Profiling the proteoforms of urinary prostate-specific antigen by capillary electrophoresis-mass spectrometry

Early detection of prostate cancer may lead to the overdiagnosis and overtreatment of patients as well as missing significant cancers. The current diagnostic approach uses elevated serum concentrations of prostate-specific antigen (PSA) as an indicator of risk. However, this test has been widely criticized as it shows poor specificity and sensitivity. In order to improve early detection and diagnosis, several studies have investigated whether different PSA proteoforms are correlated to prostate cancer. Until now, studies and methodologies for the comprehensive characterization of PSA proteoforms from biofluids are scarce. For this purpose, we developed an intact protein assay to analyze PSA by capillary electrophoresis-electrospray ionization-mass spectrometry after affinity purification from patients? urine. Here, we determined six proteolytic cleavage variants. In regard to glycosylation, tri-, di-, mono- and non-sialylated complex-type N-glycans were found on non-cleaved PSA, as well as the non-glycosylated variant. The performance of the intact protein assay was assessed using a pooled sample, obtaining an inter-day variability of 15%. Furthermore, urinary patient samples were analyzed by intact protein analysis and a bottom-up approach (glycopeptide analysis). This combined approach revealed complimentary information on both levels, demonstrating the benefit of using two orthogonal techniques to provide a thorough profile of urinary PSA.Significance: The detection of clinically relevant prostate cancer requires a more specific and sensitive biomarker and, in this case, several PSA proteoforms may be able to aid or improve the current PSA test. However, a comprehensive analysis of the intact PSA proteoform profile is still lacking. This study investigated the PSA proteoforms present in urine and, in particular, determined the relative contribution of cleaved PSA and noncleaved PSA forms to the total glycosylation profile. Importantly, intact protein analysis did not require further sample treatment before being measured by CE-ESI-MS. Furthermore, its glycosylation was also assessed in a bottom-up approach to provide complementary information. Overall, these results represent an important basis for future characterization and biomarker studies.Proteomic

Phase 1 study of chemoradiotherapy combined with nivolumab +/- Ipilimumab for the curative treatment of muscle-invasive bladder cancer

Background: Muscle-invasive bladder cancer (MIBC) has a poor prognosis. Chemoradiotherapy (CRT) in selected patients has comparable results to radical cystectomy. Results of neoadjuvant immune checkpoint inhibitors (ICIs) before radical cystectomy are promising. We hypothesize that ICI concurrent to CRT (iCRT) is safe and may improve treatment outcomes. Objective: To determine the safety of iCRT for MIBC. Design, setting, and participants: This multicenter, phase 1b, open-label, dose-escalation study determined the safety of CRT with three ICI regimens in patients with nonmetastatic (T2-4aN0-1) MIBC. Twenty-six patients received mitomycin C/capecitabine and 20 x 2.75 Gy to the bladder. Tolerability was evaluated in a cohort of up to ten patients. If two or fewer out of the first six patients or three or fewer of ten patients experienced dose-limiting toxicity (DLT), accrual continued in the next cohort. Intervention: Patients received nivolumab 480 mg (NIVO480), nivolumab 3 mg/kg and ipilimumab 1 mg/kg (NIVO3 + IPI1), or nivolumab 1 mg/kg and ipilimumab 3 mg/kg (IPI3 + NIVO1). Outcome measurements and statistical analysis: The primary endpoint was safety. Secondary objectives were response rate, disease-free survival, metastatic-free survival (MFS), and overall survival (OS). Results and limitations: In the NIVO480 cohort, no patients experienced DLT. The NIVO3 + IPI1 2 patients experienced DLT, thrombocytopenia (grade 4), and asystole (grade 5). IPI3 + NIVO1 was discontinued after three out of six patients experienced DLT. Clinically significant adverse events (AEs) of grade >= 3 occurred in zero, three, and five patients in the NIVO480, NIVO3 + IPI1, and IPI3 + NIVO1 groups, respectively. The most common AEs were immune related and gastrointestinal. MFS and OS were 90% at 2 yr for NIVO480 and 90% at 1 yr for NIVO3 + IPI1. Limitations include the absence of a centralized pathology and radiology review, and a lack of biomarker analysis. Conclusions: In this dose-finding study of iCRT, the regimens of nivolumab monotherapy and nivolumab 3 mg/kg with ipilimumab 1 mg/kg have acceptable toxicity. Patient summary: We tested the safety of a new bladder-sparing treatment modality for muscle-invasive bladder cancer patients, combiningimmunecheckpoint inhibitors simultaneously with chemoradiotherapy. We report that two regimens, nivolumab monotherapy and nivolumab 3 mg/kg with ipilimumab 1 mg/kg, are safe and can be used in phase 3 trials

Pair-matched patient-reported quality of life and early oncological control following focal irreversible electroporation versus robot-assisted radical prostatectomy

Purpose: The design, conduct and completion of randomized trials for curative prostate cancer (PCa) treatments are challenging. To evaluate the effect of robot-assisted radical prostatectomy (RARP) versus focal irreversible electroporation (IRE) on patient-reported quality of life (QoL) and early oncological control using propensity-scored matching. Methods: Patients with T1c–cT2b significant PCa (hig

A Cluster-Randomized Trial of Two Strategies to Improve Antibiotic Use for Patients with a Complicated Urinary Tract Infection

Contains fulltext : 152505.PDF (publisher's version ) (Open Access)BACKGROUND: Up to 50% of hospital antibiotic use is inappropriate and therefore improvement strategies are urgently needed. We compared the effectiveness of two strategies to improve the quality of antibiotic use in patients with a complicated urinary tract infection (UTI). METHODS: In a multicentre, cluster-randomized trial 19 Dutch hospitals (departments Internal Medicine and Urology) were allocated to either a multi-faceted strategy including feedback, educational sessions, reminders and additional/optional improvement actions, or a competitive feedback strategy, i.e. providing professionals with non-anonymous comparative feedback on the department's appropriateness of antibiotic use. Retrospective baseline- and post-intervention measurements were performed in 2009 and 2012 in 50 patients per department, resulting in 1,964 and 2,027 patients respectively. Principal outcome measures were nine validated guideline-based quality indicators (QIs) that define appropriate antibiotic use in patients with a complicated UTI, and a QI sumscore that summarizes for each patient the appropriateness of antibiotic use. RESULTS: Performance scores on several individual QIs showed improvement from baseline to post-intervention measurements, but no significant differences were found between both strategies. The mean patient's QI sum score improved significantly in both strategy groups (multi-faceted: 61.7% to 65.0%, P = 0.04 and competitive feedback: 62.8% to 66.7%, P = 0.01). Compliance with the strategies was suboptimal, but better compliance was associated with more improvement. CONCLUSION: The effectiveness of both strategies was comparable and better compliance with the strategies was associated with more improvement. To increase effectiveness, improvement activities should be rigorously applied, preferably by a locally initiated multidisciplinary team. TRIAL REGISTRATION: Nederlands Trial Register 1742

Long-term efficacy and safety of nilutamide plus castration in advanced prostate cancer, and the significance of early prostate specific antigen normalization

Purpose: We studied the long-term efficacy and tolerability of nilutamide, a nonsteroidal antiandrogen, combined with orchiectomy in patients with advanced prostate cancer. Materials and Methods: A large double-blind trial was done on 457 patients randomized to receive nilutamide or placebo after orchiectomy. Results: At 8.5 years of followup significant benefits were found for progression and survival in favor of patients receiving nilutamide and orchiectomy. In addition, normalized prostate specific antigen levels at 3 months from the start of therapy were predictive of good long-term outcome. Moreover, combined androgen blockade with nilutamide increased the chance of patients having normal prostate specific antigen levels at 3 months. Nilutamide was well tolerated in the long term with no increase in the incidence of drug specific adverse events. Conclusions: With long-term followup of patients with advanced prostate cancer, the combination of nilutamide and orchiectomy has significant benefits in interval to progression and improved survival compared to orchiectomy and placeb

Nationwide treatment patterns and survival of older patients with prostate cancer

Contains fulltext : 203364.pdf (publisher's version ) (Closed access)OBJECTIVES: To examine the clinical features, applied treatments, and survival of older patients with prostate cancer compared with younger patients. MATERIAL AND METHODS: All patients diagnosed with prostate cancer between 2005 and 2015 in the Netherlands were identified from the nationwide population-based Netherlands Cancer Registry (NCR). Patient and tumour characteristics, as well as applied treatments, were described by age groups and prognostic risk groups. Relative survival rates were determined, including multivariable relative survival regression analyses. Additionally, to assess if age was associated with receiving curative treatment, a multivariable logistic regression analysis was performed. RESULTS: In total, 48% of all patients were 70years of age or older. Older patients had a higher prostate specific antigen (PSA) level, a higher Gleason score, as well as a higher disease stage at diagnosis. The 10-year relative survival decreased with increasing age, and after adjustment for disease stage, Gleason score, PSA level, and comorbidities, older patients had a worse survival rate. Older patients with intermediate- or high-risk disease appeared to be treated less often with curative intent compared with younger patients after adjustment for tumour stage, Gleason score, PSA level, and comorbidities. Older patients with intermediate/high risk prostate cancer treated with curative intent showed a 10-year relative survival rate similar to younger patients. CONCLUSION: The survival of older patients was worse than younger patients. This might be due to suboptimal treatment, as older patients were less often treated with curative intent. Although the increased risk of treatment complications should be considered, age alone should not be a decisive factor when offering a treatment

Laser treatment of the prostate using the Urolase fiber : the Dutch experience

Contains fulltext : 24238___.pdf (publisher's version ) (Open Access

BioXmark (R) liquid fiducial markers for image-guided radiotherapy in muscle invasive bladder cancer: a safety and performance trial

Objective: This study evaluated the performance of the novel liquid fiducial marker (BioXmark (R)) in IGRT for bladder cancer.Methods: 20 patients with muscle invasive bladder cancer were entered in this prospective, single center, Phase I--II study. The novel BioXmark (R) liquid markers were injected around the tumor using a flexible cystoscopy. Visibility and stability of the markers were evaluated on planning-CT and CBCT. Prospectively defined threshold for success was set at a visibility of 75%.Results: In total, 76 markers were implanted in 20 patients. Of those, 60 (79% 95% CI +/- 9%) were visible on CT scan. Due to the learning curve of the technique, the visibility improved in the last 75% of patients (86% visibility) compared to the first 25% of patients with 58% visibility. Concerning stability of the BioXmark (R) marker, all visible markers after CT acquisition were still detectable at the last CBCT without displacement. In 15/20 (75%) of the patients, three or more markers were visible on CT. No BioXmark (R) related adverse events were reported.Conclusion: The success rate of this novel fiducial marker was 79%, which is above the prospectively defined threshold rate. A distinct learning curve of the injection of the liquid marker was seen over the study period. The marker showed sustained visibility and positional stability during treatment phases and also appears to be safe and easy to inject.Advances in knowledge: This novel liquid BioXmark (R) marker seems to be a very promising tool in daily-adaptive IGRT for bladder preserving chemoradiotherapy in muscle invasive bladder cancer.Biological, physical and clinical aspects of cancer treatment with ionising radiatio