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

Correction:How the COVID-19 pandemic highlights the necessity of animal research (vol 30, pg R1014, 2020)

(Current Biology 30, R1014–R1018; September 21, 2020) As a result of an author oversight in the originally published version of this article, a number of errors were introduced in the author list and affiliations. First, the middle initials were omitted from the names of several authors. Second, the surname of Dr. van Dam was mistakenly written as “Dam.” Third, the first name of author Bernhard Englitz was misspelled as “Bernard” and the surname of author B.J.A. Pollux was misspelled as “Pullox.” Finally, Dr. Keijer's first name was abbreviated rather than written in full. These errors, as well as various errors in the author affiliations, have now been corrected online

Validation of a novel multivariate method of defining HIV-associated cognitive impairment

Background. The optimum method of defining cognitive impairment in virally suppressed people living with HIV is unknown. We evaluated the relationships between cognitive impairment, including using a novel multivariate method (NMM), patient– reported outcome measures (PROMs), and neuroimaging markers of brain structure across 3 cohorts. Methods. Differences in the prevalence of cognitive impairment, PROMs, and neuroimaging data from the COBRA, CHARTER, and POPPY cohorts (total n = 908) were determined between HIV-positive participants with and without cognitive impairment defined using the HIV-associated neurocognitive disorders (HAND), global deficit score (GDS), and NMM criteria. Results. The prevalence of cognitive impairment varied by up to 27% between methods used to define impairment (eg, 48% for HAND vs 21% for NMM in the CHARTER study). Associations between objective cognitive impairment and subjective cognitive complaints generally were weak. Physical and mental health summary scores (SF-36) were lowest for NMM-defined impairment (P < .05). There were no differences in brain volumes or cortical thickness between participants with and without cognitive impairment defined using the HAND and GDS measures. In contrast, those identified with cognitive impairment by the NMM had reduced mean cortical thickness in both hemispheres (P < .05), as well as smaller brain volumes (P < .01). The associations with measures of white matter microstructure and brain-predicted age generally were weaker. Conclusion. Different methods of defining cognitive impairment identify different people with varying symptomatology and measures of brain injury. Overall, NMM-defined impairment was associated with most neuroimaging abnormalities and poorer selfreported health status. This may be due to the statistical advantage of using a multivariate approac

The mitochondrial genome as a biomarker for prostate cancer

This thesis discusses the potential for the mitochondrial genome (mtDNA) to inform the prostate cancer (PCa) disease process and to be used as a biomarker. PCa is a highly prevalent cancer, with incidence increasing in modern societies with an aging population. Ensuring the best treatment for each individual patient requires a high level of tumor characterization. The possibility of using the mtDNA as a biomarker to better predict and monitor disease is explored in this thesis. Through mtDNA sequencing, we show that mutations in mtDNA are associated with pathology grade and outcome and validate clinical association in a meta-analysis. We further find that mtDNA mutations are affected by systemic therapy. We then establish possible impact of mtDNA mutations using a novel approach of combining computational prediction and protein visualization. Using this approach, we establish 24 mutations with a high likelihood of impacting mtDNA function in PCa. Additional aspects of the mtDNA are then investigated, using qPCR to confirm a dysregulated mtDNA content within PCa. Finally, we acquire additional evidence of mtDNA methylation and show a potential association with TMPRSS2-ERG fusion status and mtDNA methylation. We conclude that the inclusion of mitochondrial genome investigation in existing tumor characterization or as a stand-alone test could be used in future prostate cancer practice. We point out that much detail of mitochondrial genome function and its contribution and alteration in cancer is still poorly understood and requires further investigation to fully understand pathogenesis of prostate cancer

GAS5-encoded intronic snoRNAs produce specific sdRNAs overexpressed in aggressive prostate cancer

Small non-coding RNAs, such as miRNAs, are implicated in carcinogenesis. To investigate changes in the entire small RNA transcriptome in prostate cancer (PCa) we analyzed 11 clinical sample pools representing different stages of PCa by deep sequencing. We found that most C/D-box small nucleolar RNAs (snoRNAs) are specifically processed to smaller snoRNA-derived RNAs (sdRNAs) highly expressed in PCa. In particular, SNORD78 produces sdRNAs strongly up-regulated in PCa. Together with 9 other snoRNAs, SNORD78 is encoded in the introns of the Growth Arrest Specific 5 gene (GAS5). Examination of SNORD78 and the positioned in a neighboring intron SNORD44 showed that both snoRNAs produce predominantly one sdRNA fragment each, specifically originating from the 3'-arm (SNORD78) or the 5'-arm (SNORD44) of the precursor sequence. Inspection of the secondary structures of SNORD44 and SNORD78 revealed that they have a degenerated C'/D' box and can fold in a tight hairpin similarly to miRNAs. In contrast, SNORD74 and SNORD81 that also encoded in introns of GAS5, contain canonical C'/D' boxes and each produce three equally expressed sdRNAs. Quantitative real time PCR analysis in an independent patient cohort of 106 fresh-frozen clinical samples confirmed the significant up-regulation of all four snoRNAs and their derivative sdRNAs in PCa samples compared to normal tissue. Interestingly, the increased expression of snoRNAs and sdRNAs was not associated with elevated levels of GAS5 transcript. Based on these results, we conclude that (i) separate regulatory mechanisms control the posttranscriptional processing of the spliced GAS5 transcript and the encoded in its introns snoRNAs; (ii) SNORD44, SNORD78, SNORD74 and SNORD81 function as precursors of different sdRNAs; (iii) SNORD44, SNORD78, SNORD74 and SNORD81 and their derivative sdRNAs are significantly up-regulated in PCa and carry biomarker potential for this disease. Citation Format: Elena S. Martens-Uzunova, Anton Kalsbeek, Youri Hoogstrate, Adam Baker, Soren Jensby Nielsen, Tapio Visakorpi, Chris Bangma, Guido Jenster. GAS5-encoded intronic snoRNAs produce specific sdRNAs overexpressed in aggressive prostate cancer. [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer: Mechanisms to Medicines ; 2015 Dec 4-7; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2016;76(6 Suppl):Abstract nr A45

Initial multicentre experience of 68gallium-PSMA PET/CT guided robot-assisted salvage lymphadenectomy: acceptable safety profile but oncological benefit appears limited

ObjectivesTo evaluate the safety and short-term oncological outcomes of (68)gallium-labelled prostate-specific membrane antigen (Ga-68-PSMA) positron-emission tomography (PET)/computed tomography (CT)-directed robot-assisted salvage node dissection (RASND) for prostate cancer oligometastatic nodal recurrence

C/D-box snoRNA-derived RNA production is associated with malignant transformation and metastatic progression in prostate cancer

Small nucleolar RNAs (snoRNAs) are dynamically regulated in different tissues and affected in disease. SnoRNAs are processed further to stable smaller RNAs. We sequenced the small RNA transcriptome of prostate cancer (PCa) at different PCa stages and generated a quantified catalogue of 3927 small non-coding RNAs (sncRNAs) detected in normal and malignant prostate tissue. From these, only 1524 are microRNAs. The remaining 2401 sncRNAs represent stable sncRNAs species that originate from snoRNA, tRNA and other sncRNAs. We show that snoRNA-derived RNAs (sdRNAs) display stronger differential expression than microRNAs and are massively upregulated in PCa. SdRNAs account for at least one third of all small RNAs with expression changes in tumor compared to normal adjacent tissue. Multiple sdRNAs can be produced from one snoRNA in a manner related to the conservation of structural snoRNA motifs. Q-PCR analysis in an independent patient cohort (n=106) confirmed the processing patterns of selected snoRNAs (SNORD44, SNORD78, SNORD74 and SNORD81) and the cancer-associated up-regulation of their sdRNAs observed in sequencing data. Importantly, expression of SNORD78 and its sdRNA is significantly higher in a subset of patients that developed metastatic disease demonstrating that snoRNA and sdRNAs may present as novel diagnostic and/or prognostic biomarkers for PCa.This article has supplementary files, which can be found here:http://dx.doi.org/10.18632/oncotarget.417

Focal irreversible electroporation as primary treatment for localized prostate cancer

To determine the safety, quality of life (QoL) and short-term oncological outcomes of primary focal IRE for the treatment of localized prostate cancer. To identify potential risk factors for oncological failure. Patients that met both the consensus guidelines on patient criteria and selection methods for primary focal therapy were eligible for analysis. Focal IRE was performed for organ-confined clinically significant PCa, being high-volume Gleason sum score 6 (ISUP grade 1) or any Gleason sum score 7 (ISUP grade 2-3). Oncologic, adverse event and QoL outcome data with a minimum of 6 months follow-up were analysed. Patient characteristics and peri-operative treatment parameters were compared for patients with and without oncological failure on follow-up biopsy. Wilcoxon's Signed Rank Test, Wilcoxon's Rank Sum Test and Chi-square test were used to assess statistically significant differences in paired continuous, unpaired continuous and categorical variables respectively. A total of 63 patients met all eligibility criteria and were included for final analysis. No high-grade adverse events occurred. Quality of life questionnaire analysis demonstrated no significant change in physical (p=0.81), mental (p=0.48), bowel (p=0.25) and both urinary QoL domains (p=0.41 and p=0.25); there was a mild decrease in the sexual QoL domain (median score 66 at baseline vs 54 at 6 months, p=0.0003). Compared to baseline PSA, a decline of 70% (1.8, IQR 0.96-4.8) was seen between 6-12 months. A narrow safety margin (p=0.047) and system errors (p=0.010) were identified as potential early risk factors for in-field oncological failure. In-field and whole-gland oncological control on follow-up biopsies was 84% (38/45) and 76% (34/45); this increased to 97% (38/39) and 87% (34/39) when patients treated with a narrow safety margin and system errors were excluded. Our data supports the safety and feasibility of focal IRE as a primary treatment for localized PCa with effective short-term oncological control in carefully selected men. This article is protected by copyright. All rights reserve

Feasibility and safety of focal irreversible electroporation as salvage treatment for localized radio-recurrent prostate cancer

Objectives To evaluate the feasibility, safety, early quality-of-life (QoL) and oncological outcomes of salvage focal irreversible electroporation (IRE) for radio-recurrent prostate cancer (PCa). Patients and Methods Patients with localized, radio-recurrent PCa without evidence of metastatic or nodal disease were offered focal IRE according to the consensus guidelines. Patients with a minimum follow-up of 6 months were eligible for analysis. Adverse events were monitored using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE version 4.0). Patient-reported QoL data were collected at baseline, 6 weeks, 3, 6 and 12 months using the Expanded Prostate Cancer Index Composite (EPIC), the American Urological Association (AUA) symptom score and the 12-item short-from health survey (SF-12) physical and mental component summary questionnaires. Oncological control was evaluated according to serial prostate-specific antigen (PSA), 6-month multiparametric magnetic resonance imaging (mpMRI) and 12-month prostate biopsy. Wilcoxon's signed rank test was used to assess QoL differences over time in paired continuous variables. Results A total of 18 patients were included in the analysis. The median follow-up was 21 months. No high-grade adverse events (CTCAE >2) or recto-urethral fistulae occurred. No statistically significant declines were observed in QoL outcomes (n = 11) on the EPIC bowel domain (P = 0.29), AUA symptom score (P = 0.77), or the SF-12 physical (P = 0.17) or SF-12 mental component summary (P = 0.77) questionnaires. At 6 months, patients who had undergone salvage therapy experienced a decline in EPIC sexual domain score (median of 38-24; P = 0.028) and urinary domain (median of 96-92; P = 0.074). Pad-free continence and erections sufficient for intercourse were preserved in 8/11 patients and 2/6 patients at 6 months, respectively. The mpMRI was clear in 11/13 patients, with two single out-field lesions (true-positive and false-positive, respectively). The median (interquartile range) nadir PSA was 0.39 (0.04-0.43) mu g/L. Three and four patients experienced biochemical failure using the Phoenix and Stuttgart definitions of biochemical failure, respectively. Eight out of 10 of the patients were clear of any PCa on follow-up biopsy, whereas two patients had significant PCa on follow-up biopsy (International Society of Urological Pathology grade 5). Conclusion Our short-term safety, QoL and oncological control data show that focal IRE is a feasible salvage option for localized radio-recurrent PCa. A prospective multicentre study (FIRE trial) has been initiated that will provide further insight into the ability of focal IRE to obtain oncological control of radio-recurrent PCa with acceptable patient morbidit