Can DW-MRI,with its ADC values,be a reliable predictor of biopsy outcome in patients with suspected prostate cancer?

Purpose

To relate the multiparametric magnetic resonance imaging (mp-MRI) of patients with suspect peripheral prostate cancer (PCa) to the results of the subsequent biopsy: in particular to explore whether DWI and ADC can predict the biopsy outcome and to investigate the relation between ADC and Gleason score (GS).

Materials and methods

175 consecutive patients who underwent 1.5 T mp-MRI followed by prostate biopsy were retrospectively analyzed by two independent radiologists. ADC values were measured in the peripheral suspect lesion areas (ADC_SL) and in the contralateral zones (ADC_NSL) obtaining ADC_norm = ADC_SL/ADC_NSL. Results on T2W images, DWI, ADC values, and perfusion studies were matched to their corresponding biopsy.

Results

Negative DWI and T2W had 100% negative predictive value (NPV). When DWI was positive, ADC_SL > 0.90 × 10 > 0.90 × 10^?3 mm²/s (ADC_norm > 0.60) identified by the ROC curve (AUC = 0.80) corresponded to NPV = 85%. In positive biopsies, ADC_SL and ADC_norm decreased significantly from GS = 6 to GS ≥ 8 with Spearman coefficient ρ = ?0.40 and ROC curve AUC = 0.72.

Conclusion

mp-MRI allows a reliable prediction of a negative biopsy through the values of DWI, T2W, and ADC. In positive biopsies, there is a moderate correlation between ADC and the various GS levels.

     

Response Monitoring with [<Superscript>18</Superscript>F]FLT PET and Diffusion-Weighted MRI After Cytotoxic 5-FU Treatment in an Experimental Rat Model for Colorectal Liver Metastases

Purpose

The aim of the study was to investigate the potential of diffusion-weighted magnetic resonance imaging (DW-MRI) and 3′-dexoy-3′-[¹⁸F]fluorothymidine ([¹⁸F]FLT) positron emission tomography (PET) as early biomarkers of treatment response of 5-fluorouracil (5-FU) in a syngeneic rat model of colorectal cancer liver metastases.

Procedures

Wag/Rij rats with intrahepatic syngeneic CC531 tumors were treated with 5-FU (15, 30, or 60 mg/kg in weekly intervals). Before treatment and at days 1, 3, 7, and 14 after treatment rats underwent DW-MRI and [¹⁸F]FLT PET. Tumors were analyzed immunohistochemically for Ki67, TK1, and ENT1 expression.

Results

5-FU inhibited the growth of CC531 tumors in a dose-dependent manner. Immunohistochemical analysis did not show significant changes in Ki67, TK1, and ENT1 expression. However, [¹⁸F]FLT SUV_mean and SUV_max were significantly increased at days 4 and 7 after treatment with 5-FU (60 mg/kg) and returned to baseline at day 14 (SUV_max at days ?1, 4, 7, and 14 was 1.1 ± 0.1, 2.3 ± 0.5, 2.3 ± 0.6, and 1.5 ± 0.4, respectively). No changes in [¹⁸F]FLT uptake were observed in the nontreated animals. Furthermore, the apparent diffusion coefficient (ADC_mean) did not change in 5-FU-treated rats compared to untreated rats.

Conclusion

This study suggests that 5-FU treatment induces a flare in [¹⁸F]FLT uptake of responsive CC531 tumors in the liver, while the ADC_mean did not change significantly. Future studies in larger groups are warranted to further investigate whether [¹⁸F]FLT PET can discriminate between disease progression and treatment response.

     

Peritumoral Brain Edema in Meningiomas Depends on Aquaporin-4 Expression and Not on Tumor Grade,Tumor Volume,Cell Count,or Ki-67 Labeling Index

Purpose

The aim of this study was to investigate to which degree the peritumoral brain edema in patients with meningiomas depends on aquaporin-4 (AQP4) expression, tumor grade, tumor volume, Ki-67 expression, and cell count.

Procedures

Thirty-three patients (25 women, 8 men; mean age 56.6 ± 16.0 years) with an intracranial meningioma underwent a standardized magnetic resonance (MR) examination prior to surgical resection. Edema indices (EIs) and tumor volumes were measured on the MR images. Tumor grade was classified according to the World Health Organization, and the proliferation index was estimated on Ki-67 antigen-stained specimens. Tumor cell count was evaluated. Eighteen specimens were stained for AQP4 expressioon.

Results

Significant intergroup differences between AQP4 expression grades and EIs were observed (P = 0.03), and a positive correlation was detected between EIs and AQP4 expression grades (r = 0.54; P < 0.05). A ROC analysis with EI as a test variable revealed an AUC of 0.77 (95 % CI 0.55–0.99) for the prediction of a moderate-to-strong AQP4 expression. An EI ≥1.5 predicted a moderate-to-high AQP4 expression with a sensitivity of 77 % and a specificity of 60 %. EI values of 2.2 and 3.5 reached sensitivity/specificity values of 69/80 % and 54/100 %, respectively. The AQP4 expression did not show any significant correlations with tumor grading, tumor volume, Ki-67 expression, or cell count. Moreover, we observed no significant positive or negative correlations between the EI and tumor grading (P = 0.7), tumor volume (P = 0.19), Ki-67 index (P = 0.9), and cell count (P = 0.34).

Conclusion

Peritumoral brain edema in patients with meningiomas may depend on AQP4 expression grades and not on tumor grade, tumor volume, Ki-67 expression, and cell count. The amount of edema predicted AQP4 expressions with moderate-to-good sensitivity and specificity.

     

[<Superscript>68</Superscript>Ga]PSMA-HBED-CC Uptake in Osteolytic,Osteoblastic, and Bone Marrow Metastases of Prostate Cancer Patients

Purpose

The aim of this study was to evaluate potential differences in “Glu-NH-CO-NH-Lys” radio-labeled with [⁶⁸Ga]gallium N,N-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N-diacetic acid ([⁶⁸Ga]PSMA-HBED-CC) uptake in osteolytic, osteoblastic, mixed, and bone marrow metastases in prostate cancer (PC) patients.

Procedures

This retrospective study was approved by the local ethics committee. Patients who received [⁶⁸Ga]PSMA-HBED-CC positron emission tomography/computed tomography ([⁶⁸Ga]PSMA-PET/CT) with at least one positive bone metastasis were included in this study. Only patients who have not received systemic therapy for their PC were included. Bone metastases had to be confirmed by at least one other imaging modality or follow-up investigation. The maximum standardized uptake value (SUV_max) and mean Hounsfield units (HU_mean) of each metastasis were measured. Based on CT, each metastasis was classified as osteolytic (OL), osteoblastic (OB), bone marrow (BM), or mixed (M).

Results

One hundred fifty-four bone metastases in 30 patients were evaluated. Eighty out of 154 (51.9%) metastases were classified as OB, 21/154 (13.6%) as OL, 23/154 (14.9%) as M, and 30/154 (19.5%) as BM. The SUV_max for the different types of metastases were 10.6 ± 7.07 (OB), 24.0 ± 19.3 (OL), 16.0 ± 21.0 (M), and 14.7 ± 9.9 (BM). The SUV_max of OB vs. OL and OB vs. BM metastases differed significantly (p ≤ 0.025). A significant negative correlation between HU_mean and SUV_max (r = ?0.23, p < 0.05) was measured.

Conclusions

[⁶⁸Ga]PSMA-HBED-CC uptake is higher in osteolytic and bone marrow metastases compared to osteoblastic metastases. Information derived from [⁶⁸Ga]PSMA-PET and CT complement each other for the reliable diagnosis of the different types of bone metastases in PC patients.

     

Hybrid FDG-PET/MR compared to FDG-PET/CT in adult lymphoma patients

Purpose

The goal of this study is to evaluate the diagnostic performance of simultaneous FDG-PET/MR including diffusion compared to FDG-PET/CT in patients with lymphoma.

Methods

Eighteen patients with a confirmed diagnosis of non-Hodgkin’s (NHL) or Hodgkin’s lymphoma (HL) underwent an IRB-approved, single-injection/dual-imaging protocol consisting of a clinical FDG-PET/CT and subsequent FDG-PET/MR scan. PET images from both modalities were reconstructed iteratively. Attenuation correction was performed using low-dose CT data for PET/CT and Dixon-MR sequences for PET/MR. Diffusion-weighted imaging was performed. SUV_max was measured and compared between modalities and the apparent diffusion coefficient (ADC) using ROI analysis by an experienced radiologist using OsiriX. Strength of correlation between variables was measured using the Pearson correlation coefficient (r _p).

Results

Of the 18 patients included in this study, 5 had HL and 13 had NHL. The median age was 51 ± 14.8 years. Sixty-five FDG-avid lesions were identified. All FDG-avid lesions were visible with comparable contrast, and therefore initial and follow-up staging was identical between both examinations. SUV_max from FDG-PET/MR [(mean ± sem) (21.3 ± 2.07)] vs. FDG-PET/CT (mean 23.2 ± 2.8) demonstrated a strongly positive correlation [r _s = 0.95 (0.94, 0.99); p < 0.0001]. There was no correlation found between ADC_min and SUV_max from FDG-PET/MR [r = 0.17(?0.07, 0.66); p = 0.09].

Conclusion

FDG-PET/MR offers an equivalent whole-body staging examination as compared with PET/CT with an improved radiation safety profile in lymphoma patients. Correlation of ADC to SUV_max was weak, understating their lack of equivalence, but not undermining their potential synergy and differing importance.

     

Pooled Aquablation Results for American Men with Lower Urinary Tract Symptoms due to Benign Prostatic Hyperplasia in Large Prostates (60–150 cc)

Introduction

To present short-term safety and efficacy data of men with lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH) treated with Aquablation.

Methods

Men with LUTs secondary to BPH (60–150 cc) underwent Aquablation treatment from February 2016 to December 2017 across 17 investigational sites in the USA from two contemporary investigational device exemption (IDE) studies called WATER (NCT02505919) and WATER II (NCT03123250).

Results

One hundred seven males with mean age of 67.3?±?6.5 years were treated with Aquablation; mean prostate volume was 99.4?±?24.1 cc. The pooled results show that large prostates have an average procedure time of less than 36 min and discharge on average 1.6?±?1 days. The IPSS decreased by 16.7?±?8.1 points at 3 months and Q_max increased by 11.2?±?12.4 ml/s. The Clavien-Dindo (CD) grade 2 or higher event rate at 3 months was 29%. A non-hierarchical breakdown for CD events yielded 18% grade 2 and 19% grade 3 or higher.

Conclusion

Men with LUTS secondary to BPH (60–150 cc) in a pooled analysis were treated safely and effectively with Aquablation up to 3 months postoperatively.

Trial Registration

ClinicalTrials.gov identifiers, NCT02505919 and NCT03123250.

Funding

PROCEPT BioRobotics.

     

Uptake of Radium-223 Dichloride and Early [<Superscript>18</Superscript>F]NaF PET Response Are Driven by Baseline [<Superscript>18</Superscript>F]NaF Parameters: a Pilot Study in Castration-Resistant Prostate Cancer Patients

Purpose

The purpose of this study is to identify predictive factors on baseline [¹⁸F]NaF positron emission tomography (PET)/computed tomography (CT) of early response to radium-223 dichloride after 3 cycles of treatment in metastatic castration-resistant prostate cancer patients.

Procedures

Analysis of 152 metastases was performed in six consecutive patients who underwent [¹⁸F]NaF PET/CT at baseline and for early monitoring after 3 cycles of radium-223 dichloride. All metastases depicted on whole-body [¹⁸F]NaF PET/CT were contoured and CT (density in Hounsfield units, sclerotic, mixed, or lytic appearance) as well as [¹⁸F]NaF [maximum standardized uptake value (SUV_max), SUV_mean, and lesion volume (V_18F-NaF)] patterns were recorded. Tumor response was defined as percentage change in SUV_max and SUV_mean between baseline and post-treatment PET. Bone lesions were defined as stable, responsive, or progressive, according to thresholds derived from a recent multicentre test-retest study in [¹⁸F]NaF PET/CT. Total [¹⁸F]NaF uptake in metastases, defined as MATV × SUV_mean, was correlated to uptake of radium-223 on biodistribution scintigraphy performed 7 days after the first cycle of treatment.

Results

Among metastases, 116 involved the axial skeleton and 36 the appendicular skeleton. Lesions were sclerotic in 126 cases and mixed in 26 cases. No lytic lesion was depicted. ROC analysis showed that SUV_max and SUV_mean were better predictors of lesion response than V_18F-NaF and density on CT (P < 0.0001 and P = 0.001, respectively). SUV_max and SUV_mean were predictors of individual tumor response in separate multivariate models (P = 0.01 and P = 0.02, respectively). CT pattern (mixed versus sclerotic) and lesion density were independent predictors only when assessing response with delta SUV_max (P = 0.002 and 0.007, respectively). A good correlation between total [¹⁸F]NaF uptake within metastases and their relative radium-223 uptake assessed by two observers 7 days after treatment (r = 0.72 and 0.77, P < 0.0001) was found.

Conclusions

SUV_max and SUV_mean on baseline [¹⁸F]NaF PET/CT are independent predictors of bone lesions’ response to 3 cycles of radium-223 dichloride, supporting the use of NaF to select patients more likely to respond to treatment.

     

Complementary value of pre-treatment apparent diffusion coefficient in rectal cancer for predicting tumor recurrence

Purpose

To assess the complementary prognostic value of pre-treatment tumor apparent diffusion coefficient (ADC) for the prediction of tumor recurrence in patients with rectal cancer.

Methods

From March 2012 to March 2013, a total of 128 patients with mid/lower rectal cancer who underwent pre-treatment rectal MRI were enrolled in this retrospective study. Two radiologists in consensus evaluated conventional imaging features (C_img) in pre-treatment rectal MRI: tumor height from anal verge (≤5 cm vs. >5 cm), T stage (high vs. low), the presence or absence of lymph node metastasis, mesorectal fascia invasion, and extramural venous invasion. The mean tumor ADC values (Tumor_ADC) based on high b-value (0, 1000 × 10^?3 mm²/s) diffusion weight images were extracted. A multivariate Cox proportional hazard (CPH) regression was performed to evaluate the association of C_img and Tumor_ADC with the 3-year local recurrence (LR) rate. Predictive performance of two multivariate CPH models (C_img only vs. C_img + Tumor_ADC) was compared using Harrell’s c index (HCI).

Results

Tumor_ADC (Adjusted HR, 7.830; 95% CI 3.937–15.571) and high T stage (Adjusted HR, 8.039; 95% CI 2.405–26.874) were independently associated with the 3-year LR rate. The CPH model generated with T stage + Tumor_ADC (HCI, 0.820; 95% CI 0.708–0.932) showed significantly higher HCI than that with T stage only (HCI, 0.742; 95% CI 0.594–0.889) (P = 0.009).

Conclusions

In patients with mid/lower rectal cancer, integrating Tumor_ADC to C_img increases predictive performance of the CPH model than that with C_img alone for the prediction of LR within 3 years after surgery.

     

Increased maximum common carotid intima-media thickness is associated with smoking and hypertension in Tochigi Prefecture residents

Objective

We investigated maximum intima-media thickness of the common carotid artery (IMT-C_max) in residents of Tochigi Prefecture, who have been reported to have high stroke mortality.

Method

Our study included 840 individuals. All participants underwent carotid ultrasonography and answered a questionnaire during participation in a health festival in Tochigi Prefecture. The questionnaire was designed to collect information on age, gender, and risk factors for stroke. IMT-C_max was measured. Statistical analyses were performed to identify factors contributing to IMT-C_max values ≥1.1 mm.

Results

In total, 117 subjects had an IMT-C_max value ≥1.1 mm. IMT-C_max correlated significantly with age, current smoking, hypertension, diabetes mellitus, heart disease, and previous symptomatic stroke (p < 0.05) in univariate analysis. Current smoking (p < 0.001, odds ratio 3.88) and hypertension (p = 0.0070, odds ratio 1.83) were seen as significant contributing factors to IMT-C_max ≥1.1 mm in logistic regression analysis adjusted by age, gender, and previous symptomatic stroke.

Conclusion

We identified current smoking and hypertension as the most significant contributing factors to increased IMT-C_max in residents of Tochigi Prefecture, emphasizing the importance of routine blood pressure monitoring and anti-smoking education in this population.

     

Automatic adjustment of pressure support by a computer-driven knowledge-based system during noninvasive ventilation: a feasibility study

Objective

To evaluate the feasibility of using a knowledge-based system designed to automatically titrate pressure support (PS) to maintain the patient in a “respiratory comfort zone” during noninvasive ventilation (NIV) in patients with acute respiratory failure.

Design and setting

Prospective crossover interventional study in an intensive care unit of a university hospital.

Patients

Twenty patients.

Interventions

After initial NIV setting and startup in conventional PS by the chest physiotherapist NIV was continued for 45?min with the automated PS activated.

Measurements and results

During automated PS minute-volume was maintained constant while respiratory rate decreased significantly from its pre-NIV value (20?±?3 vs. 25?±?3?bpm). There was a trend towards a progressive lowering of dyspnea. In hypercapnic patients PaCO₂ decreased significantly from 61?±?9 to 51?±?2?mmHg, and pH increased significantly from 7.31?±?0.05 to 7.35?±?0.03. Automated PS was well tolerated. Two system malfunctions occurred prompting physiotherapist intervention.

Conclusions

The results of this feasibility study suggest that the system can be used during NIV in patients with acute respiratory failure. Further studies should now determine whether it can improve patient-ventilator interaction and reduce caregiver workload.

     

Phase 1 Evaluation of [<Superscript>64</Superscript>Cu]DOTA-Patritumab to Assess Dosimetry,Apparent Receptor Occupancy,and Safety in Subjects with Advanced Solid Tumors

Purpose

The purpose of this study was to evaluate the safety, dosimetry, and apparent receptor occupancy (RO) of [⁶⁴Cu]DOTA-patritumab, a radiolabeled monoclonal antibody directed against HER3/ERBB3 in subjects with advanced solid tumors.

Procedures

Dosimetry subjects (n?=?5) received [⁶⁴Cu]DOTA-patritumab and underwent positron emission tomography (PET)/X-ray computed tomography (CT) at 3, 24, and 48 h. Evaluable RO subjects (n?=?3 out of 6) received [⁶⁴Cu]DOTA-patritumab at day 1 and day 8 (after 9.0 mg/kg patritumab) followed by PET/CT at 24 h post-injection. Endpoints included safety, tumor uptake, and efficacy.

Results

The tumor SUV_max (±?SD) was 5.6?±?4.5, 3.3?±?1.7, and 3.0?±?1.1 at 3, 24, and 48 h in dosimetry subjects. The effective dose and critical organ dose (liver) averaged 0.044?±?0.008 mSv/MBq and 0.46?±?0.086 mGy/MBq, respectively. In RO subjects, tumor-to-blood ratio decreased from 1.00?±?0.32 at baseline to 0.57?±?0.17 after stable patritumab, corresponding to a RO of 42.1?±?3.

Conclusions

[⁶⁴Cu]DOTA-patritumab was safe. These limited results suggest that this PET-based method can be used to determine tumor-apparent RO.

     

A Randomized Trial Investigating the Pharmacokinetics,Pharmacodynamics, and Safety of Subcutaneous Semaglutide Once-Weekly in Healthy Male Japanese and Caucasian Subjects

Introduction

Semaglutide is a glucagon-like peptide-1 analogue for once-weekly subcutaneous treatment of type 2 diabetes. This trial compared the pharmacokinetics, pharmacodynamics, and safety of semaglutide in Japanese and Caucasian subjects.

Methods

In this single-center, double-blind, parallel-group, 13-week trial, 44 healthy male subjects (22 Japanese, 22 Caucasian) were randomized within each race to semaglutide 0.5 mg (n = 8), 1.0 mg (n = 8), placebo 0.5 mg (n = 3) or 1.0 mg (n = 3). The primary endpoint was semaglutide exposure at steady state [area under the curve (AUC_0–168h)].

Results

Steady-state exposure of semaglutide was similar for both populations: AUC_0–168h estimated race ratio (ERR), Japanese/Caucasian: 0.5 mg, 1.06; 1.0 mg, 0.99; maximum concentration (C_max) ERR: 0.5 mg, 1.06; 1.0 mg, 1.02. Exposure after the first dose (0.25 mg) was slightly higher in Japanese versus Caucasian subjects (AUC_0–168h ERR 1.11; C_max ERR 1.14). Dose-dependent increases in AUC_0–168h and C_max occurred in both populations. Accumulation was as expected, based on the half-life (t_1/2, ~ 1 week) and dosing interval of semaglutide. Significant body weight reductions were observed with semaglutide 0.5 mg and 1.0 mg in Japanese (both p ≤ 0.05) and Caucasian (both p ≤ 0.05) subjects versus placebo. No new safety issues were identified.

Conclusions

The pharmacokinetic, pharmacodynamic, and safety profiles of semaglutide were similar in Japanese and Caucasian subjects, suggesting that no dose adjustment is required for the clinical use of semaglutide in Japanese subjects.

Funding

Novo Nordisk A/S, Denmark.

Trial registration

ClinicalTrials.gov identifier NCT02146079. Japanese trial registration number JapicCTI-142550.

     

Determination of functional residual capacity by oxygen washin-washout: a validation study

Objective

To validate a new system for functional residual capacity (FRC) measurements using oxygen washin/washout in spontaneously breathing humans. The system (LUFU, Drägerwerk AG, Lübeck, Germany) consists of an unmodified EVITA 4 ventilator, a side-stream paramagnetic oxygen sensor and a dedicated software.

Design

Laboratory study and measurements in spontaneously breathing volunteers.

Setting

Pulmonary function laboratory of a university hospital.

Participants

20 healthy and 15 lung diseased volunteers.

Interventions

FRC was measured by LUFU (LUFU-FRC) and by helium dilution (He-FRC); intra-thoracic gas volume (ITGV) was determined by body plethysmography. Each measurement cycle consisted of four independent LUFU-FRC determinations (step change of FiO₂ from 0.21 to 0.5 and back and from 0.21 to 1.0 and back), two helium-dilution runs and two body box measurements. Repeatability and agreement between methods were determined by comparing different measurements of one technique and by comparing different techniques among each other.

Measurements and results

Repeatability of LUFU-FRC was estimated by comparing washin to washout and the different FiO₂steps. The difference of the means was 3.7% at the most. Agreement between methods resulted in the following differences (mean?±?standard deviation of differences) for healthy and lung-diseased volunteers, respectively: LUFU-FRC vs. He-FRC –0.40?±?0.50?L (0.02?±?0.95?L), LUFU-FRC vs. ITGV –0.43?±?0.54?L (–0.18?±?0.61?L) and He-FRC vs. ITGV –0.03?±?0.43?L (–0.20?±?0.98?L).

Conclusions

LUFU is a non-invasive method for the determination of FRC that requires only minor additional equipment and no modification to the ventilator. It can be used in difficult conditions such as breathing patterns with variations from breath to breath. The results of this study show that LUFU is sufficiently reliable and repeatable to warrant its clinical application.

     

A Single-Dose,Crossover-Design Bioequivalence Study Comparing Two Nicotine Gum Formulations in Healthy Subjects

Introduction

Nicotine replacement therapy (NRT) benefits smokers who wish to quit; nicotine gum represents one NRT. New formulations of nicotine gum have been developed to consider consumer preferences and needs. A new mint-flavored nicotine gum with a different texture was developed that may provide a more appealing taste and chewing experience. This study evaluated this new nicotine gum (2 and 4 mg strengths) for bioequivalence versus the original flavor sugar-free nicotine gum at corresponding dosages.

Methods

All subjects randomized in this crossover study received a single dose of all treatments, i.e., 2 and 4 mg doses of test and reference gums, separated by 2–7 days of washout between treatments. Subjects’ maximal plasma nicotine concentration (C_max) and extent of nicotine absorption (AUC_0–t) following the administration of each treatment were calculated from plasma nicotine concentrations. Ratios of test/reference for C_max and AUC_0–t were calculated to evaluate bioequivalence between the two products.

Results

Both 2 and 4 mg doses of the new mint-flavored nicotine gum were bioequivalent to the dose-matched reference product as determined by the ratio of the geometric means and their 90% confidence intervals for C_max and AUC_0–t as well as secondary pharmacokinetic parameters. The safety profiles of the test and reference gums were similar; all treatments were well tolerated.

Conclusions

A new mint-flavored nicotine gum with modified taste and texture is bioequivalent to the original flavor sugar-free nicotine gum at both the 2 and 4 mg dosage strengths and has a similar safety profile.

Funding

GlaxoSmithKline.

Trial Registration

ClinicalTrials.gov identifier NCT01847443.

     

Pharmacokinetics of a Single Dose of Azilsartan in Pediatric Patients: A Phase 3, Open-Label,Multicenter Study

Introduction

Azilsartan is an angiotensin II receptor blocker indicated for the treatment of patients with hypertension. The efficacy and safety of azilsartan are established in adults, but have not been evaluated in pediatric patients, nor has its pharmacokinetic profile been determined in pediatric patients.

Methods

In this phase 3, open-label, multicenter study, we investigated the pharmacokinetics and safety of single doses of azilsartan in six Japanese patients with hypertension, aged 9–14 years. The dose of azilsartan was 5 mg for three patients weighing less than 50 kg, with mean body weight at baseline of 27.5 kg, and 10 mg for three patients weighing at least 50 kg, with mean body weight at baseline of 65.9 kg.

Results

Mean maximum plasma concentration (C_max) of azilsartan was 888.3 and 831.3 ng/mL and median time to maximum concentration (T_max) of unchanged azilsartan was 3.0 and 4.0 h, in the 5-mg and 10-mg groups, respectively. Mean areas under the plasma concentration–time curve (AUC) from 0–24 h post-dose (AUC_0–24) and 0 h to infinity (AUC_0–inf) were 6350.3 and 6635.7 ng h/mL, respectively, in the 5-mg group, and 6871.7 and 7433.3 ng h/mL, respectively, in the 10-mg group. Both doses were well tolerated; no treatment-emergent adverse events considered to be related to azilsartan occurred during the study.

Conclusion

Our data suggest that pediatric patients weighing less than 50 kg may have? approximately 2-fold greater exposure to azilsartan than those weighing at least 50 kg at the same dose. Exposure to azilsartan in children weighing at least 50 kg is comparable to that in healthy adults at the same dose.

Trial Registration

ClinicalTrials.gov identifier, NCT02451150.

Funding

Takeda Pharmaceutical Co. Ltd.

     

Comparison of image quality and patient discomfort in prostate MRI: pelvic phased array coil vs. endorectal coil

Purpose

To compare image quality (IQ) and patient discomfort during prostate MRI using a pelvic phased array (PPA) coil and an endorectal (ER) coil.

Materials and methods

Ninety-eight patients (median age, 65.7; range 42.1–78.1) underwent prostate MRI on a 3T scanner including T2w and DWI acquired with PPA and an ER coil within the same exam. Acquisition time was kept similar for both acquisitions. Two radiologists evaluated aspects of IQ on a 5-point Likert scale and classified image artifacts. All patients completed a questionnaire on discomfort/pain regarding the ER coil using a visual analogue scale from 1 to 10.

Results

There was no significant difference in overall IQ for T2w images for both readers (reader 1, 3.27 ± 0.91 and 3.07 ± 0.84, p = 0.057; reader 2, 3.70 ± 0.75 and 3.77 ± 0.81, p = 0.555) for PPA and ER coils, respectively. Overall IQ for DWI acquired with PPA and ER coils was rated similar by reader 1 (3.03 ± 1.10 and 3.08 ± 0.80, respectively, (p = 0.67)), while reader 2 preferred ER coil images (3.27 ± 0.81 and 3.66 ± 0.85 (p < 0.05)). Susceptibility artifacts were more frequent in ER than in PPA coil images (109 vs. 75). Discomfort and pain experienced during insertion of the ER coil was low altogether (VAS score, 3.5 ± 2.1 for “discomfort” and 2.4 ± 2.4 for “pain”).

Conclusion

T2-weighted images may be acquired with comparable IQ using a PPA coil as compared to an ER coil, while DWI images showed better IQ using the ER coil for one of two readers. The insertion of the ER coil caused low to moderate discomfort and pain in patients.

     

A Novel Framework for Automated Segmentation and Labeling of Homogeneous <Emphasis Type="Italic">Versus</Emphasis> Heterogeneous Lung Tumors in [<Superscript>18</Superscript>F]FDG-PET Imaging

Purpose

Determination of intra-tumor high-uptake area using 2-deoxy-2-[¹⁸F]fluoro-d-glucose ([¹⁸F]FDG) positron emission tomography (PET) imaging is an important consideration for dose painting in radiation treatment applications. The aim of our study was to develop a framework towards automated segmentation and labeling of homogeneous vs. heterogeneous tumors in clinical lung [¹⁸F]FDG-PET with the capability of intra-tumor high-uptake region delineation.

Procedures

We utilized and extended a fuzzy random walk PET tumor segmentation algorithm to delineate intra-tumor high-uptake areas. Tumor textural feature (TF) analysis was used to find a relationship between tumor type and TF values. Segmentation accuracy was evaluated quantitatively utilizing 70 clinical [¹⁸F]FDG-PET lung images of patients with a total of 150 solid tumors. For volumetric analysis, the Dice similarity coefficient (DSC) and Hausdorff distance (HD) measures were extracted with respect to gold-standard manual segmentation. A multi-linear regression model was also proposed for automated tumor labeling based on TFs, including cross-validation analysis.

Results

Two-tailed t test analysis of TFs between homogeneous and heterogeneous tumors revealed significant statistical difference for size-zone variability (SZV), intensity variability (IV), zone percentage (ZP), proposed parameters II and III, entropy and tumor volume (p < 0.001), dissimilarity, high intensity emphasis (HIE), and SUV_min (p < 0.01). Lower statistical differences were observed for proposed parameter I (p = 0.02), and no significant differences were observed for SUV_max and SUV_mean. Furthermore, the Spearman rank analysis between visual tumor labeling and TF analysis depicted a significant correlation for SZV, IV, entropy, parameters II and III, and tumor volume (0.68 ≤ ρ ≤ 0.84) and moderate correlation for ZP, HIE, homogeneity, dissimilarity, parameter I, and SUV_min (0.22 ≤ ρ ≤ 0.52), while no correlations were observed for SUV_max and SUV_mean (ρ < 0.08). The multi-linear regression model for automated tumor labeling process resulted in R ² and RMSE values of 0.93 and 0.14, respectively (p < 0.001), and generated tumor labeling sensitivity and specificity of 0.93 and 0.89. With respect to baseline random walk segmentation, the results showed significant (p < 0.001) mean DSC, HD, and SUV_mean error improvements of 21.4 ± 11.5 %, 1.4 ± 0.8 mm, and 16.8 ± 8.1 % in homogeneous tumors and 7.4 ± 4.4 %, 1.5 ± 0.6 mm, and 7.9 ± 2.7 % in heterogeneous lesions. In addition, significant (p < 0.001) mean DSC, HD, and SUV_mean error improvements were observed for tumor sub-volume delineations, namely 5 ± 2 %, 1.5 ± 0.6 mm, and 7 ± 3 % for the proposed Fuzzy RW method compared to RW segmentation.

Conclusion

We proposed and demonstrated an automatic framework for significantly improved segmentation and labeling of homogeneous vs. heterogeneous tumors in lung [¹⁸F]FDG-PET images.

     

Effects of Ketoconazole on the Pharmacokinetics of Mifepristone,a Competitive Glucocorticoid Receptor Antagonist,in Healthy Men

Introduction

Mifepristone, a competitive glucocorticoid receptor antagonist approved for Cushing syndrome, and ketoconazole, an antifungal and steroidogenesis inhibitor, are both inhibitors of and substrates for cytochrome P450 (CYP3A4). This study evaluated the pharmacokinetic effects of concomitant ketoconazole, a strong CYP3A4 inhibitor, on mifepristone.

Methods

In an open-label, two-period, single-center study, healthy adult men received mifepristone 600 mg orally daily for 12 days (period 1) followed by mifepristone 600 mg daily plus ketoconazole 200 mg orally twice daily for 5 days (period 2). Serial pharmacokinetic blood samples were collected predose and over 24 h postdose on days 12 (period 1) and 17 (period 2). A cross-study comparison (using data on file) further examined whether systemic exposure to mifepristone plus ketoconazole exceeded the exposure following mifepristone 1200 mg orally administered for 7 days.

Results

Sixteen subjects were enrolled and 14 completed the study. Concomitant administration with ketoconazole increased the systemic exposure to mifepristone, based on geometric least squares mean ratios, by 28% for C _max and 38% for AUC_0–24. This increase was 85% and 87% of the exposure observed following mifepristone’s highest label dose of 1200 mg/day for C _max and AUC_0–24, respectively. Adverse events (AEs) were reported in 56.3% (9/16) of subjects during administration of mifepristone alone and in 57.1% (8/14) during combination with ketoconazole. No serious AEs were reported.

Conclusion

Systemic exposure to mifepristone increased following multiple doses of mifepristone 600 mg daily plus ketoconazole 200 mg twice daily. Little to no increase in AEs occurred. Dose adjustment of mifepristone may be needed when given with ketoconazole.

Funding

Corcept Therapeutics.

     

Non-invasive PET Imaging of PARP1 Expression in Glioblastoma Models

Purpose

The current study presents [¹⁸F]PARPi as imaging agent for PARP1 expression.

Procedures

[¹⁸F]PARPi was generated by conjugating a 2H-phthalazin-1-one scaffold to 4-[¹⁸F]fluorobenzoic acid. Biochemical assays, optical in vivo competition, biodistribution analysis, positron emission tomography (PET)/X-ray computed tomography, and PET/magnetic resonance imaging studies were performed in subcutaneous and orthotopic mouse models of glioblastoma.

Results

[¹⁸F]PARPi shows suitable pharmacokinetic properties for brain tumor imaging (IC₅₀?=?2.8?±?1.1 nM; logP_CHI?=?2.15?±?0.41; plasma-free fraction?=?63.9?±?12.6 %) and accumulates selectively in orthotopic brain tumor tissue. Tracer accumulation in subcutaneous brain tumors was 1.82?±?0.21 %ID/g, whereas in healthy brain, the uptake was only 0.04?±?0.01 %ID/g.

Conclusions

[¹⁸F]PARPi is a selective PARP1 imaging agent that can be used to visualize glioblastoma in xenograft and orthotopic mouse models with high precision and good signal/noise ratios. It offers new opportunities to non-invasively image tumor growth and monitor interventions.

     

Heart rate reduction with esmolol is associated with improved arterial elastance in patients with septic shock: a prospective observational study

Purpose

Ventricular–arterial (V–A) decoupling decreases myocardial efficiency and is exacerbated by tachycardia that increases static arterial elastance (Ea). We thus investigated the effects of heart rate (HR) reduction on Ea in septic shock patients using the beta-blocker esmolol. We hypothesized that esmolol improves Ea by positively affecting the tone of arterial vessels and their responsiveness to HR-related changes in stroke volume (SV).

Methods

After at least 24 h of hemodynamic optimization, 45 septic shock patients, with an HR ≥95 bpm and requiring norepinephrine to maintain mean arterial pressure (MAP) ≥65 mmHg, received a titrated esmolol infusion to maintain HR between 80 and 94 bpm. Ea was calculated as MAP/SV. All measurements, including data from right heart catheterization, echocardiography, arterial waveform analysis, and norepinephrine requirements, were obtained at baseline and at 4 h after commencing esmolol.

Results

Esmolol reduced HR in all patients and this was associated with a decrease in Ea (2.19 ± 0.77 vs. 1.72 ± 0.52 mmHg l^?1), arterial dP/dt _max (1.08 ± 0.32 vs. 0.89 ± 0.29 mmHg ms^?1), and a parallel increase in SV (48 ± 14 vs. 59 ± 18 ml), all p < 0.05. Cardiac output and ejection fraction remained unchanged, whereas norepinephrine requirements were reduced (0.7 ± 0.7 to 0.58 ± 0.5 µg kg^?1 min^?1, p < 0.05).

Conclusions

HR reduction with esmolol effectively improved Ea while allowing adequate systemic perfusion in patients with severe septic shock who remained tachycardic despite standard volume resuscitation. As Ea is a major determinant of V–A coupling, its reduction may contribute to improving cardiovascular efficiency in septic shock.