Association between PD-L1 Expression and the Prognosis and Clinicopathologic Features of Non-Clear Cell Renal Cell Carcinoma.

PD-L1 is one of the two programmed cell death 1 (PD-1) ligands and a part of an immune checkpoint system (PD-1/PD-L1) with widespread clinical application. The aim of this study was to investigate PD-L1 expression and its association with clinicopathological and prognostic significance in non-clear cell renal cell carcinoma (non-ccRCC) patients. A total of 41 papillary (pRCC) and 20 chromophobe (chRCC) RCC tumors were examined for PD-L1 expression by immunohistochemistry in the cancer cells and tumor-infiltrating mononuclear cells (TIMCs). PD-L1 positivity was detected in 36.6% pRCC and 85.0% chRCC cancer cells, while PD-L1 positivity was observed in 73.2% pRCC and 50.0% chRCC TIMCs. PD-L1 positivity in both pRCC and chRCC tumor cells was not correlated with any of the examined clinicopathological features, while PD-L1 positivity in TIMCs was associated with the age of patients with pRCC. During follow-up, the death was documented among 6 patients with pRCC. Papillary RCC patients with PD-L1-positive tumor cells were significantly associated with an increased risk of death compared with patients with PD-L1-negative cancer cells. A similar trend was observed when comparing PD-L1 expression in TIMCs. However, no differences in overall survival for PD-L1-positive pRCC patients with compared to PD-L1-negative patients were observed in tumor cells or TIMCs.

Does the Immunohistochemical Expression of CD44, MMP-2, and MMP-9 in Association with the Histopathological Subtype of Renal Cell Carcinoma Affect the Survival of Patients with Renal Cancer?

CD44, MMP-2, and MMP-9 are new potential molecular prognostic markers in renal cell carcinoma (RCC). The aim of the study was to analyze whether the expression of CD44, MMP-2, and MMP-9 in association with the histopathological subtype of RCC affects the survival of patients with renal cancer. The study population included 243 clear cell RCC (ccRCC) and 59 non-ccRCC cases. A total of 302 tumors were examined for CD44, MMP2, and MMP9 expression by immunohistochemistry. The expression levels of the proteins were scored by semi-quantitative methods, and the correlation with overall patient survival was verified. We found no significant differences in CD44 expression levels between cc-RCC and non-ccRCC cases; however, significant differences existed in the degree of MMP-2 and MMP-9 expression between cc-RCC and non-ccRCC cases. There was significantly higher MMP expression in non-ccRCC than in ccRCC cases. Univariate Cox regression analysis showed that increased CD44 expression and histopathological subtype of ccRCC were predictors of shorter overall survival. Moreover, MMP-2 overexpression slightly reduced the risk of patient death, while MMP-9 expression did not show an association with patients' survival. However, on multivariate analysis, only the histopathological subtypes of ccRCC and CD44 expression were independent risk factors for patient death.

Immunohistochemical Expression of CD44, MMP-2, MMP-9, and Ki-67 as the Prognostic Markers in Non-Clear Cell Renal Cell Carcinomas-A Prospective Cohort Study.

CD44 is the most frequently reported marker of the cancer stem cells in renal cell carcinoma (RCC). Matrix metalloproteinases MMP-2 and MMP-9 are key regulators of tumor invasion and metastasis. The aim of this study was to investigate the clinicopathologic and prognostic values of the immunohistochemical expression of CD44, MMP2, MMP9, and Ki-67 in papillary and chromophobe RCCs. In the case of papillary RCC, MMP-2 expression was positively correlated with patient age (p < 0.05), while CD44 expression was positively correlated with tumor stage (τ = 0.26, p < 0.05). Moreover, CD44 expression positively correlated with MMP-9 (τ = 0.39, p < 0.05). In the case of chromophobe RCC, only Ki-67 expression was negatively correlated with tumor stage (τ = −0.44, p < 0.05). During follow-up, a death was documented in 6 patients with papillary RCC. In these patients, CD44 expression was not a significant factor affecting the overall survival of patients (p > 0.05), whereas there was a positive correlation between increased MMP-9 expression and shorter overall survival (p < 0.05). Taken together, carcinogenesis in papillary RCC is probably dependent on both cancer stem cells and metalloproteinases activity. Expression of CD44 and MMP-9 can significantly improve the prediction of papillary RCC prognosis in the future.

Assessment of the RANTES Level Correlation and Selected Inflammatory and Pro-Angiogenic Molecules Evaluation of Their Influence on CRC Clinical Features: A Preliminary Observational Study.

Background and Objectives: Assessment of RANTES level and concentrations of inflammatory cytokines: programmed death ligand 1 (PD-L1), interferon gamma IFN-γ, tumor necrosis factor alpha (TNF-α), transforming growht factor ß (TGF-ß) (and angiogenesis factors: vascular endothelial growth factor A (VEGF-A) and vascular endothelial growth factor C (VEGF C) in tumor and margin tissues of colorectal cancer (CRC,) and evaluation of RANTES influence on histopathological parameters (microvessel density (MVD), budding, tumor-infiltrating lymphocytes (TILs)), in relation to patients' clinical features. Materials and Methods: The study used 49 samples of tumor and margin tissues derived from CRC patients. To determinate the concentration of RANTES, PD-L1, IFN-γ, TNF-α, TGF-ß, VEGF-A, and VEGF-C, we used the commercially available enzyme-linked immunosorbent assay kit. Additionally, RANTES and PD-L1 expression was assessed with the use of IHC staining in both tumor cells and TILS in randomly selected cases. MVD was assessed on CD34-stained specimens. The MVD and budding were assessed using a light microscope. Results: We found significantly higher levels of RANTES, PD-L1, IFN-γ, TNF-α, TGF-ß, VEGF-A, and VEGF-C in the tumor in comparison with the margin. The RANTES tumor levels correlated significantly with those of PD-L1, TNF-α, TGF-ß, VEGF-A, and VEGF-C. The RANTES margin levels were significantly associated with the margin levels of all proteins investigated-PD-L1, IFN-γ, TNF-α, TGF-ß, VEGF-A, and VEGF-C. Additionally, we observed RANTES- and PD-L1-positive immunostaining in TILs. In a group of 24 specimens, 6 different CRC tumors were positive for RANTES and PD-L1 immunostaining. The IFN-gamma concentration in both tumor and margin and TGF-ß in tumor correlated with TILs. TILs were negatively associated with the patients' disease stage and N parameter. Conclusions: RANTES activity might be associated with angiogenesis, lymphogenesis, and immune escape in CRC. RANTES is an important chemokine that is a part of the chemokine-cytokine network involved in the modulation of TME composition in CRC. Further research may verify which processes are responsible for the associations observed in the study.

Periostin in Angiogenesis and Inflammation in CRC-A Preliminary Observational Study.

Background and Objectives: To assess the periostin level and the concentrations of pro-inflammatory cytokines: TNFα, IFN-γ, IL-1ß and IL-17 in tumor and marginal tissues of CRC and to investigate the influence of periostin on angiogenesis by MVD (microvessel density) and concentration of VEGF-A in relation to clinicopathological parameters of patients. Materials and Methods: The study used 47 samples of tumor and margin tissues derived from CRC patients. To determinate the concentration of periostin, VEGF-A, TNFα, IFNγ, IL-1ß and IL-17, we used the commercially available enzyme- linked immunosorbent assay kit. MVD was assessed on CD34-stained specimens. The MVD and budding were assessed using a light microscope Results: We found significantly higher concentrations of periostin, VEGF-A, IFN-γ, IL-1 ß, IL-17 and TNFα in the tumor samples compared with surgical tissue margins. The tumor concentrations of periostin were correlated with tumor levels of VEGF-A, IFN-γ, IL-1ß and TNFα. We observed significant correlation between margin periostin and VEGF-A, IFN-γ, IL-17 and TNFα in tumor and margin specimens. Additionally, we found a significantly negative correlation between periostin tumor concentration and microvessel density at the invasive front. Tumor periostin levels were also correlated positively with tumor budding. Conclusions: Periostin activity may be associated with pro-inflammatory cytokine levels: TNFα, IFN-γ, IL-1ß and IL-17. Our results also suggest the role of periostin in angiogenesis in CRC and its upregulation in poorly vascularized tumors. Further research on the regulations between periostin and cytokines are necessary to understand the interactions between tumor and immune tumor microenvironment, which could be helpful in the development of new targeted therapy.

The Concentration of CMKLR1 Expression on Clinicopathological Parameters of Colorectal Cancer: A Preliminary Study.

Background and Objectives: Colorectal cancer (CRC) is the second-most common cause of cancer-related deaths worldwide. Angiogenesis is crucial for cancer growth, infiltration of surrounding tissues, and metastasis and plays a key role in the pathogenesis of CRC. Chemerin/chemokine-like receptor 1 (CMKLR1) is one of the biochemical pathways involved in the regulation of angiogenesis in solid tumors. The aim of the study was to assess the CMKLR1 level in tumor and margin tissues of CRC in relation to histopathological parameters: microvessel density (MVD), budding, tumor-infiltrating lymphocytes (TILs), TNM scale, and grading. Materials and Methods: The study involved 43 samples of tumor and margin tissues obtained from CRC patients. To assess the concentration of CMKLR1 a commercially available enzyme-linked immunosorbent assay kit was used. For 35 cases, we performed CD34 immunostaining. The MVD, budding, and TILs were assessed using a light microscope. Results: The levels of CMKLR1 in both tumor and margin were negatively correlated with MVD and budding. CMKLR1 concentration in margin was higher in tissues with lymphocytic infiltration. Conclusions: Low vascularity and low budding are associated with higher CMKLR1 expression. CMKLR1 might play a multifunctional role in CRC pathogenesis by influencing tumor budding and peritumoral lymphocytic infiltration.

Immunoexpression of RANK, RANKL and OPG in sporadic odontogenic keratocysts and their potential association with recurrence.

BACKGROUND: Odontogenic keratocysts (OKCs) are clinically aggressive lesions with relatively high recurrence rates. Dysregulation of functional equilibrium in the RANK/RANKL/OPG system is responsible for osteolysis associated with the development of OKCs. Previously published findings imply that immunoexpression of these 3 proteins may correlate with bone resorption activity in OKCs. OBJECTIVES: The rationale behind this study was to assess the potential for receptor activator of nuclear factor kappa-B (RANK), receptor activator of nuclear factor kappa-B ligand (RANKL) and osteoprotegerin (OPG) expression, as well as RANKL/OPG expression ratio, to serve as prognostic indicators for OKC recurrence. MATERIAL AND METHODS: We investigated the immunoexpression patterns of RANK, RANKL and OPG, and their correlation with recurrence rates, in 41 patients with OKCs treated with enucleation. RESULTS: We found no statistically significant differences between recurrent and non-recurrent cysts in terms of either: epithelial (p = 0.404) and stromal (p = 0.469) immunoreactivity of RANK; epithelial (p = 0.649) and stromal (p = 0.198) immunoreactivity of RANKL; or epithelial (p = 1) and stromal (p = 0.604) immunoreactivity of OPG. We also did not find significant differences in the distribution of cases with respect to ratios of RANKL/OPG immunostaining scores between recurrent and non-recurrent OKCs, both in the epithelium and in the connective tissue (p = 1 and p = 0.237, respectively). CONCLUSIONS: Our results suggest that immunoexpression levels of RANK, RANKL and OPG at the time of pathological diagnosis, as well as the RANKL/OPG ratio, are not useful as prognostic markers for OKC recurrence.

Investigation of clinicopathological parameters and expression of COX-2, bcl-2, PCNA, and p53 in primary and recurrent sporadic odontogenic keratocysts.

OBJECTIVES: Odontogenic keratocyst (OKC) presents considerable variation in aggressiveness and propensity for recurrence, yet hitherto, no explicit clinicopathological features have been determined to clearly demonstrate the potential for relapse. This retrospective study aims to investigate the prognostic relevance of various clinicopathological features as well as immunoexpression of COX-2, bcl-2, PCNA, and p53 in sporadic OKC. MATERIALS AND METHODS: Among 41 patients with OKC treated by enucleation, the frequency of recurrence for various clinicopathological features as well as immunoexpression for COX-2, bcl-2, PCNA, and p53 was evaluated. RESULTS: The mean follow-up was 8.49 years, and recurrences were ascertained in 29.27% of cases. We found significant differences between recurrent and non-recurrent cysts in terms of multilocularity (P = 0.029), cortical perforation (P = 0.001), and lesion size (P < 0.001). Hazard risk for the recurrence was 3.362 (95% CI 1.066-10.598) for multilocular cysts, 7.801 (95% CI 2.1-28.985) for evidence of cortical perforation, and 1.004 (1.002-1.006) for 1 mm2 of lesion size on panoramic radiographs. We also found that immunoexpression of PCNA significantly correlates with the radiographic evidence of cortical perforation (P = 0.048) and that there is significant positive correlation between expression of COX-2 and bcl-2 (P = 0.001) as well as significant negative correlation between immunoexpression of COX-2 and age (P = 0.002). None of the other analyzed factors were associated with the recurrence. CONCLUSIONS: Larger size, multilocularity, and cortical perforation in sporadic OKC may be correlated with the relapse. CLINICAL RELEVANCE: Immunohistochemical analyses of COX-2, bcl-2, PCNA, and p53 lack prognostic utility in sporadic OKC.