Genomic evaluation of multiparametric magnetic resonance imaging-visible and -nonvisible lesions in clinically localised prostate cancer

Background: The prostate cancer (PCa) diagnostic pathway is undergoing a radical change with the introduction of multiparametric magnetic resonance imaging (mpMRI), genomic testing, and different prostate biopsy techniques. It has been proposed that these tests should be used in a sequential manner to optimise risk stratification. Objective: To characterise the genomic, epigenomic, and transcriptomic features of mpMRI-visible and -nonvisible PCa in clinically localised disease. Design, setting, and participants: Multicore analysis of fresh prostate tissue sampled immediately after radical prostatectomy was performed for intermediate- to high-risk PCa. Intervention: Low-pass whole-genome, exome, methylation, and transcriptome profiling of patient tissue cores taken from microscopically benign and cancerous areas in the same prostate. Circulating free and germline DNA was assessed from the blood of five patients. Outcome measurement and statistical analysis: Correlations between preoperative mpMRI and genomic characteristics of tumour and benign prostate samples were assessed. Gene profiles for individual tumour cores were correlated with existing genomic classifiers currently used for prognostication. Results and limitations: A total of 43 prostate cores (22 tumour and 21 benign) were profiled from six whole prostate glands. Of the 22 tumour cores, 16 were tumours visible and six were tumours nonvisible on mpMRI. Intratumour genomic, epigenomic, and transcriptomic heterogeneity was found within mpMRI-visible lesions. This could potentially lead to misclassification of patients using signatures based on copy number or RNA expression. Moreover, three of the six cores obtained from mpMRI-nonvisible tumours harboured one or more genetic alterations commonly observed in metastatic castration-resistant PCa. No circulating free DNA alterations were found. Limitations include the small cohort size and lack of follow-up. Conclusions: Our study supports the continued use of systematic prostate sampling in addition to mpMRI, as avoidance of systematic biopsies in patients with negative mpMRI may mean that clinically significant tumours harbouring genetic alterations commonly seen in metastatic PCa are missed. Furthermore, there is inconsistency in individual genomics when genomic classifiers are applied. Patient summary: Our study shows that tumour heterogeneity within prostate tumours visible on multiparametric magnetic resonance imaging (mpMRI) can lead to misclassification of patients if only one core is used for genomic analysis. In addition, some cancers that were missed by mpMRI had genomic aberrations that are commonly seen in advanced metastatic prostate cancer. Avoiding biopsies in mpMRI-negative cases may mean that such potentially lethal cancers are missed

Chronic Antidiabetic Sulfonylureas In Vivo: Reversible Effects on Mouse Pancreatic β-Cells

In a mouse study aiming to understand why long-term treatment for type 2 diabetes with sulfonylureas eventually fails, Colin Nichols and Maria Remedi suggest that slow restoration of insulin secretion may be possible after a drug-resting period

Intranodal signal suppression in pelvic MR lymphography of prostate cancer patients: a quantitative comparison of ferumoxtran-10 and ferumoxytol

Objectives The key to MR lymphography is suppression of T2* MR signal in normal lymph nodes, while retaining high signal in metastatic nodes. Our objective is to quantitatively compare the ability of ferumoxtran-10 and ferumoxytol to suppress the MR signal in normal pelvic lymph nodes. Methods In 2010, a set of consecutive patients who underwent intravenous MR Lymphography (MRL) were included. Signal suppression in normal lymph nodes in T2*-weighted images due to uptake of USPIO (Ultra-Small Superparamagnetic Particles of Iron Oxide) was quantified. Signal suppression by two USPIO contrast agents, ferumoxtran-10 and ferumoxytol was compared using Wilcoxon’s signed rank test. Results Forty-four patients were included, of which all 44 had a ferumoxtran-10 MRL and 4 had additionally a ferumoxytol MRL. A total of 684 lymph nodes were identified in the images, of which 174 had been diagnosed as metastatic. USPIO-induced signal suppression in normal lymph nodes was significantly stronger in ferumoxtran-10 MRL than in ferumoxytol MRL (p < 0.005). Conclusions T2* signal suppression in normal pelvic lymph nodes is significantly stronger with ferumoxtran-10 than with ferumoxytol, which may affect diagnostic accuracy

Simulated required accuracy of image registration tools for targeting high-grade cancer components with prostate biopsies

Contains fulltext : 117653.pdf (publisher's version ) (Closed access)OBJECTIVES: To estimate the required spatial alignment accuracy for correctly grading 95 \% of peripheral zone (PZ) prostate cancers using a system for multiparametric magnetic resonance (MR)-guided ultrasound (US) biopsies. METHODS: PZ prostate tumours were retrospectively annotated on multiparametric MR series using prostatectomy specimens as reference standard. Tumours were grouped based on homogeneous and heterogeneous apparent diffusion coefficient (ADC) values using an automated ADC texture analysis method. The proportion of heterogeneous tumours containing a distinct, high Gleason grade tumour focus yielding low ADC values was determined. Both overall tumour and high-grade focal volumes were calculated. All high-grade target volumes were then used in a simulated US biopsy system with adjustable accuracy to determine the hit rate. RESULTS: An ADC-determined high-grade tumour focus was found in 63 \% of the PZ prostate tumours. The focal volumes were significantly smaller than the total tumour volumes (median volume of 0.3 ml and 1.1 ml respectively). To correctly grade 95 \% of the aggressive tumour components the target registration error (TRE) should be smaller than 1.9 mm. CONCLUSIONS: To enable finding the high Gleason grade component in 95 \% of PZ prostate tumours with MR-guided US biopsies, a technical registration accuracy of 1.9 mm is required. KEY POINTS : • MRI can identify foci of prostatic cancer with reduced apparent diffusion coefficients • Sixty-three per cent of prostatic peripheral zone tumours contain high-grade tumour low ADC foci • The median volume of such foci is 0.3 ml • Biopsy targets are significantly smaller than whole tumour volumes • Simulated registration accuracy is 1.9 mm for correctly grading 95 \% of tumours

MR-Guided Biopsy of the Prostate: An Overview of Techniques and a Systematic Review

Context:\ud Systematic transrectal ultrasound-guided biopsy (TRUSBx) is the gold standard for detecting prostate cancer. This systematic approach is characterized by low sensitivity (39–52%) and high specificity (81–82%). Magnetic resonance (MR)–guided biopsy techniques are becoming more and more available, but there is no current consensus on the optimal technique.\ud \ud Objective:\ud This review presents an overview of MR-guided biopsy techniques for prostate cancer detection.\ud \ud Evidence acquisition:\ud Current literature was reviewed regarding MR-guided biopsy for prostate cancer detection. A literature search was performed using the commercially available MedLine online search engine. Combinations of the following search and Medical Subject Headings terms were applied to retrieve relevant articles: “magnetic resonance,” “prostatic neoplasms,” and “biopsy.” Review articles and studies describing techniques other than MR-guided biopsy were excluded.\ud \ud Evidence synthesis:\ud Biopsy of the prostate is an essential procedure for determining optimal treatment. Systematic TRUSBx is the gold standard, but it fails to detect numerous tumors. Diagnostic MR imaging provides more accurate selection of regions in which tumors are suspected. Using these diagnostic images during an MR-directed biopsy procedure improves quality of the biopsy. In open MR scanners, the prebiopsy images often must be registered to the real-time biopsy images because open MR scanners do not provide optimal tissue contrast; thus, the patient must first be examined in a closed MR scanner and then biopsied in an open scanner. The advantage of open MR over closed MR is that the physician has easy patient access. With special equipment, prostate MR-guided biopsy is also possible in a closed system. Closed MR scanners can be used for the prebiopsy scan as well as for the biopsy procedure.\ud \ud Conclusions:\ud The combination of a diagnostic MR examination and MR-guided biopsy is a promising tool and may be used in patients with previous negative TRUSBx

On the mechanism of ADP-induced alteration of sulphonylurea sensitivity in cardiac ATP-sensitive K(+) channels

1. To study the mechanism of regulation of sulphonylurea sensitivity in ATP-sensitive K(+) (K(ATP)) channels, we used the inside-out patch clamp technique in guinea-pig ventricular myocytes. 2. In the absence of nucleotides, the half maximal concentration of tolbutamide inhibition of K(ATP) channels (IC(50)) was 0.4 mM, and it decreased to 0.1 mM when 0.1 mM ATP was added. 3. Increasing the ADP concentration from 0 to 0.1 and 0.3 mM in the absence of ATP shifted the IC(50) from 0.4 to 5.3 and 11.4 mM, respectively. Increasing the ADP concentration further to 1 and 3 mM conversely reduced the IC(50) to 9.5 and 4.4 mM, respectively. 4. In the absence of Mg(2+) and ADP, the IC(50) was calculated to 16.6 mM which was found to be less, 12.3, 5.1 and 2.5 mM, respectively, when the ADP concentration was increased to 0.1, 0.3 and 1 mM. 5. The IC(50)s for tolbutamide obtained at various concentrations of ADP in the presence of Mg(2+) were best fitted by equations reflecting a model that assumed two binding sites for ADP; one is a high affinity site that reduces the sensitivity to the sulphonylurea, while the other is a low affinity site that increases such sensitivity. Dissociation constants calculated for ADP to sites 1 and 2 were 2.6 μM and 46.7 mM, respectively. In the absence of Mg(2+), data were fitted by equations corresponding to a single site model (site 2); the dissociation constant for ADP was 25.0 mM. 6. It is concluded that ADP modifies tolbutamide sensitivity by binding to two sites. The high affinity site is strongly Mg(2+)-dependent, whereas the low affinity site is Mg(2+)-independent