Ty K. Subhawong

The phosphatidylinositol 3-kinase/Akt pathway plays a critical role in oncogenesis, and dysregulation of this pathway through loss of PTEN suppression is a particularly common phenomenon in aggressive prostate cancers. The mammalian target of rapamycin (mTOR) is a downstream signaling kinase in this pathway, exerting prosurvival influence on cells through the activation of factors involved in protein synthesis. The mTOR inhibitor rapamycin and its derivatives are cytotoxic to a number of cell lines. Recently, mTOR inhibition has also been shown to radiosensitize endothelial and breast cancer cells in vitro. Because radiation is an important modality in the treatment of prostate cancer, we tested the ability of the mTOR inhibitor RAD001 (everolimus) to enhance the cytotoxic effects of radiation on two prostate cancer cell lines, PC-3 and DU145. We found that both cell lines became more vulnerable to irradiation after treatment with RAD001, with the PTEN-deficient PC-3 cell line showing the greater sensitivity. This increased susceptibility to radiation is associated with induction of autophagy. Furthermore, we show that blocking apoptosis with caspase inhibition and Bax/Bak small interfering RNA in these cell lines enhances radiation-induced mortality and induces autophagy. Together, these data highlight the emerging importance of mTOR as a molecular target for therapeutic intervention, and lend support to the idea that nonapoptotic modes of cell death may play a crucial role in improving tumor cell kill.

Diffusion-weighted (DW) imaging is a functional magnetic resonance (MR) imaging technique that can readily be incorporated into a routine non-contrast material-enhanced MR imaging protocol with little additional scanning time. DW imaging is based on changes in the Brownian motion of water molecules caused by tissue microstructure. The apparent diffusion coefficient (ADC) is a quantitative measure of Brownian movement: Low ADC values typically reflect highly cellular microenvironments in which diffusion is restricted by the presence of cell membranes, whereas acellular regions allow free diffusion and result in elevated ADC values. Thus, with ADC mapping, one may derive useful quantitative information regarding the cellularity of a musculoskeletal lesion using a nonenhanced technique. The role of localized DW imaging in differentiating malignant from benign osseous and soft-tissue lesions is still evolving; when carefully applied, however, this modality has proved helpful in a subset of tumor types, such as nonmyxoid soft-tissue tumors. Studies of the use of DW imaging in assessing the treatment response of both osseous and soft-tissue tumors have shown that higher ADC values correlate with better response to cytotoxic therapy. Successful application of DW imaging in the evaluation of musculoskeletal lesions requires familiarity with potential diagnostic pitfalls that stem from technical artifacts and confounding factors unrelated to lesion cellularity. Further investigation is needed to evaluate the impact of DW imaging-ADC mapping on management and outcome in patients with musculoskeletal lesions.

PURPOSE: To determine the added value of functional magnetic resonance (MR) sequences (dynamic contrast material-enhanced [DCE] and quantitative diffusion-weighted [DW] imaging with apparent diffusion coefficient [ADC] mapping) for the detection of recurrent soft-tissue sarcomas following surgical resection. MATERIALS AND METHODS: This retrospective study was approved by the institutional review board. The requirement to obtain informed consent was waived. Thirty-seven patients referred for postoperative surveillance after resection of soft-tissue sarcoma (35 with high-grade sarcoma) were studied. Imaging at 3.0 T included conventional (T1-weighted, fluid-sensitive, and contrast-enhanced T1-weighted imaging) and functional (DCE MR imaging, DW imaging with ADC mapping) sequences. Recurrences were confirmed with biopsy or resection. A disease-free state was determined with at least 6 months of follow-up. Two readers independently recorded the signal and morphologic characteristics with conventional sequences, the presence or absence of arterial enhancement at DCE MR imaging, and ADCs of the surgical bed. The accuracy of conventional MR imaging in the detection of recurrence was compared with that with the addition of functional sequences. The Fisher exact and Wilcoxon rank sum tests were used to define the accuracy of imaging features, the Cohen κ and Lin interclass correlation were used to define interobserver variability, and receiver operating characteristic analysis was used to define a threshold to detect recurrence and assess reader confidence after the addition of functional imaging to conventional sequences. RESULTS: There were six histologically proved recurrences in 37 patients. Sensitivity and specificity of MR imaging in the detection of tumor recurrence were 100% (six of six patients) and 52% (16 of 31 patients), respectively, with conventional sequences, 100% (six of six patients) and 97% (30 of 31 patients) with the addition of DCE MR imaging, and 60% (three of five patients) and 97% (30 of 31 patients) with the addition of DW imaging and ADC mapping. The average ADC of recurrence (1.08 mm(2)/sec ± 0.19) was significantly different from those of postoperative scarring (0.9 mm(2)/sec ± 0.00) and hematomas (2.34 mm(2)/sec ± 0.72) (P = .03 for both). CONCLUSION: The addition of functional MR sequences to a routine MR protocol, in particular DCE MR imaging, offers a specificity of more than 95% for distinguishing recurrent sarcoma from postsurgical scarring.

OBJECTIVE: Nonelderly patients presenting with knee pain often have patellofemoral maltracking or impingement abnormalities. There is a relative paucity of literature on the incidence and significance of impingement-related edema of the superolateral aspect of Hoffa's (infrapatellar) fat pad in these cases. Our study was designed to systematically evaluate the correlation of superolateral Hoffa's fat pad edema with various anatomic parameters of trochlear morphology and patellar alignment. MATERIALS AND METHODS: We evaluated 50 knee MRI examinations in 47 patients for the presence of edema in superolateral Hoffa's fat pad and associated anatomic abnormalities of the patellofemoral joint. RESULTS: Of the 50 examinations, 25 (50%) showed superolateral Hoffa's fat pad edema, and statistically significant differences were seen between those with and without edema with respect to sex (6/22 men vs 19/28 women) and patellar tendon patellar-length ratio (1.3 ± 0.16 and 1.1 ± 0.12 for those with and without edema, respectively). CONCLUSION: The findings in our study suggest that edema in superolateral Hoffa's fat pad may be an important indicator of underlying patellofemoral maltracking or impingement in younger, symptomatic patients.