Management of Germ Cell Tumours of the Testes in Adult Patients: German Clinical Practice Guideline, PART II - Recommendations for the Treatment of Advanced, Recurrent, and Refractory Disease and Extragonadal and Sex Cord/Stromal Tumours and for the Management of Follow-Up, Toxicity, Quality of Life, Palliative Care, and Supportive Therapy.

OBJECTIVES: We developed the first German evidence- and consensus-based clinical guideline on diagnosis, treatment, and follow-up of germ cell tumours (GCT) of the testes in adult patients. We present the guideline content in 2 separate publications. The present second part summarizes therecommendations for the treatment of advanced disease stages and for the management of follow-up and late effects. MATERIALS AND METHODS: An interdisciplinary panel of 42 experts including 1 patient representative developed the guideline content. Clinical recommendations and statements were based on scientific evidence and expert consensus. For this purpose, evidence tables for several review questions, which were based on systematic literature searches (last search in March 2018), were provided. Thirty-one experts, who were entitled to vote, rated the final clinical recommendations and statements. RESULTS: Here we present the treatment recommendations separately for patients with metastatic seminoma and non-seminomatous GCT (stages IIA/B and IIC/III), for restaging and treatment of residual masses, and for relapsed and refractory disease stages. The recommendations also cover extragonadal and sex cord/stromal tumours, the management of follow-up and toxicity, quality-of-life aspects, palliative care, and supportive therapy. CONCLUSION: Physicians and other medical service providers who are involved in the diagnostics, treatment, and follow-up of GCT (all stages, outpatient and inpatient care as well as rehabilitation) are the users of the present guideline. The guideline also comprises quality indicators for measuring the implementation of the guideline recommendations in routine clinical care; these data will be presented in a future publication.

Management of Germ Cell Tumours of the Testis in Adult Patients. German Clinical Practice Guideline Part I: Epidemiology, Classification, Diagnosis, Prognosis, Fertility Preservation, and Treatment Recommendations for Localized Stages.

INTRODUCTION: This is the first German evidence- and consensus-based clinical guideline on diagnosis, treatment, and follow-up on germ cell tumours (GCTs) of the testis in adult patients. We present the guideline content in two publications. Part I covers the topic's background, methods, epidemiology, classification systems, diagnostics, prognosis, and treatment recommendations for the localized stages. METHODS: An interdisciplinary panel of 42 experts including 1 patient representative developed the guideline content. Clinical recommendations and statements were based on scientific evidence and expert consensus. For this purpose, evidence tables for several review questions, which were based on systematic literature searches (last search was in March 2018) were provided. Thirty-one experts entitled to vote, rated the final clinical recommendations and statements. RESULTS: We provide 161 clinical recommendations and statements. We present information on the quality of cancer care and epidemiology and give recommendations for staging and classification as well as for diagnostic procedures. The diagnostic recommendations encompass measures for assessing the primary tumour as well as procedures for the detection of metastases. One chapter addresses prognostic factors. In part I, we separately present the treatment recommendations for germ cell neoplasia in situ, and the organ-confined stages (clinical stage I) of both seminoma and nonseminoma. CONCLUSION: Although GCT is a rare tumour entity with excellent survival rates for the localized stages, its management requires an interdisciplinary approach, including several clinical experts. Quality of care is highly related to institutional expertise and can be reassured by established online-based second-opinion boards. There are very few studies on diagnostics with good level of evidence. Treatment of metastatic GCTs must be tailored to the risk according to the International Germ Cell Cancer Collaboration Group classification after careful diagnostic evaluation. An interdisciplinary approach as well as the referral of selected patients to centres with proven experience can help achieve favourable clinical outcomes.

Adenocarcinoma of an ileal conduit developing 8 years after cystoprostatectomy for locally advanced prostate carcinoma.

A 70-year-old patient was treated in September 2017 for a malignancy in an ileal conduit (IC) which he received in 2009 for the treatment of prostate cancer. The tumour was found incidentally during a routine sonography. A CT scan revealed a mass near the IC. An endoscopy with biopsies showed an intraepithelial neoplasia of the ileal mucosa in the IC. We performed a segmental ileal resection. Histological findings revealed an ileal adenocarcinoma. The postoperative course was uneventful. The patient has remained alive without tumour recurrence up to the most recent negative CT screening in April 2019. Secondary malignancies after urinary diversions are a well-known complication, including procedures using small bowel parts for the urinary diversion. Adenocarcinomas arising in an IC are rarely described in literature. Concerning said tumour entity, surgical removal is often recommended. There is no evidence for the success of chemotherapy or radiation due to insufficient clinical trials. When diagnosing a mass in an IC, a secondary malignancy should be taken under consideration.

Investigation on core-fucosylated prostate-specific antigen as a refined biomarker for differentiation of benign prostate hyperplasia and prostate cancer of different aggressiveness.

Prostate cancer represents a major cause of cancer death in men worldwide. Novel non-invasive methods are still required for differentiation of non-aggressive from aggressive tumors. Recently, changes in prostate-specific antigen glycosylation pattern, such as core-fucosylation, have been described in prostate cancer. The objective of this study was to evaluate whether the core-fucosylation determinant of serum prostate-specific antigen may serve as refined marker for differentiation between benign prostate hyperplasia and prostate cancer or identification of aggressive prostate cancer. A previously developed liquid chromatography-mass spectrometry/mass spectrometry-based strategy was used for multiplex analysis of core-fucosylated prostate-specific antigen (fuc-PSA) and total prostate-specific antigen levels in sera from 50 benign prostate hyperplasia and 100 prostate cancer patients of different aggressiveness (Gleason scores, 5-10) covering the critical gray area (2-10 ng/mL). For identification of aggressive prostate cancer, the ratio of fuc-PSA to total prostate-specific antigen (%-fuc-PSA) yielded a 5%-8% increase in the area under the curve (0.60) compared to the currently used total prostate-specific antigen (area under the curve = 0.52) and %-free prostate-specific antigen (area under the curve = 0.55) tests. However, our data showed that aggressive prostate cancer (Gleason score > 6) and non-aggressive prostate cancer (Gleason score ≤ 6) could not significantly (p-value = 0.08) be differentiated by usage of %-fuc-PSA. In addition, both non-standardized fuc-PSA and standardized %-fuc-PSA had no diagnostic value for differentiation of benign prostate hyperplasia from prostate cancer. The %-fuc-PSA serum levels could not improve the differentiation of non-aggressive and aggressive prostate cancer compared to conventional diagnostic prostate cancer markers. Still, it is unclear whether these limitations come from the biomarker, the used patient cohort, or the imprecision of the applied method itself. Therefore, %-fuc-PSA should be further investigated, especially by more precise methods whether it could be clinically used in prostate cancer diagnosis.

[Living with Localized Prostate Cancer - Decision-Making and Coping with the Illness]. / Leben mit einem lokal begrenzten Prostatakarzinom ­ Entscheidungsfindung und Krankheitsverarbeitung.

BACKGROUND: Men diagnosed with localized prostate cancer must make a choice between treatment strategies that differ considerably in their side effects and have different long-term requirements for coping with the disease. The aim of this study was to describe how men perceive their treatment decision retrospectively and which coping strategies they use. MATERIAL & METHODS: Fifteen men (age mean=67.13±9.38 years) diagnosed with localized prostate cancer participated in three focus groups, grouped according to the treatment strategies radical prostatectomy, radiotherapy, and active surveillance. An interview guide structured the focus group discussions. In analogy to the structured interview, the material was deductively sorted in a first step; in a second step, sub-categories were developed inductively from the material. RESULTS: The content analysis revealed four particularly relevant topics: (1) The communication of the diagnosis and the associated reactions. (2) The decision-making process and the perceived time pressure. (3) The coping strategies, which showed a broad spectrum ranging from distraction and information search to lifestyle changes. (4) The perception of the disease over time. In particular men under active surveillance highlighted the importance of deceleration in their decision making and the role of lifestyle changes. DISCUSSION: The time of the diagnosis is still very much present even a long time after the diagnosis has been communicated. It is possible that a decrease in time pressure and deceleration would lead to more men deciding in favor of an observational strategy. Lifestyle changes could especially help men who choose active surveillance to overcome the feeling of "doing nothing" and gain a sense of control. CONCLUSION: In view of the variety of possible treatment strategies, an ethic of action is required that meets the need for an individual and preference-sensitive decision.

Animacroxam, a Novel Dual-Mode Compound Targeting Histone Deacetylases and Cytoskeletal Integrity of Testicular Germ Cell Cancer Cells.

Novel approaches for the medical treatment of advanced solid tumors, including testicular germ cell tumors (TGCT), are desperately needed. Especially, TGCT patients not responding to cisplatin-based therapy need therapeutic alternatives, as there is no effective medical treatment available for this particular subgroup. Here, we studied the suitability of the novel dual-mode compound animacroxam for TGCT treatment. Animacroxam consists of an HDAC-inhibitory hydroxamate moiety coupled to a 4,5-diarylimidazole with inherent cytoskeleton disrupting potency. Animacroxam revealed pronounced antiproliferative, cell-cycle arresting, and apoptosis-inducing effects in TGCT cell lines with different cisplatin sensitivities. The IC50 values of animacroxam ranged from 0.22 to 0.42 µmol/L and were not correlated to the cisplatin sensitivity of the tumor cells. No unspecific cytotoxicity of animacroxam was observed in either cisplatin-sensitive or resistant TGCT cells, even at doses as high as 10 µmol/L. Furthermore, animacroxam induced the formation of actin stress fibers in cancer cells, thereby confirming the cytoskeleton-disrupting and antimigratory properties of its imidazole moiety. When compared with the clinically established HDAC inhibitor vorinostat, the novel dual-mode compound animacroxam exhibited superior antitumoral efficacy in vitro Animacroxam also reduced the tumor size of TGCT tumors in vivo, as evidenced by performing xenograft experiments on tumor bearing chorioallantoic membranes of fertilizes chicken eggs (CAM assay). The in vivo experiments also revealed a very good tolerability of the compound, and hence, animacroxam may be a promising candidate for innovative treatment of TGCT in general and the more so for platinum-insensitive or refractory TGCT. Mol Cancer Ther; 16(11); 2364-74. ©2017 AACR.

Predictors of dyadic planning: Perspectives of prostate cancer survivors and their partners.

OBJECTIVES: Extending individual planning of health behaviour change to the level of the dyad, dyadic planning refers to a target person and a planning partner jointly planning the target person's health behaviour change. To date, predictors of dyadic planning have not been systematically investigated. Integrating cognitive predictors of individual planning with four established predictor domains of social support provision, we propose a framework of predictors of dyadic planning. Including target persons' and partners' perspectives, we examine these predictor domains in the context of prostate cancer patients' rehabilitative pelvic floor exercise (PFE) following radical prostatectomy. DESIGN: Longitudinal data from 175 patients and their partners were analysed in a study with four post-surgery assessments across 6 months. METHODS: PFE-related dyadic planning was assessed from both partners together with indicators from four predictor domains: context, target person, partner, and relationship factors. Individual planning and social support served as covariates. RESULTS: Findings from two-level models nesting repeated assessments in individuals showed that context (patients' incontinence), target person (i.e., positive affect and self-efficacy), and relationship factors (i.e., relationship satisfaction) were uniquely associated with dyadic planning, whereas partner factors (i.e., positive and negative affects) were not. Factors predicting patients' and partners' accounts of dyadic planning differed. CONCLUSIONS: Resembling prior findings on antecedents of support provision in this context, partner factors did not prevail as unique predictors of dyadic planning, whereas indicators from all other predictor domains did. To establish predictive direction, future work should use lagged predictions with shorter intermeasurement intervals. Statement of contribution What is already known on this subject? Dyadic planning has been shown to be linked to health behaviour change. However, its role in behaviour regulation frameworks is not well investigated, especially regarding factors that might be predictive of dyadic planning. What does this study add? A framework of predictors of dyadic planning in the health behaviour change process is presented. The framework is investigated accounting for both planning partners' perspectives. Context, target person, and relationship factors were related to dyadic planning.

Patients' perceptions of mortality risk for localized prostate cancer vary markedly depending on their treatment strategy.

Treatment choice for localized prostate cancer (PCa) is a controversial issue, and mortality risk is probably the most decisive factor in this regard. The study aimed to compare prostate-cancer-specific mortality risk estimates for different treatment options assigned by patients managed with active surveillance (AS), radical prostatectomy (RP) and patients who had discontinued AS (DAS). Patients initially managed with AS or RP (N = 370) were matched according to length of therapy. All patients completed mailed questionnaires assessing their mortality risk estimates (in %) and prostate-cancer-specific anxiety. Differences in risk estimates among the three treatment groups were analyzed using ANOVA, relationships of clinical and psychosocial variables with risk estimates using standard multiple regression. In all treatment groups, the prostate- cancer-specific mortality risk was overestimated. This applied whether it was the patient's own treatment or the alternative treatment option. RP patients assigned a mortality risk to AS that was almost three times higher than that assigned to RP (50.9 ± 25.0 vs. 17.8 ± 19.7, d = 1.48; p < 0.001). Anxiety was significantly associated with risk estimates for AS (p = 0.008) and RP (p = 0.001). Compared with clinical data that suggest that the prostate-cancer-specific mortality risk for AS is low and does not significantly differ from that for RP, patients strongly overestimated the mortality risk. This was most markedly so in RP patients, who drastically overestimated the benefits of RP compared to the risk of AS. This overestimation could increase overtreatment and should therefore be corrected by better patient education.

Enabling or Cultivating? The Role of Prostate Cancer Patients' Received Partner Support and Self-Efficacy in the Maintenance of Pelvic Floor Exercise Following Tumor Surgery.

BACKGROUND: To manage incontinence following tumor surgery, prostate cancer patients are advised to perform pelvic floor exercise (PFE). Patients' self-efficacy and support from partners were shown to facilitate PFE. Whereas support may enhance self-efficacy (enabling function), self-efficacy may also cultivate support (cultivation function). PURPOSE: Cross-lagged inter-relationships among self-efficacy, support, and PFE were investigated. METHOD: Post-surgery patient-reported received support, self-efficacy, PFE, and partner-reported provided support were assessed from 175 couples at four times. Autoregressive models tested interrelations among variables, using either patients' or partners' reports of support. RESULTS: Models using patients' data revealed positive associations between self-efficacy and changes in received support, which predicted increased PFE. Using partners' accounts of support provided, these associations were partially cross-validated. Furthermore, partner-provided support was related with increases in patients' self-efficacy. CONCLUSION: Patients' self-efficacy may cultivate partners' support provision for patients' PFE, whereas evidence of an enabling function of support as a predictor of self-efficacy was inconsistent.

Individual and dyadic planning predicting pelvic floor exercise among prostate cancer survivors.

UNLABELLED: [Correction Notice: An Erratum for this article was reported in Vol 60(3) of Rehabilitation Psychology (see record 2015-40319-001). Aleksandra Luszczynska's institutional affiliation was incorrectly set as Warsaw School of Social Sciences and Humanities. It should have been University of Social Sciences and Humanities. All versions of this article have been corrected.] OBJECTIVE: Radical prostatectomy, a standard treatment for localized prostate cancer, is often followed by a recommendation to initiate and maintain pelvic floor exercise (PFE), to control postsurgery urinary incontinence. Previous studies showed that planning facilitated the uptake and maintenance of a new behavior. Whereas individual planning addresses the setting of plans by 1 person, dyadic planning refers to creating plans together with a partner on when, where, and how the individual target person will perform a behavior. Individual and dyadic planning of PFE, their development over time, and their associations with PFE were investigated. RESEARCH METHOD: In a correlational study, 175 prostate-cancer patients provided data at 1, 3, 5, and 7 months following the onset of incontinence. Individual planning of PFE by patients and dyadic planning of PFE between patients and their partners, PFE, and incontinence were assessed by patients' self-reports. RESULTS: Two-level models with repeated assessments nested in individuals revealed stable levels of individual planning of PFE over time in patients with higher incontinence severity, whereas patients with receding incontinence showed decreases. Independent of incontinence severity, a curvilinear increase followed by a decrease of dyadic planning of PFE across time emerged. Sequential associations of both planning strategies with PFE were found. Whereas individual planning was steadily associated with PFE, associations between dyadic planning and PFE were nonsignificant in the beginning, but increased over time. CONCLUSIONS: Findings point to the importance of individual planning for the adoption and maintenance of PFE, with dyadic planning being relevant for PFE maintenance only.

Calibrating Independence Goals and Partner Support: Couples Adjust to Functional Limitations after Tumor Surgery.

BACKGROUND: When patients recover from disease-related functional limitations, support received from partners may not always match patients' changing independence goals. The lines of defense (LoD) model proposes a hierarchy of independence goals (LoDs), ranging from minimising discomfort by disengagement (lowest LoD) to protection of self-reliance (highest LoD). Prostate cancer patients' LoDs were examined as moderators of the association between partner support and patients' and partners' affect during patients' recovery from postsurgical functional limitations. METHODS: Data from 169 couples were assessed four times within 7 months following patients' surgery. Patients reported on post-surgery functional limitations (i.e. incontinence), LoDs, affect, and received partner support. Partners reported on affect and support provided to patients. RESULTS: In patients endorsing lower LoDs, more received support was associated with less negative affect. Also, not endorsing high LoDs while receiving strong partner support was related to patients' lower negative and higher positive affect. Partners' support provision to patients tended to be associated with increases in partners' negative affect when patients had endorsed higher LoDs and with increases in positive affect when patients had endorsed lower LoDs. CONCLUSIONS: Matching patients' independence goals or LoDs with partners' support may be beneficial for patients' and partners' affect.

Prostate cancer patients gradually advance goals for rehabilitation after radical prostatectomy: applying a lines-of-defense model to rehabilitation.

Following tumor surgery, urinary incontinence challenges prostate cancer patients' functional health. Adjustments of functional goals (lines of defense [LoDs]) were examined during rehabilitation from incontinence. A conceptual model proposing stepwise and distinct upward adjustments of LoDs, ranging from minimizing discomfort (lowest LoD) to protecting self-reliance (highest LoD), was investigated. Within 7 months following the onset of incontinence, 175 patients completed questionnaires at 4 occasions. A theory-based hierarchy was imposed on time-invariant latent classes of LoD-endorsements. As incontinence receded, patients transitioned upward through the hierarchy of LoD-classes, matched LoDs to concurrent incontinence levels, and thus promptly claimed independent functioning with physical improvements.

The Fuhrman grading system has no prognostic value in patients with nonsarcomatoid chromophobe renal cell carcinoma.

The prognostic value of the Fuhrman nuclear grading system has been questioned for chromophobe renal cell carcinoma (chRCC) because this subtype frequently displays nuclear and nucleolar pleomorphism. The present study reevaluates this grading system in a series of patients with nonsarcomatoid chRCC. We identified 176 patients (3.6%) with nonsarcomatoid chRCC in a total of 4897 patients who underwent surgery for renal cell carcinoma at 5 centers in Germany between 1990 and 2010. The mean follow-up was 51.1 months. The 3 groups (G1 versus G2 versus G3/4) were comparable in terms of age, sex, tumor diameter, and lymph node metastasis. They only differed significantly in tumor stage (P = .01) and the incidence of synchronous visceral metastasis (P = .04). The 5-year cancer-specific survival rates were 84.4% for G1 (n = 32), 84.3% for G2 (n = 108), and 74.1% for G3/4 tumors (n = 33) (P = .58). Accordingly, multivariate analysis including age, sex, tumor stage, and metastatic disease did not identify Fuhrman grading as an independent predictor of cancer-specific survival in patients with chRCC (P = .4). We were able to demonstrate in a large multicenter cohort that the Fuhrman grading system does not qualify as a prognostic tool in patients with chRCC.

Clinical behavior of chromophobe renal cell carcinoma is less aggressive than that of clear cell renal cell carcinoma, independent of Fuhrman grade or tumor size.

Chromophobe renal cell carcinoma (chRCC) is the third most common subtype of RCC, after clear cell (ccRCC) and papillary RCC. Its lower incidence and frequent exclusion from clinical trials might be why chRCC characteristics have not been extensively studied. The aim of our study was to examine tumor characteristics and long-term prognosis of chRCC compared to ccRCC. We collected 4,210 evaluable patients subjected to surgery for chRCC (n = 176) or ccRCC (n = 4,034) at five centers in Germany (University Hospitals of Hannover, Homburg/Saar, Mainz, Ulm, and Marburg) between 1990 and 2010. Patients with chRCC were significantly younger (mean, 60.1 vs. 62.1 years) and tended to be more frequently female (43.8 vs. 36.5 %). Although Fuhrman grade and median tumor diameter were not significantly different, significantly fewer patients with chRCC than with ccRCC presented with high tumor stage or metastasis at diagnosis (18.5 vs. 43.8 %). Moreover, significantly more chRCC patients were treated with partial nephrectomy (41.5 vs. 26.2 %). Accordingly, 5-year cancer-specific survival (CSS) rates were 83.2 % for chRCC against 75.8 % for ccRCC patients (p = 0.014, log rank). However, in multivariate analysis, chromophobe subtype was not confirmed as a significant positive prognostic factor for RCC (HR 0.88, 95 % CI 0.63-1.24; p = 0.48 Cox regression). This is one of the largest studies to date showing that chRCC is associated with a significantly lower risk of locally invasive tumor growth and metastatic disease than ccRCC. We conclude that the clinical behavior of chRCC is less aggressive than that of ccRCC, independent of Fuhrman grade or tumor size.

Subgroups of familial and aggressive prostate cancer with considerable frequencies of BRCA2 mutations.

BACKGROUND: One of the known risk factors for prostate cancer (PrCa) is germline mutations in the BRCA2 gene. Previous searches for clinical characteristics which could identify a subgroup of patients enriched for mutation carriers revealed early onset and aggressive PrCa as useful parameters, but they are rather unspecific. METHODS: Identification of BRCA2 mutation carriers by sequencing all exons of BRCA2 in a German cohort of 382 familial PrCa cases and of 92 sporadic PrCa cases with early onset (≤60 years). To define a subgroup of PrCa patients enriched for BRCA2 mutation carriers, we used clinical parameters including a detailed family history (FH) for PrCa and breast cancer. RESULTS: Five BRCA2 mutations and ten variants of unknown significance (VUS) were identified. While the VUS were evenly distributed among the groups, mutation carriers were lacking from the sporadic cases and over represented among familial cases with aggressive disease. High prostate specific antigen (PSA) at diagnosis (>20 ng/ml) was the only criterion with significant enrichment of mutation carriers (6.4%, P = 0.0005). In men with aggressive disease, death from PrCa (6.3% including FH of lethal PrCa; P = 0.05) and FH of both prostate and breast cancer (4.8%; P = 0.3) increased the frequency of mutation carriers. Larger studies and/or meta-analyses are needed to validate these parameters. CONCLUSIONS: We have identified three potentially useful criteria, high PSA, death from PrCa (patient or FH), and aggressive PrCa in combination with FH of breast and prostate cancer. If confirmed, they may become useful for the decision which patients may benefit from BRCA2 testing.

Capsulotomy for treatment of compartment syndrome in patients with post extracorporeal shock wave lithotripsy renal hematomas: safe and effective, but also advisable?

PURPOSE: To examine whether surgical decompression of hematomas by capsulotomy can help to improve long-term renal function following extracorporeal shock wave lithotripsy (SWL). MATERIALS AND METHODS: This study retrospectively identified 7 patients who underwent capsulotomy for post SWL renal hematomas between 2008 and 2012. The control group comprised 8 conservatively treated patients. The median follow-up time was 22 months. RESULTS: The two groups were comparable in age, gender, body mass index, risk factors for developing hematomas (renal failure, urinary flow impairment, indwelling ureteral stent and diabetes mellitus) and the selected SWL modalities. Hematoma size was also similar. However, significantly more patients in the surgical group had purely intracapsular hematomas (85.7% vs. 37.5%) without a potentially pressure-relieving capsular rupture. There were no significant differences in the post-interventional drop in hemoglobin, rise in retention parameters or drop in glomerular filtration rate (GFR). No capsulotomy-related complications were observed, but surgery required a significantly longer hospital stay than conservative management (median, 9 days vs. 5 days). The two groups also showed comparable recovery of renal function at long-term follow-up (median change in GFR from baseline, 97.1% and 97.8%, respectively). CONCLUSION: Since renal function did not differ between the two treatment groups, the conservative management remains the standard treatment for post-SWL renal hematoma.

Stilbene induced inhibition of androgen receptor dimerization: implications for AR and ARΔLBD-signalling in human prostate cancer cells.

BACKGROUND: Advanced castration resistant prostate cancer (CRPC) is often characterized by an increase of C-terminally truncated, constitutively active androgen receptor (AR) variants. Due to the absence of a ligand binding domain located in the AR-C-terminus, these receptor variants (also termed ARΔLBD) are unable to respond to all classical forms of endocrine treatments like surgical/chemical castration and/or application of anti-androgens. METHODOLOGY: In this study we tested the effects of the naturally occurring stilbene resveratrol (RSV) and (E)-4-(2, 6-Difluorostyryl)-N, N-dimethylaniline, a fluorinated dialkylaminostilbene (FIDAS) on AR- and ARΔLBD in prostate cancer cells. The ability of the compounds to modulate transcriptional activity of AR and the ARΔLBD-variant Q640X was shown by reporter gene assays. Expression of endogenous AR and ARΔLBD mRNA and protein levels were determined by qRT-PCR and Western Blot. Nuclear translocation of AR-molecules was analyzed by fluorescence microscopy. AR and ARΔLBD/Q640X homo-/heterodimer formation was assessed by mammalian two hybrid assays. Biological activity of both compounds in vivo was demonstrated using a chick chorioallantoic membrane xenograft assay. RESULTS: The stilbenes RSV and FIDAS were able to significantly diminish AR and Q640X-signalling. Successful inhibition of the Q640X suggests that RSV and FIDAS are not interfering with the AR-ligand binding domain like all currently available anti-hormonal drugs. Repression of AR and Q640X-signalling by RSV and FIDAS in prostate cancer cells was caused by an inhibition of the AR and/or Q640X-dimerization. Although systemic bioavailability of both stilbenes is very low, both compounds were also able to downregulate tumor growth and AR-signalling in vivo. CONCLUSION: RSV and FIDAS are able to inhibit the dimerization of AR and ARΔLBD molecules suggesting that stilbenes might serve as lead compounds for a novel generation of AR-inhibitors.

Survival advantage of partial over radical nephrectomy in patients presenting with localized renal cell carcinoma.

BACKGROUND: Partial nephrectomy (PN) preserves renal function and has become the standard approach for T1a renal cell carcinoma (RCC). However, there is still an ongoing debate as to which patients will actually derive greater benefit from partial than from radical nephrectomy (RN). The aim of this study was to retrospectively evaluate the impact of the type of surgery on overall survival (OS) in patients with localized RCC. METHODS: Renal surgery was performed in 4326 patients with localized RCC (pT ≤ 3a N/M0) at six German tertiary care centers from 1980 to 2010: RN in 2955 cases (68.3%), elective (ePN) in 1108 (25.6%), and imperative partial nephrectomy (iPN) in 263 (6.1%) cases. The median follow-up for all patients was 63 months. Kaplan-Meier and Cox regression analyses were carried out to identify prognosticators for OS. RESULTS: PN was performed significantly more often than RN in patients presenting with lower tumor stages, higher RCC differentiation, and non-clear cell histology. Accordingly, the calculated 5 (10)-year OS rates were 90.0 (74.6)% for ePN, 83.9 (57.5)% for iPN, and 81.2 (64.7)% for RN (p < 0.001). However, multivariate analysis including age, sex, tumor diameter and differentiation, histological subtype, and the year of surgery showed that ePN compared to RN still qualified as an independent factor for improved OS (HR 0.79, 95% CI 0.66-0.94, p = 0.008). CONCLUSION: Even allowing for the weaknesses of this retrospective analysis, our multicenter study indicates that in patients with localized RCC, PN appears to be associated with better OS than RN irrespective of age or tumor size.