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This case series highlights the role of repeat salvage lymph node dissection (sLND) for nodal-recurrent prostate cancer. We provide a descriptive analysis of ten patients who underwent sLND in a total of 23 surgeries (mean 2.3 sLNDs per patient) and their long-term follow-up (median of 158 mo after radical prostatectomy). A complete prostate-specific antigen response was observed in nine/23 cases (39.1%), and an incomplete response in 14 (60.9%). Analysis by anatomical location revealed a trend towards more distant metastases on repeat surgery, with only three in-field recurrences in patients with previously positive nodes. Repeat sLND can be surgically challenging, and major intraoperative complications were observed in three/23 cases (13.0%). Repeat sLND for patients with nodal-recurrent prostate cancer seems to be a feasible treatment option, albeit only in carefully selected patients. Nevertheless, it remains a highly experimental approach with unclear oncological benefit.

Background: The first interim analysis of the KEYNOTE-564 study showed improved disease-free survival with adjuvant pembrolizumab compared with placebo after surgery in patients with clear cell renal cell carcinoma at an increased risk of recurrence. The analysis reported here, with an additional 6 months of follow-up, was designed to assess longer-term efficacy and safety of pembrolizumab versus placebo, as well as additional secondary and exploratory endpoints. Methods: In the multicentre, randomised, double-blind, placebo-controlled, phase 3 KEYNOTE-564 trial, adults aged 18 years or older with clear cell renal cell carcinoma with an increased risk of recurrence were enrolled at 213 hospitals and cancer centres in North America, South America, Europe, Asia, and Australia. Eligible participants had an Eastern Cooperative Oncology Group performance status of 0 or 1, had undergone nephrectomy 12 weeks or less before randomisation, and had not received previous systemic therapy for advanced renal cell carcinoma. Participants were randomly assigned (1:1) via central permuted block randomisation (block size of four) to receive pembrolizumab 200 mg or placebo intravenously every 3 weeks for up to 17 cycles. Randomisation was stratified by metastatic disease status (M0 vs M1), and the M0 group was further stratified by ECOG performance status and geographical region. All participants and investigators involved in study treatment administration were masked to the treatment group assignment. The primary endpoint was disease-free survival by investigator assessment in the intention-to-treat population (all participants randomly assigned to a treatment). Safety was assessed in the safety population, comprising all participants who received at least one dose of pembrolizumab or placebo. As the primary endpoint was met at the first interim analysis, updated data are reported without p values. This study is ongoing, but no longer recruiting, and is registered with ClinicalTrials.gov, NCT03142334. Findings: Between June 30, 2017, and Sept 20, 2019, 994 participants were assigned to receive pembrolizumab (n=496) or placebo (n=498). Median follow-up, defined as the time from randomisation to data cutoff (June 14, 2021), was 30·1 months (IQR 25·7–36·7). Disease-free survival was better with pembrolizumab compared with placebo (HR 0·63 [95% CI 0·50–0·80]). Median disease-free survival was not reached in either group. The most common all-cause grade 3–4 adverse events were hypertension (in 14 [3%] of 496 participants) and increased alanine aminotransferase (in 11 [2%]) in the pembrolizumab group, and hypertension (in 13 [3%] of 498 participants) in the placebo group. Serious adverse events attributed to study treatment occurred in 59 (12%) participants in the pembrolizumab group and one (

BACKGROUND VPM1002BC is a genetically modified Mycobacterium bovis bacillus Calmette-Guérin (BCG) strain with potentially improved immunogenicity and attenuation. OBJECTIVE To report on the efficacy, safety, tolerability and quality of life of intravesical VPM1002BC for the treatment of non-muscle-invasive bladder cancer (NMIBC) recurrence after conventional BCG therapy. DESIGN, SETTING, AND PARTICIPANTS We designed a phase 1/2 single-arm trial (NCT02371447). Patients with recurrent NMIBC after BCG induction ± BCG maintenance therapy and intermediate to high risk for cancer progression were eligible. INTERVENTION Patients were scheduled for standard treatment of six weekly instillations with VPM1002BC followed by maintenance for 1 yr. Treatment was stopped in cases of recurrence. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The primary endpoint was defined as the recurrence-free rate (RFR) in the bladder 60 wk after trial registration. The sample size was calculated based on the assumption that ≥30% of the patients would be without recurrence at 60 wk after registration. RESULTS AND LIMITATIONS After exclusion of two ineligible patients, 40 patients remained in the full analysis set. All treated tumours were of high grade and 27 patients (67.5%) presented with carcinoma in situ. The recurrence-free rate in the bladder at 60 wk after trial registration was 49.3% (95% confidence interval [CI] 32.1-64.4%) and remained at 47.4% (95% CI 30.4-62.6%] at 2 yr and 43.7% (95% CI 26.9-59.4%) at 3 yr after trial registration. At the same time, progression to muscle-invasive disease had occurred in three patients and metastatic disease in four patients. Treatment-related grade 1, 2, and 3 adverse events (AEs) were observed in 14.3%, 54.8%, and 4.8% of the patients, respectively. No grade ≥4 AEs occurred. Two of the 42 patients did not tolerate five or more instillations during induction. Limitations include the single-arm trial design and the low number of patients for subgroup analysis. CONCLUSIONS At 1 yr after treatment start, almost half of the patients remained recurrence-free after therapy with VPM100BC. The primary endpoint of the study was met and the therapy is safe and well tolerated. PATIENT SUMMARY We conducted a trial of VPM100BC, a genetically modified bacillus Calmette-Guérin (BCG) strain for treatment of bladder cancer not invading the bladder muscle. At 1 year after the start of treatment, almost half of the patients with a recurrence after previous conventional BCG were free from non-muscle-invasive bladder cancer (NMIBC). The results are encouraging and VPM1002BC merits further evaluation in randomised studies for patients with NMIBC.

Objective Prostate cancer is the most common cancer in German men and associated with various physical and psychosocial problems. This study investigated the association between mental distress and the subjective need for psychosocial support comparing subgroups of patients with different treatments and disease stages. Method We performed an observational, cross-sectional study including patients with four medical conditions: Active Surveillance, radical prostatectomy, biochemical relapse, metastasized disease. Mental distress (NCCN Distress-Thermometer), symptoms of depression and anxiety (PHQ-9, GAD-7), psychosocial needs and coping resources (self-designed questionnaire) were assessed. Results N = 130 patients were included. 33.3% showed distress, 16.5% symptoms of moderate depression and 13% symptoms of moderate anxiety. We found no significant differences between the four groups. An association was present between distress and wish for psychosocial support ( χ2 = 4.3; p Conclusions Prostate cancer patients showed low levels of mental distress, depression and anxiety with no difference in terms of disease stage and treatment modality. Therefore, careful psychosocial screening of all patients is essential to identify those in need for support. Distressed patients express a need for psychosocial support more often. Interpersonal relationships, most often wives and children, represent important coping resources.

Background Ramucirumab-an IgG1 vascular endothelial growth factor receptor 2 antagonistplus docetaxel was previously reported to improve progression-free survival in platinum-refractory, advanced urothelial carcinoma. Here, we report the secondary endpoint of overall survival results for the RANGE trial.Methods We did a randomised, double-blind, phase 3 trial in patients with advanced or metastatic urothelial carcinoma who progressed during or after platinum-based chemotherapy. Patients were enrolled from 124 investigative sites (hospitals, clinics, and academic centres) in 23 countries. Previous treatment with one immune checkpoint inhibitor was permitted. Patients were randomly assigned (1:1) using an interactive web response system to receive intravenous ramucirumab 10 mg/kg or placebo 10 mg/kg volume equivalent followed by intravenous docetaxel 75 mg/m 2 (60 mg/m 2 in Korea, Taiwan, and Japan) on day 1 of a 21-day cycle. Treatment continued until disease progression, unacceptable toxicity, or other discontinuation criteria were met. Randomisation was stratified by geographical region, Eastern Cooperative Oncology Group performance status at baseline, and visceral metastasis. Progression-free survival (the primary endpoint) and overall survival (a key secondary endpoint) were assessed in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT02426125; patient enrolment is complete and the last patient on treatment is being followed up for safety issues.Findings Between July 20, 2015, and April 4, 2017, 530 patients were randomly allocated to ramucirumab plus docetaxel (n=263) or placebo plus docetaxel (n=267) and comprised the intention-to-treat population. At database lock (March 21, 2018) for the final overall survival analysis, median follow-up was 7.4 months (IQR 3.5-13.9). In our sensitivity analysis of investigator-assessed progression-free survival at the overall survival database lock, median progression-free survival remained significantly improved with ramucirumab compared with placebo (4.1 months [95% CI 3.3-4.8] vs 2.8 months [2.6-2.9]; HR 0.696 [95% CI 0.573-0.845]; p=0.0002). Median overall survival was 9.4 months (95% CI 7.9-11.4) in the ramucirumab group versus 7.9 months (7.0-9.3) in the placebo group (stratified HR 0.887 [95% CI 0.724-1.086]; p=0.25). Grade 3 or worse treatment-related treatment-emergent adverse events in 5% or more of patients and with an incidence more than 2% higher with ramucirumab than with placebo were febrile neutropenia (24 [9%] of 258 patients in the ramucirumab group vs 16 [6%] of 265 patients in the placebo group) and neutropenia (17 [7%] of 258 vs six [2%] of 265). Serious adverse events were similar between groups (112 [43%] of 258 patients in the ramucirumab group vs 107 [40%] of 265 patients in the placebo group). Adverse events related to study treatment and leading to death occurred in eight (3%) patients in the ramucirumab group versus five (2%) patients in the placebo group.Interpretation Additional follow-up supports that ramucirumab plus docetaxel significantly improves progression-free survival, without a significant improvement in overall survival, for patients with platinum-refractory advanced urothelial carcinoma. Clinically meaningful benefit might be restricted in an unselected population. Copyright (C) 2019 Elsevier Ltd. All rights reserved.

Background Erdafitinib, a pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor, was shown to be clinically active and tolerable in patients with advanced urothelial carcinoma and prespecified FGFR alterations in the primary analysis of the BLC2001 study at median 11 months of follow-up. We aimed to assess the long-term efficacy and safety of the selected regimen of erdafitinib determined in the initial part of the study. Methods The open-label, non-comparator, phase 2, BLC2001 study was done at 126 medical centres in 14 countries across Asia, Europe, and North America. Eligible patients were aged 18 years or older with locally advanced and unresectable or metastatic urothelial carcinoma, at least one prespecified FGFR alteration, an Eastern Cooperative Oncology Group performance status of 0–2, and progressive disease after receiving at least one systemic chemotherapy or within 12 months of neoadjuvant or adjuvant chemotherapy or were ineligible for cisplatin. The selected regimen determined in the initial part of the study was continuous once daily 8 mg/day oral erdafitinib in 28-day cycles, with provision for pharmacodynamically guided uptitration to 9 mg/day (8 mg/day UpT). The primary endpoint was investigator-assessed confirmed objective response rate according to Response Evaluation Criteria In Solid Tumors version 1.1. Efficacy and safety were analysed in all treated patients who received at least one dose of erdafitinib. This is the final analysis of this study. This study is registered with ClinicalTrials.gov, NCT02365597. Findings Between May 25, 2015, and Aug 9, 2018, 2328 patients were screened, of whom 212 were enrolled and 101 were treated with the selected erdafitinib 8 mg/day UpT regimen. The data cutoff date for this analysis was Aug 9, 2019. Median efficacy follow-up was 24·0 months (IQR 22·7–26·6). The investigator-assessed objective response rate for patients treated with the selected erdafitinib regimen was 40 (40%; 95% CI 30–49) of 101 patients. The safety profile remained similar to that in the primary analysis, with no new safety signals reported with longer follow-up. Grade 3–4 treatment-emergent adverse events of any causality occurred in 72 (71%) of 101 patients. The most common grade 3–4 treatment-emergent adverse events of any cause were stomatitis (in 14 [14%] of 101 patients) and hyponatraemia (in 11 [11%]). There were no treatment-related deaths. Interpretation With longer follow-up, treatment with the selected regimen of erdafitinib showed consistent activity and a manageable safety profile in patients with locally advanced or metastatic urothelial carcinoma and prespecified FGFR alterations.

Background: Nivolumab monotherapy is approved for the treatment of advanced renal cell carcinoma (aRCC) after prior therapy on the basis of results from CheckMate 025. Objective: The NORA (NivOlumab in Renal cell cArcinoma) noninterventional study (NIS) aims to capture real-world data to complement the pivotal CheckMate 025 clinical trial. Design, setting, and participants: NORA is a prospective, multicenter NIS in Germany. Consenting patients with aRCC of any subtype who started nivolumab after previous therapy were eligible. Outcome measurements and statistical analysis: The primary objective was to estimate overall survival (OS) in the overall population and relevant subgroups. Secondary objectives included progression-free survival (PFS), the objective response rate (ORR), the duration of response (DOR), safety, and patient-reported outcomes (PROs). Baseline characteristics were summarized using descriptive statistics. OS and PFS were estimated via the Kaplan-Meier-method. Results and limitations: A total of 228 patients with aRCC were eligible. The median age was 70 yr, 71% were male, 14% had favorable, 58% had intermediate, and 15% had poor International Metastatic RCC Database Consortium risk (12% missing information). The median follow-up was 37 mo. In the overall population, median OS was 24 mo (95% confidence interval [CI] 19–28) and median PFS was 5.3 mo (95% CI 3.9–6.7). The ORR was 20% and the median DOR was 28 mo (95% CI 16–not estimable). No new safety signals emerged (46% and 15% of patients had treatment-related adverse events of all grades and grade 3–4, respectively; there was 1 treatment-related death due to liver failure). PROs did not reveal detriments during the study duration. Limitations include the lack of central pathology review and no standardization for imaging evaluation and toxicity assessment. Conclusions: Effectiveness and safety in this real-world population were in line with the pivotal clinical trial and support the use of nivolumab after prior systemic therapy in a broad aRCC population. Patient summary: Nivolumab is an antibody treatment approved for patients with advanced kidney cancer who have already received systemic therapy. Its approval was based on results from a clinical trial. Our study demonstrates its effectiveness and safety in “real-world” patients. in press

Von Hippel–Lindau disease (VHL) is a hereditary disorder associated with malignant tumors including clear cell renal cell carcinoma (ccRCC). Partial nephrectomy is complicated by multilocular tumor occurrence and a high recurrence rate. The aim of this study was to evaluate the potential of stereotactic body radiotherapy (SBRT) as an alternative treatment approach in VHL patients with multiple ccRCC. Patients with VHL and a diagnosis of ccRCC were enrolled. SBRT was conducted using five fractions of 10 Gy or eight fractions of 7.5 Gy. The primary endpoint was local control (LC). Secondary endpoints included alteration of renal function and adverse events. Seven patients with a total of eight treated lesions were enrolled. Median age was 44 years. Five patients exhibited multiple bilateral kidney cysts in addition to ccRCC. Three patients underwent at least one partial nephrectomy in the past. After a median follow-up of 43 months, 2-year LC was 100%, while 2-year CSS, 2-year PFS and 2-year OS was 100%, 85.7% and 85.7%, respectively. SBRT was very well tolerated with no acute or chronic toxicities grade ≥ 2. Mean estimated glomerular filtration rate (eGFR) at baseline was 83.7 ± 13.0 mL/min/1.73 m2, which decreased to 76.6 ± 8.0 mL/min/1.73 m2 after 1 year. Although the sample size was small, SBRT resulted in an excellent LC rate and was very well tolerated with preservation of kidney function in patients with multiple renal lesions and cysts.

Simple Summary Systematic biopsy according to the Ginsburg scheme is widely used to complement MRI-targeted biopsy for the diagnosis of prostate cancer. This is the first study to evaluate the distribution of cancerous lesions that were missed by the Ginsburg scheme. We found that significant prostate cancer lesions were missed in 3.6% of patients. The majority of the missed lesions (17/39, 43.6%) were localized within the anterior region of the prostate. Complementing the Ginsburg scheme by adding biopsy cores to this region may be considered in certain patients who were extensively pre-biopsied without a conclusive diagnosis or when targeted biopsy was not possible. Moreover, based on Ginsburg scheme sectors and newly defined blind sectors, we developed a new sector map of the prostate that can be applied to focal therapy planning and for the follow-up management of patients under active surveillance. Abstract Background: Systematic biopsy (SB) according to the Ginsburg scheme (GBS) is widely used to complement MRI-targeted biopsy (MR-TB) for optimizing the diagnosis of clinically significant prostate cancer (sPCa). Knowledge of the GBS’s blind sectors where sPCa is missed is crucial to improve biopsy strategies. Methods: We analyzed cancer detection rates in 1084 patients that underwent MR-TB and SB. Cancerous lesions that were missed or underestimated by GBS were re-localized onto a prostate map encompassing Ginsburg sectors and blind-sectors (anterior, central, basodorsal and basoventral). Logistic regression analysis (LRA) and prostatic configuration analysis were applied to identify predictors for missing sPCa with the GBS. Results: GBS missed sPCa in 39 patients (39/1084, 3.6%). In 27 cases (27/39, 69.2%), sPCa was missed within a blind sector, with 17/39 lesions localized in the anterior region (43.6%). Neither LRA nor prostatic configuration analysis identified predictors for missing sPCa with the GBS. Conclusions: This is the first study to analyze the distribution of sPCa missed by the GBS. GBS misses sPCa in few men only, with the majority localized in the anterior region. Adding blind sectors to GBS defined a new sector map of the prostate suited for reporting histopathological biopsy results.

Study aims To investigate safety and side effects of transperineal prostate biopsy without antibiotic prophylaxis. Secondary aim was to identify whether the number of cores influenced the occurrence of complications. Patients and methods A cohort of 184 patients undergoing perineal prostate biopsy without antibiotic prophylaxis from 2015 to 2017 was analyzed retrospectively. On average, 41 cores were taken via two perineal skin punctures. Demographic and clinical data were obtained from patients´ electronic medical records. Binary logistic regression was performed to identify predictors for complications with the following covariates: age, prostate specific antigen (PSA), prostate volume, Prostate Imaging Reporting and Data System score, history of prostatitis, therapeutic anticoagulation, risk factors for urinary tract infection, surgery duration, and the number of biopsy cores. Furthermore, we calculated chi-squared tests with post hoc analyses for differences in the occurrence of complications between quartiles of the above-mentioned parameters. Results The overall complication rate was 10.8% (20/185). Out of 20, 19 (95 %) complications were ≤ grade 2 according to the Clavien-Dindo classification. There were two cases of afebrile urinary tract infection, and no patient developed fever or sepsis. Acute urinary retention was reported in 10 patients (5.4 %). The total number of cores was not associated to infectious complications or acute urinary retention rates. Conclusions Transperineal prostate biopsy without antibiotic prophylaxis is a safe procedure. Neither postoperative fever nor sepsis occurred. An increased number of cores through two skin punctures was not associated with more complications.

The purpose of this analysis was primarily to analyze biochemical-recurrence free survival (BRFS) after positron emission tomography (PET)-guided salvage radiotherapy (sRT) in a large cohort, and to further compare BRFS after PSMA vs. choline PET/ computer tomography (CT)-based sRT. This retrospective analysis is based on 421 patients referred for PSMA or choline PET/CT after radical prostatectomy due to biochemically recurrent or persistent disease. BRFS (PSA: 0.2 ng/mL) was defined as the study endpoint. Cox regression analyses were performed to assess the impact of different clinical parameters on BRFS. Additionally, propensity score matching was performed to adjust patient cohorts (PSMA vs. choline PET/CT-based sRT). The median follow-up time was 30 months. BRFS at three years after sRT was 58%. In the multivariate analysis, only PSA before PET imaging and PSA before sRT were significantly associated with BRFS (p &lt, 0.05). After propensity score matching, 272 patients were further analyzed, there was no significant difference in three-year BRFS between patients with PSMA PET-based vs. choline PET-based sRT (55% vs. 63%, p = 0.197). The present analysis confirmed the overall high BRFS rates after PET-based sRT and the strong prognostic effect of PSA level prior to sRT. PSMA PET-based sRT did not have superior BRFS rates when compared with choline PET-based sRT.

Prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA PET/CT) detects prostate cancer recurrence at low PSA levels. Radiotherapy with dose escalation to the former prostate bed has been associated with improved biochemical recurrence-free survival (BRFS). Thus, we hypothesized that PSMA PET/CT-guided salvage radiotherapy leads to improved BRFS. Methods: A total of 204 consecutive patients were referred for salvage radiotherapy following radical prostatectomy. PSMA PET/CT scans were performed and patients with PSA persistence (109 patients) or evidence of distant metastases (5 patients) were excluded from this analysis. Thus, the following analysis is based on a total of 90 patients who underwent PSMA PET/CT prior to radiotherapy due to biochemical recurrence and received salvage radiotherapy. In case of PET-positive findings, antiandrogen therapy was commenced before initiation of radiotherapy. BRFS (PSA ≤ 0.2 ng/ml) was defined as the study endpoint. Results: PET-positive lesions were detected in 42/90 (47%) patients: 24/42 (27%) fossa recurrence only, 12/42 (13%) pelvic lymph nodes only and 6/42 (7%) fossa and pelvic lymph node recurrence. Median PSA before radiotherapy was 0.44 (0.11 - 6.24). Cumulatively, a total dose of 70.0 Gy (67.2 - 72 Gy) was delivered to local macroscopic tumor, 66 Gy (59.4 - 70.2 Gy) to the prostatic fossa, 60.8 Gy (54 - 66 Gy) to PET-positive lymph nodes and 50.4 Gy (45 - 50.4 Gy) to the lymphatic pathways. After a median follow-up of 23 months, BRFS was 78%. Antiandrogen therapy was ongoing in 4 patients at last follow-up. No significant difference in BRFS between PET-positive (74%) vs. PET-negative patients (82%; p>0.05) was observed at last follow-up. Two patients had late genitourinary toxicity grade 3 and no patient had gastrointestinal toxicity ≥ 3 (NCI-CTCAE v4.03). Conclusion: PSMA PET/CT-guided salvage radiotherapy is an effective and safe local treatment option. No difference in BRFS between PET-positive and PET-negative patients was observed, indicating effective targeting of PET-positive lesions. PSMA PET/CT when readily available should be offered to patients with PSA recurrence for treatment individualization.

Objective: To compare the effect of combined epidural thoracic analgesia and general anaesthesia (CEGA) in radical cystectomy (RC) with respect to the return of gastrointestinal passage, the incidence of paralytic postoperative ileus (POI) compared to general anaesthesia (GA) only. Patients and methods: We conducted a retrospective review using the electronic medical records of 236 patients who underwent RCs between July 2011 and September 2018 at the Medical Center – University of Freiburg. Results: A CEGA was administered to 202 patients, while 34 patients received only GA. The baseline characteristics of patients with and without CEGA showed no significant differences. CEGA will decrease the time required for return of gastrointestinal transit as measured by time to first defecation by about 13 hours. In the first 90 days after surgery, 82 (34.7%) patients had a POI. There was no significant difference between complications in the CEGA and GA groups. Conclusion: A CEGA accelerates the return of the gastrointestinal transit but does not reduce the incidence of postoperative ileus. Level of evidence: 2b

[18F]fluoroethylcholine (18FECH) has been shown to be a valuable PET-tracer in recurrent prostate cancer (PCa), but still has limited accuracy. RM2 is a gastrin-releasing peptide receptor (GRPr) antagonist that binds to GRPr on PCa cells. Recent studies suggest that GRPr imaging with PET/CT is a promising technique for staging and restaging of PCa. We explore the value of GRPr-PET using the 68Ga-labeled GRPr antagonist RM2 in a selected population of patients with biochemically recurrent PCa and a negative/inconclusive 18FECH-PET/CT. In this retrospective study 16 men with biochemical PCa relapse and negative (n = 14) or inconclusive (n = 2) 18FECH-PET/CT underwent whole-body 68Ga-RM2-PET/CT. Mean time from 18FECH-PET/CT to 68Ga-RM2-PET/CT was 6.1 ± 6.8 months. Primary therapies in these patients were radical prostatectomy (n = 13; 81.3%) or radiotherapy (n = 3; 18.7%). 14/16 patients (87.5%) had already undergone salvage therapies because of biochemical relapse prior to 68Ga-RM2-PET/CT imaging. Mean ± SD PSA at 68Ga-RM2-PET/CT was 19.4 ± 53.5 ng/ml (range 1.06–226.4 ng/ml). 68Ga-RM2-PET/CT showed at least one region with focal pathological uptake in 10/16 patients (62.5%), being suggestive of local relapse (n = 4), lymph node metastases (LNM; n = 4), bone metastases (n = 1) and lung metastasis with hilar LNM (n = 1). Seven of ten positive 68Ga-RM2 scans were positively confirmed by surgical resection and histology of the lesions (n = 2), by response to site-directed therapies (n = 2) or by further imaging (n = 3). Patients with a positive 68Ga-RM2-scan showed a significantly higher median PSA (6.8 ng/ml, IQR 10.2 ng/ml) value than those with a negative scan (1.5 ng/ml, IQR 3.1 ng/ml; p = 0.016). Gleason scores or concomitant antihormonal therapy had no apparent impact on the detection of recurrent disease. Even in this highly selected population of patients with known biochemical recurrence but negative or inconclusive 18FECH-PET/CT, a 68Ga-RM2-PET/CT was helpful to localize PCa recurrence in the majority of the cases. Thus, 68Ga-RM2-PET/CT deserves further investigation as a promising imaging modality for imaging PCa recurrence.

Background: By targeting the prostate-specific membrane antigen (PSMA) on prostate cancer (PCa) cells PSMA-PET/CT shows great potential in locating the site of biochemical recurrence even at low PSA (Prostate-specific antigen)-levels. Accurate imaging of PCa recurrent lymph node metastases (LNM) is crucial for metastases directed therapies such as salvage-lymph node dissection (salvage-LND). Objective: To evaluate the diagnostic accuracy of PSMA-PET/CT for detection of affected lymph-node regions at salvage-LND for nodal recurrence of PCa. Design, setting and participants: 30 patients with the suspicion of exclusively nodal PCa-relapse after primary therapy underwent a template pelvic and/or retroperitoneal salvage-LND after whole body 68-Ga-PSMA-PET/CT. The diagnostic accuracy of PET/CT was evaluated in comparison to the histopathology of 965 resected lymph nodes (LN) dissected from 68 main regions (pelvic left/right, retroperitoneal) and 289 subregions (common iliac, external iliac, obturator, internal iliac, presacral, aortic-bifurcation, aortal, caval). LNM and tumor deposits in LNM were measured bidimensionally in the histopathology. PSMA-expression was analyzed by immunohistochemistry in LNM. Results: LNM were present in 11.4% of the resected LN (110/965) resulting in 45 positive main regions and 85 positive subregions. PET/CT was true positive in 41 main regions and 69 subregions. Three PET-negative main regions and 16 PET-negative subregions finally contained LNM, the majority of these false negative subregions (13/16) were in neighboring regions of true-positive subregions. Sensitivity, specificity, positive predictive value, negative predictive value and accuracy were: main region-based 93.2%, 100%, 100%, 88.9% and 95.6%, subregion-based 81.2%, 99.5%, 98.6%, 92.7 and 94.1%. Median short diameters of tumor deposits in LNM resected from false-negative subregions (1.3 mm) were significantly smaller than in LNM removed from true-positive subregions (5.5 mm, p

Purpose The exact detection and delineation of the intraprostatic tumour burden is crucial for treatment planning in primary prostate cancer (PCa). We compared 68Ga-HBED-CC-PSMA PET/CT with multiparametric MRI (mpMRI) for diagnosis and tumour delineation in patients with primary PCa based on slice by slice correlation with histopathological reference material. Methodology Seven patients with histopathologically proven primary PCa underwent 68Ga-HBED-CC-PSMA PET/CT and MRI followed by radical prostatectomy. Resected prostates were scanned by ex-vivo CT in a special localizer and prepared for histopathology. Invasive PCa was delineated on a HE stained histologic tissue slide and matched to ex-vivo CT to obtain gross tumor volume (GTV-)histo. Ex-vivo CT including GTV-histo and MRI data were matched to in-vivo CT(PET). Consensus contours based on MRI (GTV-MRI), PSMA PET (GTV-PET) or the combination of both (GTV-union/-intersection) were created. In each in-vivo CT slice the prostate was separated into 4 equal segments and sensitivity and specificity for PSMA PET and mpMRI were assessed by comparison with histological reference material. Furthermore, the spatial overlap between GTV-histo and GTV-PET/-MRI and the Sorensen-Dice coefficient (DSC) were calculated. In the case of multifocal PCa (4/7 patients), SUV values (PSMA PET) and ADC-values (diffusion weighted MRI) were obtained for each lesion. Results PSMA PET and mpMRI detected PCa in all patients. GTV-histo was detected in 225 of 340 segments (66.2%). Sensitivity and specificity for GTV-PET, GTV-MRI, GTV-union and GTV-intersection were 75% and 87%, 70% and 82%, 82% and 67%, 55% and 99%, respectively. GTV-histo had on average the highest overlap with GTV-union (57±22%), which was significantly higher than overlap with GTV-MRI (p=0.016) and GTV-PET (p=0.016), respectively. The mean DSC for GTV-union, GTV-PET and GTV-MRI was 0.51 (±0.18), 0.45 (±0.17) and 0.48 (±0.19), respectively. In every patient with multifocal PCa there was one lesion which had both the highest SUV and the lowest ADC-value (mean and max). Conclusion In a slice by slice analysis with histopathology, 68Ga-HBED-CC-PSMA PET/CT and mpMRI showed high sensitivity and specificity in detection of primary PCa. A combination of both methods performed even better in terms of sensitivity (GTV-union) and specificity (GTV-intersection). A moderate to good spatial overlap with GTV-histo was observed for PSMA PET/CT and mpMRI alone which was significantly improved by GTV-union. Further studies are warranted to analyse the impact of these preliminary findings for diagnostic (multimodal guided TRUS biopsy) and therapeutic (focal therapy) strategies in primary PCa.

Accurate detection of prostate cancer lymph node metastases (LNM) through PET/CT before lymphadenectomy is crucial for successful therapy. PET/CT with choline derivatives used to be the standard tool for imaging metastases, whereas (68)Ga-PSMA (prostate-specific membrane antigen) PET/CT was introduced recently. Both PET techniques were investigated with respect to what extent the detection rate of LNM depends on the size of tumor deposits (TDs) within LNM. Methods: Documenting the switch from the use of (18)F-choline to (68)Ga-PSMA in 2014, we used 2 patient cohorts undergoing a template lymphadenectomy because of a PET/CT indicating LNM. Forty-four and 40 patients underwent PET/CT with (18)F-choline or (68)Ga-PSMA ligand, respectively. In total, 226 LNM (125 (18)F-choline, 101 (68)Ga-PSMA) originated from 73 salvage lymphadenectomies at biochemical recurrence and from 11 primary lymphadenectomies at radical prostatectomy. LNM eligible for direct correlation of PET/CT to histopathology were identified from lymphadenectomies conducted in small anatomic subregions, with 1 LNM (condition 1) or 1–2 LNM (condition 2). Longitudinal and short diameters of TD within LNM were determined by histopathology, allowing linking of the size of TD in LNM to the detection threshold of PET/CT. Diameters associated with a detection rate of 50% and 90% (d(50%), d(90%)) were calculated on the basis of logistic growth curve models fitted. Results: Gleason score, number of removed LNs, and subregions for lymphadenectomy per patient did not differ significantly between the (18)F-choline and (68)Ga-PSMA groups. The median prostate-specific antigen level at imaging and number of LNM per patient were significantly higher in the (18)F-choline group (3.4 ng/mL, n = 34) than in the (68)Ga-PSMA group (2.2 ng/mL, n = 28; both P < 0.05). Longitudinal and short diameters of TD in LNM to reach d(90%) were 11.2 and 7.4 mm, respectively, for (18)F-choline PET/CT and 6.3 and 4.9 mm, respectively, for (68)Ga-PSMA PET/CT. Corresponding diameters to reach d(50%) were 5.5 and 3.3 mm, respectively, for (18)F-choline PET/CT and 3.7 and 2.3 mm, respectively, for (68)Ga-PSMA PET/CT. Detection rates were significantly higher under (68)Ga-PSMA (P = 0.005 and 0.04 for longitudinal and short diameter). Conclusion: (68)Ga-PSMA PET/CT is superior to (18)F-choline PET/CT in the detection of LNM. Whether those results will lead to an improved patient outcome after (68)Ga-PSMA PET–guided therapy needs to be investigated by further studies.

Objective. In this study, we compared prostate cancer detection rates between MRI-TRUS fusion targeted and systematic biopsies using a robot-guided, software based transperineal approach. Methods and Patients. 52 patients received a MRIT/TRUS fusion followed by a systematic volume adapted biopsy using the same robot-guided transperineal approach. The primary outcome was the detection rate of clinically significant disease (Gleason grade ≥ 4). Secondary outcomes were detection rate of all cancers, sampling efficiency and utility, and serious adverse event rate. Patients received no antibiotic prophylaxis. Results. From 52 patients, 519 targeted biopsies from 135 lesions and 1561 random biopsies were generated (total n=2080). Overall detection rate of clinically significant PCa was 44.2% (23/52) and 50.0% (26/52) for target and random biopsy, respectively. Sampling efficiency as the median number of cores needed to detect clinically significant prostate cancer was 9 for target (IQR: 6–14.0) and 32 (IQR: 24–32) for random biopsy. The utility as the number of additionally detected clinically significant PCa cases by either strategy was 0% (0/52) for target and 3.9% (2/52) for random biopsy. Conclusions. MRI/TRUS fusion based target biopsy did not show an advantage in the overall detection rate of clinically significant prostate cancer.

Background/aim The combination of bevacizumab (BEV) plus interferon alpha-2a (IFN) constitutes an option for first-line treatment of metastatic renal cell carcinoma. Real-world data from routine clinical practice are rare and were, therefore, collected during this non-interventional study (NIS). Patients and methods A total of 359 patients received at least one dose of BEV (safety set population; SAF), 354 patients had at least one post-dose effectiveness assessment and formed the full analysis set (FAS) of the final analysis. Results Progression-free survival (10.2 months, 95% CI=8.6-12.6) and overall response rate (27.2%) outcomes match the results from the phase III trials AVOREN and CALGB 90206. Longer overall survival (28.7 months, 95% CI=24.5-38.3) probably is an effect of patient characteristics and follow-up therapies. Safety findings were comparable to the results of the Phase III trials, although comprehensive severity assessments were not provided. Conclusion Overall, efficacy and safety data from BEV plus IFN administered in routine clinical practice in an observational NIS are in line with results from the controlled phase III trials. (NCT02627144).

Prostate-specific membrane antigen (PSMA) PET/CT detects prostate cancer recurrence at low levels of prostate-specific antigen (PSA). Radiotherapy with dose escalation to the former prostate bed has been associated with improved biochemical recurrence-free survival (BRFS). Thus, we hypothesized that PSMA PET/CT-guided salvage radiotherapy leads to improved BRFS. Methods: In total, 204 consecutive patients were referred for salvage radiotherapy after radical prostatectomy. PSMA PET/CT scans were performed, and patients with PSA persistence (109 patients) or evidence of distant metastases (5 patients) were excluded from this analysis. Thus, the following analysis is based on a total of 90 patients who underwent PSMA PET/CT before radiotherapy due to biochemical recurrence and received salvage radiotherapy. In cases of PET-positive findings, antiandrogen therapy was commenced before initiation of radiotherapy. BRFS (PSA ≤ 0.2 ng/mL) was defined as the study endpoint. Results: PET-positive lesions were detected in 42 of 90 (47%) patients, 24 of 42 (27%) being fossa recurrence only, 12 of 42 (13%) pelvic lymph node only, and 6 of 42 (7%) both fossa and pelvic lymph node. The median PSA before radiotherapy was 0.44 ng/mL (range, 0.11–6.24 ng/mL). Cumulatively, a total dose of 70.0 Gy (range, 67.2–72 Gy) was delivered to local macroscopic tumor, 66 Gy (range, 59.4–70.2 Gy) to the prostatic fossa, 60.8 Gy (range, 54–66 Gy) to PET-positive lymph nodes, and 50.4 Gy (range, 45–50.4 Gy) to the lymphatic pathways. After a median follow-up of 23 mo, BRFS was 78%. Antiandrogen therapy was ongoing in 4 patients at the last follow-up. No significant difference in BRFS between PET-positive patients (74%) and PET-negative patients (82%; P > 0.05) was observed at the last follow-up. Two patients had late genitourinary toxicity, grade 3, and no patient had gastrointestinal toxicity of grade 3 or higher (National Cancer Institute common terminology criteria for adverse events, version 4.03). Conclusion: PSMA PET/CT-guided salvage radiotherapy is an effective and safe local treatment option. No difference in BRFS between PET-positive and PET-negative patients was observed, indicating effective targeting of PET-positive lesions. PSMA PET/CT when readily available should be offered to patients with PSA recurrence for treatment individualization.

Introduction Platelet-derived growth factor receptor-α (PDGFRα) is expressed in primary prostate adenocarcinoma and in associated skeletal metastases. Olaratumab is a fully human monoclonal antibody that binds PDGFRα and blocks downstream signalling. This phase II study assessed the efficacy and safety of olaratumab in combination with mitoxantrone and prednisone (M/P) versus M/P alone in patients with metastatic castration-resistant prostate cancer (mCRPC) who progressed after docetaxel. Methods Patients were randomised to receive 21-d cycles of olaratumab (15 mg/kg, Days 1 and 8) plus mitoxantrone (12 mg/m2, Day 1) and prednisone (5 mg, twice daily) or M/P alone. Progression-free survival (PFS) was the primary end-point. Secondary end-points included overall survival (OS), safety, and circulating tumour cell (CTC) counts. Results A total of 123 patients were randomised, 63 to olaratumab + M/P and 60 to M/P. Median PFS was 2.3 months for olaratumab + M/P and 2.4 months for M/P (hazard ratio [HR] = 1.29; 95% confidence interval [CI] = 0.87–1.90). Median OS was 14.2 months for olaratumab + M/P and 12.8 months for M/P (HR = 1.08; 95% CI = 0.72–1.61). Both treatment arms had similar toxicity profiles; neutropenia (24% versus 15%), anaemia (13% versus 14%) and fatigue (11% versus 9%) (olaratumab + M/P versus M/P, respectively) were the most common grade ≥3 events. High CTC count was associated with poorer OS in both arms. Patients with very high cell counts (>37 cells/7.5 ml) exhibited improved OS with olaratumab + M/P (interaction P = 0.043). Conclusions Olaratumab + M/P had an acceptable safety profile but did not improve the efficacy of M/P chemotherapy. Further study with selected patient populations and earlier in the disease course might be considered.

Intraoperative identification of lymph node (LN) metastases (LNM) detected on preoperative PSMA PET/CT may be facilitated by PSMA radioguided surgery with the use of a gamma probe. We evaluated the uptake ofSix patients with prostate cancer (PCa) with suspicion of LNM on preoperative PSMA PET/CT underwentOverall 310 LN (mean 52 ± 19.7) were removed from 74 subregions (mean 12 ± 3.7). Of the 310 LN, 35 turned out to be LNM on histopathology. Separation of the samples from all subregions resulted in 318 single specimens: 182 PCa-negative LN samples with 275 LN, 35 single LNM samples, 3 non-nodal PCa tissue samples and 98 fibrofatty tissue samples. The median SULs of nonaffected LN (0.16) and affected LN (13.2) were significantly different (p 0.0001). Based on 38 tumour-containing and 182 tumour-free specimens, ROC analysis revealed an area under the curve of 0.976 (95% CI 0.95-1.00, p 0.0001). Using a SUL cut-off value of 1.136, sensitivity, specificity, positive predictive value, negative predictive value and accuracy in discriminating affected from nonaffected LN were 92.1% (35/38), 98.9% (180/182), 94.6% (35/37), 98.4% (180/183) and 97.7% (215/220), respectively.Ex situ analysis at the level of single LN showed that

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.

PURPOSE: Intraoperative identification of lymph node (LN) metastases (LNM) detected on preoperative PSMA PET/CT may be facilitated by PSMA radioguided surgery with the use of a gamma probe. We evaluated the uptake of 111In-labelled PSMA ligand DKFZ-617 (referred to as 111In-PSMA-617) in unaffected LN and LNM at the level of single LN. METHODS: Six patients with prostate cancer (PCa) with suspicion of LNM on preoperative PSMA PET/CT underwent 111In-PSMA-617-guided lymphadenectomy (LA; four salvage LA and two primary LA). 111In-PSMA-617 (109 ± 5 MBq). was injected Intravenously 48 h prior to surgery Template LAs were performed in small subregions: common, external, obturator and internal iliac vessels, and presacral and retroperitoneal subregions (n = 4). Samples from each subregion were isolated aiming at the level of single LN. Uptake was measured ex situ using a germanium detector. Receiver operating characteristic (ROC) analysis was performed based on 111In-PSMA-617 uptake expressed as standardized uptake values normalized to lean body mass (SUL). RESULTS: Overall 310 LN (mean 52 ± 19.7) were removed from 74 subregions (mean 12 ± 3.7). Of the 310 LN, 35 turned out to be LNM on histopathology. Separation of the samples from all subregions resulted in 318 single specimens: 182 PCa-negative LN samples with 275 LN, 35 single LNM samples, 3 non-nodal PCa tissue samples and 98 fibrofatty tissue samples. The median SULs of nonaffected LN (0.16) and affected LN (13.2) were significantly different (p

[In this retrospective study 16 men with biochemical PCa relapse and negative (n = 14) or inconclusive (n = 2)Even in this highly selected population of patients with known biochemical recurrence but negative or inconclusive

Summary Background Few treatments with a distinct mechanism of action are available for patients with platinum-refractory advanced or metastatic urothelial carcinoma. We assessed the efficacy and safety of treatment with docetaxel plus either ramucirumab—a human IgG1 VEGFR-2 antagonist—or placebo in this patient population. Methods We did a randomised, double-blind, phase 3 trial in patients with advanced or metastatic urothelial carcinoma who progressed during or after platinum-based chemotherapy. Patients were enrolled from 124 sites in 23 countries. Previous treatment with one immune-checkpoint inhibitor was permitted. Patients were randomised (1:1) using an interactive web response system to receive intravenous docetaxel 75 mg/m 2 plus either intravenous ramucirumab 10 mg/kg or matching placebo on day 1 of repeating 21-day cycles, until disease progression or other discontinuation criteria were met. The primary endpoint was investigator-assessed progression-free survival, analysed by intention-to-treat in the first 437 randomised patients. This study is registered with ClinicalTrials.gov, number NCT02426125. Findings Between July, 2015, and April, 2017, 530 patients were randomly allocated either ramucirumab plus docetaxel (n=263) or placebo plus docetaxel (n=267). Progression-free survival was prolonged significantly in patients allocated ramucirumab plus docetaxel versus placebo plus docetaxel (median 4·07 months [95% CI 2·96–4·47] vs 2·76 months [2·60–2·96]; hazard ratio [HR] 0·757, 95% CI 0·607–0·943; p=0·0118). A blinded independent central analysis was consistent with these results. An objective response was achieved by 53 (24·5%, 95% CI 18·8–30·3) of 216 patients allocated ramucirumab and 31 (14·0%, 9·4–18·6) of 221 assigned placebo. The most frequently reported treatment-emergent adverse events, regardless of causality, in either treatment group (any grade) were fatigue, alopecia, diarrhoea, decreased appetite, and nausea. These events occurred predominantly at grade 1–2 severity. The frequency of grade 3 or worse adverse events was similar for patients allocated ramucirumab and placebo (156 [60%] of 258 vs 163 [62%] of 265 had an adverse event), with no unexpected toxic effects. 63 (24%) of 258 patients allocated ramucirumab and 54 (20%) of 265 assigned placebo had a serious adverse event that was judged by the investigator to be related to treatment. 38 (15%) of 258 patients allocated ramucirumab and 43 (16%) of 265 assigned placebo died on treatment or within 30 days of discontinuation, of which eight (3%) and five (2%) deaths were deemed related to treatment by the investigator. Sepsis was the most common adverse event leading to death on treatment (four [2%] vs none [0%]). One fatal event of neutropenic sepsis was reported in a patient allocated ramucirumab. Interpretation To the best of our knowledge, ramucirumab plus docetaxel is the first regimen in a phase 3 study to show superior progression-free survival over chemotherapy in patients with platinum-refractory advanced urothelial carcinoma. These data validate inhibition of VEGFR-2 signalling as a potential new therapeutic treatment option for patients with urothelial carcinoma. Funding Eli Lilly and Company.

Purpose 18F-Fluoroethylcholine (18F-FECh) is excreted via the urinary system with high activity accumulation in the urinary bladder. Furosemide and oral hydration can be administered concomitantly to reduce urinary activity to provide better detectability of retroperitoneal and pelvic lesions. Currently it is unknown if there is any effect of furosemide on 18F-FECh uptake in organs, tissues and tumour lesions and the extent to which image quality along the urinary tract may be improved by furosemide.

We evaluated the impact of salvage lymph node dissection with adjuvant radiotherapy in patients with nodal recurrence of prostate cancer. By default, nodal recurrence of prostate cancer is treated with palliative antihormonal therapy, which causes serious side effects and invariably leads to the development of hormone refractory disease.A total of 47 patients with nodal recurrence of prostate cancer based on evidence of (11)C-choline/(18)F-choline ((18)F-fluorethylcholine) positron emission tomography-computerized tomography underwent primary (2 of 52), secondary (45 of 52), tertiary (4 of 52) and quaternary (1 of 52) salvage lymph node dissection with histological confirmation. Of 52 salvage lymph node dissections 27 were followed by radiotherapy. Biochemical response was defined as a prostate specific antigen less than 0.2 ng/ml after salvage therapy. The Kaplan-Meier method, binary logistic regression and Cox regression were used to analyze survival as well as predictors of biochemical response and clinical progression.Mean prostate specific antigen at salvage lymph node dissection was 11.1 ng/ml. A mean of 23.3 lymph nodes were removed per salvage lymph node dissection. Median followup was 35.5 months. Of 52 salvage lymph node dissections 24 resulted in complete biochemical response followed by 1-year biochemical recurrence-free survival of 71.8%. Gleason 6 or less (OR 7.58, p = 0.026), Gleason 7a/b (OR 5.91, p = 0.042) and N0 status at primary therapy (OR 8.01, p = 0.011) were identified as independent predictors of biochemical response. Gleason 8-10 (HR 3.5, p = 0.039) as a preoperative variable, retroperitoneal positive lymph nodes (HR 3.76, p = 0.021) and incomplete biochemical response (HR 4.0, p = 0.031) were identified as postoperative predictors of clinical progression. Clinical progression-free survival was 25.6% and cancer specific survival was 77.7% at 5 years.Based on (11)C/(18)F-choline positron emission tomography-computerized tomography as a diagnostic tool, salvage lymph node dissection is feasible for the treatment of nodal recurrence of prostate cancer. Most patients experience biochemical recurrence after salvage lymph node dissection. However, a specific population has a lasting complete prostate specific antigen response.

In cancer, extracellular vesicles (EV) contribute to tumor progression by regulating local and systemic effects. Being released into body fluids, EV may be used in nanomedicine as a valuable source for diagnostic biomarkers. In this work, infrared and Raman spectroscopy were used for comprehensive comparative analysis of cancer versus non-cancer EV and patient screening. Two different EV fractions enriched in exosomes and microvesicles were isolated by differential centrifugation from serum and plasma of cancer and non-cancer patients and from serum and plasma of a healthy donor. The EV fractions were then subjected to drop-coating deposition and drying on calcium fluoride substrates. Reduction of alpha-helix-rich proteins and enhancement of beta-sheet-rich proteins as a cancer-specific blood EV signature was determined, and subsequently this feature was applied for a pilot study aiming to detect prostate cancer in a test cohort of patients with high-grade prostate carcinoma and benign hypoplasia.

INTRODUCTION AND OBJECTIVES: Accurate imaging of lymph node metastases (LNM) is a prerequisite for metastases directed therapies such as salvage lymph node dissection (salvage-LND) in nodal recurrent prostate cancer (PCa). Our aim was to evaluate the diagnostic accuracy of 68PSMA-PET/CT (DKFZ-11) for nodal relapse of PCa according to different topographical locations and the size of tumor deposits in lymph nodes (LN). METHODS: 25 patients with the suspicion of nodal PCa-relapse after primary therapy underwent pelvic and/or retroperitoneal salvage-LND after a whole body PET/CT with 68Ga-PSMA showing PET-positive lesions. Time from PET/CT to salvage-LND was median 2.3 months. Diagnostic accuracy of PET/CT for dissected main-regions (pelvic left/right, retroperitoneal) and subregions (common, external, internal iliac, obturatoria, presacral, aortic-bifurcation, aortal, caval, interaortocaval) was determined by comparing histopathologic results with PET/CT-findings. Size ofmetastatic infiltration inLNwasmeasuredbasedonhistopathology. RESULTS: Mean PSA at salvage-LND was 3.03 ng/ml (SD 3.2 / median 1.74 ng/ml). Overall, 833 LN were resected in 25 patients, containing 98 LNM, corresponding to a mean of 33.3 LN and 3.9 LNM per patient. In 5 patients (8 subregions) tissue containing solid non-nodal local relapse was additionally resected. LN were removed in portions out of 10 subregions per patient leading to 251 subregions available for evaluation. Median 3 LN were removed per subregion. For 2/25 patients and in 7/251 subregions, the suspected tumor involvement was verified by follow-up PET/CT showing progress of the lesions and PSA increase. 35/60 (58.3%) of the main regions and 63/251 (25%) of the subregions were PET-positive. Sensitivity, specifity, positive predictive value (PPV), negative predictive value (NPV) and accuracy based on a main-region analysis was 92.1% (35/38), 100% (22/22), 100% (35/35), 88.0% (22/25) and 95.0% (57/60). Based on a subregion-analyses sensitivity, specifity, PPV, NPV and accuracy was 80.7 % (63/78), 100% (173/173), 100% (63/63), 92.0% (173/188) and 94.0% (236/251). Median diameter (6 mm) of tumor deposits in LNM removed from true-positive subregions was significantly different to LNM resected from false-negative subregions (2 mm) (p

Objective: To evaluate the growth kinetics of renal cell carcinoma (RCC) in von Hippel-Lindau (VHL) disease in a large trial by CT/MRI scan. VHL disease is a multisystemic disorder predisposing to renal cysts and cancer. There is a general assumption that VHL-associated RCC presents slower growth rates than sporadic RCC. Patients and Methods: We describe growth kinetics of 96 renal tumours in 64 VHL patients with analysed germline mutation (54/64 treated, 10/64 active surveillance) over a mean follow-up of 54.9 months. We calculated tumour volume, growth rate, multiplication of tumour volume per year and overall, as well as tumour volume doubling time. Results: The mean growth rate of 96 tumours was 4.4 mm/year (SD 3.2, median 4.1 mm/year), mean volume doubling time was 25.7 months (SD 20.2, median 22.2 months). We saw a median 1.4-fold increase in tumour volume per year. At treatment time point, VHL kidneys comprised 39% tumour and 15.7% cyst volume fraction. We saw no correlation between tumour size and growth parameters. Conclusion: VHL-associated RCC show large variances in tumour growth behaviour. Compared to the literature, in our study the growth rates (mm/year) of RCC in VHL disease did not differ from those of sporadic RCC. Fast tumour growth increases the risk for metastases.

BACKGROUND The prostate specific membrane antigen (PSMA) represents an attractive antigen for antibody-based diagnostic and therapeutic intervention in prostate cancer, since it is highly restricted to the prostate and overexpressed in all tumor stages. The present work describes the in vitro characterization of the three anti-PSMA monoclonal antibodies (mAbs) 3/A12, 3/E7, and 3/F11 in comparison to the mAb J591. METHODS The mAbs were tested for saturation and competitive binding on C4-2 prostate cancer cells by flow cytometry. Immunohistochemical staining was conducted on frozen prostate normal and cancer tissues as well as on lymph node metastases. Similarly, potential crossreactivities were tested on a broad panel of human normal tissues. RESULTS The anti-PSMA mAbs showed a strong binding to C4-2 cells with mean half-maximal saturation concentrations of about 14 nM for 3/A12, 17 nM for 3/E7, 9 nM for 3/F11, and 16 nM for J591. Competitive binding studies revealed that our three mAbs bind to different extracellular PSMA epitopes. The mAbs showed comparable staining of epithelial cells for all tested normal and tumorous prostate tissues. Extraprostatic staining was observed on secretory cells of the salivary glands and on the brush border of the duodenal columnar epithelium. J591 additionally showed positive staining of the normal breast epithelium. CONCLUSIONS Due to their specific binding characteristics, the anti-PSMA mAbs 3/A12, 3/E7, and 3/F11 show great promise for diagnostic and therapeutic applications in prostate cancer. Prostate 70: 562–569, 2010. © 2009 Wiley-Liss, Inc.

Objective Prostate carcinoma is the most frequent tumor in men. The psychosocial distress associated with the diagnosis and the relevant treatment approaches available are summarized and critically evaluated based on the present literature. Methods A computer search for appropriate studies was done using previously defined inclusion and exclusion criteria. The studies were evaluated for methodological quality based on the criteria of the Cochrane Collaboration. Results 47 cross-sectional and longitudinal studies of psychosocial distress and 13 controlled studies with mostly psychoeducative interventions were identified for the period from 1980 to 2007. Psychosocial distress resulted from urinary incontinence, erectile dysfunction, and the related lack of role confidence as well as problems in partnership. The intervention studies reveal their efficacy especially with respect to improved coping with disease in prostate-specific problems. Some studies also show a decrease in depressive symptoms and loss of confidence, improved communication in the partnership and improved physical and emotional well-being of the partner. Discussion Because of the broad heterogeneity of the interventions and measuring instruments used, a metaanalysis could not be performed. The results show that even low-threshold, brief interventions may lead to small to moderate effects in disease-specific problems. No intervention studies have yet been performed in Germany.

Background Although cancer of the prostate is one of the most commonly diagnosed cancers in men, no curative treatment currently exists after its progression beyond resectable boundaries. Therefore, new agents for targeted treatment strategies are needed. Cross-linking of tumor antigens with T-cell associated antigens by bispecific monoclonal antibodies have been shown to increase antigen-specific cytotoxicity in T-cells. Since the prostate-specific membrane antigen (PSMA) represents an excellent tumor target, immunotherapy with bispecific diabodies could be a promising novel treatment option for prostate cancer. Methods A heterodimeric diabody specific for human PSMA and the T-cell antigen CD3 was constructed from the DNA of anti-CD3 and anti-PSMA single chain Fv fragments (scFv). It was expressed in E. coli using a vector containing a bicistronic operon for co-secretion of the hybrid scFv VHCD3-VLPSMA and VHPSMA-VLCD3. The resulting PSMAxCD3 diabody was purified from the periplasmic extract by immobilized metal affinity chromatography (IMAC). The binding properties were tested on PSMA-expressing prostate cancer cells and PSMA-negative cell lines as well as on Jurkat cells by flow cytometry. For in vitro functional analysis, a cell viability test (WST) was used. For in vivo evaluation the diabody was applied together with human peripheral blood lymphocytes (PBL) in a C4-2 xenograft-SCID mouse model. Results By Blue Native gel electrophoresis, it could be shown that the PSMAxCD3 diabody is mainly a tetramer. Specific binding both to CD3-expressing Jurkat cells and PSMA-expressing C4-2 cells was shown by flow cytometry. In vitro, the diabody proved to be a potent agent for retargeting PBL to lyze C4-2 prostate cancer cells. Treatment of SCID mice inoculated with C4-2 tumor xenografts with the diabody and PBL efficiently inhibited tumor growth. Conclusions The PSMAxCD3 diabody bears the potential for facilitating immunotherapy of prostate cancer and for the elimination of minimal residual disease.

Radical prostatectomy for prostate cancer is followed by PSA recurrence in up to 40% of patients. One third of patients with biochemical relapse progress to uncurable metastatic disease. Therefore, alternative treatment modalities are needed both in the situation of PSA recurrence and in hormone-refractory disease. Dendritic cells (DC) are the most powerful antigen-presenting cells, able to prime naïve T-cells and to break peripheral tolerance and thus induce tumor immune responses. More than 400 prostate cancer patients have been treated with DC-based immunotherapy to date, and immune responses have been reported in two-thirds of these, resulting in clinical responses in almost half of the patients treated. Most responses, however, were modest and transient. Therefore, mechanisms of treatment failure and possibilities to improve vaccination efficacy are being discussed.

Background CV9103 is a prostate-cancer vaccine containing self-adjuvanted mRNA (RNActive®) encoding the antigens PSA, PSCA, PSMA, and STEAP1. This phase I/IIa study evaluated safety and immunogenicity of CV9103 in patients with advanced castration-resistant prostate-cancer. Methods 44 Patients received up to 5 intra-dermal vaccinations. Three dose levels of total mRNA were tested in Phase I in cohorts of 3–6 patients to determine a recommended dose. In phase II, 32 additional patients were treated at the recommended dose. The primary endpoint was safety and tolerability, the secondary endpoint was induction of antigen specific immune responses monitored at baseline and at weeks 5, 9 and 17. Results The most frequent adverse events were grade 1/2 injection site erythema, injection site reactions, fatigue, pyrexia, chills and influenza-like illness. Possibly treatment related urinary retention occurred in 3 patients. The recommended dose was 1280 μg. A total of 26/33 evaluable patients treated at 1280 μg developed an immune response, directed against multiple antigens in 15 out of 33 patients. One patient showed a confirmed PSA response. In the subgroup of 36 metastatic patients, the Kaplan-Meier estimate of median overall survival was 31.4 months [95 % CI: 21.2; n.a]. Conclusions The self-adjuvanted RNActive® vaccine CV9103 was well tolerated and immunogenic. The technology is a versatile, fast and cost-effective platform allowing for creation of vaccines. The follow-up vaccine CV9104 including the additional antigens prostatic acid phosphatase (PAP) and Muc1 is currently being tested in a randomized phase IIb trial to assess the clinical benefit induced by this new vaccination approach. Trial registration EU Clinical Trials Register: EudraCT number 2008-003967-37, registered 27 Jan 2009. Electronic supplementary material The online version of this article (doi:10.1186/s40425-015-0068-y) contains supplementary material, which is available to authorized users.

// Malte Kronig 1 , Max Walter 1 , Vanessa Drendel 2 , Martin Werner 2 , Cordula A. Jilg 1 , Andreas S. Richter 3, 4 , Rolf Backofen 3 , David McGarry 1 , Marie Follo 5 , Wolfgang Schultze-Seemann 1 , Roland Schule 1 1 Medical Center, University of Freiburg, Department of Urology, 79106 Freiburg, Germany 2 Medical Center, University of Freiburg, Department of Pathology, 79106 Freiburg, Germany 3 University of Freiburg, Department of Computer Science, 79110 Freiburg, Germany 4 Max Planck Institute of Immunbiology and Epigenetics, 79108 Freiburg, Germany 5 Medical Center, University of Freiburg, Department of Medicine I, 79106 Freiburg, Germany Correspondence to: Roland Schule, e-mail: roland.schuele@uniklinik-freiburg.de Keywords: prostate cancer, RNA detection, living cells, needle biopsy, gene expression, tumor heterogeneity Received: August 06, 2014 Accepted: November 11, 2014 Published: December 01, 2014 ABSTRACT A lack of cell surface markers for the specific identification, isolation and subsequent analysis of living prostate tumor cells hampers progress in the field. Specific characterization of tumor cells and their microenvironment in a multi-parameter molecular assay could significantly improve prognostic accuracy for the heterogeneous prostate tumor tissue. Novel functionalized gold-nano particles allow fluorescence-based detection of absolute mRNA expression levels in living cells by fluorescent activated flow cytometry (FACS). We use of this technique to separate prostate tumor and benign cells in human prostate needle biopsies based on the expression levels of the tumor marker alpha-methylacyl-CoA racemase (AMACR). We combined RNA and protein detection of living cells by FACS to gate for epithelial cell adhesion molecule (EPCAM) positive tumor and benign cells, EPCAM/CD45 double negative mesenchymal cells and CD45 positive infiltrating lymphocytes. EPCAM positive epithelial cells were further sub-gated into AMACR high and low expressing cells. Two hundred cells from each population and several biopsies from the same patient were analyzed using a multiplexed gene expression profile to generate a cell type resolved profile of the specimen. This technique provides the basis for the clinical evaluation of cell type resolved gene expression profiles as pre-therapeutic prognostic markers for prostate cancer.

Subcutaneous pyelovesical bypass graft (SPBG) is a urinary diversion treatment option for ureteral obstruction. Initially its use was limited to palliative care patients. However, the indication profile has been extended to selected patients with benign conditions causing ureteral obstruction and hydronephrosis. Occlusion of SPBGs is rarely reported and mostly related to infections. We describe the clinical case of a patient with SPBG after iatrogenic ureteral stricture who was not suitable for other reconstructive treatment forms due to distinct retroperitoneal scarring after multiple previous surgeries. Several months after the SPBG insertion, the patient developed complete occlusion of the system with uric acid stone material. Sufficient endoscopic intervention was not feasible. After forced chemolitholysis, the stone mass could be completely dissolved. Since then the patient has remained symptom-free.