No abstract

The purpose of this study was to evaluate the long-term clinical outcome of operative versus nonoperative treatment of anterior cruciate ligament (ACL) deficiency and to define its relationship with sports activity. Forty-six patients (37 male, 9 female, mean age, 33.6 +/- 8.0 years) who underwent open ACL reconstruction using patellar tendon autograft and 25 patients (18 male, 7 female, mean age, 32.3 +/- 9.9 years) who were treated nonoperatively were evaluated by the same two examiners at 5 - 7 and 10 - 13 years following injury. The evaluations included objective and subjective scoring (Lysholm, OAK, IKDC), instrumented testing (Cybex, KT 1000), radiographic evaluation, and assessments of sports activity, with respect to type, frequency and associated symptoms. According to Lysholm, OAK and IKDC scores, the operative group performed significantly (p < 0.05) better and was able to maintain increased involvement in sports, although both groups participated less over time. However, risks for degenerative joint changes were similar for both the operative and the nonoperative group. A significant (p < 0.05) correlation between participation in high-risk pivoting sports, such as soccer or basketball and osteoarthritic changes could be found for the nonoperative group, only. Sports activity represents an important variable not only affecting the outcome, but also influencing treatment decisions following ACL injuries.

Purpose: PIK3CA mutations are frequent in breast cancer and activate the PI3K/Akt pathway. Unexpectedly, PIK3CA mutation appears in general to be associated with better outcome. In a cohort of patients where both primary and metastatic lesions were available, the objective was to assess changes in PIK3CA mutations. We wished to discern whether selective pressures occur and the influence of PIK3CA mutation on time to recurrence.Experimental Design: Formalin-fixed paraffin-embedded tumor blocks were obtained from 104 patients with paired samples from primary tumors and corresponding asynchronous metastatic breast tumors. Samples were analyzed for PIK3CA mutations (exons 9 and 20) as well as immunohistochemical evaluation for PTEN, pAKT, Ki67, ER, and HER2.Results: PIK3CA mutation was detected in 45% of the primary tumors. Overall, there was a net gain in mutation in metastatic disease, to 53%; nonetheless, there were instances where metastases were wild type in patients with PIK3CA mutant primary tumors. Laser capture microdissection on a subset of cases revealed microheterogeneity for PIK3CA mutational status in the primary tumor. PIK3CA mutants overall showed a significantly longer time to first recurrence than wild type cases (P ¼ 0.03).Conclusion: PIK3CA mutations occur at high frequency in primary and metastatic breast cancer; these may not necessarily confer increased aggressiveness as mutants had a longer time to recurrence. Because PIK3CA status quite frequently changes between primary and metastatic disease, it emphasizes the necessity of assessing the PIK3CA status in the metastatic lesion for selection of PIK3CA inhibitor therapy. Clin Cancer Res; 17(4); 667-77. Ó2010 AACR.

The aberrant vascular architecture of solid tumors results in hypoxia that limits the efficacy of radiotherapy. Vascular normalization using antiangiogenic agents has been proposed as a means to improve radiation therapy by enhancing tumor oxygenation, but only short-lived effects for this strategy have been reported so far. Here, we show that NVP-BEZ235, a dual inhibitor of phosphoinositide-3-kinase (PI3K) and mTOR, can improve tumor oxygenation and vascular structure over a prolonged period that achieves the aim of effective vascular normalization. Because PI3K inhibition can radiosensitize tumor cells themselves, our experimental design explicitly distinguished effects on the blood vasculature versus tumor cells. Drug administration coincident with radiation enhanced the delay in tumor growth without changing tumor oxygenation, establishing that radiosensitization is a component of the response. However, the enhanced growth delay was substantially greater after induction of vascular normalization, meaning that this treatment enhanced the tumoral radioresponse. Importantly, changes in vascular morphology persisted throughout the entire course of the experiment. Our findings indicated that targeting the PI3K/mTOR pathway can modulate the tumor microenvironment to induce a prolonged normalization of blood vessels. The substantial therapeutic gain observed after combination of NVP-BEZ235 with irradiation has conceptual implications for cancer therapy and could be of broad translational importance. Cancer Res; 72(1); 239-48. Ó2011 AACR.