Interaction between race and prostate cancer treatment benefit in the Veterans Health Administration.

BACKGROUND: Studies have demonstrated that Black men may undergo definitive prostate cancer (CaP) treatment less often than men of other races, but it is unclear whether they are avoiding overtreatment of low-risk disease or experiencing a reduction in appropriate care. The authors' aim was to assess the role of race as it relates to treatment benefit in access to CaP treatment in a single-payer population. METHODS: The authors used the Veterans Health Administration (VHA) Corporate Data Warehouse to perform a retrospective cohort study of veterans diagnosed with low- or intermediate-risk CaP between 2011 and 2017. RESULTS: The authors identified 35,427 men with incident low- or intermediate-risk CaP. When they controlled for covariates, Black men had 1.05 times the odds of receiving treatment in comparison with non-Black men (P < .001), and high-treatment-benefit men had 1.4 times the odds of receiving treatment in comparison with those in the low-treatment-benefit group (P < .001). The interaction of race and treatment benefit was significant, with Black men in the high-treatment-benefit category less likely to receive treatment than non-Black men in the same treatment category (odds ratio, 0.89; P < .001). CONCLUSIONS: Although race does appear to influence the receipt of definitive treatment in the VHA, this relationship varies in the context of the patient's treatment benefit, with Black men receiving less definitive treatment in high-benefit situations. The influence of patient race at high treatment benefit levels invites further investigation into the driving forces behind this persistent disparity in this consequential group.

Performance of native and gadoxetate-enhanced liver and spleen T1 mapping for noninvasive diagnosis of clinically significant portal hypertension: preliminary results.

PURPOSE: In this preliminary study, our aim was to assess the utility of quantitative native-T1 (T1-pre), iron-corrected T1 (cT1) of the liver/spleen and T1 mapping of the liver obtained during hepatobiliary phase (T1-HBP) post-gadoxetate disodium, compared to spleen size/volume and APRI (aspartate aminotransferase-to-platelet ratio index) for noninvasive diagnosis of clinically significant portal hypertension [CSPH, defined as hepatic venous pressure gradient (HVPG) ≥ 10 mm Hg]. METHODS: Forty-nine patients (M/F: 27/22, mean age 53y) with chronic liver disease, HVPG measurement and MRI were included. Breath-held T1 and cT1 measurements were obtained using an inversion recovery Look-Locker sequence and a T2* corrected modified Look-Locker sequence, respectively. Liver T1-pre (n = 49), spleen T1 (obtained pre-contrast, n = 47), liver and spleen cT1 (both obtained pre-contrast, n = 30), liver T1-HBP (obtained 20 min post gadoxetate disodium injection, n = 36) and liver T1 uptake (ΔT1, n = 36) were measured. Spleen size/volume and APRI were also obtained. Spearman correlation coefficients were used to assess the correlation between each of liver/spleen T1/cT1 parameters, spleen size/volume and APRI with HVPG. ROC analysis was performed to determine the performance of measured parameters for diagnosis of CSPH. RESULTS: There were 12/49 (24%) patients with CSPH. Liver T1-pre (r = 0.287, p = 0.045), liver T1-HBP (r = 0.543, p = 0.001), liver ΔT1 (r = - 0.437, p = 0.008), spleen T1 (r = 0.311, p = 0.033) and APRI (r = 0.394, p = 0.005) were all significantly correlated with HVPG, while liver cT1, spleen cT1 and spleen size/volume were not. The highest AUCs for the diagnosis of CSPH were achieved with liver T1-HBP, liver ΔT1 and spleen T1: 0.881 (95%CI 0.76-1.0, p = 0.001), 0.852 (0.72-0.98, p = 0.002) and 0.781 (0.60-0.95, p = 0.004), respectively. CONCLUSION: Our preliminary results demonstrate the potential of liver T1 mapping obtained during HBP post gadoxetate disodium for the diagnosis of CSPH. These results require further validation.

Liver cT1 decreases following direct-acting antiviral therapy in patients with chronic hepatitis C virus.

PURPOSE: Direct-acting antiviral therapies (DAAs) for treatment of chronic hepatitis C virus (HCV) have excellent rates of viral eradication, but their effect on regression of liver fibrosis is unclear. The primary aim was to use magnetic resonance imaging (MRI) and spectroscopy (MRS) to evaluate changes in liver fibrosis, liver fat and liver iron content (LIC) in patients with chronic HCV following treatment with DAAs. METHODS: In this prospective study, 15 patients with chronic HCV due to start treatment with DAAs and with transient elastography (TE) > 8 kPa were recruited consecutively. Patients underwent MRI and MRS at baseline (before treatment), and at 24 weeks and 48 weeks after the end of treatment (EoT) for the measurement of liver cT1 (fibroinflammation), liver fat and T2* (LIC). RESULTS: All patients achieved a sustained virological response. Liver cT1 showed significant decreases from baseline to 24 weeks post EoT (876 vs 806 ms, p = 0.002, n = 15), baseline to 48 weeks post EoT (876 vs 788 ms, p = 0.0002, n = 13) and 24 weeks post EoT to 48 weeks post EoT (806 vs 788 ms, p = 0.016, n = 13). Between baseline and 48 weeks EoT significant reduction in liver fat (5.17% vs 2.65%, p = 0.027) and an increase in reported LIC (0.913 vs 0.950 mg/g, p = 0.021) was observed. CONCLUSION: Liver cT1 decreases in patients with chronic HCV undergoing successful DAA treatment. The relatively fast reduction in cT1 suggests a reduction in inflammation rather than regression of fibrosis.

A Clinical Reminder Order Check Intervention to Improve Guideline-concordant Imaging Practices for Men With Prostate Cancer: A Pilot Study.

OBJECTIVE: To understand how to potentially improve inappropriate prostate cancer imaging rates we used National Comprehensive Cancer Network's guidelines to design and implement a Clinical Reminder Order Check (CROC) that alerts ordering providers of potentially inappropriate imaging orders in real-time based on patient features of men diagnosed with low-risk prostate cancer. METHODS: We implemented the CROC at VA New York Harbor Healthcare System from April 2, 2015 to November 15, 2017. We then used VA administrative claims from the VA's Corporate Data Warehouse to analyze imaging rates among men with low-risk prostate cancer at VA New York Harbor Healthcare System before and after CROC implementation. We also collected and cataloged provider responses in response to overriding the CROC in qualitative analysis. RESULTS FIFTY SEVEN PERCENT: (117/205) of Veterans before CROC installation and 73% (61/83) of Veterans post-intervention with low-risk prostate cancer received guideline-concordant care. CONCLUSION: While the decrease in inappropriate imaging during our study window was almost certainly due to many factors, a Computerized Patient Record System-based CROC intervention is likely associated with at least moderate improvement in guideline-concordant imaging practices for Veterans with low-risk prostate cancer.

Repeatability and reproducibility of multiparametric magnetic resonance imaging of the liver.

As the burden of liver disease reaches epidemic levels, there is a high unmet medical need to develop robust, accurate and reproducible non-invasive methods to quantify liver tissue characteristics for use in clinical development and ultimately in clinical practice. This prospective cross-sectional study systematically examines the repeatability and reproducibility of iron-corrected T1 (cT1), T2*, and hepatic proton density fat fraction (PDFF) quantification with multiparametric MRI across different field strengths, scanner manufacturers and models. 61 adult participants with mixed liver disease aetiology and those without any history of liver disease underwent multiparametric MRI on combinations of 5 scanner models from two manufacturers (Siemens and Philips) at different field strengths (1.5T and 3T). We report high repeatability and reproducibility across different field strengths, manufacturers, and scanner models in standardized cT1 (repeatability CoV: 1.7%, bias -7.5ms, 95% LoA of -53.6 ms to 38.5 ms; reproducibility CoV 3.3%, bias 6.5 ms, 95% LoA of -76.3 to 89.2 ms) and T2* (repeatability CoV: 5.5%, bias -0.18 ms, 95% LoA -5.41 to 5.05 ms; reproducibility CoV 6.6%, bias -1.7 ms, 95% LoA -6.61 to 3.15 ms) in human measurements. PDFF repeatability (0.8%) and reproducibility (0.75%) coefficients showed high precision of this metric. Similar precision was observed in phantom measurements. Inspection of the ICC model indicated that most of the variance in cT1 could be accounted for by study participants (ICC = 0.91), with minimal contribution from technical differences. We demonstrate that multiparametric MRI is a non-invasive, repeatable and reproducible method for quantifying liver tissue characteristics across manufacturers (Philips and Siemens) and field strengths (1.5T and 3T).

A new method for estimating the importance of hydrophobic groups in the binding site of a protein.

Interactions between the hydrophobic regions of a binding site and those of a complementary ligand are often observed to provide the driving force for binding. We present a new method for the analysis of hydrophobic regions in the binding site of a protein that considers not only atom type but also the nonadditive effects arising from the shape and extent of a nonpolar region. The method has been parametrized using a purpose-built genetic algorithm to optimize its ability to identify those regions that are more likely to form a strong interaction with a nonpolar ligand group. We demonstrate the ability of this method to account for changes in the shape and extent of the exposed nonpolar surface, using both artificial and protein examples. The method is also able to rationalize differences in binding affinity for ligand-protein complexes with largely hydrophobic binding sites.

The assessment of time-of-flight on image quality and quantification with reduced administered activity and scan times in 18F-FDG PET.

OBJECTIVES: The last decade has seen considerable technological innovations in PET detectors with the availability, among other advances, of time-of-flight (TOF). TOF has been shown to increase the signal-to-noise ratio (SNR), which should allow for a reduction in acquired counts while maintaining image quality. METHODS: Fifty-eight patients referred for routine F-flurodeoxyglucose ((18)F-FDG) oncology PET studies were included in this study. Patients with weight below or above 100 kg were prescribed 350 or 400 MBq of (18)F-FDG, respectively. Listmode data were acquired for 2.5 min per bed position and reconstructed with ordered-subset expectation maximization (OSEM) reconstruction. TOF reconstruction was performed on reduced-count data, with two levels of reduction (-20 and -40% for patients <100 kg and -16 and -30% for patients >100 kg) achieved by clipping the listmode data. Liver SNR, mediastinum mean standardized uptake value (SUV(mean)), and lesion maximum standardized uptake value (SUV(max)) were measured in all images. All images were visually assessed as adequate or suboptimal. RESULTS: No significant difference was seen in mediastinum SUV(mean) or lesion SUV(max) when comparing reduced-count TOF with full-count OSEM images. Compared with the original OSEM images, liver SNR was higher for TOF images using the more conservative -20% reduction of counts (P < 0.001, Wilcoxon's signed-rank test), whereas no significant statistical difference was seen with -40% reductions. CONCLUSION: Incorporation of TOF allows for a reduction in acquired counts; this method has been implemented at our institution, with administered activity reduced for all patients to 280 MBq and a reduction in scan times for all but the largest patients. This has significantly reduced the patient radiation dose and improved scanner flexibility and throughput.

Insight on automated lesion delineation methods for PET data.

BACKGROUND: Defining tumour volume for treatment response and radiotherapy planning is challenging and prone to inter- and intra-observer variability. Various automated tumour delineation methods have been proposed in the literature, each having abilities and limitations. Therefore, there is a need to provide clinicians with practical information on delineation method selection. METHODS: Six different automated positron emission tomography (PET) delineation methods were evaluated and compared using National Electrical Manufacturer Association image quality (NEMA IQ) phantom data and three in-house synthetic phantoms with clinically relevant lesion shapes including spheres with necrotic core and irregular shapes. The impact of different contrast ratios, emission counts, realisations and reconstruction algorithms on delineation performance was also studied using similarity index (SI) and percentage volume error (%VE) as performance measures. RESULTS: With the NEMA IQ phantom, contrast thresholding (CT) performed best on average for all sphere sizes and parameter settings (SI = 0.83; %VE = 5.65% ± 24.34%). Adaptive thresholding at 40% (AT40) was the next best method and required no prior parameter tuning (SI = 0.78; %VE = 23.22% ± 70.83%). When using SUV harmonisation filtering prior to delineation (EQ.PET), AT40 remains the best method without prior parameter tuning (SI = 0.81; %VE = 11.39% ± 85.28%). For necrotic core spheres and irregular shapes of the synthetic phantoms, CT remained the best performing method (SI = 0.83; %VE = 26.31% ± 38.26% and SI = 0.62; %VE = 24.52% ± 46.89%, respectively). The second best method was fuzzy locally adaptive Bayesian (FLAB) (SI = 0.83; %VE = 29.51% ± 81.79%) for necrotic core sphere and AT40 (SI = 0.58; %VE = 25.11% ± 32.41%) for irregular shapes. When using EQ.PET prior to delineation, AT40 was the best performing method without prior parameter tuning for both necrotic core (SI = 0.83; %VE = 27.98% ± 59.58%) and complex shapes phantoms (SI = 0.61; %VE = 14.83% ± 49.39%). CONCLUSIONS: CT and AT40/AT50 are recommended for all lesion sizes and contrasts. Overall, considering background uptake information improves PET delineation accuracy. Applying EQ.PET prior to delineation improves accuracy and reduces coefficient of variation (CV) across different reconstructions and acquisitions.

Impact of point spread function modelling and time of flight on FDG uptake measurements in lung lesions using alternative filtering strategies.

BACKGROUND: The use of maximum standardised uptake value (SUVmax) is commonplace in oncology positron emission tomography (PET). Point spread function (PSF) modelling and time-of-flight (TOF) reconstructions have a significant impact on SUVmax, presenting a challenge for centres with defined protocols for lesion classification based on SUVmax thresholds. This has perhaps led to the slow adoption of these reconstructions. This work evaluated the impact of PSF and/or TOF reconstructions on SUVmax, SUVpeak and total lesion glycolysis (TLG) under two different schemes of post-filtering. METHODS: Post-filters to match voxel variance or SUVmax were determined using a NEMA NU-2 phantom. Images from 68 consecutive lung cancer patients were reconstructed with the standard iterative algorithm along with TOF; PSF modelling - Siemens HD·PET (HD); and combined PSF modelling and TOF - Siemens ultraHD·PET (UHD) with the two post-filter sets. SUVmax, SUVpeak, TLG and signal-to-noise ratio of tumour relative to liver (SNR(T-L)) were measured in 74 lesions for each reconstruction. Relative differences in uptake measures were calculated, and the clinical impact of any changes was assessed using published guidelines and local practice. RESULTS: When matching voxel variance, SUVmax increased substantially (mean increase +32% and +49% for HD and UHD, respectively), potentially impacting outcome in the majority of patients. Increases in SUVpeak were less notable (mean increase +17% and +23% for HD and UHD, respectively). Increases with TOF alone were far less for both measures. Mean changes to TLG were <10% for all algorithms for either set of post-filters. SNR(T-L) were greater than ordered subset expectation maximisation (OSEM) in all reconstructions using both post-filtering sets. CONCLUSIONS: Matching image voxel variance with PSF and/or TOF reconstructions, particularly with PSF modelling and in small lesions, resulted in considerable increases in SUVmax, inhibiting the use of defined protocols for lesion classification based on SUVmax. However, reduced partial volume effects may increase lesion detectability. Matching SUVmax in phantoms translated well to patient studies for PSF reconstruction but less well with TOF, where a small positive bias was observed in patient images. Matching SUVmax significantly reduced voxel variance and potential variability of uptake measures. Finally, TLG may be less sensitive to reconstruction methods compared with either SUVmax or SUVpeak.

SUVref: reducing reconstruction-dependent variation in PET SUV.

BACKGROUND: We propose a new methodology, reference Standardised Uptake Value (SUVref), for reducing the quantitative variation resulting from differences in reconstruction protocol. Such variation that is not directly addressed by the use of SUV or the recently proposed PERCIST can impede comparability between positron emission tomography (PET)/CT scans. METHODS: SUVref applies a reconstruction-protocol-specific phantom-optimised filter to clinical PET scans for the purpose of improving comparability of quantification. The ability of this filter to reduce variability due to differences in reconstruction protocol was assessed using both phantom and clinical data. RESULTS: SUVref reduced the variability between recovery coefficients measured with the NEMA image quality phantom across a range of reconstruction protocols to below that measured for a single reconstruction protocol. In addition, it enabled quantitative conformance to the recently proposed EANM guidelines. For the clinical data, a significant reduction in bias and variance in the distribution of differences in SUV, resulting from differences in reconstruction protocol, greatly reduced the number of hot spots that would be misclassified as undergoing a clinically significant change in SUV. CONCLUSIONS: SUVref significantly reduces reconstruction-dependent variation in SUV measurements, enabling increased confidence in quantitative comparison of clinical images for monitoring treatment response or disease progression. This new methodology could be similarly applied to reduce variability from scanner hardware.

Comparative analysis of the surface interaction properties of the binding sites of CDK2, CDK4, and ERK2.

Recently developed hydrogen-bonding and hydrophobic analysis algorithms were used to investigate the interaction properties of the ATP binding sites of CDK2, CDK4, and ERK2. We were able to prioritise those hydrogen-bonding groups that are observed to bind the native ATP ligand, as well as to identify other important groups found to bind inhibitors of these enzymes. However, as the hydrogen-bonding groups in the ATP binding sites of these enzymes are fairly well-conserved, we have confirmed that inhibitor selectivity may be predominantly due to differences in either the hydrophobic or steric properties of their binding sites. In particular, the hydrophobic properties of regions outside the specificity surface were observed to provide a rationale for the differences in specificity between various inhibitors to these enzymes. Our method was thus able to identify variations in hydrophobicity. The greater hydrophobicity of certain regions of CDK4 over analogous regions in CDK2 was detectable; likewise, it was possible to distinguish variations in hydrophobicity for regions of CDK2 against those in ERK2, despite the fact that these regions are largely composed of similar residue types.

Expanded interaction fingerprint method for analyzing ligand binding modes in docking and structure-based drug design.

An expanded interaction fingerprint method has been developed for analyzing the binding modes of ligands in docking and structure-based design methods. Taking the basic premise of representing a ligand in terms of a binary string that denotes its interactions with a target protein, we have expanded the method to include additional interaction-specific information. By considering the hydrogen-bonding strength and/or accessibility of the hydrogen bonding groups within a binding site as well as their geometric arrangement we aim to provide a better representation of a ligand-protein interaction. These expanded methods have been applied to the postprocessing of binding poses generated in a docking study for 220 different proteins and to the analysis of ligands generated by an automated ligand-generation algorithm for the anthrax oedema factor. In the docking study, the application of the interaction fingerprint method as a postprocessing tool resulted in an increased success rate in identifying the crystallographic binding mode. In the analysis of the ligands generated for the anthrax oedema factor, the incorporation of additional interaction-specific information resulted in a more intuitive and comprehensive analysis of automated ligand-generation output.

A new method for estimating the importance of hydrogen-bonding groups in the binding site of a protein.

We introduce a new method to estimate the importance of hydrogen-bonding sitepoints in the binding site of a protein as part of a structure-based design strategy. Our method identifies hydrogen-bonding sitepoints within a binding pocket and ranks them according to both the accessibility of their hydrogen bonding regions to incoming ligands and their hydrogen-bonding strength. The combination of these components produces a prioritised list of sitepoints that are more likely to be involved in hydrogen bonding with an incoming ligand. A dataset of known protein-ligand interactions was used to compare the prioritisation of sitepoints identified by our method with those observed to be engaged in hydrogen bonding in their crystal structures. Our method was able to remove those sitepoints unable to bind the ligand due to a low accessibility or an unfavourable orientation and to award significantly higher hydrogen-bonding ranking values to those sitepoints observed to form hydrogen bonds. Our method can thus be used to identify hydrogen-bonding sitepoints that should be targeted preferentially in a drug design strategy.