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16 beta-F-18-fluoro-5 alpha-dihydrotestosterone (F-18-FDHT) is a radiopharmaceutical that has been investigated as a diagnostic agent for the assessment of androgen receptor (AR) density in prostate cancer using PET. However, F-18-FDHT is rapidly metabolized in humans and excreted via the kidneys into the urine, potentially compromising the detection of tumor lesions close to the prostate. Enzalutamide is an AR signaling inhibitor currently used in different stages of prostate cancer. Enzalutamide and its primary metabolite N-desmethylenzalutamide have an AR affinity comparable to that of FDHT but are excreted mainly via the hepatic route. Radiolabeled enzalutamide could thus be a suitable candidate PET tracer for AR imaging. Here, we describe the radiolabeling of enzalutamide with F-18. Moreover, the in vitro and in vivo behavior of F-18-enzalutamide was evaluated and compared with the current standard, F-18-FDHT. Methods: F-18-enzalutamide was obtained by fluorination of the nitro precursor. In vitro cellular uptake studies with F-18-enzalutamide and F-18-FDHT were performed in LNCaP (AR-positive) and HEK293 (AR-negative) cells. Competition assays with both tracers were conducted on the LNCaP (AR-positive) cell line. In vivo PET imaging, ex vivo biodistribution, and metabolite studies with F-18-enzalutamide and F-18-FDHT were conducted on athymic nude male mice bearing an LNCaP xenograft in the shoulder. Results: F-18-enzalutamide was obtained in 1.4% +/- 0.9% radiochemical yield with an apparent molar activity of 6.2 +/- 10.3 GBq/mu mol. F-18-FDHT was obtained in 1.5% +/- 0.8% yield with a molar activity of more than 25 GBq/mu mol. Coincubation with an excess of 5 alpha-dihydrotestosterone or enzalutamide significantly reduced the cellular uptake of F-18-enzalutamide and F-18-FDHT to about 50% in AR-positive LNCaP cells but not in AR-negative HEK293 cells. PET and biodistribution studies on male mice bearing a LnCaP xenograft showed about 3 times higher tumor uptake for F-18-enzalutamide than for F-18-FDHT. Sixty minutes after tracer injection, 93% of F-18-enzalutamide in plasma was still intact, compared with only 3% of F-18-FDHT. Conclusion: Despite its lower apparent molar activity, F-18-enzalutamide shows higher tumor uptake and better metabolic stability than F-18-FDHT and thus seems to have more favorable properties for imaging of AR with PET. However, further evaluation in other oncologic animal models and patients is warranted to confirm these results.

Contains fulltext : 251789.pdf (Publisher’s version ) (Closed access) OBJECTIVE: To analyse if exposure to sunitinib in the Immediate Surgery or Surgery After Sunitinib Malate in Treating Patients With Metastatic Kidney Cancer (SURTIME) trial, which investigated opposite sequences of cytoreductive nephrectomy (CN) and systemic therapy, is associated with the overall survival (OS) benefit observed in the deferred CN arm. PATIENTS AND METHODS: A post hoc analysis of SURTIME trial data. Variables analysed included number of patients receiving sunitinib, time from randomisation to start sunitinib, overall response rate by Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1, and duration of drug exposure and dose in the intention-to-treat population of the immediate and deferred arm. Descriptive methods and 95% confidence-intervals (CI) were used. RESULTS: In the deferred arm, 97.7% (95% CI 89.3-99.6%; n = 48) received sunitinib vs 80% (95% CI 66.9-88.7%, n = 40) in the immediate arm. Following immediate CN, 19.6% progressed 4 weeks after CN and the median time to start sunitinib was 39.5 vs 4.5 days in the deferred arm. At week 16, 46.0% had progressed at metastatic sites in the immediate CN arm vs 32.7% in the deferred arm. Sunitinib dose reductions, escalations and interruptions were not statistically significantly different between arms. Among patients who received sunitinib in the immediate or deferred arm the median total sunitinib treatment duration was 172.5 vs 248 days. Reduction of target lesions was more profound in the deferred arm. CONCLUSIONS: In comparison to the deferred CN approach, immediate CN impairs administration, onset, and duration of sunitinib. Starting with systemic therapy leads to early and more profound disease control and identification of progression prior to planned CN, which may have contributed to the observed OS benefit.

Background: Impaired cognition can be a late effect after treatment in long-term testicular cancer (TC) survivors, negatively affecting their daily life. However, little data is available beyond 20 years post-treatment. We assessed cognitive impairment in very long-term TC survivors after CT or RT and compared the results with stage I TC survivors and controls. Methods: In this cross-sectional multicenter cohort study, we enrolled TC survivors (treated with orchiectomy followed by CT or RT or orchiectomy only)—with a follow-up duration ≥ 20 years—and age-matched healthy controls. Cognitive testing included the Auditory Verbal Learning Test, Letter Fluency Test, Category Fluency Test, and Trail Making Test. We used fasting blood samples to assess the presence of hypogonadism and measured cardiovascular aging parameters, including carotid pulse wave velocity (c-PWV) and advanced glycation end products (AGEs). Results: We included 184 TC survivors (66 CT patients, 53 RT patients, and 65 orchiectomy-only patients) and 70 healthy controls. The median follow-up was 26 years (range: 20–42). TC survivors had a lower combined score of the cognitive tests (mean cumulative Z-score −0.85, 95% CI −1.39 to −0.33) compared to controls (mean 0.67, 95% CI −0.21 to 1.57, p &lt, 0.01). In univariate analysis, the presence of hypogonadism (β −1.50, p &lt, 0.01), high c-PWV (β −0.35, p = 0.09), and high AGEs (β −1.27, p = 0.02) were associated with lower cognitive scores, while only AGEs (β −1.17, p = 0.03) remained a significant predictor in multivariate analysis (Model R2 0.31, p &lt, 0.01). Conclusions: Long-term TC survivors performed worse on cognitive tests compared to controls. Physicians and patients should be informed about timely cardiovascular risk management and testosterone supplementation therapy during follow-up to reduce the risk of cognitive impairment. Trial Registration: NCT02572934.

The European Organisation for Research and Treatment of Cancer SURTIME trial explored timing of sunitinib, a tyrosine kinase inhibitor (TKI), and cytoreductive nephrectomy (CN) in patients with metastatic renal cell carcinoma. Previous retrospective studies suggest increased surgeryrelated adverse events (AEs) after presurgical TKI. We report surgical safety from a randomised comparison of CN before or after sunitinib. In-hospital mortality, 30-d readmission rate, and intraoperative and 30-d postoperative AEs according to Common Terminology Criteria for Adverse Events version 4 and Clavien-Dindo (CD) were analysed. Patients were randomised 1:1 to immediate CN followed by sunitinib versus sunitinib followed by deferred CN 24 h after the last dose of sunitinib. None of the tumours in the deferred arm became unresectable, and only two patients had a sunitinib-related delay of CN of >2 wk. AEs related to surgery (all grades) in the immediate and deferred arms occurred in 52% and 53% after CN, respectively, although the number of intraoperative surgery-related AEs was higher in the immediate arm. Postoperative AEs (CD >= 3), 30-d readmission, and in-hospital mortality rates were 6.5%, 13%, and 4.3% in the immediate arm and 2.5%, 7.5%, and 2.5% in the deferred arm, respectively. There were no differences in surgery time, blood loss, and hospital stay.Patient summary: Patients with metastatic kidney cancer do not have more surgical complications irrespective of whether they are treated with systemic therapy before or after surgery. (C) 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Importance: In clinical practice, patients with primary metastatic renal cell carcinoma (mRCC) have been offered cytoreductive nephrectomy (CN) followed by targeted therapy, but the optimal sequence of surgery and systemic therapy is unknown. Objective: To examine whether a period of sunitinib therapy before CN improves outcome compared with immediate CN followed by sunitinib. Design, Setting, and Participants: This randomized clinical trial began as a phase 3 trial on July 14, 2010, and continued until March 24, 2016, with a median follow-up of 3.3 years and a clinical cutoff date for this report of May 5, 2017. Patients with mRCC of clear cell subtype, resectable primary tumor, and 3 or fewer surgical risk factors were studied. Interventions: Immediate CN followed by sunitinib therapy vs treatment with 3 cycles of sunitinib followed by CN in the absence of progression followed by sunitinib therapy. Main Outcomes and Measures: Progression-free survival was the primary end point, which needed a sample size of 458 patients. Because of poor accrual, the independent data monitoring committee endorsed reporting the intention-to-treat 28-week progression-free rate (PFR) instead. Overall survival (OS), adverse events, and postoperative progression were secondary end points. Results: The study closed after 5.7 years with 99 patients (80 men and 19 women; mean [SD] age, 60 [8.5] years). The 28-week PFR was 42% in the immediate CN arm (n = 50) and 43% in the deferred CN arm (n = 49) (P =.61). The intention-to-treat OS hazard ratio of deferred vs immediate CN was 0.57 (95% CI, 0.34-0.95; P =.03), with a median OS of 32.4 months (95% CI, 14.5-65.3 months) in the deferred CN arm and 15.0 months (95% CI, 9.3-29.5 months) in the immediate CN arm. In the deferred CN arm, 48 of 49 patients (98%; 95% CI, 89%-100%) received sunitinib vs 40 of 50 (80%; 95% CI, 67%-89%) in the immediate arm. Systemic progression before planned CN in the deferred CN arm resulted in a per-protocol recommendation against nephrectomy in 14 patients (29%; 95% CI, 18%-43%). Conclusions and Relevance: Deferred CN did not improve the 28-week PFR. With the deferred approach, more patients received sunitinib and OS results were higher. Pretreatment with sunitinib may identify patients with inherent resistance to systemic therapy before planned CN. This evidence complements recent data from randomized clinical trials to inform treatment decisions in patients with primary clear cell mRCC requiring sunitinib. Trial Registration: ClinicalTrials.gov identifier: NCT01099423., SCOPUS: cp.j, info:eu-repo/semantics/published

Background Late effects of cisplatin-based chemotherapy in testicular cancer survivors (TCS) include cardiovascular morbidity, but little data is available beyond 20 years. The objective was to assess vascular damage in very long-term TCS. Methods TCS (treated with chemotherapy or orchiectomy only) and age-matched healthy controls were invited. Study assessment included vascular stiffness with ultrasound measurement of carotid-femoral pulse wave velocity (cf-PWV). Results We included 127 TCS consisting of a chemotherapy group (70 patients) and an orchiectomy group (57 patients) along with 70 controls. Median follow-up was 28 years (range: 20–42). The cf-PWV (m/s) was higher in TCS than in controls (geometrical mean 8.05 (SD 1.23) vs. 7.60 (SD 1.21), p = 0.04). The cf-PWV was higher in the chemotherapy group than in the orchiectomy group (geometrical mean 8.39 (SD 1.22) vs. 7.61 (SD 1.21), p b 7.59 × 10−3 vs. 4.04 × 10−3; p = 0.03). Conclusion Very long-term TCS treated with cisplatin-based chemotherapy show increased vascular damage compatible with “accelerated vascular aging” and continue to be at risk for cardiovascular morbidity, thus supporting the need for intensive cardiovascular risk management. Clinical trial registration The clinical trial registration number is NCT02572934.

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BACKGROUND: Dupuytren, Peyronie, and Ledderhose diseases are related fibroproliferative disorders characterized by abnormalities in the connective tissue of the palm of the hand, the tunica albuginea of the penis, and the sole of the foot, respectively. Concomitant prevalence rates of these diseases have only been described in a few small populations. This article aims to report on a large population and to raise awareness in surgeons treating Dupuytren disease for concurring related fibroproliferative disorders.METHODS: Patients diagnosed as having Dupuytren disease were recruited from outpatient clinics in the northern part of the Netherlands from 2007 to 2016. Questionnaires concerning demographics, clinical characteristics, the coexistence of Ledderhose and/or Peyronie diseases, and other factors were filled in by the participants and by plastic surgeons.RESULTS: For 730 men with Dupuytren disease, the surgeons' reported prevalence rate of Peyronie disease was 7.8 percent and of Ledderhose disease was 16.1 percent. The participants themselves reported prevalence rates of 8.8 percent for Peyronie disease and of 22.0 percent for Ledderhose disease.CONCLUSIONS: In the Dupuytren patient cohort, the prevalence of Peyronie disease was lower than that described in the literature. The prevalence of Ledderhose disease corresponded with the rates from the literature. However, both were underreported by plastic surgeons, which calls for a rise in awareness, recognition, and referral to a urologist when the conditions are bothersome or symptomatic.

Background Although testicular cancer (TC) treatment has been associated with severe late morbidities, including second malignant neoplasms (SMNs) and ischemic heart disease (IHD), cause‐specific excess mortality has been rarely studied among patients treated in the platinum era. Methods In a large, multicenter cohort including 6042 patients with TC treated between 1976 and 2006, cause‐specific mortality was compared with general population mortality rates. Associations with treatment were assessed with proportional hazards analysis. Results With a median follow‐up of 17.6 years, 800 patients died; 40.3% of these patients died because of TC. The cumulative mortality was 9.6% (95% confidence interval [CI], 8.5%‐10.7%) 25 years after TC treatment. In comparison with general population mortality rates, patients with nonseminoma experienced 2.0 to 11.6 times elevated mortality from lung, stomach, pancreatic, rectal, and kidney cancers, soft‐tissue sarcomas, and leukemia; 1.9‐fold increased mortality (95% CI, 1.3‐2.8) from IHD; and 3.9‐fold increased mortality (95% CI, 1.5‐8.4) from pneumonia. Seminoma patients experienced 2.5 to 4.6 times increased mortality from stomach, pancreatic, bladder cancer and leukemia. Radiotherapy and chemotherapy were associated with 2.1 (95% CI, 1.8‐2.5) and 2.5 times higher SMN mortality (95% CI, 2.0‐3.1), respectively, in comparison with the general population. In a multivariable analysis, patients treated with platinum‐containing chemotherapy had a 2.5‐fold increased hazard ratio (HR; 95% CI, 1.8‐3.5) for SMN mortality in comparison with patients without platinum‐containing chemotherapy. The HR for SMN mortality increased 0.29 (95% CI, 0.19‐0.39) per 100 mg/m2 platinum dose administered (P trend, Platinum‐containing chemotherapy is associated with a dose‐dependent increase in the risk of cancer mortality among patients with testicular cancer. Patients with testicular cancer experience increased mortality from second malignancies as well as causes other than cancer, particularly ischemic heart diseases.

In de www.nvukwaliteit.nl registratie van de Nederlandse Vereniging voor Urologie (NVU) is het aantal ingevoerde cystectomieen de afgelopen jaren stabiel gebleven. Wel is er een trend naar meer robot-geassisteerde ingrepen maar deze is ruim minder dan de helft van het totaal. Er is een dalende trend naar het aantal ingevoerde orthotope urinedeviaties en een dalende trend van de 30-dagenmortaliteit.

Introduction In Europe and the United States, verteporfin (Visudyne; VP) is registered and used in treating macular degeneration. Research showed that VP decreased expression of fibrotic genes in fibroblasts collected from nodules of patients suffering from Dupuytren’s disease, plausibly by de-activating transcription in the Yes Activated Protein (YAP) pathway. Aim To analyze the effect of VP on myofibroblasts cultured from Peyronie’s disease (PD) plaques. Methods At surgery for PD we took biopsies from the plaques of 5 patients. By immunostaining, the presence of the pathologic myofibroblasts was determined. After culturing cells, VP was dispensed in starvation medium for 24 and 48 hours and messenger(m)RNA levels of COL1A1, ACTA2, COL5A1, EDA-FN, LOXL2, CCN2, SERPINH1, PLOD2, and YAP were quantified and compared with controls with real-time polymerase chain reaction. Main Outcome Measure mRNA-levels of COL1A1, ACTA2, COL5A1, EDA-FN, LOXL2, CCN2, SERPINH1, PLOD2, and YAP. Results The pathologic phenotype of cells isolated from PD plaques was confirmed with baseline immunofluorescent stainings that showed considerable levels of α-smooth muscle actin, being a marker for the presence of myofibroblasts. The mRNA ratios of all the genes related to fibrosis (COL1A1, etc.) except YAP decreased significantly after treatment with VP within 24 and 48 hours. These results suggest inhibition of fibrosis in the YAP cascade, downstream of YAP. Conclusion In our opinion, urologists must move the focus to disease before deformity, and the search for new oral or intralesional agents, well-tolerated and effective in both the acute and chronic phase of PD must continue. VP blocked the expression of genes related to fibrosis in the YAP cascade in myofibroblasts derived from PD plaque.

There is increasing interest in PET/CT with prostate-specific membrane antigen (PSMA) tracers for imaging of prostate cancer because of the higher detection rates of prostate cancer lesions than with PET/CT with choline. For Ga-68-PSMA-11 tracers, late imaging at 180 min after injection instead of imaging at 45-60 min after injection improves the detection of prostate cancer lesions. For (18)F-DCFPyL, improved detection rates have recently been reported in a small pilot study. In this study, we report the effects of PET/CT imaging at 120 min after injection of (18)F-DCFPyL in comparison to images acquired at 60 min after injection in a larger clinical cohort of 66 consecutive patients with histopathologically proven prostate cancer. Methods: Images were acquired 60 and 120 min after injection of (18)F-DCFPyL. We report the positive lesions specified for anatomic locations (prostate, seminal vesicles, local lymph nodes, distant lymph nodes, bone, and others) at both time points by visual analysis, the image quality at both time points, and a semiquantitative analysis of the tracer activity in both prostate cancer lesions as well as normal tissues at both time points. Results: Our data showed a significantly increasing uptake of (18)F-DCFPyL between 60 and 120 min after injection in 203 lesions characteristic for prostate cancer (median, 10.78 vs. 12.86, P Conclusion: (18)F-DCFPyL PET/CT images at 120 min after injection yield a higher detection rate of prostate cancer characteristic lesions than images at 60 min after injection. Further studies are needed to elucidate the best imaging time point for (18)F-DCFPyL.

INTRODUCTION/AIM: Correct staging of patients with prostate cancer is important for treatment planning and prognosis. Although bone scintigraphy with (99m)Tc-phosphonates (BS) is generally advised for staging by guidelines in high risk prostate cancer, this imaging technique is hampered by a high rate of inconclusive results and moderate accuracy. Potentially better imaging techniques for detection of bone metastases such as (18)F-sodiumfluoride PET/CT (NaF PET/CT) are therefore being evaluated. In this observational cohort study we evaluate the performance and clinical impact of both BS and NaF PET/CT in primary staging of patients with prostate cancer.METHODS: The first of two cohorts consisted of patients who received a BS while the second included patients who received a NaF PET/CT for primary staging of prostate cancer. For both cohorts the number of positive, negative and equivocal findings, calculated diagnostic performance of the imaging modality in terms of sensitivity and specificity, as well as the impact on clinical management were studied. The ranges of the diagnostic performance were calculated both assuming that equivocal findings were positive and assuming that they were negative for bone metastases. For the NaF PET/CT cohort the number of patients with signs of lymph node metastases on low dose CT were also recorded, including the impact of these findings on clinical management.RESULTS: One-hundred-and-four patients underwent NaF PET/CT, whereas 122 patients underwent BS. Sensitivities of 97-100 and 84-95% and specificities of 98-100 and 72-100% were found on a patient basis for detection of bone metastases with NaF PET/CT and BS, respectively. Equivocal findings warranted further diagnostic procedures in 2% of the patients in the NaF cohort and in 16% in the BS cohort. In addition NaF PET/CT demonstrated lymph node metastases in 50% of the included patients, of which 25% showed evidence of lymph node metastases only.CONCLUSION: Our data indicate better diagnostic performance of NaF PET/CT compared to BS for detection of bone metastases in primary staging of prostate cancer patients. Less equivocal findings are encountered with NaF PET/CT. Moreover, NaF PET/CT has additional value over BS since lymph node metastases are encountered frequently.

Background: Intermittent androgen deprivation therapy (IAD) is commonly used in prostate cancer because of the benefits of the off-treatment period (OTP). The off-treatment time for patients depends on cancer progression, often measured as a rise in prostate-specific antigen (PSA). Objective: To evaluate if certain factors can predict OTP duration following 7-mo degarelix therapy. Design, setting, and participants: This multivariable analysis included 191 prostate cancer patients with baseline PSA 4–50 ng/ml or PSA doubling time 4 ng/ml. Despite a study-defined OTP maximum of 24 mo, a 50% failure rate was not observed within certain strata. A Weibull distribution was used to estimate median time to PSA >4 ng/ml adjusted for the following variables: age; baseline (or end of induction period [EOI]) PSA; baseline testosterone; cancer stage/previous curative treatment; and Gleason score. According to the results and the utility of these factors in clinical practice, the model was reduced in a stepwise manner. Time to testosterone recovery (testosterone >0.5 and >2.2 ng/ml) was estimated in a similar manner. Results: The full five-factor model showed that baseline PSA (p < 0.0001), age (p = 0.004), prostate cancer stage/previous therapy (p = 0.023), and baseline testosterone (p = 0.039) influenced OTP. A reduced two-factor model (baseline PSA, age) showed that only baseline PSA influenced OTP (p < 0.0001), and patients with baseline PSA ≤4 ng/ml had the longest OTP. In addition, EOI PSA (p < 0.0001) and age (p = 0.050) significantly influenced OTP. The times to testosterone >0.5 and >2.2 ng/ml were longer for older patients and those with lower baseline testosterone levels. Conclusion: Patients with lower baseline and EOI PSA, and older patients can stay off therapy longer and therefore may benefit more from degarelix IAD. These factors may help in proposing an algorithm to predict the OTP and optimise visit frequency. Patient summary: We describe extended analysis results for a trial in which patients with prostate cancer received intermittent androgen deprivation treatment. Prostate-specific antigen levels at baseline and at the end of the induction period, as well as older age, predicted the duration of the off-treatment period. Testosterone recovery was slower in older patients and in patients who had lower pretreatment testosterone levels. These factors may help in deciding whether to choose continuous or intermittent treatment as a strategy. Trial registration: Clinicaltrials.gov NCT00801242 Age and prostate-specific antigen levels before and at the end of active treatment seem to predict off-treatment duration for degarelix as intermittent androgen deprivation treatment (ADT). This information could be valuable in proposing an algorithm to predict the off-treatment period, optimise visit schedules, and set the restart sate for ADT.

Een 68-jarige patient presenteerde zich met flankpijn ten gevolge van een grote renale massa. Onder verdenking van een renaalcelcarcinoom werd een nefrectomie verricht. Pathologisch onderzoek toonde een diffuus grootcellig B‑cellymfoom. Primair renale manifestatie van een lymfoom komt weinig voor. De diagnose wordt vaak gemist of pas gesteld na het verrichten van een nefrectomie. Een primair renaal lymfoom moet overwogen worden als er radiologisch sprake is van een hypovasculair, diffuus groeiend proces, waarbij de voor renaalcelcarcinoom kenmerkende calcificaties en vasculaire tumorinvasie ontbreken. Indien histologisch bewezen, kan curatieve behandeling middels chemo-immunotherapie gestart worden. In dit artikel worden de diagnostische overwegingen en kenmerken van een renaal lymfoom besproken.

Peyronie's disease (PD) is a fibroproliferative disease of the penis. Since little is known about the molecular pathogenesis of PD, we compared the biochemical make-up of PD plaques with normal tunica albuginea to clarify pathological processes in the scarred tissue. Protein and mRNA levels were measured in plaques and in unaffected pieces of the tunica albuginea. We investigated the presence of myofibroblasts, the deposition of collagens, and some key elements of Wnt and YAP1 signaling at protein level. The expression of 45 genes, all related to collagen homeostasis and extracellular matrix proteins, was quantified. In plaques, more myofibroblasts were present, and we observed an activation of Wnt signaling and YAP1 signaling. Increased levels of the collagens types I and III confirm the fibrotic nature of plaques. The mRNA ratio of collagen types III, IV, and VI to type I was increased. The expression of lysyl hydroxylase 3 was higher, whereas a decreased expression level was seen for fibronectin and cathepsin K. The biochemical composition of plaques was different from unaffected tunica albuginea: the relative and absolute abundance of various extracellular matrix proteins were changed, as well as the quality of collagen and the level of the collagen-degrading enzyme cathepsin K.

Poor translation from animal studies to human clinical trials is one of the main hurdles in the development of new drugs. Here, we used precision-cut kidney slices (PCKS) as a translational model to study renal fibrosis and to investigate whether inhibition of tyrosine kinase receptors, with the selective inhibitor nintedanib, can halt fibrosis in murine and human PCKS. We used renal tissue of murine and human origins to obtain PCKS. Control slices and slices treated with nintedanib were studied to assess viability, activation of tyrosine kinase receptors, cell proliferation, collagen type I accumulation, and gene and protein regulation. During culture, PCKS spontaneously develop a fibrotic response that resembles in vivo fibrogenesis. Nintedanib blocked culture-induced phosphorylation of platelet-derived growth factor receptor and vascular endothelial growth factor receptor. Furthermore, nintedanib inhibited cell proliferation and reduced collagen type I accumulation and expression of fibrosis-related genes in healthy murine and human PCKS. Modulation of extracellular matrix homeostasis was achieved already at 0.1 μM, whereas high concentrations (1 and 5 μM) elicited possible nonselective effects. In PCKS from human diseased renal tissue, nintedanib showed limited capacity to reverse established fibrosis. In conclusion, nintedanib attenuated the onset of fibrosis in both murine and human PCKS by inhibiting the phosphorylation of tyrosine kinase receptors; however, the reversal of established fibrosis was not achieved.

232 Background: Androgen deprivation is the mainstay in the treatment of metastatic prostate cancer. During treatment, the majority of patients will develop progressive disease despite castrate levels of testosterone; castration-resistant prostate cancer (CRPC). In vivo determination of androgen receptor status by 18F-FDHT PET/CT could be of use to predict treatment response timely and objectively. The objective of this study is to assess the value of early 18F-FDHT PET/CT to predict treatment response of enzalutamide in mCRPC. Methods: This pilot study was performed in 18 chemotherapy naïve men with mCRPC. 18F-FDHT PET/CT was performed at baseline and after 4 weeks of treatment with enzalutamide. Standard Uptake Value (SUV)max and SUVpeak of the 5 most intense and/or all bone, pleura and lymph node metastases were determined per patient. Area under the curve (AUC), sensitivity (Se) and specificity (Sp) of different characteristics of 18F-FDHT PET/CT were performed by ROC analysis. Response was determined at 12 weeks of treatment according to PCCTWG. Results: A total of 477 lesions (411 bone, 3 pleura and 63 lymph node) were found. At 12 weeks, response was seen in 16 patients, whereas 2 patients showed no response. The characteristics of 18F-FDHT PET/CT are shown in table 1. Baseline median SUVpeak of all metastatic lesions showed an AUC of 0.79 to predict response. AUC values using the 5 most intense lesions only or using the delta between baseline and 5 weeks were less accurate. Clinical trial information: NTR4086. Conclusions: Baseline 18F-FDHT PET/CT using SUVpeak of all metastatic lesions predicts treatment response in mCRPC treated with enzalutamide with an AUC of 0.79.[Table: see text]

PURPOSE: To investigate the effect of reader experience and zonal location on the occurrence of false positives (FPs) in PIRADS (V2) 3, 4, and 5 lesions on multiparametric (MP)-MRI of the prostate.MATERIALS AND METHODS: This retrospective study included 139 patients who had consecutively undergone an MP-MRI of the prostate in combination with a transrectal ultrasound MRI fusion-guided biopsy between 2014 and 2017. MRI exams were prospectively read by a group of inexperienced radiologists (cohort 1; 54 patients) and an experienced radiologist (cohort 2; 85 patients). Multivariable logistic regression analysis was performed to determine the association of experience of the radiologist and zonal location with a FP reading. FP rates were compared between readings by inexperienced and experienced radiologists according to zonal location, using Chi-square (χ2) tests.RESULTS: A total of 168 lesions in 139 patients were detected. Median patient age was 68 years (Interquartile range (IQR) 62.5-73), and median PSA was 10.9 ng/mL (IQR 7.6-15.9) for the entire patient cohort. According to multivariable logistic regression, inexperience of the radiologist was significantly (P = 0.044, odds ratio 1.927, 95% confidence interval [CI] 1.017-3.651) and independently associated with a FP reading, while zonal location was not (P = 0.202, odds ratio 1.444, 95% CI 0.820-2.539). In the transition zone (TZ), the FP rate of the inexperienced radiologists 59% (17/29) was significantly higher (χ2P = 0.033) than that of the experienced radiologist 33% (13/40).CONCLUSION: Inexperience of the radiologist is significantly and independently associated with a FP reading, while zonal location is not. Inexperienced radiologists have a significantly higher FP rate in the TZ.

Chronic kidney disease is a major health concern, and experimental models bridging the gap between animal studies and clinical research are currently lacking. Here, we evaluated precision-cut kidney slices (PCKSs) as a potential model for renal disease. PCKSs were prepared from human cortical tissue obtained from tumor nephrectomies and cultured up to 96 hours. Morphology, cell viability, and metabolic functionality (ie, uridine 5'-diphospho-glucuronosyltransferase and transporter activity) were determined to assess the integrity of PCKSs. Furthermore, inflammatory and fibrosis-related gene expressions were characterized. Finally, to validate the model, renal fibrogenesis was induced using transforming growth factor beta 1 (TGF-beta 1). Preparation of PCKSs induced an inflammatory tissue response, whereas long-term incubation (96 hours) induced fibrogenesis as shown by an increased expression of collagen type 1A1 (COL1A1) and fibronectin 1 (FN1). Importantly, PCKSs remained functional for more than 48 hours as evidenced by active glucuronidation and phenolsulfonphthalein uptake. In addition, cellular diversity appeared to be maintained, yet we observed a clear loss of nephrin messenger RNA levels suggesting that our model might not be suitable to study the role of podocytes in renal pathology. Moreover, TGF-beta 1 exposure augmented fibrosis, as illustrated by an increased expression of multiple fibrosis markers including COL1A1, FN1, and alpha-smooth muscle actin. In conclusion, PCKSs maintain their renal phenotype during culture and appear to be a promising model to investigate renal diseases, for example, renal fibrosis. Moreover, the human origin of PCKSs makes this model very suitable for translational research.

Imaging modalities using tumor-directed monoclonal antibodies may be of value to improve the pre- and intraoperative detection and resection of lymph node (LN) metastatic disease in penile squamous cell carcinoma (PSCC). We investigated the expression of prostate-specific membrane antigen (PSMA), vascular endothelial growth factor (VEGF), epidermal growth factor receptor (EGFR) and epithelial cell adhesion molecule (EpCAM) to analyze their potency for diagnostic applications. Antigen expression was determined in primary tumors and LNs with and without metastases of 22 patients with PSCC. The total immunostaining score (TIS, 0–12) was determined as the product of a proportion score (PS, 0–4) and an intensity score (IS, 0–3). EGFR and VEGF expression were high in primary tumor (median TIS 8) and LN metastases (median TIS 6 and 8, respectively). No EGFR expression was seen in LNs without metastases. However, LNs without metastases did show VEGF expression (median TIS 6). No EpCAM or PSMA expression was seen in PSCC. This study shows that VEGF and EGFR expression is moderate to high in LN metastases of PSCC. Both VEGF and EGFR warrant further clinical evaluation to determine their value as a target for pre- and intraoperative imaging modalities in the detection of LN metastases in PSCC.

5542 Background: Ra-223, a targeted alpha therapy, showed a survival benefit and favorable safety profile over 3 years’ (yrs) follow-up in mCRPC pts (ALSYMPCA trial). REASSURE (NCT02141438) is a global, prospective, single-arm, observational study of long-term Ra-223 safety in routine clinical practice in mCRPC pts (planned 7-yr follow-up). Methods: This analysis, based on the second prespecified interim analysis (data cutoff 3-20-2019) of REASSURE (N = 1465), evaluated safety/OS in the pt subset that was chemotherapy-naïve at Ra-223 administration but received subsequent taxane therapy any time after Ra-223 completion. Results: 182 pts received taxane therapy after Ra-223. Most (58%) had unresected primary tumors, 69% had ≥6 metastases, 99% received prior systemic anticancer therapy (Table). 143 (79%) completed 5 or 6 Ra-223 injections. Subsequent anticancer therapies included docetaxel (95%), enzalutamide (25%), cabazitaxel (24%), abiraterone (12%), lutetium-177-prostate-specific membrane antigen (4%), and sipuleucel-T (1%). During/up to 30 days after taxane therapy, 15 pts (8%) had grade 3/4 hematologic adverse events: anemia (erythropenia) (n = 11, 6%), neutropenia (n = 3, 2%), and thrombocytopenia (n = 2, 1%). Median OS was 24.3 (95% CI: 20.9–27.5) months from Ra-223 initiation and 11.8 (95% CI: 10.6–14.1) months from subsequent taxane initiation. Conclusions: In this cohort where Ra-223 was integrated prior to taxane therapy, most pts received multiple subsequent anticancer therapies. It appears that sequencing of multiple treatment modalities with different mechanisms of action may contribute to improved OS. Taxane therapy in routine clinical practice in pts previously treated with Ra-223 had acceptable hematologic safety/tolerability profiles. Clinical trial information: NCT02141438 . [Table: see text]

Animal models are a valuable tool in preclinical research. However, limited predictivity of human biological responses in the conventional models has stimulated the search for reliable preclinical tools that show translational robustness. Here, we used precision-cut kidney slices (PCKS) as a model of renal fibrosis and investigated its predictive capacity for screening the effects of anti-fibrotics. Murine and human PCKS were exposed to TGF&beta, or PDGF pathway inhibitors with established anti-fibrotic efficacy. For each treatment modality, we evaluated whether it affected: (1) culture-induced collagen type I gene expression and interstitial accumulation, (2) expression of markers of TGF&beta, and PDGF signaling, and (3) expression of inflammatory markers. We summarized the outcomes of published in vivo animal and human studies testing the three inhibitors in renal fibrosis, and drew a parallel to the PCKS data. We showed that the responses of murine PCKS to anti-fibrotics highly corresponded with the known in vivo responses observed in various animal models of renal fibrosis. Moreover, our results suggested that human PCKS can be used to predict drug efficacy in clinical trials. In conclusion, our study demonstrated that the PCKS model is a powerful predictive tool for ex vivo screening of putative drugs for renal fibrosis.

De kennis omtrent de ziekte van Peyronie (ZvP) is in de afgelopen decennia duidelijk toegenomen, maar helaas behoort een curatieve medicamenteuze behandeling nog niet tot de mogelijkheden. Een deel van de patienten zal voorlopig dus afhankelijk blijven van niet-curatieve, al dan niet chirurgische, symptomatische behandelingen. Uit de meest recente Amerikaanse en Europese richtlijnen en literatuur werd een overzichtsartikel gedestilleerd. We gaan kort in op het ziektebeeld, epidemiologische en historische aspecten en beschrijven vervolgens de bestaande ideeen over de pathofysiologie, pathogenese en de therapeutische mogelijkheden anno 2018.

BACKGROUND. Abiraterone Acetate (AA) and Enzalutamide (Enz) are effective hormonal treatments in mCRPC patients. Retrospective studies suggested clinical cross-resistance between Enz and AA. However, 12.8-39.1% of patients previously treated with docetaxel (Doc) and AA do respond to Enz. These responders have not been characterized. METHODS. 102 Enz treated mCRPC patients after AA and Doc treatment were included in this study. Differences in patient characteristics and previous treatment outcomes between PSA responders and non-responders on Enz were evaluated. RESULTS. Median Progression-Free Survival was 12.2 weeks (95% CI 11.7-14.3) and Overall Survival 43.5 weeks (95% CI 37.4-61.2). There were 26 (25%) Enz-responders and 76 (75%) non-responders. Significant higher percentages of Gleason scores >= 8 and PSA doubling times (PSA-DT) = 40 (68 patients) revealed significant differences in baseline PSA levels, PSA-DT = 8 and IAE's between Enz responders and non-responders. CONCLUSIONS. PSA response to Enz after previous AA and Doc treatment was associated with a longer IAE, a higher Gleason score and a PSA-DT

Purpose Testicular cancer (TC) treatment increases risk of subsequent malignant neoplasms (SMNs). It is unknown whether changes in TC treatment over time have affected SMN risk. Methods Solid SMN risk was evaluated in a multicenter cohort comprising 5,848 1-year survivors treated for TC before age 50 years between 1976 and 2007. SMN incidence was compared with cancer incidence in the general population. Treatment-specific risks were assessed using multivariable regression in a case-cohort design. Results After a median follow-up of 14.1 years, 350 solid SMNs were observed, translating into a 1.8-fold (95% CI, 1.6-2.0) increased risk compared with general population rates. Solid SMN risk was increased in patients with seminoma and those with nonseminoma (standardized incidence ratio, 1.52 and 2.21, respectively). Patients with nonseminoma experienced increased risk of SMNs of the thyroid, lung, stomach, pancreas, colon, and bladder and of melanoma and soft tissue sarcoma, whereas those with seminoma experienced increased risk of SMNs of the small intestine, pancreas, and urinary bladder. The 25-year cumulative incidence of solid SMNs was 10.3% (95% CI, 9.0% to 11.6%). In multivariable analysis, platinum-based chemotherapy was associated with increased risk of a solid SMN (hazard ratio [HR], 2.40; 95% CI, 1.58 to 3.62), colorectal SMN (HR, 3.85; 95% CI, 1.67 to 8.92), and noncolorectal GI SMN (HR, 5.00; 95% CI, 2.28 to 10.95). Receipt of platinum 400 to 499 and ≥ 500 mg/m2 increased solid SMN risk compared with surgery only (HR, 2.43; 95% CI, 1.40 to 4.23 and HR, 2.42; 95% CI, 1.50 to 3.90, respectively), whereas risk was not significantly increased with lower doses (HR, 1.75; 95% CI, 0.90 to 3.43). The HR of a GI SMN increased by 53% (95% CI, 26% to 80%) per 100 mg/m2 of platinum-containing chemotherapy. The HR of an infradiaphragmatic SMN increased by 8% per Gray of radiation dose administered (95% CI, 6% to 9%; P < .001). Conclusion Radiotherapy and platinum-containing chemotherapy are associated with increased solid SMN risk, specifically with GI SMNs.

Background Patients with sleep-related painful erections (SRPEs) have frequent awakenings from deep penile pain during nocturnal erections. This results in severe sleep deprivation. Aim To review the current literature on SRPEs and discuss the pathophysiologic theories and risks and benefits of medical treatments. Methods PubMed was searched using the terms sleep-related painful erections, nocturnal priapism, treatment, and sleep-related erections. Outcome Variables included patient demographics, medical history, diagnostics, hypotheses on pathophysiology, and treatment modalities and their effect on SRPE in the short and long term. Results The search yielded in 66 SRPE cases that were analyzed, including our mono-institutional series of 24 patients. The phenomenon of SRPEs is not well understood. Theories about pathophysiology concerned increased serum testosterone levels, altered autonomic function, compression of the lateral preoptic area, coexistent obstructive sleep apnea syndrome, the existence of a “compartment syndrome,” and psychosomatic factors. Except for polysomnographic findings that showed sleep fragmentation and decreased sleep efficiency in all patients, other diagnostic results varied widely. Multiple agents were tried. Baclofen and, to lesser degree, clonazepam showed noticeable results, most likely due to their influence on the γ-aminobutyric acid system and, hence, suppression of glutamate release. In addition, baclofen relaxes the ischiocavernosus and bulbospongiosus muscles, which are involved in penile erection. Clinical Implications By providing a critical analysis and complete overview on the limited literature about this overlooked and undermanaged condition, this review contributes to a better understanding of the pathophysiology and provides directions for future research on the treatment of SRPE. Strengths and Limitations Because the literature on SRPEs includes only case reports and small case series, the level of evidence of treatment advice is limited. Conclusion The pathophysiology of SRPEs is not yet clarified. Further diagnostic evaluation, including electromyography of the ischiocavernosus and bulbospongiosus muscles to elucidate the pathophysiology, is recommended. Prospective controlled investigations are warranted to assess the efficacy and safety of long-term use of baclofen and develop evidence-based treatment advice.

In this retrospective pilot study, the feasibility of the epithelial cell adhesion molecule (EpCAM) as an imaging target for lymph node (LN) metastatic disease of urothelial cell carcinoma (UCC) of the bladder was investigated. LN metastases and LNs without metastases of patients who underwent pelvic lymph node dissection because of muscle invasive bladder cancer (MIBC) were used. Primary tumors of the same patients were used from cystectomy specimen, transurethral resections, and biopsies. A pathologist, blinded to clinical data, scored EpCAM immunoreactivity. This method determines a total immunostaining score, which is the product of a proportion score and an intensity score. EpCAM expression was observed in 19/20 (95%) LNs with UCC metastases and in 11/12 (92%) of the primary tumors. EpCAM expression was absent in 14/14 (100%) LNs without metastases. Median EpCAM expression (TIS) in LN metastases was 5 (IQR 2.0-8.0) and in the primary tumors 6 (IQR 2.3-11.0). Based on the absence of staining in LNs without metastases, EpCAM show high tumor distinctiveness. EpCAM seems to be a feasible imaging target in LN metastases of UCC of the bladder. Pre- and perioperative visualization of these metastases will improve disease staging and improve the complete resection of LN metastases in MIBC.

Currently, biomarkers that predict the efficacy of everolimus in metastatic renal cell carcinoma (mRCC) patients are lacking. Everolimus inhibits vascular endothelial growth factor A (VEGF-A) expression. We performed PET scans on mRCC patients with 89Zr-bevacizumab, a VEGF-A–binding antibody tracer. The aims were to determine a change in tumor tracer uptake after the start of everolimus and to explore whether 89Zr-bevacizumab PET can identify patients with early disease progression. Methods: 89Zr-bevacizumab PET was done before and 2 and 6 wk after the start of everolimus, 10 mg/d, in mRCC patients. Routine CT scans were performed at baseline and every 3 mo thereafter. Tumor tracer uptake was quantified using SUVmax. The endpoints were a change in tumor tracer uptake and treatment response on CT after 3 mo. Results:Thirteen patients participated. The median SUVmax of 94 tumor lesions was 7.3 (range, 1.6–59.5). Between patients, median tumor SUVmax varied up to 8-fold. After 2 wk, median SUVmax was 6.3 (1.7–62.3), corresponding to a mean decrease of 9.1% (P < 0.0001). Three patients discontinued everolimus early. At 6 wk, a mean decrease in SUVmax of 23.4% compared with baseline was found in 70 evaluable lesions of 10 patients, with a median SUVmax of 5.4 (1.1–49.4, P < 0.0001). All 10 patients who continued treatment had stable disease at 3 mo. Conclusion: Everolimus decreases 89Zr-bevacizumab tumor uptake. Further studies are warranted to evaluate the predictive value of 89Zr-bevacizumab PET for everolimus antitumor efficacy.

201 Background: Currently, there is no imaging modality that can accurately discriminate between locally and distant recurrent prostate cancer after treatment with curative intent. Major drawback of the available techniques is that they are not prostate cancer specific. Selecting patients for salvage cryotherapy of the prostate or salvage prostatectomy by excluding distant metastases proves a diagnostic challenge. In this retrospective pilot study expression of prostate-specific membrane antigen (PSMA), epithelial cell adhesion molecule (EpCAM), vascular endothelial growth factor (VEGF) and gastrin-releasing peptide receptor (GRPR) in locally recurrent prostate cancer after brachytherapy or external beam radiotherapy (EBRT) was investigated and their adequacy for targeted imaging was analyzed. Methods: Prostate cancer specimens were collected of 17 patients who underwent salvage prostatectomy because of locally recurrent prostate cancer after brachytherapy or EBRT. Local recurrence was based on rises in PSA and prostate biopsies. Immunohistochemistry was performed on the radical prostatectomy specimens. A pathologist blinded to clinical and pathological data scored the immunoreactivity on a four point scale in prostate cancer and in stroma. Results: Staining for PSMA was seen in 100% (17 out of 17), EpCAM in 82.3% (14 out of 17), VEGF in 82.3% (14 out of 17) and GRPR in 100% (17 out of 17) of prostate cancer specimens. Staining for PSMA, EpCAM, and VEGF was seen in 0% (0 out of 17) and for GRPR in 100% (17 out of 17) of specimens’ stromal compartments. In 11.8% (2 out of 17) of cases GRPR staining intensity of prostate cancer was higher than that of stroma, while in the remaining 88.2% (15 out of 17) of cases GRPR staining in cancer and stroma was equal. Conclusions: Based on the absence of stromal staining PSMA, EpCAM, and VEGF had a high tumor distinctiveness. GRPR had a low tumor distinctiveness as a result of the high stromal expression. Therefore, PSMA, EpCAM, and VEGF can be used for targeted imaging of locally recurrent prostate cancer after radiotherapy.

Our study assessed whether rising age, socioeconomic status (SES) and the presence of serious comorbidity affected treatment choice and survival in a population-based series of patients with muscle-invasive bladder cancer (MIBC) in The Netherlands. Therefore, a consecutive series was studied, including all patients diagnosed with MIBC between 1995 and 2009 in the Eindhoven Cancer Registry, preceding centralization of cystectomy. The independent effects of age, SES and serious comorbidity on therapy choice and their effects on overall survival were estimated by multivariate logistic regression and multivariate Cox proportional hazard analyses, respectively. Out of the 2,445 patients, 38% were aged ≥ 75 years at diagnosis and 63% had at least one serious comorbid condition. Higher age and serious comorbidity were independent predictors for abstaining from cystectomy, where SES was not (61-74 vs. ≤ 60: odds ratio [OR], 0.8; 95% confidence interval [CI], 0.6-1.0; ≥ 75 vs. ≤ 60: OR, 0.1; 95% CI,0.1-0.2; one comorbid condition vs. none: OR, 0.7; 95% CI, 0.5-0.9; two vs. none: OR, 0.6; 95% CI, 0.5-0.8). Patients undergoing cystectomy, external beam radiotherapy or interstitial radiotherapy survived longer independent of age, SES and serious comorbidity (hazard ratio [HR]: 0.4; 95% CI: 0.4-0.5; HR: 0.8; 95% CI: 0.7-0.9; HR: 0.4; 95% CI: 0.3-0.5, respectively). Consequently, preceding centralization of cystectomy, higher age and serious comorbidity were independent predictors for abstaining from cystectomy owing to an expected high rate of short-term medical problems. As cystectomy is associated with a better survival, independently of age, SES and serious comorbidity, it can be questioned whether cystectomy has been underutilised in elderly and in patients with serious comorbidity. Centralization might be a solution for this suggested underutilisation.

BACKGROUND: Enzalutamide (Enz) and abiraterone acetate (AA) are hormone treatments that have a proven survival advantage in patients with metastatic, castration-resistant prostate cancer who previously received docetaxel (Doc). Recently, limited activity of AA after Enz and of Enz after AA was demonstrated in small cohort studies. Here, the authors present the activity and tolerability of Enz in patients who previously received AA and Doc in the largest cohort to date. METHODS: The efficacy and tolerability of Enz were investigated in men with progressive, metastatic, castrate-resistant prostate cancer who previously received Doc and AA. Toxicity, progression-free survival, time to prostate-specific antigen (PSA) progression, and overall survival were retrospectively evaluated. RESULTS: Sixty-one patients were included in the analysis. The median age was 69 years (interquartile range [IQR], 64-74 years), 57 patients (93%) had an Eastern Cooperative Oncology Group performance status from 0 to 2, 48 patients (79%) had bone metastases, 33 patients (54%) had lymph node metastases, and 13 patients (21%) had visceral metastases. The median duration of Enz treatment was 14.9 weeks (IQR, 11.1-20.0 weeks), and 13 patients (21%) had a maximum PSA decline >/=50%. The median progression-free survival was 12.0 weeks (95% confidence interval [CI], 11.1-16.0 weeks), the median time to PSA progression was 17.4 weeks (95% CI, >16.0 weeks), and the median overall survival was 31.6 weeks (95% CI, >28.7 weeks). Enz was well tolerated, and fatigue and musculoskeletal pain were the most frequent grade >/=2 adverse events. The PSA response to Doc and AA did not predict the PSA response to Enz. CONCLUSIONS: Enz has modest clinical activity in patients with metastatic, castrate-resistant prostate cancer who previously received Doc and AA. PSA response to Doc and AA does not predict for PSA response to ENz. Cancer 2014;120:968-975. (c) 2013 American Cancer Society.

Rationale The peptide bombesin (BBN) and its derivatives exhibit high binding affinity for the gastrin-releasing peptide receptor (GRPR), which is highly expressed in prostate cancer. We used the BBN-based radiopharmaceutical 99m Technetium-HYNIC(tricine/TPPTS)-Aca-Bombesin(7-14) ( 99m Tc-HABBN) to perform a first-in-man clinical pilot study to evaluate the feasibility of 99m Tc-HABBN SPECT/CT for detection of prostate cancer in patients. Methods Eight patients with biopsy-proven prostate cancer who were scheduled for either radical prostatectomy or external beam radiotherapy underwent 99m Tc-HABBN scintigraphy and SPECT/CT prior to treatment. Serial blood samples were taken to assess blood radioactivity and to determine in vivo metabolic stability. Clinical parameters were measured and reported side effects, if present, were recorded. Prostate cancer specimens of all patients were immunohistochemically stained for GRPR. Results 99m Tc-HABBN was synthesized with high radiochemical yield, purity and specific activity. There were no significant changes in clinical parameters, and there were no adverse or subjective side effects. Low metabolic stability was observed, as less than 20% of 99m Tc-HABBN was intact after 30min. Immunohistochemical staining for GRPR was observed in the prostate cancer specimens in all patients. 99m Tc-HABBN scintigraphy and SPECT/CT did not detect prostate cancer in patients with proven disease. Conclusions 99m Tc-HABBN SPECT/CT for visualization of prostate cancer is safe but hampered by an unexpected low in vivo metabolic stability in man. The difference between the excellent in vitro stability of 99m Tc-HABBN in human serum samples determined in our previous study regarding 99m Tc-HABBN and the low in vivo metabolic stability determined in this study, is striking. This issue warrants further study of peptide-based radiopharmaceuticals.

Current salvage treatments for recurrent prostate cancer after primary radiation therapy include radical prostatectomy, cryosurgery and brachytherapy. Because toxicity and failure rates are considerable, salvage treatments are not commonly performed. As most centers perform only one preferred salvage technique, the literature only describes single-center outcomes from a single salvage technique with a limited number of patients. In this overview, five high-volume Dutch centers describe their toxicity and outcome data using different salvage techniques. This provides a view on how salvage is performed in clinical practice in the Netherlands.A total of 129 patients from five different centers in the Netherlands were retrospectively analyzed. Biochemical failure (BF) was defined as PSA > 0.1 ng/ml for the salvage prostatectomy group (n = 44) and PSA nadir + 2.0 ng/ml (Phoenix definition) for the salvage cryosurgery (n = 54) and salvage brachytherapy group (n = 31). Toxicity was scored according to the Common Toxicity Criteria for Adverse events (CTCAE v3.0).BF occurred in 25 (81 %) patients in the brachytherapy group (mean follow-up 29 +/- A 24 months), 29 (66 %) patients in the prostatectomy group (mean follow-up 22 +/- A 25 months) and 33 (61 %) patients in the cryosurgery group (mean follow-up 14 +/- A 11 months). Severe (grade > 3) genitourinary and gastrointestinal toxicity was observed in up to 30 % of patients in all three groups.This overview shows clinical practice of prostate cancer salvage. Significant failure and toxicity rates are observed, regardless of salvage technique. Patients should be selected with great care before offering these salvage treatment strategies.

There is an urgent need for new imaging modalities in prostate carcinoma staging. A non-invasive modality that can assess lymph node and bone metastases simultaneously is preferred. Epithelial cell adhesion molecule (EpCAM) is a membranous protein of interest as an imaging target since it is overexpressed in prostatic carcinoma compared with benign prostate epithelium and compared with stroma. However, EpCAM expression in lymph node metastases is sparsely available in the literature and EpCAM expression in bone metastases is yet unknown. The current study evaluates the expression of EpCAM in prostate carcinoma lymph nodes, in matched normal lymph nodes, in prostate carcinoma bone metastases, and in normal bone by immunohistochemistry. EpCAM was expressed in 100% of lymph node metastases (21 out of 21), in 0% of normal lymph nodes (0 out of 21), in 95% of bone metastases (19 out of 20), and in 0% of normal bone (0 out of 14). Based on these results, EpCAM may be a feasible imaging target in prostate carcinoma lymph node and bone metastases. Prospective clinical trials are needed to confirm current results. Preoperative visualization of prostate carcinoma metastases will improve disease staging and will prevent unnecessary invasive surgery.

Background: Prediction models need validation to assess their value outside the development setting.Objective: To assess the external validity of the European Randomised study of Screening for Prostate Cancer (ERSPC) Risk Calculator (RC) in a contemporary clinical cohort.Methods: The RC calculates the probability of a positive sextant prostate biopsy (P(posb)) using serum prostate-specific antigen (PSA), results of digital rectal examination, transrectal ultrasound (TRUS) and ultrasound assessed prostate volume. We prospectively validated the RC in 320 biopsied men (55-75 years), with no previous prostate biopsy, included in five Dutch hospitals in 2008-2011. If the P(posb) was >= 20% a biopsy was recommended. The performance of the RC was tested by comparing the observed outcomes to predicted probabilities, using the area under the curve (AUC) and decision curves analyses.Results: Compared to the screening cohort, men in the clinical cohort differed. They had higher PSA levels (median 6.8 versus 4.3 ng/ml, p Conclusions: The ERSPC RC performs well in a Dutch clinical cohort in men with previous PSA tests and contemporary biopsy schemes, and outperforms a PSA and DRE-based approach in the decision to perform a biopsy. (C) 2012 Elsevier Ltd. All rights reserved.

Contains fulltext : 110464.pdf (Publisher’s version ) (Open Access) Several in vitro and in vivo models have revealed the key role of CXCR4/CXCL12 axis in tumor-stroma interactions. Stromal cells present in the tumor microenvironment express high levels of CXCL12 protein, directly stimulating proliferation and migration of CXCR4-expressing cancer cells. This specific prosurvival influence of stromal cells on tumor cells is thought to protect them from cytotoxic chemotherapy and is postulated as a possible explanation for the minimal residual disease in hematological and solid cancers. Therefore, CXCR4/CXCL12 signaling is an attractive therapeutic target in cancer, as proven in preclinical leukemia mouse models, where CXCR4 inhibition sensitized cancer cells to conventional chemotherapy. This study investigates whether inhibition of CXCR4 with the specific inhibitor AMD3100 sensitizes human prostate cancer cells to docetaxel. We showed that both mouse and human stromal cell lines have a protective effect on PC3-luc cells by promoting their survival after chemotherapy. Furthermore, we demonstrated that AMD3100 sensitizes PC3-luc cells to docetaxel. In a subcutaneous xenograft mouse model of human prostate carcinoma, we showed that a combination of docetaxel and AMD3100 exerts increased antitumor effect compared with docetaxel alone. We concluded that CXCR4 inhibition chemosensitizes prostate cancer cells, both in vitro and in vivo. To explore the relevance of these findings, we analyzed CXCR4 expression levels in human prostate cancer samples. We found that cancer cells present in bone metastatic lesions express higher CXCR4 levels relative to the cells present in primary tumors and lymph node metastatic lesions. These findings underscore the potential of CXCR4 inhibitors as chemosensitizing agents. 01 augustus 2012

PURPOSE: To evaluate the effect of total PSA (tPSA) and PSA kinetics on the detection rates of (11)C-Choline PET in patients with biochemical recurrence (BCR) after radical prostatectomy (RP) or external beam radiotherapy (EBRT).METHODS: We included 185 patients with BCR after RP (PSA >0.2 ng/ml) or after EBRT (ASTRO definition). After injection of 400 MBq 11C-Choline i.v., a scan was made using the ECAT HR + PET camera with CT fusion images or Siemens mCT PET/CT. Biopsy-proven histology, confirmative imaging (CT or bone scan) and/or clinical follow-up (PSA) were used as composite reference. Statistical analysis was performed using PASW Statistics 18.RESULTS: 11C-Choline PET was positive in 124/185 cases (65%) (in 22/61 (36%) after RP, 102/124 (82%) after EBRT). In 79 patients a local recurrence was identified, and 45 patients showed locoregional metastases on PET/CT. In 20 cases a proven false-negative PET scan was observed. Positive PET scans were confirmed by histology in 87/124 (70%) cases, by confirmatory imaging in 34/124 (28%) and by clinical follow-up after salvage treatment in 3 (2%) cases. The ROC analysis to detect a recurrence showed significant difference in area under the curve (AUC) of tPSA 0.721(p < 0.001) and PSA velocity 0.730 (p < 0.001). PSA doubling time showed no significant difference with an AUC of 0.542 (p = 0.354). Detection rates are CONCLUSIONS: Total serum PSA and PSA velocity have significant effect on the detection rates of 11C-Choline PET/CT in men with a BCR after RP or EBRT.

Study Type – Diagnostic (cohort) Level of Evidence 2b What's known on the subject? and What does the study add? So far, few publications have shown that a prediction model influences the behaviour of both physicians and patients. To our knowledge, it was unknown whether urologists and patients are compliant with the recommendations of a prostate cancer risk calculator and their reasons for non-compliance. Recommendations of the European Randomized study of Screening for Prostate Cancer risk calculator (ERSPC RC) about the need of a prostate biopsy were followed in most patients. In most cases of non-compliance with ‘no biopsy’ recommendations, a PSA level ≥3 ng/mL was decisive to opt for biopsy. Before implementation of the ERSPC RC in urological practices at a large scale, it is important to obtain insight into the use of guidelines that might counteract the adoption of the use of the RC as a result of opposing recommendations. OBJECTIVES • To assess both urologist and patient compliance with a ‘no biopsy’ or ‘biopsy’ recommendation of the European Randomized study of Screening for Prostate Cancer (ERSPC) Risk Calculator (RC), as well as their reasons for non-compliance. • To assess determinants of patient compliance. PATIENTS AND METHODS • The ERSPC RC calculates the probability on a positive sextant prostate biopsy (Pposb) using serum prostate-specific antigen (PSA) level, outcomes of digital rectal examination and transrectal ultrasonography, and ultrasonographically assessed prostate volume. A biopsy was recommended if Pposb≥20%. • Between 2008 and 2011, eight urologists from five Dutch hospitals included 443 patients (aged 55–75 years) after a PSA test with no previous biopsy. • Urologists calculated the Pposb using the RC in the presence of patients and completed a questionnaire about compliance. • Patients completed a questionnaire about prostate cancer knowledge, attitude towards prostate biopsy, self-rated health (12-Item Short Form Health Survey), anxiety (State Trait Anxiety Inventory-6, Memorial Anxiety Scale for Prostate Cancer) and decision-making measures (Decisional Conflict Scale). RESULTS • Both urologists and patients complied with the RC recommendation in 368 of 443 (83%) cases. • If a biopsy was recommended, almost all patients (96%; 257/269) complied, although 63 of the 174 (36%) patients were biopsied against the recommendation of the RC. • Compliers with a ‘no biopsy’ recommendation had a lower mean Pposb than non-compliers (9% vs 14%; P < 0.001). • Urologists opted for biopsies against the recommendations of the RC because of an elevated PSA level (≥3 ng/mL) (78%; 49/63) and patients because they wanted certainty (60%; 38/63). CONCLUSIONS • Recommendations of the ERSPC RC on prostate biopsy were followed in most patients. • The RC hence may be a promising tool for supporting clinical decision-making.

Purpose: To evaluate the pattern of care in patients with high risk non muscle invasive bladder cancer (NMIBC) in the Comprehensive Cancer Center North-Netherlands (CCCN) and to assess factors associated with the choice of treatment, recurrence and progression free survival rates.Materials and Methods: Retrospective analysis of 412 patients with newly diagnosed high risk NMIBC. Clinical, demographic and follow-up data were obtained from the CCCN Cancer Registry and a detailed medical record review. Uni and multivariate analysis was performed to identify factors related to choice of treatment and 5 year recurrence and progression free survival.Results: 74/412 (18%) patients with high risk NMIBC underwent a transurethral resection (TUR) as single treatment. Adjuvant treatment after TUR was performed in 90.7% of the patients treated in teaching hospitals versus 71.8 % in non-teaching hospitals (p 80 years OR 0.1 p = 0.001) and treatment in non-teaching hospitals (OR 0.25; p Conclusion: In this pattern of care study in high risk NMIBC, 18% of the patients were treated with TUR as single treatment. Age and treatment in non-teaching hospitals were associated with less adjuvant treatment after TUR. None of the variables sex, age, comorbidity, hospital type, stage and year of treatment was associated with 5 year recurrence or progression rates.

OBJECTIVE: To assess treatments and survival of patients with muscle invasive bladder cancer (MIBC) in the Comprehensive Cancer Center Northern Netherlands (CCCN) region.STUDY DESIGN AND SETTING: Retrospective cohort analysis. Data of 548 patients with MIBC diagnosed between 1997 and 2002 were collected from the CCCN cancer registry. All had a follow-up of at least 5 years. Logistic regression analysis on treatments as well as survival analysis was performed.RESULTS: The treatments were radical cystectomy in 205/548 (37.5%) patients. TUR plus radiotherapy in 246 (44.9%) and palliation in 97 (17.7%). Multivariate analysis identified TNM stage (P < 0.0001) and age (P < 0.0001) as independent variables for cystectomy. Hospital type and year of diagnosis were not significant different between patients treated by cystectomy versus other type of treatment. TNM stage (P < 0.0001), age (P = 0.0043), and comorbidity (P = 0.0028) were independent variables for disease-specific survival (DSS) after cystectomy.CONCLUSION: In the CCCN region, only 1/3 of patients with MIBC were treated with radical cystectomy. TNM stage and age were identified as main variables for the choice for cystectomy. TNM stage, age, and comorbidity were independent variables for disease-specific survival after cystectomy.

PURPOSE: An elevated serum prostate-specific antigen (PSA) level cannot distinguish between local-regional recurrences and the presence of distant metastases after treatment with curative intent for prostate cancer. With the advent of salvage treatment such as cryotherapy, it has become important to localize the site of recurrence (local or distant). In this study, the potential of (11)C-choline positron emission tomography (PET) to identify site of recurrence was investigated in patients with rising PSA after external-beam radiotherapy (EBRT).METHODS AND MATERIALS: Seventy patients with histologically proven prostate cancer treated with EBRT and showing biochemical recurrence as defined by American Society for Therapeutic Radiology and Oncology consensus statement and 10 patients without recurrence underwent a PET scan using 400 MBq (11)C-choline intravenously. Biopsy-proven histology from the site of suspicion, findings with other imaging modalities, clinical follow-up and/or response to adjuvant therapy were used as comparative references.RESULTS: None of the 10 patients without biochemical recurrence had a positive PET scan. Fifty-seven of 70 patients with biochemical recurrence (median PSA 9.1 ng/mL; mean PSA 12.3 ng/mL) showed an abnormal uptake pattern (sensitivity 81%). The site of recurrence was only local in 41 of 57 patients (mean PSA 11.1 ng/mL at scan), locoregionally and/or distant in 16 of 57 patients (mean PSA 17.7 ng/mL). Overall the positive predictive value and negative predictive value for (11)C-choline PET scan were 1.0 and 0.44 respectively. Accuracy was 84%.CONCLUSIONS: (11)C-choline PET scan is a sensitive technique to identify the site of recurrence in patients with PSA relapse after EBRT for prostate cancer.