Osseous Pseudoprogression in Vertebral Bodies Treated with Stereotactic Radiosurgery: A Secondary Analysis of Prospective Phase I/II Clinical Trials.

BACKGROUND AND PURPOSE: Osseous pseudoprogression on MR imaging can mimic true progression in lesions treated with spine stereotactic radiosurgery. Our aim was to describe the prevalence and time course of osseous pseudoprogression to assist radiologists in the assessment of patients after spine stereotactic radiosurgery. MATERIALS AND METHODS: A secondary analysis of 2 prospective trials was performed. MRIs before and after spine stereotactic radiosurgery were assessed for response. "Osseous pseudoprogression" was defined as transient growth in signal abnormality centered at the lesion with a sustained decline on follow-up MR imaging that was not attributable to chemotherapy. RESULTS: From the initial set of 223 patients, 37 lesions in 36 patients met the inclusion criteria and were selected for secondary analysis. Five of the 37 lesions (14%) demonstrated osseous pseudoprogression, and 9 demonstrated progressive disease. There was a significant association between single-fraction therapy and the development of osseous pseudoprogression (P = .01), and there was a significant difference in osseous pseudoprogression-free survival between single- and multifraction regimens (P = .005). In lesions demonstrating osseous pseudoprogression, time-to-peak size occurred between 9.7 and 24.4 weeks after spine stereotactic radiosurgery (mean, 13.9 weeks; 95% CI, 8.6-19.1 weeks). The peak lesion size was between 4 and 10 mm larger than baseline. Most lesions returned to baseline size between 23 and 52.4 weeks following spine stereotactic radiosurgery. CONCLUSIONS: Progression on MR imaging performed between 3 and 6 months following spine stereotactic radiosurgery should be treated with caution because osseous pseudoprogression may be seen in more than one-third of these lesions. Single-fraction spine stereotactic radiosurgery may be associated with osseous pseudoprogression. The possibility of osseous pseudoprogression should be incorporated into the prospective criteria for assessment of local control following spine stereotactic radiosurgery.

Nuclear EGFR contributes to acquired resistance to cetuximab.

Epidermal growth factor receptor (EGFR) is a ubiquitously expressed receptor tyrosine kinase involved in the etiology of several human cancers. Cetuximab is an EGFR-blocking antibody that has been approved for the treatment of patients with head and neck squamous cell carcinoma and metastatic colorectal cancer. Previous reports have shown that EGFR translocation to the nucleus is associated with cell proliferation. Here we investigated mechanisms of acquired resistance to cetuximab using a model derived from the non-small cell lung cancer line H226. We demonstrated that cetuximab-resistant cells overexpress HER family ligands including epidermal growth factor (EGF), amphiregulin, heparin-binding EGF and beta-cellulin. Overexpression of these ligands is associated with the nuclear translocation of the EGFR and this process was mediated by the Src family kinases (SFK). Treatment of cetuximab-resistant cells with the SFK inhibitor, dasatinib, resulted in loss of nuclear EGFR, increased membrane expression of the EGFR and resensitization to cetuximab. In addition, expression of a nuclear localization sequence-tagged EGFR in cetuximab-sensitive cells increased resistance to cetuximab both in vitro and in mouse xenografts. Collectively, these data suggest that nuclear expression of EGFR may be an important molecular determinant of resistance to cetuximab therapy and provides a rationale for investigating nuclear EGFR as a biomarker for cetuximab response. Further, these data suggest a rationale for the design of clinical trials that examine the value of treating patients with cetuximab-resistant tumors with inhibitors of SFKs in combination with cetuximab.

Binge pattern ethanol exposure in adolescent and adult rats: differential impact on subsequent responsiveness to ethanol.

BACKGROUND: Recent evidence indicates that adolescent animals are more sensitive than adults to the disruptive effects of acute ethanol exposure on spatial learning. It is not yet known whether adolescent animals are also more sensitive than adults to the enduring neurobehavioral effects of repeated ethanol exposure. In this study, animals were exposed to ethanol in a binge-pattern during either adolescence or adulthood. At a time when all subjects were adults, spatial working memory was examined in the absence and presence of an acute ethanol challenge. METHODS: Rats were exposed to ethanol (5.0 g/kg intraperitoneally) or isovolumetric saline at 48 hr intervals over 20 days. Exposure began on either postnatal day 30 (adolescent group) or 70 (adult group). Twenty days after the final injection, a time at which all animals were adults, the subjects were tested on an elevated plus maze and then were trained to perform a spatial working memory task on an eight-arm radial maze. At the beginning of each session of training on the working memory task, subjects retrieved food rewards on four of the eight arms. After a delay, subjects were placed on the maze and allowed to retrieve food from the remaining four arms. RESULTS: Prior exposure to ethanol did not influence behavior on the plus maze. Performance of the groups did not differ during acquisition of the spatial working memory task with a 5 min delay or during subsequent testing with a 1 hr delay. However, animals treated with ethanol during adolescence exhibited larger working memory impairments during an ethanol challenge (1.5 g/kg intraperitoneally) than subjects in the other three groups. CONCLUSIONS: The findings indicate that binge pattern exposure to ethanol during adolescence enhances responsiveness to the memory-impairing effects of ethanol in adulthood.