The Value of PSA Density in Combination with PI-RADS™ for the Accuracy of Prostate Cancer Prediction

ObjectivesTo identify areas of agreement and disagreement in the implementation of multi-parametric magnetic resonance imaging (mpMRI) of the prostate in the diagnostic pathway. Materials and MethodsFifteen UK experts in prostate mpMRI and/or prostate cancer management across the UK (involving nine NHS centres to provide for geographical spread) participated in a consensus meeting following the Research and Development Corporation and University of California-Los Angeles (UCLA-RAND) Appropriateness Method, and were moderated by an independent chair. The experts considered 354 items pertaining to who can request an mpMRI, prostate mpMRI protocol, reporting guidelines, training, quality assurance (QA) and patient management based on mpMRI levels of suspicion for cancer. Each item was rated for agreement on a 9-point scale. A panel median score of 7 constituted agreement' for an item; for an item to reach consensus', a panel majority scoring was required. ResultsConsensus was reached on 59% of items (208/354); these were used to provide recommendations for the implementation of prostate mpMRI in the UK. Key findings include prostate mpMRI requests should be made in consultation with the urological team; mpMRI scanners should undergo QA checks to guarantee consistently high diagnostic quality scans; scans should only be reported by trained and experienced radiologists to ensure that men with unsuspicious prostate mpMRI might consider avoiding an immediate biopsy. ConclusionsOur consensus statements demonstrate a set of criteria that are required for the practical dissemination of consistently high-quality prostate mpMRI as a diagnostic test before biopsy in men at risk.

/pdf/national-implementation-of-multi-parametric-magnetic-20kkc6y8ti.pdf

National implementation of multi‐parametric magnetic resonance imaging for prostate cancer detection – recommendations from a UK consensus meeting

DNA double-strand breaks (DSBs) are toxic lesions, which if improperly repaired can result in cell death or genomic instability. DSB repair is usually facilitated by the classical non-homologous end joining (C-NHEJ), or homologous recombination (HR) pathways. However, a mutagenic alternative NHEJ pathway, microhomology-mediated end joining (MMEJ), can also be deployed. While MMEJ is suppressed by C-NHEJ, the relationship between HR and MMEJ is less clear. Here, we describe a role for HR genes in suppressing MMEJ in human cells. By monitoring DSB mis-repair using a sensitive HPRT assay, we found that depletion of HR proteins, including BRCA2, BRCA1 or RPA, resulted in a distinct mutational signature associated with significant increases in break-induced mutation frequencies, deletion lengths and the annealing of short regions of microhomology (2-6 bp) across the break-site. This signature was dependent on CtIP, MRE11, POLQ and PARP, and thus indicative of MMEJ. In contrast to CtIP or MRE11, depletion of BRCA1 resulted in increased partial resection and MMEJ, thus revealing a functional distinction between these early acting HR factors. Together these findings indicate that HR factors suppress mutagenic MMEJ following DSB resection.

A role for human homologous recombination factors in suppressing microhomology-mediated end joining.

While cancer, and especially testicular cancer and Hodgkin’s disease, affects male fertility in many ways, the current increase of survival of male cancer patients of reproductive age or earlier has emerged as a new challenge to their subsequent ability to father children. Cancer treatments, including surgery, radiotherapy and chemotherapy, can have a transitory as well as a permanent detrimental impact on male fertility. Gonadotoxic effects and the length of time for sperm recovery after radiotherapy depends not only on initial semen quality, but also on gonadal dosage and the delivery method after chemotherapy, on the type of regimens and dosages and on the spermatogenesis phase that each drug impacts. Combination treatment with radiotherapy and chemotherapy will induce more gonadotoxicity than either modality alone. Although efforts to prevent gonadal toxicity in cancer treatment are routinely applied, sperm cryopreservation remains the gold standard to maintain male fertility after cancer survival. Fertility preservation for prepubertal boys presents the greatest problem due to the absence of mature sperm in their gonads. In this area, research efforts are concentrated on cryopreservation of immature gametes and, in particular, techniques for their maturation and proliferation after thawing.

/pdf/impact-of-cancer-and-cancer-treatment-on-male-fertility-20olu2b889.pdf

Impact of cancer and cancer treatment on male fertility.

The Efficacy of Multiparametric Magnetic Resonance Imaging and Magnetic Resonance Imaging Targeted Biopsy in Risk Classification for Patients with Prostate Cancer on Active Surveillance

Objectives This exploratory pilot study aimed to evaluate whether adding imaging biomarkers to conventional staging improves complete excision rates after undergoing radical prostatectomy (RP) in the United Kingdom for patients who have not undergone population prostate specific antigen screening. We primarily considered estimates of lesion volume and location based on computer-aided analysis of ultrasound (US) raw radiofrequency (RF) data acquired during trans-rectal ultrasound. The imaging analysis device used had been shown to accurately detect tumor loci within the prostate in previous studies. Methods and materials US raw RF data were collected from motorized trans-rectal ultrasound of 68 consecutive men with operable prostate cancer. In this cohort (group 1), locations and volume measurements of lesions suspected of harboring cancer on US raw RF data analysis by prostate HistoScanning, were added to conventional presurgical staging.The unexposed control group comprised 100 men who underwent conventional presurgical staging only (group 2): 50 were operated before and 50 operated after group 1 recruitment. Changes to pre-operative surgical planning and positive lateral margins of RP prostate pathological specimens were the primary outcomes. Data were collected using a Microsoft Excel database and analyzed using Stata. Results Baseline demographics were comparable. In group 1, consideration of the additional imaging biomarkers led to changes in 27 (19.9%) operative surgical plans. Absolute rate reduction of a positive surgical margin (PSM) attributable to the imaging-biomarkers was 13.3% ( P = 0.029). For stage pT3, PSM rate was reduced from 45.8% ( n = 44) to 21.2% ( n = 11) ( P = 0.0028). Conclusions Obtaining quantitative measurements of preoperative imaging biomarkers appears to improve PSM rates of patients undergoing RP. The greatest PSM rate reduction was observed for pT3 tumors.

Using imaging biomarkers to improve the planning of radical prostatectomies

There are an estimated 35 million people living with human immunodeficiency virus (HIV) globally, 19 million of whom are unaware of their HIV status and, in the absence of antiretroviral therapy (ART), will have a shortened life expectancy. Although ART remains the "gold standard" for treatment of HIV infection, the requirement for lifelong treatment poses multiple challenges for the patient. These include stigma, an untenable pill burden, side effects, and the threat of viral resistance in the case of non-compliance. This review evaluates the challenges of accessing, delivering, and sustaining ART for people living with HIV and will discuss the case for pursuing a goal of HIV cure, the potential benefits of such a cure for the individual patient, and the current potential candidates for such a cure.

Lifelong antiretroviral therapy or HIV cure: The benefits for the individual patient.

Understanding the mechanisms of chromosomal double-strand break repair (DSBR) provides insight into genome instability, oncogenesis and genome engineering, including disease gene correction. Research into DSBR exploits rare-cutting endonucleases to cleave exogenous reporter constructs integrated into the genome. Multiple reporter constructs have been developed to detect various DSBR pathways. Here, using a single endogenous reporter gene, the X-chromosomal disease gene encoding hypoxanthine phosphoribosyltransferase (HPRT), we monitor the relative utilization of three DSBR pathways following cleavage by I-SceI or CRISPR/Cas9 nucleases. For I-SceI, our estimated frequencies of accurate or mutagenic non-homologous end-joining and gene correction by homologous recombination are 4.1, 1.5 and 0.16%, respectively. Unexpectedly, I-SceI and Cas9 induced markedly different DSBR profiles. Also, using an I-SceI-sensitive HPRT minigene, we show that gene correction is more efficient when using long double-stranded DNA than single- or double-stranded oligonucleotides. Finally, using both endogenous HPRT and exogenous reporters, we validate novel cell cycle phase-specific I-SceI derivatives for investigating cell cycle variations in DSBR. The results obtained using these novel approaches provide new insights into template design for gene correction and the relationships between multiple DSBR pathways at a single endogenous disease gene.

/pdf/use-of-the-hprt-gene-to-study-nuclease-induced-dna-double-4rbdz4mzd4.pdf

Use of the HPRT gene to study nuclease-induced DNA double-strand break repair

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Using imaging biomarkers to improve the planning of radical prostatectomies

Lifelong antiretroviral therapy or HIV cure: The benefits for the individual patient.

Use of the HPRT gene to study nuclease-induced DNA double-strand break repair