Faculty Bibliography

BACKGROUND: Despite its initial positive response to hormone ablation therapy, prostate cancers invariably recur in more aggressive, treatment resistant forms. The lack of our understanding of underlying genetic alterations for the transition from androgen-dependent (AD) to ADI prostate cancer growth hampers our ability to develop target-driven therapeutic strategies for the efficient treatment of ADI prostate cancer. METHODOLOGY/PRINCIPAL FINDINGS: By screening a library of activated human kinases, we have identified TPL2, encoding a serine/threonine kinase, as driving ADI prostate cancer growth. TPL2 activation by over-expressing either wild-type or a constitutively activated form of TPL2 induced ADI growth, whereas the suppression of TPL2 expression and its kinase activity in ADI prostate cancer cells inhibited cell proliferation under androgen-depleted conditions. Most importantly, TPL2 is upregulated in ADI prostate cancers of both the Pten deletion mouse model and the clinical prostate cancer specimens. CONCLUSIONS/SIGNIFICANCE: Together these data suggest that TPL2 kinase plays a critical role in the promotion of ADI prostate cancer progression. Furthermore, the suppression of TPL2 diminishes ADI prostate cancer growth and a high frequency of TPL2 overexpression in human ADI prostate cancer samples validates TPL2 as a target for the treatment of this deadly disease

Osteoclastoma-like giant cell tumor of the renal pelvis, similar to the entity more commonly occurring in bone, is very rare, having been reported in twelve previous cases to our knowledge. This is the first report of this entity, to our knowledge, to include its cross-sectional imaging appearance. A hyperdense area within the lesion on non-contrast CT may correspond with extensive hemorrhagic content of the lesion identified histologically. As in most prior cases, an adjacent smaller urothelial carcinoma of the renal pelvis was also identified. In the limited reported cases, this entity has exhibited highly aggressive behavior with poor prognosis

OBJECTIVES: To evaluate the accuracy and potential clinical value of intraoperative frozen section analysis (FSA) on urethral margin (UM) tissue during radical prostatectomy. Positive surgical margins increase the risk of post-operative cancer recurrence. Positive surgical margins are frequently found at the apex. The utility of intraoperative FSA of the margins is controversial. METHODS: We reviewed a consecutive series of radical prostatectomy cases (n = 1669) performed at our institution, in which UMs were routinely evaluated by intraoperative FSA. RESULTS: The submitted UM tissue contained cancer glands in 111 cases (6.7%). On FSA, the pathologists detected cancer in 55 cases (3.3%), missed cancer in 38 (2.3%), and reported atypical glands in 18 (1.1%). FSA of the UMs had a sensitivity of 59.1%, specificity of 99.8%, and positive and negative predictive value of 94.8% and 97.6%, respectively. The low sensitivity resulted from a substantial false-negative rate (n = 38), which was largely attributed to limited sampling on FSA (n = 31). Of the 55 patients (3.3%) whose positive UMs were detected by FSA, 20 (1.2%) had cancer-free margins after tissue re-excision. A positive final UM was associated with greater biochemical recurrence (P = .0073). However, the few patients limited the statistical analysis of the benefit of margin conversion through tissue re-excision (P = .35). CONCLUSIONS: Although experienced pathologists can evaluate the UMs on FSA with good accuracy, FSA has a relatively low sensitivity. Our data have indicated a low yield and a questionable value of routine FSA during radical prostatectomy

PURPOSE: To retrospectively assess the utility of fusion of T2-weighted images (T2WI) and high b-value diffusion-weighted images (DWI) for prostate cancer detection and localization. MATERIALS AND METHODS: In this IRB-approved HIPAA-compliant study, 42 patients with prostate cancer underwent MRI including multiplanar T2WI and axial DWI before prostatectomy. Two independent radiologists first assessed multiplanar T2WI and axial DWI(b-1000) images and recorded whether tumor was present in each sextant. Axial T2WI was then fused with axial DWI(b-1000) images, and the radiologists re-evaluated each sextant for tumor. Accuracy was compared using generalized estimating equations based on a binary logistic regression model. RESULTS: The accuracy, sensitivity, specificity, PPV, and NPV for tumor detection on a sextant-basis using separate and fused image sets was 65.1%, 50.8%, 78.0%, 67.8%, and 63.6% and 71.0%, 60.8%, 80.3%, 73.7%, and 69.3%, respectively, for reader 1, and 54.0%, 42.5%, 64.4%, 52.0%, and 55.2%, and 61.1%, 56.7%, 65.2%, 59.6%, and 62.3%, respectively, for reader 2. The improvements in accuracy, sensitivity, and NPV using fused images were statistically significant for both readers, as was the improvement in PPV for reader 2 (P ranging from <0.0001 to 0.041). With either separate or fused images, there was greater sensitivity for tumors of higher grade or larger size (P ranging from <0.001 to 0.099). CONCLUSION: Fusion of T2WI and high b-value DWI resulted in significant improvements in sensitivity and accuracy for tumor detection on a sextant-basis, with similar specificity. J. Magn. Reson. Imaging 2011;. (c) 2011 Wiley-Liss, Inc

Renal replacement lipomatosis is a rare benign entity in which extensive fibrofatty proliferation of the renal sinus is associated with marked renal atrophy. In this report, we present a case of massive renal replacement lipomatosis demonstrated on MRI. The presentation was atypical given an absence of associated renal calculus disease, and an initial CT scan was interpreted as suspicious for a liposarcoma. The differential diagnosis and key MRI findings that served to establish this specific diagnosis are reviewed. Histopathological correlation is also presented, as the patient underwent nephroureterectomy

PURPOSE: High mobility group AT-hook 1 (HMGA1) is a non-histone nuclear binding protein that is developmentally regulated. HMGA1 is significantly overexpressed in and associated with high grade and advance stage of prostate cancer (PC). The oncogenic role of HMGA1 is at least mediated through chromosomal instability and structural aberrations. However, regulation of HMGA1 expression is not well understood. Identification of microRNA mediated HMGA1 regulation will provide a promising therapeutic target in treating PC. Experimental Designs: In this study, we examined the functional relation between miR-296 and HMGA1 expression in several prostate cancer cell lines and a large prostate cancer cohort. We further examined the oncogenic property of HMGA1 regulated by miR-296. RESULTS: Here we report that miR-296, a microRNA predicted to target HMGA1, specifically represses HMGA1 expression by promoting degradation and inhibiting HMGA1translation . Repression of HMGA1 by miR-296 is direct and sequence-specific. Importantly, ectopic miR-296 expression significantly reduced prostate cancer cell proliferation and invasion, in part through the down-regulation of HMGA1. Examining prostate cancer patient samples, we found an inverse correlation between HMGA1 and miR-296 expression: high levels of HMGA1 were associated with low miR-296 expression and strongly linked to more advanced tumor grade and stage. CONCLUSIONS: Our results indicate miR-296 regulates HMGA1 expression and is associated with PC growth and invasion

OBJECTIVE: The purpose of our study was to compare the visibility of prostate cancer on trace diffusion-weighted (DW) images and the apparent diffusion coefficient (ADC) map. MATERIALS AND METHODS: In this retrospective study, 45 patients with prostate cancer underwent preoperative MRI, including DW imaging (DWI) (b values 0, 500, and 1,000 s/mm(2)). A single observer reviewed the images in conjunction with tumor maps constructed from prostatectomy. For 132 peripheral zone (PZ) tumor foci, the visibility and contrast relative to benign PZ were recorded for T2-weighted imaging, trace DWI b500 images, trace DWI b1,000 images, and ADC maps. Trace DWI b1,000 images and ADC maps were compared in terms of Gleason score, size, normalized T2 signal intensity, ADC, and normalized ADC of visible tumors. RESULTS: For each image set, the percentage of visible tumor foci and contrast relative to benign PZ were as follows: T2-weighted imaging, 80.3% and 0.411; trace DWI b500, 26.5% and 0.131; trace DWI b1,000, 46.2% and 0.119; and ADC maps, 62.1% and 0.309. Forty-seven tumor foci were visible on both trace DWI b1,000 images and ADC maps, 14 only on trace DWI b1,000 images, 35 only on ADC maps, and 36 on neither image set. There was no significant difference in Gleason score, size, normalized T2 signal intensity, ADC, or normalized ADC between tumors visible only on trace DWI b1,000 images and those visible only on ADC maps. CONCLUSION: Given a greater proportion of tumors visible on the ADC map than trace DWI and greater contrast relative to benign PZ on the ADC map, we suggest that, when performing DWI of the prostate, careful attention be given to the ADC map for tumor identification