Adrenal fast-track and enhanced recovery in retroperitoneoscopic surgery for primary aldosteronism improving patient outcome and efficiency.

PURPOSE: No data exist on perioperative strategies for enhancing recovery after posterior retroperitoneoscopic adrenalectomy (PRA). Our objective was to determine whether a multimodality adrenal fast-track and enhanced recovery (AFTER) protocol for PRA can reduce recovery time, improve patient satisfaction and maintain safety. METHODS: Thirty primary aldosteronism patients were included. Fifteen patients were treated with 'standard-of-care' PRA and compared with 15 in the AFTER protocol. The AFTER protocol contains: a preoperative information video, postoperative oral analgesics, early postoperative mobilisation and enteral feeding, and blood pressure monitoring at home. The primary outcome was recovery time. Secondary outcomes were length of hospital stay, postoperative pain and analgesics requirements, patient satisfaction, perioperative complications and quality of life (QoL). RESULTS: Recovery time was much shorter in both groups than anticipated and was not significantly different (median 28 days). Postoperative length of hospital stay was significantly reduced in AFTER patients (mean 32 vs 42 h, CI 95%, p = 0.004). No significant differences were seen in pain, but less analgesics were used in the AFTER group. Satisfaction improved amongst AFTER patients for time of admission and postoperative visit to the outpatient clinic. There were no significant differences in complication rates or QoL. CONCLUSION: Despite no difference in recovery time between the two groups, probably due to small sample size, the AFTER protocol led to shorter hospital stays and less analgesic use after surgery, whilst maintaining and even enhancing patient satisfaction for several aspects of perioperative care. Complication rates and QoL are comparable to standard-of-care.

Phase I study to assess safety, biodistribution and radiation dosimetry for 89Zr-girentuximab in patients with renal cell carcinoma.

PURPOSE: In this phase I study, we evaluated the safety, biodistribution and dosimetry of [89Zr]Zr-DFO-girentuximab (89Zr-girentuximab) PET/CT imaging in patients with suspicion of clear cell renal cell carcinoma (ccRCC). METHODS: Ten eligible patients received an intravenous administration of 37 MBq (± 10%) of 89Zr-girentuximab at mass doses of 5 mg or 10 mg. Safety was evaluated according to the NCI CTCAE (version 4.03). Biodistribution and normal organ dosimetry was performed based on PET/CT images acquired at 0.5, 4, 24, 72 and 168 h post-administration. Additionally, tumour dosimetry was performed in patients with confirmed ccRCC and visible tumour uptake on PET/CT imaging. RESULTS: 89Zr-girentuximab was administered in ten patients as per protocol. No treatment-related adverse events ≥ grade 3 were reported. 89Zr-girentuximab imaging allowed successful differentiation between ccRCC and non-ccRCC lesions in all patients, as confirmed with histological data. Dosimetry analysis using OLINDA/EXM 2.1 showed that the organs receiving the highest doses (mean ± SD) were the liver (1.86 ± 0.40 mGy/MBq), the kidneys (1.50 ± 0.22 mGy/MBq) and the heart wall (1.45 ± 0.19 mGy/MBq), with a mean whole body effective dose of 0.57 ± 0.08 mSv/MBq. Tumour dosimetry was performed in the 6 patients with histologically confirmed ccRCC resulting in a median tumour-absorbed dose of 4.03 mGy/MBq (range 1.90-11.6 mGy/MBq). CONCLUSIONS: This study demonstrates that 89Zr-girentuximab is safe and well tolerated for the administered activities and mass doses and allows quantitative assessment of 89Zr-girentuximab PET/CT imaging in patients with suspicion of ccRCC. TRIAL REGISTRATION: NCT03556046-14th of June, 2018.

Follow-up imaging after cryoablation of clear cell renal cell carcinoma is feasible using single photon emission computed tomography with 111In-girentuximab.

PURPOSE: Detection of residual or recurrent vital renal tumor on follow-up (FU) cross-sectional imaging after ablative therapy is challenging. The specific and high expression levels of carbonic anhydrase IX (CAIX) in clear cell renal cell carcinoma (ccRCC) makes it a suitable target for imaging using radiolabeled anti-CAIX antibody girentuximab. The objective of this study was to evaluate the feasibility of targeted FU imaging 1 month after cryoablation of ccRCC using single photon emission computed tomography (SPECT) after 111In-labeled girentuximab administration. METHODS: In this prospective study 16 patients underwent 111In-girentuximab-SPECT before MR-guided renal cryoablation between February 2015 and September 2018. In case of tumor targeting 111In-girentuximab-SPECT was repeated 1 month following MR-guided cryoablation. Presence of residual or recurrent vital tumor was assessed on contrast-enhanced cross-sectional imaging during further FU. The standard FU imaging protocol consisted of MRI/CT scans at 1, 3, 6, 12, and 18 months and annually thereafter. RESULTS: A total of 10 (63%) patients showed positive tumor targeting on 111In-girentuximab-SPECT before cryoablation and 9 ( 56%) were eligible to undergo FU SPECT. Of the 9 111In-girentuximab-SPECT FU scans, 8 (89%) were considered negative. One (11%) scan showed uptake suggestive for residual vital tumor. Six months after treatment, FU CT showed contrast enhancement suggestive for residual/recurrent disease in the ablated zone at the site of the 111In-girentuximab uptake after treatment. During a mean FU of 21 months (range 1-33) no other cases with residual/recurrent disease were detected. CONCLUSION: FU imaging with 111In-girentuximab-SPECT is feasible after ccRCC cryoablation and may contribute to early detection of residual or recurrent disease.

Contrast-enhanced ultrasound with dispersion analysis for the localization of prostate cancer: correlation with radical prostatectomy specimens.

PURPOSE: To determine the value of two-dimensional (2D) contrast-enhanced ultrasound (CEUS) imaging and the additional value of contrast ultrasound dispersion imaging (CUDI) for the localization of clinically significant prostate cancer (csPCa). METHODS: In this multicentre study, subjects scheduled for a radical prostatectomy underwent 2D CEUS imaging preoperatively. CUDI maps were generated from the CEUS recordings. Both CEUS recordings and CUDI maps were scored on the likelihood of presenting csPCa (any Gleason ≥ 4 + 3 and Gleason 3 + 4 larger than 0.5 mL) by five observers and compared to radical prostatectomy histopathology. An automated three-dimensional (3D) fusion protocol was used to match imaging with histopathology. Receiver operator curve (ROC) analysis was performed per observer and imaging modality. RESULTS: 133 of 216 (62%) patients were included in the final analysis. Average area under the ROC for all five readers for CEUS, CUDI and the combination was 0.78, 0.79 and 0.78, respectively. This yields a sensitivity and specificity of 81 and 64% for CEUS, 83 and 56% for CUDI and 83 and 55% for the combination. Interobserver agreement for CEUS, CUDI and the combination showed kappa values of 0.20, 0.18 and 0.18 respectively. CONCLUSION: The sensitivity and specificity of 2D CEUS and CUDI for csPCa localization are moderate. Despite compressing CEUS in one image, CUDI showed a similar performance to 2D CEUS. With a sensitivity of 83% at cutoff point 3, it could become a useful imaging procedure, especially with 4D acquisition, improved quantification and combination with other US imaging techniques such as elastography.

MRI as a tool to assess surgical margins and pseudocapsule features directly following partial nephrectomy for small renal masses.

PURPOSE: To evaluate the feasibility of ex vivo 7T MRI to assess surgical margins (SMs) and pseudocapsule (PC) features after partial nephrectomy (PN). MATERIALS AND METHODS: In this prospective, IRB-approved study, seven patients undergoing a PN for nine tumours between November 2014 and July 2015 were included for analysis after obtaining informed consent. MRI of the specimen was acquired using a 7T small bore scanner. The imaging protocol consisted of anatomical T1-, T2- and diffusion-weighted imaging. After formalin fixation, specimens were cut for pathology work-up in the same orientation as the MR images were obtained. The entire specimen was processed into H&E slides that were digitally scanned, annotated and correlated with radiological findings for negative SMs, PC presence, PC continuity and extra-PC-extension (EPCE). Sensitivity and specificity of MRI for assessment of these endpoints were calculated. RESULTS: The sensitivity and specificity for assessment of the SM were 100% and 75%, respectively. Two false-positive outcomes were reported, both in case of EPCE and a SM ≤0.5 mm. For the presence of a PC, sensitivity and specificity were 100% and 33%, respectively. Two false-positive scans with anatomical structures mimicking the presence of a PC occurred. If a PC was present, continuity and EPCE were assessed with a sensitivity and specificity of 75% and 100% and 67% and 100%, respectively. CONCLUSION: Ex vivo 7T MRI is a feasible tool for perioperative evaluation of SMs, and if present, PC features after PN. This may facilitate maximal sparing of renal parenchyma without compromising oncological outcomes. KEY POINTS: • Ex vivo MRI may contribute to improvement of negative surgical margins during partial nephrectomy. • Due to the assessment of surgical margins within a limited time span from obtaining the partial nephrectomy specimen, surgery for more complex tumours is possible with maximum sparing of healthy renal parenchyma without compromising oncological outcomes. • The intra operative assessment of pseudocapsule continuity along the resection margin enables maximal sparing of healthy renal parenchyma without delayed diagnosis of incomplete resection.

Epigenetic markers in circulating cell-free DNA as prognostic markers for survival of castration-resistant prostate cancer patients.

BACKGROUND: Noninvasive biomarkers to guide personalized treatment for castration-resistant prostate cancer (CRPC) are needed. In this study, we analyzed hypermethylation patterns of two genes (GSTP1 and APC) in plasma cell-free DNA (cfDNA) of CRPC patients. The aim of this study was to analyze the cfDNA concentrations and levels of the epigenetic markers and to assess the value of these biomarkers for prognosis. METHODS: In this prospective study, patients were included before starting new treatment after developing CRPC. The blood samples were collected prior to start of the treatment and at three time points thereafter. cfDNA was extracted from 1.5 mL of plasma and before performing a methylation-specific PCR, bisulfate modification was carried out. RESULTS: The median levels of cfDNA, GSTP1, and APC copies in the baseline samples of CRPC patients (n = 47) were higher than in controls (n = 30). In the survival analysis, the group with baseline marker levels below median had significant less PCa-related deaths (P-values <0.02) and did not reach the median survival point. The survival distributions for the groups were statistically significant for the cfDNA concentration, GSTP1 and APC copies, as well as PSA combined with GSTP1 + APC (P-values <0.03). Furthermore, there were strong positive correlations between PSA and marker response after starting treatment (P-values <0.04). CONCLUSIONS: In conclusion, this study showed the kinetics of methylated cfDNA (GSTP1 and APC) in plasma of CRPC patients after starting treatment. Furthermore, the value of the markers before treatment is prognostic for overall survival. These results are promising for developing a test to guide treatment-decision-making for CRPC patients.

A urinary biomarker-based risk score correlates with multiparametric MRI for prostate cancer detection.

BACKGROUND: Prostate cancer (PCa) diagnostics would greatly benefit from more accurate, non-invasive techniques for the detection of clinically significant disease, leading to a reduction of over-diagnosis and over-treatment. The aim of this study was to determine the association between a novel urinary biomarker-based risk score (SelectMDx), multiparametric MRI (mpMRI) outcomes, and biopsy results for PCa detection. METHODS: This retrospective observational study used data from the validation study of the SelectMDx score, in which urine was collected after digital rectal examination from men undergoing prostate biopsies. A subset of these patients also underwent a mpMRI scan of the prostate. The indications for performing mpMRI were based on persistent clinical suspicion of PCa or local staging after PCa was found upon biopsy. All mpMRI images were centrally reviewed in 2016 by an experienced radiologist blinded for the urine test results and biopsy outcome. The PI-RADS version 2 was used. RESULTS: In total, 172 patients were included for analysis. Hundred (58%) patients had PCa detected upon prostate biopsy, of which 52 (52%) had high-grade disease correlated with a significantly higher SelectMDx score (P < 0.01). The median SelectMDx score was significantly higher in patients with a suspicious significant lesion on mpMRI compared to no suspicion of significant PCa (P < 0.01). For the prediction of mpMRI outcome, the area-under-the-curve of SelectMDx was 0.83 compared to 0.66 for PSA and 0.65 for PCA3. There was a positive association between SelectMDx score and the final PI-RADS grade. There was a statistically significant difference in SelectMDx score between PI-RADS 3 and 4 (P < 0.01) and between PI-RADS 4 and 5 (P < 0.01). CONCLUSIONS: The novel urinary biomarker-based SelectMDx score is a promising tool in PCa detection. This study showed promising results regarding the correlation between the SelectMDx score and mpMRI outcomes, outperforming PCA3. Our results suggest that this risk score could guide clinicians in identifying patients at risk for significant PCa and selecting patients for further radiological diagnostics to reduce unnecessary procedures.

Improved Intraoperative Detection of Ovarian Cancer by Folate Receptor Alpha Targeted Dual-Modality Imaging.

Complete resection of tumor lesions in advanced stage ovarian cancer patients is of utmost importance, since the extent of residual disease after surgery strongly affects survival. Intraoperative imaging may be useful to improve surgery in these patients. Farletuzumab is a humanized IgG1 antibody that specifically recognizes the folate receptor alpha (FRα). Labeled with a radiolabel and a fluorescent dye, farletuzumab may be used for the intraoperative detection of ovarian cancer lesions. The current aim is to demonstrate the feasibility of FRα-targeted dual-modality imaging using 111In-farletuzumab-IRDye800CW in an intraperitoneal ovarian cancer model. Biodistribution studies were performed 3 days after injection of 3, 10, 30, or 100 µg of 111In-farletuzumab-IRDye800CW in mice with subcutaneous IGROV-1 tumors (5 mice per group). In mice with intraperitoneal IGROV-1 tumors the nonspecific uptake of 111In-farletuzumab-IRDye800CW was determined by coinjecting an excess of unlabeled farletuzumab. MicroSPECT/CT and fluorescence imaging were performed 3 days after injection of 10 µg of 111In-farletuzumab-IRDye800CW. FRα expression in tumors was determined immunohistochemically. Optimal tumor-to-blood-ratios (3.4-3.7) were obtained at protein doses up to 30 µg. Multiple intra-abdominal tumor lesions were clearly visualized by microSPECT/CT, while uptake in normal tissues was limited. Fluorescence imaging was used to visualize and guide resection of superficial tumors. Coinjection of an excess of unlabeled farletuzumab significantly decreased tumor uptake of 111In-farletuzumab-IRDye800CW (69.4 ± 27.6 versus 18.3 ± 2.2% ID/g, p < 0.05). Immunohistochemical analyses demonstrated that the radioactive and fluorescent signal corresponded with FRα-expressing tumor lesions. FRα-targeted SPECT/fluorescence imaging using 111In-farletuzumab-IRDye800CW can be used to detect ovarian cancer in vivo and could be a valuable tool for enhanced intraoperative tumor visualization in patients with intraperitoneal metastases of ovarian cancer.

Percutaneous MR Imaging-Guided Cryoablation of Small Renal Masses in a 3-T Closed-Bore MR Imaging Environment: Initial Experience.

PURPOSE: To assess the feasibility of percutaneous magnetic resonance (MR) imaging-guided cryoablation of small renal masses (SRMs) in a 3-T environment and to evaluate intraprocedural imaging, procedural safety, and initial outcomes. MATERIALS AND METHODS: The analysis included 9 patients (4 men; median age, 72 y; range, 70-82 y) with 9 SRMs (diameter, 12-30 mm). Lesions underwent biopsy, and cryoneedles were inserted under ultrasound guidance. Verification of needle positions and ice-ball monitoring were performed by T1-weighted volumetric interpolated breath-hold examination and T2-weighted half-Fourier acquired single-shot turbo spin-echo sequences. On image analysis, needle positioning was considered appropriate if the target lesion border was visible, the needle tip was inside the target lesion, and the ice ball was expected to cover the target lesion with a 5-mm margin. If these criteria could not be assessed, imaging was considered inadequate. Technical success was defined as tumor coverage with a 5-mm margin and no residual disease on 1-mo follow-up MR imaging. RESULTS: Median total procedure time was 170 min (range, 135-193 min). Intraoperative imaging allowed adequate needle visualization in 67% of acquired scans (4 of 7 T1-weighted and 6 of 8 T2-weighted). Appropriate positioning of two or three needles used for each procedure was confirmed in all cases on T1- or T2-weighted imaging. Ice-ball formation was adequately visualized in all patients. Technical success rate was 100%. No local recurrences were detected on follow-up imaging at a median of 12 mo (range, 3-22 mo). CONCLUSIONS: Percutaneous MR-guided cryoablation of SRMs in a 3-T MR imaging environment is safe and feasible, showing adequate intraoperative imaging capabilities with promising short-term clinical outcomes.

Abiraterone in metastatic prostate cancer without previous chemotherapy.

BACKGROUND: Abiraterone acetate, an androgen biosynthesis inhibitor, improves overall survival in patients with metastatic castration-resistant prostate cancer after chemotherapy. We evaluated this agent in patients who had not received previous chemotherapy. METHODS: In this double-blind study, we randomly assigned 1088 patients to receive abiraterone acetate (1000 mg) plus prednisone (5 mg twice daily) or placebo plus prednisone. The coprimary end points were radiographic progression-free survival and overall survival. RESULTS: The study was unblinded after a planned interim analysis that was performed after 43% of the expected deaths had occurred. The median radiographic progression-free survival was 16.5 months with abiraterone-prednisone and 8.3 months with prednisone alone (hazard ratio for abiraterone-prednisone vs. prednisone alone, 0.53; 95% confidence interval [CI], 0.45 to 0.62; P<0.001). Over a median follow-up period of 22.2 months, overall survival was improved with abiraterone-prednisone (median not reached, vs. 27.2 months for prednisone alone; hazard ratio, 0.75; 95% CI, 0.61 to 0.93; P=0.01) but did not cross the efficacy boundary. Abiraterone-prednisone showed superiority over prednisone alone with respect to time to initiation of cytotoxic chemotherapy, opiate use for cancer-related pain, prostate-specific antigen progression, and decline in performance status. Grade 3 or 4 mineralocorticoid-related adverse events and abnormalities on liver-function testing were more common with abiraterone-prednisone. CONCLUSIONS: Abiraterone improved radiographic progression-free survival, showed a trend toward improved overall survival, and significantly delayed clinical decline and initiation of chemotherapy in patients with metastatic castration-resistant prostate cancer. (Funded by Janssen Research and Development, formerly Cougar Biotechnology; ClinicalTrials.gov number, NCT00887198.).

The value of magnetic resonance imaging and ultrasonography (MRI/US)-fusion biopsy platforms in prostate cancer detection: a systematic review.

Despite limitations considering the presence, staging and aggressiveness of prostate cancer, ultrasonography (US)-guided systematic biopsies (SBs) are still the 'gold standard' for the diagnosis of prostate cancer. Recently, promising results have been published for targeted prostate biopsies (TBs) using magnetic resonance imaging (MRI) and ultrasonography (MRI/US)-fusion platforms. Different platforms are USA Food and Drug Administration registered and have, mostly subjective, strengths and weaknesses. To our knowledge, no systematic review exists that objectively compares prostate cancer detection rates between the different platforms available. To assess the value of the different MRI/US-fusion platforms in prostate cancer detection, we compared platform-guided TB with SB, and other ways of MRI TB (cognitive fusion or in-bore MR fusion). We performed a systematic review of well-designed prospective randomised and non-randomised trials in the English language published between 1 January 2004 and 17 February 2015, using PubMed, Embase and Cochrane Library databases. Search terms included: 'prostate cancer', 'MR/ultrasound(US) fusion' and 'targeted biopsies'. Extraction of articles was performed by two authors (M.G. and A.A.) and were evaluated by the other authors. Randomised and non-randomised prospective clinical trials comparing TB using MRI/US-fusion platforms and SB, or other ways of TB (cognitive fusion or MR in-bore fusion) were included. In all, 11 of 1865 studies met the inclusion criteria, involving seven different fusion platforms and 2626 patients: 1119 biopsy naïve, 1433 with prior negative biopsy, 50 not mentioned (either biopsy naïve or with prior negative biopsy) and 24 on active surveillance (who were disregarded). The Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool was used to assess the quality of included articles. No clear advantage of MRI/US fusion-guided TBs was seen for cancer detection rates (CDRs) of all prostate cancers. However, MRI/US fusion-guided TBs tended to give higher CDRs for clinically significant prostate cancers in our analysis. Important limitations of the present systematic review include: the limited number of included studies, lack of a general definition of 'clinically significant' prostate cancer, the heterogeneous study population, and a reference test with low sensitivity and specificity. Today, a limited number of prospective studies have reported the CDRs of fusion platforms. Although MRI/US-fusion TB has proved its value in men with prior negative biopsies, general use of this technique in diagnosing prostate cancer should only be performed after critical consideration. Before bringing MRI/US fusion-guided TB in to general practice, there is a need for more prospective studies on prostate cancer diagnosis.

3D Navigo™ versus TRUS-guided prostate biopsy in prostate cancer detection.

INTRODUCTION: To overcome the limitations regarding transrectal ultrasound (TRUS)-guided biopsies in prostate cancer (PCa) detection, there is a focus on new imaging technologies. The Navigo™ system (UC-care, Israel) uses regular TRUS images and electrospatial monitoring to generate a 3D model of the prostate. The aim of this study was to compare cancer detection rates between the Navigo™ system and conventional TRUS, in patients without a history of PCa. METHODS: We performed a retrospective study by collecting data from all patients who underwent 12-core prostate biopsies from lateral peripheral zones between September 2013 and February 2015 at the Jeroen Bosch Hospital in 's-Hertogenbosch (Netherlands). RESULTS: A total of 325 patients met our inclusion criteria. 77.8 % of biopsy sessions were performed using the Navigo™ system. There was no statistically significant difference in PCa detection (39.9 vs 46.2 % with Navigo™ system and TRUS, respectively). Using the Navigo™ system for taking prostate biopsies proved not to be associated with the presence of PCa at biopsy, likewise for clinically significant PCa and for both subgroups. LIMITATIONS: The limitations of the study include its retrospective design, the limited number of patients in the conventional TRUS group, the statistically significant different number of biopsy sessions and the ones performed by an advanced physician in both groups. CONCLUSION: In our study, there is no added value of 3D TRUS using Navigo™ system compared to conventional 2D TRUS regarding PCa detection in biopsy-naive men and men with prior negative biopsy.

Endoscopy in patients with diarrhea during treatment with vascular endothelial growth factor receptor tyrosine kinase inhibitors: Is the cause in the mucosa?

BACKGROUND: Diarrhea is a frequently occurring adverse event during treatment with vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR TKIs) and is mostly accompanied by abdominal cramps, flatulence and pyrosis. These complaints impair quality of life and lead to dose reductions and treatment interruptions. It is hypothesized that the diarrhea might be due to ischemia in bowel mucosa or inflammation, but the exact underlying pathophysiological mechanism of the diarrhea is still unknown. We aimed at exploring the mechanism for diarrhea in these patients by thorough endoscopic and histological assessment. MATERIALS AND METHODS: Endoscopies of the upper and lower gastrointestinal (GI) tract in 10 patients with metastatic renal cell carcinoma (mRCC) who developed diarrhea during treatment with VEGFR TKIs were performed. RESULTS: Ten patients were included. The results showed endoscopically normal mucosa in the lower GI tract in seven patients without signs of ischemic colitis or inflammation. Gastroduodenoscopy revealed gastro-esophageal reflux disease, bulbitis and/or duodenitis with ulcers in eight patients. In three selected patients with bulbitis/duodenitis additional video capsule endoscopy was performed but revealed no additional intestinal abnormalities. CONCLUSION: We observed frequent mucosal abnormalities in the upper GI tract in VEGFR TKI-treated mRCC patients with diarrhea. Although these abnormalities provide insufficient explanation for the occurrence of diarrhea, we suggest to perform routine upper GI endoscopy in VEGFR TKI-treated patients with GI complaints.

Comparative analysis of prostate cancer specific biomarkers PCA3 and ERG in whole urine, urinary sediments and exosomes.

BACKGROUND: PCA3 and ERG are mRNA-based prostate cancer (PCa) specific biomarkers that can be detected in urine. However, urine is a complex substrate that can be separated in several fractions. In this study we compared the levels of PCa-specific biomarkers (PCA3 and ERG) and KLK3 as prostate-specific reference gene in three urine substrates-whole urine, urinary sediment (cell pellet) and exosomes-and evaluated the influence of performing a digital rectal examination (DRE) prior to urine sampling. METHODS: First-voided urine samples were prospectively obtained before and after DRE from 29 men undergoing prostate biopsies. The urine was separated in whole urine, cell pellet and exosomes and the biomarker levels were measured with RT-qPCR. RESULTS: PCa was identified in 52% (15/29) of men. In several samples the mRNA levels were below the analytical limit of detection (BDL). The biomarker levels were highest in whole urine and significantly higher after DRE in all substrates. In PCa patients higher levels of PCA3 and ERG were found in all urine substrates after DRE compared to non-PCa patients. CONCLUSIONS: This is the first study in which urinary PCa-specific biomarker levels were compared directly in three separate urine fractions. These results suggest that whole urine could be the urine substrate of choice for PCa-diagnostics based on analytical sensitivity, which is reflected directly in the high informative rate. Moreover, the significant positive effect of performing a DRE prior to urine sampling is confirmed. These findings could be of influence in the development of PCa-diagnostic urine tests.

Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study.

BACKGROUND: Abiraterone acetate plus prednisone significantly improved radiographic progression-free survival compared with placebo plus prednisone in men with chemotherapy-naive castration-resistant prostate cancer at the interim analyses of the COU-AA-302 trial. Here, we present the prespecified final analysis of the trial, assessing the effect of abiraterone acetate plus prednisone on overall survival, time to opiate use, and use of other subsequent therapies. METHODS: In this placebo-controlled, double-blind, randomised phase 3 study, 1088 asymptomatic or mildly symptomatic patients with chemotherapy-naive prostate cancer stratified by Eastern Cooperative Oncology performance status (0 vs 1) were randomly assigned with a permuted block allocation scheme via a web response system in a 1:1 ratio to receive either abiraterone acetate (1000 mg once daily) plus prednisone (5 mg twice daily; abiraterone acetate group) or placebo plus prednisone (placebo group). Coprimary endpoints were radiographic progression-free survival and overall survival analysed in the intention-to-treat population. The study is registered with ClinicalTrials.gov, number NCT00887198. FINDINGS: At a median follow-up of 49.2 months (IQR 47.0-51.8), 741 (96%) of the prespecified 773 death events for the final analysis had been observed: 354 (65%) of 546 patients in the abiraterone acetate group and 387 (71%) of 542 in the placebo group. 238 (44%) patients initially receiving prednisone alone subsequently received abiraterone acetate plus prednisone as crossover per protocol (93 patients) or as subsequent therapy (145 patients). Overall, 365 (67%) patients in the abiraterone acetate group and 435 (80%) in the placebo group received subsequent treatment with one or more approved agents. Median overall survival was significantly longer in the abiraterone acetate group than in the placebo group (34.7 months [95% CI 32.7-36.8] vs 30.3 months [28.7-33.3]; hazard ratio 0.81 [95% CI 0.70-0.93]; p=0.0033). The most common grade 3-4 adverse events of special interest were cardiac disorders (41 [8%] of 542 patients in the abiraterone acetate group vs 20 [4%] of 540 patients in the placebo group), increased alanine aminotransferase (32 [6%] vs four [<1%]), and hypertension (25 [5%] vs 17 [3%]). INTERPRETATION: In this randomised phase 3 trial with a median follow-up of more than 4 years, treatment with abiraterone acetate prolonged overall survival compared with prednisone alone by a margin that was both clinically and statistically significant. These results further support the favourable safety profile of abiraterone acetate in patients with chemotherapy-naive metastatic castration-resistant prostate cancer. FUNDING: Janssen Research & Development.

Radionuclide and Fluorescence Imaging of Clear Cell Renal Cell Carcinoma Using Dual Labeled Anti-Carbonic Anhydrase IX Antibody G250.

PURPOSE: Tumor targeted optical imaging using antibodies labeled with near infrared fluorophores is a sensitive imaging modality that might be used during surgery to assure complete removal of malignant tissue. We evaluated the feasibility of dual modality imaging and image guided surgery with the dual labeled anti-carbonic anhydrase IX antibody preparation (111)In-DTPA-G250-IRDye800CW in mice with intraperitoneal clear cell renal cell carcinoma. MATERIALS AND METHODS: BALB/c nu/nu mice with intraperitoneal SK-RC-52 lesions received 10 µg DTPA-G250-IRDye800CW labeled with 15 MBq (111)In or 10 µg of the dual labeled irrelevant control antibody NUH-82 (20 mice each). To evaluate when tumors could be detected, 4 mice per group were imaged weekly during 5 weeks with single photon emission computerized tomography/computerized tomography and the fluorescence imaging followed by ex vivo biodistribution studies. RESULTS: As early as 1 week after tumor cell inoculation single photon emission computerized tomography and fluorescence images showed clear delineation of intraperitoneal clear cell renal cell carcinoma with good concordance between single photon emission computerized tomography/computerized tomography and fluorescence images. The high and specific accumulation of the dual labeled antibody conjugate in tumors was confirmed in the biodistribution studies. Maximum tumor uptake was observed 1 week after inoculation (mean ± SD 58.5% ± 18.7% vs 5.6% ± 2.3% injected dose per gm for DTPA-G250-IRDye800CW vs NUH-82, respectively). High tumor uptake was also observed at other time points. CONCLUSIONS: This study demonstrates the feasibility of dual modality imaging with dual labeled antibody (111)In-DTPA-G250-IRDye800CW in a clear cell renal cell carcinoma model. Results indicate that preoperative and intraoperative detection of carbonic anhydrase IX expressing tumors, positive resection margins and metastasis might be feasible with this approach.

Efficacy and Safety of Abiraterone Acetate in Elderly (75 Years or Older) Chemotherapy Naïve Patients with Metastatic Castration Resistant Prostate Cancer.

PURPOSE: Metastatic castration resistant prostate cancer primarily affects elderly men. In this post hoc analysis we investigated the safety and efficacy of abiraterone acetate in elderly (age 75 years or greater) and younger (less than 75 years) patient subgroups at the prespecified interim analysis (55% of total overall survival events) for the COU-AA-302 (Abiraterone Acetate in Asymptomatic or Mildly Symptomatic Patients with Metastatic Castration-Resistant Prostate Cancer) trial. MATERIALS AND METHODS: Patients were stratified and randomized 1:1 to abiraterone acetate 1,000 mg plus prednisone/prednisolone 5 mg twice daily (abiraterone-prednisone) vs placebo plus prednisone/prednisolone 5 mg twice daily (prednisone alone). Co-primary end points were radiographic progression-free and overall survival. Median time to event and HR were estimated using the Kaplan-Meier method and a Cox model, respectively. RESULTS: A total of 350 elderly patients treated with abiraterone-prednisone had significant improvements in overall and radiographic progression-free survival vs those with prednisone alone (HR 0.71, 95% CI 0.53-0.96 vs HR 0.63, 95% CI 0.48-0.83), similar to 738 younger patients (HR 0.81, 95% CI 0.63-1.03 vs HR 0.49, 95% CI 0.40-0.59). All secondary end points favored the abiraterone-prednisone arm for both age subgroups. Specific adverse events with abiraterone-prednisone were similar between the age subgroups. Elderly patients in both treatment arms had higher rates of fluid retention and cardiac disorders than younger patients, although rates of dose reduction or treatment interruptions due to adverse events were low in both age subgroups. CONCLUSIONS: Abiraterone acetate demonstrated clinical benefit and was well tolerated in elderly and younger men with chemotherapy naïve, metastatic castration resistant prostate cancer. Thus, findings support it as a treatment option for elderly patients who may not tolerate other therapies with greater toxicity.

Enzalutamide in European and North American men participating in the AFFIRM trial.

OBJECTIVE: To explore any differences in efficacy and safety outcomes between European (EU) (n = 684) and North American (NA) (n = 395) patients in the AFFIRM trial (NCT00974311). PATIENTS AND METHODS: Phase III, double-blind, placebo-controlled, multinational AFFIRM trial in men with metastatic castration-resistant prostate cancer (mCRPC) after docetaxel. Participants were randomly assigned in a 2:1 ratio to receive oral enzalutamide 160 mg/day or placebo. The primary end point was overall survival (OS) in a post hoc analysis. RESULTS: Enzalutamide significantly improved OS compared with placebo in both EU and NA patients. The median OS in EU patients was longer than NA patients in both treatment groups. However, the relative treatment effect, expressed as hazard ratio and 95% confidence interval, was similar in both regions: 0.64 (0.50, 0.82) for EU and 0.63 (0.47, 0.83) for NA. Significant improvements in other end points further confirmed the benefit of enzalutamide over placebo in patients from both regions. The tolerability profile of enzalutamide was comparable between EU and NA patients, with fatigue and nausea the most common adverse events. Four EU patients (4/461 enzalutamide-treated, 0.87%) and one NA patient (1/263 enzalutamide-treated, 0.38%) had seizures. The difference in median OS was related in part to the timing of development of mCRPC and baseline demographics on study entry. CONCLUSION: This post hoc exploratory analysis of the AFFIRM trial showed a consistent OS benefit for enzalutamide in men with mCRPC who had previously progressed on docetaxel in both NA- and EU-treated patients, although the median OS was higher in EU relative to NA patients. Efficacy benefits were consistent across end points, with a comparable safety profile in both regions.

Optimizing lutetium 177-anti-carbonic anhydrase IX radioimmunotherapy in an intraperitoneal clear cell renal cell carcinoma xenograft model.

A new approach in the treatment of clear cell renal carcinoma (ccRCC) is radioimmunotherapy (RIT) using anti-carbonic anhydrase IX (CAIX) antibody G250. To investigate the potential of RIT with lutetium 177 (177Lu)-labeled G250, we conducted a protein dose escalation study and subsequently an RIT study in mice with intraperitoneally growing ccRCC lesions. Mice with intraperitoneal xenografts were injected with 1, 3, 10, 30, or 100 µg of G250 labeled with 10 MBq indium 111 (111In) to determine the optimal protein dose. The optimal protein dose determined with imaging and biodistribution studies was used in a subsequent RIT experiment in three groups of 10 mice with intraperitoneal SK-RC-52 tumors. One group received 13 MBq 177Lu-DOTA-G250, a control group received 13 MBq nonspecific 177Lu-MOPC21, and the second control group was not treated and received 20 MBq 111In-DOTA-G250. The optimal G250 protein dose to target ccRCC in this model was 10 µg G250. Treatment with 13 MBq 177Lu-DOTA-G250 was well tolerated and resulted in significantly prolonged median survival (139 days) compared to controls (49-53 days, p  =  .015), indicating that RIT has potential in this metastatic ccRCC model.

KLK3, PCA3, and TMPRSS2-ERG expression in the peripheral blood mononuclear cell fraction from castration-resistant prostate cancer patients and response to docetaxel treatment.

BACKGROUND: To monitor systemic disease activity, the potential of circulating tumor cells (CTCs) bears great promise. As surrogate for CTCs we measured KLK3, PCA3, and TMPRSS2-ERG messenger RNA (mRNA) in the peripheral blood mononuclear cell (PBMC) fraction from a castration-resistant prostate cancer (CRPC) patient cohort and three control groups. Moreover, biomarker response to docetaxel treatment was evaluated in the patient group. METHODS: Blood samples from 20 CRPC patients were analyzed at four different time points (prior to docetaxel treatment, at 9 weeks, 27 weeks, and 2 months after treatment). Blood was drawn once from three control groups (10 age-matched men, 10 men under 35 years of age, 12 women). All samples were analyzed for KLK3, PCA3, and TMPRSS2-ERG mRNA by using a quantitative nucleic acid amplification assay with gene-specific primers in the complementary DNA synthesis. RESULTS: At baseline, mRNA for KLK3 was detected in 17 (89%, 95% CI 76-100%), PCA3 in 10 (53%, 95% CI 30-75%), and TMPRSS2-ERG in seven of 19 evaluable patients (37%, 95% CI 15-59%). In contrast, the blood samples from all 32 healthy volunteers were reproducible negative for all markers. In response to docetaxel treatment, KLK3 levels decreased in 80% (95% CI 60-100%), PCA3 in 89% (95% CI 68-100%), and TMPRSS2-ERG in 86% (95% CI 60-100%) of patients. CONCLUSIONS: The feasibility of a highly sensitive modified nucleic acid amplification assay to assess KLK3, PCA3, and TMPRSS2-ERG mRNA in the PBMC fraction from CRPC patients was demonstrated. Moreover, response of these markers to systemic treatment was shown.