Postoperative Radiotherapy of Prostate Cancer: Adjuvant versus Early Salvage.

Results of three randomized clinical trials (RCTs) comparing adjuvant radiotherapy (ART) and early salvage radiotherapy (eSRT) of prostate carcinoma and a subsequent meta-analysis of the individual patient data from these RCTs were recently published. The results suggest that early eSRT is as effective and potentially less toxic than ART. Therefore, eSRT should be considered the standard of care. However, due to limitations in the RCTs, ART remains a valid treatment option in patients with the combination of high-risk features such as Gleason Score (GS) 8-10, positive surgical margins (R1) and pathological T-stage 3 or 4 (pT3/4). This article provides a critical appraisal of the RCTs and the rationale for recommendations adopted in the current national guidelines regarding patients with high-risk features after radical prostatectomy (RP): ART should be offered in case of pT3/pT4 and R1 and Gleason Score 8-10; ART can be offered in case of pT3/pT4 and R0 and Gleason Score 8-10 as well as in case of multifocal R1 (including pT2) and Gleason Score 8-10. In any case, the alternative treatment option of eSRT in case of rising PSA should be discussed with the patient

Increasing the attractiveness of surgical disciplines for students: Implications of a robot-assisted hands-on training course for medical education

BackgroundStructured implementation of robot-assisted surgery in the field of medical education is lacking. We assessed students' interest in robot-assisted surgery and tested if the implementation of a hands-on robotic course into the curriculum could increase the interest to join a surgical discipline in general and especially in female students, since women are clearly underrepresented in surgical disciplines.MethodsAfter a prostate cancer focused seminar, 100 students were 1:1 randomized into two groups. Group B: Baseline characteristics and professional interest were assessed prior and after a hands-on robotic course, using a da Vinci® console with simulator (da Vinci® Surgical training, Intuitive Surgical Inc., USA). Group A served as post-interventional consistency control group, received the questionnaire only once after the hands-on training.ResultsThe male to female ratio of students was 54% and 46%. The interest to turn into urology/surgery, categorized as yes”, “no”, “maybe” changed from 18 to 16%, 36 to 30% and 46 to 54% respectively after the hands-on robotic course (p < 0.001). Also, the positive attitude towards the surgical field significantly increased (20 vs. 48%; p < 0.001). Comparing male and female students, virtually identical proportions (23 vs. 23%) opted for joining urology or surgery as a discipline, whereas rejection (45 vs. 25%) and perchance (32 vs. 50%) of that notion differed between genders (p = 0.12).ConclusionOur results demonstrate great demand for implementing robotic training into medical education for an up-to-date curriculum. Although the decision process on career choice is widely multifactorial, stereotypes associated with surgical disciplines should be eliminated. This could have a particularly positive effect on the recruitment of female medical students since women are clearly underrepresented in surgical disciplines although currently and with increasing proportions, more female students are enrolled in medical schools then male

Prognostic Significance of Incidental Prostate Cancer at Radical Cystoprostatectomy for Bladder Cancer

Objective: The aim of the study was to evaluate the impact of the clinical significance of incidental prostate cancer (PC) on overall survival (OS) after radical cystoprostatectomy (RC) for bladder cancer (BC). Methods: A total of 822 consecutive men underwent RC in 3 academic centers between 1996 and 2011. The clinical significance of incidental PC was determined according to the Epstein criteria. The Kaplan-Meier analysis with log-rank was used to investigate the impact of PC on OS and univariate and multivariate Cox regression analyses for risk factors of OS. The median follow-up was 36 months (interquartile range 10-49). Results: Of the 822 men, 117 (14.2%) had clinically significant, 243 (29.6%) insignificant and 462 (56.2) no PC at RC. Men with PC were at higher risk for lymphovascular invasion (LVI) of BC compared to men without PC (p < 0.001). The 5-year OS for men with clinically significant, insignificant and no PC was 33.3, 51.3 and 51.5%, respectively (p = 0.050). In the subgroup of pN0 patients (n = 601), clinically significant PC was significantly associated with inferior OS (p = 0.044) but not in multivariable analysis (p = 0.46). Conclusions: We did not find the clinical significance of incidental PC to be an independent predictor. However, the positive correlation between incidental PC and LVI of BC deserves further investigation. (C) 2016 S. Karger AG, Base

Inspired by Sea Urchins: Warburg Effect Mediated Selectivity of Novel Synthetic Non-Glycoside 1,4-Naphthoquinone-6S-Glucose Conjugates in Prostate Cancer

The phenomenon of high sugar consumption by tumor cells is known as Warburg effect. It results from a high glycolysis rate, used by tumors as preferred metabolic pathway even in aerobic conditions. Targeting the Warburg effect to specifically deliver sugar conjugated cytotoxic compounds into tumor cells is a promising approach to create new selective drugs. We designed, synthesized, and analyzed a library of novel 6-S-(1,4-naphthoquinone-2-yl)-d-glucose chimera molecules (SABs)&mdash;novel sugar conjugates of 1,4-naphthoquinone analogs of the sea urchin pigments spinochromes, which have previously shown anticancer properties. A sulfur linker (thioether bond) was used to prevent potential hydrolysis by human glycoside-unspecific enzymes. The synthesized compounds exhibited a Warburg effect mediated selectivity to human prostate cancer cells (including highly drug-resistant cell lines). Mitochondria were identified as a primary cellular target of SABs. The mechanism of action included mitochondria membrane permeabilization, followed by ROS upregulation and release of cytotoxic mitochondrial proteins (AIF and cytochrome C) to the cytoplasm, which led to the consequent caspase-9 and -3 activation, PARP cleavage, and apoptosis-like cell death. These results enable us to further clinically develop these compounds for effective Warburg effect targeting

The Effect of Chronic Kidney Disease on Adverse In-Hospital Outcomes at Radical Prostatectomy

ObjectiveRadical prostatectomy (RP) may be a treatment option for prostate cancer in patients with chronic kidney disease (CKD). However, the effect of CKD on adverse in-hospital outcomes after RP is not well known. MethodsDescriptive analyses, propensity score matching (PSM), and multivariable logistic and Poisson regression models were used to address National Inpatient Sample RP patients between 2005 and 2019. CKD severity was stratified as mild (stage I/II) versus moderate (stage III) versus severe (stage IV/V). ResultsOf 191 050 RP patients, 4349 (2.3%) had CKD. Of those, 2301 (52.9%), 1416 (32.6%), and 632 (14.5%) were classified as mild, moderate, or severe CKD, respectively. The CKD rate increased from 0.3% to 5.6% (2005-2019, EAPC: + 15.3%, p &lt; 0.001). CKD patients invariably exhibited higher rates of adverse in-hospital outcomes, except for in-hospital mortality. The absolute differences were largest for overall complications (+ 12.5%), length of stay &gt; 2 days (+ 11.8%), and blood transfusions (+ 3.7%, all p &lt; 0.001). CKD was an independent predictor in all comparisons except for in-hospital mortality (p &lt; 0.05). The detrimental effect was most pronounced for dialysis for acute kidney failure (multivariable odds ratio [OR] 10.49), genitourinary complications (OR: 2.47), and critical care therapies (OR: 2.45, all p &lt; 0.001). Finally, a dose-response relationship of CKD severity (mild vs. moderate vs. severe) and its effect on adverse in-hospital outcomes was observed in seven of 14 comparisons. ConclusionsCKD patients invariably exhibited higher rates of adverse in-hospital outcomes after RP. The presence of CKD should be carefully considered when RP represents a management option

Successful Targeting of the Warburg Effect in Prostate Cancer by Glucose-Conjugated 1,4-Naphthoquinones

Treatment of castration-resistant prostate cancer (CRPC) remains challenging due to the development of drug resistance. The Warburg effect describes the ability of cancer cells to consume larger amounts of glucose compared to normal tissues. We identified derivatives of natural 1,4-naphthoquinones to be active in CRPC and further synthetically modified them via glucose conjugation to increase selectivity by Warburg effect targeting. Mechanisms of action were examined by quantitative proteomics followed by bioinformatical analysis and target validation. Four synthesized molecules revealed the highest selectivity towards human CRPC cells, which correlated with higher GLUT-1 activity and expression. The compounds were able to induce pro-apoptotic signs and to inhibit the pro-survival processes and mechanisms of drug resistance (i.e., AR-signaling and autophagy). Proteome analysis suggested a disruption of the mitochondria/oxidative phosphorylation, which was validated by further functional analysis: thus, mitochondria depolarization, elevated levels of cytotoxic ROS, an increase of Bax/Bcl-2 ratio as well as release of mitochondrial AIF and cytochrome C to cytoplasm were observed. In conclusion, glucose-conjugated 1,4-naphthoquinones show potent activity and selectivity in human CRPC exerted via mitochondrial targeting. The compounds can overcome drug resistance against current standard therapies and suppress pro-survival mechanisms. This unique combination of properties makes them new promising candidates for the treatment of CRPC

Preoperative Risk-Stratification of High-Risk Prostate Cancer: A Multicenter Analysis

Background: Cancer-specific survival (CSS) within high-risk non-metastatic prostate cancer varies dramatically. It is likely that within this heterogenous population there are subgroup(s) at extraordinary risk, burdened with an exaptational poor prognosis. Establishing the characteristics of these group(s) would have significant clinical implications since high quality preoperative risk stratification remains the cornerstone of therapeutic decision making to date. Objective: To stratify high-risk prostate cancer based on preoperative characteristics and evaluate cancer specific survival after radical prostatectomy. Method: The EMPaCT multi-center database offers an international population of non-metastatic high-risk prostate cancer. Preoperative characteristics such as age, biopsy Gleason score, PSA and clinical stage were subcategorized. A multivariate analysis was performed using predictors showing significant survival heterogeneity after stratification, as observed by a univariate analysis. Based upon the hazard ratios of this multivariate analysis, a proportional score system was created. The most ideal group distribution was evaluated trough different score cut-off's. The predictive value was tested by the herald C index. Results: An overall 5-years CSS of 94% was noted within the entire high-risk cohort (n = 4,879). Except for age, all preoperative risk factors showed a significantly differing CSS. Multivariate analysis indicated, T4 stage as being the strongest predictor of CSS (HR: 3.31), followed by ISUP grade 5 group (HR 3,05). A score system was created by doubling the hazard ratios of this multivariate analysis and rounding off to the nearest complete number. Multivariate analysis suggested 0, 4, 8, and 12 pts as being the most optimal group distribution (p-value: 0.0015). Five-years CSS of these groups were 97, 93, 87, and 70%, respectively. The calculated Herald C-index of the model was 0.77. Conclusion: An easy-to-use pre-operative model for risk stratification of newly diagnosed high-risk prostate cancer is presented. The heterogeneous CSS of high-risk non-metastatic prostate cancer after radical prostatectomy is illustrated. The model is clinically accessible through an online calculator, presenting cancer specific survival based on individualized patient characteristics

PITX1 is a regulator of TERT expression in prostate cancer with prognostic power

Simple Summary Most prostate cancer is of an indolent form and is curable. However, some prostate cancer belongs to rather aggressive subtypes leading to metastasis and death, and immediate therapy is mandatory. However, for these, the therapeutic options are highly invasive, such as radical prostatectomy, radiation or brachytherapy. Hence, a precise diagnosis of these tumor subtypes is needed, and the thus far applied diagnostic means are insufficient for this. Besides this, for their endless cell divisions, prostate cancer cells need the enzyme telomerase to elongate their telomeres (chromatin endings). In this study, we developed a gene regulatory model based on large data from transcription profiles from prostate cancer and chromatin-immuno-precipitation studies. We identified the developmental regulator PITX1 regulating telomerase. Besides observing experimental evidence of PITX1′s functional role in telomerase regulation, we also found PITX1 serving as a prognostic marker, as concluded from an analysis of more than 15,000 prostate cancer samples. Abstract The current risk stratification in prostate cancer (PCa) is frequently insufficient to adequately predict disease development and outcome. One hallmark of cancer is telomere maintenance. For telomere maintenance, PCa cells exclusively employ telomerase, making it essential for this cancer entity. However, TERT, the catalytic protein component of the reverse transcriptase telomerase, itself does not suit as a prognostic marker for prostate cancer as it is rather low expressed. We investigated if, instead of TERT , transcription factors regulating TERT may suit as prognostic markers. To identify transcription factors regulating TERT , we developed and applied a new gene regulatory modeling strategy to a comprehensive transcriptome dataset of 445 primary PCa. Six transcription factors were predicted as TERT regulators, and most prominently, the developmental morphogenic factor PITX1. PITX1 expression positively correlated with telomere staining intensity in PCa tumor samples. Functional assays and chromatin immune-precipitation showed that PITX1 activates TERT expression in PCa cells. Clinically, we observed that PITX1 is an excellent prognostic marker, as concluded from an analysis of more than 15,000 PCa samples. PITX1 expression in tumor samples associated with (i) increased Ki67 expression indicating increased tumor growth, (ii) a worse prognosis, and (iii) correlated with telomere length