Prediction models of incontinence and sexual function one year after radical prostatectomy based on data from 20 164 prostate cancer patients.

BACKGROUND: Incontinence and sexual dysfunction are long-lasting side effects after surgical treatment (radical prostatectomy, RP) of prostate cancer (PC). For an informed treatment decision, physicians and patients should discuss expected impairments. Therefore, this paper firstly aims to develop and validate prognostic models that predict incontinence and sexual function of PC patients one year after RP and secondly to provide an online decision making tool. METHODS: Observational cohorts of PC patients treated between July 2016 and March 2021 in Germany were used. Models to predict functional outcomes one year after RP measured by the EPIC-26 questionnaire were developed using lasso regression, 80-20 splitting of the data set and 10-fold cross validation. To assess performance, R2, RMSE, analysis of residuals and calibration-in-the-large were applied. Final models were externally temporally validated. Additionally, percentages of functional impairment (pad use for incontinence and firmness of erection for sexual score) per score decile were calculated to be used together with the prediction models. RESULTS: For model development and internal as well as external validation, samples of 11 355 and 8 809 patients were analysed. Results from the internal validation (incontinence: R2 = 0.12, RMSE = 25.40, sexual function: R2 = 0.23, RMSE = 21.44) were comparable with those of the external validation. Residual analysis and calibration-in-the-large showed good results. The prediction tool is freely accessible: https://nora-tabea.shinyapps.io/EPIC-26-Prediction/. CONCLUSION: The final models showed appropriate predictive properties and can be used together with the calculated risks for specific functional impairments. Main strengths are the large study sample (> 20 000) and the inclusion of an external validation. The models incorporate meaningful and clinically available predictors ensuring an easy implementation. All predictions are displayed together with risks of frequent impairments such as pad use or erectile dysfunction such that the developed online tool provides a detailed and informative overview for clinicians as well as patients.

Lessons learned after one year of COVID-19 from a urologist and radiotherapist view: A German survey on prostate cancer diagnosis and treatment.

INTRODUCTION: Since the beginning of the pandemic in 2020, COVID-19 has changed the medical landscape. International recommendations for localized prostate cancer (PCa) include deferred treatment and adjusted therapeutic routines. MATERIALS AND METHODS: To longitudinally evaluate changes in PCa treatment strategies in urological and radiotherapy departments in Germany, a link to a survey was sent to 134 institutions covering two representative baseline weeks prior to the pandemic and 13 weeks from March 2020 to February 2021. The questionnaire captured the numbers of radical prostatectomies, prostate biopsies and case numbers for conventional and hypofractionation radiotherapy. The results were evaluated using descriptive analyses. RESULTS: A total of 35% of the questionnaires were completed. PCa therapy increased by 6% in 2020 compared to 2019. At baseline, a total of 69 radiotherapy series and 164 radical prostatectomies (RPs) were documented. The decrease to 60% during the first wave of COVID-19 particularly affected low-risk PCa. The recovery throughout the summer months was followed by a renewed reduction to 58% at the end of 2020. After a gradual decline to 61% until July 2020, the number of prostate biopsies remained stable (89% to 98%) during the second wave. The use of RP fluctuated after an initial decrease without apparent prioritization of risk groups. Conventional fractionation was used in 66% of patients, followed by moderate hypofractionation (30%) and ultrahypofractionation (4%). One limitation was a potential selection bias of the selected weeks and the low response rate. CONCLUSION: While the diagnosis and therapy of PCa were affected in both waves of the pandemic, the interim increase between the peaks led to a higher total number of patients in 2020 than in 2019. Recommendations regarding prioritization and fractionation routines were implemented heterogeneously, leaving unexplored potential for future pandemic challenges.

Variation across operating sites in urinary and sexual outcomes after radical prostatectomy in localized and locally advanced prostate cancer.

PURPOSE: The extent of variation in urinary and sexual functional outcomes after radical prostatectomy (RPE) between prostate cancer (PC) operating sites remains unknown. Therefore, this analysis aims to compare casemix-adjusted functional outcomes (EPIC-26 scores incontinence, irritative/obstructive function and sexual function) between operating sites 12 months after RPE. MATERIALS AND METHODS: Analysis of a cohort of 7065 men treated with RPE at 88 operating sites (prostate cancer centers, "PCCs") between 2016 and 2019. Patients completed EPIC-26 and sociodemographic information surveys at baseline and 12 months after RPE. Survey data were linked to clinical data. EPIC-26 domain scores at 12 months after RPE were adjusted for relevant confounders (including baseline domain score, clinical and sociodemographic information) using regression analysis. Differences between sites were described using minimal important differences (MIDs) and interquartile ranges (IQR). The effects of casemix adjustment on the score results were described using Cohen's d and MIDs. RESULTS: Adjusted domain scores at 12 months varied between sites, with IQRs of 66-78 (incontinence), 89-92 (irritative/obstructive function), and 20-29 (sexual function). Changes in domain scores after casemix adjustment for sites ≥ 1 MID were noted for the incontinence domain (six sites). Cohen's d ranged between - 0.07 (incontinence) and - 0.2 (sexual function), indicating a small to medium effect of casemix adjustment. CONCLUSIONS: Variation between sites was greatest in the incontinence and sexual function domains for RPE patients. Future research will need to identify the factors contributing to this variation. TRIAL REGISTRY: The study is registered at the German Clinical Trial Registry ( https://www.drks.de/drks_web/ ) with the following ID: DRKS00010774.

German S3 Evidence-Based Guidelines on Focal Therapy in Localized Prostate Cancer: The First Evidence-Based Guidelines on Focal Therapy.

BACKGROUND: Focal therapy (FT) is an option to treat localized prostate cancer (PCa) and preserve healthy prostate tissue in order to reduce known side effects from primary whole-gland treatment. The available FT modalities are manifold. Until now, national and international PCa guidelines have been cautious to propose recommendations regarding FT treatment since data from prospective controlled trials are lacking for most FT modalities. Moreover, none of the international guidelines provides a separate section on FT. In this purpose, we provide a synopsis of the consensus-based German S3 guidelines for a possible international use. SUMMARY: The recently published update of the German S3 guidelines, an evidence- and consensus-based guideline, provides a section on FT with recommendations for diagnostic work-up, indications, modalities, and follow-up. This section consists of 12 statements and recommendations for FT in the treatment of localized PCa. KEY MESSAGE: The German S3 guidelines on PCa are the first to incorporate recommendations for FT based on evidence and expert consensus including indication criteria for FT, pretreatment, and follow-up diagnostic pathways as well as an extended overview of FT techniques and the current supportive evidence.

Oncological Long-term Outcome After Whole-gland High-intensity Focused Ultrasound for Prostate Cancer-21-yr Follow-up.

BACKGROUND: Owing to the morbidity of established radical treatment options for prostate cancer, alternative whole-gland and focal treatment strategies have emerged. High-intensity focused ultrasound (HIFU) is one of the most studied sources for tissue ablation and has been used since the 1990s. OBJECTIVE: To provide 21-yr oncological long-term follow-up data of an unselected series of patients who underwent whole-gland HIFU for nonmetastatic prostate cancer. DESIGN, SETTING, AND PARTICIPANTS: A total of 674 patients were treated between November 1997 and November 2012 in one university center. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The oncological outcome was assessed by biopsy failure-free survival (BFFS), salvage treatment-free survival (STFS), metastasis-free survival (MFS), cancer-specific survival (CSS), and overall survival (OS). Multivariable Cox proportional hazard regression analyses were performed to estimate the prognostic relevance of clinical variables. RESULTS AND LIMITATIONS: In total, 560 patients were included into the evaluation and the median follow-up was 15.1 yr, with a range up to 21.4 yr. At 15 yr, CSS rates for low-, intermediate-, and high-risk patients were 95%, 89%, and 65%, respectively; MFS, STFS-1 (salvage treatment other than HIFU), STFS-2 (salvage treatment including repeat HIFU), and BFFS rates were 91%, 85%, and 58%; 77%, 63%, and 29%; 67%, 52%, and 28%; and 82%, 73%, and 47%, respectively. Preoperative high-risk category was an independent predictor of inferior OS, CSS, MFS, STFS, and BFFS. CONCLUSIONS: Although whole-gland HIFU achieved good long-term cancer control in low- and intermediate-risk patients, high-risk patients should not be treated routinely by HIFU. Intermediate-risk patients achieve high CSS and MFS rates, but a relevant salvage treatment rate has to be reckoned with. Long-term data after whole-gland therapy might help derive implications for focal treatment sources and patient selection. PATIENT SUMMARY: Long-term data after whole-gland high-intensity focused ultrasound (HIFU) therapy are crucial to prove its oncological efficacy, and may help derive implications for focal treatment strategies and patient selection. In this context, whole-gland HIFU achieved good long-term cancer control up to 21 yr in low- and intermediate-risk prostate cancer (PCa) patients. Owing to considerably inferior long-term cancer control, it should not routinely be used in high-risk PCa patients.

Predictors for the utilization of social service counseling by prostate cancer patients.

PURPOSE: Social service counseling (SSC) is an important instrument to support cancer patients, for example, regarding legal support, or rehabilitation. Several countries have established on-site SSC in routine care. Previous analyses have shown that SSC utilization varies across cancer centers. This analysis investigates patient and center-level predictors that explain variations in SSC utilization between centers. METHODS: Logistic multilevel analysis was performed with data from 19,865 prostate cancer patients from 102 prostate cancer centers in Germany and Switzerland. Data was collected within an observational study between July 2016 and June 2020 using survey (online and paper) and tumor documentation. RESULTS: The intraclass correlation coefficient for the null model implies that 51% of variance in SSC utilization is attributable to the center a patient is treated in. Patients aged 80 years and older, with higher education, private insurance, without comorbidities, localized intermediate risk, and undergoing androgen deprivation therapy before study inclusion were less likely to utilize SSC. Undergoing primary radiotherapy, active surveillance, or watchful waiting as compared to prostatectomy was associated with a lower likelihood of SSC utilization. Significant negative predictors at the center level were university hospital, center's location in Switzerland, and a short period of certification. CONCLUSION: The results show that patient and center characteristics contribute to explaining the variance in SSC utilization in prostate cancer centers to a large extent. The findings may indicate different organizational processes in the countries included and barriers in the sectoral structure of the healthcare system. In-depth analyses of processes within cancer centers may provide further insights into the reasons for variance in SSC utilization.

High-intensity focused ultrasound (HIFU) hemiablation of the prostate: Late follow-up MRI findings in non-recurrent patients.

OBJECTIVES: Focal therapy with high-intensity focused ultrasound (HIFU) is an emerging option for the treatment of prostate cancer and often followed up by MRI. Image assessment of treatment failure, however, requires proper knowledge about typical procedure-related changes in prostate MRI, which is sparse, in particular for unilateral HIFU treatment and late follow up (beyond 6 months). The goal of this study was therefore to compile the type and frequency of such MRI findings in selected patients without recurrent cancer 12 months after prostate hemiablation. METHODS: Data from a prospective multicenter trial on HIFU hemiablation were reviewed retrospectively. Trial patients have had a late follow-up by MRI (at around 12 months) and either MRI/transrectal ultrasound (TRUS) fusion or standard TRUS-guided biopsy. This work deliberately included patients with non-recurrent cancer in the treated prostate lobe in per-protocol biopsy leaving 30 men with initial International Society of Urological Pathology (ISUP) Grade Group of 1 or 2. Six categories of potential HIFU-related MRI features were assessed by an expert committee and then evaluated by two readers in consensus: 1. shrinkage of the treated lobe, 2. residual prostate tissue, 3. fluid-filled cavity, 4. fibrosis, 5. hematoma residuals (in the prostate or seminal vesicles) and 6. contrast enhancement of the ablated area. RESULTS: Shrinkage of the ablated lobe was seen in 93% of the cases with an average percent volume change of -37% (range: -70% to +108%). In the contralateral lobe, the volume remained practically the same (-2% on average, p = 0.804). In the ablated lobe, the frequency of fibrosis was 97%. Residual prostate tissue was seen in 93% of the cases. The frequency for fluid-filled cavities was 97%, with the wide majority (90%) contiguous with the urethra. Hematoma residuals in the prostate and in seminal vesicles were found in 47% and 10% of the patients, respectively. Contrast enhancement was both rim-like (50%) as well as diffuse (33%) within the ablated area. CONCLUSION: In our case series of HIFU hemiablation in the prostate, shrinkage, residual prostate tissue, fluid-filled cavities contiguous with the urethra and fibrosis were very common late MRI findings of the ablated lobe in non-recurrent patients. Rim-like contrast enhancement or diffuse one within the ablated area were less frequent.

Triggers and oncologic outcome of salvage radical prostatectomy, salvage radiotherapy and active surveillance after focal therapy of prostate cancer.

PURPOSE: Due to the tissue preserving approach of focal therapy (FT), local cancer relapse can occur. Uncertainty exists regarding triggers and outcome of salvage strategies. METHODS: Patients with biopsy-proven prostate cancer (PCa) after FT for localized PCa from 2011 to 2020 at eight tertiary referral hospitals in Germany that underwent salvage radical prostatectomy (S-RP), salvage radiotherapy (S-RT) or active surveillance (AS) were reported. Prostate specific antigen (PSA) changes, suspicious lesions on mpMRI and histopathological findings on biopsy were analyzed. A multivariable regression model was created for adverse pathological findings (APF) at S-RP specimen. Kaplan-Meier curves were generated to determine oncological outcomes. RESULTS: A total of 90 men were included. Cancer relapse after FT was detected at a median of 12 months (IQR 9-16). Of 50 men initially under AS 13 received S-RP or S-RT. In total, 44 men underwent S-RP and 13 S-RT. At cancer relapse 17 men (38.6%) in the S-RP group [S-RT n = 4 (30.8%); AS n = 3 (6%)] had ISUP > 2. APF (pT ≥ 3, ISUP ≥ 3, pN + or R1) were observed in 23 men (52.3%). A higher ISUP on biopsy was associated with APF [p = 0.006 (HR 2.32, 97.5% CI 1.35-4.59)] on univariable analysis. Progression-free survival was 80.4% after S-RP and 100% after S-RT at 3 years. Secondary therapy-free survival was 41.7% at 3 years in men undergoing AS. Metastasis-free survival was 80% at 5 years for the whole cohort. CONCLUSION: With early detection of cancer relapse after FT S-RP and S-RT provide sufficient oncologic control at short to intermediate follow-up. After AS, a high secondary-therapy rate was observed.

To defer or not to defer? A German longitudinal multicentric assessment of clinical practice in urology during the COVID-19 pandemic.

INTRODUCTION: After the outbreak of COVID-19 unprecedented changes in the healthcare systems worldwide were necessary resulting in a reduction of urological capacities with postponements of consultations and surgeries. MATERIAL AND METHODS: An email was sent to 66 urological hospitals with focus on robotic surgery (RS) including a link to a questionnaire (e.g. bed/staff capacity, surgical caseload, protection measures during RS) that covered three time points: a representative baseline week prior to COVID-19, the week of March 16th-22nd and April 20th-26th 2020. The results were evaluated using descriptive analyses. RESULTS: 27 out of 66 questionnaires were analyzed (response rate: 41%). We found a decrease of 11% in hospital beds and 25% in OR capacity with equal reductions for endourological, open and robotic procedures. Primary surgical treatment of urolithiasis and benign prostate syndrome (BPS) but also of testicular and penile cancer dropped by at least 50% while the decrease of surgeries for prostate, renal and urothelial cancer (TUR-B and cystectomies) ranged from 15 to 37%. The use of personal protection equipment (PPE), screening of staff and patients and protection during RS was unevenly distributed in the different centers-however, the number of COVID-19 patients and urologists did not reach double digits. CONCLUSION: The German urological landscape has changed since the outbreak of COVID-19 with a significant shift of high priority surgeries but also continuation of elective surgical treatments. While screening and staff protection is employed heterogeneously, the number of infected German urologists stays low.

Oncological long-term outcome of whole gland HIFU and open radical prostatectomy: a comparative analysis.

PURPOSE: To compare the oncological long-term efficacy of whole gland high-intensity focused ultrasound (HIFU) therapy and radical prostatectomy (RP) in patients with clinically localized prostate cancer. METHODS: 418 patients after open RP (1997-2004) were compared with 469 patients after whole gland HIFU (1997-2009) without preselection. Oncological follow-up focused on biochemical relapse, salvage treatment, life status and cause-specific mortality. The univariate log rank test was used to compare both treatment options regarding overall survival (OS), cancer-specific survival (CSS), biochemical failure-free survival (BFS) and salvage treatment-free survival (STS). To adjust the treatment effect for further prognostic baseline variables, a multivariable Cox proportional hazards regression model was calculated for each end point. RESULTS: Median follow-up was 13.3 years in the RP group and 6.5 years in the HIFU group. OS/CSS/BFS/STS rates at 10 years were 91/98/80/80% after RP and 76/94/70/71% after HIFU. HIFU therapy (reference RP) was a significant and independent predictor for an inferior OS, CSS and STS. In subgroup analysis, HIFU provided significantly reduced CSS for intermediate- (p = 0.010) and high-risk patients (p = 0.048); whereas no difference was observed in the low-risk group, intermediate-risk HIFU patients showed a significantly inferior STS (p = 0.040). CONCLUSIONS: While whole gland HIFU offers a comparable long-term efficacy for low-risk patients, sufficient cancer control for high-risk patients is more than doubtful. For the subgroup of intermediate-risk patients, CSS rates seem to be comparable up to 10 years suggesting that HIFU may be an alternative for older patients, although a higher risk of salvage treatment should be expected.

Prospective Multicenter Phase II Study on Focal Therapy (Hemiablation) of the Prostate with High Intensity Focused Ultrasound.

PURPOSE: We evaluated focal therapy with high intensity focused ultrasound hemiablation in a prospective trial. MATERIALS AND METHODS: We performed a prospective, multicenter, single arm study in patients with unilateral low/intermediate risk prostate cancer who were treated from April 2013 through March 2016 in Germany in AUO (Arbeitsgemeinschaft Urologische Onkologie) Study Protocol AP 68/11. Unilateral prostate cancer was assessed by transrectal ultrasound guided biopsy and multiparametric magnetic resonance imaging. Hemiablation was done using the Ablatherm® or the Focal One® device. The oncologic outcome was assessed by the salvage treatment rate, multiparametric magnetic resonance imaging and rebiopsy at 12 months. Functional outcome, quality of life, anxiety and depression were measured by validated questionnaires at baseline and every 3 months. RESULTS: Of the 54 recruited patients 51 completed 12-month or greater visits. Mean ± SD followup was 17.4 ± 4.5 months. Mean prostate specific antigen decreased from 6.2 ± 2.0 to 2.9 ± 1.9 ng/ml at 12 months (p <0.001). Biopsy at 12 months was positive for any prostate cancer and for clinically significant prostate cancer in 13 (26.5%) and 4 (8.2%) of the 49 patients, respectively. Posttreatment multiparametric magnetic resonance imaging had limited 25% sensitivity for clinically significant prostate cancer. Ten patients (19.6%) underwent salvage treatment. Potency was maintained in 21 of the 30 men who were potent preoperatively. There was no increase in incontinence. Quality of life, anxiety and depression did not change postoperatively. The study was limited by a short followup and the lack of a control arm. CONCLUSIONS: Focal therapy hemiablation is safe with little alteration of functional outcome. The oncologic outcome is acceptable on short-term followup. Followup multiparametric magnetic resonance imaging performed poorly and should not replace repeat biopsy. Focal therapy has no impact on posttreatment anxiety and depression.

Salvage high-intensity focused ultrasound (HIFU) for locally recurrent prostate cancer after failed radiation therapy: Multi-institutional analysis of 418 patients.

OBJECTIVE: To report the oncological outcome of salvage high-intensity focused ultrasound (S-HIFU) for locally recurrent prostate cancer after external beam radiotherapy (EBRT) from a multicentre database. PATIENTS AND METHODS: This retrospective study comprises patients from nine centres with local recurrent disease after EBRT treated with S-HIFU from 1995 to 2009. The biochemical failure-free survival (bFFS) rate was based on the 'Phoenix' definition (PSA nadir + 2 ng/mL). Secondary endpoints included progression to metastasis and cancer-specific death. Kaplan-Meier analysis was performed examining overall (OS), cancer-specific (CSS) and metastasis-free survival (MFS). Adverse events and quality of life status are reported. RESULTS: In all, 418 patients with a mean (SD) follow-up of 3.5 (2.5) years were included. The mean (SD) age was 68.6 (5.8) years and the PSA level before S-HIFU was 6.8 (7.8) ng/mL. The median PSA nadir after S-HIFU was 0.19 ng/mL. The OS, CSS and MFS rates at 7 years were 72%, 82% and 81%, respectively. At 5 years the bFFS rate was 58%, 51% and 36% for pre-EBRT low-, intermediate- and high-risk patients, respectively. The 5-year bFFS rate was 67%, 42% and 22% for pre-S-HIFU PSA level ≤4, 4-10 and ≥10 ng/mL, respectively. Complication rates decreased after the introduction of specific post-RT parameters: incontinence (grade II or III) from 32% to 19% (P = 0.002); bladder outlet obstruction or stenosis from 30% to 15% (P = 0.003); recto-urethral fistula decreased from 9% to 0.6% (P < 0.001). Study limitations include being a retrospective analysis from a registry with no control group. CONCLUSION: S-HIFU for locally recurrent prostate cancer after failed EBRT is associated with 7-year CSS and MFS rates of >80% at a price of significant morbidity. S-HIFU should be initiated early following EBRT failure.

Optimised photodynamic diagnosis for transurethral resection of the bladder (TURB) in German clinical practice: results of the noninterventional study OPTIC III.

PURPOSE: White light cystoscopy (WLC) is the standard procedure for visualising non-muscle invasive bladder cancer (NMIBC). However, WLC can fail to detect all cancerous lesions, and outcomes with transurethral resection of the bladder differ between institutions, controlled trials, and possibly between trials and routine application. This noninterventional study assessed the benefit of hexaminolevulinate blue light cystoscopy (HALC; Hexvix®, Ipsen Pharma GmbH, Germany) plus WLC versus WLC alone in routine use. METHODS: From May 2013 to April 2014, 403 patients with suspected NMIBC were screened from 30 German centres to perform an unprecedented detailed assessment of the additional detection of cancer lesions with HALC versus WLC alone. RESULTS: Among the histological results for 929 biopsy samples, 94.3 % were obtained from suspected cancerous lesions under either WLC or HALC: 59.5 % were carcinoma tissue and 40.5 % were non-cancerous tissue. Of all cancer lesions, 62.2 % were staged as Ta, 20.1 % as T1, 9.3 % as T2, 7.3 % as carcinoma in situ (CIS), and 1.2 % were unknown. Additional cancer lesions (+6.8 %) and CIS lesions (+25 %, p < 0.0001) were detected by HALC plus WLC versus WLC alone. In 10.0 % of patients, ≥1 additional positive lesion was detected with HALC, and 2.2 % of NMIBC patients would have been missed with WLC alone. No adverse events were observed. CONCLUSIONS: The results of this study demonstrate that HALC significantly improves the detection of NMIBC versus WLC alone in routine clinical practice in Germany. While this benefit is statistically significant across all types of NMIBC, it seems most relevant in CIS.

Correlation of pretreatment clinical parameters and PSA nadir after high-intensity focused ultrasound (HIFU) for localised prostate cancer.

OBJECTIVE: To determine which pretreatment clinical parameters were predictive of a low prostate-specific antigen (PSA) nadir following high-intensity focused ultrasound (HIFU) treatment. PATIENTS AND METHODS: Retrospective study of patients with clinically localised prostate cancer undergoing HIFU at a single centre between December 1997 and September 2009. Whole-gland treatment was applied. Patients also included if they had previously undergone transurethral resection of the prostate (TURP). TURP was also conducted simultaneously to HIFU. Biochemical failure based on Phoenix definition (PSA nadir + 2). Univariate and multivariate analysis of pretreatment clinical parameters conducted to assess those factors predictive of a PSA nadir ≤0.2 and >0.2 ng/ml. RESULTS: Mean (SD) follow-up was 6.2 (2.8) years; median (range) was 6.3 (1.1-12.2) years. Kaplan-Meier estimate of biochemical disease-free survival rate at 8 years was 83 and 48 % for patients achieving a PSA nadir of ≤0.2 and >0.2 ng/ml, respectively. Prostate volume and incidental finding of cancer were significant predictors of low PSA nadir (≤0.2 ng/ml). CONCLUSIONS: Prostate volume and incidental finding of cancer could be predictors for oncologic success of HIFU based on post-treatment PSA nadir.

Immune humanization of immunodeficient mice using diagnostic bone marrow aspirates from carcinoma patients.

Tumor xenografts in immunodeficient mice, while routinely used in cancer research, preclude studying interactions of immune and cancer cells or, if humanized by allogeneic immune cells, are of limited use for tumor-immunological questions. Here, we explore a novel way to generate cancer models with an autologous humanized immune system. We demonstrate that hematopoietic stem and progenitor cells (HSPCs) from bone marrow aspirates of non-metastasized carcinoma patients, which are taken at specialized centers for diagnostic purposes, can be used to generate a human immune system in NOD-scid IL2rγ(null) (NSG) and HLA-I expressing NSG mice (NSG-HLA-A2/HHD) comprising both, lymphoid and myeloid cell lineages. Using NSG-HLA-A2/HHD mice, we show that responsive and self-tolerant human T cells develop and human antigen presenting cells can activate human T cells. As critical factors we identified the low potential of bone marrow HSPCs to engraft, generally low HSPC numbers in patient-derived bone marrow samples, cryopreservation and routes of cell administration. We provide here an optimized protocol that uses a minimum number of HSPCs, preselects high-quality bone marrow samples defined by the number of initially isolated leukocytes and intra-femoral or intra-venous injection. In conclusion, the use of diagnostic bone marrow aspirates from non-metastasized carcinoma patients for the immunological humanization of immunodeficient mice is feasible and opens the chance for individualized analyses of anti-tumoral T cell responses.

Fourteen-year oncological and functional outcomes of high-intensity focused ultrasound in localized prostate cancer.

UNLABELLED: WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: High-intensity focused ultrasound (HIFU) is an alternative treatment option for localized prostate cancer (PCa), which is applied for over 15 years. There are conflicting recommendations for HIFU among urological societies, which can be explained by the lack of prospective controlled studies, reports on preselected patient populations and limited follow-up providing little information on overall and cancer-specific survival. We report on a large, unselected consecutive patient series of patients who have undergone primary HIFU for clinically localized PCa with the longest follow-up in current literature. Our results improve the understanding of the oncological efficacy, morbidity and side effects of primary HIFU. OBJECTIVE: To assess the safety, functional and oncological long-term outcomes of high-intensity focused ultrasound (HIFU) as a primary treatment option for localized prostate cancer (PCa). PATIENTS AND METHODS: We conducted a retrospective single-centre study on 538 consecutive patients who underwent primary HIFU for clinically localized PCa between November 1997 and September 2009. Factors assessed were: biochemical disease-free survival (BDFS) according to Phoenix criteria (prostate-specific antigen nadir + 2 ng/mL); metastatic-free, overall and PCa-specific survival; salvage treatment; side effects; potency; and continence status. RESULTS: The mean (sd; range) follow-up was 8.1 (2.9; 2.1-14.0) years. The actuarial BDFS rates at 5 and 10 years were 81 and 61%, respectively. The 5-year BDFS rates for low-, intermediate- and high-risk patients were 88, 83 and 48%, while the 10-year BDFS rates were 71, 63 and 32%, respectively. Metastatic disease was reported in 0.4, 5.7 and 15.4% of low-, intermediate- and high-risk patients, respectively. The salvage treatment rate was 18%. Seventy-five (13.9%) patients died. PCa-specific death was registered in 18 (3.3%) patients (0, 3.8 and 11% in the low-, intermediate- and high-risk groups, respectively). Side effects included bladder outlet obstruction (28.3%), Grade I, II and III stress urinary incontinence (13.8, 2.4 and 0.7%, respectively) and recto-urethral fistula (0.7%). Preserved potency was 25.4% (in previously potent patients). CONCLUSIONS: The study demonstrates the efficacy and safety of HIFU for localized PCa. HIFU is a therapeutic option for patients of advanced age, in the low- or intermediate-risk groups, and with a life expectancy of ∼10 years.

Does heparin coating reduce encrustation of biliary plastic endoprostheses? A prospective randomized trial.

OBJECTIVE: Common bile duct stenting is widely performed for bridging benign and malignant obstructions. A major limitation is early stent occlusion making regular stent exchange necessary. Covalent binding of glycosaminoglycanes to polyethylene stents proved to reduce encrustation in urological implants. Since development of urological and biliary stent occlusion shows parallels, the aim of the study was to evaluate the efficacy of heparin coating of biliary endoprostheses in preventing encrustation. MATERIAL AND METHODS: In a prospective randomized trial, heparin-coated and native stents were endoscopically placed for almost 90 days on average. After removal, all stents were dried (50°C, 24 h), weighed and after longitudinal incision visible encrustation and discoloration recorded. Fifty-three patients (21 females/32 males, 70 ± 12 (42-87) years) were included; 13 patients (4 females/9 males, 58-79 years) completed the study according to the protocol. RESULTS: After removal, mean weight of encrustation in native stents was more than double as high as of covered stents (native: 37.9 ± 19.8 (16-93) mg; covered: 17.6 ± 6.7 (9-33) mg). In 12 of 13 cases, the encrustation weight of the native stent was higher than that of the corresponding covered stent in the same patient. Premature stent explantation became necessary in 3 of 13 native stents, because of recurrent jaundice or cholangitis but only in 1 of 13 covered stents. After longitudinal incision, the three uncovered stents showed excessive encrustation whereas no significant encrustation was found in the covered prosthesis. Altogether, covered stents showed less visible accumulation of clogging material and discoloration than native stents. CONCLUSIONS: Covalent bound heparin is highly effective in preventing encrustation of biliary polyethylene endoprostheses.

Correlation of prostate-specific antigen nadir and biochemical failure after high-intensity focused ultrasound of localized prostate cancer based on the Stuttgart failure criteria - analysis from the @-Registry.

OBJECTIVE: •To determine if the prostate-specific antigen (PSA) nadir after high-intensity focused ultrasound (HIFU) can be used as a predictor of the biochemical disease-free survival rate (DFSR). PATIENTS AND METHODS: •Patient data were derived from the multicentre-based @-Registry, the largest registry to report outcomes in patients with localized prostate cancer after Ablatherm® HIFU. •PSA level was measured at 3-month intervals. Patients were stratified into four PSA nadir groups: group 1, ≤0.2 ng/mL; group 2, 0.21-0.5 ng/mL; group 3, 0.51-1 ng/mL; and group 4, >1 ng/mL. •Biochemical treatment failure was defined according to the Stuttgart definition (PSA nadir + 1.2 ng/mL) and the Phoenix definition (PSA nadir + 2 ng/mL). •Biopsy was performed at 3-6 months post-HIFU or if a PSA level was recorded that was considered clinically relevant. RESULTS: •The present study included 804 patients. Biochemical treatment success rates at 5 years according to the Stuttgart definition for the four PSA nadir sub-groups were as follows: 84, 64, 40 and 30% for groups 1-4, respectively. •The equivalent 5-year biochemical success rates using the Phoenix definition were 94, 74, 66 and 47%, respectively. •Significantly more patients had a negative biopsy in the lowest PSA nadir group than in the other sub-groups (91.6 vs 73.1%; P < 0.001). •The present study is limited by its retrospective nature and variations in clinical practice across participating centres. CONCLUSION: •This multicentre analysis confirms that PSA nadir after HIFU predicts biochemical DFSR in a statistically significant manner.

Anatomical description of the periprostatic nerves in the male rhesus monkey (Macaca mulatta).

OBJECTIVES: Recent publications have revealed a variable course of the periprostatic nerves in humans. It is unclear to what extent nerves outside the dorsolateral region of the prostate are involved in the physiology of erectile function. As functional studies in humans are limited by ethical aspects investigations in animal models could provide further insight. The intention of this study was to give a detailed description of the topographical anatomy of autonomic nerves along the seminal vesicles and the prostate in male rhesus monkeys (Macaca mulatta) to investigate its suitability as an animal model for future physiological studies. METHODS: Wholemount serial sections of pelvic organ blocks of ten male rhesus monkeys were investigated. Autonomic nerves were stained with an antibody against S100. RESULTS: Autonomic nerves were dispersed along the dorsolateral to the ventrolateral aspect of the capsule of the prostate within a layer of connective tissue. There was no accumulation of vessels and nerves in the dorsolateral position of the prostate. The prostate is located dorsally to the urethra and does not encircle it. No adjacent nerves were found in the cranial two-thirds of the seminal vesicles. CONCLUSIONS: The male rhesus monkey is limited suitable as an animal model for studies on the periprostatic nerves provided the following differences to humans are considered: the special topography of the prostate, the nerve course along the seminal vesicles and the missing nerve accumulation dorsolaterally to the prostate.