In this study we compare oxygen tension (PO2) histograms measured with O2 microelectrodes and a new optical PO2 measurement device, the OxyLite, in normal tissues (mouse spleen and thymus) and in tumors (R3230Ac in rats) (n = 5-6). The transient response to glucose infusion or 100% O2 breathing (hyperoxia) was also measured in tumors. PO2 histograms of spleen and thymus with the two devices were not different. The OxyLite tumor PO2 histogram, however, was left-shifted compared with the microelectrode (median PO2 1.0 vs. 4.0 mmHg, P = 0.016). Both probes responded to acute hyperglycemia with a mean increase of 3-6 mmHg, but the microelectrode change was not significant. The OxyLite consistently recorded large PO2 increases (approximately 28 mmHg) with hyperoxia, whereas the microelectrode response was variable. The OxyLite averages PO2 over an area that contains interstitial and vascular components, whereas the microelectrode measures a more local PO2. This study demonstrates the importance of considering the features of the measurement device when studying tissues with heterogeneous PO2 distributions (e.g., tumors).

BACKGROUND Fibrin formation is required for tumor angiogenesis, metastasis, and invasion. D‐dimer, a fibrin degradation product, is produced when crosslinked fibrin is degraded by plasmin. The current study prospectively examined D‐dimer levels in patients with metastatic colorectal carcinoma treated in a Phase II randomized trial comparing bevacizumab (Avastin, Genentech, South San Francisco, CA) plus 5‐fluorouracil/leucovorin (5‐FU/LV) with 5‐FU/LV alone. METHODS At least one circulating D‐dimer level was evaluable in 98 of the 104 previously untreated patients with metastatic colorectal carcinoma in the current trial. Plasma D‐dimer levels were determined using a quantitative immunoassay kit at enrollment, before each treatment, and at the time of trial completion or disease progression. RESULTS At trial enrollment, 86 of 104 patients (88%) had elevated D‐dimer levels (> 20 ng/mL), and 86 of 102 patients (84%) had elevated carcinoembryonic antigen (CEA) levels (> 3 ng/mL). Baseline D‐dimer levels were correlated with the following baseline characteristics: CEA (Pearson coefficient, 0.31; P = 0.002), albumin levels (Pearson coefficient, −0.32; P = 0.002), tumor burden (Pearson coefficient, 0.30; P = 0.003), and number of metastatic sites (Pearson coefficient, 0.21; P = 0.04). At the time of progression, plasma D‐dimer levels reached a maximum postbaseline value in 51 of 61 patients (84%), whereas the CEA level was at its maximum postbaseline value in 39 of 55 patients (71%). Baseline D‐dimer levels were a strong predictor of overall survival on univariate analysis (P = 0.008) and multivariate analysis (P = 0.03). Overall, treatment with bevacizumab (5 mg/kg) and baseline D‐dimer levels were the only predictors of overall survival (P < 0.05). CONCLUSIONS The current study indicates that fibrin remodeling is an important prognostic feature in metastatic colorectal carcinoma. D‐dimer levels should be incorporated into prognostic models, and D‐dimer may represent a useful biomarker for patients treated with antiangiogenic agents. Cancer 2004. © 2004 American Cancer Society.

Background-Premenopausal women treated for early stage breast cancer (ESBC) are at risk for chemotherapy-related amenorrhea (CRA). Prospectively-validated, predictive markers of CRA are needed.

Tumour hypoxia has been shown to increase mutation rate, angiogenesis, and metastatic potential, and decrease response to conventional therapeutics. Improved tumour oxygenation should translate into increased treatment response. Exogenous recombinant erythropoietin (rEpo) has been recently shown to increase tumour oxygenation in a mammary carcinoma model. The mechanism of this action is not yet understood completely. The presence of Epo and its receptor (EpoR) have been demonstrated on several normal and neoplastic tissues, including blood vessels and various solid tumours. In addition, rEpo has been shown in two recent prospective, randomized clinical trials to negatively impact treatment outcome. In this study, we attempt to characterize the direct effects of rEpo on tumour growth and angiogenesis in two separate rodent carcinomas. The effect of rEpo on R3230 rat mammary adenocarcinomas, CT-26 mouse colon carcinomas, HCT-116 human colon carcinomas, and FaDu human head and neck tumours, all of which express EpoR, was examined. There were no differences in tumour growth or proliferation (measured by Ki-67) between placebo-treated and rEpo-treated tumours. In the mammary window chamber, vascular length density (VLD) measurements in serial images of both placebo-treated and Epo-treated rats revealed no difference in angiogenesis between the Epo-treated tumours and placebo-treated tumours at any time point. These experiments are important because they suggest that the recent clinical detriment seen with the use of Epo is not due to its tumour growth effects or angiogenesis. These studies also suggest that further preclinical studies need to examine rEpo's direct tumour effects in efforts to improve the therapeutic benefits of Epo in solid tumour patients.

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