Prognostic Significance of Carbonic Anhydrase IX Expression in Cancer Patients: A Meta-Analysis

Hypoxia is a characteristic of many solid tumors and an adverse prognostic factor for treatment outcome. Hypoxia increases the expression of carbonic anhydrase IX, an enzyme that is predominantly found on tumor cells and is involved in maintaining the cellular pH balance. Many clinical studies investigated the prognostic value of carbonic anhydrase IX expression, but most have been inconclusive, partly due to small numbers of patients included. The present meta-analysis was therefore performed utilizing the results of all clinical studies to determine the prognostic value of carbonic anhydrase IX expression in solid tumors. Renal cell carcinoma was excluded from this meta-analysis due to an alternative mechanism of upregulation. 958 papers were identified from a literature search performed in Pubmed and Embase. These papers were independently evaluated by two reviewers and 147 studies were included in the analysis. The meta-analysis revealed strong significant associations between CAIX expression and all endpoints: overall survival (HR=1.76, 95%CI 1.58 – 1.98), disease-free survival (HR=1.87, 95%CI 1.62 – 2.16), locoregional control (HR=1.54, 95%CI 1.22 – 1.93), disease-specific survival (HR=1.78, 95%CI 1.41 – 2.25), metastasis-free survival (HR=1.82, 95%CI 1.33 – 2.50), and progression-free survival (HR=1.58, 95%CI 1.27 – 1.96). Subgroup analyses revealed similar associations in the majority of tumor sites and types. In conclusion, these results show that patients having tumors with high carbonic anhydrase IX expression have higher risk of locoregional failure, disease progression, and higher risk to develop metastases, independent of tumor type or site. The results of this meta-analysis further support the development of a clinical test to determine patient prognosis based on CAIX expression and may have important implications for the development of new treatment strategies

Nitroglycerin as a radiosensitizer in non-small cell lung cancer: Results of a prospective imaging-based phase II trial

Background: Nitroglycerin is proposed as an agent to reduce tumour hypoxia by improving tumour perfusion. We investigated the potent

Homologous recombination deficiency scar: mutations and beyond—implications for precision oncology

Homologous recombination deficiency (HRD) is a prevalent in approximately 17% of tumors and is associated with enhanced sensitivity to anticancer therapies inducing double-strand DNA breaks. Accurate detection of HRD would therefore allow improved patient selection and outcome of conventional and targeted anticancer therapies. However, current clinical assessment of HRD mainly relies on determining germline BRCA1/2 mutational status and is insufficient for adequate patient stratification as mechanisms of HRD occurrence extend beyond functional BRCA1/2 loss. HRD, regardless of BRCA1/2 status, is associated with specific forms of genomic and mutational signatures termed HRD scar. Detection of this HRD scar might therefore be a more reliable biomarker for HRD. This review discusses and compares different methods of assessing HRD and HRD scar, their advances into the clinic, and their potential implications for precision oncology

Monitoring PAI-1 and VEGF levels in 6 human squamous cell carcinoma xenografts during fractionated irradiation.

PURPOSE: Previous studies have shown that the plasminogen activator inhibitor type-1 (PAI-1) and vascular endothelial growth factor (VEGF) are regulated by hypoxia and irradiation and are involved in neoangiogenesis. The aim of this study was to determine in vivo whether changes in PAI-1 and VEGF during fractionated irradiation could predict for radiation resistance. METHODS AND MATERIALS: Six xenografted tumor lines from human squamous cell carcinomas (HSCC) of the head and neck were irradiated with 0, 3, 5, 10, and 15 daily fractions of 2 Gy. The PAI-1 and VEGF antigen levels in tumor lysates were determined by enzyme-linked immunosorbent assay kits. The amounts of PAI-1 and VEGF were compared with the dose to cure 50% of tumors (TCD(50)). Colocalization of PAI-1, pimonidazole (hypoxia), CD31 (endothelium), and Hoechst 33342 (perfusion) was examined by immunofluorescence. RESULTS: Human PAI-1 and VEGF (hVEGF) expression levels were induced by fractionated irradiation in UT-SCC-15, UT-SCC-14, and UT-SCC-5 tumors, and mouse VEGF (msVEGF) was induced only in UT-SCC-5 tumors. High hVEGF levels were significantly associated with radiation sensitivity after 5 fractions (P=.021), and high msVEGF levels were significantly associated with radiation resistance after 10 fractions (P=.007). PAI-1 staining was observed in the extracellular matrix, the cytoplasm of fibroblast-like stroma cells, and individual tumor cells at all doses of irradiation. Colocalization studies showed PAI-1 staining close to microvessels. CONCLUSIONS: These results indicate that the concentration of tumor-specific and host-specific VEGF during fractionated irradiation could provide considerably divergent information for the outcome of radiation therapy