Markus Graefen

Martini Ziekenhuis, Groningen, Groningen, Netherlands

Are you Markus Graefen?

Claim your profile

Publications (753)3485.42 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: The evidence on the association between anthropometric measures quantifying body fatness and prostate cancer (PCa) risk is not entirely consistent. Associations among waist circumference (WC), waist-hip ratio, body mass index (BMI), and PCa risk were assessed in a population-based case-control study. The study included 1933 incident PCa cases diagnosed between 2005 and 2009. Population controls were 1994 age-matched (±5y) Montreal residents selected from electoral lists. Information on sociodemographics, medical history including PCa screening, height, weight, and waist and hip circumferences was collected through interviews. Logistic regression was used to assess odds ratios (ORs) for the association between anthropometric measures, and overall and grade-specific PCa. After adjustment for BMI, an excess risk of high-grade PCa (Gleason≥7) was associated with a WC ≥102cm (OR = 1.47 [1.22-1.78]) and with a waist-hip ratio >1.0 (OR = 1.20 [1.01-1.43]). Men with a BMI≥30kg/m(2) had a lower risk of PCa, regardless of grade. Restricting to subjects recently screened for PCa did not alter findings. Elevated BMI was associated with a lower risk of PCa, regardless of grade. Contrastingly, abdominal obesity, when adjusted for BMI, yielded results in the opposite direction. Taken together, our observations suggest that the specific body fat distribution (abdominal), for a given BMI, is a predictor of PCa risk, whereas BMI alone is not. BMI and abdominal obesity, especially when measured by the WC, should be examined conjointly in future studies on this issue and may require consideration at patient counseling. Copyright © 2015 Elsevier Inc. All rights reserved.
    Urologic Oncology 08/2015; DOI:10.1016/j.urolonc.2015.07.006 · 3.36 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The effect of preservation of neurovascular bundles (NVBs) during radical prostatectomy (RP) on continence remains controversial. To analyze if the differing surgical techniques of nerve-sparing (NS) versus non-nerve-sparing (NNS) RP and not the preservation of the NVB itself may be responsible for differences in continence rates. A total of 18 427 men who underwent RP from 2002 to 2014 in a single high-volume center were analyzed retrospectively. Patients with bilateral NS RP, with primary NNS RP, and with bilateral secondary resection of the NVBs for positive frozen-section results after an initial bilateral nerve sparing (secNNS) RP were studied. NS, NNS, or secNNS RP. Multivariable and propensity score matched analyses adjusting for age, prostate volume, and year of surgery were performed to assess differences in continence rates after RP. Continence was defined as the use of no or one safety pad per day. Post-RP urinary continence rates at 1 wk, 3 mo, and 12 mo were 59.8%, 76.2%, 85.4% in the NS group, 39.5%, 59.5%, and 87.0% in the secNNS group, and 29.1%, 52.8%, and 70.5% in the NNS group. Continence rates at 12 mo after surgery did not differ significantly between patients who had bilateral NS and patients who had resection of both NVBs after an initial nerve-sparing technique (secNNS). In contrast, when comparing the NNS study groups with initial NNS versus secNNS, the latter group had significantly higher continence rates after 12 mo. Our results indicate that the meticulous apical dissection associated with the NS RP technique rather than the preservation of the NVBs itself may have a positive impact on long-term urinary continence rates. We looked at continence rates after nerve-sparing (NS) versus non-NS radical prostatectomy (RP). NS surgery technique but not the preservation of the neurovascular bundles led to improved long-term continence rates after RP. Copyright © 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.
    European Urology 08/2015; DOI:10.1016/j.eururo.2015.07.037 · 12.48 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Follow-up of patients after curative treatment of urological cancer is an important component of the treatment of patients. The aim of the follow-up is to monitor the success of treatment and to identify local or distant recurrences early to be able to initiate further treatment. Investigations used for the monitoring should follow the principle "as much as necessary, as little as possible". The interval and method of follow-up investigations should be based on the risk of recurrence for the individual patient. In recent years follow-up schemes have been improved and, for example in testicular cancer, have been adjusted to the individual risk group. In contrast, for other tumors, such as metastatic bladder carcinoma, recommendations for follow-up do not seem to be individualized. This article therefore gives an overview on current recommendations and evidence for the follow-up of the most important genitourinary tumor types.
    Der Urologe 08/2015; DOI:10.1007/s00120-015-3936-7 · 0.44 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The D'Amico risk stratification, Cancer of the Prostate Risk Assessment (CAPRA) score, and Stephenson nomogram are widely used prediction tools for biochemical recurrence and survival after radical prostatectomy (RP). These models have not been compared with respect to cancer-specific mortality (CSM) prediction. To validate and compare the prediction tools for 10-yr CSM. Overall, 2485 prostate cancer patients underwent RP in a European tertiary care center. Three preoperative models (D'Amico, CAPRA, and Stephenson) were compared in terms of their ability to predict 10-yr CSM; therefore, accuracy tests (area under the receiver operating characteristic curve [AUC]), calibration plots, and decision curve analysis (DCA) were assessed for each model. CSM at 10 yr was 3.6%. The AUC was 0.76, 0.77, and 0.80 for the D'Amico, CAPRA, and Stephenson models, respectively. In calibration plots, predicted probabilities were close to the observed probabilities for the D'Amico model but showed underestimation of CSM for the Stephenson nomogram and overestimation of CSM for the CAPRA score. DCA identified a benefit for the CAPRA score. These results apply to patients treated at a European tertiary care center. Despite good discriminatory power, all tested models had some shortcomings in terms of prediction of 10-yr CSM. All three models showed good performance in North American cohorts, but our results suggested a lack of generalizability to European patients. To overcome this issue, local recalibration of the variable weights could be performed. Another possibility is the development of more universal markers that are independent of regional practice differences or, alternatively, the development of better tools to quantify clinical practice differences. Prediction tools can predict cancer survival prior surgery, relying on points for age, prostate-specific antigen levels, aggressiveness, and percentage of cancer at biopsy. These tools are reliable in North American patients but have shortcomings for identifying patients at high risk of prostate cancer death in Europe. Copyright © 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.
    European Urology 08/2015; DOI:10.1016/j.eururo.2015.07.051 · 12.48 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: To verify the reliability of HistoScanning™-based, true targeting (TT)-derived prostate biopsy. We relied on 40 patients suspicious for prostate cancer who underwent standard and TT-derived prostate biopsy. Sensitivity, specificity, positive predictive value, negative predictive value and the area under the curve (AUC) were assessed for the prediction of biopsy results per octant by HistoScanning™, using different HistoScanning™ signal volume cutoffs (>0, >0.2 and >0.5 ml). Overall, 319 octants were analyzed. Of those, 64 (20.1 %) harbored prostate cancer. According to different HistoScanning™ signal volume cutoffs (>0, >0.2 and >0.5 ml), the AUCs for predicting biopsy results were: 0.51, 0.51 and 0.53, respectively. Similarly, the sensitivity, specificity, positive predictive and negative predictive values were: 20.7, 78.2, 17.4 and 81.6 %; 20.7, 82.0, 20.3 and 82.3 %; and 12.1, 94.6, 33.3 and 82.9 %, respectively. Prediction of biopsy results based on HistoScanning™ signals and TT-derived biopsies was unreliable. Moreover, the AUC of TT-derived biopsies was low and did not improve when additional signal volume cutoffs were applied (>0.2 and >0.5 ml). We cannot recommend a variation of well-established biopsy standards or reduction in biopsy cores based on HistoScanning™ signals.
    World Journal of Urology 07/2015; DOI:10.1007/s00345-015-1637-x · 3.42 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Deletion of 12p is a recurrent alteration in prostate cancer, but the prevalence and clinical consequences of this alteration have not been studied in detail. Dual labeling fluorescence in situ hybridization using probes for 12p13 (CDKN1B; p27) and centromere 12 as a reference was used to successfully analyze more than 3700 prostate cancers with clinical follow-up data assembled in a tissue microarray format. CDKN1B was selected as a probe because it is located in the center of the deletion, which spans > 10 Mb and includes > 50 genes in 80% of cancers with 12p deletion. Deletion of 12p was found in 13.7% of cancers and included 13.5% heterozygous and 0.2% homozygous deletions. 12p deletion were linked to advanced tumor stage (p < 0.0001), high Gleason grade (p < 0.0001), rapid tumor cell proliferation (p < 0.0001), lymph node metastasis (p = 0.0004), and biochemical recurrence (p = 0.0027). Multivariate analysis including pT stage (p < 0.0001), Gleason grade (p < 0.0001), pN status (p = 0.0001), preoperative PSA levels (p = 0.0001), and resection margin status (p = 0.0001) revealed an independent prognostic value of 12p deletion (p = 0.0014). Deletion of 12p was unrelated to the ERG fusion status. Deletion of 12p was only marginally linked to reduced p27 expression, which by itself was unrelated to clinical outcome. This argues against p27 as the key target gene of 12p deletions. In summary, the results of our study demonstrate that 12p deletion is frequent in prostate cancer and provides independent prognostic information. 12p deletion analysis alone, or in combination with other prognostic parameters may thus have clinical utility.
    Oncotarget 07/2015; · 6.63 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Intermediate-risk prostate cancer (PCa) represents a heterogeneous disease, where a non-negligible proportion of patients harbor favorable pathologic characteristics and are potentially eligible for active surveillance (AS). We aimed at developing a model for the identification of pathologically favorable PCa at radical prostatectomy (RP) among intermediate-risk patients. Overall, 3,821 intermediate-risk patients treated with RP at two centers between 2005 and 2013 were identified. Pathologically favorable PCa was defined as low-grade organ-confined disease. Age, biopsy Gleason, PSA density (PSAD), and the percentage of positive cores were included in multivariable logistic regression analyses predicting favorable PCa and formed the basis for a logistic regression-based risk calculator. The internally validated discrimination and calibration of the risk calculator were quantified using 200 bootstrap resamples. Decision curve analysis (DCA) provided an estimate of the net benefit obtained using this model versus treating no one and treating everyone. Overall, 10.0% of all intermediate risk patients had favorable disease. In multivariable analyses, patients with biopsy Gleason score ≤6 had higher probability of favorable disease compared to those with higher-grade disease (P < 0.001). Similarly, age, PSAD, and percentage of positive cores were associated with the probability of favorable disease (all P ≤ 0.01). The risk calculator achieved a validated accuracy of 82.5%. The DCA showed that our prediction model is better than both treating no one and treating everyone. One out of ten intermediate-risk patients harbors favorable disease at RP. Our novel, pre-operative, validated risk calculator may help clinicians identifying patients who could be considered for conservative therapy approaches such as AS. Prostate 9999: XX-XX, 2015. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    The Prostate 07/2015; DOI:10.1002/pros.23040 · 3.57 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Cancer is a leading cause of thrombosis. We identify a new procoagulant mechanism that contributes to thromboembolism in prostate cancer and allows for safe anticoagulation therapy development. Prostate cancer-mediated procoagulant activity was reduced in plasma in the absence of factor XII or its substrate of the intrinsic coagulation pathway, factor XI. Prostate cancer cells and secreted prostasomes expose long chain polyphosphate on their surface that co-localized with active factor XII and initiated coagulation in a factor XII-dependent manner. Polyphosphate content correlated with the procoagulant activity of prostasomes. Inherited deficiency in factors XI, XII or high molecular weight kininogen, but not plasma kallikrein, protected mice from prostasome-induced lethal pulmonary embolism. Targeting polyphosphate or factor XII conferred resistance to prostate cancer-driven thrombosis in mice, without increasing bleeding. Inhibition of factor XII with recombinant 3F7 antibody reduced the increased prostasome-mediated procoagulant activity in patient plasma. The data illustrate a critical role for polyphosphate/factor XII-triggered coagulation in prostate cancer-associated thrombosis with implications for anticoagulation without therapy-associated bleeding in malignancies. Copyright © 2015 American Society of Hematology.
    Blood 07/2015; DOI:10.1182/blood-2015-01-622811 · 10.43 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Prostate-specific membrane antigen (PSMA) is a suggested target for antibody-based therapy of prostate cancer, potentially involved in the regulation of cell migration. As heterogeneity may limit the applicability of targeted therapies, this study was undertaken to estimate the degree of heterogeneity of PSMA expression in prostate cancer. For heterogeneity analysis, a prostate cancer heterogeneity TMA containing samples from 10 different tumor blocks of 189 consecutive prostate cancers was used. PSMA expression was analyzed by immunohistochemistry. PSMA expression was found in 97.6% of 1171 interpretable tissue spots including 260 (22.2%) with weak, 345 (29.5%) with moderate, and 538 (45.9%) with strong positivity. On a patient level, a positive PSMA immunostaining was found in 172 of 173 analyzable patients (99.4%) with at least a weak staining reaction. PSMA immunostaining was homogenously positive in 161 prostate cancers (93.6%), whereas heterogenous PSMA positivity was seen in 11 of 172 positive cases (6.4%). In these cases, heterogeneity was intrafocal in 8 cases (72.7%) and interfocal in 27.3% cases. PSMA expression was completely absent in 1 patient. Given the high frequency and high homogeneity of PSMA expression in prostate cancer, we conclude that increased PSMA expression may occur early in prostate cancer development. High homogeneity of PSMA expression is a strong argument for a high utility of PSMA as a prostate cancer drug target.
    Applied immunohistochemistry & molecular morphology: AIMM / official publication of the Society for Applied Immunohistochemistry 07/2015; 23(6):449-55. DOI:10.1097/PAI.0000000000000110 · 2.06 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Positive surgical margins (PSM) after radical prostatectomy have been shown to be associated with impaired outcome. In pT3pN0 patients with PSM either immediate radiotherapy or clinical and biological monitoring followed by salvage radiotherapy is recommended by the latest guidelines of the European Association of Urology. A retrospective, multicenter study of eight urological centers was conducted on 536 prostatectomy patients with pT3aN0/NxR1 tumors and no neoadjuvant/adjuvant therapy. A pathological re-review of all prostate specimens was performed. Association of clinical and pathological features with biochemical recurrence (BCR) was analyzed using univariate and multivariate analysis. With 48months median follow-up, BCR occurred in 39.7%. Preoperative PSA value, performance of pelvic lymph node dissection and Gleason score were significantly associated with BCR. In multivariate analysis, Gleason score was the only independent prognostic factor (p<0.001) for BCR. Five-year BCR-free survival rates were 74%, 70%, 38%, and 51% with Gleason score 6, 3+4=7a, 4+3=7b, and 8-10, respectively. In pT3aN0/NxR1 patients with no adjuvant/neoadjuvant treatment, Gleason Score permits independent prediction of the risk for BCR. These findings could help to estimate and discuss the individual risk for BCR with our patients on an individual basis. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved. -------------------------------------------------------- Full text available here until September 26, 2015: http://authors.elsevier.com/a/1RV9z_3qCvUQgQ
    Radiotherapy and Oncology 06/2015; 116:119-124. DOI:10.1016/j.radonc.2015.06.021 · 4.86 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Long-term cancer control outcomes in clinically high-risk prostate cancer (PCa) patients treated with robot-assisted radical prostatectomy (RARP) remain unknown. To report on long-term biochemical recurrence (BCR)-free survival, clinical recurrence (CR)-free survival, and salvage therapy rates in these patients. Given the heterogeneity of high-risk patients, a second objective was to stratify them according to their BCR risk (using preoperative parameters), in an effort to counsel them better preoperatively regarding their cancer control outcomes. We evaluated 1100 D'Amico high-risk PCa patients who underwent RARP between 2002 and 2013 at three tertiary care centers. Outcomes consisted of BCR-free survival, CR-free survival, and salvage therapy rates. Regression tree analysis stratified patients into novel risk groups based on preoperative characteristics and corresponding BCR risk. Kaplan-Meier curves estimated BCR-free survival, CR-free survival, and salvage therapy rates in the entire cohort and after stratification according to the novel risk groups (RGs). Median age and prostate-specific antigen (PSA) were 63 yr and 6.5 ng/ml, respectively. Biopsy Gleason score (GS) was ≥8 in 57.7%. Mean follow-up was 53 mo (median: 49 mo). At 10 yr, BCR-free survival, CR-free survival, and salvage therapy rates were 50%, 87%, and 37%, respectively. Regression tree analysis stratified patients into five novel RGs): RG1, very low risk (GS ≤6); RG2, low risk (PSA ≤10 ng/ml; GS: 7); RG3, intermediate risk (PSA ≤10 ng/ml; GS ≥8); RG4, high risk (PSA >10 ng/ml; GS: 7); RG5, very high risk (PSA >10 ng/ml; GS ≥8). In these RGs, the 10-yr BCR-free survival rates were 86%, 70%, 36%, 31%, and 26% (p<0.001), respectively; the 10-yr CR-free survival rates were 99%, 96%, 85%, 67%, and 55% (p<0.001), respectively; and the 10-yr salvage therapy rates were 9.8%, 16%, 42%, 47%, and 64% (p<0.001), respectively. Most patients with clinically high-risk PCa treated with RARP alone remain CR free at long term. Nonetheless, almost 37% of the patients at 10 yr require salvage therapy. Our novel tool allows accurate stratification of these heterogeneous patients according to their BCR, CR, and salvage therapy risks. This may help inform patients preoperatively about their cancer control outcomes postoperatively. Robot-assisted radical prostatectomy confers lasting long-term oncologic control in most high-risk prostate cancer patients. Our novel risk grouping might serve as a useful tool for setting expectations and counseling patients regarding their cancer control outcomes. Copyright © 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.
    European Urology 06/2015; DOI:10.1016/j.eururo.2015.06.020 · 12.48 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The objective of the current study was to test generalizability and clinical value of a recently published nomogram to predict specimen-confined disease (SCD, pT2-pT3a+R0+pN0) at radical prostatectomy (RP) in patients with clinical high-risk prostate cancer (HRPCa). The nomogram allows improved decision making with curative intent within this heterogeneous patient cohort, which is important, as RP in patients with clinical HRPCa remains a topic of controversy. We externally validated the nomogram in 1,669 men with clinical HRPCa who underwent RP and extended pelvic lymph node dissection between 1992 and 2011. A Kaplan-Meier analysis to estimate 5- and 10-year biochemical recurrence-free survival was performed. To investigate the SCD model׳s performance, the previously reported regression coefficients of the SCD nomogram were applied. Within loess calibration plots, the extent of overestimation or underestimation was graphically explored. Finally, decision curve analysis (DCA) to assess the clinical value of the SCD nomogram was performed. Overall, 49% of men showed SCD after RP. The 5- and 10-year biochemical recurrence rates for men with SCD were 66% and 56%, respectively, vs. 32% and 20%, respectively, for men without SCD (log-rank test P<0.001). External validation demonstrated comparable accuracy in relation to accuracy derived from internal validation (68.1% vs. 72.0%). Calibration was suboptimal, showing a tendency to underestimate SCD probability. In DCA, the nomogram׳s usage was associated with a clinical net benefit relative to both treating all and none. Within our cohort, the nomogram׳s use was associated with a clinical net benefit according to DCA. However, one-third of men were falsely classified as having SCD or non-SCD. Nevertheless, in the absence of superior tools, the SCD nomogram represents a useful clinical decision aid. Copyright © 2015 Elsevier Inc. All rights reserved.
    Urologic Oncology 06/2015; DOI:10.1016/j.urolonc.2015.02.017 · 3.36 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: DNA ligases are essential for the maintenance of genome integrity as they are indispensable for DNA replication, recombination and repair. The present study was undertaken to gain insights into the prevalence and clinical significance of ligase IV (LIG4) expression in prostate cancer. A total of 11,152 prostate cancer specimens were analyzed by immunohistochemistry for LIG4 expression. Results were compared to follow-up data, ERG status and deletions at PTEN, 3p13, 5q21 and 6q15. LIG4 expression was predominantly localized in the nucleus of the cells with increased intensities in malignant as compared to benign prostate epithelium. In prostate cancer, LIG4 expression was found in 91% of interpretable tumors, including 12% cancers with weak, 23% with moderate and 56% with strong LIG4 positivity. Strong LIG4 expression was tightly linked to advanced Gleason score (P<0.0001) and positive nodal involvement (P=0.03). There was a remarkable accumulation of strong LIG4 expression in tumors harboring TMPRSS2:ERG fusion and PTEN deletions (P<0.0001 each). High LIG4 expression was also tightly related to early biochemical recurrence when all tumors (P<0.0001) or the subsets of ERG-negative (P=0.0004) or ERG-positive prostate cancers (P=0.006) were analyzed. Multivariate analysis including parameters that are available before surgery demonstrated independent association with biochemical recurrence for advanced Gleason grade on biopsy, high preoperative PSA level, high clinical stage (P<0.0001 each) and for LIG4 immunostaining (P=0.03). Our study identifies LIG4 as a predictor of an increased risk for early PSA recurrence in prostate cancer. Moreover, the strong association with TMPRSS2:ERG fusion and PTEN deletions suggest important interactions between these pathways in prostate cancers.
    Oncology Reports 06/2015; DOI:10.3892/or.2015.4080 · 2.19 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: We relied on a population-based case-control study (PROtEuS) to examine a potential association between the presence of histologically confirmed prostate cancer (PCa) and history of genitourinary infections, e.g., prostatitis, urethritis, orchitis and epididymitis. Cases were 1933 men with incident PCa, diagnosed across Montreal hospitals between 2005 and 2009. Population controls were 1994 men from the same residential area and age distribution. In-person interviews collected information about socio-demographic characteristics, lifestyle and medical history, e.g., self-reported history of several genitourinary infections, as well as on PCa screening. Logistic regression analyses tested overall and grade-specific associations, including subgroup analyses with frequent PSA testing. After multivariable adjustment, prostatitis was associated with an increased risk of any PCa (OR 1.81 [1.44-2.27]), but not urethritis (OR 1.05 [0.84-1.30]), orchitis (OR 1.28 [0.92-1.78]) or epididymitis (OR 0.98 [0.57-1.68]). The association between prostatitis and PCa was more pronounced for low-grade PCa (Gleason ≤ 6: OR 2.11 [1.61-2.77]; Gleason ≥ 7: OR 1.59 [1.22-2.07]). Adjusting for frequency of physician visits, PSA testing frequency or restricting analyses to frequently screened subjects did not affect these results. Prostatitis was associated with an increased probability for detecting PCa even after adjustment for frequency of PSA testing and physician visits, but not urethritis, orchitis or epididymitis. These considerations may be helpful in clinical risk stratification of individuals in whom the risk of PCa is pertinent.
    World Journal of Urology 06/2015; DOI:10.1007/s00345-015-1625-1 · 3.42 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Prostate-specific membrane antigen (PSMA) overexpression theoretically enables targeting of prostate cancer (PCa) metastases using gallium Ga 68 ((68)Ga)-labeled PSMA ligands for positron emission tomography/computed tomography (PET/CT) imaging. Promising detection rates have been reported when using this approach for functional imaging of recurrent PCa; however, until now, the diagnostic accuracy of (68)Ga-PSMA PET/CT for preoperatively identifying lymph node metastases (LNMs) had not been assessed. We retrospectively compared preoperative (68)Ga-PSMA PET/CT lymph node (LN) findings with histologic work-up after radical prostatectomy (RP). Overall, 608 LNs containing 53 LNMs were detected during RP. LNMs were present in 12 of 30 patients (40%). The (68)Ga-PSMA PET/CT scans identified 4 patients (33.3%) as LN true positive and 8 patients (66.7%) as false negative. Median size of (68)Ga-PSMA-PET/CT-detected versus undetected LNMs was 13.6 versus 4.3mm (p<0.05). Overall sensitivity, specificity, positive predictive value, and negative predictive value of (68)Ga-PSMA PET/CT for LNM detection were 33.3%, 100%, 100%, and 69.2%, respectively. Per-side analyses revealed corresponding values of 27.3%, 100%, 100%, and 52.9%. Conversely, (68)Ga-PSMA PET/CT enabled tumor visualization in the prostate. In 92.9% of patients, the intraprostatic tumor foci were correctly predicted. Overall, (68)Ga-PSMA PET/CT is a promising tool for functional imaging; however, our initial experience revealed substantial influence of LNM size on the diagnostic accuracy of (68)Ga-PSMA PET/CT. We assessed the diagnostic accuracy of (68)Ga-PSMA PET/CT in high-risk prostate cancer patients prior to radical prostatectomy. We found that lymph node metastasis detection rates were substantially influenced by lymph node metastasis size. Copyright © 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.
    European Urology 06/2015; DOI:10.1016/j.eururo.2015.06.010 · 12.48 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The impact of prostate volume (PV) on oncologic, perioperative and functional outcomes after radical prostatectomy (RP) remains controversial, as recent studies present inconsistent results. We studied the influence of PV on outcomes in a large single center dataset and summarized the existing literature. 5,477 patients who underwent RP between January 2008 and December 2011 were analyzed. The impact of PV on biochemical recurrence (BCR) and metastasis-free survival (MFS) was assessed using Kaplan-Meier curves and multivariate Cox proportional hazard model. Uni- and multivariate logistic regressions were used to estimate the impact of PV on surgical margin (SM), 1-week, 3-months and 12-months continence and 3-months and 12-months potency. Finally, the impact of PV on intraoperative blood loss was analyzed using uni- and multivariate linear regressions. Median follow-up was 36.1 months. Overall, 16.5% of patients recurred during the follow-up period. The mean preoperative PV was 43.3 ml. One-week, 3-months and 12-months continence rates were 55.6%, 69.3%, and 87.4% for patients with PV ≥ 70 compared to 64.4%, 78.3%, and 92.1% for patients with PV < 30, respectively. Three-months and 12-months potency rates were 37.1% and 54.8% for men with large glands (≥70) and 56.3% and 65.0% for men with PV < 30. In multivariate analysis, continence at 1 week, 3 months and 12 months was significantly worse in patients with glands ≥70 ml, while potency was not influenced by PV in multivariate analysis. There was a higher mean blood loss (P < 0.001) in patients with larger glands. In univariate analysis, higher PV was significantly associated with lower BCR (P = 0.019), but not with metastasis free survival (P = 0.112). PV significantly influences BCR-free survival only in univariate analysis. Especially early (1-week and 3-months) postoperative continence is negatively affected by higher PV in multivariate analysis, while PV did not influence potency after adjusting for further covariates in a specialized high-volume institution. Prostate © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    The Prostate 06/2015; DOI:10.1002/pros.23023 · 3.57 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Low-risk prostate cancer is found in about half of newly diagnosed men subjected to PSA screening. To define the role of active surveillance and focal therapy in low- and intermediate-risk prostate cancers, an invited international panel of practicing physicians in the field of localized prostate cancer discussed the available literature in three consecutive meetings to come to a broad interpretation of the available data. The panel ("new prostate cancer management group," npm) agreed on the following observations. In most men with a low-volume Gleason 6 tumor, initial conservative management is appropriate. In men with a larger unifocal Gleason score 6 or 3 + 4 lesion, focal therapy, although still considered an investigational approach, appears to be a suitable option in early non-randomized comparison studies. Furthermore, in patients with multifocal small satellite Gleason 6 lesions in the presence of a larger index lesion, focal therapy of the index lesion is an option. For patients with high-grade, large-volume disease, or in young men with evidence of high-volume multifocal low-grade prostate cancer, whole-gland treatment should be considered. Active surveillance is a preferred and safe option for low-risk prostate cancer. Focal therapy is still under investigation, but the available phase II data are promising. Clinical benefits must be shown in prospective trials. With improved imaging, focal therapy may be an option for patients not choosing active surveillance with low-risk disease, progression upon active surveillance or intermediate-risk cancers with a localizable lesion.
    World Journal of Urology 06/2015; 33(7). DOI:10.1007/s00345-015-1603-7 · 3.42 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Prostate cancer (PCa) detection is accompanied by overdiagnosis and mischaracterization of PCa. Therefore, new imaging modalities like shear wave elastography (SWE) are required. The aim of this study was to evaluate per-core detection rates (DRs) of targeted biopsies and systematic biopsies and to test if SWE findings can predict presence of clinically significant PCa (csPCa) at biopsy. Overall, 95 patients scheduled for prostate biopsy in our center underwent SWE. SWE findings were classified into suspicious or normal. Targeted biopsies were taken in up to 3 SWE-suspicious areas. csPCa was defined as the presence of Gleason pattern ≥4, level of prostate-specific antigen ≥10 ng/ml or >2 positive cores. Overall DR for csPCa in our study cohort was 40%. Per-core DR for exclusively SWE-targeted cores versus systematic samples cores was 10.5 vs. 8.6% (p = 0.3). In the logistic regression models, individuals with suspicious SWE findings are at 6.4-fold higher risk of harboring csPCa (p = 0.03). Gain in predictive accuracy was 2.3% (0.82 vs. 0.84, p = 0.01). Presence of suspicious SWE findings is an independent predictor of csPCa. Therefore, SWE may be helpful in selecting patients for biopsy. Nonetheless, per-core DR for SWE-targeted cores was not statistically significant higher than DR of systematic sampled cores. Therefore, additional systematic biopsy is mandatory. © 2015 S. Karger AG, Basel.
    Urologia Internationalis 06/2015; DOI:10.1159/000431233 · 1.15 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: 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. 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. 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). 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. Copyright © 2015 Elsevier Ltd. All rights reserved.
    European Journal of Surgical Oncology 06/2015; DOI:10.1016/j.ejso.2015.05.008 · 2.89 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The transcription factor SOX9 plays a crucial role in normal prostate development and has been suggested to drive prostate carcinogenesis in concert with PTEN inactivation. To evaluate the clinical impact of SOX9 and its relationship with key genomic alterations in prostate cancer, SOX9 expression was analyzed by immunohistochemistry on a tissue microarray containing 11,152 prostate cancers. Data on ERG status and deletions of PTEN, 3p13, 5q21 and 6q15 were available from earlier studies. SOX9 expression levels were comparable in luminal cells of normal prostate glands (50% SOX9 positive) and 3,671 cancers lacking TMPRSS2:ERG fusion (55% SOX9 positive), but was markedly increased in 3,116 ERG-fusion positive cancers (81% SOX9 positive, p<0.0001). While no unequivocal changes in the SOX9 expression levels were found in different stages of ERG-negative cancers, a gradual decrease of SOX9 paralleled progression to advanced stage, high Gleason grade, metastatic growth, and presence of PTEN deletions in ERG-positive cancers (p<0.0001 each). SOX9 levels were unrelated to deletions of 3p, 5q, and 6q. Down-regulation of SOX9 expression was particularly strongly associated with PSA recurrence in ERG-positive tumors harboring PTEN deletions (p=0.001), but had no significant effect in ERG-negative cancers or in tumors with normal PTEN copy numbers. In summary, the results of our study argue against a tumor-promoting role of SOX9 in prostate cancer, but demonstrate that loss of SOX9 expression characterizes a particularly aggressive subset of ERG positive cancers harboring PTEN deletions.
    PLoS ONE 06/2015; 10(6):e0128525. DOI:10.1371/journal.pone.0128525 · 3.23 Impact Factor

Publication Stats

11k Citations
3,485.42 Total Impact Points

Institutions

  • 2015
    • Martini Ziekenhuis
      Groningen, Groningen, Netherlands
  • 1998–2015
    • University Medical Center Hamburg - Eppendorf
      • Department of Urology
      Hamburg, Hamburg, Germany
  • 2006–2014
    • Prostate Cancer Research Institute
      Los Ángeles, California, United States
  • 2013
    • Ruhr-Universität Bochum
      Bochum, North Rhine-Westphalia, Germany
  • 1997–2013
    • University of Hamburg
      • Department of Urology
      Hamburg, Hamburg, Germany
  • 2012
    • Cornell University
      Итак, New York, United States
  • 2011
    • Institut Paoli Calmettes
      Marsiglia, Provence-Alpes-Côte d'Azur, France
  • 2006–2011
    • Université de Montréal
      • Department of Surgery
      Montréal, Quebec, Canada
  • 2010
    • Krankenhaus Düren gem. GmbH
      Düren, North Rhine-Westphalia, Germany
    • CUNY Graduate Center
      New York City, New York, United States
  • 2009–2010
    • Schön Klinik Hamburg
      Hamburg, Hamburg, Germany
    • University Hospital Essen
      • Klinik für Urologie
      Essen, North Rhine-Westphalia, Germany
  • 2003–2009
    • Memorial Sloan-Kettering Cancer Center
      New York, New York, United States
  • 2007–2008
    • Università Vita-Salute San Raffaele
      Milano, Lombardy, Italy
    • University of Milan
      Milano, Lombardy, Italy
  • 2002–2004
    • Erasmus Universiteit Rotterdam
      Rotterdam, South Holland, Netherlands
  • 2000
    • Lund University
      • Department of Chemistry
      Lund, Skåne, Sweden