RESUMEN
The presence of circulating Hsp70 levels and their influence on the immunophenotype of circulating lymphocyte subsets were examined as diagnostic/prognostic biomarkers for the overall survival (OS) in patients with IDH-mutant WHO grade 3 oligodendroglioma, astrocytoma, and IDH-wildtype grade 4 glioblastoma (GBM). Vesicular and free Hsp70 in the plasma/serum was measured using the Hsp70-exo and R&D Systems DuoSet® Hsp70 ELISAs. The immunophenotype and membrane Hsp70 status was determined by multiparameter flow cytometry on peripheral blood lymphocytes and single-cell suspensions of tumor specimens and cultured cells. Compared to healthy controls, circulating vesicular Hsp70 levels were significantly increased in patients with GBM, concomitant with a significant decrease in the proportion of CD3+/CD4+ helper T cells, whereas the frequency of NK cells was most prominently increased in patients with grade 3 gliomas. Elevated circulating Hsp70 levels and a higher prevalence of activated CD3-/CD56+/CD94+/CD69+ NK cells were associated with an improved OS in grade 3 gliomas, whereas high Hsp70 levels and low CD3+/CD4+ frequencies were associated with an adverse OS in GBM. It is assumed that a reduced membrane Hsp70 density on grade 4 versus grade 3 primary glioma cells and reduced CD3+/CD4+ T cell counts in GBM might drive an immunosuppressive tumor microenvironment.
RESUMEN
Despite rapid progress in the treatment of many cancers, glioblastoma remains a devastating disease with dismal prognosis. The aim of this study was to identify chaperone- and immune-related biomarkers to improve prediction of outcome in glioblastoma. Depending on its intra- or extracellular localization the major stress-inducible heat shock protein 70 (Hsp70) fulfills different tasks. In the cytosol Hsp70 interferes with pro-apoptotic signaling pathways and thereby protects tumor cells from programmed cell death. Extracellular Hsp70 together with pro-inflammatory cytokines are reported to stimulate the expression of activatory NK cell receptors, recognizing highly aggressive human tumor cells that present Hsp70 on their cell surface. Therefore, intra-, extracellular and membrane-bound Hsp70 levels were assessed in gliomas together with activatory NK cell receptors. All gliomas were found to be membrane Hsp70-positive and high grade gliomas more frequently show an overexpression of Hsp70 in the nucleus and cytosol. Significantly elevated extracellular Hsp70 levels are detected in glioblastomas with large necrotic areas. Overall survival (OS) is more favorable in patients with low Hsp70 serum levels indicating that a high Hsp70 expression is associated with an unfavorable prognosis. The data provide a first hint that elevated frequencies of activated NK cells at diagnosis might be associated with a better clinical outcome.
RESUMEN
Earlier osteodensitometric results of femoral periprosthetic bone showed that postoperative antiresorptive treatment with alendronate following total hip arthroplasty (THA) reduces the periprosthetic bone loss that commonly occurs in the first months after surgery. However, whether alendronate can prevent periprosthetic bone loss over the long term, or if bone loss occurs after discontinuing alendronate is unknown. Femoral periprosthetic bone mineral density (BMD) was assessed in 49 patients 6 years after cementless total hip arthroplasty using dual energy X-ray absorptiometry. Twenty-nine patients were treated postoperatively with alendronate and 20 control patients received no treatment. All patients were followed up at 12 months after surgery in a prospective randomized study. The bone mineral density was evaluated in 7 regions of interest according to the Gruen protocol. Six years after total hip arthroplasty, no significant changes were detected in femoral periprosthetic BMD when compared with results at 1 year, and the bone loss in patients with postoperative alendronate treatment was still significantly less than those without treatment. These results suggest that the prevention of femoral periprosthetic bone loss following THA achieved by postoperative antiresorptive treatment with alendronate is of long-standing effect, and further bone loss does not occur after the first postoperative year.