Comparative analysis of GMO regulatory requirements for AAV vectors in the EU and Japan focusing on the shedding data and containment measures.

INTRODUCTION: Recombinant viral-based gene therapy products, such as those incorporating adeno-associated viruses (AAVs), fall under the category of genetically modified organisms (GMOs). The European Union (EU) countries and Japan must obtain environmental risk assessment (ERA) approval for the use of GMOs before starting any clinical trials. It has been reported that the development of GMO-containing products in these two regions encounters several regulatory obstacles due to the longer regulatory procedures and document preparation for ERA. AREAS COVERED: In this article, we comparatively analyzed the ERA document requirements in the EU and Japan for AAV-based recombinant medicinal products to highlight the differences in the context of potential future attempts of convergence. Additionally, we analyzed non-clinical and clinical shedding data requirements, which are key components of ERA reviews in the EU and Japan. Lastly, we compared the containment measures to minimize the spread of GMOs in the environment in the EU and Japan. EXPERT OPINION: Based on our comparative analysis, we present several policy recommendations of standardizing and simplifying the application materials and procedures for the ERA regulations on GMOs in the EU and Japan in the mid-, and long-term timeframe to achieve global regulatory convergence.

Application of estimand framework to the design and analysis of multi-regional clinical trials.

With the increasing globalization of drug development and the publication of the International Council for Harmonisation (ICH) E17 guideline (ICH International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use 2017), multi-regional clinical trials (MRCTs) have become a preferred option to accelerate the availability of new medical products by design, execution and simultaneous submission under one protocol. MRCTs, with the participation of all major regions including countries from both developed and emerging markets, surely make new drug development more efficient. Even though the proposed estimand framework (ICH E9 (R1) (2019), came later in 2019 and was not mentioned in ICH E17, the application of the estimand framework has the potential to enhance the design, execution, and analysis in MRCTs. Defining an estimand within the regional context in MRCTs is an important issue that requires careful consideration. Given that consistency evaluation of treatment effects across regions is critical in MRCTs, the utilization of the estimand framework for regional consistency evaluation is also worth discussion. This paper aims to address these two questions. The five attributes of the estimand definition are discussed within a multi-regional context. It is imperative to thoroughly consider regional intrinsic/extrinsic factors when planning the estimand and estimation of MRCTs. A holistic approach is summarized to conduct consistency evaluation. When a regional inconsistency is observed, the possible reasons need to be further explored under five attributes of the estimand framework. Two real case studies are discussed to illustrate the application of the estimand framework in the consistency evaluation.

Simultaneous Global Drug Development and Multiregional Clinical Trials (MRCT): 5 Years After Implementation of ICH E17 Guidelines.

The ICH E17 guidelines (2014-2017) on Multiregional Clinical Trials (MRCT) was a joint effort by the regulators and industry to facilitate simultaneous global drug development and registration through taking a strategic approach for clinical trials. In other words, the objective was to reduce the time it takes to bringing medications to patients around the world through minimizing unnecessary duplication of local or regional studies, which may add the regulatory burden to cost and time of bringing new therapies to patients. Under the auspices of ICH, training materials were created and provided to various stakeholders. Despite the successful promotion of the benefits of ICH E17 MRCT guidelines across the different regions, the uptake of some concepts (e.g., pooling strategy) in the ICH E17 guidelines has been slow. This paper describes various factors which could affect the conduct of MRCT at a global level, including ambiguity in definition of "region" (in MRCT), new regulatory requirements to enroll a diverse patient population, the use of decentralized clinical trials, use of data sources other than randomized clinical trials (e.g., use of Real Word Data), and the impact of the COVID-19 pandemic on the conduct of MRCT.

Regional consistency assessment in multiregional clinical trials.

Multiregional clinical trials (MRCTs) have become a favored strategy for new drug development. The accurate evaluation of treatment effects across different regions is crucial for interpreting the results of MRCTs. Consistency between regional and overall results ensures the extrapolability of the overall conclusions to individual regions. While numerous statistical methods have been proposed for consistency assessment, a notable proportion necessitate a substantial escalation in sample size, particularly in scenarios involving more than four regions within MRCTs. This, paradoxically, undermines the fundamental intent of MRCTs. In addition, standardized statistical criteria for concluding consistency are yet to be established. In this paper, we develop further consistency assessment approaches in the framework of two multivariate likelihood ratio test-based methods, namely mLRTa and mLRTb, wherein consistency is cast as the alternative and null hypotheses. Notably, our exploration unveils that qualitative methods such as the funnel approach and PMDA methods are special instances of mLRTa. Furthermore, our work underscores that these three qualitative methodologies roughly share the same level of assurance probability (AP). Intriguingly, when the number of regions in an MRCT surpasses five, even when the overall sample size guarantees a power of 90% or more and the true treatment effects remain uniform across regions, the AP remains below the 70% mark. Drawing from our meticulous examination of operational attributes, we recommend mLRTa with positive treatment effects in all regions in the alternative hypothesis with significance level 0.5 or mLRTb with all regional treatment effects being equal in the null and significance level of 0.2.

Multimodal imaging and photothermal/chemodynamic therapy of cervical cancer using GSH-responsive MoS2@MnO2 theranostic nanoparticles.

The development of nanoparticles capable of inducing reactive oxygen species (ROS) formation has become an important strategy for cancer therapy. Simultaneously, the preparation of multifunctional nanoparticles that respond to the tumor microenvironment is crucial for the diagnosis and treatment of tumors. In this study, we designed a Molybdenum disulfide (MoS2) core coated with Manganese dioxide (MnO2), which possessed a good photothermal effect and could produce Fenton-like Mn2+ in response to highly expressed glutathione (GSH) in the tumor microenvironment, thereby generating a chemodynamic therapy (CDT). The nanoparticles were further modified with Methoxypoly(Ethylene Glycol) 2000 (mPEG-NH2) to improve their biocompatibility, resulting in the formation of MoS2@MnO2-PEG. These nanoparticles were shown to possess significant Magnetic Resonance Imaging (MRI) and Computed Tomography (CT) imaging capabilities, making them useful in tumor diagnosis. In vitro and in vivo experiments demonstrated the antitumor ability of MoS2@MnO2-PEG, with a significant killing effect on tumor cells under combined treatment. These nanoparticles hold great potential for CDT/photothermal therapy (PTT) combined antitumor therapy and could be further explored in biomedical research.

Silk Fibroin-Induced Gadolinium-Functionalized Gold Nanoparticles for MR/CT Dual-Modal Imaging-Guided Photothermal Therapy.

The development of multifunction nanoplatforms integrating accurate diagnosis and efficient therapy is of great significance for the precise treatment of tumors. Gold nanoparticles (AuNPs) possessing hallmark features of computed tomography (CT) imaging and photothermal conversion capability hold great potential in tumor theranostics. In this study, taking the advantages of outstanding biocompatibility, interesting anti-inflammatory and immunomodulatory properties, and abundant amino acid residues of silk fibroin (SF), a multifunctional Gd-hybridized AuNP nanoplatform was constructed using SF as a stabilizer and reductant via a facile one-pot biomimetic method, denoted as Gd:AuNPs@SF. The obtained Gd:AuNPs@SF possessed fascinating biocompatibility and excellent photothermal conversion efficiency. Functionalized with Gd, Gd:AuNPs@SF exhibited super tumor-contrasted imaging performance in magnetic resonance (MR) and CT imaging modalities. Moreover, Gd:AuNPs@SF, with strong NIR absorbance, demonstrated that it could effectively kill tumor cells in vitro, and was also proved to successfully ablate tumor tissues through MR/CT imaging-guided photothermal therapy (PTT) without systemic toxicity in Pan02 xenograft C57BL/6 mouse models. We successfully synthesized Gd:AuNPs@SF for MR/CT dual-mode imaging-guided PTT via a facile one-pot biomimetic method, and this biomimetic strategy can also be used for the construction of other multifunction nanoplatforms, which is promising for precise tumor theranostics.

The Plug-Type Patch Results in Immediate and Postoperative Advantages in Graft-to-Bone Integration for Bridging Massive Rotator Cuff Tears in a Chronic Rabbit Model.

BACKGROUND: Various patches have been used to bridge massive rotator cuff tears (MRCTs) by reconnecting the cuff tendons to the humeral head, but the outcomes continue to be suboptimal. Notably, the graft-bone junction is a vulnerable site for failure, which requires optimization in patch design and techniques to enhance initial and postoperative fixation strength at the graft-bone interface. HYPOTHESIS: The plug-type patch (Plug-Pat) through intratunnel fixation would optimize mechanical characteristics in initial graft-to-bone fixation and subsequently improve postoperative biomechanical and histological properties in graft-to-bone healing when compared with the routine rectangular patch (Rect-Pat). STUDY DESIGN: Controlled laboratory study. METHODS: A total of 60 mature male New Zealand White rabbits underwent acute rotator cuff defects to create chronic models with MRCTs. The fascia lata autograft was then harvested to prepare a Plug-Pat, which was distally rooted in the bone tunnel and proximally sutured to native tendons in a horizontal mattress fashion to reconnect the humeral head and cuff tendons. The control group was repaired with a routine Rect-Pat that was secured onto the bone surface for graft-bone fixation. After surgery, the cuff-graft-bone complexes of rabbits in both groups were harvested immediately (0 weeks) for time-zero initial fixation strength and refreshed contact area assessment, and at 6 or 12 weeks for postoperative biomechanical and histological evaluation. RESULTS: The Plug-Pat significantly enhanced initial fixation strength in comparison with the Rect-Pat (mean ± SD; failure load, 36.79 ± 4.53 N vs 24.15 ± 2.76 N; P < .001) and decreased failure at the graft-bone interface of the construct at 0 weeks, with a significantly increased refreshed bone bed contact area (52.63 ± 2.97 mm2 vs 18.28 ± 1.60 mm2; P < .001) between the graft and bone. At 6 and 12 weeks postoperatively, the Plug-Pat similarly resulted in greater failure load (43.15 ± 4.53 N vs 33.74 ± 2.58 N at 6 weeks; P = .001; 76.65 ± 5.04 N vs 58.17 ± 5.06 N at 12 weeks; P < .001) and stiffness (10.77 ± 2.67 N/mm vs 8.43 ± 0.86 N/mm at 6 weeks; P = .066; 16.98 ± 2.47 N/mm vs 13.21 ± 1.66 N/mm at 12 weeks; P = .011), with less specimen failure at the graft-bone interface than the Rect-Pat. In histological analyses, the Plug-Pat had a higher postoperative graft-bone integration score than the Rect-Pat, showing a more mature intratunnel healing interface with fibrocartilage tidemark formation, improved collagen properties, and more oriented cells when compared with those at the surface healing interface in the Rect-Pat. CONCLUSION: The Plug-Pat enhanced initial fixation strength and enlarged the refreshed contact area for graft-bone connection at time zero and subsequently improved postoperative biomechanical properties and graft-bone integration at the graft-bone healing interface when compared with the Rect-Pat. CLINICAL RELEVANCE: The Plug-Pat using intratunnel fixation may be a promising strategy for patch design to optimize its initial and postoperative graft-bone connection for bridging reconstruction of MRCTs.

Potential Future Drug Development Lag in Japan Based on an Analysis of Multiregional Clinical Trials in the US, Europe, and East Asia.

Although the "drug lag"-namely, the delay in drug approval time in Japan relative to the United States and/or European Union (US/EU)-has been shortened for drugs approved in Japan, there remain many new drugs that have been approved in the US/EU, but not in Japan. To assess the possibility of a future drug lag, this study has examined the current lag in drug development in Japan based on "ClinicalTrials.gov" data from multiregional clinical trials (MRCTs) conducted in the US/EU and East Asia. Among 828 MRCTs registered as of April 5th, 2021, the percentage of MRCTs in which Japan participated (jMRCTs) was 57.1%. jMRCTs were common for some diseases such as "nervous system" and "visual system" disorders, but less common for "neoplasm," infection," "mental," and "circulatory" disorders. Regarding the investigational drugs in non-jMRCTs (i.e., MRCTs without Japanese participation) in the latter four therapeutic areas (i.e., neoplasm, infection, mental and circulatory disorders), approximately 80% (313/399) of drugs were not being developed in Japan. Furthermore, many of these drugs were being developed by the top 50 pharmaceutical companies by sales, and the majority would be recognized as a new active ingredient with a new mode of action in Japan. This study has highlighted the possibility of a future drug lag in Japan, especially in the therapeutic areas of neoplasm, infection, mental, and circulatory disorders. Such a lag may arise not only between Japan and the US/EU, but also between Japan and other countries in the East Asian region.

In phantom evaluation of targeting accuracy in MRI-based brain radiosurgery.

PURPOSE: To determine the targeting accuracy of brain radiosurgery when planning procedures employing different MRI and MRI + CT combinations are adopted. MATERIALS AND METHOD: A new phantom, the BrainTool, has been designed and realized to test image co-registration and targeting accuracy in a realistic anatomical situation. The phantom was created with a 3D printer and materials that mimic realistic brain MRI and CT contrast using a model extracted from a synthetic MRI study of a human brain. Eight markers distributed within the BrainTool provide for assessment of the accuracy of image registrations while two cavities that host an ionization chamber are used to perform targeting accuracy measurements with an iterative cross-scan method. Two procedures employing 1.5 T MRI-only or a combination of MRI (taken with 1.5 T or 3 T scanners) and CT to carry out Gamma Knife treatments were investigated. As distortions can impact targeting accuracy, MR images were preliminary evaluated to assess image deformation extent using GammaTool phantom. RESULTS: MR images taken with both scanners showed average and maximum distortion of 0.3 mm and 1 mm respectively. The marker distances in co-registered images resulted below 0.5 mm for both MRI scans. The targeting mismatches obtained were 0.8 mm, 1.0 mm and 1.2 mm for MRI-only and MRI + CT (1,5T and 3 T), respectively. CONCLUSIONS: Procedures using a combination of MR and CT images provide targeting accuracies comparable to those of MRI-only procedures. The BrainTool proved to be a suitable tool for carrying out co-registration and targeting accuracy of Gamma Knife brain radiosurgery treatments.

Excretable, ultrasmall hexagonal NaGdF4:Yb50% nanoparticles for bimodal imaging and radiosensitization.

BACKGROUND: In this study, we report on the synthesis, imaging, and radiosensitizing properties of ultrasmall ß-NaGdF4:Yb50% nanoparticles as a multifunctional theranostic platform. The synthesized nanoparticles act as potent bimodal contrast agents with superior imaging properties compared to existing agents used for magnetic resonance imaging (MRI) and computed tomography (CT). Clonogenic assays demonstrated that these nanoparticles can act as effective radiosensitizers, provided that the nanoparticles are taken up intracellularly. RESULTS: Our ultrasmall ß-NaGdF4:Yb50% nanoparticles demonstrate improvement in T1-weighted contrast over the standard clinical MR imaging agent Gd-DTPA and similar CT signal enhancement capabilities as commercial agent iohexol. A 2 Gy dose of X-ray induced ~ 20% decrease in colony survival when C6 rat glial cells were incubated with non-targeted nanoparticles (NaGdF4:Yb50%), whereas the same X-ray dose resulted in a ~ 60% decrease in colony survival with targeted nanoparticles conjugated to folic acid (NaGdF4:Yb50%-FA). Intravenous administration of nanoparticles resulted in clearance through urine and feces within a short duration, based on the ex vivo analysis of Gd3+ ions via ICP-MS. CONCLUSION: These biocompatible and in vivo clearable ultrasmall NaGdF4:Yb50% are promising candidates for further evaluation in image-guided radiotherapy applications.

Deep learning-based T1-enhanced selection of linear attenuation coefficients (DL-TESLA) for PET/MR attenuation correction in dementia neuroimaging.

PURPOSE: The accuracy of existing PET/MR attenuation correction (AC) has been limited by a lack of correlation between MR signal and tissue electron density. Based on our finding that longitudinal relaxation rate, or R1 , is associated with CT Hounsfield unit in bone and soft tissues in the brain, we propose a deep learning T1 -enhanced selection of linear attenuation coefficients (DL-TESLA) method to incorporate quantitative R1 for PET/MR AC and evaluate its accuracy and longitudinal test-retest repeatability in brain PET/MR imaging. METHODS: DL-TESLA uses a 3D residual UNet (ResUNet) for pseudo-CT (pCT) estimation. With a total of 174 participants, we compared PET AC accuracy of DL-TESLA to 3 other methods adopting similar 3D ResUNet structures but using UTE R2∗ , or Dixon, or T1 -MPRAGE as input. With images from 23 additional participants repeatedly scanned, the test-retest differences and within-subject coefficient of variation of standardized uptake value ratios (SUVR) were compared between PET images reconstructed using either DL-TESLA or CT for AC. RESULTS: DL-TESLA had (1) significantly lower mean absolute error in pCT, (2) the highest Dice coefficients in both bone and air, (3) significantly lower PET relative absolute error in whole brain and various brain regions, (4) the highest percentage of voxels with a PET relative error within both ±3% and ±5%, (5) similar to CT test-retest differences in SUVRs from the cerebrum and mean cortical (MC) region, and (6) similar to CT within-subject coefficient of variation in cerebrum and MC. CONCLUSION: DL-TESLA demonstrates excellent PET/MR AC accuracy and test-retest repeatability.

End-to-end unsupervised cycle-consistent fully convolutional network for 3D pelvic CT-MR deformable registration.

OBJECTIVE: To improve the efficiency of computed tomography (CT)-magnetic resonance (MR) deformable image registration while ensuring the registration accuracy. METHODS: Two fully convolutional networks (FCNs) for generating spatial deformable grids were proposed using the Cycle-Consistent method to ensure the deformed image consistency with the reference image data. In all, 74 pelvic cases consisting of both MR and CT images were studied, among which 64 cases were used as training data and 10 cases as the testing data. All training data were standardized and normalized, following simple image preparation to remove the redundant air. Dice coefficients and average surface distance (ASD) were calculated for regions of interest (ROI) of CT-MR image pairs, before and after the registration. The performance of the proposed method (FCN with Cycle-Consistent) was compared with that of Elastix software, MIM software, and FCN without cycle-consistent. RESULTS: The results show that the proposed method achieved the best performance among the four registration methods tested in terms of registration accuracy and the method was more stable than others in general. In terms of average registration time, Elastix took 64 s, MIM software took 28 s, and the proposed method was found to be significantly faster, taking <0.1 s. CONCLUSION: The proposed method not only ensures the accuracy of deformable image registration but also greatly reduces the time required for image registration and improves the efficiency of the registration process. In addition, compared with other deep learning methods, the proposed method is completely unsupervised and end-to-end.

Lessons Learned From Multi-regional Trials With Signals of Treatment Effect Heterogeneity.

Inconsistent results across regions have been reported in a number of recent large trials. In this research, by reviewing results from studies that showed inconsistent treatment effects, and summarizing lessons learned, we provide some recommendations for minimizing the chance of inconsistency and allowing more accurate interpretation when such signs of heterogeneity arise, for example: keep the number of regions for consistency evaluation at a minimum to avoid observing false inconsistency signals; proactively address in the protocol the differences in culture, medical practices, and other factors that are potentially different across regions; closely monitor the blinded data from early-enrolled patients to more effectively identify and address issues such as imbalance of baseline covariates or inconsistency of primary outcome rates across regions. For treatments of life-threatening conditions, the stakes for accurate interpretation of MRCT results are high; the criteria for decisions warrant careful consideration.

Generation of Synthetic CT Images From MRI for Treatment Planning and Patient Positioning Using a 3-Channel U-Net Trained on Sagittal Images.

A novel deep learning architecture was explored to create synthetic CT (MRCT) images that preserve soft tissue contrast necessary for support of patient positioning in Radiation therapy. A U-Net architecture was applied to learn the correspondence between input T1-weighted MRI and spatially aligned corresponding CT images. The network was trained on sagittal images, taking advantage of the left-right symmetry of the brain to increase the amount of training data for similar anatomic positions. The output CT images were divided into three channels, representing Hounsfield Unit (HU) ranges of voxels containing air, soft tissue, and bone, respectively, and simultaneously trained using a combined Mean Absolute Error (MAE) and Mean Squared Error (MSE) loss function equally weighted for each channel. Training on 9192 image pairs yielded resulting synthetic CT images on 13 test patients with MAE of 17.6+/-3.4 HU (range 14-26.5 HU) in soft tissue. Varying the amount of training data demonstrated a general decrease in MAE values with more data, with the lack of a plateau indicating that additional training data could further improve correspondence between MRCT and CT tissue intensities. Treatment plans optimized on MRCT-derived density grids using this network for 7 radiosurgical targets had doses recalculated using the corresponding CT-derived density grids, yielding a systematic mean target dose difference of 2.3% due to the lack of the immobilization mask on the MRCT images, and a standard deviation of 0.1%, indicating the consistency of this correctable difference. Alignment of MRCT and cone beam CT (CBCT) images used for patient positioning demonstrated excellent preservation of dominant soft tissue features, and alignment comparisons of treatment planning CT scans to CBCT images vs. MRCT to CBCT alignment demonstrated differences of -0.1 (σ 0.2) mm, -0.1 (σ 0.3) mm, and -0.2 (σ 0.3) mm about the left-right, anterior-posterior and cranial-caudal axes, respectively.

MRIgRT dynamic lung motion thorax anthropomorphic QA phantom: Design, development, reproducibility, and feasibility study.

PURPOSE: To design, manufacture, and evaluate a dynamic magnetic resonance imaging/computed tomography (MRI/CT)-compatible anthropomorphic thorax phantom used to credential MR image-guided radiotherapy (MRIgRT) systems participating in NCI-sponsored clinical trials. METHOD: The dynamic anthropomorphic thorax phantom was constructed from a water-fillable acrylic shell that contained several internal structures representing radiation-sensitive organs within the thoracic region. A custom MR/CT visible cylindrical insert was designed to simulate the left lung with a centrally located tumor target. The surrounding lung tissue was constructed from a heterogeneous in-house mixture using petroleum jelly and miniature (2-4 mm diameter) styrofoam balls and the tumor structure was manufactured from liquid PVC plastic. An MR conditional pneumatic system was developed to allow the MRIgRT insert to move in similar inhale/exhale motions. TLDs and radiochromic EBT3 film were inserted into the phantom to measure absolute point doses and dose distributions, respectively. The dynamic MRIgRT thorax phantom was evaluated through a reproducibility study and a feasibility study. Comprehensive end-to-end examinations were done where the phantom was imaged on a CT, an IMRT treatment plan was created and an MR image was captured to verify treatment setup. Then, the phantom was treated on an MRIgRT system. The reproducibility study evaluated how well the phantom could be reproduced in an MRIgRT system by irradiating three times on an Elekta's 1.5 T Unity system. The phantom was shipped to three independent institutions and was irradiated on either an MRIdian cobalt-60 (60 Co) or an MRIdian linear accelerator system. Treatment evaluations used TLDs and radiochromic film to compare the planned treatment reported on the treatment planning software against the measured dose on the dosimeters. RESULTS: The phantom on the Unity system had reproducible TLD doses measurements (SD < 1.5%). The measured TLD to calculated dose ratios from the reproducibility and feasibility studies ranged from 0.93 to 1.01 and 0.96 to 1.03, respectively. Using a 7%/5 mm gamma analysis criteria, the reproducibility and feasibility studies resulted in an average passing rate of 93.3% and 96.8%, respectively. No difference was noted in the results between the MRIdian 60 Co and MRIdian 6 MV linac delivery to the phantom and all treatment evaluations were within IROC-Houston's acceptable criterion. CONCLUSIONS: A dosimetrically tissue equivalent, CT/MR visible, motion-enabled anthropomorphic MRIgRT thorax phantom was constructed to simulate a lung cancer patient and was evaluated as an appropriate NIH credentialing tool used for MRIgRT systems.

Feasibility of MR-only radiation planning for hypofractionated stereotactic radiotherapy of schwannomas using non-coplanar volumetric modulated arc therapy.

PURPOSE: To compare the dose calculation accuracy of plans done on a CT density-assigned MR image set for hypofractionated stereotactic radiotherapy (HSRT) using volumetric modulated radiation therapy containing non-coplanar beams. METHODS: Eighteen patients diagnosed with schwannoma treated with HSRT were selected retrospectively. These patients underwent planning CT (pCT) for radiation therapy (RT) and contrast-enhanced three-dimensional fast-spoiled gradient-echo image (3D FSPGR) to assist tumor delineation. CTplan is plan done on pCT. The structures body, bone, and air are contoured exclusively on MR image and assigned Hounsfield units of 25, + 1000, and - 1000, respectively. This is termed as MRCT. After registration, original plans from pCT are pasted on the MRCT. Dose calculation is done in two ways: (1) with preset MU values (DDC) and (2) with optimization (OPT_DC). Conformity indices and Dmax and D0.5cc of brainstem, gamma agreement index and correlation coefficient are analyzed. ANOVA test is carried out to find the significance of difference between plans. RESULTS: The mean deviations of Dmax and D0.5cc of brainstem for CTplan versus DDC are 2.49% and 1.45% respectively. The mean deviations of Dmax and D0.5cc of brainstem for CTplan versus OPT_DC are - 1.56% and - 1.97%, respectively. Mean deviations of conformity index for DDC and OPT_DC are 0.84% and 0.89%, respectively. No significant difference was found with ANOVA test. CONCLUSION: Results show that there is no difference between plans generated with actual CT data and MRCT data. Thus MR scans could be employed for radiation planning provided the verification image is available. This gives us confidence to reduce treatment margins where image registration process is avoided.

Facile Preparation of Gold-Decorated Fe3O4 Nanoparticles for CT and MR Dual-Modal Imaging.

The development of a multifunctional nanoprobe capable of non-invasive multimodal imaging is crucial for precise tumour diagnosis. Herein, we report a facile polymer-assisted method to produce Au-Fe3O4 nanocomposites (NCPs) for the dual-modal magnetic resonance (MR) and X-ray computed tomography (CT) imaging of tumours. In this approach, amino-functionalized Au nanospheres were first obtained by surface modification of the bifunctional polymer SH-PEG-NH2. Hydrophilic and carboxyl-functionalized Fe3O4 nanoparticles were produced by phase transfer of reverse micelle oxidation in our previous work. The Au nanoparticles were conjugated with hydrophilic Fe3O4 nanoparticles through an amide reaction. The obtained Au-Fe3O4 nanocomposites display a high r2 relativity (157.92 mM-1 s-1) and a Hounsfield units (HU) value (270 HU) at Au concentration of 8 mg/mL and could be applied as nanoprobes for the dual-modal MR/CT imaging of a xenografted tumour model. Our work provides a facile method to prepare Au-Fe3O4 nanocomposites for dual-modal MR/CT imaging, and this method can be extended to prepare other multifunctional nanoparticles for multimodal bioimaging.

Identification of Drug Characteristics for Implementing Multiregional Clinical Trials Including Japan.

PURPOSE: Multiregional clinical trials (MRCT) are a standard strategy used to improve global drug approval efficiency and the feasibility of clinical trials. Japan is the world's third largest drug market with a unique health care system, making it a key inclusion as an operational region for MRCT (MRCT-JP) for global drug development. We aimed to identify the factors required for efficient drug development by comprehensively reviewing the clinical trials of drugs approved in Japan to identify the factors associated with whether or not MRCT-JP is implemented. METHODS: We surveyed the review reports and summaries of application data published by the Pharmaceuticals and Medical Devices Agency. We identified drugs for which the clinical trial data package included MRCT-JP and selected the same number of drugs for which the clinical trial data package did not include MRCT-JP from the most recent survey period for comparison. We also examined other publication information, in addition to the review reports, as necessary. The influence of each explanatory variable was analyzed by logistic regression analysis, with whether or not MRCT-JP was implemented as the explanatory variable. Statistical significance was set at 5%. FINDINGS: In the survey period up to September 2017, 165 drugs developed with MRCT-JP were approved for manufacture and sale in Japan. "Respiratory system," "inhalation," "biological drug," and "under review" evaluation status for the United States, European Union, and other areas, "approved" evaluation status for the United States, "new ingredients," "priority review," "non-Japanese firm," and "Top 1-10" and "Top 11-20" drug sales rankings for pharmaceutical companies were identified as potential factors leading to the implementation of MRCT-JP. In contrast, "general anti-infectives for systemic use," "various," "external," "chemical compound," "unsubmitted" evaluation status for both the United States and European Union, and "Top 51+" drug sales rankings were potential factors for not implementing MRCT-JP. IMPLICATIONS: Therapeutic classification and agent type, in addition to capital type and United States and European Union evaluation status suggested by a previous study, were associated with implementing MRCT-JP. It is important to determine the best way to utilize MRCT-JP to maximize the value of products. Our findings were based on successful cases and may therefore be helpful for designing clinical development plans. Appropriate use of MRCT-JP will improve productivity in the pharmaceutical industry.

A 3D Hermite-based multiscale local active contour method with elliptical shape constraints for segmentation of cardiac MR and CT volumes.

Analysis of cardiac images is a fundamental task to diagnose heart problems. Left ventricle (LV) is one of the most important heart structures used for cardiac evaluation. In this work, we propose a novel 3D hierarchical multiscale segmentation method based on a local active contour (AC) model and the Hermite transform (HT) for LV analysis in cardiac magnetic resonance (MR) and computed tomography (CT) volumes in short axis view. Features such as directional edges, texture, and intensities are analyzed using the multiscale HT space. A local AC model is configured using the HT coefficients and geometrical constraints. The endocardial and epicardial boundaries are used for evaluation. Segmentation of the endocardium is controlled using elliptical shape constraints. The final endocardial shape is used to define the geometrical constraints for segmentation of the epicardium. We follow the assumption that epicardial and endocardial shapes are similar in volumes with short axis view. An initialization scheme based on a fuzzy C-means algorithm and mathematical morphology was designed. The algorithm performance was evaluated using cardiac MR and CT volumes in short axis view demonstrating the feasibility of the proposed method.

A nested group sequential framework for regional evaluation in global drug development program.

The primary objective of a multiregional clinical trial (MRCT) is to assess the efficacy of all participating regions and evaluate the probability of applying the overall results to a specific region. The consistency assessment of the target region with the overall results is the most common way of evaluating the efficacy in a specific region. Recently, Huang et al. (2012) proposed an additional trial in the target region to an MRCT to evaluate the efficacy in the target ethnic (TE) population under the framework of simultaneous global drug development program (SGDDP). However, the operating characteristics of this statistical framework were not well considered. Therefore, a nested group sequential program for regional efficacy evaluation is proposed in this paper. It is an extension of Huang's SGDDP framework and allows interim analysis after MRCT and in the course of local clinical trial (LCT) phase. It is able to well control the family-wise type I error in the program level and enhances the flexibility of the program. In LCT sample size estimation, we introduce virtual trial, which is transformed from the original program by using discounting factor, and an iteration method is employed to calculate the sample size and stopping boundaries of interim analyses. The proposed sample size estimation method is validated in the simulations and the effect of varied weight, effect size of TE population, and design setting is explored. Examples with normal end point, binary end point, and survival end point are shown to illustrate the application of the proposed nested group sequential program.