Paul Sved

ICUD-EAU international consultation on bladder cancer 2012: Non-muscle-invasive urothelial carcinoma of the bladder

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.

Oncogenic Action of Secreted Phospholipase A2 in Prostate Cancer

Mortality from prostate cancer is associated with progression of tumors to androgen-independent growth and metastasis. Eicosanoid products of both the cyclooxygenase (COX) and lipoxygenase (LOX) pathways are important mediators of the proliferation of prostate cancer cells in culture and regulate tumor vascularization and metastasis in animal models. Pharmacologic agents that block either COX or LOX products effectively reduce the size of prostate cancer xenografts. Phospholipase A2 (PLA2) enzymes regulate the provision of arachidonic acid to both COX- and LOX-derived eicosanoids, and a secreted form of the enzyme (sPLA2-IIA) is elevated in prostate cancer tissues. Here, we show by immunohistochemistry, in patients receiving androgen ablation therapy, that sPLA2-IIA remains elevated in remaining cancer cells relative to benign glands after treatment. Furthermore, sPLA2-IIA expression seen in benign glands is substantially decreased after androgen depletion, whereas cytosolic PLA2-α (cPLA2-α) levels are unchanged. sPLA2-IIA mRNA expression is detectable and inducible by androgen (0.01–10 nmol/L) in the androgen-sensitive cell line LNCaP, and exogenous addition of sPLA2-IIA (1–100 nmol/L), but not an inactive sPLA2-IIA mutant (H48Q), results in a dose-dependent increase in cell numbers or the fraction of cells in G2-M phase, which is inhibited by sPLA2-IIA-selective inhibitors. The effect of exogenous sPLA2-IIA can also be blocked by inhibition of cPLA2-α, suggesting a role for cPLA2-α in mediating sPLA2-IIΑ action. sPLA2-IIA inhibitors suppressed basal proliferation in LNCaP cells and in the androgen-independent, sPLA2-positive cell line PC3 but not in the sPLA2-IIA-negative androgen-independent cell line DU145. Established PC3 xenograft tumors grew more slowly in mice treated with sPLA2-IIA inhibitors than those treated with saline only. The PLA2 enzymes, and sPLA2-IIA in particular, thus represent important targets for the treatment of sPLA2-IIA-positive androgen-independent prostate cancer.

Small cell carcinoma of the bladder.

(a) Derivation from the amine precursor uptake and decarboxylation (APUD) system. APUD cells are ubiquitous neuroendocrine cells next to the basal lamina of epithelial surfaces including the bladder [6]. These cells contain dense cytoplasmic granules thought to be the origin of peptide-hormone secretion. Such neurosecretory granules may also be identified in SCC. The prevalence of neurosecretory granules as well as neuroendocrine markers in SCC prompted many authors to believe that extrapulmonary SCC derives from APUD cells [3–6]. APUD cells are known to give rise to adenomas, carcinomas and carcinoid-like tumours. Despite the morphological similarity between APUD cells and some SCCs, this theory fails to explain the finding that a high proportion of extrapulmonary SCC coexist with malignancies of epithelial origin such as TCC [2].

16 T Diffusion microimaging of fixed prostate tissue: Preliminary findings

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 μm 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 × 10−3 mm2/sec). Diffusion in the fibromuscular stromal matrix is relatively less restricted (D = 0.7 ± 0.1 × 10−3 mm2/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 × 10−3 mm2/sec). Distinct stromal and epithelial diffusion compartments are the most likely origin of biexponential diffusion decay observed in vivo. Magn Reson Med, 2011.

Information Theoretic Ranking of Four Models of Diffusion Attenuation in Fresh and Fixed Prostate Tissue Ex Vivo

To compare the theoretical information content of four popular models of diffusion‐weighted signal attenuation.

Microscopic diffusion anisotropy in formalin fixed prostate tissue: preliminary findings.

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 (P < 0.01, Students 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. Magn Reson Med, 2012.

Biexponential diffusion decay in formalin‐fixed prostate tissue: Preliminary findings

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 × 160 × 160 μm3 in each sample were correlated with underlying epithelial and stromal compartment partial volumes estimated from high‐resolution apparent diffusion coefficient (ADC) data (40 × 40 × 40 μm3 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 ∼60% low ADC and ∼40% high ADC component. Stromal voxels appeared to be composed of ∼20% low ADC and ∼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.

Assessment of non-Gaussian diffusion with singly and doubly stretched biexponential models of diffusion-weighted MRI (DWI) signal attenuation in prostate tissue.

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 Akaikes 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

Effect of formalin fixation on biexponential modeling of diffusion decay in prostate tissue.

To evaluate the effect of formalin fixation on biexponential modeling of diffusion decay in prostate tissue.

Microscopic diffusivity compartmentation in formalin-fixed prostate tissue.

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 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 μm2/ms for epithelium‐containing voxels, 0.91 ± 0.17 μm2/ms for stroma, and 2.20 ± 0.04 μm2/ms for saline‐filled ducts. The means from the histogram method were also significantly different (P < 0.001): 0.45 ± 0.08 μm2/ms for epithelium‐containing voxels, 0.83 ± 0.16 μm2/ms for stroma, 2.21 ± 0.02 μm2/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.