Free-breathing 3D whole-heart joint T₁/T₂ mapping and water/fat imaging at 0.55 T

Purpose: To develop and validate a highly efficient motion compensated free-breathing isotropic resolution 3D whole-heart joint T 1/T 2 mapping sequence with anatomical water/fat imaging at 0.55 T. Methods: The proposed sequence takes advantage of shorter T 1 at 0.55 T to acquire three interleaved water/fat volumes with inversion-recovery preparation, no preparation, and T 2 preparation, respectively. Image navigators were used to facilitate nonrigid motion-compensated image reconstruction. T 1 and T 2 maps were jointly calculated by a dictionary matching method. Validations were performed with simulation, phantom, and in vivo experiments on 10 healthy volunteers and 1 patient. The performance of the proposed sequence was compared with conventional 2D mapping sequences including modified Look-Locker inversion recovery and T 2-prepared balanced steady-SSFP sequence. Results: The proposed sequence has a good T 1 and T 2 encoding sensitivity in simulation, and excellent agreement with spin-echo reference T 1 and T 2 values was observed in a standardized T 1/T 2 phantom (R 2 = 0.99). In vivo experiments provided good-quality co-registered 3D whole-heart T 1 and T 2 maps with 2-mm isotropic resolution in a short scan time of about 7 min. For healthy volunteers, left-ventricle T 1 mean and SD measured by the proposed sequence were both comparable with those of modified Look-Locker inversion recovery (640 ± 35 vs. 630 ± 25 ms [p = 0.44] and 49.9 ± 9.3 vs. 54.4 ± 20.5 ms [p = 0.42]), whereas left-ventricle T 2 mean and SD measured by the proposed sequence were both slightly lower than those of T 2-prepared balanced SSFP (53.8 ± 5.5 vs. 58.6 ± 3.3 ms [p &lt; 0.01] and 5.2 ± 0.9 vs. 6.1 ± 0.8 ms [p = 0.03]). Myocardial T 1 and T 2 in the patient measured by the proposed sequence were in good agreement with conventional 2D sequences and late gadolinium enhancement. Conclusion: The proposed sequence simultaneously acquires 3D whole-heart T 1 and T 2 mapping with anatomical water/fat imaging at 0.55 T in a fast and efficient 7-min scan. Further investigation in patients with cardiovascular disease is now warranted.</p

Epigenetic modulators as therapeutic targets in prostate cancer

Prostate cancer is one of the most common non-cutaneous malignancies among men worldwide. Epigenetic aberrations, including changes in DNA methylation patterns and/or histone modifications, are key drivers of prostate carcinogenesis. These epigenetic defects might be due to deregulated function and/or expression of the epigenetic machinery, affecting the expression of several important genes. Remarkably, epigenetic modifications are reversible and numerous compounds that target the epigenetic enzymes and regulatory proteins were reported to be effective in cancer growth control. In fact, some of these drugs are already being tested in clinical trials. This review discusses the most important epigenetic alterations in prostate cancer, highlighting the role of epigenetic modulating compounds in pre-clinical and clinical trials as potential therapeutic agents for prostate cancer management

Persistent neutrophil to lymphocyte ratio >3 during treatment with enzalutamide and clinical outcome in patients with castration-resistant prostate cancer

The baseline value of neutrophil to lymphocyte ratio (NLR) has been found to be prognostic in patients with metastatic castration resistant prostate cancer (CRPC). We evaluated the impact of baseline NLR and its change in patients receiving enzalutamide. We included consecutive metastatic CRPC patients treated with enzalutamide after docetaxel and studies the change of NLR (&gt;3 vs ≤3) after week 4 and 12 weeks. Progression-free survival (PFS), overall survival (OS) and their 95% Confidence Intervals (95% CI) were estimated by the Kaplan-Meier method and compared with the log-rank test. The impact of NLR on PFS and OS was evaluated by Cox regression analyses and on prostate-specific antigen response rates (PSA RR; PSA decline &gt;50%) were evaluated by binary logistic regression. Data collected on 193 patients from 9 centers were evaluated. Median age was 73.1 years (range, 42.8–90.7). The median baseline NLR was 3.2. The median PFS was 3.2 months (95% CI = 2.7–4.2) in patients with baseline NLR &#62;3 and 7.4 months (95% CI = 5.5–9.7) in those with NLR ≤3, p &#60; 0.0001. The median OS was 10.4 months (95% CI = 6.5–14.9) in patients with baseline NLR &gt;3 and 16.9 months (95% CI = 11.2–20.9) in those with baseline NLR ≤3, p &#60; 0.0001. In multivariate analysis, changes in NLR at 4 weeks were significant predictors of both PFS [hazard ratio (HR) 1.24, 95% confidence interval (95% CI) 1.07–1.42, p = 0.003, and OS (HR 1.29, 95% CI 1.10–1.51, p = 0.001. A persistent NLR &#62;3 during treatment with enzalutamide seems to have both prognostic and predictive value in CRPC patients

Are practical recommendations practiced? A national multi-centre cross-sectional study on frequency of visual field testing in glaucoma

Aim: To estimate current clinical practice for frequency of visual field (VF) monitoring in glaucoma in England. Methods: A cross-sectional review of all patients with chronic open angle glaucoma (COAG) attending specialist glaucoma clinics at six hospitals in England was performed. The number of VF tests undertaken prior to the study date and during the first 2 years since diagnosis were recorded and compared with European Glaucoma Society (EGS) guidelines for newly-diagnosed patients. Clinician-requested monitoring intervals were compared with intervals from the National Institute of Clinical Excellence (NICE) guidelines, and the relationships with disease severity, intraocular pressure (IOP) and glaucoma progression status were reviewed. Results: One-hundred and four patients with COAG were included. 73 patients had at least 2 years of follow-up. Median (IQR) total number of VF tests and in the first 2 years of diagnosis were 4 (2–7) and 2 (2–3), respectively. No patients met EGS guidelines, but 87% of patients had their monitoring intervals requested in accordance with NICE guidelines. These intervals were not related to disease severity or VF stability (Kruskal–Wallis test, p=0.25) but shortened significantly when IOP control was inadequate or when the overall clinical impression was disease progression (p<0.001). Conclusions Most newly-diagnosed COAG patients receive less than three VFs in the first 2 years following diagnosis and an average of 0.7 VF per year over the duration of follow-up

Randomized phase II study investigating pazopanib versus weekly paclitaxel in relapsed or progressive urothelial cancer

Purpose: Two previous single-arm trials have drawn conflicting conclusions regarding the activity of pazopanib in urothelial cancers after failure of platinum-based chemotherapy. Patients and Methods: This randomized (1:1) open-label phase II trial compared the efficacy of pazopanib 800 mg orally with paclitaxel (80 mg/m2 days 1, 8, and 15 every 28 days) in the second-line setting. The primary end point was overall survival (OS). Results: Between August 2012 and October 2014, 131 patients, out of 140 planned, were randomly assigned. The study was terminated early on the recommendation of the independent data monitoring committee because of futility. Final analysis after the preplanned number of deaths (n = 110) occurred after a median follow-up of 18 months. One hundred fifteen deaths had occurred at the final data extract presented here. Median OS was 8.0 months for paclitaxel (80% CI, 6.9 to 9.7 months) and 4.7 months for pazopanib (80% CI, 4.2 to 6.4 months). The hazard ratio (HR) adjusted for baseline stratification factors was 1.28 (80% CI, 0.99 to 1.67; one-sided P = .89). Median progression-free survival was 4.1 months for paclitaxel (80% CI, 3.0 to 5.6 months) and 3.1 months for pazopanib (80% CI, 2.7 to 4.6 months; HR, 1.09; 80% CI, 0.85 to 1.40; one-sided P = .67). Discontinuations for toxicity occurred in 7.8% and 23.1% for paclitaxel and pazopanib, respectively. Conclusion: Pazopanib did not have greater efficacy than paclitaxel in the second-line treatment of urothelial cancers. There was a trend toward superior OS for paclitaxel

Susceptibility to glaucoma: differential comparison of the astrocyte transcriptome from glaucomatous African American and Caucasian American donors

Comparison of gene expression in normal and glaucomatous eyes from Caucasian American and African American donors reveals differences that might reflect different susceptibility to glaucoma

A randomised Phase II trial of carboplatin and gemcitabine ± vandetanib in first-line treatment of patients with advanced urothelial cell cancer not suitable to receive cisplatin

ObjectivesTo assess the efficacy and tolerability of the dual epidermal growth factor receptor/vascular endothelial growth factor receptor inhibitor, vandetanib, in combination with carboplatin and gemcitabine in the first‐line treatment of patients with advanced transitional cell carcinoma urothelial cancer (UC) who were unsuitable for cisplatin.Patients and methodsFrom 2011 to 2014, 82 patients were randomised from 16 hospitals across the UK into the TOUCAN double‐blind, placebo‐controlled randomised Phase II trial, receiving six 21‐day cycles of intravenous carboplatin (target area under the concentration versus time curve 4.5, day 1) and gemcitabine (1000 mg/m2 days 1 and 8) combined with either oral vandetanib 100 mg or placebo (once daily). Progression‐free survival (PFS; primary endpoint), adverse events, tolerability and feasibility of use, objective response rate and overall survival (OS) were evaluated. Intention‐to‐treat and per‐protocol analyses were used to analyse the primary endpoint.ResultsThe 82 patients were randomised 1:1 to vandetanib (n = 40) or placebo (n = 42), and 25 patients (30%) completed six cycles of all allocated treatment. Toxicity Grade ≥3 was experienced in 80% (n = 32) and 76% (n = 32) of patients in the vandetanib and placebo arms, respectively. The median PFS was 6.8 and 8.8 months for the vandetanib and placebo arms, respectively (hazard ratio [HR] 1.07, 95% confidence interval [CI] 0.65–1.76; P = 0.71); the median OS was 10.8 vs 13.8 months (HR 1.41, 95% CI 0.79–2.52; P = 0.88); and radiological response rates were 50% and 55%.ConclusionThere is no evidence that vandetanib improves clinical outcome in this setting. Our present data do not support its adoption as the regimen of choice for first‐line treatment in patients with UC who were unfit for cisplatin

Evaluating Atezolizumab in Patients with Urinary Tract Squamous Cell Carcinoma (AURORA): Study Protocol for a Single Arm, Open-Label, Multicentre, Phase II Clinical Trial

BACKGROUND: Bladder and urinary tract cancers account for approximately 21,000 new diagnoses and 5,000 deaths annually in the UK. Approximately 90% are transitional cell carcinomas where advanced disease is treated with platinum based chemotherapy and PD-1/PD-L1 directed immunotherapy. Urinary tract squamous cell carcinoma (UTSCC) accounts for about 5% of urinary tract cancers overall making this a rare disease. We have yet to establish definitive systemic treatment options for advanced UTSCC. Preliminary translational data, from UTSCC patient tumour samples, indicate high PD-L1 expression and tumour infiltrating lymphocytes in a proportion of cases. Both of these features are associated with differential gene expression consistent with a tumour/immune microenvironment predicted to be susceptible to immune checkpoint directed immunotherapy which we will evaluate in the AURORA trial. METHODS: AURORA is a single arm, open-label, multicentre,UK phase II clinical trial. 33 patients will be recruited from UK secondary care sites. Patients with UTSCC, suitable for treatment with palliative intent, will receive atezolizumab PD-L1 directed immunotherapy (IV infusion, 1680 mg, every 28 days) for one year if tolerated. Response assessment, by cross sectional imaging will occur every 12 weeks. AURORA uses a Simon\u27s 2-stage optimal design with best overall objective response rate (ORR, by RECIST v1.1) at a minimum of 12 weeks from commencing treatment as the primary endpoint. Secondary endpoints will include overall survival, progression-free survival, duration of response, magnitude of response using waterfall plots of target lesion measurements, quality of life using the EORTC QLQ-C30 tool, safety and tolerability (CTCAE v5) and evaluation of potential biomarkers of treatment response including PD-L1 expression. Archival tumour samples and blood samples will be collected for translational analyses. DISCUSSION: If this trial shows atezolizumab to be safe and effective it may lead to a future late phase randomised controlled trial in UTSCC. Ultimately, we hope to provide a new option for treatment for such patients

The dual action of human antibodies specific to Plasmodium falciparum PfRH5 and PfCyRPA: Blocking invasion and inactivating extracellular merozoites

The Plasmodium falciparum reticulocyte-binding protein homolog 5 (PfRH5) is the current leading blood-stage malaria vaccine candidate. PfRH5 functions as part of the pentameric PCRCR complex containing PTRAMP, CSS, PfCyRPA and PfRIPR, all of which are essential for infection of human red blood cells (RBCs). To trigger RBC invasion, PfRH5 engages with RBC protein basigin in a step termed the RH5-basigin binding stage. Although we know increasingly more about how antibodies specific for PfRH5 can block invasion, much less is known about how antibodies recognizing other members of the PCRCR complex can inhibit invasion. To address this, we performed live cell imaging using monoclonal antibodies (mAbs) which bind PfRH5 and PfCyRPA. We measured the degree and timing of the invasion inhibition, the stage at which it occurred, as well as subsequent events. We show that parasite invasion is blocked by individual mAbs, and the degree of inhibition is enhanced when combining a mAb specific for PfRH5 with one binding PfCyRPA. In addition to directly establishing the invasion-blocking capacity of the mAbs, we identified a secondary action of certain mAbs on extracellular parasites that had not yet invaded where the mAbs appeared to inactivate the parasites by triggering a developmental pathway normally only seen after successful invasion. These findings suggest that epitopes within the PfCyRPA-PfRH5 sub-complex that elicit these dual responses may be more effective immunogens than neighboring epitopes by both blocking parasites from invading and rapidly inactivating extracellular parasites. These two protective mechanisms, prevention of invasion and inactivation of uninvaded parasites, resulting from antibody to a single epitope indicate a possible route to the development of more effective vaccines

Radiological response heterogeneity is of prognostic significance in metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted therapy

Background: Response evaluation criteria in solid tumours (RECIST) is widely used to assess tumour response but is limited by not considering disease site or radiological heterogeneity (RH). Objective: To determine whether RH or disease site has prognostic significance in patients with metastatic clear-cell renal cell carcinoma (ccRCC). Design, setting, and participants: A retrospective analysis was conducted of a second-line phase II study in patients with metastatic ccRCC (NCT00942877), evaluating 138 patients with 458 baseline lesions. Intervention: The phase II trial assessed vascular endothelial growth factor-targeted therapy ± Src inhibition. Outcome measurements and statistical analysis: RH at week 8 was assessed within individual patients with two or more lesions to predict overall survival (OS) using Kaplan-Meier method and Cox regression model. We defined a high heterogeneous response as occurring when one or more lesion underwent a ≥10% reduction and one or more lesion underwent a ≥10% increase in size. Disease progression was defined by RECIST 1.1 criteria. Results and limitations: In patients with a complete/partial response or stable disease by RECIST 1.1 and two or more lesions at week 8, those with a high heterogeneous response had a shorter OS compared to those with a homogeneous response (hazard ratio [HR] 2.01; 95% confidence interval [CI]: 1.39–2.92; p &lt; 0.001). Response by disease site at week 8 did not affect OS. At disease progression, one or more new lesion was associated with worse survival compared with &gt;20% increase in sum of target lesion diameters only (HR 2.12; 95% CI: 1.43–3.14; p &lt; 0.001). Limitations include retrospective study design. Conclusions: RH and the development of new lesions may predict survival in metastatic ccRCC. Further prospective studies are required. Patient summary: We looked at individual metastases in patients with kidney cancer and showed that a variable response to treatment and the appearance of new metastases may be associated with worse survival. Further studies are required to confirm these findings