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Alexander Combes,1 Simon McQueen,2 Catalina Alejandra Palma,1 David Benz,2 Scott Leslie,1,3– 5 Paul Sved,1,5 John Boulas,1,5 Arthur Vasilaras,1,5 Chris Rogan,2,5 Ilias Drivas,2 David Robert Eisinger,1 Richard Waugh2 1Department of Urology, Royal Prince Alfred Hospital, Camperdown, NSW, 2050, Australia; 2Department of Radiology, Royal Prince Alfred Hospital, Camperdown, NSW, 2050, Australia; 3RPA Institute of Academic Surgery, Sydney, NSW, Australia; 4Faculty of Medicine, University of Sydney, Sydney, NSW, Australia; 5Department of Urology, Chris O’Brien Lifehouse, Sydney, NSW, AustraliaCorrespondence: Alexander Combes, Department of Urology, Royal Prince Alfred Hospital, 50 Missenden Road, Camperdown, NSW, 2050, Australia, Tel +612 9515 7773, Fax +612 9515 7774, Email combes_08@hotmail.comPurpose: Renal angiomyolipoma (AML) is the most common benign renal tumor. Whilst generally asymptomatic, they can cause life-threatening bleeding. Selective angioembolization (SAE) may be used to treat large symptomatic and asymptomatic AMLs. We aimed to evaluate the efficacy of SAE for symptomatic and asymptomatic renal AMLs and determine characteristics that predict spontaneous bleeding.Patients and Methods: Data were retrospectively collected from a prospectively maintained database from July 2011 to April 2022. Patients were included if AML was > 4cm and they underwent subsequent SAE. Follow-up imaging was analyzed to calculate mean reduction in AML size. Clinical notes were reviewed to analyze lesion characteristics including vascularity, fat content and presence of aneurysm as well as post-procedural complications.Results: 26 patients with 30 AMLs were identified. Interval of follow-up imaging ranged from 1 to 60 months. 25 AMLs were embolized electively with 5 emergency embolizations performed for bleeding. Mean reduction in AML volume was 41% at 3 months (p=0.013) and 63% at 12 months (p=0.007). All 5 bleeding AMLs had a rich vascularity with 60% also having either aneurysms or a low fat content. Complications included post-embolic syndrome (n=9), segmental renal parenchyma devascularization (n=3), acute bleeding requiring re-embolization (n=2), nephrectomy for ongoing bleeding (n=1) and delayed bleeding managed conservatively (n=1). No deterioration in renal function was observed.Conclusion: SAE is an effective procedure for managing symptomatic and asymptomatic renal AML, with minimal significant complications. AML vascularity, fat content and aneurysms may be useful characteristics to assess future risk of bleeding in patients with renal AML.Keywords: selective angioembolization, aneurysm, fat content, tuberosclerosis complex

Introduction: Renal colic is a common emergency department (ED) presentation. Variations in assessment and management of suspected renal colic may have significant implications on patient and hospital outcomes. We developed a clinical practice guideline to standardize the assessment and management of renal colic in the ED. We subsequently compared outcomes before and after guideline implementation. Methods: The guidelines standardized the analgesia regimen, urology consult criteria, imaging modality, patient education, and followup instructions. This is a single-center, observational cohort study of patients presenting to the ED with renal colic prospectively collected after guideline implementation (December 2018 to May 2019), compared to a control group retrospectively collected before guideline implementation (December 2017 to May 2018). A total of 528 patients (pre-guideline n=283, post-guideline n=245) were included. Statistical analysis was performed with SPSS using multivariate linear regression. Results: ED length of stay (LOS) was significantly shorter after guideline implementation (pre-guideline 295.82±178.8 minutes vs. post-guideline 253.2±118.2 minutes, p=0.017). The number of computed tomography (CT) scans patients received was significantly less after guideline implementation (pre guideline 1.35±1.34 vs. post-guideline 1.00±0.68, p=0.034). Patients discharged for conservative management had a lower re-presentation rate in the post-guideline group (12.6%) than the pre-guideline group (17.2%); however, this did not reach statistical significance (p=0.18). Conclusions: Implementation of a clinical practice guideline for ureteric stones reduces the ED LOS and the total number of CT scan in patients who present with renal colic. Standardizing assessment and management of ureteric stones can potentially improve patient and hospital outcomes without compromising the quality of care.

Background Prostate cancers (PCs) with similar characteristics at the time of diagnosis can have very different disease outcomes. Conventional biomarkers of PC still lack precision in identifying individuals at high risk of PC recurrence. While many candidate biomarkers are proposed in the literature, few are in clinical practice as they lack rigorous validation. This study prospectively enrolled an independent phase III cohort to evaluate the clinical utility of zinc-alpha 2-glycoprotein (AZGP1) as a prognostic biomarker in localized PC. Patients and methods In our multicentre, prospective phase III study, AZGP1 status in 347 radical prostatectomy specimens was assayed by immunohistochemistry in a NATA-accredited laboratory. The AZGP1 score was assessed in a multivariable model incorporating established prognostic factors. We also report extended outcomes from our previous phase II study. The primary endpoint was biochemical relapse-free survival (BRFS). Secondary endpoints were metastasis-free survival (MFS) and PC-specific survival (PCSS). Results In the phase II cohort, with a median follow-up of 15.8 years, low/absent AZGP1 expression was an independent predictor of poor BRFS (HR, 1.4; 95% CI, 1.1–1.9; P = 0.03), MFS (HR, 2.8; 95% CI, 1.2–6.6;P = 0.02) and PCSS (HR, 3.8; 95% CI, 1.5–9.5;P = 0.005). These results were validated in our prospective phase III cohort. Low/absent AZGP1 expression independently predicted for BRFS (HR, 1.9; 95% CI, 1.1–3.3;P = 0.02), with shorter MFS (HR, 2.0; 95% CI, 1.1–3.4;P = 0.02). AZGP1 improved the discriminatory value when incorporated into existing prognostic risk models. Conclusion Our study provides prospective phase III validation that absent/low AZGP1 expression provides independent prognostic value in PC. This study provides robust evidence for the incorporation of this biomarker into clinical practice.

Background Total cystectomy and subsequent reconstruction of the urinary tract may be required for primary malignancy of the bladder, or in the context of multi-visceral resection for more advanced pelvic tumors. Complications following urinary diversion are a major source of morbidity, particularly in pelvic exenteration (PE) patients. Methods All patients who underwent radical cystectomy alone or during PE at a single tertiary referral centre between 2008 and 2014 were reviewed. Postoperative urological complications were collected and compared between groups. Results Two hundred and thirty-one patients underwent en bloc cystectomy (98 cystectomy alone, 133 as part of a PE). Postoperative urological complications occurred in 33% of the cystectomy alone group and 59% of the PE group (P

This study compares the theoretical information content of single- and multi-compartment models of diffusion-weighted signal attenuation in prostate tissue. Diffusion-weighted imaging (DWI) was performed at 9.4 T with multiple diffusion times and an extended range of b values in four whole formalin-fixed prostates. Ten models, including different combinations of isotropic, anisotropic and restricted components, were tested. Models were ranked using the Akaike information criterion. In all four prostates, two-component models, comprising an anisotropic Gaussian component and an isotropic restricted component, ranked highest in the majority of voxels. Single-component models, whether isotropic (apparent diffusion coefficient, ADC) or anisotropic (diffusion tensor imaging, DTI), consistently ranked lower than multi-component models. Model ranking trends were independent of voxel size and maximum b value in the range tested (1.6-16 mm(3) and 3000-10,000 s/mm(2)). This study characterizes the two major water components previously identified by biexponential models and shows that models incorporating both anisotropic and restricted components provide more information-rich descriptions of DWI signals in prostate tissue than single- or multi-component anisotropic models and models that do not account for restricted diffusion.

Aims Ductal adenocarcinoma is a rare variant of prostate cancer, and as such clinical outcomes and best management are not well defined. This series demonstrates the atypical presentation and unusual clinical behaviour of ductal adenocarcinoma and proposes management guidelines to assist clinicians. Materials and methods A retrospective review of pure (nine patients) and mixed (18 patients) ductal adenocarcinoma of the prostate referred to the Departments of Radiation Oncology of the Sydney Cancer Centre, Royal Prince Alfred Hospital and Northern Sydney Cancer Centre, Royal North Shore Hospital, between 2000 and 2015. Results Twenty-seven patients were treated with definitive radiotherapy, nine patients (33%) with pure ductal and 18 (67%) with mixed ductal-acinar adenocarcinoma. The median follow-up was 38 months. Four patients (15%) failed locally, all of whom received less than 80 Gy, or no brachytherapy boost. Five patients (19%) failed distantly, four with biopsy-proven lung metastases. All distant failures occurred with a prostate-specific antigen (PSA) Conclusion This series shows the atypical clinical presentation of this entity, as well as its propensity to metastasise to unusual sites. Relapse may occur at low absolute PSA values and is often asymptomatic. Ductal cancer should not simply be regarded as a high Gleason grade cancer. We propose management guidelines, including regular computed tomography examinations (rather than relying solely on PSA levels) as part of the follow-up for patients with any component of ductal adenocarcinoma.

Aberrant increase in protein kinase B (AKT) phosphorylation (pAKT), due to a gain-of-function mutation of phosphatidylinositol-3-kinase (PI3K) or loss-of-function mutation or deletion of phosphatase and tensin homolog (PTEN), is a common alteration in prostate cancer and associated with poor prognosis. Cytosolic phospholipase A2α (cPLA2α) is a lipid modifying enzyme by catalyzing the hydrolysis of arachidonic acid from membrane phospholipid. The released arachidonic acid and its metabolites contribute to survival and proliferation of prostate cancer cells. In this mini-review, we summarize the relationship between pAKT and cPLA2α in prostate cancer cells. There was a concordant increase in pAKT and cPLA2α levels in prostate tissue of prostate epithelial-specific PTEN-knockout mice compared to PTEN-wild type mice. Restoration of PTEN expression or inhibition of PI3K action decreased cPLA2α expression in PTEN-mutated or deleted prostate cancer cells. An increase in AKT phosphorylation elevated, whereas inhibition of AKT phosphorylation diminished, cPLA2α protein levels. pAKT had no influence on cPLA2α expression at mRNA levels but stabilized cPLA2α at protein levels by protecting it from degradation. Conversely, an induction of cPLA2α expression led to an increase in pAKT levels in PTEN-mutated or deleted prostate cancer cells, while silencing of cPLA2α expression or pharmacological blocking cPLA2α action decreased pAKT levels. The diminishment of pAKT by either genetic silencing or pharmacological blocking of cPLA2α was mitigated by the addition of arachidonic acid. The stimulatory effect of arachidonic acid on pAKT levels was lessened by inhibiting the production of arachidonic acid metabolites. These studies have revealed a link between oncogenic pathway and lipid metabolism and provided potential molecular targets for treating prostate cancer.

Purpose To investigate diffusion anisotropy in whole human prostate specimens Methods Seven whole radical prostatectomy specimens were obtained with informed patient consent and institutional ethics approval. Diffusion tensor imaging was performed at 9.4 Tesla. Diffusion tensors were calculated from the native acquired data and after progressive downsampling Results Fractional anisotropy (FA) decreased as voxel volume increased, and differed widely between prostates. Fixation decreased mean FA by ∼0.05–0.08 at all voxel volumes but did not alter principle eigenvector orientation. In unfixed tissue high FA (> 0.6) was found only in voxels of volume 0.25. FA decreased at longer diffusion times (Δ = 60 or 80 ms compared with 20 ms), but only by ∼0.02 at typical clinical voxel volume. Peripheral zone FA was significantly lower than transition zone FA in five of the seven prostates Conclusion FA varies widely between prostates. The very small proportion of clinical size voxels with high FA suggests that in clinical DWI studies ADC based on three-direction measurements will be minimally affected by anisotropy. Magn Reson Med, 2015. © 2015 Wiley Periodicals, Inc.

// Mu Yao 1, 2 , Chanlu Xie 1, 2, 3 , Mei-Yee Kiang 1, 2 , Ying Teng 1, 2 , David Harman 4 , Jessamy Tiffen 5, 6 , Qian Wang 5, 6 , Paul Sved 7 , Shisan Bao 8 , Paul Witting 8 , Jeff Holst 5, 6 , Qihan Dong 1, 2, 3 1 Department of Endocrinology, Royal Prince Alfred Hospital, Camperdown, NSW 2050, Australia 2 Central Clinical School and Bosch Institute, The University of Sydney, Sydney, NSW 2006, Australia 3 School of Biomedical and Health Sciences, University of Western Sydney, Parramatta, NSW 2751, Australia 4 Molecular Medicine Research Group, University of Western Sydney, Parramatta, NSW 2751, Australia 5 Origins of Cancer Laboratory, Centenary Institute, Camperdown, NSW 2050, Australia 6 Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia 7 Department of Urology, Royal Prince Alfred Hospital, Camperdown, NSW 2050, Australia 8 Department of Pathology, The University of Sydney, Sydney, NSW 2006, Australia Correspondence to: Qihan Dong, e-mail: q.dong@uws.edu.au Mu Yao, e-mail: mu.yao@sydney.edu.au Keywords: prostate cancer, phospholipase A2α, cell cycle re-entry, p27, Skp2 Received: May 15, 2015 Accepted: September 14, 2015 Published: September 24, 2015 ABSTRACT Cell cycle re-entry of quiescent cancer cells has been proposed to be involved in cancer progression and recurrence. Cytosolic phospholipase A 2 α (cPLA 2 α) is an enzyme that hydrolyzes membrane glycerophospholipids to release arachidonic acid and lysophospholipids that are implicated in cancer cell proliferation. The aim of this study was to determine the role of cPLA 2 α in cell cycle re-entry of quiescent prostate cancer cells. When PC-3 and LNCaP cells were rendered to a quiescent state, the active form of cPLA 2 α with a phosphorylation at Ser 505 was lower compared to their proliferating state. Conversely, the phospho-cPLA 2 α levels were resurgent during the induction of cell cycle re-entry. Pharmacological inhibition of cPLA 2 α with Efipladib upon induction of cell cycle re-entry inhibited the re-entry process, as manifested by refrained DNA synthesis, persistent high proportion of cells in G 0 /G 1 and low percentage of cells in S and G 2 /M phases, together with a stagnant recovery of Ki-67 expression. Simultaneously, Efipladib prohibited the emergence of Skp2 while maintained p27 at a high level in the nuclear compartment during cell cycle re-entry. Inhibition of cPLA 2 α also prevented an accumulation of cyclin D1/CDK4, cyclin E/CDK2, phospho-pRb, pre-replicative complex proteins CDC6, MCM7, ORC6 and DNA synthesis-related protein PCNA during induction of cell cycle re-entry. Moreover, a pre-treatment of the prostate cancer cells with Efipladib during induction of cell cycle re-entry subsequently compromised their tumorigenic capacity in vivo . Hence, cPLA 2 α plays an important role in cell cycle re-entry by quiescent prostate cancer cells.

Non-Gaussian diffusion dynamics was investigated in the two distinct water populations identified by a biexponential model of diffusion in prostate tissue. Diffusion-weighted MRI (DWI) signal attenuation was measured ex vivo in two formalin-fixed prostates at 9.4 T with diffusion times Δ = 10, 20 and 40 ms, and b values in the range 0.017–8.2 ms/µm2. A conventional biexponential model was compared with models in which either the lower diffusivity component or both of the components of the biexponential were stretched. Models were compared using Akaike's Information Criterion (AIC) and a leave-one-out (LOO) test of model prediction accuracy. The doubly stretched (SS) model had the highest LOO prediction accuracy and lowest AIC (highest information content) in the majority of voxels at Δ = 10 and 20 ms. The lower diffusivity stretching factor (α2) of the SS model was consistently lower (range ~0.3–0.9) than the higher diffusivity stretching factor (α1, range ~0.7–1.1), indicating a high degree of diffusion heterogeneity in the lower diffusivity environment, and nearly Gaussian diffusion in the higher diffusivity environment. Stretched biexponential models demonstrate that, in prostate tissue, the two distinct water populations identified by the simple biexponential model individually exhibit non-Gaussian diffusion dynamics. Copyright © 2015 John Wiley & Sons, Ltd.

Radiation therapy is used to treat cancer by radiation-induced DNA damage. Despite the best efforts to eliminate cancer, some cancer cells survive irradiation, resulting in cancer progression or recurrence. Alteration in DNA damage repair pathways is common in cancers, resulting in modulation of their response to radiation. This article focuses on the recent findings about molecules and pathways that potentially can be targeted to sensitize prostate cancer cells to ionizing radiation, thereby achieving an improved therapeutic outcome.

// Soma Vignarajan 1 , Chanlu Xie 1,6 , Mu Yao 1 , Yuting Sun 2 , Ulla Simanainen 3 , Paul Sved 4 , Tao Liu 2,5 , Qihan Dong 1,6 1 Discipline of Endocrinology, Central Clinical School, Bosch Institute, Royal Prince Alfred Hospital, and Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia 2 Children’s Cancer Institute Australia for Medical Research, Sydney, Australia 3 ANZAC Research institute, The University of Sydney, Sydney, NSW, Australia 4 Sydney Cancer Centre, Royal Prince Alfred Hospital, Camperdown, NSW, Australia 5 School of Women’s and Children’s Health, UNSW Medicine, Sydney, Australia, Australia 6 School of Science and Health, The University of Western Sydney, Sydney, Australia Correspondence: Qihan Dong, email: // Keywords : cytosolic phospholipase A2, AKT, PTEN, prostate cancer Received : June 06, 2014 Accepted : July 07, 2014 Published : July 09, 2014 Abstract Aberrant increase in pAKT, due to a gain-of-function mutation of PI3K or loss-of-function mutation or deletion of PTEN, occurs in prostate cancer and is associated with poor patient prognosis. Cytosolic phospholipase A 2 α (cPLA 2 α) is a lipid modifying enzyme by catalyzing the hydrolysis of membrane arachidonic acid. Arachidonic acid and its metabolites contribute to survival and proliferation of prostate cancer cells. We examined whether AKT plays a role in promoting cPLA 2 α action in prostate cancer cells. We found a concordant increase in pAKT and cPLA 2 α levels in prostate tissue of prostate epithelial-specific PTEN -knockout but not PTEN -wide type mice. Restoration of PTEN expression or inhibition of PI3K action decreased cPLA 2 α expression in PTEN -mutated or deleted prostate cancer cells. An increase in AKT by Myr-AKT elevated cPLA 2 α protein levels, which could be diminished by inhibition of AKT phosphorylation without noticeable change in total AKT levels. pAKT levels had no influence on cPLA 2 α at mRNA levels but reduced cPLA 2 α protein degradation. Anti-AKT antibody co-immunoprecipitated cPLA 2 α and vice versa. Hence, AKT plays a role in enhancing cPLA 2 α protein stability in PTEN-null prostate cancer cells, revealing a link between oncogenic pathway and lipid metabolism.

Purpose To compare the theoretical information content of four popular models of diffusion-weighted signal attenuation. Method Four whole prostates were imaged fresh unfixed and fixed at 9.4T. Biexponential, kurtosis, stretched exponential, and monoexponential models were ranked using Akaike's Information Criterion (AIC) with validation by a leave-one-out test of model prediction error. Results For unfixed tissue measurements (b-value range: 17–2104 s/mm2) the biexponential and kurtosis models had similar information content to each other and this was distinctly higher than for the stretched and monoexponential models. In fixed-tissue measurements (b-value range: 17–8252 s/mm2), the biexponential model had much higher information content than the three other models. Conclusion AIC-based model ranking is consistent with an independent prediction accuracy test. Biexponential and kurtosis models consistently perform better than stretched and monoexponential models. The biexponential model has increasing superiority over all three other models as maximum b-value increases above ∼2000 s/mm2. Magn Reson Med 72:1418–1426, 2014. © 2013 Wiley Periodicals, Inc.

Item does not contain fulltext CONTEXT: Our aim was to present a summary of the Second International Consultation on Bladder Cancer recommendations on the diagnosis and treatment options for non-muscle-invasive urothelial cancer of the bladder (NMIBC) using an evidence-based approach. OBJECTIVE: To critically review the recent data on the management of NMIBC to arrive at a general consensus. EVIDENCE ACQUISITION: A detailed Medline analysis was performed for original articles addressing the treatment of NMIBC with regard to diagnosis, surgery, intravesical chemotherapy, and follow-up. Proceedings from the last 5 yr of major conferences were also searched. EVIDENCE SYNTHESIS: The major findings are presented in an evidence-based fashion. We analyzed large retrospective and prospective studies. CONCLUSIONS: Urothelial cancer of the bladder staged Ta, T1, and carcinoma in situ (CIS), also indicated as NMIBC, poses greatly varying but uniformly demanding challenges to urologic care. On the one hand, the high recurrence rate and low progression rate with Ta low-grade demand risk-adapted treatment and surveillance to provide thorough care while minimizing treatment-related burden. On the other hand, the propensity of Ta high-grade, T1, and CIS to progress demands intense care and timely consideration of radical cystectomy.

Total cystectomy and subsequent reconstruction of the urinary tract may be required for primary malignancy of the bladder, or in the context of multi-visceral resection for more advanced pelvic tumors. Complications following urinary diversion are a major source of morbidity, particularly in pelvic exenteration (PE) patients.All patients who underwent radical cystectomy alone or during PE at a single tertiary referral centre between 2008 and 2014 were reviewed. Postoperative urological complications were collected and compared between groups.Two hundred and thirty-one patients underwent en bloc cystectomy (98 cystectomy alone, 133 as part of a PE). Postoperative urological complications occurred in 33% of the cystectomy alone group and 59% of the PE group (P 0.001). PE for recurrence had higher complications than PE for primary malignancy (67% vs. 48%, P = 0.035). Urological leaks occurred in 3%, 6%, and 14% of patient who had cystectomy alone, PE for primary malignancy and PE for recurrence. Major blood loss and previous pelvic radiotherapy independently predicted conduit-associated complications in PE patients (P = 0.002 and 0.035).Urological complications of cystectomy, particularly urine leaks and sepsis, are more common in patients undergoing PE compared to those with cystectomy alone. Prior pelvic radiotherapy, the extent of surgical resection and major blood loss may contribute to urological morbidity. J. Surg. Oncol. 2017;115:307-311. © 2016 Wiley Periodicals, Inc.

Purpose To evaluate the effect of formalin fixation on biexponential modeling of diffusion decay in prostate tissue. Methods Three whole prostate specimens were imaged unfixed immediately postsurgery, and again after formalin fixation. Diffusion-weighted imaging was performed over an extended range of b-values and a biexponential model fitted to the signal decay curves. Results Tissue fixation resulted in a 35%, 20%, and 20% reduction in mean apparent diffusion coefficient of the higher diffusivity fit component for the three organs, respectively, and a 64%, 57%, and 45% reduction in mean apparent diffusion coefficient of the lower diffusivity component. The mean signal fraction of the higher diffusivity component was increased by 23%, 5%, and 1%, respectively. The effect of fixation did not appear to vary according to tissue type or glandular zone. Conclusion Formalin fixed tissue appears to provide a stable model for detailed investigation of the microscopic biophysical basis of diffusion phenomena observed in vivo. Diffusivity changes that result from fixation may provide information about the microscopic environments of the biexponential components. Magn Reson Med, 70:1160–1166, 2013. © 2012 Wiley Periodicals, Inc.

Diffusion tensor microimaging at 16.4 T with 40 mu m isotropic voxels was used to investigate anisotropic water diffusion in prostate tissue at spatial resolution approaching the cellular scale. Nine normal glandular tissue samples were collected from the peripheral zone of six formalin fixed radical prostatectomy specimens. Fibromuscular stromal tissue exhibited microscopic diffusion anisotropy (mean fractional anisotropy range 0.470.66) significantly higher (P < 0.01, Student's t-test) than in epithelium-containing voxels (mean fractional anisotropy range 0.310.54) in six of the seven normal tissue samples in which both compartments could be measured. Fiber tracking demonstrated principle stromal fiber directions consistent with myocyte orientation seen on light microscopy of the same sample. Diffusion tensor microimaging may be valuable for investigation of variable results from attempts to measure diffusion anisotropy in the prostate in vivo. Magn Reson Med, 2012. (c) 2012 Wiley Periodicals, Inc.

MR microimaging at 16.4 T with 40-mu m isotropic voxels was used to investigate compartmentation of water diffusion in formalin-fixed prostate tissue. Ten tissue samples (similar to 28 mm3 each) from five organs were imaged. The mean diffusivity of epithelial, stromal, and ductal/acinar compartments was estimated by two methods: (1) manual region of interest selection and (2) Gaussian fitting of voxel diffusivity histograms. For the region of interest-method, the means of the tissue sample compartment diffusivities were significantly different (P < 0.001): 0.54 +/- 0.05 mu m2/ms for epithelium-containing voxels, 0.91 +/- 0.17 mu m2/ms for stroma, and 2.20 +/- 0.04 mu m2/ms for saline-filled ducts. The means from the histogram method were also significantly different (P < 0.001): 0.45 +/- 0.08 mu m2/ms for epithelium-containing voxels, 0.83 +/- 0.16 mu m2/ms for stroma, 2.21 +/- 0.02 mu m2/ms for duct. Estimated partial volumes of epithelial, stromal, and ductal/acinar compartments in a tissue only subvolume of each sample were significantly different (P < 0.02) between cancer and normal tissue for all three compartments. It is concluded that the negative correlation between apparent diffusion coefficient and cancer Gleason grade observed in vivo results from an increase of partial volume of epithelial tissue and concomitant decrease of stromal tissue and ductal space. Magn Reson Med, 2012. (C) 2011 Wiley Periodicals, Inc.

We have developed a blend of food extracts commonly consumed in the Mediterranean and East Asia, named blueberry punch (BBP), with the ultimate aim to formulate a chemoprevention strategy to inhibit prostate cancer progression in men on active surveillance protocol. We demonstrated previously that BBP inhibited prostate cancer cell proliferationin vitroandin vivo. The purpose of this study was to determine the molecular mechanism responsible for the suppression of prostate cancer cell proliferation by BBP. Treatment of lymph node-metastasised prostate cancer cells (LNCaP) and bone-metastasised prostate cancer cells (PC-3 and MDA-PCa-2b) with BBP (up to 0·8 %) for 72 h increased the percentage of cells at the G0/G1phase and decreased those at the S and G2/M phases. The finding was supported by the reduction in the percentage of Ki-67-positive cells and of DNA synthesis measured by the incorporation of 5-ethynyl-2′-deoxyuridine. Concomitantly, BBP treatment decreased the protein levels of phosphorylated retinoblastoma, cyclin D1 and E, cyclin-dependent kinase (CDK) 4 and 2, and pre-replication complex (CDC6 and MCM7) in LNCaP and PC-3 cells, whereas CDK inhibitor p27 was elevated in these cell lines. In conclusion, BBP exerts its anti-proliferative effect on prostate cancer cells by modulating the expression and phosphorylation of multiple regulatory proteins essential for cell proliferation.

Diffusion tensor microimaging was used to investigate the water diffusion properties of formalin-fixed prostate tissue at spatial resolution approaching the cellular scale. Diffusion tensor microimaging was performed at 16.4 T with 40 mu m isotropic voxels. Diffusion tensor microimaging clearly demonstrated distinct microscopic diffusion environments and tissue architecture consistent with that seen on light microscopy of the same tissue. The most restricted diffusion environment is the secretory epithelial cell layer (voxel bulk mean diffusivity, D = 0.4 +/- 0.1 x 10(-3) mm(2)/sec). Diffusion in the fibromuscular stromal matrix is relatively less restricted (D = 0.7 +/- 0.1 x 10(-3) mm(2)/sec). In tumor tissue (Gleason pattern 4+4) distinct glandular and ductal structures are absent in the diffusion-weighted images and diffusivity is low (D = 0.5 +/- 0.1 x 10(-3) mm(2)/sec). Distinct stromal and epithelial diffusion compartments are the most likely origin of biexponential diffusion decay observed in vivo. Magn Reson Med 66:244-247, 2011. (C) 2011 Wiley-Liss, Inc.

The eicosanoid pathway is activated in many types of cancers including prostate. Eicosanoids are synthesized from intracellular arachidonic acid (AA), which is released from membrane glycerophospholipids mainly by the action of cytosolic phospholipase A(2)alpha (cPLA(2)alpha). Thus, targeting cPLA(2)alpha has been proposed as a treatment option. The aim of this study was to determine the effect of cPLA(2)alpha inhibition on cyclooxygenase (COX) expression and PGE(2) production. Inhibition of cPLA(2)alpha expression by siRNA or activity by Efipladib in prostate cancer cell lines (PC3 and LNCaP) led to an increase in COX-1 protein and PGE(2) levels in a dose-dependent manner from 24 to 72 h. The COX-2 response was less evident. Efipladib treatment increased COX-1 promoter transcriptional activity without changing the rate of COX-1 protein degradation. Treatment with Efipladib also led to a decrease in most LOX products (HETEs) as measured by LC/MS/MS. Replenishing 5- and 12-HETEs abolished Efipladib-induced COX-1 and PGE(2) levels. Decreasing 5- and 12-HETE production, as a result of treating cells with inhibitors MK886 and Baicalein, respectively, mimicked the effect of Efipladib on COX-1 and PGE(2) levels. Hence, the mechanism underlying the cPLA(2)alpha inhibition-induced COX-1 is likely due to a decrease in LOX products, which may exert a negative feedback on COX-1 gene expression in prostate cancer cells. Considering that PGE(2) is a potent promoter of cancer cell proliferation and survival, understanding the mechanism coupling cPLA(2)alpha with COX-1 is of potential clinical significance.

Experimentation with the progenitor/stem cells in adult prostate epithelium can be inconvenient due to a tight time line from tissue acquisition to cell isolation and to downstream experiments. To circumvent this inconvenience, we developed a simple technical procedure for culturing epithelial cells derived from human prostate tissue. In this study, benign prostate tissue was enzymatically digested and fractionated into epithelium and stroma, which were then cultured in the medium designed for prostate epithelial and stromal cells, respectively. The cultured cells were analyzed by immunocytochemical staining and flow cytometry. Prostate tissue-regenerating capacity of cultured cells in vitro was determined by co-culturing epithelial and stromal cells in dihydrotestosterone-containing RPMI. Cell lineages in formed acini-like structures were determined by immunohistochemistry. The culture of epithelial cells mainly consisted of basal cells. A minor population was negative for known lineage markers and positive for CD133. The culture also contained cells with high activity of aldehyde dehydrogenase. After co-culturing with stromal cells, the epithelial cells were able to form acini-like structures containing multiple cell lineages. Thus, the established culture of prostate epithelial cells provides an alternative source for studying progenitor/stem cells of prostate epithelium.

This study compares the theoretical information content of single- and multi-compartment models of diffusion-weighted signal attenuation in prostate tissue. Diffusion-weighted imaging (DWI) was performed at 9.4 T with multiple diffusion times and an extended range of b values in four whole formalin-fixed prostates. Ten models, including different combinations of isotropic, anisotropic and restricted components, were tested. Models were ranked using the Akaike information criterion. In all four prostates, two-component models, comprising an anisotropic Gaussian component and an isotropic restricted component, ranked highest in the majority of voxels. Single-component models, whether isotropic (apparent diffusion coefficient, ADC) or anisotropic (diffusion tensor imaging, DTI), consistently ranked lower than multi-component models. Model ranking trends were independent of voxel size and maximum b value in the range tested (1.6-16 mm(3) and 3000-10,000 s/mm(2)). This study characterizes the two major water components previously identified by biexponential models and shows that models incorporating both anisotropic and restricted components provide more information-rich descriptions of DWI signals in prostate tissue than single- or multi-component anisotropic models and models that do not account for restricted diffusion.

To investigate diffusion anisotropy in whole human prostate specimensSeven whole radical prostatectomy specimens were obtained with informed patient consent and institutional ethics approval. Diffusion tensor imaging was performed at 9.4 Tesla. Diffusion tensors were calculated from the native acquired data and after progressive downsamplingFractional anisotropy (FA) decreased as voxel volume increased, and differed widely between prostates. Fixation decreased mean FA by ∼0.05-0.08 at all voxel volumes but did not alter principle eigenvector orientation. In unfixed tissue high FA (0.6) was found only in voxels of volume0.5 mm(3) , and then only in a small fraction of all voxels. At typical clinical voxel volumes (4-16 mm(3) ) less than 50% of voxels had FA 0.25. FA decreased at longer diffusion times (Δ = 60 or 80 ms compared with 20 ms), but only by ∼0.02 at typical clinical voxel volume. Peripheral zone FA was significantly lower than transition zone FA in five of the seven prostatesFA varies widely between prostates. The very small proportion of clinical size voxels with high FA suggests that in clinical DWI studies ADC based on three-direction measurements will be minimally affected by anisotropy. Magn Reson Med 76:626-634, 2016. © 2015 Wiley Periodicals, Inc.

To investigate the hypothesis that the clinically observed decrease in apparent diffusion coefficient (ADC) at diffusion-weighted magnetic resonance imaging with increasing prostate cancer Gleason grade can be attributed to an increasing volume of low-diffusivity epithelial cells and corresponding decreasing volumes of higher-diffusivity stroma and lumen space rather than to increased cell density.Tissue samples were acquired after institutional ethics review committee approval and informed consent from patients were obtained. Nuclear count, nuclear area, and gland component volumes (epithelium, stroma, lumen space) were measured in tissue from 14 patients. Gland component volumes and cellularity metrics were correlated with Gleason pattern (Spearman rank correlation coefficient) and measured ADC (Pearson correlation coefficient) in six prostates ex vivo. Differences between metrics for cancerous tissue and those for normal tissue were assessed by using a two-tailed two-sample t test. Linear mixed models with a post hoc Fisher least significant difference test were used to assess differences between gland component volumes and cellularity metrics for multiple groups. To adjust for a clustering effect due to repeated measures, the organ mean value of the measured metric for each tissue type was used in the analysis.There were significant differences between Gleason patterns for gland component volumes (P.05) but not nuclear count (P = .100) or area (P = .141). There was a stronger correlation of Gleason pattern with gland component volumes (n = 553) of epithelium (Spearman ρ = 0.898, P.001), stroma (ρ = -0.651, P.001), and lumen space (ρ = -0.912, P = .007) than with the cellularity metrics (n = 288) nuclear area (ρ = 0.422, P = .133) or nuclear count (ρ = 0.082, P = .780). There was a stronger correlation between measured ADC and lumen volume (r = 0.688, P.001) and epithelium volume (r = -0.647, P.001) than between ADC and nuclear count (r = -0.598, P.001) or nuclear area (r = -0.569, P.001) (n = 57).Differences in the gland compartment volumes of prostate tissue having distinct diffusivities, rather than changes in the conventionally cited "cellularity" metrics, are likely to be the major contributor to clinically observed variations of ADC in prostate tissue.

Aberrant increase in protein kinase B (AKT) phosphorylation (pAKT), due to a gain-of-function mutation of phosphatidylinositol-3-kinase (PI3K) or loss-of-function mutation or deletion of phosphatase and tensin homolog (PTEN), is a common alteration in prostate cancer and associated with poor prognosis. Cytosolic phospholipase A2α (cPLA2α) is a lipid modifying enzyme by catalyzing the hydrolysis of arachidonic acid from membrane phospholipid. The released arachidonic acid and its metabolites contribute to survival and proliferation of prostate cancer cells. In this mini-review, we summarize the relationship between pAKT and cPLA2α in prostate cancer cells. There was a concordant increase in pAKT and cPLA2α levels in prostate tissue of prostate epithelial-specific PTEN-knockout mice compared to PTEN-wild type mice. Restoration of PTEN expression or inhibition of PI3K action decreased cPLA2α expression in PTEN-mutated or deleted prostate cancer cells. An increase in AKT phosphorylation elevated, whereas inhibition of AKT phosphorylation diminished, cPLA2α protein levels. pAKT had no influence on cPLA2α expression at mRNA levels but stabilized cPLA2α at protein levels by protecting it from degradation. Conversely, an induction of cPLA2α expression led to an increase in pAKT levels in PTEN-mutated or deleted prostate cancer cells, while silencing of cPLA2α expression or pharmacological blocking cPLA2α action decreased pAKT levels. The diminishment of pAKT by either genetic silencing or pharmacological blocking of cPLA2α was mitigated by the addition of arachidonic acid. The stimulatory effect of arachidonic acid on pAKT levels was lessened by inhibiting the production of arachidonic acid metabolites. These studies have revealed a link between oncogenic pathway and lipid metabolism and provided potential molecular targets for treating prostate cancer.

Mortality from prostate cancer is a result of progression of cancer cells to become androgen-refractory and metastatic. Eicosanoid products of the cyclooxygenase (COX) and lipoxygenase (LOX) pathways are important mediators of the proliferation of prostate cancer cells in culture and regulate tumour vascularisation and metastasis in animal models. Pharmacological agents that block either COX or LOX products effectively reduce the size of prostate cancer xenografts. Recently, phospholipase A(2) (PLA(2)) enzymes, which regulate the provision of arachidonic acid to both COX- and LOX-derived eicosanoids, are found to also regulate the growth of prostate cancer cells and tumours, with one enzyme, secreted PLA(2)-IIA, being increased in prostate cancer tissues. Annexin A1 and A2, known inhibitors of cytosolic phospholipase A(2)-alpha activity, are absent in prostate cancer tissues. We propose that PLA(2) enzyme function is dysregulated by aberrant up regulation of secreted enzymes and downregulation of endogenous inhibitors of cytosolic phospholipase A(2) activity in prostate cancer and that this dysregulation contributes to the pathogenesis of prostate cancer. Thus, in addition to COX and LOX enzymes, PLA(2) enzymes represent important targets for the treatment of prostate cancer.

Background Omental adipose tissue is a pure depot of visceral adipose tissue. We investigated the regulation of lipid metabolism in human omental tissue in vivo by the arterio-venous technique. Materials and methods Six adults were studied while undergoing elective colonic surgery. Their omental vein was cannulated intraoperatively, and after obtaining the baseline blood samples, 50 ml of 50% dextrose solution was given intravenously and simultaneous arterio-venous samples were taken for the next 2 h. Concentration differences of lipid metabolites, glucose, and lactate were measured across the arterio-venous bed. The rates of action of hormone-sensitive lipase (HSL) and lipoprotein lipase (LPL) were calculated by stoichiometric analysis and the rate of re-esterification of nonesterified fatty acids (NEFA) was determined. Results After an overnight fast there was a significant release of NEFA and glycerol from the omental adipose tissue (P Conclusion The net release of NEFA by omental adipose tissue is primarily regulated by their local re-esterification. The change in the rate of action of HSL and LPL plays a minor role in the net release of NEFA by omental adipose tissue.

The purpose of this study was to measure and model the diffusion time dependence of apparent diffusion coefficient (ADC) and fractional anisotropy (FA) derived from conventional prostate diffusion-weighted imaging methods as used in recommended multiparametric MRI protocols. Diffusion tensor imaging (DTI) was performed at 9.4 T with three radical prostatectomy specimens, with diffusion times in the range 10–120 ms and b-values 0–3000 s/mm2. ADC and FA were calculated from DTI measurements at b-values of 800 and 1600 s/mm2. Independently, a two-component model (restricted isotropic plus Gaussian anisotropic) was used to synthesize DTI data, from which ADC and FA were predicted and compared with the measured values. Measured ADC and FA exhibited a diffusion time dependence, which was closely predicted by the two-component model. ADC decreased by about 0.10–0.15 μm2/ms as diffusion time increased from 10 to 120 ms. FA increased with diffusion time at b-values of 800 and 1600 s/mm2 but was predicted to be independent of diffusion time at b = 3000 s/mm2. Both ADC and FA exhibited diffusion time dependence that could be modeled as two unmixed water pools — one having isotropic restricted dynamics, and the other unrestricted anisotropic dynamics. These results highlight the importance of considering and reporting diffusion times in conventional ADC and FA calculations and protocol recommendations, and inform the development of improved diffusion methods for prostate cancer imaging.

Non-Gaussian diffusion dynamics was investigated in the two distinct water populations identified by a biexponential model of diffusion in prostate tissue. Diffusion-weighted MRI (DWI) signal attenuation was measured ex vivo in two formalin-fixed prostates at 9.4 T with diffusion times Δ = 10, 20 and 40 ms, and b values in the range 0.017-8.2 ms/µm(2) . A conventional biexponential model was compared with models in which either the lower diffusivity component or both of the components of the biexponential were stretched. Models were compared using Akaike's Information Criterion (AIC) and a leave-one-out (LOO) test of model prediction accuracy. The doubly stretched (SS) model had the highest LOO prediction accuracy and lowest AIC (highest information content) in the majority of voxels at Δ = 10 and 20 ms. The lower diffusivity stretching factor (α2 ) of the SS model was consistently lower (range ~0.3-0.9) than the higher diffusivity stretching factor (α1 , range ~0.7-1.1), indicating a high degree of diffusion heterogeneity in the lower diffusivity environment, and nearly Gaussian diffusion in the higher diffusivity environment. Stretched biexponential models demonstrate that, in prostate tissue, the two distinct water populations identified by the simple biexponential model individually exhibit non-Gaussian diffusion dynamics.

Localized surgical therapy and surveillance examines the evidence and practice of two of the most important aspects of management of localized bladder cancer. The first part, surgical therapy, comprises preoperative assessment (including preoperative imaging studies, laboratory investigations, and antibiotic prophylaxis) followed by transurethral resection of bladder tumor. This section explores the principles of TURBT, including resection depth, staged resections, and bladder drainage. Specific circumstances such as tumors at the ureteral orifices, lateral/anterior walls, within diverticulae and reresection are specifically addressed.

Pain is a significant problem following spinal cord injury (SCI) and has a major influence on quality of life and the ability to engage in rehabilitation. Surgery is often indicated in the management of spinal cord injury to stabilise the spine and prevent further neurological deficit. However, the relationship between surgical intervention and the presence of pain following SCI is unclear. We performed a prospective, longitudinal study of 100 individuals with traumatic SCI to determine the prevalence of different types of SCI pain at 2, 4, 8, 13, 26 and 52 weeks following SCI and to determine whether there was a relationship between surgical intervention and the presence or absence of specific types of SCI pain. We found that surgical intervention was associated with a significantly higher prevalence of musculoskeletal pain at 2 weeks but not at 4, 8, 13, 26 and 52 weeks following injury, when compared with those who did not have surgery. There were no significant differences in the prevalence of visceral, neuropathic at level or neuropathic below level pain in the surgical and non-surgical groups at any stage. The results from this study suggest that apart from an increased prevalence of musculoskeletal pain at 2 weeks following SCI in those who undergo surgery, there is no significant relationship between surgical intervention and the presence of SCI pain.

To compare the theoretical information content of four popular models of diffusion-weighted signal attenuation.Four whole prostates were imaged fresh unfixed and fixed at 9.4T. Biexponential, kurtosis, stretched exponential, and monoexponential models were ranked using Akaike's Information Criterion (AIC) with validation by a leave-one-out test of model prediction error.For unfixed tissue measurements (b-value range: 17-2104 s/mm(2)) the biexponential and kurtosis models had similar information content to each other and this was distinctly higher than for the stretched and monoexponential models. In fixed-tissue measurements (b-value range: 17-8252 s/mm(2)), the biexponential model had much higher information content than the three other models.AIC-based model ranking is consistent with an independent prediction accuracy test. Biexponential and kurtosis models consistently perform better than stretched and monoexponential models. The biexponential model has increasing superiority over all three other models as maximum b-value increases above ∼2000 s/mm(2).

To evaluate the effect of formalin fixation on biexponential modeling of diffusion decay in prostate tissue.Three whole prostate specimens were imaged unfixed immediately postsurgery, and again after formalin fixation. Diffusion-weighted imaging was performed over an extended range of b-values and a biexponential model fitted to the signal decay curves.Tissue fixation resulted in a 35%, 20%, and 20% reduction in mean apparent diffusion coefficient of the higher diffusivity fit component for the three organs, respectively, and a 64%, 57%, and 45% reduction in mean apparent diffusion coefficient of the lower diffusivity component. The mean signal fraction of the higher diffusivity component was increased by 23%, 5%, and 1%, respectively. The effect of fixation did not appear to vary according to tissue type or glandular zone.Formalin fixed tissue appears to provide a stable model for detailed investigation of the microscopic biophysical basis of diffusion phenomena observed in vivo. Diffusivity changes that result from fixation may provide information about the microscopic environments of the biexponential components.

Magnetic resonance microimaging was used to measure diffusion decay over an extended b-factor range in a formalin-fixed normal prostate sample and a Gleason pattern 3+4 cancer tissue sample. The coefficients of biexponential fits to diffusion decay data from 1600 voxels of dimension 160 x 160 x 160 mu m3 in each sample were correlated with underlying epithelial and stromal compartment partial volumes estimated from high-resolution apparent diffusion coefficient (ADC) data (40 x 40 x 40 mu m3 voxels) from the same tissue. In the normal tissue sample, the signal fractions of the low and high ADC components of the biexponential fits correlated linearly with partial volumes of epithelial tissue (R2 = 0.6) and stromal tissue (R2 = 0.5), respectively. Similar but weaker correlations were observed in the cancer sample. Epithelium-containing high spatial resolution voxels appeared to be composed of similar to 60% low ADC and similar to 40% high ADC component. Stromal voxels appeared to be composed of similar to 20% low ADC and similar to 80% high ADC component. This preliminary report suggests that distinctly different diffusion properties in microscopically adjacent cell types contribute to the multiexponential diffusion decay phenomenon in prostate tissue. Magn Reson Med, 2012. (c) 2011 Wiley Periodicals, Inc.

Diffusion tensor microimaging at 16.4 T with 40 μm isotropic voxels was used to investigate anisotropic water diffusion in prostate tissue at spatial resolution approaching the cellular scale. Nine normal glandular tissue samples were collected from the peripheral zone of six formalin fixed radical prostatectomy specimens. Fibromuscular stromal tissue exhibited microscopic diffusion anisotropy (mean fractional anisotropy range 0.47-0.66) significantly higher (P0.01, Student's t-test) than in epithelium-containing voxels (mean fractional anisotropy range 0.31-0.54) in six of the seven normal tissue samples in which both compartments could be measured. Fiber tracking demonstrated principle stromal fiber directions consistent with myocyte orientation seen on light microscopy of the same sample. Diffusion tensor microimaging may be valuable for investigation of variable results from attempts to measure diffusion anisotropy in the prostate in vivo.

MR microimaging at 16.4 T with 40-μm isotropic voxels was used to investigate compartmentation of water diffusion in formalin-fixed prostate tissue. Ten tissue samples (~ 28 mm(3) each) from five organs were imaged. The mean diffusivity of epithelial, stromal, and ductal/acinar compartments was estimated by two methods: (1) manual region of interest selection and (2) Gaussian fitting of voxel diffusivity histograms. For the region of interest-method, the means of the tissue sample compartment diffusivities were significantly different (P0.001): 0.54 ± 0.05 μm(2)/ms for epithelium-containing voxels, 0.91 ± 0.17 μm(2)/ms for stroma, and 2.20 ± 0.04 μm(2)/ms for saline-filled ducts. The means from the histogram method were also significantly different (P0.001): 0.45 ± 0.08 μm(2)/ms for epithelium-containing voxels, 0.83 ± 0.16 μm(2)/ms for stroma, 2.21 ± 0.02 μm(2)/ms for duct. Estimated partial volumes of epithelial, stromal, and ductal/acinar compartments in a "tissue only" subvolume of each sample were significantly different (P0.02) between cancer and normal tissue for all three compartments. It is concluded that the negative correlation between apparent diffusion coefficient and cancer Gleason grade observed in vivo results from an increase of partial volume of epithelial tissue and concomitant decrease of stromal tissue and ductal space.