Solitary fibrous tumor (SFT) is characterized by the inv12(q13q13)-derived NAB2-STAT6 fusion, which exhibits variable breakpoints and drives STAT6 nuclear expression. The implications of NAB2-STAT6 fusion variants in pathological features and clinical behavior remain to be characterized in a large cohort of SFTs. We investigated the clinicopathological correlates of this genetic hallmark and analyzed STAT6 immunoexpression in 28 intrathoracic, 37 extrathoracic, and 23 meningeal SFTs. These 88 tumors were designated as histologically nonmalignant in 75 cases and malignant in 13, including 1 dedifferentiated SFT. Eighty cases had formalin-fixed and/or fresh samples to extract assessable RNAs for RT-PCR assay, which revealed NAB2-STAT6 fusion variants comprising 12 types of junction breakpoints in 73 fusion-positive cases, with 65 (89%) falling into 3 major types. The predominant NAB2ex4-STAT6ex2 (n = 33) showed constant breakpoints at the ends of involved exons, whereas the NAB2ex6-STAT6ex16 (n = 16) and NAB2ex6-STAT6ex17 (n = 16) might exhibit variable breakpoints and incorporate NAB2 or STAT6 intronic sequence. Including 73 fusion-positive and 7 CD34-negative SFTs, STAT6 distinctively labeled 87 (99%) SFTs in nuclei, exhibited diffuse reactivity in 73, but did not decorate 98 mimics tested. In seven fusion-negative cases, 6 were STAT6-positive, suggesting rare fusion variants not covered by RT-PCR assay. Regardless of histological subtypes, intrathoracic SFTs affected older patients (P = 0.035) and tended to be larger in size (P = 0.073). Compared with other variants, NAB2ex4-STAT6ex2/4 fusions were significantly predominant in the SFTs characterised by intrathoracic location (Po 0.001), older age (P = 0.005), decreased mitoses (P = 0.0028), and multifocal or diffuse STAT6 staining (P = 0.013), but not found to correlate with disease-free survival. Conclusively, STAT6 nuclear expression was distinctive in the vast majority of SFTs, including all fusion-positive tumors, and exploitable as a robust diagnostics of CD34-negative cases. Despite the associations of NAB2-STAT6 fusion variants with several clincopathological factors, their prognostic relevance should be further validated in large-scale prospective studies of SFTs.
Purpose: To investigate how single or fractionated doses of radiation change the microenvironment in transgenic adenocarcinoma of the mouse prostate (TRAMP)-C1tumors with respect to vascularity, hypoxia, and macrophage infiltrates. Experimental Design: Murine prostate TRAMP-C1 tumors were grown in C57BL/6J mice to 4 mm tumor diameter and were irradiated with either 25 Gy in a single dose or 60 Gy in 15 fractions. Changes in vascularity, hypoxia, and macrophage infiltrates were assessed by immunohistochemistry and molecular assays. Results: Tumor growth was delayed for 1week after both radiation schedules. Tumor microvascular density (MVD) progressively decreased over a 3-week period to nadirs of 25% and 40% of unirradiated tumors for single or fractionated treatment, respectively. In accord with the decrease in MVDs, mRNA levels of endothelial markers, such as CD31, endoglin, and TIE, decreased over the same time period after irradiation. Central dilated vessels developed surrounded by avascularized hypoxic regions that became infiltrated with aggregates of CD68+ tumorassociated macrophages, reaching a maximum at 3 weeks after irradiation. Necrotic regions decreased and were more dispersed. Conclusion: Irradiation of TRAMP-C1tumors with either single or fractionated doses decreases MVD, leading to the development of disperse chronic hypoxic regions, which are infiltrated with CD68+ tumor-associated macrophages. Approaches to interfere in the development of these effects are promising strategies to enhance the efficacy of cancer radiotherapy.
Object. Symptomatic thoracic ossification of the ligamentum flavum (OLF) is rare, and its prognostic factors remain unclear. The authors retrospectively studied 24 patients with surgically treated thoracic OLF to delineate its prognostic factor.Methods. The clinical manifestations, radiological studies, surgical records, and pathological findings were reviewed. Preoperative and postoperative neurological data were reappraised using the American Spinal Injury Association and modified Japanese Orthopaedic Association (JOA) scoring systems. Spearman rank-correlation coefficients and nonparametric tests were used to analyze the correlations between the variables of patient characteristics, preoperative duration of symptoms, preoperative neurological status, associated spinal disorder(s) other than thoracic OLF, and the final functional outcome.Conclusions. Decompressive surgery is indicated in patients in whom symptomatic thoracic spinal cord compression is caused by intruding OLF. Magnetic resonance imaging can provide sufficient clues for the diagnosis of thoracic OLF. Higher preoperative modified JOA scores of 3 and 4 are positively correlated with better postoperative functional recovery than lower scores. Surgery should be performed as soon as possible before independent ambulatory function is impaired.
Overexpression of stress-induced phosphoprotein 1 (STIP1) − a co-chaperone of heat shock protein (HSP) 70/HSP90 – and activation of the JAK2-STAT3 pathway occur in several tumors. Combined treatment with a HSP90 inhibitor and a JAK2 inhibitor exert synergistic anti-cancer effects. Here, we show that STIP1 stabilizes JAK2 protein in ovarian and endometrial cancer cells. Knock-down of endogenous STIP1 decreased JAK2 and phospho-STAT3 protein levels. The N-terminal fragment of STIP1 interacts with the N-terminus of JAK2, whereas the C-terminal DP2 domain of STIP1 mediates the interaction with HSP90 and STAT3. A peptide fragment in the DP2 domain of STIP1 (peptide 520) disrupted the interaction between STIP1 and HSP90 and induced cell death through JAK2 suppression. In an animal model, treatment with peptide 520 inhibited tumor growth. In summary, STIP1 modulates the function of the HSP90-JAK2-STAT3 complex. Peptide 520 may have therapeutic potential in the treatment of JAK2-overexpressing tumors.
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