RoActemra 20 mg/ml, concentrado para solución para perfusión tocilizumab
1. Qué es RoActemra y para qué se utiliza
It has been suggested that PROK2 mediate BMDC-dependent angiogenesis in tumors (Shojaei et al. 2007b). It is not known whether PROK2 and its other family members contribute to the angiogenesis and the immune response in human tumors. The clinical correlates of the prokineticin protein family members were studied in MCC. MCC is
a rare human skin cancer that may have viral origin (Feng et al. 2008), and the immune system has likely significant influence on its onset and progression (Sihto et al. 2012). The study population consisted of 98 MCC patients diagnosed in Finland between 1979 and 2004.
Immunohistochemical analysis of tumor tissue microarrays revealed that expression of PROK2 and PROKR2 was more frequently present in cancer cells of the primary tumors than PROK1 or PROKR1 expression. PROK2 expression was found in 45.5% of the MCCs (41/90) and PROKR2 in 51.1% (47/92) of the tumors, while PROK1 was expressed in 22.9% (21/92) and PROKR1 in 9.1% (8/88) of the cancers. Most tumors showed weak or moderate expression levels of these proteins in tumor cells (+), and high expression (++) was uncommon.
PROKR2 expression in tumor cells was associated with the presence of MCPyV DNA in tumor. From 60 MCPyV DNA-positive MCCs, 36 (60%) expressed PROKR2 compared to 5 (25%) of the 20 cancers that were MCPyV DNA-negative (p = 0.007). Also the MCPyV large T antigen was frequently expressed in PROKR2-positive cancers (36 out of the 46 PROKR2-positive tumors compared to 22 out of the 44 PROKR2-negative cancers, p = 0.005). MCPyV-positive MCCs frequently express the retinoblastoma protein (Sihto et al. 2011). PROKR2-positive cancers expressed the retinoblastoma protein more frequently than PROKR2-negative cancers (36 of the 61 MCCs that expressed Rb expressed also PROKR2 compared to only 10 out of the 29 Rb-negative MCCs, p = 0.03). Tumor cell expression of PROK1, PROK2 or PROKR1 was not associated with the presence of MCPyV DNA or viral large T antigen expression in tumor.
Expression of the prokineticin ligands and receptors in tumor cells was associated with certain subsets of tumor infiltrating leukocytes. Different tumor infiltrating subsets were analyzed from whole tumor sections by counting the numbers of intratumoral leukocytes from three high power fields of the microscope (Sihto et al. 2012). Tumor cell PROK1 expression tended to be associated with a higher than the median number (5.3 cells/high power field) of CD68+ macrophages (p = 0.054), PROK2 expression with a higher than the median number (3.3/high power field) of CD8+ CTLs (p = 0.030), and tended to be associated with a higher than the median (3.7/high power field) number of CD163+ macrophages (p = 0.062). PROKR2 expression was associated with a higher than the median (4.7/high power field) number of CD3+ T lymphocytes (p = 0.055) and small CD16+ cells (representing mostly NK cells) (p = 0.001). Prokineticin ligands or the receptors did not associate with tumor infiltrating helper T cell (CD4+) or regulatory T cell (FoxP3+) counts (p >0.10 for each comparison).
Tumor PROK1 and PROK2 mRNA content was measured with qPCR from whole tumor sections. Most MCCs (76 out of 98) did not contain detectable PROK1 mRNA and were classified as PROK1 mRNA- negative or –positive, whereas all tumors contained detectable PROK2 mRNA, the target gene (PROK2) to the reference gene (TBP) ratio ranging from 0.02 to 4.02 (median, 0.571). A higher than the median tumor PROK2 mRNA content was significantly associated with a lower than the median tumor cell proliferation rate (as assessed with the Ki-67 staining), presence of MCPyV DNA, expression of the viral large T antigen protein and retinoblastoma protein. The presence of PROK1 mRNA in tumor was associated with absence of MCPyV DNA, and absence of large T antigen and retinoblastoma protein expression (all p-
values < 0.05). Furthermore, higher than median PROK2 content tended to associate with the absence of p53 expression (p = 0.087), whereas presence of PROK1 expression tended to associate with p53 expression (p = 0.056). The PROK2 mRNA content was associated with a higher than the median number of intratumoral CD68+ cells (p = 0.031) and CD163+ macrophages (p = 0.015). Similar associations were not found between PROK1 mRNA and the tumor infiltrating leukocyte subsets.
Intratumoral vascular density was analyzed, and it ranged from 0 up to 27.5 vessels/high power field (median 6.5). Tumor PROK1 or PROK2 mRNA contents were not associated with tumor microvascular density in the MCCs regardless of whether the microvascular density and PROK1 and PROK2 mRNA contents were studied as continuous variables or as categorized variables using the medians as the cut-offs (p >0.10 for all comparisons). In immunohistochemical examination, PROKR1 or PROKR2 expression was not detected in the MCC vascular endothelium.
Patients with a higher than median PROK2 mRNA content in MCC had more favorable overall survival compared to patients whose tumor contained less PROK2 mRNA (hazard ratio [HR] 0.53, 95% CI 0.34- 0.84; p = 0.005) as well as more favorable MCC-specific survival (HR 0.42, 95% CI 0.19-0.97; p = 0.042). Presence of PROK1 mRNA in the tumor, in turn, tended to be associated with unfavorable overall survival (HR 1.61, 95% CI 0.99-2.79; p = 0.052). Prokineticin protein expression in tumor cells did not associate with survival (p >0.10 in each analysis).
The independence of PROK1 and PROK2 mRNA contents as prognostic factors was tested with a Cox multivariable model. Factors that were significantly associated with survival in a univariate survival analysis were tested in the model together with PROK1 (present vs. absent) and PROK2 (< median vs. > median) mRNA content. Other factors were age (as continuous variable), tumor stage (1, 2 vs. 3, four patients with distant metastases were excluded), presence of MCPyV DNA in tumor (present vs. absent), and tumor CD3-positive T cell count (< median vs. > median). Analysis showed that neither PROK1 (HR 0.77, 95% Cl 0.38-1.59, P = 0.48) or PROK2 (HR 0.59, 95% Cl 0.31-1.11, P = 0.104) are independent prognostic factors whereas tumor stage (HR 3.46, 95% Cl 1.58-7.58, P = 0.002), age (HR 1.05, 95% 1.02- 1.09, P < 0.001), presence of MCPyV in tumor (HR 0.54, 95% Cl 0.30- 0.95, P= 0.033), and CD3 cell count (HR 0.53, 95% Cl 0.30-0.92, P = 0.012) independently influence the overall survival.