Safety and effectiveness of the radium-223-taxane treatment sequence in patients with metastatic castration-resistant prostate cancer in a global observational study (REASSURE).

BACKGROUND: Radium-223 and taxane chemotherapy each improve survival of patients with metastatic castration-resistant prostate cancer (mCRPC). Whether the radium-223-taxane sequence could extend survival without cumulative toxicity was explored. METHODS: The global, prospective, observational REASSURE study (NCT02141438) assessed real-world safety and effectiveness of radium-223 in patients with mCRPC. Using data from the prespecified second interim analysis (data cutoff, March 20, 2019), hematologic events and overall survival (OS) were evaluated in patients who were chemotherapy-naive at radium-223 initiation and subsequently received taxane chemotherapy starting ≤90 days ("immediate") or >90 days ("delayed") after the last radium-223 dose. RESULTS: Following radium-223 therapy, 182 patients received docetaxel (172 [95%]) and/or cabazitaxel (44 [24%]); 34 patients (19%) received both. Seventy-three patients (40%) received immediate chemotherapy and 109 patients (60%) received delayed chemotherapy. Median time from last radium-223 dose to first taxane cycle was 3.6 months (range, 0.3-28.4). Median duration of first taxane was 3.7 months (range, 0-22.0). Fourteen patients (10 in the immediate and four in the delayed subgroup) had grade 3/4 hematologic events during taxane chemotherapy, including neutropenia in two patients in the delayed subgroup and thrombocytopenia in one patient in each subgroup. Median OS was 24.3 months from radium-223 initiation and 11.8 months from start of taxane therapy. CONCLUSIONS: In real-world clinical practice settings, a heterogeneous population of patients who received sequential radium-223-taxane therapy had a low incidence of hematologic events, with a median survival of 1 year from taxane initiation. Thus, taxane chemotherapy is a feasible option for those who progress after radium-223. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02141438. PLAIN LANGUAGE SUMMARY: Radium-223 and chemotherapy are treatment options for metastatic prostate cancer, which increase survival but may affect production of blood cells as a side effect. We wanted to know what would happen if patients received chemotherapy after radium-223. Among the 182 men treated with radium-223 who went on to receive chemotherapy, only two men had severe side effects affecting white blood cell production (neutropenia) during chemotherapy. On average, the 182 men lived for 2 years after starting radium-223 and 1 year after starting chemotherapy. In conclusion, patients may benefit from chemotherapy after radium-223 treatment without increasing the risk of side effects.

Real-world outcomes of second novel hormonal therapy or radium-223 following first novel hormonal therapy for mCRPC.

Aim: To evaluate real-world clinical outcomes of radium-223 or alternative novel hormonal therapy (NHT) following first-line NHT for metastatic castration-resistant prostate cancer (mCRPC). Patients & methods: Retrospective analysis of the US Flatiron database (ClinicalTrials.gov identifier: NCT03896984). Results: In the radium-223 cohort (n = 120) versus the alternative NHT cohort (n = 226), proportionally more patients had prior symptomatic skeletal events and bone-only metastases, and first-line NHT duration was shorter. Following second-line therapy, 49 versus 39% of patients received subsequent life-prolonging therapy; of these, 47 versus 76% received taxane. Median overall survival was 10.8 versus 11.2 months. Conclusion: Real-world patients with mCRPC had similar median overall survival following second-line radium-223 or alternative NHT after first-line NHT. Many patients received subsequent therapy, with less taxane use after radium-223.

Lay abstract Patients with metastatic castration-resistant prostate cancer are often first treated with novel hormonal therapy (NHT) using abiraterone or enzalutamide. To aid decisions about what treatment to use next, we reviewed information about patients who were treated with an alternative NHT (226 patients) or the nuclear medicine radium-223 (120 patients) after the first NHT. Most patients given radium-223 had cancer that had spread to their bones only, whereas many patients given an alternative NHT had cancer in their bones and other parts of their body. Around one in four patients given radium-223 and one in five given an alternative NHT had symptoms related to their bone metastases after starting treatment. Five in every ten patients given radium-223 received further therapy, including chemotherapy in 50% of these patients, while four in every ten patients given an alternative NHT received further therapy, including chemotherapy in 75%. On average, patients lived for almost a year after starting radium-223 or an alternative NHT.

Functional Outcome and Complications following Ileal Neobladder Reconstruction in Male Patients without Tumor Recurrence. More than 35 Years of Experience from a Single Center.

PURPOSE: There is a lack of data on true long-term functional outcome of orthotopic bladder substitution. The primary study objective was to report our 35-year clinical experience. MATERIALS AND METHODS: Since October 1985, 259 male patients from a large single center radical cystectomy series with complete followup of more than 60 months (median 121, range 60-267) without recurrence, irradiation or undiversion that might have affected the functional outcome, were included. RESULTS: Median age at radical cystectomy and at survey was 63 (range 23-81) and 75 (range 43-92) years, respectively. Overall 87% of patients voided spontaneously and residual-free. This rate decreased with increasing age at the time of surgery (less than 50 years old 94%, 70 years old or older 82%). Overall day/nighttime continence rates were 90%/82%. These rates decreased with increasing age at the time of surgery from 100%/88% to 87%/80%. The overall pad-free rate was 71%/47%. Bicarbonate use decreased from 51% (5 years) to 19% (25 years). Patients with a followup of more than 20 years had the lowest rate of residual urine and clean intermittent catheterization (0.0%) as well as use of more than 1 pad at daytime/nighttime (6.3%/12.5%) and mucus obstruction (0.0%). Serum creatinine showed only the age related increase. The surgical complication rate was 27% and correlated inversely with functional results (chi-squared 11.227, p <0.005), even when the younger age at the time of surgery (younger than 60 years) was related to higher rates of surgical complications (chi-squared 6.80, p <0.05). CONCLUSIONS: The ileal neobladder represents an excellent long-term option for urinary diversion with an acceptable complication rate.

Does the Side Matter? A Retrospective Cohort Study Comparing Left and Right Pure Laparoscopic Donor Nephrectomies.

OBJECTIVES: Right laparoscopic donor nephrectomy (RLDN) is no longer regarded inferior to left LDN (LLDN). However, this knowledge is based on many studies suffering from inherent learning curves, center-specific imbalances, and different laparoscopic techniques. METHODS: Pure LDNs at a high-volume referral center from 2011 to 2016 were retrospectively analyzed. Patient, graft characteristics, outcomes of LDNs, and corresponding open kidney transplantations were compared between LLDN and RLDN including a follow-up. RESULTS: 160 (78.4%) LLDNs and 44 (21.6%) RLDNs only differed regarding graft characteristics, as more right grafts had multiple veins (34.1 vs. 6.9%, p < 0.001) and worse scintigraphic function (44 vs. 51%, p < 0.001). RLDNs were shorter (201 vs. 220 min, p = 0.032) with longer warm ischemia time (165 vs. 140 s, p < 0.001), but left grafts were transplanted faster (160 vs. 171 min, p = 0.048). Recipients of right kidneys had more postoperative complications (grade 3: 25.6 vs. 11.3%, p = 0.020). At a follow-up of 45 (range 6-79) months, neither the kidney function, nor death-censored graft (5-year: LLDN 89 vs. 92%, p = 0.969) and patient survival (5-year: LLDN 95 vs. 98%, p = 0.747) differed. CONCLUSIONS: Pure LLDN and RLDN can have different outcomes at high-volume centers, especially higher complications for recipients of right grafts. However, long-term function and graft survival are the same irrespective of the chosen side.

Transurethral en bloc submucosal hydrodissection vs conventional resection for resection of non-muscle-invasive bladder cancer (HYBRIDBLUE): a randomised, multicentre trial.

OBJECTIVE: To determine whether transurethral en bloc submucosal hydrodissection of bladder tumours (TUEB) improves the quality of the resection compared to conventional transurethral resection of bladder tumour (TURBT) in patients with non-muscle-invasive bladder cancer (NMIBC). PATIENTS AND METHODS: A randomised, multicentre trial (HYBRIDBLUE) was conducted with a superiority design. Six German academic centres participated between September 2012 and August 2015. Based on literature analysis, a sample size for accurate histopathological assessment concerning muscle invasion was assumed to be feasible in 50% (P0 = 0.5) of TURBT and 80% of TUEB cases. After pre-screening of a total of 305 patients, participants were allocated to two study arms: Group I: hexaminolevulinate (HAL)-guided TUEB; Group II: conventional HAL-guided TURBT. The primary endpoint was the proportion of specimens that could be reliably evaluated pathologically concerning muscle invasiveness. Secondary endpoints included rates of histopathological completeness of the resection, muscularis propria content, recurrence, and complication rates. RESULTS: A total of 115 patients (TUEB 56; TURBT 59) were eligible for final analysis. Adequate histopathological assessment, which included muscularis propria content and tumour margins (R0 vs R1), was present in 48/56 (86%) TUEB patients compared to 37/59 (63%; P = 0.006) in the TURBT group. R0 was confirmed in 30/56 TUEB patients (57%) and five of 59 TURBT patients (9%; P < 0.001). No complications of Grade ≥III were observed in both arms. At 3 and 12 months, three and 19 patients recurred in the TUEB group vs seven and 11 patients in the TURBT group, respectively (P = 0.33 and P = 0.08). CONCLUSIONS: In this randomised study, TUEB was shown to be clinically safe regarding perioperative endpoints. An adequate histopathological assessment concerning muscle invasion was significantly better assessable in the TUEB arm compared to standard TURBT. This finding indicates the clinical potential for reducing the rate of early re-resections. Yet, a larger study with recurrence-free survival as the primary endpoint is needed to assess the oncological efficacy between both techniques.

Analysis of quality of life and late biochemical predictors for localized cancer recurrence following radical prostatectomy.

BACKGROUND: Patients with localized prostate cancer (PCa) experience biochemical recurrence (BCR) despite a curatively intended radical prostatectomy (RP). The aim of this study was to describe the quality of life (QoL) of patients with a BCR while identifying predictors of early (ER) and late recurrence (LR). METHODS: For this purpose, a total of 330 PCa patients with a BCR following RP at Charité University Hospital in Berlin were analyzed. BCR was defined as two consecutive PSA values ≥ 0.2 after a previous non-detectable level. LR was defined as a BCR after 3 years post-RP. Differences in overall survival (OS) were calculated using the log-rank testing. A logistic regression model was applied to identify predictors of ER and LR. We further evaluated difference between ER and LR with respect to functional outcomes in urinary and sexual domains as well as the patients QoL. RESULTS: Out of 330 patients, 180 patients showed late BCR. Patients rated their global QoL with 64.5% in ER and 68.8% LR as good (EORTC quality of life Questionnaire, question 29 and 30). The questionnaire did not reveal QoL differences in terms of sexual and urinary function within ER and LR. The main predictor for LR was preoperative serum prostate-specific antigen (PSA) levels with a relative risk (RR) of 0.96 (p = 0.011). OS for patients with LR was significant longer than for patients with ER (154.3 vs. 143.2 months, p = 0.018). CONCLUSION: Patients with a BCR show a good quality of life possibly irrespective of the time point of BCR. We further identified preoperative PSA levels as a predictor of LR and noted that patients with LR patients lived longer. Further studies are needed.

Validation of the PI-RADS language: predictive values of PI-RADS lexicon descriptors for detection of prostate cancer.

OBJECTIVES: To assess the discriminatory power of lexicon terms used in PI-RADS version 2 to describe MRI features of prostate lesions. METHODS: Four hundred fifty-four patients were included in this retrospective, institutional review board-approved study. Patients received multiparametric (mp) MRI and subsequent prostate biopsy including MRI/transrectal ultrasound fusion biopsy and 10-core systematic biopsy. PI-RADS lexicon terms describing lesion characteristics on mpMRI were assigned to lesions by experienced readers. Positive and negative predictive values (PPV, NPV) of each lexicon term were assessed using biopsy results as a reference standard. RESULTS: From a total of 501 lesions, clinically significant prostate cancer (csPCa) was present in 175 lesions (34.9%). Terms related to findings of restricted diffusion showed PPVs of up to 52.0%/43.9% and NPV of up to 91.8%/89.7% (peripheral zone or PZ/transition zone or TZ). T2-weighted imaging (T2W)-related terms showed a wide range of predictive values. For PZ lesions, high PPVs were found for "markedly hypointense," "lenticular," "lobulated," and "spiculated" (PPVs between 67.2 and 56.7%). For TZ lesions, high PPVs were found for "water-drop-shaped" and "erased charcoal sign" (78.6% and 61.0%). The terms "encapsulated," "organized chaos," and "linear" showed to be good predictors for benignity with distinctively low PPVs between 5.4 and 6.9%. Most T2WI-related terms showed improved predictive values for TZ lesions when combined with DWI-related findings. CONCLUSIONS: Lexicon terms with high discriminatory power were identified (e.g., "markedly hypointense," "water-drop-shaped," "organized chaos"). DWI-related terms can be useful for excluding TZ cancer. Combining T2WI- with DWI findings in TZ lesions markedly improved predictive values. KEY POINTS: • Lexicon terms describing morphological and functional features of prostate lesions on MRI show a wide range of predictive values for prostate cancer. • Some T2-related terms have favorable PPVs, e.g., "water-drop-shaped" and "organized chaos" while others show less distinctive predictive values. DWI-related terms have noticeable negative predictive values in TZ lesions making DWI feature a useful tool for exclusion of TZ cancer. • Combining DWI- and T2-related lexicon terms for assessment of TZ lesions markedly improves PPVs. Most T2-related lexicon terms showed a significant decrease in PPV when combined with negative findings for "DW hyperintensity."

Additive Value of Transrectal Systematic Ventral Biopsies in Combination with Magnet Resonance Imaging/Ultrasound Fusion-Guided Biopsy in Patients with 3 or More Negative Prostate Biopsies.

INTRODUCTION: Patients with consistent suspicion for prostate cancer (PCa) and multiple negative prebiopsies prior to multiparametric magnetic resonance imaging (mpMRI) are still frequently evaluated for an image-guided biopsy and are reported with heterogeneous detection rates. The inclusion of a systematic biopsy (SB) is also still recommended with predominant sampling within the posterior/peripheral zone of the prostate. The aim of this study was (I) to evaluate PCa detection rates using a modified 10 core SB template including anterior biopsies in combination with mpMRI/ultrasound fusion-guided targeted biopsy (TB) in patients with 3 or more negative prebiopsies and (II) to compare mpMRI index lesion localization with histologically confirmed locali-zation from associated prostatectomy samples. METHODS: Overall 1,337 consecutive patients underwent sensor-based registration TB of the prostate and a subsequent 10-core SB between January 2012 and December 2015 at our institution. For this study, 101 patients with ≥3 negative prebiopsies and prostate imaging - reporting data system lesions ≥3 were pooled prospectively and underwent TB and a modified SB including 2 ventral (anterior) biopsies. Detection rates were estimated for the modified SB, TB, and its combination. A subgroup analysis of 35 patients undergoing prostatectomy was performed by a head-to-head comparison of mpMRI index lesion and histologically confirmed PCa index lesion localization. RESULTS: The overall detection rate for PCa was 54.5%. The combination of TB and SB detected 14 (25.4%) more cases missed by TB alone (p < 0.001) and 7 (12.7%) more cases missed by SB alone (p = 0.016), respectively. A postoperative Gleason upgrade was seen in 12/35 (34.3%) cases within the TB group and in 14/35 (40.0%) in the SB group, respectively. The subgroup analysis showed a predominant location of PCa index lesions anteriorly at the level of the midgland. The MRI detection rate of the anteriorly located index lesions was 70.4% (15/21 cases) with a clinically significant Gleason score (≥3 + 4 = 7a [International Society of Urological Pathology grade 2]) in 80.9%. Interestingly a modified SB template detected 90.5% (19/21) of the anteriorly located index lesions. CONCLUSION: Our data suggest that in patients with multiple prebiopsies PCa seems to be predominantly located anteriorly. We suggest the general integration of anterior biopsies despite TB in repeat biopsy patients.

Addition of radium-223 to abiraterone acetate and prednisone or prednisolone in patients with castration-resistant prostate cancer and bone metastases (ERA 223): a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Abiraterone acetate plus prednisone or prednisolone improves progression-free survival and overall survival in patients with metastatic castration-resistant prostate cancer. Radium-223 improves overall survival and delays the onset of symptomatic skeletal events in patients with castration-resistant prostate cancer and bone metastases. We assessed concurrent treatment with abiraterone acetate plus prednisone or prednisolone and radium-223 in such patients. METHODS: We did a randomised, double-blind, placebo-controlled, phase 3 trial at 165 oncology and urology centres in 19 countries. Eligible patients were aged 18 years or older, and had histologically confirmed, progressive, chemotherapy-naive, asymptomatic or mildly symptomatic castration-resistant prostate cancer and bone metastases, Eastern Cooperative Oncology Group performance status of 0 or 1, life expectancy of at least 6 months, and adequate haematological, renal, and liver function. Participants were randomly assigned (1:1) according to a permuted block design (block size 4) via interactive response technology to receive up to six intravenous injections of radium-223 (55 kBq/kg) or matching placebo once every 4 weeks. All patients were also scheduled to receive oral abiraterone acetate 1000 mg once daily plus oral prednisone or prednisolone 5 mg twice daily during and after radium-223 or placebo treatment. The primary endpoint was symptomatic skeletal event-free survival, which was assessed in the intention-to-treat population. Safety analyses were done in all patients who received at least one dose of any study drug. This trial is registered with ClinicalTrials.gov, number NCT02043678. Enrolment has been completed, and follow-up is ongoing. FINDINGS: Between March 30, 2014, and Aug 12, 2016, 806 patients were randomly assigned to receive radium-223 (n=401) or placebo (n=405) in addition to abiraterone acetate plus prednisone or prednisolone. The study was unblinded prematurely, on Nov 17, 2017, after more fractures and deaths were noted in the radium-223 group than in the placebo group (in an unplanned ad-hoc analysis), but all patients had completed radium-223 or placebo before this date. At the primary analysis (data cutoff Feb 15, 2018), 196 (49%) of 401 patients in radium-223 group had had at least one symptomatic skeletal event or died, compared with 190 (47%) of 405 patients in the placebo group (median follow-up 21·2 months [IQR 17·0-25·8]). Median symptomatic skeletal event-free survival was 22·3 months (95% CI 20·4-24·8) in the radium-223 group and 26·0 months (21·8-28·3) in the placebo group (hazard ratio 1·122 [95% CI 0·917-1·374]; p=0·2636). Fractures (any grade) occurred in 112 (29%) of 392 patients in the radium-223 group and 45 (11%) of 394 patients in the placebo group. The most common grade 3-4 treatment-emergent adverse events were hypertension (43 [11%] patients in the radium-223 group vs 52 [13%] patients in the placebo group), fractures (36 [9%] vs 12 [3%]) and increased alanine aminotransferase concentrations (34 [9%] vs 28 [7%]). Serious treatment-emergent adverse events occurred in 160 (41%) patients in the radium-223 group and 155 (39%) in the placebo group. Treatment-related deaths occurred in two (1%) patients in the radium-223 group (acute myocardial infarction and interstitial lung disease) and one (<1%) in the placebo group (arrhythmia). INTERPRETATION: The addition of radium-223 to abiraterone acetate plus prednisone or prednisolone did not improve symptomatic skeletal event-free survival in patients with castration-resistant prostate cancer and bone metastases, and was associated with an increased frequency of bone fractures compared with placebo. Thus, we do not recommend use of this combination. FUNDING: Bayer.

Radium-223 in asymptomatic patients with castration-resistant prostate cancer and bone metastases treated in an international early access program.

BACKGROUND: Radium-223, a targeted alpha therapy, is used to treat symptomatic patients with castration-resistant prostate cancer (CRPC) and bone metastases. Data for radium-223 in asymptomatic CRPC patients with bone metastases are lacking. METHODS: This was a prospective, single-arm phase 3b study. Patients with metastatic CRPC (malignant lymphadenopathy not exceeding 6 cm was allowed, visceral disease was excluded) received radium-223, 55 kBq/kg intravenously, every 4 weeks for up to 6 cycles. Co-primary endpoints were safety and overall survival. Post hoc analyses were performed according to baseline asymptomatic or symptomatic disease status. Asymptomatic status was defined as no pain and no opioid use at baseline. RESULTS: Seven hundred eight patients received ≥1 radium-223 injection: 548 (77%) were symptomatic to various degrees, and 135 (19%) were asymptomatic. Asymptomatic patients had more favorable baseline disease characteristics than symptomatic. A lower proportion of asymptomatic versus symptomatic patients had received prior abiraterone (25% vs 35%) and prior docetaxel (52% vs 62%). A higher proportion of asymptomatic (71%) versus symptomatic (55%) patients completed radium-223 treatment. Overall survival (hazard ratio [HR] 0.486), time to disease progression (HR 0.722) and time to first symptomatic skeletal event (HR 0.328) were better in asymptomatic than symptomatic patients. Alkaline phosphatase (ALP) response rates were similar (46% vs 47%), and ALP normalization (44% vs 25%) and prostate-specific antigen response rates (21% vs 13%) were higher in asymptomatic than symptomatic patients. A lower proportion of asymptomatic patients reported treatment-emergent adverse events (TEAEs, 61% vs 79%), grade 3-4 TEAEs (29% vs 40%) and drug-related TEAEs (28% vs 44%). There were two treatment-related deaths, both in patients with baseline symptomatic disease. CONCLUSIONS: Using radium-223 earlier in the disease course, when patients are asymptomatic or minimally symptomatic, may enable patients to complete treatment and optimize treatment outcome compared to symptomatic patients, and therefore may allow sequencing with other life-prolonging therapies. TRIAL REGISTRATION: The study was registered with ClinicalTrials.gov , number NCT01618370 on June 13, 2012 and the European Union Clinical Trials Register, EudraCT number 2012-000075-16 on April 4, 2012.

Correction to: Outcome of kidney function after ischaemic and zero-ischaemic laparoscopic and open nephron-sparing surgery for renal cell cancer.

Following publication.

Outcome of kidney function after ischaemic and zero-ischaemic laparoscopic and open nephron-sparing surgery for renal cell cancer.

BACKGROUND: Nephron-sparing surgery (NSS) remains gold standard for the treatment of localised renal cell cancer (RCC), even in case of a normal contralateral kidney. Compared to radical nephrectomy, kidney failure and cardiovascular events are less frequent with NSS. However, the effects of different surgical approaches and of zero ischaemia on the postoperative reduction in renal function remain controversial. We aimed to investigate the relative short- and long-term changes in estimated glomerular filtration rate (eGFR) after ischaemic or zero-ischaemic open (ONSS) and laparoscopic NSS (LNSS) for RCC, and to analyse prognostic factors for postoperative acute kidney injury (AKI) and chronic kidney disease (CKD) stage ≥3. METHODS: Data of 444 patients (211 LNSS, 233 ONSS), including 57 zero-ischaemic cases, were retrospectively analysed. Multiple regression models were used to predict relative changes in renal function. Natural cubic splines were used to demonstrate the association between ischaemia time (IT) and relative changes in renal function. RESULTS: IT was identified as significant risk factor for short-term relative changes in eGFR (ß = - 0.27) and development of AKI (OR, 1.02), but no effect was found on long-term relative changes in eGFR. Natural cubic splines revealed that IT had a greater effect on patients with baseline eGFR categories ≥G3 concerning short-term decrease in renal function and development of AKI. Unlike LNSS, ONSS was significantly associated with short-term decrease in renal function (ß = - 13.48) and development of AKI (OR, 3.87). Tumour diameter was associated with long-term decrease in renal function (ß = - 1.76), whereas baseline eGFR was a prognostic factor for both short- (ß = - 0.20) and long-term (ß = - 0.29) relative changes in eGFR and the development of CKD stage ≥3 (OR, 0.89). CONCLUSIONS: IT is a significant risk factor for AKI. The short-term effect of IT is not always linear, and the impact also depends on baseline eGFR. Unlike LNSS, ONSS is associated with the development of AKI. Our findings are helpful for surgical planning, and suggest either the application of a clampless NSS technique or at least the shortest possible IT to reduce the risk of short-time impairment of the renal function, which might prevent AKI, particularly regarding patients with baseline eGFR category ≥G3.

CodY-Mediated c-di-GMP-Dependent Inhibition of Mammalian Cell Invasion in Listeria monocytogenes.

Elevated levels of the second messenger c-di-GMP suppress virulence in diverse pathogenic bacteria, yet mechanisms are poorly characterized. In the foodborne pathogen Listeria monocytogenes, high c-di-GMP levels inhibit mammalian cell invasion. Here, we show that invasion is impaired because of the decreased expression levels of internalin genes whose products are involved in invasion. We further show that at high c-di-GMP levels, the expression of the entire virulence regulon is suppressed, and so is the expression of the prfA gene encoding the master activator of the virulence regulon. Analysis of mechanisms controlling prfA expression pointed to the transcription factor CodY as a c-di-GMP-sensitive component. In high-c-di-GMP strains, codY gene expression is decreased, apparently due to the lower activity of CodY, which functions as an activator of codY transcription. We found that listerial CodY does not bind c-di-GMP in vitro and therefore investigated whether c-di-GMP levels affect two known cofactors of listerial CodY, branched-chain amino acids and GTP. Our manipulation of branched-chain amino acid levels did not perturb the c-di-GMP effect; however, our replacement of listerial CodY with the streptococcal CodY homolog, whose activity is GTP independent, abolished the c-di-GMP effect. The results of this study suggest that elevated c-di-GMP levels decrease the activity of the coordinator of metabolism and virulence, CodY, possibly via lower GTP levels, and that decreased CodY activity suppresses L. monocytogenes virulence by the decreased expression of the PrfA virulence regulon.IMPORTANCEListeria monocytogenes is a pathogen causing listeriosis, a disease responsible for the highest mortality rate among foodborne diseases. Understanding how the virulence of this pathogen is regulated is important for developing treatments to decrease the frequency of listerial infections in susceptible populations. In this study, we describe the mechanism through which elevated levels of the second messenger c-di-GMP inhibit listerial invasion in mammalian cells. Inhibition is caused by the decreased activity of the transcription factor CodY that coordinates metabolism and virulence.

Validation of Prostate Imaging Reporting and Data System Version 2 for the Detection of Prostate Cancer.

PURPOSE: The second version of the PI-RADS™ (Prostate Imaging Reporting and Data System) was introduced in 2015 to standardize the interpretation and reporting of prostate multiparametric magnetic resonance imaging. Recently low cancer detection rates were reported for PI-RADS version 2 category 4 lesions. Therefore the aim of the study was to evaluate the cancer detection rate of PI-RADS version 2 in a large prospective cohort. MATERIALS AND METHODS: The study included 704 consecutive men with primary or prior negative biopsies who underwent magnetic resonance imaging/ultrasound fusion guided targeted biopsy and 10-core systematic prostate biopsy between September 2015 and May 2017. All lesions were rated according to PI-RADS version 2 and lesions with PI-RADS version 2 category 3 or greater were biopsied. An ISUP (International Society of Urological Pathology) score of 2 or greater (ie Gleason 3 + 4 or greater) was defined as clinically significant prostate cancer. RESULTS: The overall cancer detection rate of PI-RADS version 2 categories 3, 4 and 5 was 39%, 72% and 91% for all prostate cancer, and 23%, 49% and 77% for all clinically significant prostate cancer, respectively. If only targeted biopsy had been performed, 59 clinically significant tumors (16%) would have been missed. The PI-RADS version 2 score was significantly associated with the presence of prostate cancer (p <0.001), the presence of clinically significant prostate cancer (p <0.001) and the ISUP grade (p <0.001). CONCLUSIONS: PI-RADS version 2 is significantly associated with the presence of clinically significant prostate cancer. The cancer detection rate of PI-RADS version 2 category 4 lesions was considerably higher than previously reported. When performing targeted biopsy, the combination with systematic biopsy still provides the highest detection of clinically significant prostate cancer.

Primary magnetic resonance imaging/ultrasonography fusion-guided biopsy of the prostate.

OBJECTIVE: To examine the performance of a primary magnetic resonance imaging (MRI)/ultrasonography (US) fusion-guided targeted biopsy (TB), and in combination with an added systematic biopsy (SB). PATIENTS AND METHODS: Analysis of 318 consecutive biopsy-naïve men with suspicious multiparametric MRI (mpMRI; Prostate Imaging Reporting and Data System [PI-RADS] score ≥3) undergoing transrectal TB and 10-core SB between January 2012 and December 2016. The indication for performing mpMRI was based on clinical parameters and decided by the treating urologist before admission. TB was performed with a sensor-based MRI/US fusion-guided platform. Clinically significant prostate cancer was defined as Gleason score ≥4 + 3 = 7 (International Society of Urological Pathology Grade [ISUP] grade 3) or maximum cancer core length of ≥6 mm. RESULTS: A median (interquartile range) of 14 (13-14) biopsies per case were taken. The overall cancer detection rate (CDR) was 77% (245/318). The TB alone detected 67% of prostate cancers and the SB alone detected 70%. The PI-RADS dependent CDR for the combination of TB/SB were 38% (21/55), 78% (120/154) and 95% (104/109) for PI-RADS scores of 3/4/5, respectively. Clinically significant prostate cancer was diagnosed by the combination of TB and SB in 195 men (61%) and by TB alone in 163 cases (51%). The number of missed or underestimated prostate cancers with a Gleason score ≥8 for TB alone was 31 (10%, P < 0.001) and 21 (7%, P < 0.001) for SB alone in comparison with the results of the combination of TB and SB. The rate of insignificant prostate cancer was comparable for the combination of TB and SB and TB alone (50/318, 16% vs 50/318, 16%). CONCLUSIONS: Pre-biopsy mpMRI is of incremental value in increasing the detection of clinically significant prostate cancer in biopsy-naïve patients with suspicion of prostate cancer. Combining TB with SB further improved the diagnostic accuracy without increasing the rate of insignificant prostate cancer.

Intermittent vs continuous docetaxel therapy in patients with metastatic castration-resistant prostate cancer - a phase III study (PRINCE).

OBJECTIVE: To investigate non-inferiority of intermittent docetaxel compared to continuous docetaxel in patients with metastatic castration-resistant prostate cancer (mCRPC). PATIENT AND METHODS: The investigator initiated randomised phase III study included 187 chemotherapy-naïve patients with mCRPC who were allocated to two treatment arms: intermittent docetaxel and continuous docetaxel. Docetaxel was applied in both arms as weekly (35 mg/m2 ) or 3-weekly (75 mg/m2 ). The primary endpoint was 1-year survival, which was tested for non-inferiority (margin δ = 0.125). The secondary endpoints were: overall survival (OS), progression-free survival (PFS), median time to treatment failure (TTF), and toxicity. RESULTS: Of 156 eligible patients, 78 were allocated to each arm. The intermittent treatment met the non-inferiority criteria for 1-year survival (two-sided 95% confidence interval, -0.12, 18, P = 0.022), but not for OS, according to the result of a post hoc analysis. The differences between the study arms in PFS and TTF were not significant. The median (range) treatment holiday in the intermittent arm was 110 (13-486) days, or 38% of the overall treatment duration. Safety profiles of both study arms were comparable. The main limitation of this study was that the planned number of patients could not be recruited. CONCLUSION: Intermittent docetaxel chemotherapy was non-inferior to continuous therapy for 1-year survival; non-inferiority in regard to OS was not reached.

Influences of Surgical Volume on Perioperative and Oncological Outcomes Following Radical Prostatectomy.

INTRODUCTION: The purpose of this study was to evaluate whether the number of radical prostatectomies per hospital per year is associated with stage distribution, surgical techniques or quality related outcome in Germany. MATERIALS AND METHODS: A German Internet-based database was analyzed. Hospitals were categorized according to their yearly radical prostatectomy (RP) volume. Patient's characteristics, RP techniques, and outcome-related parameters were compared between the different hospital volume categories. RESULTS: A total of 6,447 patients were analyzed. The highest rate of organ-confined disease and the lowest rate of extracapsular invasion have been demonstrated in very low-volume centres (72.6%

Perioperative Changes and Progress in Photoselective Vaporization of the Prostate with GreenLight XPS 180 W System: A Single Center Experience.

PURPOSE: The study aimed to evaluate progression of GreenLight-XPS 180 W photoselective vaporization of the prostate (GL-XPS) with respect to effectiveness, efficacy, and safety over time at a tertiary referral high volume center. METHODS: The retrospective study included 375 men who underwent GL-XPS for symptomatic benign prostate obstruction (BPO) between June 2010 and February 2015. Primary outcome measurements were operation time (OT; min) and effective laser time (LT; min of OT) analyzed with regard to prostatic volume (PV; mL) (group 1 <40 mL up to 4 >80 mL in 20 mL steps) and the year of surgery (2010-2015). RESULTS: The median age was 72 years (range 64-79), the median PV was 58 mL (range 33-98) and the median PV increased from 42 mL in 2012 to 80 mL in 2015. The OT and LT clearly correlated with the PV, being doubled for glands of median 95 mL compared to median 30 mL while the applied laser energy per LT likewise steadily increased. Overall, both OT and LT could be significantly reduced each year by 37% (OT; p < 0.05) and 36% (LT; p < 0.05) within 5 years. The hospital stay (days) and catheterization time (days) remained constant, without any changes over time. The overall complication rate (Clavien-Dindo >2) ranged from 36 to 15% between 2010 and 2015. The pre (median 22 + 4) and postoperative International Prostate Symptom Score-Quality of Life (median 5 + 1) showed a sufficient reduction in symptomatic BPO. CONCLUSION: GL-XPS is a safe and effective surgical method for symptomatic BPO. Our single center experience showed a significant improvement of both OT and effective LT within 5 years whilst maintaining stable low complication rate and high patient satisfaction.

Enzalutamide in metastatic prostate cancer before chemotherapy.

BACKGROUND: Enzalutamide is an oral androgen-receptor inhibitor that prolongs survival in men with metastatic castration-resistant prostate cancer in whom the disease has progressed after chemotherapy. New treatment options are needed for patients with metastatic prostate cancer who have not received chemotherapy, in whom the disease has progressed despite androgen-deprivation therapy. METHODS: In this double-blind, phase 3 study, we randomly assigned 1717 patients to receive either enzalutamide (at a dose of 160 mg) or placebo once daily. The coprimary end points were radiographic progression-free survival and overall survival. RESULTS: The study was stopped after a planned interim analysis, conducted when 540 deaths had been reported, showed a benefit of the active treatment. The rate of radiographic progression-free survival at 12 months was 65% among patients treated with enzalutamide, as compared with 14% among patients receiving placebo (81% risk reduction; hazard ratio in the enzalutamide group, 0.19; 95% confidence interval [CI], 0.15 to 0.23; P<0.001). A total of 626 patients (72%) in the enzalutamide group, as compared with 532 patients (63%) in the placebo group, were alive at the data-cutoff date (29% reduction in the risk of death; hazard ratio, 0.71; 95% CI, 0.60 to 0.84; P<0.001). The benefit of enzalutamide was shown with respect to all secondary end points, including the time until the initiation of cytotoxic chemotherapy (hazard ratio, 0.35), the time until the first skeletal-related event (hazard ratio, 0.72), a complete or partial soft-tissue response (59% vs. 5%), the time until prostate-specific antigen (PSA) progression (hazard ratio, 0.17), and a rate of decline of at least 50% in PSA (78% vs. 3%) (P<0.001 for all comparisons). Fatigue and hypertension were the most common clinically relevant adverse events associated with enzalutamide treatment. CONCLUSIONS: Enzalutamide significantly decreased the risk of radiographic progression and death and delayed the initiation of chemotherapy in men with metastatic prostate cancer. (Funded by Medivation and Astellas Pharma; PREVAIL ClinicalTrials.gov number, NCT01212991.).

Systemic therapy in metastatic renal cell carcinoma.

PURPOSE: Current systemic treatment of targeted therapies, namely the vascular endothelial growth factor-antibody (VEGF-AB), VEGF receptor tyrosine kinase inhibitor (TKI) and mammalian target of rapamycin (mTOR) inhibitors, have improved progression-free survival and replaced non-specific immunotherapy with cytokines in metastatic renal cell carcinoma (mRCC). METHODS: A panel of experts convened to review currently available phase 3 data for mRCC treatment of approved agents, in addition to available EAU guideline data for a collaborative review as the plurality of substances offers different options of first-, second- and third-line treatment with potential sequencing. RESULTS: Sunitinib and pazopanib are approved treatments in first-line therapy for patients with favorable- or intermediate-risk clear cell RCC (ccRCC). Temsirolimus has proven benefit over interferon-alfa (IFN-α) in patients with non-clear cell RCC (non-ccRCC). In the second-line treatment TKIs or mTOR inhibitors are treatment choices. Therapy options after TKI failure consist of everolimus and axitinib. Available third-line options consist of everolimus and sorafenib. Recently, nivolumab, a programmed death-1 (PD1) checkpoint inhibitor, improved overall survival benefit compared to everolimus after failure of one or two VEGFR-targeted therapies, which is likely to become the first established checkpoint inhibitor in mRCC. Data for the sequencing of agents remain limited. CONCLUSIONS: Despite the high level of evidence for first and second-line treatment in mRCC, data for third-line therapy are limited. Possible sequences include TKI-mTOR-TKI or TKI-TKI-mTOR with the upcoming checkpoint inhibitors in perspective, which might settle a new standard of care after previous TKI therapy.