Baseline neutrophil-to-lymphocyte ratio as a predictive and prognostic biomarker in patients with metastatic castration-resistant prostate cancer treated with cabazitaxel versus abiraterone or enzalutamide in the CARD study.

BACKGROUND: There is growing evidence that a high neutrophil-to-lymphocyte ratio (NLR) is associated with poor overall survival (OS) for patients with metastatic castration-resistant prostate cancer (mCRPC). In the CARD study (NCT02485691), cabazitaxel significantly improved radiographic progression-free survival (rPFS) and OS versus abiraterone or enzalutamide in patients with mCRPC previously treated with docetaxel and the alternative androgen-receptor-targeted agent (ARTA). Here, we investigated NLR as a biomarker. PATIENTS AND METHODS: CARD was a multicenter, open-label study that randomized patients with mCRPC to receive cabazitaxel (25 mg/m2 every 3 weeks) versus abiraterone (1000 mg/day) or enzalutamide (160 mg/day). The relationships between baseline NLR [< versus ≥ median (3.38)] and rPFS, OS, time to prostate-specific antigen progression, and prostate-specific antigen response to cabazitaxel versus ARTA were evaluated using Kaplan-Meier estimates. Multivariable Cox regression with stepwise selection of covariates was used to investigate the prognostic association between baseline NLR and OS. RESULTS: The rPFS benefit with cabazitaxel versus ARTA was particularly marked in patients with high NLR {8.5 versus 2.8 months, respectively; hazard ratio (HR) 0.43 [95% confidence interval (CI) 0.27-0.67]; P < 0.0001}, compared with low NLR [7.5 versus 5.1 months, respectively; HR 0.69 (95% CI 0.45-1.06); P = 0.0860]. Higher NLR (continuous covariate, per 1 unit increase) independently associated with poor OS [HR 1.05 (95% CI 1.02-1.08); P = 0.0003]. For cabazitaxel, there was no OS difference between patients with high versus low NLR (15.3 versus 12.9 months, respectively; P = 0.7465). Patients receiving an ARTA with high NLR, however, had a worse OS versus those with low NLR (9.5 versus 13.3 months, respectively; P = 0.0608). CONCLUSIONS: High baseline NLR predicts poor outcomes with an ARTA in patients with mCRPC previously treated with docetaxel and the alternative ARTA. Conversely, the activity of cabazitaxel is retained irrespective of NLR.

Kinetics and extent of T cell activation as measured with the calcium signal.

We have characterized the calcium response of a peptide-major histocompatibility complex (MHC)-specific CD4(+) T lymphocyte line at the single cell level using a variety of ligands, alone and in combination. We are able to distinguish four general patterns of intracellular calcium elevation, with only the most robust correlating with T cell proliferation. Whereas all three antagonist peptides tested reduce the calcium response to an agonist ligand, two give very different calcium release patterns and the third gives none at all, arguing that (a) antagonism does not require calcium release and (b) it involves interactions that are more T cell receptor proximal. We have also measured the time between the first T cell-antigen-presenting cell contact and the onset of the calcium signal. The duration of this delay correlates with the strength of the stimulus, with stronger stimuli giving a more rapid response. The dose dependence of this delay suggests that the rate-limiting step in triggering the calcium response is not the clustering of peptide-MHC complexes on the cell surface but more likely involves the accumulation of some intracellular molecule or complex with a half-life of a few minutes.

Update on systemic therapies of metastatic renal cell carcinoma.

PURPOSE: Recent advances in understanding the molecular biology of advanced and metastatic renal cell carcinoma (RCC) have led to the development of several targeted agents that show impressive antitumor efficacy. The integration of these drugs into clinical practice has revolutionized the therapeutic management of RCC. METHODS: We reviewed data on all approved targeted agents in the first-line and second-line setting, as well as, studies involving sequential therapy. Data from phase III trials are discussed, and an optional therapeutic algorithm is presented. RESULTS: Sunitinib should be used as the first-line treatment of choice for good- and intermediate-risk patients according to Memorial Sloan-Kettering Cancer Center (MSKCC) criteria, whereas temsirolimus is recommended for the poor-risk group. The combination of bevacizumab and INF-alpha can be regarded as an alternative to sunitinib. After cytokine failure, patients should be recommended to sorafenib. Everolimus must be considered after first-line failure of a tyrosine kinase inhibitor (TKI); furthermore, recent evidence suggests sequential use of TKIs before administration of everolimus. CONCLUSIONS: A range of potent drugs are available to patients with metastatic RCC. Treatment decisions should be made carefully taking into consideration that all targeted agents only have a palliative effect with prolongation of life, but do not cure metastatic RCC.

[The "triple F" campaign of the German Society of Urology: what have we reached so far?] / Die "Triple F-Kampagne" der Deutschen Gesellschaft für Urologie: Was haben wir erreicht?

Urology is an important medical discipline for men, women and children due to the variety and frequency of urologic diseases-a fact which is unknown to the majority of the population. In 2016, the "triple F" campaign was initiated in order to inform about both the role of urology and the importance of timely urologic investigations as well as prostate-specific antigen (PSA)-based early examination. With the Roth brothers as the face of the campaign, a homepage was created with information about the main important urologic diseases. Flyers and posters for physicians and their patients were sent to 3500 urologists, a urologist search tool for patients with so far 2200 registered urologists is available on the homepage, etc. Further activities using social media are planned with the objective of increasing participation of German urologists and their patients.

[Changes in the treatment of metastatic prostate cancer-new data and open questions]. / Therapie des metastasierten Prostatakarzinoms im Wandel ­ neue Daten und offene Fragen.

The availability of taxane-based chemotherapy and androgen-receptor-targeted agents (ARTAs) have significantly broadened the therapeutic options for patients with metastatic prostate cancer and may also result in longer patient survival. The therapeutic sequence of ARTAs and taxanes may influence outcome and therefore decisions should be made on an individual basis. This article provides guidance for therapeutic decision-making in daily clinical practice by working out criteria that can be used to support individual therapeutic decisions. The focus is on metastatic castration-naive prostate cancer, oligometastatic disease as well as non-metastatic and metastatic castration-resistant prostate cancer.

A receptor/cytoskeletal movement triggered by costimulation during T cell activation.

During T cell activation, the engagement of costimulatory molecules is often crucial to the development of an effective immune response, but the mechanism by which this is achieved is not known. Here, it is shown that beads attached to the surface of a T cell translocate toward the interface shortly after the start of T cell activation. This movement appears to depend on myosin motor proteins and requires the engagement of the major costimulatory receptor pairs, B7-CD28 and ICAM-1-LFA-1. This suggests that the engagement of costimulatory receptors triggers an active accumulation of molecules at the interface of the T cell and the antigen-presenting cell, which then increases the overall amplitude and duration of T cell signaling.

Differential clustering of CD4 and CD3zeta during T cell recognition.

Whereas T helper cells recognize peptide-major histocompatibility complex (MHC) class II complexes through their T cell receptors (TCRs), CD4 binds to an antigen-independent region of the MHC. Using green fluorescent protein-tagged chimeras and three-dimensional video microscopy, we show that CD4 and TCR-associated CD3zeta cluster in the interface coincident with increases in intracellular calcium. Signaling-, costimulation-, and cytoskeleton-dependent processes then stabilize CD3zeta in a single cluster at the center of the interface, while CD4 moves to the periphery. Thus, the CD4 coreceptor may serve primarily to "boost" recognition of ligand by the TCR and may not be required once activation has been initiated.

[Attending physicians in urology working at university centers or non-university centers-what are the differences? : Results of a web-based cross-sectional study at German hospitals]. / Urologische Oberärztinnen und Oberärzte an universitären oder nicht-universitären Kliniken ­ welche Unterschiede gibt es? : Ergebnisse einer webbasierten Querschnittstudie an deutschen Kliniken.

BACKGROUND: Attending physicians (AP) in urology represent a very heterogeneous group covering various clinical priorities and career objectives. To date, there are no reliable data on professional, personal and position-linked aspects of AP in urology working in university centers (univ-AP) opposed to those working in non-university centers (n-univ-AP). MATERIALS AND METHODS: The objective of this study was to analyze individual professional perspectives, professional and personal settings, specific job-related activities and individual professional goals of univ-AP opposed to n­univ-AP. Thus, a web-based survey containing 55 items was designed to perform a cross-sectional study that was then forwarded using a link which was sent via a mailing list of the German Society of Urology. The survey was available for completion by AP at German urological centers from February to April 2019. Group-specific differences were evaluated using bootstrap-adjusted multivariate logistic regression models. RESULTS: Of the 192 evaluable surveys, 61 (31.8%) and 131 (68.2%) were part of the univ-AP and n­univ-AP study group, respectively. Participating n­univ-AP compared to univ-AP held the position of AP (p = 0.022) significantly longer and were on call significantly more frequently (p < 0.001). AP in urology (self)-assessed themselves as autonomously confident in performing robotic, laparoscopic, open, endo-urologic, and plastic-reconstructive surgery in 12.4%, 25%, 59.6%, 92.1%, and 25.7%, respectively, with no significant differences between the two groups among all above mentioned surgical subdomains based on multivariate analysis. AP in urology were (very) content in 92% concerning the choice of their discipline, in 73.9% concerning their actual working circumstances, and in 60.2% concerning their level of surgical expertise. Only 27.1% and 19.9% were (very) content with the amount of available time for their personal professional development and for private affairs, respectively. As opposed to n­univ-AP, univ-AP would choose a career in clinical centers once again significantly more frequently (OR 2.87; p(BS) = 0.041), but assess the position of AP as their definitive career goal significantly less frequently (OR 0.42; p(BS) = 0.40). Univ-AP state significantly more frequently that they were running for the position of head of department or full professor (OR 5.64; p(BS) = 0.001). CONCLUSION: In this first survey study world-wide on AP in urology divided according to their academic background, similarities and variances were analyzed, baring the potential to further improve identification of AP for a career in clinical centers.

[Treatment situation in metastastic Castration Naive Prostate Cancer (mCRPC) and the implications on clinical routine]. / Therapiesituation beim metastasierten kastrationsnaiven Prostatakarzinom (mCNPC) und die Auswirkungen im klinischen Alltag.

There is an ongoing change of paradigm in the treatment of metastatic prostate cancer (mPC). Taxan-based chemotherapy demonstrated a prolonged survival of patients in several randomized phase III trials. This is true in the situation of metastatic castration-resistent prostate cancer (mCRPC) as well as in the hormone-naïve stage (metastatic castration-naive PC [mCNPC]). In patients with mCNPC, treatment with docetaxel in combination with androgen deprivation therapy (ADT) prolonged the median total survival time by 15 months in comparison to ADT alone. Comparable results were obtained by the endocrine combination treatment with ADT/abiraterone. With the current data in mind it seems to be useful to discuss the value of early combination therapy with ADT/docetaxel or ADT/abiraterone as well as the impact on further treatment options in the mCRPC setting and to define criteria for treatment decisions in clinical practice.

Lymphangiogenesis in kidney cancer: expression of VEGF-C, VEGF-D and VEGFR-3 in clear cell and papillary renal cell carcinoma.

The vascular endothelial growth factors VEGF-C, VEGF-D and its receptor, VEGFR-3, are overexpressed in different malignancies and associated with lymph node metastasis and poor prognosis. We analysed these factors in clear cell (ccRCC) and papillary (pRCC) renal cell carcinoma (RCC). The results were correlated with various clinicopathological parameters (CPP). We constructed a tissue microarray with tumor samples of 135 (81%) ccRCC and 31 (19%) pRCC. After immunohistochemical staining using polyclonal antibodies for VEGF-C, VEGF-D and VEGFR-3, a semiquantitative analysis was performed to determine the levels of expression. The results were compared between the two subgroups and were correlated with CPP. In the two subgroups the expression of VEGF-C was significantly correlated with that of VEGF-D (p<0.001). There was an increased expression of VEGF-C in 11% of ccRCC and 36% of pRCC (p=0.002). VEGF-D expression was positive by means of analysis in 22% of ccRCC and 42% of pRCC (p=0.039). There was no significant difference regarding the expression of VEGFR-3 between the subgroups (44% ccRCC and 61% pRCC, p=0.11). No correlation was found between the expression of the analysed parameters and CPP (TNM, grading, progression-free survival and overall survival) in either the entire group or in the two subgroups. In summary, ccRCC and pRCC show a different expression pattern of the analysed lymphangiogenic factors. Further studies are necessary to confirm these results and to determine whether the VEGF-C/VEGF-D/VEGFR-3-axis can play a role as a prognostic tool or a target for therapeutic intervention in renal cell carcinoma.

[Retroperitoneoscopic excision of an adrenal cyst]. / Die retroperitoneoskopische exzision einer nebennierenzyste.

INTRODUCTION: Laparoscopic management of adrenal benign cysts is the method of choice today. In contrast to the transabdominal laparoscopic approach, retroperitoneoscopy is rarely performed, although it seems to be a comparable method and alternative technique for cyst resection. CASE REPORT: A thin 27-year-old woman in good condition presented with epigastric and left flank pain as well as reflux of gastric acid. A large adrenal cystic lesion was detected on ultrasonography and computed tomography of the abdomen. The question of whether the cyst arose from the upper pole of the left kidney or from the adrenal gland could not be answered. Retroperitoneoscopic excision of the cystic lesion was performed. The histopathological work-up revealed the finding of an adrenal pseudocyst. Symptoms of epigastric and left flank pain as well as reflux of gastric acid resolved after pseudocyst removal. CONCLUSIONS: The retroperitoneoscopic approach for symptomatic adrenal cyst resection represents an effective, cost-reducing and durable treatment.

[New markers for pharmacological targeting in bladder cancer with lymph node metastasis]. / Neue Marker für das pharmakologische Targeting beim lymphogen metastasierten Harnblasenkarzinom.

PURPOSE: VECF-C, -D and their receptor Flt-4 are associated with lymph node metastasis and a poor prognosis in many tumour entities. We have analysed the expression of these factors in transitional cell carcinoma of the bladder with positive lymph nodes. MATERIALS AND METHODS: We constructed "tissue microarrays" (TMAs) from bladder cancer specimens (BC-array) and corresponding lymph node metastases (LN-array) of 73 patients, who all underwent radical cystectomy and bilateral lymphadenectomy. After immunohistochemical staining, semiquantitative analysis was performed using polyclonal antibodies for VEGF-C, -D and Flt-4. The results were correlated with various histopathological and clinical variables. RESULTS: VEGF-C (p = 0.007) and Flt-4 (p = 0.019) were significantly higher expressed in the LN-array compared to the BC-array. In the LN-array VEGF-D correlated with T-(p = 0.013) and N-stage (p = 0.030) Flt-4 correlated with N-stage (p = 0.011) and distant metastasis (p = 0.011) in the BC-array, as well as with T-(p = 0.004) and N-stage (p = 0.014) in the LN-array. Accordingly, in the LN-array VEGF-D positive patients showed both a shorter disease-free survival (p = 0.028) and a poorer overall survival (p = 0.014). Similarly, Flt-4 positive patients had a shorter overall survival (p = 0.033). CONCLUSIONS: Patients with transitional bladder cancer and lymph node metastasis have a poorer prognosis when they overexpress VEGF-D and Flt-4 in their lymph nodes. Pharmacological targeting of these factors could improve their overall survival.

[Decision aids for patients are widely accepted by German urologists : A survey among members of the German Society of Urology (DGU) and the Federation of German Urologists (BDU)]. / Entscheidungshilfen für Patienten finden bei deutschen Urologen breite Akzeptanz : Umfrage unter Mitgliedern von DGU und BDU.

BACKGROUND: Treatment decision making remains a complex task for localized prostate cancer. Decision aids for patients can support the medical consultation. However, it is not known if German urologists accept decision aids for patients. Comparative data exist from a current survey among american urologists and radio oncologists. MATERIALS AND METHODS: From October through November 2014 we conducted an online survey consisting of 11 multiple-choice questions and an optional free text commentary among the members of DGU and BDU. All data was processed anonymously. We received 464 complete responses for a 6.6 % return rate. For group comparison we applied the Chi2-test. RESULTS: Respondents' median age was 50 (range 26-87) years and 15 % were female. 7 % were residents, 31 % employed at a clinic, and 57 % in private practice. Due to the low response rate of younger colleagues the results were not representative for the basic population. Regardless of age (p = 0.2) and professional environment (p = 1) shared decision making was preferred by 89 %. When counseling their patients with localized prostate cancer 20 % relied exclusively on conversation. To support their conversation 63 % used print media, 49 % decision aids, 33 % contact offers to support groups, 24 % Internet resources and 13 % video material. From using decision aids 86 % expected positive effects for patients and 78 % for physicians (p = 0.017). 15 % expected a change of the treatment decision. 77 % would motivate their patients to use a decision aid. CONCLUSIONS: In comparison to the opinion of american urologists and radio oncologists the acceptance of decision aids for patients among German urologists is significantly higher.

[Evaluation of the decision aid "Entscheidungshilfe Prostatakrebs" from the patients' view : Results from the first three months]. / Evaluation der Entscheidungshilfe Prostatakrebs aus Patientensicht : Ergebnisse der ersten 3 Monate.

BACKGROUND: The decision aid "Entscheidungshilfe Prostatakrebs" is available online free of charge since June 2016. It is designed to support patients with their treatment decision-making and to lighten the burden on their treating urologists. This study evaluates usage data from the first 3 months. MATERIALS AND METHODS: The ICHOM standard set was applied to allow a personalised presentation and to collect relevant data for subsequent counselling. Additionally, personal preferences and psychological burden were assessed amongst others. We collected anonymous data. A multivariate model evaluated predictors for high user satisfaction. RESULTS: From June through August 2016 a total of 319 patients used the decision aid, showing a continuous monthly increase in the number of users. There were n = 219 (68.7%) complete questionnaires. Median age was 66.1 ± 8.0 years. The oncological risk was low in 30.3%, intermediate in 43.6% and high in 26.1%. A majority of 57.5% used the decision aid together with their partner, 35.1% alone and 5.5% with their children. In all, 54.8% were "very satisfied" and 32.0% were "satisfied" with the decision aid for a total satisfaction rate of about 87%. The only predictors of total satisfaction were the usage mode and reported distress level. CONCLUSIONS: As shown by the continuously increasing number of users this decision aid is becoming well established in German urology. Patients' overall ratings are very positive. The majority of patients use the decision aid with their partner. This represents a significant advantage of a multimedia approach compared to print media.

Correctly folded T-cell receptor fragments in the periplasm of Escherichia coli. Influence of folding catalysts.

The T-cell receptor is the central recognition molecule in cellular immunity. Its extracellular domains are homologous with and thought to be structurally similar to an antibody Fab fragment. Despite the biological importance of the TCR and the ease of bacterial expression of antibody fragments, there are only few reports of TCR-fragment expression in E. coli. In order to understand the difficulties of expressing correctly folded TCR fragments in E. coli, we have characterized the expression behavior of single-chain Fv analogs of three different TCRs (scTCR). All of them can be folded into the correct conformation in the periplasm of E. coli, yet the extent of correct folding varies greatly. In order to overcome the folding problems of some of the scTCRs, we have developed a system with enhanced in vivo folding capability based on the simultaneous induction of the heat-shock response and over-expression of the E. coli disulfide isomerase DsbA at low temperature. We present a model describing the folding of the scTCRs in the periplasm of E. coli and possible points of folding assistance. The role of the periplasm as an independent folding compartment is emphasized and the existence of a general periplasmic chaperone is postulated. We have also shown that a bivalent scTCR, dimerized in vivo with helix-turn-helix modules, can be expressed in a correctly folded form.

[Bilateral renal angiomyolipomas with a thrombus in the inferior caval vein. Rare growth pattern of a benign tumor]. / Bilaterale renale Angiomyolipome mit Thrombus in der Vena cava inferior. Seltenes Wachstumsverhalten eines benignen Tumors.

Renal angiomyolipomas are mesenchymal tumors that are composed of fat tissue, smooth muscle cells and vessels. These are benign tumors, but in rare cases they show a more aggressive growth pattern with invasion into the venous system but without revealing any signs of malignancy. We report a new case of bilateral renal angiomyolipomas with a caval thrombus in a 36 year old female patient with tuberous sclerosis, and give a brief review of the related literature.

[Therapy of hormone refractory prostate cancer: new standards, new trends]. / Die Behandlung des hormonrefraktären Prostatakarzinoms -- neue Standards, neue Trends.

Hormone-refractory prostate cancer is diagnosed with increasing incidence and has become a growing challenge for urologists. The improved understanding of the tumor biological mechanisms of the hormone-refractory state has led to innovative therapeutic developments in the field of hormonal and cytotoxic therapies. Recently, two large randomized Phase III trials with docetaxel-based chemotherapy were able to show prolonged survival and a positive influence on pain and quality of life, establishing a new standard of care for these patients. Moreover, bisphosphonates seem to have positive influence on selected patients. In the growing field of molecular targeted therapy, first trials with compounds, such as tyrosine kinase inhibitors, anti-sense oligonucleotides, angiogenesis inhibitors and endothelin receptor antagonists, show promising results in the treatment of patients with hormone-refractory prostate cancer.

[Obstructive uropathy in adults]. / Obstruktive Uropathie bei Erwachsenen.

Urinary tract obstruction is a common clinical problem. The obstruction of the urinary flow may be acute or chronic, partial or complete, unilateral or bilateral, and may occur at any site of the urinary tract. The major causes of urinary tract obstruction vary with the age of the patient. Anatomic abnormalities, e. g. ureteropelvic junction obstruction, account for the majority of cases in children. In comparison, calculi are most common in young adults, while prostatic hyperplasia or carcinoma, retroperitoneal or pelvic neoplasms, and calculi are the primary causes in older patients. Urinary tract obstruction results in different pathophysiological changes causing various symptoms. In addition to the aetiology, pathophysiology and clinical presentation of obstructive uropathy in adults, modern diagnostic and therapeutic options are presented in this review.

[Expression of Her2/neu in locally advanced bladder cancer: implication for a molecular targeted therapy]. / Die Her2/neu-Expression beim lokal fortgeschrittenen Harnblasenkarzinom: Ansatz für eine molekulare Therapie?

PURPOSE: The Her2/neu oncoprotein, belonging to the erbB-receptor family, is known to contribute to physiological mechanisms of cell proliferation by intrinsic tyrosine-kinase-activity. Overexpression has been shown for several tumors and is known to influence malignant cell proliferation, metastasis and angiogenesis. The clinical use of Her2-targeting agents has emerged in clinical research. In our study, we analyzed Her2/neu expression in urothelial tumors. MATERIALS AND METHODS: Her2/neu expression was evaluated immunohistochemically (IHC) in 127 patients undergoing radical cystectomy (DAKO- Herceptest). Additionally, fluorescent-in-situ-hybridisation (FISH) was carried out in all immunohistochemically "2+" cases (n = 41) to assess gene amplification. After grading the Her2/neu-overall status, Her2/neu expression was correlated with clinicopathological parameters and survival data. RESULTS: An immunohistochemical Her2/neu expression was found in 95 of 127 cases (74.8 %). Of all 41 cases with "2+" staining (32.2 %), 11 cases (26.8 %) showed positive amplification by FISH. Therefore, including the IHC 3+ cases, a Her2/neu overall status of 22 positive (17.3 %) tumors was assessed. Correlation with clinical data showed a relation to lymph node metastasis (P = 0.06), lymph vessel invasion (P = 0.07) and metastasis (P = 0.002). No further associations with other parameters nor with overall survival (P = 0.73) or disease-free survival (P = 0.63) were found. CONCLUSIONS: Her2/neu upregulation is found in invasive bladder cancer with significant differences in protein expression and gene amplification. The association with lymphogenic and distant metastases implicates a late event in carcinogenesis. Moreover, there was no further association with clinicopathological parameters and survival. The possible role of a molecular targeted therapy of advanced bladder cancer with Her2/neu targeting agents should be assessed in further clinical trials.

A versatile and highly repressible Escherichia coli expression system based on invertible promoters: expression of a gene encoding a toxic product.

A very flexible and tightly regulatable expression system has been constructed. It uses the principle of invertible promoters [Podhajska et al., Gene 40 (1985) 163-168]. Here, we describe the construction of a plasmid that provides the integrase, which causes promoter inversion in a tightly regulated fashion, as well as modified plasmids carrying the invertible module. The way the integrase is provided on a separate plasmid closely mimicks expression of the integrase from a lambda lysogen. Thus, the flexibility of the original system is considerably extended by making it strain-independent without compromising the tight regulation. We present the expression of a single-chain T-cell receptor fragment as an example of application, in order to illustrate the properties of this expression system.