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This study aimed at analysing long-term oncologic outcomes in prostate cancer patients with limited nodal disease (1–2 positive lymph nodes) without adjuvant therapy after radical prostatectomy (RP). We retrospectively analysed data of 209 pN1 patients who underwent RP between January 1998 and 2010 with one (160) or two (49) histologically proven positive lymph nodes (LNs) without adjuvant treatment. Biochemical recurrence-free survival, metastasis-free survival and cancer-specific survival (CSS) were reported. In multivariable regression analyses further prognosticators of oncologic outcome in these patients were analysed. Median follow-up was 60.2 months. There was no significant difference in oncologic outcome between patients with one and two positive LNs. 73.1% (76.7%) of patients with one (two) positive LNs had biochemical recurrence during the follow-up period, 20.0% (25.6%) developed metastasis and 8.1% (6.1%) died of their disease. The only factors significantly associated with oncologic outcome in multivariable analysis were Gleason score and pT-stage. Patients with limited nodal disease (1–2 positive LNs) without adjuvant therapy showed favourable CSS-rates above 94% after 5 years. A subgroup of these patients (37%) remained metastasis-free without need of salvage treatment.

We validated the current NCCN (National Comprehensive Cancer Network®) classification of very high risk patients, and compared the pathological, functional and oncologic outcomes between surgically treated high risk and very high risk patients.We retrospectively analyzed 4,041 patients stratified into high risk or very high risk groups who underwent radical prostatectomy between 1992 and 2016. Kaplan-Meier as well as multivariable logistic and Cox regression analyses were used to compare outcomes between the groups.After radical prostatectomy the rate of adverse pathological features was higher in 1,369 very high risk vs 2,672 high risk cases. Functional outcomes were similar between the groups, with 1-year continence and potency rates of 81.0% and 43.6% in the very high risk compared to 81.9% and 45.2% in the high risk group, respectively (p = 0.7 and p = 0.9). In a subset of 1,835 patients who underwent radical prostatectomy between 1992 and 2011 (median followup 58.8 months, IQR 36.5-84.6), those with very high risk disease had significantly worse 5 and 8-year biochemical recurrence-free survival, metastatic progression-free survival, prostate cancer specific mortality-free survival and overall survival rates compared to those with high risk disease.Despite the relatively poor prognosis of patients with high risk prostate cancer, radical prostatectomy results in favorable 5 and 8-year metastatic progression-free survival, prostate cancer specific mortality-free survival and overall survival rates. Relative to high risk cases, their very high risk counterparts have significantly worse pathological and oncologic outcomes, and more frequently require additional therapies. These observations validate the stratification between high risk and very high risk in European patients with prostate cancer. Interestingly, very high risk patients treated with radical prostatectomy did not have a worse functional outcome than their high risk counterparts.

The A Disintegrin and Metalloproteinase (ADAM) family of endopeptidases plays a role in many solid cancers and includes promising targets for anticancer therapies. Deregulation of ADAM15 has been linked to tumor aggressiveness and cell line studies suggest that ADAM15 overexpression may also be implicated in prostate cancer. To evaluate the impact of ADAM15 expression and its relationship with key genomic alterations, a tissue microarray containing 12,427 prostate cancers was analyzed by immunohistochemistry. ADAM15 expression was compared to phenotype, prognosis and molecular features including TMPRSS2:ERG fusion and frequent deletions involving PTEN, 3p, 5q and 6q. Normal prostate epithelium did not show ADAM15 staining. In prostate cancers, negative, weak, moderate, and strong ADAM15 staining was found in 87.7%, 3.7%, 5.6%, and 3.0% of 9826 interpretable tumors. Strong ADAM15 staining was linked to high Gleason grade, advanced pathological tumor stage, positive nodal stage and resection margin. ADAM15 overexpression was also associated with TMPRSS2:ERG fusions and PTEN deletions (P

Background While the optimal use and timing of secondary therapy after radical prostatectomy (RP) remain controversial, there are limited data on patient-reported outcomes following multimodal therapy. Objective To assess the impact of additional radiation therapy (RT) and/or androgen deprivation therapy (ADT) on urinary continence, potency, and quality of life (QoL) after RP. Design, setting, and participants Among 13150 men who underwent RP from 1992 to 2013, 905 received RP + RT, 407 RP + ADT and 688 RP + RT + ADT. Outcome measurements and statistical analyses Urinary function, sexual function, and overall QoL were evaluated annually using self-administered validated questionnaires. Propensity score–matched and bootstrap analyses were performed, and the distributions for all functional outcomes were analyzed as a function of time after RP. Results and limitations Patients who received RP + RT had a 4% higher overall incontinence rate 3 yr after surgery, and 1% higher rate for severe incontinence (>3 pads/24h) compared to matched RP-only patients. ADT further increased the overall and severe incontinence rates by 4% and 3%, respectively, compared to matched RP + RT patients. RP + RT was associated with an 18% lower rate of potency compared to RP alone, while RP + RT + ADT was associated with a further 17% reduction compared to RP + RT. Additional RT reduced QoL by 10% and additional ADT by a further 12% compared to RP only and RP + RT, respectively. The timing of RT after RP had no influence on continence, but adjuvant compared to salvage RT was associated with significantly lower potency (37% vs 45%), but higher QoL (60% vs 56%). Limitations of our study include the observational study design and potential for selection bias in the treatments received. Conclusions Secondary RT and ADT after RP have an additive negative influence on urinary function, potency, and QoL. Patients with high-risk disease should be counseled before RP on the potential net impairment of functional outcomes due to multimodal treatment. Patient summary Men with high-risk disease choosing surgery upfront should be counseled on the potential need for additional radiation and or androgen deprivation, and the potential net impairment of functional outcomes arising from multimodal treatment.

Selecting patients suspected of having prostate cancer (PCa) for a prostate biopsy remains a challenge. Prostate-specific antigen (PSA)-based testing is hampered by its low specificity that often leads to negative biopsy results or detection of clinically insignificant cancers, especially in the 2-10 ng/mL range. The objective was to evaluate a novel diagnostic test called Proclarix incorporating thrombospondin-1 and cathepsin D alongside total and free PSA as well as age for predicting clinically significant PCa.The test was developed following a retrospective study design using biobanked samples of 955 men from two reference centres. A multivariate approach was used for model development followed by validation to discriminate significant (grade group ≥2) from insignificant or no cancer at biopsy. The test specificity, positive predictive value (PPV) and negative predictive value (NPV) at a fixed sensitivity of 90% were compared to percent free PSA (%fPSA) alone. The number of avoidable prostate biopsies deemed to be representative of clinical utility was also assessed.In the targeted patient population, the test displayed increased diagnostic accuracy compared to %fPSA alone. Application of the established model on 955 patients at a fixed sensitivity of 90% for significant disease resulted in a specificity of 43%, NPV of 95% and a PPV of 25%. This is in comparison to a specificity of 17%, NPV of 89% and PPV of 19% for %fPSA alone and had the potential to reduce the total number of biopsies needed to identify clinically significant cancer. Further, the test score correlated with significance of cancer assessed on prostate biopsy.The Proclarix test can be used as an aid in the decision-making process if to biopsy men in this challenging patient population. The use of the test could reduce the number of biopsies performed avoiding invasive procedures, anxiety, discomfort, pain and complications.

Claudin-1 is a membrane-tight junction protein and important for the sealing of the paracellular cleft in epithelial and endothelial cells. Differential expression of Claudin-1 is linked to disease outcome in various cancers. To evaluate the potential relevance of Claudin-1 expression in prostate cancer, a tissue microarray containing samples of 17,747 tumors with annotated clinico-pathological and molecular data was immunohistochemically analyzed for Claudin-1 expression. In normal prostate, glandular cells were always Claudin-1-negative while there was a strong staining of gland-surrounding basal cells. In contrast to normal prostatic glands, a positive Claudin-1 immunostaining, was found, however, in 38.7% of 12,441 interpretable cancers and was considered weak in 12.7%, moderate in 13.2%, and strong in 12.8% of cases. Positive Claudin-1 immunostaining was associated with favorable tumor features like low pT (p = 0.0032), low Gleason grade (p

INTRODUCTION AND OBJECTIVES:Reliable data on comparisons of open retropubic radical prostatectomy (ORP) vs. robot-assisted laparoscopic radical prostatectomy (RARP) is scarce and remains inconclusi...

INTRODUCTION AND OBJECTIVES:To describe oncological outcomes of patients with high lymph node burden (≥4 positive nodes) and to assess the impact of adjuvant therapies.METHODS:We retrospectively analyzed 273 patients with ≥4 positive lymph nodes after radical prostatectomy (RP) and lymph node dissection between 2007 and 2015. Patients received adjuvant androgen deprivation therapy (aADT), aADT plus adjuvant radiation (aRT) or observation (including salvage ADT). Kaplan-Meier curves as well as multivariable Cox-regression analyses compared biochemical recurrence (BCR), metastatic progression (MP) and overall mortality (OM) between the different treatment modalities.RESULTS:Overall 55 patients received aADT, 34 aADT + aRT and 184 observation (including 96 with salvage ADT). For the entire cohort 2-year BCR-free survival, MP-free survival and overall survival rates were 33.0% (27.2-40.1%), 76.6% (71.0-82.8%) and 90.3% (86.1-94.8%). While patients with aADT + aRT had significantly better BCR-free survival rat...

INTRODUCTION AND OBJECTIVES:A statistical model based on a panel of four kallikrein (4K) markers in blood-commercially available as 4Kscore-can accurately predict high-grade (≥Grade Group [GrdGrp] ...

INTRODUCTION AND OBJECTIVES:Several definitions of high-risk prostate cancer (PCa) exist. We examined the impact of different pre-treatment definitions on metastasis-free survival (MFS), cancer-spe...

INTRODUCTION AND OBJECTIVES:In the perioperative setting, temporary interruption of direct oral anticoagulants (DOACs) is recommended. However, the safety of these recommendations is based on non-u...

OBJECTIVE To compare oncological, functional and surgical outcomes of open retropubic radical prostatectomy (ORP) vs robot-assisted laparoscopic radical prostatectomy (RARP). PATIENTS AND METHODS We identified 10 790 consecutive treated patients within our prospective database (2008-2016) who underwent either ORP (7007 patients) or RARP (3783). All procedures were performed by seven highly trained surgeons performing both surgical approaches regularly. Oncological (48-month biochemical recurrence [BCR] rate), functional (urinary continence, erectile function), and surgical outcomes (rate of nerve-sparing [NS] procedures, lymph node yield, surgical margin [SM] status, length of hospital stay [LOS], operation time, blood loss, transfusion rate, time to catheter removal) were assessed. Kaplan-Meier, multivariable Cox and logistic regression models were used to test for BCR and functional outcome differences. RESULTS No statistically significant difference regarding oncological outcome distinguished between ORP vs RARP. For functional outcomes, the 1-week continence rates were higher in the ORP group (25.8% vs 21.8%, P

5037 Background: In the double-blind PBO-controlled ACIS study, investigator-assessed radiographic progression-free survival (rPFS) was significantly improved with APA + AAP vs PBO + AAP in chemo-naive mCRPC, with no significant new safety signals (Rathkopf ASCO GU 2021). Among prespecified subgroups, efficacy and safety were explored in two difficult to treat subgroups: pts with visceral disease (VD; liver, lung, and/or adrenal gland metastasis) or age ≥ 75 y. Methods: Pts with mCRPC with ongoing ADT and no prior life-prolonging treatment were randomized 1:1 to APA (240 mg QD) + AA (1000 mg QD) + P (5 mg BID) or PBO + AAP. Stratified: presence or absence of VD, ECOG PS 0 or 1, geographic region. Primary end point: rPFS (randomization to radiographic progression or death); secondary end points: overall survival (OS), time to initiation of cytotoxic chemotherapy, time to chronic opioid use, time to pain progression, safety. Results: 982 pts enrolled. 14.6% had VD and 35.9% were ≥ 75 y. Median rPFS, OS, and time to pain progression favored APA + AAP vs AAP (HR < 1) in both subgroups (Table). For pts ≥ 75 y, rPFS and OS were ≥ 7 mo longer with APA + AAP. Overall, treatment-emergent adverse events (TEAEs) were similar (all > 94%) in pts with VD, ≥ 75 y, and overall safety population; hypertension was more frequent with APA + AAP vs AAP mainly in pts ≥ 75 y (31.7% vs 17.6%). Grade 3/4 TEAEs (APA + AAP vs AAP): VD, 60.8%, n = 74 vs 48.5%, n = 68; ≥ 75 y, 71.5%, n = 186 vs 68.5%, n = 165; overall, 63.3%, n = 490 vs 56.2%, n = 489. TEAEs leading to discontinuation: VD, 17.6% vs 5.9%; ≥ 75 y, 26.3% vs 20.6%; overall, 16.9% vs 12.5%. TEAEs leading to death: VD, 6.8% vs 5.9%; ≥ 75 y, 5.4% vs 13.9%; overall, 3.5% vs 7.6%. Conclusions: In this analysis of two difficult to treat subgroups, addition of APA to AAP favored rPFS and OS. Safety, while generally consistent with the overall population, showed higher hypertension rate in ≥ 75 y and TEAEs leading to discontinuation in VD. Clinical trial information: NCT02257736. [Table: see text]

The aim of this study was to investigate the impact of lymph-node involvement on oncological outcomes in patients with pathologically organ-confined prostate cancer (pT2 CaP) after radical prostatectomy (RP).We retrospectively analyzed 9,631 pT2 CaP patients who underwent RP at a single institution between 1998 and 2018. Kaplan-Meier plots and Cox regression models (CRMs) assessed biochemical recurrence (BCR)-free survival and metastasis-free survival (MFS) according to N-stage. In subgroup analyses of N1 patients, Kaplan-Meier plots and CRMs were stratified according to adjuvant treatment.Of 9,631 pT2 staged patients, 241 (2.5%) harbored lymph-node metastases after RP (pN1). The median follow-up was 60.8 months. No pT2 N1-staged patient died due to CaP. The 5-year BCR-free survival rates were 54.7 vs. 88.4% in pT2 N1 vs. pT2 N0 patients, respectively (P0.001). The 5-year MFS rates were 92.5 vs. 98.9% in pT2 N1 vs. pT2 N0 patients, respectively (P0.001). Within pT2 N1 patients, presence of ≥3 positive lymph nodes was an independent risk factor for BCR (hazard ratio [HR] 3.4, P0.001) and for metastatic progression (HR 1.7, P = 0.04). Finally, 3-year BCR-free survival was improved in pT2 N1 patients treated with adjuvant radiation therapy (87.1% vs. 63.7% for patients who received other treatment options [P0.001]).Patients with pathologically organ-confined but lymph node-positive CaP exhibited favorable oncological outcomes after RP. Presence of ≥3 positive LNs predicted higher rates of BCR and metastatic progression. In consequence, in pT2 N1 patients treated with RP with ≥3 positive LNs, adjuvant treatment may be considered.9.

9 Background: As mCRPC is driven by activated androgen receptors and elevated intratumoral androgens, androgen annihilation may require dual inhibition. APA and AA are approved prostate cancer therapies that have distinct receptor inhibition and ligand suppression actions, respectively. ACIS compared radiographic progression-free survival (rPFS) of APA + AAP vs PBO + AAP in chemo-naive mCRPC. Methods: mCRPC pts with ongoing androgen deprivation therapy (ADT) but no other life-prolonging treatment since diagnosis were randomized 1:1 to APA (240 mg po QD) + AA (1000 mg po QD) + P (5 mg po BID) or PBO + AAP (stratified by presence or absence of visceral metastases, Eastern Cooperative Oncology Group performance status 0 or 1, and geographic region). The primary end point was rPFS (investigator assessed; defined from randomization date to radiographic progression date or death). Secondary/other end points included prostate-specific antigen (PSA) response, overall survival (OS), safety, time to PSA progression, chronic opioid use, initiation of cytotoxic chemotherapy, and pain progression. Results: 982 pts were enrolled (Dec 2014 to Aug 2016). Median rPFS was extended 6 mos with APA + AAP (22.6 mos) vs AAP (16.6 mos) (HR 0.69 [95% CI 0.58-0.83]; p < 0.0001) at the final analysis for rPFS, coinciding with the first interim analysis of OS (median follow-up time 25.7 mo). At final analysis, treatment with APA + AAP vs AAP showed a significantly higher rate of confirmed ≥ 50% PSA decline. Although not statistically significant, treatment with APA + AAP vs AAP showed a longer median OS. Time to PSA progression, chronic opioid use, initiation of cytotoxic chemotherapy, and pain progression did not differ statistically significantly between arms. The safety profile was consistent with prior drug experience, with no new safety concerns. Grade 3/4 treatment-emergent adverse events (TEAEs) were reported in 63.3% (310/490) of APA + AAP–treated pts vs 56.2% (275/489) of AAP-treated pts, with more grade 3 (56.1%, 275/490 vs 45.6%, 223/489) and less grade 4 (7.1%, 35/490 vs 10.6%, 52/489) TEAEs, respectively. Results based on biomarker subpopulations and quality of life will be presented. Conclusions: The ACIS final analysis met the primary end point and demonstrated a 31% reduction in risk of radiographic progression or death in chemo-naive mCRPC pts treated with the combination of APA + AAP with ADT vs AAP with ADT. Funding: Janssen Research & Development. Trial registration: NCT02257736. Clinical trial information: NCT02257736. [Table: see text]

The trend of marine 87Sr/86Sr against stratigraphic level through sections, whether linear or not, can identify hiatuses and changing rates of sedimentation through those sections and so be a valuable constraint on attempts to assign numerical ages to sediments on the basis of astrochronology or U/Pb dating of zircons. Here we illustrate that value for the Campanian, Pliensbachian, Toarcian, and Valanginian ages by comparing 87Sr/86Sr profiles for different localities and comparing those to the 87Sr/86Sr profile through time. The analysis reveals possible problems both with current time scales and with some astrochronological calibrations. Our analysis is neither comprehensive nor final; rather, with a few examples, we show how Sr-isotope stratigraphy can be used to moderate other methods of assigning numerical ages to sediments.

Background 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. Objective To validate and compare the prediction tools for 10-yr CSM. Design, setting, and participants Overall, 2485 prostate cancer patients underwent RP in a European tertiary care center. Outcome measurements and statistical analysis 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. Results and limitations 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. Conclusions 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. Patient summary 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.

Purpose: Aberrant DNA content has been discussed as a potential prognostic feature in prostate cancer. Experimental Design: We analyzed the clinical significance of DNA ploidy in combination with prognostic relevant deletions of PTEN and 6q15 in 3,845 prostate cancers. Result: The DNA status was diploid in 67.8%, tetraploid in 25.6%, and aneuploid in 6.8% of tumors, and deletions of PTEN and 6q15 occurred in 17.8% and 20.3% of tumors. Abnormal DNA content and deletions were linked to high Gleason score, advanced tumor stage, and positive nodal stage (P < 0.0001 each). The risk of PSA recurrence increased from diploid to tetraploid and from tetraploid to aneuploid DNA status (P < 0.0001 each). However, 40% of patients with Gleason score ≥4+4 and 55% of patients with PSA recurrence had diploid cancers. This fraction decreased to 21% (Gleason ≥4+4) and 29% (PSA recurrence) if PTEN and/or 6q deletion data were added to ploidy data to identify cancers with an aberrant DNA status. The significance of combining both deletions and ploidy was further demonstrated in a combined recurrence analysis. Presence of deletions increased the risk of PSA recurrence in diploid (P < 0.0001), tetraploid (P < 0.0001), and aneuploid cancers (P = 0.0049), and the combination of ploidy data and deletions provided clinically relevant information beyond the CAPRA-S nomogram. Multivariate modeling including preoperatively and postoperatively available parameters identified the “combined DNA status” as a strong independent predictor of poor patient outcome. Conclusions: The combinatorial DNA content analysis involving general (ploidy) and specific events (deletions) has the potential for clinical utility in prostate cancer. Clin Cancer Res; 22(11); 2802–11. ©2016 AACR.

Background The effect of preservation of neurovascular bundles (NVBs) during radical prostatectomy (RP) on continence remains controversial. Objective 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. Design, setting, and participants 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. Intervention NS, NNS, or secNNS RP. Outcome measurements and statistical analysis 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. Results and limitations 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. Conclusions 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. Patient summary 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.

Background Gleason grading is the strongest prognostic parameter in prostate cancer. Gleason grading is categorized as Gleason ≤6, 3+4, 4+3, 8, and 9–10, but there is variability within these subgroups. For example, Gleason 4 components may range from 5–45% in a Gleason 3+4=7 cancer. Objective To assess the clinical relevance of the fractions of Gleason patterns. Design, setting, and participants Prostatectomy specimens from 12823 consecutive patients and of 2971 matched preoperative biopsies for which clinical data with an annual follow-up between 2005 and 2014 were available from the Martini-Klinik database. Outcome measurements and statistical analysis To evaluate the utility of quantitative grading, the fraction of Gleason 3, 4, and 5 patterns seen in biopsies and prostatectomies were recorded. Gleason grade fractions were compared with prostatectomy findings and prostate-specific antigen recurrence. Results and limitations Our data suggest a striking utility of quantitative Gleason grading. In prostatectomy specimens, there was a continuous increase of the risk of prostate-specific antigen recurrence with increasing percentage of Gleason 4 fractions with remarkably small differences in outcome at clinically important thresholds (0% vs 5%; 40% vs 60% Gleason 4), distinguishing traditionally established prognostic groups. Also, in biopsies, the quantitative Gleason scoring identified various intermediate risk groups with respect to Gleason findings in corresponding prostatectomies. Quantitative grading may also reduce the clinical impact of interobserver variability because borderline findings such as tumors with 5%, 40%, or 60% Gleason 4 fractions and very small Gleason 5 fractions (with pivotal impact on the Gleason score) are disclaimed. Conclusions Quantitative Gleason pattern data should routinely be provided in addition to Gleason score categories, both in biopsies and in prostatectomy specimens. Patient summary Gleason score is the most important prognostic parameter in prostate cancer, but prone to interobserver variation. The results of our study show that morphological aspects that define the Gleason grade in prostate cancer represent a continuum. Quantitation of Gleason patterns provides clinically relevant information beyond the traditional Gleason grading categories ≤3+3, 3+4, 4+3, 8, 9–10. Quantitative Gleason scoring can help to minimize variations between different pathologists and substantially aid in optimized therapy decision-making.

The background to the preparation of the rudist sections for the ongoing complete revision of the Bivalvia volumes of the ‘Treatise on Invertebrate Palaeontology’ is described. The progress on publication is reported. The plans for further work are outlined. Three introductory chapters on rudists have already been published in ‘Treatise Online’ (University of Kansas, Paleontological Institute). Future work will be devoted to the preparation of the taxonomic descriptions of genera and a synoptic example of which is provided for the genus Pachytraga.

Nach definitiver kurativ intendierter Therapie kommt es bei einem Teil der Patienten mit Prostatakarzinom zu einem biochemischen Rezidiv. In solchen Fallen erfolgt meist anhand klinischer Parameter die Einschatzung, ob es sich um ein lokales oder ein systemisches Rezidiv handelt. Wahrend nach radikaler Prostatektomie die Salvage-Bestrahlung die Standardbehandlung beim lokalisierten Rezidiv darstellt, existiert beim Lokalrezidiv nach primarer Strahlentherapie kein Standardvorgehen, wenngleich die Salvage-Prostatektomie eine Behandlungsoption darstellt. Bildgebende Untersuchungen wurden beim beginnenden PSA(prostataspezifisches Antigen)-Rezidiv traditionell eher zuruckhaltend empfohlen. Eine PSMA(prostataspezifisches Membranantigen)-PET(Positronenemissionstomographie)/CT(Computertomographie) zeigt jedoch bereits bei niedrigen PSA-Werten hohe Detektionsraten, sodass nach Leitlinienempfehlung eine solche durchgefuhrt werden kann, wenn sich dadurch die weitere Therapie entscheidend verandern konnte. Ein positiver Einfluss auf die onkologischen Langzeitergebnisse konnte dabei aktuell noch nicht nachgewiesen werden.

Imaging modalities with high accuracy are essential for proper selection of patients for salvage lymph node dissection (sLND). Unlike nodal staging before radical prostatectomy, data on prostate-specific membrane antigen (PSMA) positron emission tomography (PET) before sLND are scarce. We analyzed 23 patients undergoing

OBJECTIVES To analyse time trends and contemporary rates of postoperative complications after radical prostatectomy (RP) and to compare the complication profile of open RP (ORP) and robot-assisted laparoscopic RP (RALP) using standardised reporting systems. PATIENTS AND METHODS Retrospective analysis of 13 924 RP patients in a single institution (2005-2015). Complications were collected during hospital stay and via standardised questionnaire 3 months after, and grouped into eight schemes. Since 2013, the revised Clavien-Dindo classification was used (n = 4 379). Annual incidence rates of different complications were graphically displayed. Multivariable logistic regression analyses compared complications between ORP and RALP after inverse probability of treatment weighting (IPTW). RESULTS After the introduction of standardised classification systems, complication rates have increased with a contemporary rate of 20.6% (2013-2015). While minor Clavien-Dindo grades represented the majority (I: 10.6%; II: 7.9%), severe complications (Grades IV-V) were rare (

This special issue of the Canadian Journal of Earth Science, which is entitled “Advances in low–temperature geochemistry, diagenesis, seawater and climate evolution through the Earth’s history: A special tribute to J. Veizer” is in honor of Professor Dr. Jan Veizer who is the Distinguished University Professor (emeritus) of Earth Sciences at the University of Ottawa and former Chair of Sedimentary and Isotope Geology, Institute for Geology, Mineralogy und Geophysics, of Ruhr University (Bochum, Germany).

Im Marz 2015 fand erstmalig die Advanced Prostate Cancer Consensus Conference (APCCC) in St. Gallen statt. Kontroversen rund um das fortgeschrittene Prostatakarzinom wurden von 41 Experten aus 17 Landern diskutiert mit dem Ziel, Konsensusempfehlungen auszusprechen. Die Ergebnisse wurden aktuell in der Fachzeitschrift „Annals of Oncology“ publiziert. Obwohl ein Grosteil der in St. Gallen ausgesprochenen Empfehlungen nachvollziehbar ist, sind einige Stellungnahmen kritisch zu betrachten. Als deutsches Expertengremium nehmen wir hierzu Stellung. Im hormonnaiven metastasierten Stadium sollte die kontinuierliche Androgendeprivation (ADT) als Standard gesehen werden. Fur eine Uberlegenheit der primar maximalen Androgenblockade gibt es keine Evidenz. Nach aktueller Datenlage sollte Patienten mit gutem Allgemeinzustand, insbesondere bei hoher Tumorlast, eine Kombinationstherapie aus ADT plus Taxanen angeboten werden. Im metastasierten kastrationsresistenten Stadium ist als Erstlinientherapie eine Hormonmanipulation mit neuartigen endokrinen Medikamenten Therapie der Wahl in der Mehrheit der Patienten. Taxane haben eine primare Indikation bei ungunstigen Prognoseparametern. Radium-223 ist eine Option bei ossarer Metastasierung. Von einer nochmaligen Hormonmanipulation nach Versagen von Abirateron oder Enzalutamid in der Erstlinie sollte wenn moglich Abstand genommen werden. Bei Patienten mit gutem Allgemeinzustand sollte Cabazitaxel einen festen Stellenwert in der Sequenztherapie haben. Fur das initiale Staging im kastrationsresistenten Stadium ist ein CT-Abdomen/-Thorax plus Knochenszintigramm empfehlenswert. Eine erneute Bildgebung empfiehlt sich bei Tumorprogress, ansonsten alle 4–6 Monate. Bezuglich der Biomarker sollte eine Bestimmung von Serum-PSA und AP alle 2–4 Monate erfolgen.

There is an abundance of evidence for short intervals of cold climatic conditions during the Early Cretaceous. However, the lack of a high-resolution, long-term Early Cretaceous paleotemperature record hampers a full-scale synthesis of these putative “cold snap” episodes, as well as a more holistic approach to Early Cretaceous climate changes. We present an extended compilation of belemnite-based oxygen, carbon and strontium isotope records covering the Berriasian–middle Albian from the Vocontian Basin (SE France). This dataset clearly demonstrates three intervals of cold climatic conditions during the Early Cretaceous (late Valanginian–earliest Hauterivian, late early Aptian, latest Aptian–earliest Albian). Each of these intervals is associated with rapid and high amplitude sea-level fluctuations, supporting the hypothesis of transient growth of polar ice caps during the Early Cretaceous. As evidenced by positive carbon isotope excursions, each cold episode is associated with enhanced burial of organic matter on a global scale. Moreover, there is a relatively good match between the timing and size of large igneous province eruptions and the amplitude of Early Cretaceous warming episodes. Altogether, these observations confirm the instrumental role of atmospheric CO2 variations in driving Early Cretaceous climate change. From a long-term perspective, the coupling of global paleotemperature and seawater strontium isotopic ratio during the Early Cretaceous is best explained by temperature-controlled changes of continental crust weathering rates.

Hintergrund Zur Behandlung von Patienten mit kastrationsresistentem Prostatakarzinom (CRPC) stehen heute verschiedene therapeutische Optionen mit unterschiedlichen Wirkmechanismen zur Verfugung.

Experimental evidence suggests that phosphodiesterase type 5 inhibitors may suppress tumor growth, postpone metastasis and prolong survival, but clinical data are lacking. We studied the effect of phosphodiesterase type 5 inhibitors on biochemical recurrence after radical prostatectomy for prostate cancer.The study was comprised of 4,752 consecutive patients with localized prostate cancer treated with bilateral nerve sparing radical prostatectomy between January 2000 and December 2010. Of these patients 1,110 (23.4%) received phosphodiesterase type 5 inhibitors postoperatively while 3,642 (76.6%) did not. The risk of biochemical recurrence was compared between the phosphodiesterase type 5 inhibitor group and the nonphosphodiesterase type 5 inhibitor group. Cox multivariate proportional hazard models and confidence intervals were used to estimate the hazard ratio of biochemical recurrence associated with phosphodiesterase type 5 inhibitor use. Propensity score matched analysis was performed.Median followup was 60.3 months (IQR 36.7-84.5). Five-year biochemical recurrence-free survival estimates in the phosphodiesterase type 5 inhibitor vs nonphosphodiesterase type 5 inhibitor groups were 84.7% (95% CI 82.1-87.0) and 89.2% (95% CI 88.1-90.3), respectively (p=0.0006). Multivariate regression analysis showed that phosphodiesterase type 5 inhibitor use was an independent risk factor for biochemical recurrence (HR 1.38, 95% CI 1.11-1.70, p=0.0035) and this was also true after propensity score matching.Contrary to experimental data, the use of phosphodiesterase type 5 inhibitors after radical prostatectomy may adversely impact biochemical recurrence. Further studies are needed to validate our results.

Background Most prostate cancer (PCa) patients with a biochemical failure following primary multimodality treatment (surgery and postoperative radiotherapy) relapse in the nodes. Objective To perform a matched-case analysis in men with lymph node recurrent PCa comparing standard of care (SOC) with metastasis-directed therapy (MDT). Design, setting, and participants PCa patients with a prostate-specific antigen (PSA) progression following multimodality treatment were included in this retrospective multi-institutional analysis. Intervention The SOC cohort ( n =1816) received immediate or delayed androgen deprivation therapy administered at PSA progression. The MDT cohort ( n =263) received either salvage lymph node dissection ( n =166) or stereotactic body radiotherapy ( n =97) at PSA progression to a positron emission tomography-detected nodal recurrence. Outcome measurements and statistical analysis The primary endpoint, cancer-specific survival (CSS), was analyzed using the Kaplan-Meier method, log-rank test, Cox proportional hazards models, and propensity score-matched analyses. Results and limitations At a median follow-up of 70 (interquartile range: 48–98) mo, MDT was associated with an improved CSS on univariate ( p =0.029) and multivariate analysis (hazard ratio: 0.33, 95% confidence interval [CI]: 0.17–0.64) adjusted for the year of radical prostatectomy (RP), age at RP, PSA at RP, time from RP to PSA progression, Gleason score, surgical margin status, pT- and pN-stage. In total, 659 men were matched (3:1 ratio). The 5-yr CSS was 98.6% (95% CI: 94.3–99.6) and 95.7% (95% CI: 93.2–97.3) for MDT and SOC, respectively ( p =0.005, log-rank). The main limitations of our study are its retrospective design and lack of standardization of systemic treatment in the SOC cohort. Conclusions MDT for nodal oligorecurrent PCa improves CSS as compared with SOC. These retrospective data from a multi-institutional pooled analysis should be considered as hypothesis-generating and inform future randomized trials in this setting. Patient summary Prostate cancer patients experiencing a lymph node recurrence might benefit from local treatments directed at these lymph nodes.

Background: We hypothesized that a cut-off in positive lymph node (LN) counts may discriminate between cancer-specific mortality (CSM) rates in clinically localized prostate cancer patients treated with radical prostatectomy (RP). Objective: To test this relationship, we relied on different LN count cut-offs, as well as the continuously coded number of positive LNs (NPN). Methods: Within the Surveillance, Epidemiology, and End Results database (2004-2014), we identified patients with D'Amico intermediate- or high-risk characteristics who underwent RP and pelvic LN dissection, regardless of pathologic LN stage. Kaplan-Meier analyses and multivariable Cox regression models tested the effect of LN invasion (LNI) on CSM, according to the NPN. Results: Of 30. 016 patients treated with RP, 6.2% (n = 1869) exhibited LNI, with respectively higher rates of LNI in patients with D'Amico high- versus intermediate-risk characteristics (11.6% vs 3.4%). Overall, the median age was 63. yr, median prostate-specific antigen value was 6.6. ng/ml and the median number of removed LNs was six. At 60 mo after RP, CSM rates were, respectively, 6.0% versus 0.8% for patients with and without LNI: multivariable hazard ratio (HR) 4.4 (p

Nodal metastasis (N1) is a strong prognostic parameter in prostate cancer; however, lymph node evaluation is always incomplete.To study the prognostic value of lymphatic invasion (L1) and whether it might complement or even replace lymph node analysis in clinical practice.Retrospective analysis of pathological and clinical data from 14 528 consecutive patients.Radical prostatectomy.The impact of L1 and N1 on patient prognosis was measured with time to biochemical recurrence as the primary endpoint.Nodal metastases were found in 1602 (12%) of 13 070 patients with lymph node dissection. L1 was seen in 2027 of 14 528 patients (14%) for whom lymphatic vessels had been visualized by immunohistochemistry. N1 and L1 continuously increased with unfavorable Gleason grade, advanced pT stage, and preoperative prostate-specific antigen (PSA) values (p0.0001 each). N1 was found in 4.3% of 12 501 L0 and in 41% of 2027 L1 carcinomas (p0.0001). L1 was seen in 11% of 9868 N0 and in 61% of 1360 N1 carcinomas (p0.0001). Both N1 and L1 were linked to PSA recurrence (p0.0001 each). This was also true for 17 patients with isolated tumor cells (ie,200 unequivocal cancer cells without invasive growth) and 193 metastases ≤1mm. Combined analysis of N and L status showed that L1 had no prognostic effect in N1 patients but L1 was strikingly linked to PSA recurrence in N0 patients. N0L1 patients showed a similar outcome as N1 patients.Analysis of lymphatic invasion provides comparable prognostic information than lymph node analysis. Even minimal involvement of the lymphatic system has pivotal prognostic impact in prostate cancer. Thus, a thorough search for lymphatic involvement helps to identify more patients with an increased risk for disease recurrence.Already minimal amounts of tumor cells inside the lymph nodes or intraprostatic lymphatic vessels have a severe impact on patient prognosis.

Purpose of review Although cytoreductive surgery is accompanied with prolonged survival in many other malignancies in a metastatic stage, its role in oligometastatic prostate cancer is unclear. Recent findings Radical prostatectomy (RP) in patients with oligometastatic prostate cancer seems to be feasible. Perioperative complication rates vary between 20 and 50% (Clavien 1-3) and are comparable to patients with locally advanced tumors. Postoperative functional outcomes (urinary continence and erectile function) can be slightly worse than in patients with locally advanced tumor. In literature, an oncological benefit of surgery is so far only described for retrospective multiinstitutional databases and a case-control study but not for prospective studies. Still, men undergoing RP clearly seem to develop severe local complications less frequently than patients receiving best systemic therapy (up to more than 50% versus less than10%). Summary Patients should be counseled about the potential significant reduction of local complications whenever undergoing RP for oligometastatic prostate cancer. Nevertheless, as complication rates are relatively high, functional outcome can be slightly worse compared with RP with curative intent and especially as oncological benefit so far is shown using retrospective but not prospective data, patients should only undergo surgery within the ongoing prospective, randomized trials.

Die radikale retropubische Prostatektomie (RRP) bei adiposen Patienten („Body Mass Index“, BMI ≥ 30) ist mit erhohter perioperativer Morbiditat und schlechterem funktionellen Ergebnis assoziiert. Ziel dieser Studie ist es zu uberprufen, ob die roboterassistierte radikale Prostatektomie (RARP) bei adiposen Patienten eine geringere Morbiditat und ein besseres funktionelles Ergebnis gegenuber der RRP ermoglicht. Wir identifizierten 255 Patienten mit einem Prostatakarzinom (PCA) und BMI ≥ 30, die zwischen 1/2009 und 12/2011 radikal prostatektomiert wurden. Per „propensity score matching“ anhand von Risikofaktoren fur eine erhohte perioperative Morbiditat (Nerverhaltung, Lymphadenektomie, Prostatavolumen) wurden gleiche Paare (n = 115/Gruppe) gebildet. Beide Gruppen (RARP vs. RRP) wurden hinsichtlich ihres histopathologischen Ergebnisses, peri- und postoperativen (30 Tage) Morbiditat und Kontinenz und Potenz verglichen. Es zeigte sich kein Unterschiede bezuglich der histopathologischen Charakteristika in beiden Gruppen (pT/pN-Stadien, Gleason-Grad, R-Status; alle p > 0,05). Mittlerer Blutverlust (276 ml vs. 937 ml), Transfusionsrate (0,9 % vs. 8,7 %) sowie die Rate der 30-Tage-Komplikationen nach der Clavien-Klassifikation (Clavien ≥ 2; 9,5 % vs. 22,6 %) waren niedriger in der RARP-Gruppe gegenuber RRP (alle p

Objective To quantify the incremental detection rate (DR) of a targeted biopsy in addition to a randomized 10-core biopsy. Patients and Methods This retrospective study analysed 1024 patients who consecutively underwent a four-core real-time elastography (RTE) targeted biopsies in addition to a randomized 10-core transrectal ultrasonography (TRUS)-guided biopsy in a primary or rebiopsy setting. The overall DR, the DR of a 10-core randomized, RTE targeted biopsy and the incremental DR were calculated. Results Overall, randomized and RTE targeted biopsy DRs (for the combination, the 10-core and the four-core RTE biopsy scheme) were 46.2% (n = 473), 39.1% (n = 400) and 29.0% (n = 297), respectively. Four-core RTE targeted biopsies detected an additional 73 patients not detected by the 10-core randomized biopsies (increase in the overall DR of 7.1%). This represented a relative increase in DR of 18.3%. The incremental DR was better in rebiopsy patients (24.8%) than in patients having their first biopsy (14.7%). Within all patients diagnosed by RTE targeted biopsy only, 34 patients harboured significant Gleason 4 or 5 prostate cancer (PCa), diagnosed by four-core RTE biopsy only. Moreover, PCa with a Gleason grade of 4 or 5 was detected by four-core RTE biopsies in 30 patients, who showed low-grade PCa ≤ Gleason 3 only in the systematic 10-core biopsy. Conclusions Real-time elastography targeted biopsy seems to be an appropriate method for increasing the DR of PCa. Nevertheless, RTE targeted biopsies missed a high proportion of patients with PCa and should therefore be considered as an addition to randomized biopsies.

In the Triassic-Jurassic (T-J) interval, only a few continuous carbonate sections have been reported, and detailed studies about ooids and their significance are scarce. This study focuses on abundant ooids in potentially continuous T-J carbonate sections representing equatorial, shallow marine environments. Mineralogical changes of ooids are proposed as a marker for transitional marine chemistry including carbonate saturation after ocean acidification and provide information about crisis and recovery scenarios for the initial CIE (carbon isotope excursion) and subsequent positive CIE. In the Ghalilah Formation, United Arab Emirates (UAE), the Sakhra Member is deposited immediately above the T-J boundary. Based on field work and thin section observation, the Sakhra Member can be divided into three coarsening-upward cycles (in ascending order, named C1–C3), each of which consists of peloidal mudstone/wackestone in the lower part and oolitic packstone/grainstone in the upper part. Petrological observation (thin section, SEM), stable isotope (inorganic carbon and oxygen) and elemental analysis suggest temporal change of original mineralogy from C1 to C3 ooids: from high-Mg calcite in C1 ooids to aragonite in C2 and C3 ooids. The mineralogical change of ooids is possibly related to variations in seawater carbonate saturation. The lower carbonate saturation indicated by C1 ooids reflects a transitional period before recovery from ocean acidification due to massive and rapid release of acidic gases (CO2 and SO2) by CAMP eruptions. Subsequently, from C1 to C3 ooids, seawater gradually experienced increasing carbonate saturation and increasing microbial carbonate precipitation. Increased microbial activities combined with elevated terrestrial influx may have significantly reduced the atmospheric CO2 concentration and restored carbonate saturation, which laid the foundation for full biotic recovery.

Derzeit wird das prostataspezifische Antigen in Kombination mit Ergebnissen der digitalen rektalen Untersuchung (DRU) herangezogen, um bei Verdacht auf ein Prostatakarzinom die Indikation fur eine Prostatabiopsie zu stellen. Eine hohe Anzahl der Prostatabiopsien bringt jedoch ein negatives Ergebnis, sodass hier Verbesserungspotential in der Diagnose und somit der Indikationsstellung besteht.