[The impact of the androgen receptor splice variant AR-V7 on the prognosis and treatment of advanced prostate cancer]. / Bedeutung der Androgenrezeptor-Spleißvariante AR-V7 für Prognose und Therapie des fortgeschrittenen Prostatakarzinoms.

A recently discovered mechanism enabling prostate cancer cells to escape the effects of endocrine therapies consists in the synthesis of C-terminally truncated, constitutively active androgen receptor (AR) splice variants (AR-V). Devoid of a functional C-terminal hormone/ligand binding domain, various AR-Vs are insensitive to therapies targeting the androgen/AR signalling axis. Preliminary studies suggest that AR-V7, the most common AR-V, is a promising predictive tumour marker and a relevant selection marker for the treatment of advanced prostate cancer. This review critically outlines recent advances in AR-V7 diagnostics and presents an overview of current AR-V7 targeted therapies.

Pelvic cellulitis caused by Raoultella planticola in a neutropenic patient.

Raoultella planticola is a gram-negative, encapsulated, aerobic bacterium within the Enterobacteriaceae family. It has been primarily described as pathogen in cases with pneumonia and gastrointestinal infections. Here we describe a case of severe pelvic cellulitis in a patient with neutropenia following induction therapy for myeloid sarcoma. The patient experienced a septic shock and was treated successfully with antibiotic therapy. A literature review is provided to put this case in context with previous reports on R. planticola. This report highlights that awareness for uncommon pathogens is crucial in the clinical management of infections in neutropenic patients.

[Splice variant AR-V7 : Is it time for its routine use as a predictive marker in prostate cancer?] / Spleißvariante AR-V7 : Ist die Zeit reif für ihre routinemäßige Anwendung als prädiktiver Marker beim Prostatakarzinom?

Androgen receptor splice variants (AR-Vs), if overexpressed, lack the ligand-binding domain conveying metastasized castration-resistant prostate cancer with a therapeutic resistance to androgen receptor signaling inhibitors. Particularly AR-V7 has recently been proposed as a potential predictive biomarker to identify patients who would probably benefit most from taxane-based cytotoxic treatment. Several assays to substantiate or quantify AR-V7 expression have recently been proposed. However, their broad clinical value is still debatable. This contemporary update aims to shed light on the current evidence in the field and draw distinct practical conclusions.

[Antihormonal therapy in prostate cancer : Side effects]. / Antihormonelle Therapie beim Prostatakarzinom : Nebenwirkungen.

Androgen deprivation is still standard therapy for prostate cancer, either as primary androgen deprivation therapy or with the use of secondary hormonal drugs including abiraterone and enzalutamide. However, especially the clinically occult side effects like metabolic changes or cardiovascular complications and effects on the psyche of the patient are often not recognized in daily practice. Active monitoring of such side effects is essential for prevention and early intervention. In addition, the efficacy of androgen deprivation therapies is limited by primary and secondary resistance. The underlying molecular mechanism including splice variants of the androgen receptor in contrast to mutations are usually reversible and should be regarded as a sign of efficacy of the current treatment. Therefore, the clever, timely use of androgen deprivation or even the use of a bipolar androgen therapy should enable reversal of resistance to again render tumor cells sensitive to androgen-deprivation therapy.

Normative 3D acetabular orientation measurements by the low-dose EOS imaging system in 102 asymptomatic subjects in standing position: Analyses by side, gender, pelvic incidence and reproducibility.

BACKGROUND: Three-dimensional (3D) acetabular orientation is a fundamental topic in orthopedic surgery. Computed tomography (CT) allows 3D measurement of native acetabular orientation, but with a substantial radiation dose. The EOS imaging system was developed to perform this kind of evaluation, but has not been validated in this indication with specific attention to the acetabulum. We therefore performed a prospective study using EOS to assess: (1) the reproducibility of the 3D acetabulum orientation measures; (2) normative asymptomatic acetabular morphology in standing position, according to side and gender; and (3) the relationship between acetabular anteversion and pelvic incidence. HYPOTHESIS: The low-dose EOS imaging system is a reproducible method for measuring 3D acetabular orientation in standing position. PATIENTS AND METHODS: In a previous prospective study of spine sagittal balance, 165 asymptomatic volunteers were examined on whole-body EOS biplanar X-ray; 102 had appropriate images for pelvic and acetabular analysis, with an equal sex-ratio (53 female, 49 male). These EOS images were reviewed using sterEOS 3D software, allowing automatic measurement of acetabular parameters (anteversion and inclination) and pelvic parameters (pelvic incidence, pelvic tilt and sacral slope) in an anatomical (anterior pelvic plane: APP) and a functional reference plane (patient vertical plane: PVP). RESULTS: Both intra- and inter-observer analysis showed good agreement (ICC>0.90); Bland-Altman plot distributions were good. Acetabular anatomical anteversion and inclination relative to APP (AAAPP and AIAPP, respectively) were significantly greater in women than in men, with no effect of side (right AAA: women 21.3°±3.4° vs. men 16.1°±3.3° (P<0001); right AIAPP: women 55.3°±3.7° vs. men 52.5°±3.0° (P<0001); left AAAPP: women 20.9°±3.5° vs. men 15.6°±4.0° (P<0001); left AIAPP: women 54.6°±3.5° vs. men 52.7°±2.8° (P=0003)). The same differences between men and women were observed when measurements were related to PVP. Pelvic incidence subgroup (<44°; 44-62°; >62°) correlated significantly with functional acetabular orientation in standing position: PVP functional anteversion decreased by 5° relative to APP anteversion with incidence <44°, was equal to APP with incidence 44-62°, and or was greater by 4° relative to APP with incidence >62°. DISCUSSION: The use of a 3D sterEOS software prototype version for 3D reconstruction of the native acetabulum from standard EOS X-ray was shown to be a reliable and reproducible method. This innovative method enabled the reference values of 3D acetabular orientation in standing position to be measured for the first time. The results reinforced the concept of hip-spine relationships, and involved very low radiation dose. LEVEL OF EVIDENCE: IV prospective study without control group.

[Mechanisms of Resistance in Antihormone Therapies of Advanced Prostate Cancer]. / Resistenzmechanismen unter antihormoneller Therapie des fortgeschrittenen Prostatakarzinoms.

With the development of Abiraterone and Enzalutamide new treatment option have become available in addition to Docetaxel for first-line treatment of castration resistant prostate cancer. However, resistance and ultimately failure occurs inevitably with all available treatment options. Moreover, cross-resistance leads to considerably reduced efficacy in second-line treatment. Preclinical data suggest discriminative mechanisms of resistance development for Abiraterone and Enzalutamide. Clinical confirmation of these putative mechanisms for treatment failure might facilitate recommendations for future sequencing of these drugs.

Alterations in androgen deprivation enhanced prostate-specific membrane antigen (PSMA) expression in prostate cancer cells as a target for diagnostics and therapy.

BACKGROUND: Prostate-specific membrane antigen (PSMA) is a promising target for diagnostics and therapy of prostate carcinoma (PCa). Based on the hypothesis that PSMA expression can be modulated by variations in androgen deprivation therapy (ADT), we investigated the binding of a PSMA-directed radiopharmaceutical in vitro in order to get an insight of the interactions between altered premedication and PSMA expression before repetitive PSMA-directed PET/CT for therapy response and targeted therapy implementation. METHODS: The human castration-resistant PCa cell line VCaP (CRPC) was treated with either 1 nmol/L testosterone (T) over 20 passages yielding the androgen-sensitive cell line (revCRPC) or with 5 µmol/L abiraterone acetate (AA) generating the abiraterone-tolerant subtype CRPCAA. In these cell lines, T and AA were varied by either supply or withdrawal of T and AA. PSMA expression of the three cell culture models was detected by Western blot and immunohistochemical staining. For quantitative measurement of tracer uptake, 0.3 nmol/L (68)Ga-labelled PSMA-HBED-CC peptide (100-300 kBq/ml) was added to different treated parallel cultures (n = 9 each). Time-dependent uptake per 10(6) cells of each culture was calculated and evaluated. PSMA mRNA expression was investigated by qPCR. RESULTS: PSMA expression increased dependently on intensified ADT in all three basic cell lines. (68)Ga-PSMA-HBED-CC uptake almost doubled during 3 h in all cell lines (p < 0.01). Compared to the basic cells, pre-incubation with abiraterone for 48 h resulted in a significant increased uptake in CRPC (p < 0.001). In revCRPC, 48-h AA pre-incubation resulted in an eightfold higher uptake after 3 h (p < 0.001). Additional withdrawal of external testosterone increased the uptake up to tenfold (p < 0.01). The increase of PSMA expression upon ADT and AA treatments was confirmed by qPCR and Western blot data. Furthermore, in CRPCAA, 48-h AA withdrawal increased the uptake up to fivefold (p < 0.01). CONCLUSIONS: The investigated three PCa cell culture subtypes represent a serial preclinical model of androgen deprivation therapy as a proxy for clinical situations with differing basal PSMA expression. The uptake of PSMA-binding tracers could be stimulated by therapeutic effective short-term variation in premedication in all stages of ADT response. These complex interactions have to be considered in the interpretation of diagnostic imaging using PSMA ligands as well as in the optimal timing of PSMA-based therapies.

Estrogen receptor beta: tissue distribution and the still largely enigmatic physiological function.

UNLABELLED: In 1996, the molecular biology of E2 had to be reevaluated: in an effort to identify novel nuclear receptors or unknown isoforms of existing receptors Kuiper and colleague described the expression of a novel subtype of the estrogen receptor (ER) in rat prostate and ovary. Upon this pioneering discovery the already known ER was renamed ERα while the newly described ER was termed ERß. In this review an attempt is made to summarize the current knowledge regarding the expression and function of ERß in selected reproductive and non-reproductive organs under physiological conditions. The data suggest that ERß may be considered as a dominant-negative regulator of ERα modulating transcriptional responses to estrogens. The ratio of ER α vs. ß. within a cell may determine the cell sensitivity to estrogens and its biological responses to the hormone. CONCLUSION: It is not the ligand, it is the multiplicity of receptors which determines the plethora of estrogen actions. This article is part of a Special Issue entitled 'Phytoestrogens'.

Measuring femoral and rotational alignment: EOS system versus computed tomography.

INTRODUCTION: Computed tomography (CT) is currently the reference standard for measuring femoral and tibial rotational alignment. The EOS System is a new biplanar low-dose radiographic device that allows 3-dimensional lower-limb modelling with automated measurements of femoral and tibial rotational alignment (torsion). HYPOTHESIS: Femoral and tibial torsion measurements provided by the EOS System are equivalent to those obtained using CT. MATERIALS AND METHODS: In a retrospective analysis of 43 lower limbs in 30 patients, three senior radiologists measured femoral and tibial torsion on both CT and EOS images. Agreement between CT and EOS values was assessed by computing Pearson's correlation coefficient and interobserver reproducibility by computing the intraclass correlation coefficient (ICC). RESULTS: Femoral torsion was 13.4° by EOS vs. 13.7° by CT (P=0.5) and tibial torsion was 30.8° by EOS vs. 30.3° by CT (P=0.4). Strong associations were found between EOS and CT values for both femoral torsion (P=0.93) and tibial torsion (P=0.89). With EOS, the ICC was 0.93 for femoral torsion and 0.86 for tibial torsion; corresponding values with CT were 0.90 and 0.92. DISCUSSION: The EOS system is a valid alternative to CT for lower-limb torsion measurement. EOS imaging allows a comprehensive evaluation in all three planes while substantially decreasing patient radiation exposure. LEVEL OF EVIDENCE: Level III, case-control.

Impact of ureteral stenting prior to ureterorenoscopy on stone-free rates and complications.

OBJECTIVE: To date, only few studies have evaluated the impact of ureteral stenting prior to ureterorenoscopy. This study is to clarify the role of preoperative ureteral stenting in the treatment for ureteral stones. METHODS: We retrospectively reviewed 550 ureterorenoscopies from 1998 to 2008. Patients were classified into two groups depending on whether they had a stent placed before URS. Baseline characteristics of patients and stone properties, stone-free rates, complications, and operation times were compared between both groups. Subanalysis was performed regarding stone localization. We retrospectively reviewed data from patient documentation, X-ray imagery, intravenous urography, and operation reports. RESULTS: Baseline characteristics of patients were similar in both groups. The majority of patients underwent stent placement before the ureteroscopic stone treatment (88.4%). The mean operation time in the prestented group was longer (43.3 vs. 38.4 min). Stone-free rate of patients with stent was 72.2%, compared to 59.4% without preoperative stenting. The rate of minor complications was 4.7% with stent versus 9.4% without stent, major complications 0.6% versus 1.6%, respectively. Patients with distal ureter stones had similar stone-free rates regardless of a stent placement (90.1% with stent vs. 87.6% without), and no difference in complication rates was observed (3.5% with stent vs. 3.1% without), respectively. CONCLUSIONS: Stent placement prior to ureteroscopic stone treatment in distal ureter is not reasonable and does not considerably improve stone-free rates.

[Prolapse surgery. With abdominal or vaginal meshes?]. / Prolapschirurgie. Mit abdominal oder vaginal eingesetzten Netzen?

In prolapse surgery several surgical techniques are available. The different open, laparoscopic and vaginal approaches are distinguished by distinct success and relapse rates and operation-specific complications. A safe and optimal therapeutic pelvic floor surgery should be based on the three support levels according to DeLancy and be individually adjusted for every patient. The vaginal approach may be used for all kinds of female genital prolapse and is a comparatively less invasive technique with a short time of convalescence. Apart from stress incontinence there is no need for synthetic meshes in primary approaches and excellent results with low complication and relapse rates can be achieved. An uncritical application of synthetic material is to be avoided in vaginal repair at all times. Abdominal surgical techniques, both open and laparoscopic, present their strengths in the therapeutic approach to level 1 defects or stress incontinence. They provide excellent functional and anatomical corrections and low relapse rates. Abdominally inserted meshes have lower complication rates than vaginal ones.

[Intermittent androgen deprivation as therapy for androgen-sensitive prostate cancer. Sense or nonsense?]. / Intermittierende Hormontherapie beim androgensensiblen Prostatakarzinom. Sinn oder Unsinn?

Androgen deprivation is the predominant therapy for advanced prostate cancer. There is accumulating evidence that phases of intermission in androgen deprivation may have benefits regarding side effects, albeit there is as yet no general recommendation for intermittent androgen deprivation therapy. Recent systematic reviews at least substantiate a benefit from such regimens for general quality of life without therapy compromisation. In addition, preclinical data revealed further potential strategies for intermittent androgen deprivation therapy. Future studies must prove, however, that such approaches can be implemented in the clinical situation.

[Laser now also to be used in organ-preserving kidney surgery?]. / Laser nun auch in der organerhaltenden Nierenchirurgie?

Kidney surgery is subject to continuous change. Partial nephrectomy is the prevailing method for small and medium-sized tumours and proven to be superior to radical nephrectomy. The conventional technique usually includes clamping the renal vessels. The duration of the ischaemia caused determines the outcome of the remaining renal function. The shorter the ischaemic time the more likely the renal function will be preserved. Thus, new techniques are needed to abandon renal vessel clamping. Essential is a combination of good cutting abilities and assured haemostasis. To date, the commonly used techniques for cutting in partial nephrectomy only partially fulfil these requirements. Establishment of laser in urology offers a new surgical technique that combines both. In spite of the still limited data on laser use in kidney surgery, this method can be assessed favourably. Laser offers a possibility of both open and laparoscopic partial nephrectomy avoiding renal vessel clamping without additional risks or complications.

Expression and function of the vitamin D receptor in malignant germ cell tumour of the testis.

Testicular germ cell tumours (TGCTs) are the most common malignancy in young men aged 18-35 years. They are clinically and histologically subdivided into seminomas and non-seminomas. 1,25-Dihydroxyvitamin D (1,25(OH)(2)D(3)) is the active form of vitamin D and exerts its actions via a specific intracellular vitamin D receptor (VDR). Several investigations in the recent years have revealed, in addition to a physiological occurrence of the VDR in various tissues, VDR expression in different human malignancies. Furthermore, 1,25(OH)(2)D(3) plays an important role in the regulation of cell proliferation and differentiation. In different normal and malignant cell types, antiproliferative and pro-differentiating effects of 1,25(OH)(2)D(3) are described. We investigated whether TGCT express the VDR, wether differences exist between the histological subtypes and if vitamin D has a function on the proliferation of tumour cells. Furthermore, we investigated the potential function of the vitamin D-regulated genes nuclear receptor co-repressor 1(NCOR1), nuclear receptor co-repressor 2 (NCOR2), thyroid receptor interacting protein 15 (TRIP15), Growth Arrest and DNA Damage (GADD45), MAP kinase-activated protein kinase 2 (MAPKAPK2), Cytochrome P450, family 24, subfamily A, polypeptide 1 (CYP24A1) and Cytochrome P450, family 27, subfamily B, polypeptide 1 (CYP27B1) in the pathogenesis of TGCT. We demonstrate, for the first time, that primary TGCT as well as TGCT cell lines, express VDR mRNA and protein. Vitamin D and VDR may play a role in the pathogenesis of TGCTs. Furthermore, vitamin D inhibits proliferation of TGCT cell-lines, potentially via an increase in expression of GADD45. Our data suggest that vitamin D could play a role in antitumour therapy.

[Antiandrogen strategies in prostate cancer: reconstitution of oestrogen receptor beta]. / Antiandrogene Strategien im Prostatakarzinom : Rekonstitution des beta-Ostrogenrezeptors.

In advanced prostate cancer, albeit castration resistant, an active androgen receptor is still pivotal for growth and cell survival. Recent therapies involving more effective antiandrogens such as MDV3100 proved to be successful. Furthermore, blocking de novo intracrine androgen synthesis, e.g. with abiraterone acetate, provides additional benefit. Besides these antiandrogen measures, compounds which enable the reconstitution of the oestrogen receptor beta as a tumour suppressor restrain aberrant androgen receptor signalling.

[Vaginal pelvic repair. Always with mesh or not?]. / Vaginaler Beckenbodenrepair. Immer mit Netz?

Several surgical methods are possible when aiming at reconstruction of pelvic organ prolapse in women, and the experienced surgeon implements the knowledge gained from open, laparoscopic, and vaginal techniques. These feature different rates of success and relapse as well as different complication risks. Because of the accumulating morbidity of aging patients, there is a search for a safe minimally invasive technique. With the advent of synthetic meshes, surgeons have used them frequently and often uncritically for reconstruction of the female pelvic floor. In these cases the vaginal approach is preferred as opposed to alternative techniques, as it is less invasive and allows for better convalescence. Furthermore, this approach leads to low complication and relapse rates even when synthetic meshes are omitted.

[Molecular principles of alternative treatment approaches for hormone-refractory prostate cancer]. / Molekulare Grundlagen alternativer Therapieansätze für das hormonrefraktäre Prostatakarzinom.

Prostate cancer is more frequently diagnosed in men from Western countries than from Asian societies. Therefore, nutritional factors such as phyto-oestrogens from soya are considered to cause this prostate cancer prevention effect. As there is no curative therapy for hormone-refractory prostate cancer, new strategies are in demand which might include phyto-oestrogens or inhibitors of histone deacetylases. Both approaches have in common the potential to reduce the aberrant androgen receptor and IGF receptor signalling. Furthermore, invasiveness and acquired survival strategies of tumours can be diminished. Reduced tumour cell proliferation and PSA secretion coincide with altered gene expression in the aforementioned processes. In addition, selective knock-down of genes by RNA interference afforded functional analyses regarding impact and succession of expression events involved in the beneficial effects caused by phyto-oestrogens and histone deacetylase inhibitors.

Expression and function of protein phosphatase PP2A in malignant testicular germ cell tumours.

Testicular germ cell tumours (TGCT) represent the most common malignancy in young males. We reported previously that two prototype members of the mitogen-activated protein kinase (MAPK) family, the MAPK ERK kinase (MEK) and extracellular signal-regulated kinase (ERK), are inactive in malignant testicular germ cells and become active after drug stimulation, leading to apoptosis of tumour cells. In this study, we asked whether the protein phosphatase PP2A, a known inhibitor of the MEK-ERK pathway, participates in the proliferation and/or apoptosis of primary TGCT (n = 48) as well as two TGCT cell lines (NTERA and NCCIT). Quantitative RT-PCR, immunohistochemistry, western blot analyses and phosphatase assay indicate that primary TGCT as well as TGCT cell lines express PP2A and that PP2A is active in TGCT cell lines. The inhibition of PP2A by application of two PP2A inhibitors, cantharidic acid (CA) and okadaic acid (OA), results in a significant increase in caspase-3-mediated apoptosis of TGCT cell lines. Thereby, PP2A inhibition was accompanied by phosphorylation and activation of MEK and ERK. Functional assays using the MEK inhibitor PD98059 demonstrated that the phosphorylation of MEK and ERK was required for the induction of caspase-3-mediated apoptosis of malignant germ cells. Thus, our data suggest that inhibition of PP2A mediates its apoptosis-inducing effect on TGCT through activation of the MEK-ERK signalling pathway that leads to caspase-3-mediated apoptosis of tumour cells. In addition our results support previous observations that PP2A exerts an anti-apoptotic effect on malignant tumour cells.

[Pharmacological potential of phytoestrogens in the treatment of prostate cancer]. / Das pharmakologische Potential von Phytoöstrogenen in der Therapie des Prostatakarzinoms.

INTRODUCTION: Phytoestrogenes are plant-derived compounds that have been shown to exert an antiproliferative potential on prostate cancer cells, although the exact mechanisms are still unclear. In prostate cancer cells proliferation is regulated by modulation of the IGF-1 receptor (IGF-R-1) by the androgen receptor (AR) and its co-activator prostate derived Ets factor (PDEF). Phytooestrogenes interact with these mechanisms as demonstrated exemplarily in the presented study with the isoflavone tectorigenin derived from Belamcanda chinensis. MATERIAL AND METHODS: Cultured androgen-sensitive LNCaP prostate cancer cells were treated with tectorigenin of 100 microM for 24 hours. The mRNA-expression of AR, PSA, PDEF, hTERT, TIMP-3 and IGF-R-1 were quantified by real-time RT-PCR. Furthermore, the expression or activity of PSA, telomerase and IGF-R-1 was measured on the protein level. In addition, we investigated in nude mice the influence of a diet of extracts of Belamcanda chinensis on the growth of subcutaneously injected LNCaP cells versus a control group of animals fed with a soy-free diet. RESULTS: In cultured LNCaP cells treatment with tectorigenin resulted in a significant down-regulation of the gene expression of AR, PDEF, PSA, IGF-R-1 and hTERT. On the protein level PSA secretion and the activity of telomerase and IGF-R-1 expression was also decreased. The gene expression of TIMP-3 was distinctly up-regulated by tectorigenin. Nude mice fed with Belamcanda chinensis extract showed a significantly decreased incidence and tumor growth compared to controls. CONCLUSIONS: Tectorigenin shows an inhibition of the IGF-1-R modulated cell proliferation of PCa-Cells, due to modulation of the activity the co-activator PDEF independently from the AR. Furthermore, tectorigenin has pro-apoptotic effects and decreases tissue invasion by up-regulation of TIMP-3. Therefore, phytooestrogenes are an interesting option in the therapy of prostate especially advanced prostate cancer.

Expression of augmenter of liver regeneration (ALR) in human liver cirrhosis and carcinoma.

AIMS: To determine the expression of a protein termed augmenter of liver regeneration (ALR), recently found to have a specific and beneficial effect on the process of liver regeneration in normal and diseased human liver. METHODS AND RESULTS: ALR expression in normal and cirrhotic human livers with various underlying diseases as well as in tissue samples of hepatocellular carcinoma (HCC) and cholangiocellular carcinoma (CCC) was analysed by immunohistochemistry and quantitative reverse transciptase-polymerase chain reaction (RT-PCR). Expression analysis of ALR in total liver protein extracts by Western blotting showed mainly dimeric ALR protein. Immunohistochemically, cytosolic and perinuclear immunosignals were found in hepatocytes and cholangiocytes in normal, cirrhotic or cancerous liver tissue and only weak signals in some endothelial cells in normal livers. Quantitative mRNA analysis revealed significantly increased ALR expression in cirrhosis compared with normal liver tissue. In HCC and CCC ALR mRNA expression was also significantly enhanced compared with normal liver tissue, but expression levels did not differ from the matching non-neoplastic tissue in the same patient. CONCLUSIONS: The findings suggest an important role for ALR in hepatocellular regeneration in liver cirrhosis as well as in hepatocarcinogenesis and therefore its potential value in the clinical diagnosis of hepatic cirrhosis and cancer.