While cancer research has been focused on tumor cells for many years, evidence is growing that the tumor stroma and in particular cancer-associated fibroblasts (CAFs) in particular play essential roles in the progression of human malignant disease. In human lung cancer, CAFs expressing the transmembrane protein podoplanin were shown to have significant influence on the patients' prognosis. In this study, we investigated the presence and prognostic role of podoplanin-expressing CAFs in a large series of patients with invasive breast cancer. Podoplanin expression was evaluated immunohistochemically in 367 breast cancers. Tumors with ≥10% distinct podoplanin staining were considered as positive (CAF+). Cytoplasmic podoplanin expression of tumor cells was considered as positive when ≥5% of tumor cells showed a distinct podoplanin expression. In normal breast tissue, no podoplanin-expressing fibrocytes were found. Thirty-three patients (9%) with breast cancer showed podoplanin expression in CAFs. In 28 patients (8%), a podoplanin expression in tumor cells was observed. A strong negative correlation of CAF+ with estrogen receptor status (p<0.001), and a significant association with higher histological grading (p<0.001) was seen. In multivariable analysis, CAFs+ was an independent prognostic factor for disease free (1.78 Hazard ratio; p=0.026) and overall survival (2.304 Hazard ratio; p=0.002) in patients with breast cancer. Podoplanin-expressing CAFs contribute to the prognosis of invasive breast cancer, indicating a highly aggressive subgroup. CAFs may present a highly selective target for anti-cancer therapies in patients with invasive breast cancer.

To analyze the prognostic value of the extent of peritumoral brain edema in patients operated for single brain metastases (BM), we retrospectively evaluated pre-operative magnetic resonance images in a discovery cohort of 129 patients and a validation cohort of 118 patients, who underwent neurosurgical resection of a single BM in two different hospitals. We recorded clinical parameters and immunohistochemically assessed the Ki67 index, the microvascularization patterns and the expression of hypoxia-induced factor 1 alpha (HIF1a) in the BM tissue specimens retrieved at neurosurgery. Statistical analysis including uni- and multivariate survival analyses were performed. Baseline characteristics were well balanced between the discovery and validation cohorts. In univariate analysis, we found a significant association of favorable overall survival time with young patient age, high Karnofsky performance score, low graded prognostic assessment (GPA) class, absence of extracranial metastases, adjuvant treatment with whole brain radiotherapy and, surprisingly, large brain edema. In multivariate analysis, only GPA and extent of brain edema remained independent prognostic parameters. The prognostic impact of the extent of brain edema was consistent in the two patient cohorts. Furthermore, we found a significant correlation of small brain edema with brain-invasive tumor growth pattern as assessed intraoperatively by the neurosurgeon, low neo-angiogenic activity and low expression of HIF1a. Extent of brain edema independently correlates with prognosis in patients operated for single BM. In conclusion, patients with small peritumoral edema have shorter survival times and their tumors are characterized by a more brain-invasive growth, lower HIF1a expression and less angiogenic activity.

Supramolecular Pt(ii) quadrangular boxes bind native and G-quadruplex DNA motifs in a size-dependent fashion. Three Pt molecular squares of distinct size show biological activity against cancer cells and heavily influence the expression of genes known to form G-quadruplexes in their promoter regions. The smallest Pt-box displays less activity but more selectivity for a quadruplex formed in the c-Kit gene.