Towards reliable diagnostics of prostate cancer via breath.

Early detection of cancer is a key ingredient for saving many lives. Unfortunately, cancers of the urogenital system are difficult to detect at early stage. The existing noninvasive diagnostics of prostate cancer (PCa) suffer from low accuracy (< 70%) even at advanced stages. In an attempt to improve the accuracy, a small breath study of 63 volunteers representing three groups: (1) of 19 healthy, (2) 28 with PCa, (3) with 8 kidney cancer (KC) and 8 bladder cancer (BC) was performed. Ultrabroadband mid-infrared Fourier absorption spectroscopy revealed eight spectral ranges (SRs) that differentiate the groups. The resulting accuracies of supervised analyses exceeded 95% for four SRs in distinguishing (1) vs (2), three for (1) vs (3) and four SRs for (1) vs (2) + (3). The SRs were then attributed to volatile metabolites. Their origin and involvement in urogenital carcinogenesis are discussed.

[Role of pressure and temperature in ureterorenoscopy and percutaneous nephrolitholapaxy : Pressure and temperature changes during stone treatment]. / Die Rolle von Druck und Temperatur bei Ureterorenoskopie und perkutaner Nephrolitholapaxie : Druck- und Temperaturveränderungen im Rahmen der Steintherapie.

Ureterorenoscopy and percutaneous nephrolitholapaxy are minimally invasive procedures and are the standard procedures for the treatment of kidney stones and ureteral calculi. To achieve an adequate view, in both methods an optimal and sufficient irrigation flow is necessary. The intrarenal pressure is influenced by the irrigation pressure and irrigation volume and has to be controlled. Pathologically elevated intrarenal pressure can lead to irreversible damage of the kidneys. Lasers are frequently used for stone fragmentation. It has been shown in studies that the laser energy can lead to an increase in the temperature and that thermal effects can also damage the kidneys. This article provides the surgeon with an overview about the effects of temperature and pressure changes during ureterorenoscopy and percutaneous nephrolitholapaxy and how damages can be avoided.

[Management of ureteral injuries]. / Management von Harnleiterverletzungen.

Ureteral injuries account for less than 3% of genitourinary injuries. Most of them are caused iatrogenically during abdominal surgery. The symptoms are often non-specific and do not aid in diagnosis. The later the injury is detected, the more often complications occur. Therefore, in such situations it is important to consider the possibility of ureteral injury and initiate further diagnostic steps as soon as possible. A variety of diagnostic tests are available. In addition to the direct inspection of the ureters and retrograde ureteropyelography, computed tomography (CT) urography is routinely used. Based on the time of diagnosis as well as the extent and the localization of the injury, the further procedure can be determined. For minor injuries, the insertion of a ureteral splint is usually the treatment of choice. In the case of higher grade damage, operative reconstruction by one of several possible surgical procedures is indicated.

[Value of imaging in upper urinary tract tumors]. / Wertigkeit der Bildgebung bei Tumoren des oberen Harntraktes.

BACKGROUND: Staging of bladder cancer, hematuria as well as the evaluation of unclear findings of the kidneys and ureters are the most frequent indications for imaging of the upper urinary tract (UUT). Endourological assessment of the UUT is much more invasive compared to imaging of the bladder, raising the question of the optimal imaging technique. Several technical improvements regarding computed tomography (CT) as well as magnetic resonance imaging (MRI) were implemented in recent years. OBJECTIVES: To compare the efficacy and limitations of the most important imaging techniques regarding the UUT. MATERIALS AND METHODS: Systematic review of the literature and current German, European, and American guidelines regarding bladder cancer, urothelial carcinoma of the UUT and hematuria. RESULTS: The CT-based urography has superseded excretory urography and is the first choice for imaging of the UUT. In case of contraindications, MRI is a feasible alternative. In all cases, a urography phase is indispensable. CONCLUSIONS: Imaging of the UUT has to be used in a reasonable combination together with endourological methods and cytology. Optical coherence tomography, confocal laser endomicroscopy and scientific innovations such as radiomics might improve UUT imaging and differential diagnosis of UUT lesions in the future.

[Stricture of the vesicourethral anastomosis after radical prostatectomy]. / Die Striktur der vesikourethralen Anastomose nach radikaler Prostatektomie.

BACKGROUND: The development of a stricture of the vesicourethral anastomosis is a serious complication after radical prostatectomy. Strictures occur in 5-8% of patients after radical prostatectomy. SYMPTOMS: Usually the clinical symptoms include an irritative and obstructive component similar to benign prostatic hyperplasia. In rare cases, patients suffer from partial or complete stress incontinence as a result of the anastomotic stricture. DIAGNOSTICS: The diagnostic workup is similar to the procedure for urethral strictures. In addition to uroflowmetry, a cystourethrogram (CUG) or, if necessary, a micturating cystourethrogram (MCU) can be performed. A urethrocystoscopy can be performed to ensure the diagnosis. THERAPY: In most cases, endoscopic procedures were performed for treatment. Beside a transurethral dilation of the stricture or the Sachse urethrotomy, the most common procedure is transurethral resection to treat the stricture. However, all procedures are associated with a high recurrence rate. In recurrent strictures, open surgical procedures, usually a perineal reanastomosis, should performed early. CONCLUSION: Endourological procedures like transurethral resection are a good treatment option, but due to the high recurrence rates, open surgical procedures should be discussed and if necessary should be performed early.

[Diagnostic workup of urethral strictures]. / Diagnostischer Workup bei der Harnröhrenstriktur.

Urethral stricture is a narrowing of the urethra due to scar tissue. It causes obstructive voiding dysfunction and can lead to long-term damage of the entire urinary tract. The probability of therapeutic success is dampened by a high rate of recurrence. Therefore, a careful taking of the patient's history and further diagnostics are crucial for finding the appropriate form of therapy. This review highlights the clinical presentation and diagnostic workup of urethral strictures.

[Urethral stricture : From diagnostics to appropriate treatment]. / Urethrastriktur : Von der Diagnostik bis zur sinnvollen Therapie.

Before making a treatment decision for patients presenting with a urethral stricture, following anamnesis and general examinations, appropriate diagnostics are necessary. This includes at least uroflowmetry and cystourethrography and the use of ultrasound and cystoscopy may be of additional help. The curative treatment of a urethral stricture is always an operation. Besides endourological procedures, open surgery for urethral reconstruction is also performed. This article aims to give an overview about the necessary diagnostic measures and the pros and cons of the different operative therapies.

Dual energy can accurately differentiate uric acid-containing urinary calculi from calcium stones.

PURPOSE: To retrospectively evaluate the accuracy of dual-energy CT (DECT) in the detection of the chemical composition of urinary calculi in correlation with infrared spectroscopic stone analysis. METHODS: We reviewed the CT scans of 255 patients who underwent DECT due to a clinical suspicion of urolithiasis. Out of this group, we included 64 patients with clinically symptomatic urolithiasis requiring stone removal. After surgical removal of the stone by ureterorenoscopy, chemical composition was analyzed with infrared spectroscopy. We correlated DECT stone characterization results with chemical stone composition based on dual-energy indices (DEI). A total of 213 renal and ureteral stones could be removed and chemically analyzed. RESULTS: A total of 213 calculi were evaluated. Thirty eight out of sixty four (59 %) patients had >1 stone. DECT was used to differentiate stones by using DEI. Stones harboring calcium (CA) were color-coded in blue, while stones containing uric acid (UA) were colored red. Median DEI in UA-containing stones were 0.001. Non-UA-containing stones had a DEI between 0.073 for pure CA stones and 0.077 containing CA and other substances (p = 0.001; p = 0.03, respectively). Sensitivity of DECT was 98.4 % for differentiation of UA from non-UA-containing calculi. Specificity was 98.1 %. Mean effective radiation dose of DECT was 4.18 mSv (0.44-14.27 mSv), thus comparable to conventional CT scans of the abdomen. Conventional measurement of Hounsfield units did not correlate with stone composition. CONCLUSION: DECT with image post-processing reliably discriminates UA-containing calculi from all other stones, but the study offered limitations. Discrimination within the non-UA stones cannot be reliably achieved but is clinically insignificant.

Inhibition of prostate smooth muscle contraction and prostate stromal cell growth by the inhibitors of Rac, NSC23766 and EHT1864.

BACKGROUND AND PURPOSE: Medical therapy of lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH) targets smooth muscle contraction in the prostate, or prostate growth. However, current therapeutic options are insufficient. Here, we investigated the role of Rac in the control of smooth muscle tone in human prostates and growth of prostate stromal cells. EXPERIMENTAL APPROACH: Experiments were performed using human prostate tissues from radical prostatectomy and cultured stromal cells (WPMY-1). Expression of Rac was examined by Western blot and fluorescence staining. Effects of Rac inhibitors (NSC23766 and EHT1864) on contractility were assessed in the organ bath. The effects of Rac inhibitors were assessed by pull-down, cytotoxicity using a cell counting kit, cytoskeletal organization by phalloidin staining and cell growth using an 5-ethynyl-2'-deoxyuridine assay. KEY RESULTS: Expression of Rac1-3 was observed in prostate samples from each patient. Immunoreactivity for Rac1-3 was observed in the stroma, where it colocalized with the smooth muscle marker, calponin. NSC23766 and EHT1864 significantly reduced contractions of prostate strips induced by noradrenaline, phenylephrine or electrical field stimulation. NSC23766 and EHT1864 inhibited Rac activity in WPMY-1 cells. Survival of WPMY-1 cells ranged between 64 and 81% after incubation with NSC23766 (50 or 100 µM) or EHT1864 (25 µM) for 24 h. NSC23766 and EHT1864 induced cytoskeletal disorganization in WPMY-1 cells. Both inhibitors impaired the growth of WPMY-1 cells. CONCLUSIONS AND IMPLICATIONS: Rac may be a link connecting the control of prostate smooth muscle tone with proliferation of smooth muscle cells. Improvements in LUTS suggestive of BPH by Rac inhibitors appears possible.

Reduction of obstruction related bladder overactivity by the guanylyl cyclase modulators BAY 41-2272 and BAY 60-2770 alone or in combination with a phosphodiesterase type 5 inhibitor.

AIMS: To assess the urodynamic effects of soluble guanylyl cyclase (sGC) stimulator, BAY 41-2272, and activator, BAY 60-2770, (which both are able to induce cGMP synthesis even in the absence of nitric oxide (NO)) alone or in combination with a phosphodiesterase type 5 (PDE5) inhibitor, vardenafil, in a model of partial urethral obstruction (PUO) induced bladder overactivity (BO). METHODS: Fifty-six male Sprague-Dawley rats were used, 31 of them underwent PUO. Fourteen rats were used for Western blots to assess PDE5 and sGC expression. For drug evaluation cystometry without anesthesia was performed three days following bladder catheterization. RESULTS: Obstructed rats showed higher micturition frequency and bladder pressures than non-obstructed animals (Intermicturition Interval, IMI, 2.28 ± 0.55 vs. 3.60 ± 0.60 min (± standard deviation, SD); maximum micturition pressure, MMP, 70.1 ± 8.0 vs. 48.8 ± 7.2 cmH2O; both P < 0.05). In obstructed rats vardenafil, BAY 41-2272, and BAY 60-2770 increased IMI (2.77 ± 1.12, 2.62 ± 0.52, and 3.22 ± 1.04 min; all P < 0.05) and decreased MMP (54.4 ± 2.8, 61.5 ± 11.3, and 51.2 ± 6.3 cmH2O; all P < 0.05). When vardenafil was given following BAY 41-2272 or BAY 60-2770 no further urodynamic effects were observed. PDE5 as well as sGC protein expression was reduced in obstructed bladder tissue. CONCLUSIONS: Targeting sGC via stimulators or activators, which increase the levels of cGMP independent of endogenous NO, is as effective as vardenafil to reduce urodynamic signs of BO. Targeting the NO/cGMP pathway via compounds acting on sGC might become a new approach to treat BO.

[Urine marker systems for diagnosis of urothelial cancer]. / Urinmarkersysteme zur Diagnostik des Urothelkarzinoms.

Cystoscopy and urinary cytology are standard tools in the diagnostics of urothelial cancer of the urinary bladder; however, cystoscopy is invasive and urinary cytology lacks accuracy for the diagnosis of low grade tumors. More recently several alternative urinary test systems were developed with the aim to make the diagnostics of urothelial tumors more reliable; however, in general all protein-based point of care test systems have a high rate of false positive test results, especially in patients with benign disorders. Fluorescence in situ hybridization, which is highly sensitive and specific, may be a reasonable supplement to the diagnostic spectrum in patients after instillation therapy or bladder replacement. Additionally, there are several new test systems which still need to be tested in large clinical studies with respect to diagnostic accuracy.

[Management of ureteral stones]. / Management des Uretersteins.

Ureteral stones are normally clinically symptomatic as colic or flank pain. The investigation of acute flank pain by diagnostic imaging targets on the confirmation of the suspected ureteral stone and the exclusion of other diseases. Furthermore, imaging using unenhanced computed tomography (NCCT) or excretory urography (IVU) serves as a basis for treatment planning. Depending on the size and location of ureteral stones a spontaneous stone passage, medical expulsive therapy (MET), extracorporeal shock wave lithotripsy (SWL), ureterorenoscopy (URS) or initially just simple stenting can be considered. The aim of this review is to provide the reader with the necessary decision criteria for optimal care of patients in the daily routine.

[Imaging for diagnostics of urolithiasis including dual-energy CT]. / Bildgebung zur Diagnostik der Urolithiasis einschließlich Dual-Energy-CT.

Patients with stone disease usually present to the urologist with acute colic pain. For the right choice of therapy the diagnosis needs to be confirmed using one of many imaging methods, including ultrasonography, abdominal radiography, intravenous urography, non-contrast-enhanced computed tomography (CT), CT and magnetic resonance imaging (MRI) urography and dual-energy CT. The techniques differ in the availability, diagnostic sensitivity and specificity and level of radiation exposure. Compared to the others dual-energy CT allows distinction between different stone compositions with high accuracy and can affect the choice of therapy. This article on imaging and diagnosis of urolithiasis discusses the different imaging methods and highlights dual-energy CT and its distinctive features.

[Etiology and pathophysiology of benign prostate hyperplasia]. / Ätiologie und Pathophysiologie der benignen Prostatahyperplasie.

The pathogenesis of benign prostate hyperplasia (BPH) is still unclear. It is a common disease affecting exclusively humans in its full clinical appearance. There is a broad variety of possible underlying mechanisms which most likely interact in the pathogenesis of the disease: inflammatory processes taking place predominantly in the stroma and inducing proliferation of all tissues within the transitional zone, an imbalance of androgens and estrogens and their receptors, hyperinsulinemia and hypercholesterolemia (metabolic syndrome) as direct promoters of glandular growth and autosomal dominant inheritance. The detrusor muscle responds to the increased outflow resistance with muscular hypertrophy. Decreased compliance of the bladder wall results in voiding difficulties while electric instability of the hypertrophied detrusor muscle and increased recruiting of otherwise silent afferent fibres cause storage symptoms.

[Importance of adrenoceptor blockers and alpha reductase inhibitors : Monotherapy for treatment of benign prostate syndrome]. / Stellenwert der α1-Adrenozeptorblocker und 5α-Reduktaseinhibitoren : Monotherapie bei der Behandlung des benignen Prostatasyndroms.

Medicinal treatment is the primary conservative treatment option for patients with moderate to severe lower urinary tract symptoms (LUTS). Monotherapy with alpha-blockers may be a suitable option for patients with a low risk of progression and with moderate to severe LUTS due to the rapid onset of action. However, alpha-blockers do not have any impact on disease progression and 5-alpha-reductase inhibitors (5-ARIs) are not recommended as initial monotherapy due to a slow onset of action. In the medium and long term 5-ARIs have been shown to have a positive effect on symptoms and the maximum flow rate and are also the only substance group to have a positive effect on disease progression. The positive effects of 5-ARIs on prevention of benign prostate syndrome are based on scientific findings but the use is not yet recommended in any guidelines.

[Surgical treatment of male lower urinary tract symptoms (LUTS)]. / Operative Therapie des benignen Prostatasyndroms (BPS).

Surgical treatment of lower urinary tract symptoms (LUTS) due to benign prostatic obstruction (BPO) comprises a variety of treatment modalities. Transurethral resection of the prostate (TURP) is considered the gold standard. In the last decade various new techniques have emerged with encouraging functional results. However, long-term data are missing in order to evaluate the efficacy and safety. This review aims to describe new widely available techniques and to assess the underlying evidence.

[Medical therapy of lower urinary tract symptoms [corrected]]. / Medikamentöse Therapie des benignen Prostatasyndroms.

Male lower urinary tract symptoms (LUTS) include storage and voiding disorders and should be carefully evaluated before the start of any treatment. Medical therapy is directed at improving symptoms and reducing the risk of progression in order to improve quality of life and prevent complications, such as acute urinary retention, or the need for surgical intervention. Careful assessment of the individual complaints helps to identify the best drug which should be adapted to each individual patient's risk profile. At present, α(1)-adrenoreceptor inhibitors and 5-alpha reductase inhibitors and their combination form the gold standard for pharmacological treatment. In addition, anticholinergic agents are increasingly being used as monotherapy or in combination with α1-adrenocepetor inhibitors for patients with predominant storage disorders while phosphodiesterase 5 (PDE5) inhibitors may be suitable for patients suffering from LUTS and concomitant erectile dysfunction.

Inhibition of adrenergic human prostate smooth muscle contraction by the inhibitors of c-Jun N-terminal kinase, SP600125 and BI-78D3.

BACKGROUND AND PURPOSE α(1) -Adrenoceptor-induced contraction of prostate smooth muscle is mediated by calcium- and Rho kinase-dependent mechanisms. In addition, other mechanisms, such as activation of c-jun N-terminal kinase (JNK) may be involved. Here, we investigated whether JNK participates in α(1)-adrenoceptor-induced contraction of human prostate smooth muscle. EXPERIMENTAL APPROACH Prostate tissue was obtained from patients undergoing radical prostatectomy. Effects of the JNK inhibitors SP600125 (50 µM) and BI-78D3 (30 µM) on contractions induced by phenylephrine, noradrenaline and electric field stimulation (EFS) were studied in myographic measurements. JNK activation by noradrenaline (30 µM) and phenylephrine (10 µM), and the effects of JNK inhibitors of c-Jun phosphorylation were assessed by Western blot analyses with phospho-specific antibodies. Expression of JNK was studied by immunohistochemistry and fluorescence double staining. KEY RESULTS The JNK inhibitors SP600125 and BI-78D3 reduced phenylephrine- and noradrenaline-induced contractions of human prostate strips. In addition, SP600125 reduced EFS-induced contraction of prostate strips. Stimulation of prostate tissue with noradrenaline or phenylephrine in vitro resulted in activation of JNK. Incubation of prostate tissue with SP600125 or BI-78D3 reduced the phosphorylation state of c-Jun. Immunohistochemical staining demonstrated the expression of JNK in smooth muscle cells of human prostate tissue. Fluorescence staining showed that α(1A)-adrenoceptors and JNK are expressed in the same cells. CONCLUSIONS AND IMPLICATIONS Activation of JNK is involved in α(1)-adrenoceptor-induced prostate smooth muscle contraction. Models of α(1)-adrenoceptor-mediated prostate smooth muscle contraction should include this JNK-dependent mechanism.

Detection of prostate cancer with complexed PSA and complexed/total PSA ratio - is there any advantage?

OBJECTIVE: To evaluate the performance of total PSA (tPSA), the free/total PSA ratio (f/tPSA), complexed PSA (cPSA) and the complexed/total PSA ratio (c/tPSA) in prostate cancer detection. METHODS: Frozen sera of 442 patients have been analysed for tPSA, free PSA (fPSA) and cPSA. 131 patients had prostate cancer and 311 patients benign prostatic hyperplasia. RESULTS: Differences in the distribution of the biomarkers were seen as follows: tPSA, cPSA and c/tPSA were significantly higher in the PC group, and f/tPSA was significantly higher in the BPH group. In the tPSA-range of 0-4 ng/ml none of the biomarkers showed a significant difference in the distribution between both groups. In the tPSA-ranges of 0-10 ng/ml, 2-10 ng/ml, 4-10 ng/ml and <10 ng/ml, f/tPSA showed the highest specificity at high sensitivtities, followed by c/tPSA, cPSA, and tPSA, respectively. In tPSA-ranges greater than 10 ng/ml, cPSA offered the best discriminatory ability. CPSA compared to tPSA offered better specificity at high sensitivities in all tPSA-ranges. CONCLUSION: F/tPSA offers the best ability to distinguish between both groups in lower tPSA-ranges, followed by c/tPSA. CPSA compared to tPSA offers a better ability to discriminate between both groups in all PSA-ranges and could be used as an initial test for PC.

Current status of ultrasound imaging in prostate cancer.

Carcinoma of the prostate (PC) is the most common cancer in men. Ultrasound (US)-guided prostate biopsy with 10-12 cores is considered to be the gold standard in the diagnosis of PC, although a systematic biopsy may miss a considerable percentage of prostate cancer. Substantial efforts have been made to improve the detection rates with extensive prostate biopsy schemes. Today, the most promising tools to improve the detection rate are various imaging procedures. This review focuses on the current stautus of ultrasound imaging in the detection of PC, such as contrast-enhanced colour Doppler ultrasound and real-time elastography. With the use of these techniques, it is the intention not only to improve the detection rate but they could also serve beneficial for staging and in order to reduce the number of biopsy cores. However, further clinical trials will be needed to determine the value of these new US advances.