Mesalazine Modified-Release Tablet in the Treatment of Ulcerative Colitis in the Remission Phase: A Chinese,Multicenter, Single-Blind,Randomized Controlled Study

Introduction

This study aimed to compare the efficacy and safety of two mesalazine formulations in the treatment of Chinese patients with ulcerative colitis (UC) in the remission phase.

Methods

In this multicenter, single-blind, randomized controlled study conducted from November 2010 to August 2012, 251 patients with UC from 18 hospitals were enrolled. The patients were randomized to treatment with mesalazine modified-release tablets (MR group, n = 126) or other enteric-coated tablets (EC group, n = 125), at 800 mg three-times daily for 48 weeks. The primary efficacy parameter was the rate of non-emergence of bloody stool. If the lower limit of the 95% confidence interval (CI) of the primary efficacy measure was over ?10%, the modified-release tablets were considered non-inferior to the enteric-coated tablets. The secondary efficacy parameters included the period of non-emergence of bloody stool and the period of non-recurrence of UC. The incidences of adverse events and adverse drug reactions were compared between the two groups.

Results

At 48 weeks of maintenance treatment, the rates of non-emergence of bloody stool were 82.99% (95% CI 73.53–92.45%) and 73.30% (95% CI 64.04–82.56%) in the MR and EC groups, respectively, and the difference between the two groups was 9.69% (95% CI ?1.15–20.53%). There was no significant difference in the period of non-emergence of bloody stool and the period of non-recurrence of UC between the two groups (P > 0.05). The incidences of adverse events were 48.78% (60/123) and 48.00% (60/125) in the MR and EC groups, respectively (P = 0.902). The incidences of adverse drug reactions were 16.26% (20/123) and 13.60% (17/125) in the MR and EC groups, respectively (P = 0.556).

Conclusion

Mesalazine modified-release tablets were non-inferior to the enteric-coated tablets and may be considered an effective and safe treatment alternative for the maintenance of remission in Chinese patients with UC.

Trial registration

ClinicalTrials.gov identifier: NCT01257399.

Funding

Tillotts Pharma AG.

     

Lack of a Pharmacokinetic Interaction Between SYM-1219 Granules Containing 2 Grams of Secnidazole and a Combined Oral Contraceptive in a Phase 1, Randomized,Open-Label Study in Healthy Female Volunteers

Introduction

Bacterial vaginosis (BV) is a serious infection that is the most common vaginal infection in women of childbearing potential. SYM-1219 is a novel, granule formulation containing 2 g of secnidazole that is being developed as a single, oral dose to treat women with BV. Because many of the women diagnosed with BV use hormonal contraception, the effect of SYM-1219 on the pharmacokinetics (PK) of commonly prescribed oral contraceptive drugs, ethinyl estradiol (EE2), and norethindrone (NET) was evaluated.

Methods

This two-period, randomized, open-label study examined effects in 54 healthy female subjects. During the first period of the study, each subject received EE2 0.035-mg/NET 1-mg tablets. During the second period of the study, subjects were randomized to receive either EE2 0.035-mg/NET 1-mg tablets with concomitant 2-g SYM-1219 or 2-g SYM-1219 followed by EE2 0.035-mg/NET 1-mg tablets 1 day later. The PK of EE2 and NET were analyzed for 24 h following administration.

Results

Coadministration of SYM-1219 and EE2/NET, either on the same day or 1 day apart, had no clinically relevant effects on the bioavailability of EE2 or NET. The combined use of SYM-1219 with EE2/NET was well tolerated. Taken together, these results indicate that contraceptive efficacy should be maintained during coadministration of SYM-1219 and EE2/NET.

Conclusion

SYM-1219 is a valuable single-dose treatment option for women with BV that will not interfere with combined oral contraceptive methods.

Funding

Symbiomix Therapeutics.

     

Effect of synbiotic therapy on the incidence of ventilator associated pneumonia in critically ill patients: a randomised,double-blind,placebo-controlled trial

Objective

To investigate the effect of enteral Synbiotic 2000 FORTE^® (a mixture of lactic acid bacteria and fibre) on the incidence of ventilator associated pneumonia (VAP) in critically ill patients.

Design

Prospective, randomised, double blind, placebo controlled trial.

Setting

Tertiary referral centre, general Adult Intensive Care Unit (ICU).

Patients and participants

259 enterally fed patients requiring mechanical ventilation for 48 h or more were enrolled.

Intervention

All patients were enterally fed as per a standard protocol and randomly assigned to receive either synbiotic 2000 FORTE^® (twice a day) or a cellulose-based placebo for a maximum of 28 days.

Measurements and results

Treatment group (n = 130) was well matched with placebo group (n = 129) for age (mean 49.5 and 50 years, respectively) and APACHE II score (median 17 for both). Oropharyngeal microbial flora and colonisation rates were unaffected by synbiotics. The overall incidence of VAP was lower than anticipated (11.2%) and no statistical difference was demonstrated between groups receiving synbiotic and placebo in the incidence of VAP (9 and 13%, P = 0.42), VAP rate per 1,000 ventilator days (13 and 14.6, P = 0.91) or hospital mortality (27 and 33%, P = 0.39), respectively.

Conclusions

Enteral administration of Synbiotic 2000 FORTE^® has no statistically significant impact on the incidence of VAP in critically ill patients.

     

MR comparative study of combined hepatocellular-cholangiocarcinoma in normal,fibrotic, and cirrhotic livers

Purpose

To compare MR imaging features of combined hepatocellular-cholangiocarcinoma (cHCC-CC) in normal, fibrotic, and cirrhotic livers.

Methods

A total of 64 patients with 67 pathologically proven cHCC-CCs were retrospectively analyzed. Patients were classified into three groups according to the patients’ liver condition: patients with normal liver (F0, group 1), fibrosis without cirrhosis (F1–3, group 2), and cirrhosis (F4, group 3). The morphological and MR signal features on T1- and T2-weighted, dynamic contrast-enhanced, diffusion-weighted imaging, as well as the accompanying imaging findings, were evaluated and compared.

Results

There were 12, 19, and 33 patients in groups 1, 2, and 3, respectively. Tumors in the fibrotic and cirrhotic livers were smaller than those in the normal liver, and tumors with cirrhosis had the smallest size (P = 0.0326). No statistical difference was found when comparing the signal intensity on T2-weighted imaging (P = 0.496), but iso- or hypointense lesions were only found in the fibrosis (n = 2) or cirrhosis group (n = 2). Enhancement pattern was different between groups, the washout pattern was more often seen in the cirrhosis group (P = 0.049), and the accompanying mosaic architecture was also more commonly seen in the cirrhosis group (P = 0.048). The ADC values of the lesions were not different among the three groups (P = 0.899).

Conclusion

MRI may provide valuable information for the diagnosis and differential diagnosis of cHCC-CC in normal, fibrotic, and cirrhotic livers. The nodule size, enhancement pattern, and the presence of mosaic architecture in cHCC-CC differ between different degrees of background liver disease.

     

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.

     

MR-imaging features of hepatocellular carcinoma capsule appearance in cirrhotic liver: comparison of gadoxetic acid and gadobenate dimeglumine

Purpose

The purpose of the study is to compare the MR-imaging features of hepatocellular carcinoma (HCC) capsule appearance on gadoxetic acid and gadobenate dimeglumine-enhanced MR imaging, using imaging-based presumptive diagnosis of HCC as the reference standard.

Methods

Gadoxetic acid and gadobenate dimeglumine-enhanced MR imaging of 51 patients with 71 HCCs were retrospectively reviewed. Three readers graded in consensus, using a five-point scale, the presence (score 4–5) of capsule appearance on images obtained during T1-weighted GRE portal venous phase (PVP), 3-min phase, and hepatobiliary phase (HBP). The Fisher's exact test and the t student unpaired test were performed.

Results

A hyperintense capsule appearance was present either on PVP or 3-min phase in 11/46 and in 24/25 HCCs imaged with gadoxetic acid and gadobenate dimeglumine-enhanced MR imaging, respectively (24% vs. 96% p < 0.001). A hypointense capsule appearance was present on HBP in 8/46 and 0/22 HCCs evaluated with gadoxetic acid and gadobenate dimeglumine-enhanced MR imaging, respectively (17% vs. 0% p = 0.046). A capsule appearance was detected either on PVP, 3-min phase, or HBP in 17/46 (37%) HCCs after gadoxetic acid injection and in 24/25 (96%) HCCs after gadobenate dimeglumine injection (p < 0.001).

Conclusions

A capsule appearance was more frequently seen on gadobenate dimeglumine-enhanced MR imaging when compared to gadoxetic acid-enhanced MR imaging.

     

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.

     

Prolonging Time to Flare in Pediatric Atopic Dermatitis: A Randomized,Investigator-Blinded,Controlled, Multicenter Clinical Study of a Ceramide-Containing Moisturizer

Introduction

Delaying or preventing flares is important in atopic dermatitis (AD) management. The objective of the study was to evaluate whether using a ceramide-containing moisturizer in addition to a body wash during latent AD can delay flares.

Methods

This was a randomized, investigator-blinded, parallel-group, controlled study among Chinese children with a history of mild to moderate AD, within 1 week of successful treatment with a topical corticosteroid. Subjects were randomized to receive moisturizer twice daily and body wash once daily, or body wash alone once daily for 12 weeks. The primary efficacy endpoint was time to flare [necessitating medical therapy and/or Investigator Global Assessment (IGA) > 1 (at least mild AD)]. Other efficacy endpoints were AD characteristics and emollient effects. The patient-reported outcome comprised satisfaction at week 12. The safety endpoint was incidence of undesirable events.

Results

A total of 64 subjects aged 2–12 years were randomized. Median time to flare was delayed by nearly 2 months for moisturizer/body wash compared to body wash alone (89 vs. 27 days, respectively). A significantly earlier onset of action in terms of fewer flares favoring moisturizer was found at week 4 (31 vs. 59%, respectively, p = 0.022), and after 12 weeks, fewer flares occurred (50 vs. 72%). At week 12 for flare-free subjects, nearly half in both groups had clear IGA, and an emollient effect in terms of less dryness or burning was more marked for moisturizer/body wash. Both products led to high patient satisfaction and were well tolerated.

Conclusion

A regimen incorporating a moisturizer plus body wash delayed AD flares by nearly 2 months compared to body wash alone, and yielded high patient satisfaction.

Funding

Galderma R&D.

Trial Registration

ClinicalTrials.gov identifier, NCT02589392.

     

A Randomized,Clinical Trial to Evaluate Efficacy and Tolerability of Trypsin:Chymotrypsin as Compared to Serratiopeptidase and Trypsin:Bromelain:Rutoside in Wound Management

Introduction

Systemic enzyme therapy can play an important role in maintaining normal inflammatory processes within the body and thereby helps support and speed up healing. In the course of the anti-inflammatory action, enzymes degrade damaged cells and necrotic material and, through the inactivation of mediators and toxic products, they restrict the edema and pain.

Method

The study conducted at Grant Medical College, Mumbai, India was a clinical trial comparing the efficacy and tolerability of three oral enzyme treatment groups—oral tablets containing trypsin:chymotrypsin (TC) (Chymoral Forte^®), serratiopeptidase (S) 5 mg oral tablets, and oral enzyme tablets containing trypsin 48 mg, bromelain 90 mg, and rutoside 100 mg (TBR)—to evaluate their healing potential in surgical wounds after orthopedic surgery.

Results

A total of 75 patients were screened, randomized, and divided into three groups in 1:1:1 ratio receiving either of the three treatments. In the TC group, erythema was significantly reduced from 3.44 on day 3 to 1.16 on day 10 (p < 0.01). There was significantly better reduction in erythema scores in the TC group as compared to S and TBR groups (p < 0.05) at each follow-up visit. Similarly reduction in the local irritation, wound discharge, edema, induration, and tenderness score with TC treatment at the end of the study was significantly higher than that observed in the other two groups. In addition TC showed significant reduction in pain on the VAS scale (p < 0.01). Global assessment of response to therapy for efficacy and tolerability was reported to be good to excellent in 88% and 92% of the patients on TC as compared to 12% and 8% with S and 12% and 8% with TBR.

Conclusion

TC provides a better resolution of symptoms of inflammation after orthopedic surgery as compared to S and TBR, thus facilitating better wound healing. Further studies are warranted to confirm the findings.

Trial Registration

Clinical Trial Registry of India (Reg. No. CTRI/2011/07/001920).

     

The Effectiveness of Trimetazidine Treatment in Patients with Stable Angina Pectoris of Various Durations: Results from the CHOICE-2 Study

Introduction

Trimetazidine (TMZ) has been shown to reduce angina symptoms and to increase exercise capacity in randomized clinical trials, but more extensive data would be useful to assess its effects in real-world clinical practice and in patients with different durations of disease.

Methods

CHOICE-2 was a Russian, multicenter, 6-month, open-label, prospective observational study that assessed the effect of adding TMZ modified release 35 mg bid to antianginal treatment in a real-world setting. The present analysis of CHOICE-2 results explored the effects of adding TMZ to background antianginal therapies with regard to the duration of stable angina.

Results

A total of 741 patients with known durations of disease were divided into four groups according to stable angina pectoris (AP) duration, ranging from less than 1 year to more than 9 years. Addition of TMZ led to a significant decrease in the frequency of angina attacks and in the use of short-acting nitrates in all groups. In patients with recently diagnosed angina (AP duration < 1 year), the average number of angina attacks per week decreased significantly from 3.75 ± 4.63 to 0.67 ± 1.51 and in those with advanced disease (AP duration > 9 years) from 5.63 ± 5.24 to 1.32 ± 2.07. Angina-free walking distance also improved significantly. Addition of TMZ also improved patient well-being. Results were achieved rapidly (within 2 weeks), were maintained over 6 months, and were obtained in all patient groups regardless of angina duration.

Conclusion

TMZ added to other antianginal therapies proved to be effective for reducing angina attacks and short-acting nitrate use, increasing angina-free walking distance, and improving patient well-being in a real-life setting, irrespective of angina duration, including patients with recently diagnosed angina. This provides an opportunity for intensification of treatment early on in the disease process, with the aim of decreasing angina burden and improving patient quality of life.

Funding

Servier.

Trial Registration

ISRCTN identifier ISRCTN65209863.

Plain Language Summary

Plain language summary available for this article.

     

Can diffusion-weighted magnetic resonance imaging predict tumor recurrence of uterine cervical cancer after concurrent chemoradiotherapy?

Purpose

To retrospectively investigate the utility of diffusion-weighted imaging (DWI) for predicting clinical outcome after concurrent chemoradiotherapy (CCRT) in uterine cervical cancer.

Materials and methods

Seventy-four consecutive patients with biopsy-proven cervical cancer who received CCRT underwent DWI at 3T. All patients had MR examinations before therapy (preTx) and at 4 weeks of initiating therapy (midTx). At each point, ADC (apparent diffusion coefficient) was measured in the tumors and ADC change between preTx and midTx were also calculated. For predicting tumor recurrence, MR variables and clinical variables were evaluated and the results were compared.

Results

During a mean follow-up of 32.1 months, tumor recurrence developed in 15 (20%) patients: local recurrence (n = 7), distant metastasis (n = 5), and both (n = 3). MidTx tumor ADCs and tumor ADC changes between preTx and midTx were significantly different between the recurrence and non-recurrence groups (P < 0.05), while preTx tumor ADCs were not significantly different between the groups (P = 0.892). Univariate analysis revealed that histologic type, stage, preTx tumor size and volume, and tumor ADC change were significantly related to tumor recurrence (all P < 0.05). However, on multivariate analysis, tumor ADC changes [hazard ratio (HR) 0.886; 95% confidence interval (CI) 0.836–0.940; P = 0.001] and histological type (HR 6.063; 95% CI 1.404–26.187; P = 0.016) were the significant independent predictors of tumor recurrence.

Conclusion

Tumor ADC changes between preTx and midTx might be a useful biomarker for the prediction of cervical cancer recurrence after CCRT.

     

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.

     

Efficacy and Safety of Vedolizumab in Ulcerative Colitis and Crohn’s Disease Patients Stratified by Age

Introduction

The efficacy and safety of vedolizumab, a gut-selective α₄β₇ integrin antibody, were demonstrated in the GEMINI 1 and GEMINI 2 clinical trials of adults aged 18–80 years. We investigated the efficacy and safety of vedolizumab in patients stratified by age from the GEMINI trials.

Methods

Safety and efficacy, including clinical response, clinical remission, and corticosteroid-free remission, at week 6 and/or 52 were determined post hoc in patients aged <35, 35 to <55, and ≥55 years.

Results

At baseline, 353, 412, and 130 ulcerative colitis (UC) and 582, 443, and 90 Crohn’s disease (CD) patients were aged <35, 35 to <55, and ≥55. Of these patients, 56 were aged ≥65 years (UC: 33, CD: 23). Trends favoring vedolizumab over placebo were observed for most efficacy endpoints irrespective of patient age; some variability between subgroups was observed. Safety profiles of vedolizumab and placebo were similar in all age groups. Vedolizumab-treated patients aged ≥55 had the lowest incidence of serious infections (0.9 per 100 person–years) and adverse events leading to hospitalization (14.8 per 100 person–years). There were no age-related differences in the incidence of adverse hematological events, malignancy, or death.

Conclusions

The safety and efficacy of vedolizumab in patients with UC or CD were similar for all age groups. The number of patients in the oldest age group in these analyses was small; thus further studies of vedolizumab in larger cohorts of elderly patients are warranted.

Funding

Millennium Pharmaceuticals, Inc. (d/b/a Takeda Pharmaceuticals International Co.).

     

Histogram analysis of noncancerous liver parenchyma on gadoxetic acid-enhanced MRI: predictive value for liver function and pathology

Purpose

To clarify whether the heterogeneity of hepatic parenchyma in the hepatobiliary phase on gadoxetic acid-magnetic resonance (MR) imaging is correlated with liver damage.

Materials and methods

We retrospectively examined the cases of 98 patients with or without chronic liver disease who underwent gadoxetic acid-enhanced 3T MR imaging before a hepatectomy between December 2010 and October 2014. For the evaluation of the heterogeneity of the signal intensity in the hepatobiliary phase, we placed the region of interest on the hepatic parenchyma, and the skewness and kurtosis were calculated using ImageJ software. A discriminant analysis was performed to examine the routine preoperative laboratory test results including indocyanine green retention at 15 min (ICG-R15), necro-inflammation grade, and liver fibrosis stage according to the METAVIR system: A0/1 (n = 69) and A2 (n = 29); F0/1 (n = 47), F2/3 (n = 31), and F4 (n = 20).

Results

The combination of skewness and kurtosis could discriminate the high ICG-R15 (>20) and low (<20) groups (lambda; 0.925, p = 0.025), necro-inflammatory grade (lambda; 0.926, p = 0.026), and fibrosis stage (lambda; 0.752, p < 0.0001) with statistical significance. The difference between the patients with normal values and those with an abnormal platelet count or aspartate transaminase level was also detectable (lambda; 0.901, p < 0.007, and lambda; 0.864, p = 0.001, respectively).

Conclusion

Histogram analyses of the hepatobiliary phase of gadoxetic acid-enhanced MR imaging have potential as a biomarker for the assessment of liver function, liver fibrosis, and necro-inflammation.

     

Cost-Effectiveness of Posaconazole Tablets for Invasive Fungal Infections Prevention in Acute Myelogenous Leukemia or Myelodysplastic Syndrome Patients in Spain

Introduction

Posaconazole is superior to fluconazole (FLU) and itraconazole (ITRA) in the prevention of invasive fungal diseases (IFDs) in neutropenic patients with acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS). A new tablet formulation of posaconazole with improved pharmacokinetic and pharmacodynamic properties compared to posaconazole oral solution has recently been approved. The objective of this study is to estimate the cost-effectiveness of the newly developed posaconazole tablets versus FLU oral suspension or ITRA oral solution for preventing IFDs in high-risk neutropenic patients with AML or MDS and from the perspective of the Spanish National Health System (NHS).

Methods

A previously validated economic model was used. The probabilities of experiencing an IFD, an IFD-related death or death from other causes over 100 days were based on clinical trial data and input into a decision tree. Surviving patients were entered into a Markov model to calculate total costs, number of IFDs and number of life-years gained per patient over a lifetime horizon in each disease and treatment group. Two health states, alive and dead, were considered. Health effects were discounted using a rate of 3%. Univariate and probabilistic sensitivity analyses were conducted.

Results

During the first 100 days, posaconazole tablets were associated with a lower risk of IFDs (0.046 vs. 0.111), longer life expectancy (2.92 vs. 2.69 years) and lower total costs (€5906.06 vs. €7847.20 per patient) over the patients’ lifetimes compared to FLU or ITRA treatments. Thus, posaconazole tablets were more effective and less costly than FLU or ITRA. Probabilistic sensitivity analysis indicated that there was a 79.9% probability of posaconazole tablets being cost-saving compared to FLU or ITRA.

Conclusion

From the Spanish NHS perspective, posaconazole tablets are cost-effective compared to FLU or ITRA in AML or MSD patients with chemotherapy-induced neutropenia and at high risk for IFDs.

Funding

MSD Sharp & Dohme.

     

Burden of Atopic Dermatitis in the United States: Analysis of Healthcare Claims Data in the Commercial,Medicare, and Medi-Cal Databases

Introduction

Comparative data on the burden of atopic dermatitis (AD) in adults relative to the general population are limited. We performed a large-scale evaluation of the burden of disease among US adults with AD relative to matched non-AD controls, encompassing comorbidities, healthcare resource utilization (HCRU), and costs, using healthcare claims data. The impact of AD disease severity on these outcomes was also evaluated.

Methods

Adult AD patients in the Commercial (n = 83,106), Medicare (n = 31,060), and Medi-Cal (n = 5550) databases were matched (1:1) to non-AD controls by demographic characteristics. AD patients were stratified by disease severity (higher, lower) using treatment as a surrogate measure of severity. The comorbidity burden, HCRU, and costs were evaluated during a 12-month follow-up period.

Results

In the Commercial, Medicare, and Medi-Cal populations, patients with AD had a significantly higher overall comorbidity burden (P < 0.0001), an increased risk of asthma and allergic rhinitis (both P < 0.0001), higher HCRU (P < 0.05), and higher mean total per patient costs (Commercial: US$10,461 versus US$7187; Medicare: US$16,914 versus US$13,714; Medi-Cal; US$19,462 versus US$10,408; all P < 0.0001), compared with matched non-AD controls. Higher disease severity was associated with an increased comorbidity burden (P < 0.0001), HCRU (P < 0.05), and total costs (Commercial: US$14,580 versus US$7192; Medicare: US$21,779 versus US$12,490; Medi-Cal; US$22,123 versus US$16,639; all P < 0.0001) relative to lower severity disease.

Conclusion

In this large-scale, healthcare claims database analysis, AD patients had a significantly higher comorbidity burden, HCRU, and costs compared with matched non-AD controls. Higher disease severity was associated with an even greater comorbidity and economic burden.

Funding

Sanofi and Regeneron Pharmaceuticals, Inc.

     

Deformable registration of preoperative MR,pre-resection ultrasound,and post-resection ultrasound images of neurosurgery

Purpose

Sites that use ultrasound (US) in image-guided neurosurgery (IGNS) of brain tumors generally have three sets of imaging data: preoperative magnetic resonance (MR) image, pre-resection US, and post-resection US. The MR image is usually acquired days before the surgery, the pre-resection US is obtained after the craniotomy but before the resection, and finally, the post-resection US scan is performed after the resection of the tumor. The craniotomy and tumor resection both cause brain deformation, which significantly reduces the accuracy of the MR–US alignment.

Method

Three unknown transformations exist between the three sets of imaging data: MR to pre-resection US, pre- to post-resection US, and MR to post-resection US. We use two algorithms that we have recently developed to perform the first two registrations (i.e., MR to pre-resection US and pre- to post-resection US). Regarding the third registration (MR to post-resection US), we evaluate three strategies. The first method performs a registration between the MR and pre-resection US, and another registration between the pre- and post-resection US. It then composes the two transformations to register MR and post-resection US; we call this method compositional registration. The second method ignores the pre-resection US and directly registers the MR and post-resection US; we refer to this method as direct registration. The third method is a combination of the first and second: it uses the solution of the compositional registration as an initial solution for the direct registration method. We call this method group-wise registration.

Results

We use data from 13 patients provided in the MNI BITE database for all of our analysis. Registration of MR and pre-resection US reduces the average of the mean target registration error (mTRE) from 4.1 to 2.4 mm. Registration of pre- and post-resection US reduces the average mTRE from 3.7 to 1.5 mm. Regarding the registration of MR and post-resection US, all three strategies reduce the mTRE. The initial average mTRE is 5.9 mm, which reduces to 3.3 mm with the compositional method, 2.9 mm with the direct technique, and 2.8 mm with the group-wise method.

Conclusion

Deformable registration of MR and pre- and post-resection US images significantly improves their alignment. Among the three methods proposed for registering the MR to post-resection US, the group-wise method gives the lowest TRE values. Since the running time of all registration algorithms is less than 2 min on one core of a CPU, they can be integrated into IGNS systems for interactive use during surgery.

     

Fully automatic cross-modality localization and labeling of vertebral bodies and intervertebral discs in 3D spinal images

Purpose

We present a cross-modality and fully automatic pipeline for labeling of intervertebral discs and vertebrae in volumetric data of the lumbar and thoracolumbar spine. The main goal is to provide an algorithm that is applicable to a wide range of different sequences and acquisition protocols, like T1- and T2- weighted MR scans, MR Dixon data, and CT scans. This requires that the learned models generalize without retraining to modalities and scans with unseen image contrasts.

Methods

We address this challenge by automatically localizing the sacral region combining local entropy-optimized texture models with convolutional neural networks. For subsequent labeling, local three-disc entropy models are matched iteratively to the spinal column. Every model-matched position is further refined by an intensity-based template-matching approach, based solely on the reduced intensity scale provided by the entropy models.

Results

We evaluated our method on 161 publicly available scans, acquired on various scanners. We showed that our method can deal with a wide range of different MR protocols as well as with CT data. We achieved a sacrum detection rate of 93.6%. Mean center accuracies ranged from 2.5 ± 1.5 to 5.7 ± 3.8 mm for the different sets of scans.

Conclusion

We present a novel spine labeling framework that is applicable to a highly heterogeneous set of scans without retraining of the method. Our approach achieves high sacrum localization accuracy and shows promising labeling results. To the best of our knowledge, an algorithm able to deal with such a diverse set of MR and CT scans has not yet been presented in the literature.