PBX3 is a putative biomarker of aggressive prostate cancer.

There is a great need to identify new and better prognostic and predictive biomarkers to stratify prostate cancer patients for optimal treatment. The aims of this study were to characterize the expression profile of pre-B cell leukemia homeobox (PBX) transcription factors in prostate cancer with an emphasis on investigating whether PBX3 harbours any prognostic value. The expression profile of PBX3 and PBX1 in prostate tissue was determined by immunohistochemical and immunoblot analysis. Furthermore, the expression of PBX3 transcript variants was analyzed by RT-PCR, NanoString Technologies®, and by analyzing RNA sequence data. The potential of PBX3 to predict prognosis, either at mRNA or protein level, was studied in four independent cohorts. PBX3 was mainly expressed in the nucleus of normal prostate basal cells, while it showed cytosolic expression in prostatic intraepithelial neoplasia and cancer cells. We detected four PBX3 transcript variants in prostate tissue. Competing risk regression analysis revealed that high PBX3 expression was associated with slower progression to castration resistant prostate cancer (sub-hazard ratio (SHR) 0.18, 95% CI: 0.081-0.42, p values < 0.001). PBX3 expression had a high predictive accuracy (area under the curve (AUC) = 0.82) when combined with Gleason score and age. Patients undergoing radical prostatectomy, with high levels of PBX3 mRNA, had improved prostate cancer specific survival compared to patients expressing low levels (SHR 0.21, 95% CI: 0.46-0.93, p values < 0.001, and AUC = 0.75). Our findings strongly indicate that PBX3 has potential as a biomarker, both as part of a larger gene panel and as an immunohistochemical marker, for aggressive prostate cancer.

Preoperative magnetic resonance imaging for detecting uni- and bilateral extraprostatic disease in patients with prostate cancer.

OBJECTIVE: The objective of the study was to evaluate the diagnostic accuracy of preoperative magnetic resonance imaging (MRI) for detecting uni- and bilateral extraprostatic disease (T3) in patients with prostate cancer (PCa). MATERIALS AND METHODS: This prospective study included 199 patients with biopsy-proven PCa who underwent MRI prior to radical prostatectomy from December 2009 to July 2012. Extraprostatic extension and seminal vesicle invasion represented T3 disease, and was classified as uni- (right or left) or bilateral. MRI detection of T3 disease was assessed by descriptive statistics and odds ratio (OR). Whole-mount histopathology was used as the reference standard. RESULTS: The overall prevalence of pT3 was 105/199 (53 %), unilateral in 81/105 (77 %) and bilateral in 24/105 (23 %). The sensitivity of MRI for predicting pT3 was 76/105 (72 %), specificity 61/94 (65 %), accuracy 137/199 (69 %), and OR 4.8 (95 % CI 2.7-8.8). A complete match with respect to the laterality of pT3 was found in 52/105 (50 %), and the side-specific accuracy was 113/199 (57 %). When unilateral pT3 was found, MRI falsely suggested contralateral T3 in 4/81 (5 %) and bilateral in 8/81 (10 %). When bilateral pT3 was found, MRI falsely suggested unilateral T3 in 12/24 (50 %). CONCLUSION: Magnetic resonance imaging (MRI) detected 72 % of all patients with T3 disease, and the accuracy dropped from 69 to 57 % when considering the laterality of T3. Thus far, the MRI technique is not yet adequate to meet the increasing demands of accurate diagnosis of locally advanced disease, and the contemporary MRI staging should be careful.

Reduction of lower urinary tract symptoms in prostate cancer patients treated with robot assisted laparoscopic prostatectomy.

PROBLEM: The aim of this study was to evaluate the change in LUTS in patients treated with RALP and to assess factors that may predict an improvement of LUTS. MATERIALS AND METHOD: In our institutional prospective research registry, 1935 patients operated in the period between 2009 and 2021 with complete baseline- and 12-month EPIC-26 questionnaire were eligible for the study. Also SF-12 data estimating general quality of life (QoL) were analyzed. A LUTS summary score was constructed from the two questions concerning voiding stream/residual and frequency, and transformed linearly to a 0-100 scale with higher scores representing less symptoms  A change of 6 points or more were considered Meaningful Clinical Differences (MCD). Two summary scores were calculated from the SF-12 - a mental component score (MCS-12) and a physical component score (PCS-12). Multivariate regression was used to estimate covariates associated with postoperative MCD, MCS-12 and PCS-12. RESULTS: Mean change of LUTS-score showed an increase of 10 points 12-months post-RALP.  52% of patients achieved MCD. In multivariate logistic regression, preoperative LUTS was statistically significant associated with MCD. Reduction of LUTS was associated improved mean score of MCS-12 and PCS-12. DISCUSSION AND CONCLUSION: Along with information about risk for urinary incontinence after RALP, patients with LUTS at baseline must be informed that these symptoms may be reduced after RALP. In our study, this LUTS reduction was associated with better general QoL.

Five-year progression-free survival in 577 patients operated on with laparoscopic radical prostatectomy for localized prostate cancer.

OBJECTIVE: Laparoscopic radical prostatectomy (LRP) was introduced in the Department of Urology, Oslo University Hospital, in 2002. The aim of this study was to report mid-term oncology results and survival data. MATERIAL AND METHODS: From February 2002 to November 2007, 582 consecutive patients with localized prostate cancer underwent LRP. Data were collected prospectively into a database. RESULTS: Mean and median follow-up after LRP was 30.3 months (± 15.5) and 36.0 months (range 3-72). Five patients (1%) were lost during follow-up. Two patients died of prostate cancer during the study period and 10 patients died of other causes. The overall positive surgical margin (PSM) rate was 29% and decreased to 13% for the last 100 patients. The overall PSA progression-free survival (PFS) was 85% at 3 years and 73% at 5 years. Gleason score in the tumour specimen, pT stage and surgical margins were statistical significant independent predictors of biochemical PFS. CONCLUSION: These oncology results and 5-year PFS data after LRP are in line with other reports.

Low Blood Levels of LRG1 Before Radical Prostatectomy Identify Patients with High Risk of Progression to Castration-resistant Prostate Cancer.

Background: After radical prostatectomy (RP), depending on stage, up to 40% of patients with prostate cancer (PCa) will experience biochemical failure (BF). Despite salvage therapy, approximately one-third of these patients will need permanent hormone therapy (pHT) and are at risk of progression to castration-resistant PCa (CRPC). Prognostic markers herald the need for neoadjuvant, adjuvant, or multimodal treatment. Objective: To evaluate the added value of blood LRG1 in predicting treatment failure in patients who have undergone radical prostatectomy (RP). Design setting and participants: We quantified LRG1 in serum or plasma sampled before radical prostatectomy from patients from the Martini-Klinik (Martini; n = 423), the Danish CuPCa cohort (CuPCa; n = 182), and Oslo University Hospital (OUH; n = 145). Outcome measurements and statistical analysis: The endpoints were BF, pHT, and CRPC. The association between LRG1 and survival outcomes was evaluated using Kaplan-Meier estimation and Cox proportional-hazards modeling. The added predictive value of LRG1 in nested models was estimated using the concordance index, time-dependent area under the receiver operating characteristic curve, and decision curve analysis. Results and limitations: In multivariable Cox models using preoperative characteristics, LRG1 was associated with an estimated lower risk of BF in the Martini cohort (adjusted hazard ratio [aHR] 0.68, 95% confidence interval [CI] 0.52-0.90) and in the CuPCa cohort (aHR 0.47, 95% CI 0.30-0.73). Using preoperative prognostic variables, our data showed that doubling of LRG1 was also associated with a lower risk of pHT receipt in the CuPCa cohort (aHR 0.43, 95% CI 0.20-0.93) and of CRPC development in the OUH cohort (aHR 0.32, 95% CI 0.15-0.69). Similar aHR values were observed using either preoperative or postoperative variables for all endpoints. Conclusions: PCa patients with high blood LRG1 are at lower risk of BF, pHT receipt, and progression to CRPC. Since LRG1 adds value to established prognostic models, new prognostic factor combinations including LRG1 should be considered in future studies. Patient summary: We measured concentrations of the blood-based protein LRG1 before surgery for prostate cancer. Patients with high LRG1 levels had better disease-free survival, suggesting that LRG1 can help in predicting prognosis.

Robotic salvage pelvic lymph node dissection for locoregional recurrence after radical prostatectomy: a single institution experience.

OBJECTIVES: To assess treatment response (PSA < 0.2 ng/ml), need for additional therapy and complication rate after robot assisted salvage pelvic lymph node dissection (sPLND). MATERIAL AND METHODS: Analysis of outcomes data from radical prostatectomy (RP) patients consecutively operated with robot assisted sPLND due to biochemical recurrence and positron-emission tomography (PET)/computed tomography (CT)-detected nodal recurrence of pelvic lymph nodes. RESULTS: Sixty-nine patients underwent robotic sPLND after a median time of 47 months post- RP. Sixty-four patients (93%) had malignant lymph nodes upon histological assessment of sPLND specimen. Twenty patients (29%) achieved PSA < 0.2 ng/ml 6 weeks postoperatively. After median (IQR) follow-up of 15 months (10-27), fourteen patients (20%) still had PSA < 0.2 ng/ml without additional therapy and forty-one patients (59%) had started additional therapy. No significant predictor for treatment response was found. Postoperative complications occurred in 14 patients (20%). Eleven of these complications were classified as Clavien-Dindo grade 1. CONCLUSION: Oncological benefit of sPLND as the only salvage procedure seems to be limited, though almost one third of patients achieved treatment response. Clinical trials are needed to determine if sPLND as part of a multimodal treatment may improve outcome.

Improved patient-reported functional outcomes after nerve-sparing radical prostatectomy by using NeuroSAFE technique.

Purpose: To explore whether prostatectomized men report improved post-operative erectile function and urinary control dependent on the application of intra-operative frozen section examination (NeuroSAFE) during nerve-sparing radical prostatectomies (NS-RPs).Methods: Pre- and post-RP responses to the sexual domain and the urinary incontinence subscale of EPIC-26 were analyzed in 95 and 312 men from a NeuroSAFEGroup (Martini-Klinik, Hamburg, Germany) and a Non-NeuroSAFE Group (Oslo University Hospital, Norway), respectively, undergoing NS-RPs for ≤ cT2 prostate cancer. All patients had intra-prostatic tumors as evaluated by Digital Rectal Examination. Statistical significance in bivariate and multi-variable analyses: p < 0.05.Results: With similar oncological outcomes and not associated with the performance of bilateral or unilateral NS-RP within each group patients from the NeuroSAFE Group had better sexuality outcomes than those from the NonNeuroSAFE Group (p < 0.01). Age and pre-RP sexual function represented significant co-variables. In pre-RP potent men, erectile function was preserved in 74% of men in the NeuroSAFE Group and in 46% in those from the NonNeuroSAFE Group (p < 0.01). Any superior continence-saving effect of NeuroSAFE was limited. The non-randomized small-sized observational study design represents the observations' main limitation.Conclusions: Our study indicates that NeuroSAFE contributes to preservation of post-RP erectile function. If confirmed in a randomized trial the NeuroSAFE should be applied in patients undergoing NS-RP for maximal preservation of post-RP sexual function.

Switching from laparoscopic radical prostatectomy to robot assisted laparoscopic prostatectomy: comparing oncological outcomes and complications.

OBJECTIVES: To compare oncological outcomes and complication rates based on the Clavien classification between laparoscopic radical prostatectomies (LRP) and robot-assisted laparoscopic radical prostatectomies (RALP). MATERIAL AND METHODS: In a prospective quality registry clinical data were consecutively entered for 544 LRP and 1081 RALP patients operated from 2003 to the end of 2012. Complications within 90 days postoperatively were assessed according to the Clavien classification and compared between LRP and RALP patients. Univariate and multivariate analyses of logistic regression were used to fit oncological outcomes and complication data. RESULTS: The mean operation time was 213 and 135 minutes in LRP and RALP patients, respectively. Pathological T3a stage (pT3a) in the RALP group was more frequent than in the LRP group, 32.4% versus 17.8%, respectively. For pT2 tumours, positive surgical margins (PSM) rate for LRP and RALP, was 20.3% vs 10.6%, respectively (p < .001). In the LRP group 74 patients (13.6%) reported 104 and in the RALP group 141 patients (13.0%) reported 177 complications (p = .75). Seventeen (3.1%) LRP patients and 15 (1.4%) RALP patients had Clavien grade IIIb complications (p = .017). Surgical reintervention was necessary in 14 patients (2.6%) and 17 patients (1.6%) in the LRP and RALP group, respectively (p = .04). CONCLUSION: Switching from LRP to RALP resulted in a much shorter operation time without compromising oncological outcome. There was no statistically significant difference in overall complication-rates between LRP and RALP. However, LRP patients had more serious complications and increased need for surgical reintervention compared to RALP patients.

Preclinical Amyloid-ß and Axonal Degeneration Pathology in Delirium.

BACKGROUND: The clinical relevance of brain ß-amyloidosis in older adults without dementia is not established. As delirium and dementia are strongly related, studies on patients with delirium may give pathophysiological clues. OBJECTIVE: To determine whether the Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers amyloid-ß 1-42 (Aß42), total tau (T-tau), and phosphorylated tau (P-tau) are associated with delirium in hip fracture patients with and without dementia. METHODS: CSF was collected in conjunction to spinal anesthesia in 129 patients. Delirium was assessed using the Confusion Assessment Method once daily in all patients, both pre- and postoperatively. The diagnosis of dementia at admission was based upon clinical consensus. CSF levels of Aß42, T-tau, and P-tau were analyzed. RESULTS: In patients without dementia, we found lower CSF Aß42 levels (median, 310 ng/L versus 489 ng/L, p = 0.006), higher T-tau levels (median, 505 ng/L versus 351 ng/L, p = 0.02), but no change in P-tau in patients who developed delirium (n = 16) compared to those who remained lucid (n = 49). Delirious patients also had lower ratios of Aß42 to T-tau (p < 0.001) and P-tau (p = 0.001) relative to those without delirium. CSF Aß42 and T-tau remained significantly associated with delirium status in adjusted analyses. In patients with dementia, CSF biomarker levels did not differ between those with (n = 54) and without delirium (n = 10). CONCLUSION: The reduction in CSF Aß42, indicating ß-amyloidosis, and increase in T-tau, indicating neurodegeneration, in hip fracture patients without dementia developing delirium indicates that preclinical AD brain pathology is clinically relevant and possibly plays a role in delirium pathophysiology.

Tomato-based randomized controlled trial in prostate cancer patients: Effect on PSA.

BACKGROUND & AIMS: The effect of lycopene-containing foods in prostate cancer development remains undetermined. We tested whether a lycopene-rich tomato intervention could reduce the levels of prostate specific antigen (PSA) in prostate cancer patients. METHODS: Prior to their curative treatment, 79 patients with prostate cancer were randomized to a nutritional intervention with either 1) tomato products containing 30 mg lycopene per day; 2) tomato products plus selenium, omega-3 fatty acids, soy isoflavones, grape/pomegranate juice, and green/black tea (tomato-plus); or 3) control diet for 3 weeks. RESULTS: The main analysis, which included patients in all risk categories, did not reveal differences in changes of PSA-values between the intervention and control groups. Post-hoc, exploratory analyses within intermediate risk (n = 41) patients based on tumor classification and Gleason score post-surgery, revealed that median PSA decreased significantly in the tomato group as compared to controls (-2.9% and +6.5% respectively, p = 0.016). In separate post-hoc analyses, we observed that median PSA-values decreased by 1% in patients with the highest increases in plasma lycopene, selenium and C20:5 n-3 fatty acid, compared to an 8.5% increase in the patients with the lowest increase in lycopene, selenium and C20:5 n-3 fatty acid (p = 0.003). Also, PSA decreased in patients with the highest increase in lycopene alone (p = 0.009). CONCLUSIONS: Three week nutritional interventions with tomato-products alone or in combination with selenium and n-3 fatty acids lower PSA in patients with non-metastatic prostate cancer. Our observation suggests that the effect may depend on both aggressiveness of the disease and the blood levels of lycopene, selenium and omega-3 fatty acids.

A Randomized Controlled Trial To Assess and Compare the Outcomes of Two-core Prostate Biopsy Guided by Fused Magnetic Resonance and Transrectal Ultrasound Images and Traditional 12-core Systematic Biopsy.

BACKGROUND: Prostate biopsy guided by computer-assisted fusion of magnetic resonance imaging (MRI) and transrectal ultrasound (TRUS) images (MRI group) has not yet been compared with 12-core random biopsy (RB; control group) in a randomized controlled trial (RCT). OBJECTIVE: To compare the rate of detection of clinically significant prostate cancer (csPCa) between the two groups. DESIGN, SETTING, AND PARTICIPANTS: This RCT included 175 biopsy-naïve patients with suspicion for prostate cancer, randomized to an MRI group (n=86) and a control group (n=89) between September 2011 and June 2013. INTERVENTION: In the MRI group, two-core targeted biopsy (TB) guided by computer-assisted fusion of MRI/TRUS images of MRI-suspicious lesions was followed by 12-core RB. In the control group, both two-core TB for abnormal digital rectal examination (DRE) and/or TRUS-suspicious lesions and 12-core RB were performed. In patients with normal MRI or DRE/TRUS, only 12-core RB was performed. OUTCOMES MEASUREMENTS AND STATISTICAL ANALYSIS: The detection rates for any cancer and csPCa were compared between the two groups and between TB and RB. RESULTS AND LIMITATIONS: Detection rates for any cancer (MRI group 51/86, 59%; control group 48/89, 54%; p=0.4) and csPCa (38/86, 44% vs 44/89, 49%; p=0.5) did not significantly differ between the groups. Detection of csPCa was comparable between two-core MRI/TRUS-TB (33/86, 38%) and 12-core RB in the control group (44/89, 49%; p=0.2). In a subset analysis of patients with normal DRE, csPCa detection was similar between two-core MRI/TRUS-TB (14/66, 21%) and 12-core RB in the control group (15/60, 25%; p=0.7). Among biopsy-proven csPCas in MRI group, 87% (33/38) were detected by MRI/TRUS-TB. The definition of csPCa was only based on biopsy outcomes. CONCLUSION: Overall csPCa detection was similar between the MRI and control groups. Two-core MRI/TRUS-TB was comparable to 12-core RB for csPCa detection. PATIENT SUMMARY: Our randomized controlled trial revealed a similar rate of prostate cancer detection between targeted biopsy guided by magnetic resonance imaging (MRI) and transrectal ultrasound (TRUS) and 12-core random biopsy. The traditional 12-core random biopsy may be replaced by two-core MRI/TRUS targeted biopsy for detection of clinically significant prostate cancer.

Does preoperative magnetic resonance imaging reduce the rate of positive surgical margins at radical prostatectomy in a randomised clinical trial?

BACKGROUND: Magnetic resonance imaging (MRI) has the potential to help the surgeon tailor radical prostatectomy (RP) more accurately according to the location and extent of the tumour and thereby reduce the rate of positive surgical margins (PSMs). OBJECTIVE: To evaluate the benefit of performing MRI prior to RP. DESIGN, SETTING, AND PARTICIPANTS: This single-institution randomised trial included 438 patients between December 2009 and June 2012 who were scheduled for robot-assisted laparoscopic prostatectomy. The study was registered (ClinicalTrials.gov identifier NCT01347320). INTERVENTION: Patients were preoperatively randomly assigned to non-MRI or MRI groups. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary end point was the difference in the PSM rates between the two groups. Secondary end points were the rates of PSMs in clinical subgroups. Summary statistics were extracted from descriptive analyses, chi-square, or Fisher exact test, and logistic regression was used to analyse the data according to the intention-to-treat principle. RESULTS AND LIMITATIONS: A total of 216 patients were randomised to non-MRI; 222 were randomised to MRI. There were 49 cases (23%) of PSMs in the non-MRI group and 43 cases (19%) in the MRI group (p=0.4). The relative and absolute risk reduction was 15% and 4%, respectively. Patients with cT1 constituted 55% of the cohort, in which the rate of PSMs was 27% in the non-MRI group and 16% in the MRI group (p=0.035). The relative and absolute risk reduction was 41% and 11%, respectively. A limitation was suboptimal communication between the radiologist and urologist. CONCLUSIONS: MRI prior to RP did not reduce the overall risk for PSMs in this patient cohort. However, at subgroup analysis we observed a possible benefit of MRI in patients with cT1. PATIENT SUMMARY: This study could not demonstrate a definite benefit of performing magnetic resonance imaging before surgery for all patients. However, there was a possible improved result in patients in which physical examination could not detect the cancer.

Does a surgeon's annual radical prostatectomy volume predict the risk of positive surgical margins and urinary incontinence at one-year follow-up? Findings from a prospective national study.

OBJECTIVE: This study aimed to assess the prevalence of positive surgical margins (PSM) and urinary incontinence (UI) in relation to surgeons' annual radical prostatectomy (RP) volume. MATERIAL AND METHODS: This national study prospectively assessed 521 preoperatively continent patients with prostate cancer (PCa), scheduled for RP by surgeons with high (>50), medium (20-50) or low annual volume (<20) at 14 urological departments in Norway. Patients responded to UI questions from the Expanded Composite prostate cancer index (EPIC-50) before and 1 year after RP. UI was defined as "use of pad(s)" and/or "a moderate or severe urinary leakage problem (ULP)". Preoperative prediction of PSMs and UI was explored in multivariate regression analyses with the following independent variables: surgeons' annual RP volume, type of hospital (university versus community), patient's health, sociodemographic features and PCa characteristics. RESULTS: Based on histopathological reports, the overall PSM rate was 26%, with differences between the high- (18%), medium- (28%) and low-volume (44%) groups. Increasing PSM rates were predicted by surgeons belonging to the low- and medium-volume categories, prostate-specific antigen> 10 µg/l, Gleason score >7, patient age >65 years and <12 years of education. At 1-year follow-up 40% reported UI, without significant differences between the volume groups. Only 46% of those who used pad(s) experienced ULP. UI was predicted by clinical category ≥T2 and community type of hospital, but not by surgeons' annual RP volume. CONCLUSIONS. Preoperative counselling should take into account the relationship between surgeon's annual RP volume and PSM rate and the current knowledge about UI and ULP.