STIM1/SOX2 proteins are co-expressed in the tumor and microenvironmental stromal cells of pancreatic ductal adenocarcinoma and ampullary carcinoma.

Pancreatic ductal adenocarcinoma (PDAC) and ampullary carcinoma (AAC) are lethal malignancies with modest benefits from surgery. SOX2 and STIM1 have been linked to anticancer activity in several human malignancies. This study included 94 tumor cases: 48 primary PDAC, 25 metastatic PDAC, and 21 primary AAC with corresponding non-tumor tissue. All cases were immunohistochemically stained for STIM1 and SOX2 and results were correlated with clinicopathologic data, patient survival, and BCL2 immunostaining results. Results revealed that STIM1 and SOX2 epithelial/stromal expressions were significantly higher in PDAC and AAC in comparison to the control groups. STIM1 and SOX2 expressions were positively correlated in the primary and metastatic PDAC (P = 0.016 and, P = 0.001, respectively). However, their expressions were not significantly associated with BCL2 expression. SOX2 epithelial/stromal expressions were positively correlated with the large tumor size in the primary AAC group (P = 0.052, P = 0.044, respectively). STIM1 stromal and SOX2 epithelial over-expressions had a bad prognostic impact on the overall survival of AAC (P = 0.002 and P = 0.001, respectively). Therefore, STIM1 and SOX2 co-expression in tumor cells and intra-tumoral stroma could contribute to the development of PDAC and AAC. STIM1/SOX2 expression is linked to a bad prognosis in AAC.

Evaluation of ARK5 and SIRT3 expression in renal cell carcinoma and their clinical significance.

BACKGROUND: Globally Renal Cell Carcinoma (RCC) represents 3% of malignant tumours in adults and 1.78% in Egypt. AMPK-related protein kinase 5 (ARK5) is mainly associated with a hypoxic microenvironment which is a feature of the major RCC subtypes. Additionally, it displays decreased mitochondrial respiration. SIRT3 is a mitochondrial deacetylase that modifies multiple mitochondrial proteins. MATERIAL AND METHODS: Fifty eight cases of RCC, and 30 non-neoplastic cases (of End-Stage Kidney Disease (ESKD) were subjected to immunohistochemistry by ARK5 and SIRT3. The results of IHC were correlated together and correlated with the available clinicopathologic and survival data. RESULTS: Although no significant difference was detected between RCC and ESKD groups regarding ARK5 expression, there was a significant association with RCC regarding H-score and nucleocytoplasmic expression (both P = 0.001). Also, SIRT3 was highly expressed in RCC in comparison to the ESKD group (H-score: P = 0.001). There were significant associations between nucleocytoplasmic ARK5 expression and higher tumour grade, low apoptotic and high mitotic indices, tumour extent, advanced tumour stage, and impaired response of tumours to chemotherapeutic drugs (P = 0.039, P = 0.001, P = 0.027, P = 0.011, P = 0.009, and P = 0.014 respectively). Moreover, the H score of ARK5 expression showed significant associations with tumour grade, apoptotic and mitotic indices, tumour extension, tumour stage, and response to therapy (P = 0.01, 0.035, 0.001, 0.004. 0.003 and 0.013). Regarding SIRT3 expression, it showed significant associations with apoptotic and mitotic indices, tumour extent, tumour stage and response to therapy (P = 0.022, 0.02, 0.042, 0.039 and 0.027). Interestingly, there was a highly significant correlation between the expression of ARK5 and SIRT3 (P = 0.009). Univariate survival analysis revealed a significant association between short survival duration and both nucleocytoplasmic expression of ARK5 and positive SIRT3 expression (P = 0.014 and 0.035). CONCLUSION: ARK5 and SIRT3 are overexpressed in RCC and associated with parameters of poor prognosis as well as short survival. Both seem to influence response to therapy in RCC. So, they could be new targets for therapy that may improve tumour response and patients' survival. There is a postulated relationship that needs more extensive investigation.

Clinical significance of immunohistochemical expression of DDR1 and ß-catenin in colorectal carcinoma.

BACKGROUND: Despite recent advances in therapy modalities of colorectal cancer (CRC), it is still the third cause of cancer-related deaths worldwide. Thus, the search for new target therapies became mandatory. DDR1 is a collagen receptor that has a suggested role in cellular proliferation, tumor invasion, and metastasis. MATERIAL AND METHODS: Forty-eight cases of CRC, 20 of CR adenoma, and 8 cases of non-tumoral colonic tissue were subjected to immunohistochemistry by DDR1 and ß-catenin antibodies. Results were compared among the different studied groups and correlated with clinicopathologic data and available survival data. Also, the expression of both proteins was compared versus each other. Results were compared among the 3 studied groups and correlated with clinicopathologic and survival data. RESULTS: It revealed a stepwise increase of DDR1 expression among studied groups toward carcinoma (P = 0.006). DDR1 expression showed a direct association with stage D in the modified Dukes' staging system (P = 0.013), higher-grade histologic types (P = 0.008), and lymph node invasion (P = 0.028) but inverse correlation with the presence of intratumoral inflammatory response (TIR) (P = 0.001). The shortest OS was associated with strong intensity of DDR1 (P = 0.012). The DDR1 and ß-catenin expressions were significantly correlated (P = 0.028), and the combined expression of both was correlated with TNM staging (P = 0.017). CONCLUSION: DDR1 overexpression is a frequent feature in CRC and CR adenoma. DDR1 is a poor prognostic factor and a suppressor of the TIR. DDR1 and ß-catenin seem to have a synergistic action.

Role of SIX1, EYA2, and E-cadherin in ovarian carcinoma. Evidence on epithelial-mesenchymal transition from an immunohistochemical study.

This study aims to investigate the expression of SIX1, EYA2, and E-cadherin in ovarian cancer (OC). It was conducted on 97 cases of surface epithelial tumors (SEOTs). Immunohistochemistry (IHC) staining for the three markers was applied to archival paraffin-embedded sections. Results of semi-quantitative scoring were statistically compared, correlated with clinic-pathologic parameters, response to therapy and with patient survival. RESULTS: There was a significant association of SIX1 expression in the intratumoral stroma (ITS) with malignant cases (P < 0.0001). There was a significant direct correlation between tumour cell expression of SIX1 and EYA2 (P = 0.03) and an inverse correlation between SIX1 and E-cadherin (P = 0.03). Additionally, there were direct correlations between SIX1 expression and larger tumour size (P = 0.05), high mitosis (P < 0.0001), and advanced FIGO stage (P = 0.06), and between EYA2 expression and LN metastasis (P = 0.02), and low apoptotic index (P = 0.007). Only SIX1 expression in ITS affected the patient survival by univariate analysis (P = 0.004). CONCLUSIONS: SIX1/EYA2 complex may have a poor prognostic role in OC. SIX1 expression in ITS may be used as a predictive marker of stromal invasion in ovarian borderline tumors and could affect patients' survival in OC. SIX1, EYA2, and E-cadherin may constitute a pathway that could be targeted to stop the progression of SEOTs.

Comparative study of immunohistochemical expression of ERG and MAGI2 in prostatic carcinoma.

Diagnosis of Prostatic adenocarcinoma (PAC) is still a problematic issue. The objective of this study was to evaluate the diagnostic and prognostic value of ERG immunohistochemical (IHC) expression compared to MAGI2. MATERIALS AND METHODS: This study was conducted on 56 cases of PAC and 29 cases of nodular prostatic hyperplasia (NPH). IHC staining for ERG and MAGI2 was applied to archival formalin-fixed paraffin-embedded blocks. Semi-quantitative scoring was compared and correlated with clinicopathologic parameters and the Ki-67 index. RESULTS: Revealed positive ERG in 51.8% of PAC while all NPH cases were negative. On the other hand, MAGI2 was detected in 91.1% of PAC versus 17.2% of NPH. Using ROC curve, the ERG showed 53.6% sensitivity, 100% specificity, 76.5% diagnostic accuracy (DA) and area under the ROC curve 0.768 in comparison to MAGI2 that showed (91.1%, 86.2%, 88.25% and 0.948 respectively). Analysis of the combined use of the two markers revealed 95% sensitivity, 100% specificity, and 94% DA when tested synchronously. Moreover, a statistically significant inverse relationship could be detected between ERG expression and the Gleason grading group (P = 0.01) and Ki-67 index (P < 0.001). In addition, high-grade prostatic intraepithelial neoplasia (HGPIN) adjacent to carcinoma; showed positive expressions in (1/11 cases, 9.11%) for ERG and (6/11 cases, 54%) for MAGI2. CONCLUSION: This study recommends using both ERG and MAGI2 in a cocktail for better diagnostic validity of PAC. Only ERG expression could be a good prognostic indicator.

Toxoplasma gondii as a possible causative pathogen of type-1 diabetes mellitus: Evidence from case-control and experimental studies.

Toxoplasma gondii is the causative parasite of an important worldwide disease. This obligate intracellular parasite can infect and replicate inside any nucleated cells including those of pancreas. Insulin is a hormone secreted by the pancreas and is responsible for controlling blood glucose concentration. Deficiency of insulin production accounts for the occurrence of type-1 diabetes mellitus (T1D). Thus, theoretically, toxoplasmosis could play a possible role in the development of T1D. However, the studies on this theory are still insufficient; therefore, this work was designed. Interestingly, in the case-control study, seropositivity of anti-Toxoplasma IgG was significantly higher among T1D (86.37%) in comparison with T2D (66.67%) and the control group (60%). Moreover, the odd ratio of chronic toxoplasmosis was 4.2 folds higher among T1D patients than among controls. The experimental study included acute and chronic Me49 T. gondii infected mice groups in addition to a control group. Pathological examination revealed the presence of T. gondii zoites adjacent to the islets of Langerhans and in pancreatic parenchyma of acutely infected mice. With chronic infection, there was a significant reduction of islets number and sizes in association with grade-1 insulitis. Additionally, the immunohistochemical study showed significant infiltration of the islets of chronically infected mice by CD8+ and CD45+ immune cells. In contrary to the control group, the islets of the chronic group showed significantly higher expression of the apoptotic marker caspase-3 and a significantly lower expression of the proliferation marker Ki69. Finally, a significant reduction of insulin expression in the islets of chronic infection group was detected in association with a significant increase in serum glucose concentrations; however, the establishment of diabetes did not occur throughout this work. Thus, this study presents an evidence for the probable role of chronic toxoplasmosis in the development of T1D which should be considered in further studies.

Diagnosis and prognosis of B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma (B-CLL/SLL) and mantle cell lymphoma (MCL).

BACKGROUND: B-cell chronic lymphocytic leukemia/ small lymphocytic lymphoma (B-CLL/SLL) and mantle cell lymphoma (MCL) show many overlapping morphologic and immunophenotyping features, however they have great difference in therapeutic regimens and prognosis. THE AIM OF THE STUDY: Is to determine the diagnostic and prognostic role of clinico-pathologic variables, CD23 and Cyclin D1 oncoprotiens in B-SLL/CLL and MCL. PATIENTS AND METHODS: This study included 25 BCLL/ SLL cases and 25 MCL cases. All cases were carefully examined and stained using CD23 and Cyclin D1 immunostaining. RESULTS: There was significant difference between BCLL/ SLL and MCL regarding several items including pattern of growth, where interfollicular pattern was restricted to B-SLL/CLL while nodular and mantle zone pattern were confined to MCL; pseudo-follicles were only present in B-CLL/SLL. Transformed cells, plasmacytoid cells, peripheral blood lymphocytosis, significant longer survival and good prognosis were statistically more prominent in favor of B-CLL/SLL. On the other hand, cell cleavage, epithelioid histiocytes, plasma cells, naked nuclei, hyalinized venules, deposited hyaline material in background and reticular fibers in addition to higher mitotic index per 20 HPF were more significantly identified in favor of MCL. CD23 was expressed as membranous pattern in 16/25 (64%) of B-CLL/SLL cases and 1/25 (4%) of MCL cases. On the other hand, Cyclin D1 was expressed as nuclear staining in 18/25 (72%) of MCL cases and only 1/25 (4%) of B-CLL/SLL cases. Regarding B-CLL/SLL, age >60 years and mitosis >or=10/20 HPF were independent prognostic factors of shorter survival by multivariate analysis. In MCL, Cyclin D1 overexpression and splenomegaly were independent prognostic factors of survival by multivariate analysis. CONCLUSION: Cyclin D1 is not only implicated in tumor genesis of MCL, but also in progression and extension of the disease when expressed in high levels (50% cut off value) and it seems to have prognostic impact in MCL. This can be used as a basis for future therapeutic strategies targeting cell cycle regulators. This study could support the concept that Cyclin D1 and CD23 immunostaining may be reliable diagnostic tools for discrimination between B-CLL/SLL and MCL.