risk of relapse and unfavorable response to standard chemotherapy regimen.

p53, Pirh2, and L1CAM as Promising Prognostic Biomarkers of Endometrial Carcinoma: An Immunohistochemical and Genetic Study.

Endometrial cancer (EC) is the most common gynecologic cancer and the current methods for the prediction of its prognosis and treatment response are unfortunately suboptimal. In this study, we evaluated the prognostic value of p53, Pirh2, and L1CAM in 60 cases of EC using immunohistochemistry (IHC) and polymerase chain reaction. TP53 missense mutations result in nuclear accumulation of p53 protein that can be detected as overexpression by IHC. This is in the form of diffuse strong nuclear positivity involving at least at least >50% of the tumor cells as a whole or if >50% of the tumor cells of a discrete geographical areas. Abnormal p53 IHC expression was expressed in 33.3% of the cases and significantly associated with the tumor grade, myometrial invasion (MI), lymphovascular invasion (LVSI), nodal metastasis, and FIGO stage, and the advanced European Society for Medical Oncology (ESMO) risk groups ( P <0.001 for each). High IHC Pirh2 expression was noted in 58.3% of the cases, and significantly associated with MI, LVSI, nodal metastasis, FIGO stage, and high-risk group ( P <0.001, P =0.011, P =0.010, P =0.024, P =0.005, respectively). There was a significant upregulation of Pirh2 mRNA expression in EC specimens as compared with the control adjacent tissues ( P =0.001). Upregulated Pirh2 mRNA expression had a significant association with Pirh2 immunostaining, tumor grade, tumor stage, MI, lymph node involvement, LVSI, and relapse ( P <0.001 for each). Positive L1CAM immunoexpression was noted in 26.7% and was significantly associated with grade, MI, LVSI, nodal metastasis, FIGO stage, and high-risk group ( P =0.003, P =0.023, P =0.003, P <0.001, P <0.001, P =0.002, respectively). Analysis of follow-up period revealed that EC with abnormal p53 IHC expression, high pirh2 and positive L1CAM expression exhibited a potent relation with tumor relapse, shorter overall survival and disease-specific survival ( P <0.001 for each). Mutant p53, high Pirh2, and L1CAM-positive EC are highly aggressive tumors with a shortened survival rate, dismal outcome, and high risk of relapse after the standard protocol of therapy.

Prognostic value of NOTCH1 and OCT4 in gastric carcinoma.

Background: NOTCH1 pathway activation has been recently described to be a key player in gastric carcinogenesis, enhance the survival and proliferation of cancer stem cells (CSCs) and mediate chemoresistance in several malignancies. Aim: This study investigated the correlation between NOTCH1 and CSC marker OCT4 (octamer binding transcription factor-4) expression and the clinicopathological properties, survival and treatment outcome in patients with gastric carcinoma (GC) receiving adjuvant chemotherapy. Materials and. Methods: NOTCH1 and OCT4 were immunohistochemically detected in 50 post-operated specimens of GC. Patients' data regarding disease-free survival (DFS), overall survival (OS), and the response to the chemotherapy was statistically analyzed. Results: NOTCH1 and OCT4 overexpression was detected in 60% and 52% of GC tissues, respectively, and that was significantly higher than the rates in adjacent non-neoplastic gastric mucosa (P < 0.05). A significant correlation was detected between overexpression of NOTCH1 and OCT4 in GC and aggressive clinicopathological features; poor differentiation (P = 0.021, P = 0.037, respectively), depth of tumor invasion (P < 0.001 for both), TNM stage (P < 0.001 for both), lymph node metastasis (P = 0.002, P = 0.003, respectively) and distant metastasis (P < 0.001 for both). NOTCH1 was positively correlated with OCT4 (P = 0.002). Survival analysis disclosed that upregulation of NOTCH1 and OCT4 was associated with worse DFS (P = 0.013, P < 0.001, respectively) and OS (P < 0.001 for both). Overexpression of NOTCH1 and OCT4 correlated with poor response to chemotherapy (P = 0.013, P = 0.005, respectively) and worse clinical outcome. Conclusion: Combined detection of these proteins might disclose even better predictive value for shorter survival and resistance to chemotherapy.

Prognostic Impact of LGR5, Prox1, and Notch1 Biomarkers in Stage II to III Colon Cancer.

The potentiation and activation of Wnt signaling pathways are now assumed to mediate the self-renewal and proliferation of colon cancer stem cells that are responsible for therapeutic resistance, tumor relapse, and metastasis. We aimed to evaluate LGR5, Prox1, and Notch1 immunohistochemical expression in stage II to III colon cancer. Their predictive role of tumor relapse, overall survival, and disease-free survival was statistically analyzed. Our results revealed that high LGR5 expression was identified in 56.7% of the patients, LGR5 expression was significantly associated with left-sided tumors (P<0.001). Moreover, its expression was significantly associated with the unfavorable tumor characteristics including high grade, deep invasion (pT), lymph node metastasis, and advanced tumor stage (P<0.001 for each). High Prox1 expression was observed in 65% of the cases, and its expression was significantly associated with tumor grade, lymph node metastasis, and the advanced tumor stage (P=0.004, 0.009, 0.016, respectively). Positive Notch1 expression was identified in 35% of patients, and it was inversely associated with high grade lymph node metastasis, deep invasion (pT), and advanced tumor stage (P<0.001 for each). During the follow-up period, the tumor relapse was significantly associated with high LGR5, high Prox1, and negative Notch1 expression. Shorter overall survival and disease-free survival were significantly associated with high LGR5, high Prox1, and negative Notch1 expression. High LGR5, high Prox1, and negative Notch1 expression are unfavorable prognostic factors in colon cancer. Prox1 is a crucial regulator of Notch-independent LGR5+ stem cells that is mostly responsible for relapse and therapeutic resistance in stage II to III colon cancer.

Predictive value of tumor-infiltrating lymphocytes (TILs) and programmed cell death-ligand 1 (PD-L1) expression in breast cancer patients treated with neoadjuvant chemotherapy / Valor predictivo de los linfocitos infiltrantes de tumor, y de la expresión del ligando del factor de muerte celular programada 1 en las pacientes de cáncer de mama tratadas con quimioterapia neoadyuvante

Introduction Immune system plays an important role in behavior of cancer. Breast cancer and its stroma display high levels of immune-cell infiltrates (tumor-infiltrating lymphocytes TILs). Programmed cell death-ligand 1 (PD-L1) is one key inhibitor mechanism for TILs. Potential of TILs and PD-L1 as predictive factors for chemotherapy response in breast cancer is a promising field of study. The aim of this work is to investigate the correlation of PD-L1, TILs and pathologic response following neoadjuvant chemotherapy (NAC) in breast cancer patients and effect of NAC on PD-L1 expression and TILs in residual tumor mass.MethodsThirty patients with invasive duct carcinoma diagnosed by core biopsy and received NAC were enrolled in this prospective study from November 2018 to October 2020. PD-L1 expression was evaluated by immunohistochemistry and relates this to TILs, clinical characteristics, and response to neoadjuvant chemotherapy and then re-evaluated in residual masses after surgery.ResultsPD-L1 expression was observed in 40% of cases in the tumor cells. High stromal TILs were detected in 46.7%. Also, 64.3% and 58.3% of patients expressed TILs and PD-L1 (respectively) in their core biopsies gained complete clinical and pathologic responses with significant difference (p value<0.001; 0.013). High PD-L1 expression and high TILs were observed in triple negative breast cancer (TNBC) and Her2 enriched cases but without significant difference.ConclusionHigh TILs and PD-L1 are associated with complete clinical and pathologic responses in breast cancer patients who receiving NAC.(AU)

Introducción El sistema inmune juega un papel importante en el comportamiento del cáncer. El cáncer de mama y su estroma exhiben altos niveles de infiltrados de las células inmunitarias (linfocitos infiltrantes de tumor [TIL]). El ligando del factor de muerte programada 1 (PD-L1) es un mecanismo inhibidor clave para los TIL. El potencial de TIL y PDL-1 como factores predictivos para la respuesta a la quimioterapia en el cáncer de mama es un campo de estudio prometedor. El objetivo de este estudio es estudiar la correlación de PD-L1, TIL y la respuesta patológica tras la quimioterapia coadyuvante (NAC) en pacientes con cáncer de mama, así como el efecto de NAC en la expresión de PDL-1 y TIL en la masa tumoral residual.MétodosSe incluyó en este estudio prospectivo a 30 pacientes con carcinoma ductal invasivo diagnosticadas mediante biopsia central, que recibieron NAC de noviembre de 2018 a octubre de 2020. La expresión de PD-L1 fue evaluada mediante inmunohistoquímica, y fue relacionada con TIL, características clínicas y respuesta a la quimioterapia neoadyuvante, reevaluándose en masas residuales tras la cirugía.ResultadosLa expresión de PD-L1 se observó en el 40% de los casos en las células tumorales. Se detectaron altos niveles de TIL estromales en el 46,7% de los casos. De igual modo, el 64,3 y el 58,3% de las pacientes con expresión de TIL y PDL-1, respectivamente, en sus biopsias centrales logró respuestas clínicas y patológicas completas con diferencia significativa (p<0,001; 0,013). La alta expresión de PDL1 y los altos niveles de TIL fueron observados en el cáncer de mama triple negativo (TNBC) y en los casos de Her2 enriquecido, aunque sin diferencia significativa.ConclusiónLa alta expresión de TIL y PDL1 se asocia a respuestas clínicas y patológicas completas en las pacientes de cáncer de mama que reciben NAC.(AU)

Fatty acid synthase, Her2/neu, and E2F1 as prognostic markers of progression in non-muscle invasive bladder cancer.

Non-muscle-invasive bladder cancer (NMIBC) is a heterogeneous disease which has an unpredictable risk of progression to muscle-invasive bladder cancer (MIBC). The selection of patients who may benefit from early radical intervention is a challenge. To define the useful prognostic markers for progression, we analyzed the immunohistochemical expression of fatty acid synthase (FASN), Her2/neu, and E2F1 in 60 cases of NMIBC who underwent TURBT and adjuvant intravesical bacillus-Calmette-Guérin (BCG). Their predicting role for tumor recurrence, progression, recurrence-free survival (RFS) and progression-free survival (PFS) was analyzed. High FASN expression was observed in 56.7% (34/60) of NMIBC cases, and FASN expression was significantly associated with the tumor size, grade, and tumor stage (p = 0.003, p < 0.001, p < 0.0001 respectively). Positive Her2/neu was noted in 18.3% (11/60) of the cases, and its expression was significantly associated with the tumor size, histologic grade, and tumor stage (p = 0.001, p = 0.002, p = 0.011 respectively). High E2F1 expression was detected in 40% of the cases, and it was associated with tumor size, histologic grade, and tumor stage (p < 0.001 for each). Analysis of follow-up period revealed that NMIBC with high FASN, positive Her2/neu, and high E2F1 expression exhibited a potent relation with tumor progression, shorter RFS, and poor PFS. Conclusions: High FASN, Her2/neu, and E2F1 are considered as adverse prognostic factors of tumor recurrence and progression in NMIBC and these patients should be followed carefully. Therefore, we suggest that FASN, Her2/neu, and E2F1 should be considered and evaluated during the selection of the appropriate management strategy for NMIBC patients.

The clinicopathological significance of CD133 and Sox2 in astrocytic glioma.

BACKGROUND: The treatment strategies of astrocytoma have not changed considerably due to the restricted appreciation of its biology. OBJECTIVES: This study aimed to evaluate the expression of the stem cell-related proteins (CD133 and Sox2) and their prognostic value in astrocytic glioma. METHODS: The immunohistochemical expression of CD133 and Sox2 in 40 patients with an astrocytic glioma of different grades was studied. The recorded data on the overall survival (OS), progression-free survival (PFS) and the response to the therapeutic protocol were collected and lastly analyzed. RESULTS: CD133 expression was observed in 87.5% of the cases, while positive Sox2 expression was found in all the studied cases. There was a significant association of CD133 expression with the histological grade and the tumor size (p< 0.001). A significant association of Sox2 with the histological grade and the tumor size was noted (p= 0.004, p= 0.006 respectively). Up-regulation of both CD133 and Sox2 had a significant association with poor clinical response to the therapy (p< 0.001 for each). Shorter OS and PFS were related to CD133 and Sox2 overexpression. CONCLUSIONS: Astrocytoma with CD133 and Sox2 overexpression had an unfavorable prognosis and poor clinical response to the current therapeutic protocol.

Prognostic impact of Apaf-1, Cyclin D1, and AQP-5 in serous ovarian carcinoma treated with the first-line chemotherapy.

Chemoresistance is the major obstacle to effective treatment in patients with serous ovarian carcinoma (SOC), which frequently related to the failure of chemotherapeutic agents to induce apoptosis. In this study, the immunohistochemical expression of Apaf-1, Cyclin D1, and Aquaporin-5 (AQP-5) was studied in 50 paraffin blocks of SOC. Data on overall survival (OS), disease-free survival (DFS) and response to the first-line chemotherapy were collected and then statistically analyzed. Apaf-1 expression was observed in 84% of the SOC cases with a significant down-regulation with higher tumor grade, lymph node metastasis, and advanced FIGO stage. Cyclin D1 expression was found in 70% of the cases with a significant up-regulation with higher tumor grade, lymph node metastasis, and advanced FIGO stage. Positive AQP-5 expression was noted in 84% of the cases with a significant positive association with higher tumor grade, lymph node metastasis, and advanced FIGO stage. During the follow-up period, the Apaf-1 expression had a significant negative association with OS and DFS (p < 0.001 for each), while both Cyclin D1 and AQP-5 expression had a significant positive association with unfavorable OS and DFS. The cases of SOC treated with suboptimal surgery revealed a significant association of low Apaf-1, high Cyclin D1, and strong AQPs with the poor response to the first-line chemotherapy (p = 0.047, p < 0.001, and 0.006 respectively). CONCLUSIONS: Down-regulation of Apaf-1 protein and the overexpression of Cyclin D1 and AQP-5 proteins possibly contribute to an aggressive SOC with a high risk of recurrence and poor response to the first-line chemotherapy.