Accuracy of Magnetic Resonance Imaging-Ultrasound Fusion-Guided and Systematic Biopsy of the Prostate.

OBJECTIVES: Prostate multiparametric magnetic resonance imaging (mpMRI) with subsequent targeted biopsy of suspicious lesions have a critical role in the diagnostic workup of prostate cancer. The objective was to evaluate the diagnostic accuracy of systematic biopsies, targeted biopsies, and the combination of both in prostate cancer detection. METHODS: From 1-1-2013 to 1-6-2022, biopsy-naïve and prior biopsy-negative patients who underwent both systematic and targeted biopsies were included. MRIs were evaluated according to PI-RADS with biopsy threshold set at PI-RADS ≥3. Systematic biopsies consisted of 8-12 cores, based on prostate volume. Overall prostate cancer and clinically significant cancer (Gleason Score ≥3 + 4) detection rates were stratified based on PI-RADS and location within the prostate, and compared between biopsy types using McNemar's test. RESULTS: Among 867 patients, 615 had prostate cancer, with 434 clinically significant cases. Overall detection rates were: PI-RADS 3 48%, PI-RADS 4 72% and PI-RADS 5 90%. Detection rates for clinically significant cancer were 21%, 53% and 72%, respectively. The combination of biopsy methods was most accurate in detecting clinically significant prostate cancer (P < 0.001). Targeted biopsies alone detected more clinically significant prostate cancer than systematic biopsies alone (43.1% versus 40.3%, P = 0.046). For posterior PI-RADS 5 lesions, no statistically significant difference was found between all biopsy methods. CONCLUSIONS: In the detection of clinically significant prostate cancer, the combination of systematic and targeted biopsies proves most effective. Targeted biopsies rarely missed significant cancer for posterior PI-RADS 5 lesions, suggesting systematic biopsies could be reserved for instances where targeted biopsy results are negative. ADVANCES IN KNOWLEDGE: This study emphasizes on the efficacy of mpMRI and targeted biopsies in suspected prostate cancer in real-world clinical context. For PI-RADS 5 lesions, systematic biopsies provide limited clinical benefit and may only be necessary when targeted biopsy results are negative.

Partial bladder outlet obstruction reduces the tissue antioxidant capacity and muscle nerve density of the guinea pig bladder.

AIMS: Reactive nitrogen and oxygen species (RNOS) likely play a role in the development of bladder dysfunction related to bladder outlet obstruction. Antioxidants protect against these free radicals. The aim of our study was to investigate the effect of bladder outlet obstruction on the endogenous antioxidant status of the bladder and to correlate this to bladder structure and function. METHODS: In 16 guinea pigs either a partial outlet obstruction or a sham operation was induced. The contractile responses of detrusor strips to electrical field stimulation (EFS), acetylcholine, potassium, and ATP were monitored 4 weeks after the operation. The nerve density in bladder tissue was determined by using the non-specific nerve marker PGP 9.5. Separate antioxidants and the total antioxidant status were assessed using the trolox equivalent antioxidant capacity (TEAC) test. RESULTS: Contractile responses of detrusor strips to EFS were for the greater part based on neurogenic stimulation. The nerve-mediated responses in strips from obstructed bladders were lower compared to the sham group. Obstructed bladders showed a patchy denervation and the nerve density was significantly lower compared to the sham group. The total antioxidant capacity, the glutathione and the glutathione reductase (GR) levels significantly decreased in obstructed bladders compared to the sham group. CONCLUSION: This study demonstrates that the antioxidant status of guinea pig bladders exposed to outlet obstruction decreased which might be associated with the observed reduction in nerve density. The results strengthen the hypothesis that oxidative stress is involved in the pathophysiology of bladder dysfunction related to obstructed bladders. Neurourol. Urodynam. 28:461-467, 2009. (c) 2008 Wiley-Liss, Inc.

Lipid peroxidation product 4-hydroxynonenal contributes to bladder smooth muscle damage.

OBJECTIVES: Bladder outlet obstruction is correlated with an increased peroxidation of lipids. The aldehyde 4-hydroxynonenal (HNE) is produced in relative large amounts during lipid peroxidation. The aim of this study was to investigate the effect of HNE on excitation-contraction coupling of detrusor smooth muscle. METHODS: We used smooth muscle strips from pig urinary bladder. Contractile responses to electrical field stimulation (EFS) (4 to 32 Hz), carbachol (10(-8) to 3.10(-5) M), and potassium (65.3 mM) were monitored before and after the addition of HNE. We investigated the effect of the synthetic thiol inactivator N-ethylmaleimide (NEM) on the stimulation pathways and compared it with the HNE-mediated effect. RESULTS: Responses of detrusor strips to EFS were for the greater part based on neurogenic stimulation and the release of acetylcholine. HNE (100 microM) diminished contractile responses to EFS and carbachol to the same extent. The pD(2) value of the carbachol concentration response curve did not decrease after exposure to HNE. The maximal effect obtained with carbachol was significantly reduced after 100 microM HNE treatment. Contractions induced by potassium were affected in a similar degree by HNE compared with EFS- and carbachol-induced responses of comparable amplitude. Incubation of bladder strips with NEM had similar effects on pharmacological responses compared with HNE exposure. CONCLUSIONS: 4-Hydroxynonenal affects pig bladder contractility. L-type calcium channels and or the contractile system of the bladder muscle are susceptible to HNE-mediated damage. The cholinergic nerves and the muscarinic receptor signaling system remain largely unaffected. The effects of HNE are most likely mediated via alkylation of sulfhydryl groups.

Damage to the bladder neck alters autonomous activity and its sensitivity to cholinergic agonists.

OBJECTIVE: To identify and describe changes to the motor component of the motor/sensory system, which contributes to sensation during the filling phase of the micturition cycle, as a result of surgically induced bladder pathology, i.e. damage to the bladder neck and outlet obstruction. MATERIALS AND METHODS: Adult male guinea pigs (294-454 g) were assigned initially into three groups: (i) normal guinea pigs with no surgical intervention (control, seven); (ii) guinea pigs which, with full surgical anaesthesia, had a silver ring implanted around the bladder neck (obstructed, 13); and (iii) guinea pigs operated to expose the bladder neck but with no implantation of a ring (sham, six). At 2-4 weeks after surgery the bladders were isolated, weighed and the pressure recordings used to identify autonomous activity. RESULTS: The bladder weights in all operated groups, including the sham, were greater than controls. Bladder weights in the obstructed guinea pigs varied considerably, reflecting the degree of pathological change. Consequently, bladders from this group were divided into those with high (OBH) and those with low bladder weight (OBL). The mean (sd) amplitudes of the autonomous contractions were 1.1 (0.1), 10.8 (1.8), 11.4 (2.5) and 17.1 (4.0) cmH(2)O in control, sham, OBL and OBH bladders, respectively, indicating a progressive alteration in function with the pathology. The changes in the sham group suggested that the pathological changes were not the result of obstruction but damage to the bladder neck, the implantation of the silver rings exacerbating the damage. There were episodes of rapid phasic activity (bursts) in 10 of 13 of the ring-implanted bladders, and in two of six in the sham group, but never in controls. Neither the autonomous activity nor the bursts were affected by tetrodotoxin (1 microm) or atropine (3 microm) but they were abolished by noradrenaline (3 microm). In control bladders, adding the muscarinic agonist arecaidine produced a transient acceleration of phasic activity and increased the amplitude of the contractions. There was a similar acceleration of activity in all the operated groups but the concentrations needed to achieve an increase in frequency were significantly lower, the relative sensitivity to arecaidine being OBH >/= OBL > sham > control. CONCLUSION: The mechanism involved in controlling the frequency of the motor component of the motor/sensory system, the 'pacemaker', appears to become progressively 'supersensitive' to cholinergic stimulation with the development of pathology. These observations are discussed in relation to the motor/sensory system and the origins of sensation in the bladder. The argument is proposed that damage to the bladder neck, not obstruction per se, results in altered nonmicturition activity which contributes to increased afferent output. In turn this contributes to the increased sensations of urge associated with bladder dysfunction. The cholinergic regulation of this altered 'pacemaker' might be the target for one of the therapeutic actions of anticholinergic drugs.

The effects of exogenous prostaglandins and the identification of constitutive cyclooxygenase I and II immunoreactivity in the normal guinea pig bladder.

OBJECTIVES: To establish the functional consequences of exposing the isolated whole bladder preparation to exogenous prostaglandins (PGE(1), PGE(2), PGF(2alpha)) and to determine which cells express cyclooxygenase (COX) types I and II, to generate PG to effect these changes in vivo. MATERIALS AND METHODS: Fifteen female guinea pigs (270-350 g) were used, i.e. seven for structural studies and eight for physiological measurement. For the structural study pieces of the lateral wall were incubated separately in Krebs' solution at 36 degrees C, gassed with 95% O(2) and 5% CO(2) with 1 mm isobutyl-methyl-xanthene. Individual pieces were then exposed to 100 microm of the nitric oxide (NO) donor NONOate for 10 min; control tissues remained in Krebs' solution. Tissues were then fixed in 4% paraformaldehyde. For the physiological experiments bladders were isolated and a cannula inserted into the urethra to monitor intravesical pressure. The bladders were suspended in a chamber containing carboxygenated physiological solution at 33-36 degrees C. All drugs were added to the abluminal bladder surface. RESULTS: In the resting bladder there were small spontaneous transient rises in pressure, i.e. autonomous activity. Exposure to PGE(2) (3-300 nM) resulted in an increase in basal pressure on which were superimposed autonomous activity, which was increased both in amplitude and frequency. The changes in the amplitude and frequency depended on the concentration of PGE(2). After a brief exposure (240 s) to PGE(2) the augmentation of the autonomous activity continued for >60 min despite regular washing. The responses were similar with PGE(1) but the responses to PGF(2alpha) and arachidonic acid were reduced. The augmented activity was reduced by the EP1/EP2 receptor blocking agent AH6809 (10 microm). Using an antibody to the 70 kDa constitutive form (COX I), COX I immunoreactivity (COX I-IR) was located in cells in the basal urothelium, in lamina propria and cells on the surface of the inner muscle bundles. There were few COX I-IR cells associated with the outer muscle bundles. The COX I-IR cells lying within the lamina propria were distinct from the suburothelial cells which respond to NO with an increase in cGMP. The lamina propria COX I-IR cells appeared to form a network surrounding muscle trabeculae within the inner muscle layer. COX II-IR was associated with the nuclei of cells in the urothelium, lamina propria and muscle. CONCLUSIONS: These data show that PGs regulate autonomous activity. Potential sources of endogenous PG were identified. It is unclear how the PGs produced by these cells alter autonomous activity. There might be a direct activation of the muscle by PGs released by the network of superficial muscle interstitial cells, or PG released from the urothelium might influence phasic contractile activity via networks of COX I-IR interstitial cells. The possible roles and importance of this mechanism for bladder physiology and pathology are discussed.

Oxidative stress reduces the muscarinic receptor function in the urinary bladder.

AIMS: Several pathophysiological conditions in the urinary bladder, for example, ischemia/reperfusion and inflammation are characterized by the formation of reactive oxygen species (ROS). The ROS are highly toxic because they can destroy proteins, DNA, and lipids. The aim of this study was to investigate the effect of oxidative stress on excitation-contraction coupling of detrusor smooth muscle. MATERIALS AND METHODS: Smooth muscle strips were dissected from pig urinary bladder and mounted in organ baths. Oxidative stress was mimicked by the addition of Cumene hydroperoxide (CHP), a lipophilic hydroperoxide, to the organ baths. Contractile responses to electrical field stimulation (EFS: 4-32 Hz), carbachol (10(-8)-3 x 10(-5) M), potassium (65.3 mM), and ATP (1 mM) were monitored before and after the addition of CHP. RESULTS: Responses of detrusor strips to EFS were for the greater part based on neurogenic stimulation and the release of acetylcholine. CHP diminished contractile responses to EFS and carbachol to the same extent. The pD(2) value of the carbachol concentration-response curve decreased significantly after exposure to 0.1 mM, 0.4 mM, 0.8 mM CHP. Furthermore the maximal effect obtained with carbachol was significantly reduced after 0.1 mM, 0.4 mM, and 0.8 mM CHP treatment. Contractions induced by potassium and ATP were significantly less affected by oxidative stress compared to EFS- and carbachol-induced responses of comparable amplitude. CONCLUSIONS: The results of our study demonstrate that oxidative stress induced by CHP affects pig bladder contractility. The muscarinic receptor signaling system is severely damaged. L-type calcium channels and the contractile system are less affected and cholinergic nerves remain largely unaffected.

Galangin protects pig detrusor nerves from repetitive field stimulation and anoxia/glucopenia injury.

OBJECTIVES: To test the capability of the flavonoid galangin to protect pig urinary bladder from damage due to a period of repetitive field stimulation as well as a period of anoxia/glucopenia and reperfusion. METHODS: Smooth muscle strips of the pig bladder were mounted for tension recording in small organ baths and the strips underwent either 1.5 hours of repetitive field stimulation at 32 Hz for 15 seconds every 5 minutes or under anoxia/glucopenia and reperfusion conditions. Galangin, at different concentrations, was added to the reperfusion Krebs solution to check the effect of this flavonoid compared with untreated strips under the same conditions. A group of experiments was performed to examine its possible underlying mechanisms. RESULTS: Repetitive field stimulation for 1.5 hours caused a progressive decrease in the maximal contractile response to electrical field stimulation (34% decrease). Galangin (10(-7) M) partially prevented the progressive decrease in the contractile response. This effect was significantly reduced when verapamil was added to the solution. Galangin significantly improved the response of strips to electrical field stimulation under anoxia/glucopenia and reperfusion conditions compared with untreated tissues. CONCLUSIONS: Galangin has a protective effect on bladder contractility by an action that at least, in part, depends on l-type calcium channels. Furthermore, galangin protects detrusor nerves against the anoxia/glucopenic and reperfusion damage.

The inhibitory effect of the flavonoid galangin on urinary bladder smooth muscle contractility is mediated in part by modulation of Ca2+ release from intracellular stores.

The present study was designed to examine the effect of the flavonoid galangin on the muscarinic receptor mediating a carbachol-induced contraction and to investigate the effect of the flavonoid on Ca (2+) release from intracellular stores in the urinary bladder of the pig. Galangin (10(-7) -10(-4)M) produced a concentration-dependent inhibition of the contractile responses to electrical field stimulation (EFS) and carbachol (10(-5)M). Galangin (3 x 10(-5)M) reduced muscle contractions evoked by carbachol (10(-5)M) in calcium-containing solution as well as contractions evoked by carbachol and caffeine (2 x 10(-2)M) in Ca(2+)-free solutions significantly. The flavonoid had a stronger effect on the maximal force of the contractions induced by caffeine, compared to contractions induced by carbachol. These results suggest that galangin has an important effect on the intracellular calcium mobilization, which might be attributed predominantly to its influence on ryanodine-receptors.

Multiple-signaling pathways are involved in the inhibitory effects of galangin on urinary bladder contractility.

AIMS: Flavonoids comprise a large group of natural polyphenolic compounds, which possess a wide spectrum of physiological and pharmacological effects. Recently, the flavonoid galangin was found to modulate smooth muscle contractility. The aim of the present study was to investigate the mechanism of actions of galangin on pig bladder smooth muscle and to characterize its potential as an alternative inhibitor of bladder smooth muscle contraction. MATERIALS AND METHODS: Strips of pig detrusor muscle were mounted in separate 6-ml organ baths containing Krebs solution. The contractile response to carbachol (10(-8)-10(-4)M), potassium (2x10(-2)-10(-1)M), and electrical field stimulation-EFS (2-32 Hz) were determined before and after the addition of galangin (3x10(-5)M). The contractile responses to carbachol in calcium-free Krebs' solution plus EGTA and L-type channel blocker were determined in the absence and presence of the flavonoid. Furthermore, the effect of galangin was also evaluated after the administration in the bath of a number of antagonists/inhibitors including a combination of propranolol, phentolamine, capsazepine, and verapamil. Student's t-test and one factor ANOVA were used to determine the statistical significance of the effects. RESULTS: Galangin inhibited the maximal contractile response to carbachol and potassium by 57.41% (P<0.01) and 33.52% (P<0.05), respectively. The maximum force of the carbachol-evoked contractions in calcium-free solution after incubation with galangin was 32% of the maximum initial force (Emax.initial: 5.8387+/-0.72 mN, Emax.Galangin: 1.9157+/-0.30 mN, P<0.01). The maximal contractile responses to EFS at 2, 4, 8, 16, and 32 Hz were reduced, compared to control, by 91.61% (P<0.01), 79.46% (P<0.01), 70.54% (P<0.01), 61.10% (P<0.01), and 9.8% (P>0.05), respectively. The inhibitory effect of galangin was unaffected by a combination of propranolol, phentolamine, and capsazepine (P>0.05). However, when verapamil was added to the medium, the inhibitory effects of galangin were partially blocked. CONCLUSIONS: Galangin, at high concentrations, exerts an inhibitory effect on pig bladder smooth muscle contractility through the inhibition of calcium influx and the modulation of intracellular calcium movement. Furthermore, we have demonstrated that the inhibitory effect of galangin involves, at least in part, L-type calcium channels pathways.

Flavonoid galangin prevents smooth muscle fatigue of pig urinary bladder.

There is increasing evidence that the generation of free radicals plays a role in the development of bladder dysfunction. Flavonoids are a group of polyphenolic compounds with broad pharmacological activity. In the present study, the protective effects of the flavonoid galangin on the progressive decrease of bladder smooth muscle contractile responses during repetitive field stimulation (RFS; a model for muscular fatigue) were demonstrated. Pig detrusor strips were mounted for tension recording in organ baths aand were subjected to RFS for 90 min at 32 Hz for 15 s every 5 min. The strips were then washed four times with fresh buffer and allowed a period of recovery for 90 min. The 90 min of RFS caused a progressive decrease in maximal contractile response to electrical field stimulation and to muscarinic agonist-induced contractions (34% and 46% decrease, respectively). Galangin (10(-7) M) prevented the decrease in contractile smooth muscle response of strips to electrical field stimulation during RFS compared with untreated tissues. The antioxidant activity of galangin was assessed by measuring its ability to inhibit the lipid peroxidation induced by iron and ascorbate in rat liver microsomes (IC50 1.7+0.12x10(-6) M). If the data are confirmed in-vivo, exogenously administered galangin may be a new approach in the prevention and/or treatment of bladder dysfunction.