No impact of blood transfusion on oncological outcome after radical prostatectomy in patients with prostate cancer.

PURPOSE: To assess the association between blood loss, blood transfusion (BT) and biochemical recurrence (BCR)-free, metastasis-free and overall survival after radical prostatectomy (RP) in a large single-center cohort of patients. Perioperative BT at oncologic surgery has been reported to be a potential risk factor for cancer recurrence and survival in several cancer entities. Current studies addressing the relationship between BT, blood loss and BCR-free survival in prostate cancer patients are controversial and include only series with fairly small patient cohorts. MATERIALS AND METHODS: The data of 11,723 patients who underwent RP between 01/1992 and 08/2011 were analyzed. Cox regression analysis, including preoperative PSA level, pT stage, lymph node status, Gleason score, margin status, blood loss, transfusion rate (allogeneic or autologous), tested the relationship between blood loss, transfusion and BCR-free, metastasis-free and overall survival. Additionally, propensity score-matching analysis was performed to adjust differences in tumor characteristics. RESULTS: There was no statistically significant relationship between blood loss or BT and BCR-free, metastasis-free or overall survival. In multivariate analysis PSA level, pT stage, Gleason score, margin status and lymph node status were independent factors for a BCR (p < 0.0001). These results were identical after propensity score matching analysis, comparing patients with and without BT. CONCLUSIONS: This large-scale analysis revealed no correlation between blood loss, blood transfusion and oncological outcome in prostate cancer patients treated with RP. Therefore, the association between higher blood loss or transfusion rate and cancer recurrence as described in other surgical treated tumor entities seems to be irrelevant in prostate cancer patients.

[Current results on PSA-based prostate cancer detection]. / Aktuelle Ergebnisse zur PSA-basierten Früherkennung des Prostatakarzinoms.

Prostate cancer is the most common cancer and the third leading cause of cancer-specific death in men in Western industrialized countries. Implementation of the prostate-specific antigen (PSA) blood test as an early detection tool has led to a significant reduction of prostate cancer mortality in the USA. Apart from an earlier detection of clinically relevant tumors, regular PSA testing increases the risk of over-detection and over-treatment of clinically indolent tumors. In our view, a reliable stratification of indolent tumors in active surveillance programs is the key in avoiding or reducing overtreatment of early diagnosed prostate cancers. Along with better risk stratification, the expansion of PSA screening should be discussed in order to reduce the still high numbers of palliative treatments, metastases, and prostate cancer-related deaths.

Prognostic relevance of Bcl-2 overexpression in surgically treated prostate cancer is not caused by increased copy number or translocation of the gene.

BACKGROUND: Overexpression of anti-apoptotic Bcl-2 plays a role in prostate cancer progression, particularly in transformation to androgen-independent disease. Androgen-independent prostate cancers have been shown to harbor Bcl-2 gene copy number gains frequently suggesting that this genetic alteration might play a role in Bcl-2 overexpression. The relation of Bcl-2 overexpression and copy number gains or translocation of the BCL-2 gene in prostate cancer under hormone-naïve conditions is unknown. METHODS: Prostate cancers of 3,261 hormone-naïve patients undergoing radical prostatectomy were arrayed in a TMA with one tissue core (diameter 0.6 mm) per tumor. Bcl-2 immunohistochemistry, analyzed for Bcl-2 expression level (negative, low, and high), was correlated with clinical, histopathological and molecular (Ki67, p53) tumor features, and biochemical failure. Cancers with high-level Bcl-2 expression were evaluated for genetic aberrations by fluorescence in situ hybridization (FISH). RESULTS: Bcl-2 expression was significantly up-regulated in tumors with aggressive phenotype as indicated by high Gleason score (P < 0.0001), advanced stage (P < 0.0001), and high proliferation index (P = 0.0114). The different Bcl-2 expression levels translated into significantly different survival curves showing better outcome for patients with lower Bcl-2 levels. The prognostic information obtained from the anti-apoptotic Bcl-2 was independent from the proliferation index (Ki67) of the cancer. FISH analysis detected no copy number gains or translocation of the Bcl-2 gene. CONCLUSION: Bcl-2 overexpression in prostate cancers under hormone-naïve conditions is not associated with increased copy numbers of the gene. This suggests that these frequently detected genetic alterations in androgen-independent tumors occur late in prostate cancer progression.

[Network medicine and health services research in urology]. / Urologische Netzwerkmedizin und Versorgungsforschung.

It is the aim of the Medical Informatics Funding Scheme and other national and local projects for digital networking in healthcare to facilitate the exchange and use of patient data between institutions in compliance with data protection regulations. This requires the integration of data from various sources-such as digital workplace systems, laboratory systems, picture archiving and communication (PAC) systems or tumor boards-into a data warehouse or research databases. Digital networking of service providers and research institutions will open access to high-performance and precision medicine (e.g., virtual molecular tumor boards) for even more patients, thereby providing data for basic and care research. Network medicine will establish the translational link between basic research (e.g., genome research) and patient care. Digitally integrated "real world" patient data will also facilitate a detailed analysis of health care and the quality of treatments.

[Precision oncology : How can high-quality healthcare remain affordable for all in the face of diagnostic and therapeutic costs?] / Präzisionsonkologie : Wie bleibt hochwertige Versorgung für alle angesichts steigender Diagnostik und Therapiekosten bezahlbar?

Medicine is becoming increasingly precise. This is particularly evident in the field of pharmaceuticals and especially in oncology. Driven by the steadily growing understanding of biomedical interrelationships and the resulting increase in precision, we are currently experiencing a paradigm shift from a one-drug-fits-all model towards an individualized biomarker-driven approach. This essentially enables the transition from efficacy to effectiveness. In order to ensure that the promise of high-quality, affordable precision medicine for all remains valid in the future, the step from efficacy in clinical studies to effectiveness in the practice of care is crucial in the next decade. This will be achieved with end-to-end precision from diagnostics to real-world evidence.

[Identification and validation of clinically relevant molecular alterations in prostate cancer]. / Identifizierung und Validierung klinisch relevanter molekularer Veränderungen im Prostatakarzinom.

Significant cellular alterations required for the development and progression of cancers are detectable at the molecular level and represent potential targets for gene-specific therapies. Modern chip techniques allow the parallel analysis of virtually all known human genes and proteins in a single experiment. Using modern high-throughput techniques, numerous potential new biomarkers for the diagnosis and prediction of prostate cancer have been identified. However, so far none of these markers has improved clinical practice. One of the most important challenges in the coming years is the extensive clinical validation of molecular data using clinically relevant end points. For this venture the pivotal prerequisite is the availability of large, comprehensively annotated and standardized high-quality bioresources.

[Identification and validation of clinically relevant molecular alterations in prostate cancer]. / Identifizierung und Validierung klinisch relevanter molekularer Veränderungen im Prostatakarzinom.

Significant cellular alterations required for the development and progression of cancers are detectable at the molecular level and represent potential targets for gene-specific therapies. Modern chip techniques allow the parallel analysis of virtually all known human genes and proteins in a single experiment. Using modern high-throughput techniques, numerous potential new biomarkers for the diagnosis and prediction of prostate cancer have been identified. However, so far none of these markers has improved clinical practice. One of the most important challenges in the coming years is the extensive clinical validation of molecular data using clinically relevant end points. For this venture the pivotal prerequisite is the availability of large, comprehensively annotated and standardized high-quality bioresources.

[Active surveillance for prostate cancer]. / Aktive Uberwachung des Prostatakarzinoms.

Active surveillance is a valuable treatment option in patients with newly diagnosed low-risk prostate cancer. Studies considering a watchful waiting approach showed favourable cancer-specific survival rates in such patients and it is assumed that patients benefit from a definitive therapy if life expectancy exceeds 10-15 years. Therefore active surveillance is especially valuable in older men and in patients with an elevated comorbidity profile. Precise identification of histologically and clinically insignificant prostate cancers is still not possible today. Active surveillance includes regular PSA measurements combined with follow-up biopsies; however, no standardized protocol exists so far. Histological progression in the follow-up biopsy and PSA elevation are the most important criteria for initiating definitive therapy. Today only a minority of low-risk patients join an active surveillance protocol and a substantial proportion of these men leave such a protocol early without evidence of progression. The psychological burden of living with an untreated cancer seems to be responsible for this. Active surveillance has the potential to lead to undertreatment as there is some evidence that prolonged treatment delay might adversely affect outcome of definitive therapy.

Simultaneous tumour-like, atypical basal cell hyperplasia and acinar adenocarcinoma of the prostate: a comparative morphological and genetic approach.

Basal cell tumours of the prostatic gland are rare, and the classification is difficult. In the present case report, a large, tumour-like proliferation of atypical basaloid cells was found incidentally in a prostatectomy specimen that otherwise contained a conventional acinar adenocarcinoma. The basaloid cells displayed a solid or adenoid-cystic growth pattern and strongly expressed high-molecular-weight cytokeratins and bcl-2. A high Ki-67 index was recorded within the atypical basaloid cells, by far exceeding the one counted in the conventional adenocarcinoma. However, there were no definite criteria for a malignant behaviour of the basal cell tumour. Comparative genomic hybridisation from microdissected tumour cells yielded losses at the short arms of chromosomes 8 and 12 in the conventional adenocarcinoma and a normal karyotype in the basal cell tumour. The pathological findings favoured the diagnosis of an atypical basal cell hyperplasia.

[Selection criteria for the expected management of localised prostate cancer]. / Selektionskriterien zum abwartenden Management des lokalisierten Prostatakarzinoms.

Prostate cancer harbours the possibility of overtreatment more than any other malignant disease. Due to its slow growth, expected management is an established therapeutic option in newly diagnosed carcinomas. Improved diagnostic methods and the widespread use of PSA lead to earlier diagnosis of cancers that would not adversely affect the life expectancy of the patient, even when they were left untreated. Several statistical models have been published to identify such insignificant cancers; however, all such nomograms suffer from limited sensitivity and specificity. For the indication of expected management, comorbidity and life expectancy must be considered using risk scores and life tables. In general, expected management is a suitable option for elderly patients with low grade cancers. Young patients and those with intermediate or high-grade cancers are most likely to benefit from active local treatment.

UAP1 is overexpressed in prostate cancer and is protective against inhibitors of N-linked glycosylation.

Prostate cancer is the second most common cause of cancer-associated deaths in men, and signaling via a transcription factor called androgen receptor (AR) is an important driver of the disease. Consequently, AR target genes are prominent candidates to be specific for prostate cancer and also important for the survival of the cancer cells. Here we assess the levels of all hexosamine biosynthetic pathway (HBP) enzymes in 15 separate clinical gene expression data sets and identify the last enzyme in the pathway, UDP-N-acetylglucosamine pyrophosphorylase 1 (UAP1), to be highly overexpressed in prostate cancer. We analyzed 3261 prostate cancers on a tissue microarray and found that UAP1 staining correlates negatively with Gleason score (P=0.0039) and positively with high AR expression (P<0.0001). Cells with high UAP1 expression have 10-fold increased levels of the HBP end-product, UDP-N-acetylglucosamine (UDP-GlcNAc). UDP-GlcNAc is essential for N-linked glycosylation occurring in the endoplasmic reticulum (ER) and high UAP1 expression associates with resistance against inhibitors of N-linked glycosylation (tunicamycin and 2-deoxyglucose) but not with a general ER stress-inducing agent, the calcium ionophore A23187. Knockdown of UAP1 expression re-sensitized cells towards inhibitors of N-linked glycosylation, as measured by proliferation and activation of ER stress markers. Taken together, we have identified an enzyme, UAP1, which is highly overexpressed in prostate cancer and protects cancer cells from ER stress conferring a growth advantage.

Adherence of the indication to European Association of Urology guideline recommended pelvic lymph node dissection at a high-volume center: Differences between open and robot-assisted radical prostatectomy.

PURPOSE: Contemporary adherence of the indication to European Association of Urology (EAU) guideline recommendation for pelvic lymph node dissection (PLND) at either open (ORP) or robot-assisted radical prostatectomy (RARP) at a high-volume center is unknown. To assess guideline recommended and observed PLND rates in a high-volume center cohort. METHODS: We relied on the Martini-Clinic database and focused on patients treated with either ORP or RARP, between 2010 and 2013. Actual performed PLND was compared to European Association of Urology (EAU) guideline recommendation defined by nomogram predicted risk of lymph node invasion >5%. Categorical and multivariable logistic regression analyses targeted two endpoints: 1) probability of guideline recommended PLND and 2) probability of no PLND, when not recommended by EAU guideline. RESULTS: Within 7868 PCa patients, adherence to EAU PLND guideline recommendation was 97.1% at ORP and 96.8% at RARP (p = 0.7). When PLND was not recommended, it was more frequently performed at RARP (71.6%) than at ORP (66.2%) (p = 0.002). Gleason score, PSA and number of positive biopsy cores were independent predictors for both either PLND when recommended, or no PLND when not recommended (all p < 0.05). Clinical tumor stage, age and surgical approach were also independent predictors for no PLND when not recommended (all p < 0.05). CONCLUSIONS: Adherence of the indication to EAU guideline recommended PLND is high at this high-volume center. Neither ORP nor RARP represent a barrier for PLND, when recommended. However, a high number of patients underwent PLND despite absence of guideline recommendation. Possible staging advantages and PLND related complications needs to be individually considered, especially, when LNI risk is low.

[Prognostic and predictive molecular markers for urologic cancers]. / Prognostische und prädiktive molekulare Marker urologischer Tumoren.

Molecular prognostic factors and genetic alterations as predictive markers for cancer-specific targeted therapies are used today in the clinic for many malignancies. In recent years, many molecular markers for urogenital cancers have also been identified. However, these markers are not clinically used yet. In prostate cancer, novel next-generation sequencing methods revealed a detailed picture of the molecular changes. There is growing evidence that a combination of classical histopathological and validated molecular markers could lead to a more precise estimation of prognosis, thus, resulting in an increasing number of patients with active surveillance as a possible treatment option. In patients with urothelial carcinoma, histopathological factors but also the proliferation of the tumor, mutations in oncogenes leading to an increasing proliferation rate and changes in genes responsible for invasion and metastasis are important. In addition, gene expression profiles which could distinguish aggressive tumors with high risk of metastasis from nonmetastasizing tumors have been recently identified. In the future, this could potentially allow better selection of patients needing systemic perioperative treatment. In renal cell carcinoma, many molecular markers that are associated with metastasis and survival have been identified. Some of these markers were also validated as independent prognostic markers. Selection of patients with primarily organ-confined tumors and increased risk of metastasis for adjuvant systemic therapy could be clinically relevant in the future.

Oncological long-term outcome of 4772 patients with prostate cancer undergoing radical prostatectomy: does the anaesthetic technique matter?

INTRODUCTION: Recent data suggest that using additional neuroaxial anaesthesia during oncological surgery is associated with favourable recurrence-free survival, when compared with general anaesthesia alone. We assessed the impact of adjunctive perioperative spinal anaesthesia and dose of opioids on the oncological long-term outcome of patients following radical prostatectomy. METHODS: We selected patients from our institutional review board-approved database who consecutively underwent radical prostatectomy between 2002 and 2007. Patients were stratified by type of anaesthesia, administered as general anaesthesia alone, or spinal anaesthesia in addition to general anaesthesia. Biochemical recurrence-free survival, metastasis-free survival and overall survival were analysed by a multivariate Cox regression model and by Kaplan-Meier analysis in propensity-score based matched cohorts, adjusted for standard clinico-pathological variables and year of surgery. RESULTS: Overall, 4772 patients were analysed. Regarding the type of anaesthesia no significant difference for biochemical recurrence-free survival, metastasis-free survival and overall survival was analysed by a multivariate Cox regression model (p = 0.5, 0.8 and 0.7). The Kaplan-Meier analyses after propensity-score matched based comparisons revealed no significant difference depending on type of anaesthesia for biochemical recurrence-free survival, metastasis-free survival and overall survival (p = 0.6, 0.1 and 0.4). The same accounted for a propensity-score matched model adjusted for the year of surgery on biochemical recurrence-free survival (p = 0.7). CONCLUSIONS: The oncological outcome after radical prostatectomy was not affected by the adjunctive use of spinal anaesthesia.

High Nr-CAM expression is associated with favorable phenotype and late PSA recurrence in prostate cancer treated by prostatectomy.

BACKGROUND: Neuron-glia-related cell-adhesion molecule (Nr-CAM) is another potential membrane-bound target molecule for specific prostate cancer therapy. The role of Nr-CAM in normal and neoplastic prostate tissue has not been extensively studied. The aim of our study is to evaluate the prevalence of Nr-CAM expression in prostate cancer and to explore its association with phenotype and clinical disease course. METHODS: A preexisting tissue microarray including more than 3000 prostate cancers that underwent prostatectomy at our center with clinical follow-up data was used. The tissue microarray (TMA) was immunhistochemically stained for Nr-CAM. RESULTS: A total of 2883 (88.4%) of tumor samples were interpretable in our TMA analysis. Membranous Nr-CAM staining was seen in 1418 (49.2%) of 2883 analyzable cases. According to predefined criteria, staining was considered weak in 778 (27.0%), moderate in 412 (14.3%) and strong in 228 (7.9%) cancers. Significant associations were found with pathological tumor stage (P=0.0015), Gleason grade (P=0.0003), nodal stage (P=0.0061), preoperative PSA (P=0.0138) and prolonged PSA recurrence-free survival (P<0.0001). CONCLUSIONS: Nr-CAM expression is frequent in prostate cancer. High level of Nr-CAM expression is associated with favorable tumor phenotype and reduced risk of PSA recurrence. The abundant presence of Nr-CAM in prostate cancer epithelium makes Nr-CAM a potential target of therapy.

Influence of low-molecular-weight heparin dosage on red blood cell transfusion, lymphocele rate and drainage duration after open radical prostatectomy.

BACKGROUND: To assess the rates of red blood cell (RBC) transfusions, pelvic lymphoceles, and prolonged drainage duration in patients after radical prostatectomy (RP) receiving perioperative bridging with low-molecular-weight heparin (LMWH). PATIENTS AND METHODS: Between 2006 and 2009, 114 RP patients receiving bridging therapy with 60 mg (n = 63) or ≥80 mg (n = 51) Enoxaparin/d were compared to 1327 consecutive RP patients receiving 40 mg Enoxaparin/d. Logistic regression models were used to test the effect of LMWH dosage on all three outcomes. Covariables included age, body mass index (BMI), Charlson comorbidity index (CCI), prostate volume, pelvic lymph node dissection, and pathological stage. RESULTS: The RBC transfusion rates in patients treated with 40, 60 and ≥80 mg were 4.9, 9.5 and 19.6%, respectively (p < 0.001). The respective lymphocele rates were 6.4, 3.2 and 2.0% (p = 0.26). The respective rates of drainage duration of ≥4 days were 6.7, 4.8 and 16.7% (p = 0.088). After adjusting for confounding factors, patients receiving ≥80 mg were 4.1-fold more likely to be transfused than patients receiving prophylactic LMWH (p = 0.02). Similarly, patients receiving ≥80 mg were 3.2-fold more likely to have a drainage duration of ≥4 days than patients receiving prophylactic LMWH (p = 0.03). CONCLUSIONS: Patients with a perioperative bridging with LMWH in RP are more likely to receive a RBC transfusion and to have prolonged drainage duration. Conversely, bridging therapy was not associated with an increased risk of lymphocele formation.

[Upper tract urothelial carcinoma. An update on clinical and pathological prognostic factors]. / Das Urothelkarzinom des oberen Harntraktes. Ein Update über klinische und pathologische prognostische Faktoren.

Upper urinary tract urothelial carcinoma (UTUC) is an uncommon but potentially lethal disease. Accurate risk stratification remains a challenge owing to the difficulty of clinical staging. Identification of risk factors may lead to individualized treatment and patient counselling and holds the potential to improve outcome. A non-systematic PubMed/Medline literature research was performed to identify and summarize clinical and pathological risk factors and urine-based markers which are associated with clinical outcome. Although knowledge of potential prognostic factors has improved over the last 5 years the overall evidence on UTUC risk factors remains limited and prospective, randomized trials are still missing. Radical nephroureterectomy is currently standard treatment for high-grade and muscle invasive UTUC. Several clinical and pathological factors (e.g. stage, grade, age, hydronephrosis, lymphovascular invasion, tumor necrosis and architecture, delay between diagnosis and surgery) were identified to be associated with outcome. Urinary cytology and fluorescence in-situ hybridization are the most commonly used urinary markers. Prospective randomized controlled trials are urgently needed to identify new risk factors and assess the efficacy. The incorporation of such prognosticators into multivariable prediction models may help to guide decision-making with regard to type of treatment, performance of lymphadenectomy and consideration of neoadjuvant or adjuvant systemic therapy.

Predicting the risk of lymph node invasion during radical prostatectomy using the European Association of Urology guideline nomogram: a validation study.

BACKGROUND: The 2011 European Association of Urology (EAU) guidelines for prostate cancer recommend a pelvic lymph node dissection (PLND) at radical prostatectomy (RP) in all individuals with a nomogram predicted lymph node invasion (LNI) risk of >7%. METHODS: To test the performing characteristics for several thresholds (1-14%) and to examine the overall accuracy and calibration plot of the EAU nomogram at our institution. The study population consisted of 3081 patients treated with RP and PLND limited to the obturator fossa and the external iliac vein between 2008 and 2010 at a single European institution from Germany. More extensive PLNDs were performed at the surgeon's discretion. RESULTS: Overall, 260 patients (9.2%) had LNI. The 7% threshold would have avoided 30% of PLNDs, at the cost of missing 8% of patients with LNI. The use of 8% and 9% threshold would have allowed the avoidance of respectively 39% and 48% of PLNDs, at the cost of missing respectively 12% and 14% of patients with LNI. The accuracy of the LNI nomogram was 78%, and the unadjusted departure from ideal calibration was 5.3%. CONCLUSIONS: We confirmed adequate accuracy and calibration of the LNI nomogram. The 7% cut-off may be overly conservative. Better trade-offs between avoided PLNDs and missed LNI cases may be achieved with a limit of 8 or even 9%.