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Supplementary Figures 1-5, Methods from 4-1BB Ligand as an Effective Multifunctional Immunomodulator and Antigen Delivery Vehicle for the Development of Therapeutic Cancer Vaccines

Therapeutic subunit vaccines based on tumor-associated antigens (TAA) represent an attractive approach for the treatment of cancer. However, poor immunogenicity of TAAs requires potent adjuvants for therapeutic efficacy. We recently proposed the tumor necrosis factor family costimulatory ligands as potential adjuvants for therapeutic vaccines and, hence, generated a soluble form of 4-1BBL chimeric with streptavidin (SA-4-1BBL) that has pleiotropic effects on cells of innate, adaptive, and regulatory immunity. We herein tested whether these effects can translate into effective cancer immunotherapy when SA-4-1BBL was also used as a vehicle to deliver TAAs in vivo to dendritic cells (DCs) constitutively expressing the 4-1BB receptor. SA-4-1BBL was internalized by DCs upon receptor binding and immunization with biotinylated antigens conjugated to SA-4-1BBL resulted in increased antigen uptake and cross-presentation by DCs, leading to the generation of effective T-cell immune responses. Conjugate vaccines containing human papillomavirus 16 E7 oncoprotein or survivin as a self-TAA had potent therapeutic efficacy against TC-1 cervical and 3LL lung carcinoma tumors, respectively. Therapeutic efficacy of the vaccines was associated with increased CD4+ T and CD8+ T-cell effector and memory responses and higher intratumoral CD8+ T effector/CD4+CD25+Foxp3+ T regulatory cell ratio. Thus, potent pleiotropic immune functions of SA-4-1BBL combined with its ability to serve as a vehicle to increase the delivery of antigens to DCs in vivo endow this molecule with the potential to serve as an effective immunomodulatory component of therapeutic vaccines against cancer and chronic infections. Cancer Res; 70(10); 3945–54. ©2010 AACR.

The COVID-19 pandemic forced cystic fibrosis (CF) care programs to rapidly shift from in-person care delivery to telehealth. Our objective was to provide a qualitative exploration of facilitators and barriers to: 1) implementing high-quality telehealth and 2) navigating reimbursement for telehealth services.We used data from the 2020 State of Care CF Program Survey (n=286 U.S. care programs) administered in August-September to identify two cohorts of programs, with variation in telehealth quality (n=12 programs) and reimbursement (n=8 programs). We conducted focus groups and semi-structured interviews with CF program directors and coordinators in December 2020, approximately 9 months from onset of the pandemic. We used the Consolidated Framework for Implementation Research to identify facilitators and barriers of implementation, and inductive thematic analysis to identify facilitators and barriers of reimbursement.Factors differentiating programs with greater and lower perceived telehealth quality included telehealth characteristics (perceived advantage over in-person care, cost, platform quality); external influences (needs and resources of those served by the CF program), characteristics of the CF program (compatibility with workflows, relative priority, available resources); characteristics of team members (individual stage of change), and processes for implementation (engaging patients and teams). Reimbursement barriers included documentation to optimize billing; reimbursement of multi-disciplinary team members, remote monitoring, and telephone-only telehealth; and lower volume of patients.A number of factors are associated with successful implementation and reimbursement of telehealth. Future efforts should provide guidance and incentives that support telehealth delivery and infrastructure, share best practices across CF programs, and remove barriers.

Purpose Gliomas are the most common primary tumor of the brain and are classified into grades I-IV of the World Health Organization (WHO), based on their invasively histological appearance. Gliomas grading plays an important role to determine the treatment plan and prognosis prediction. In this study we propose two novel methods for automatic, non-invasively distinguishing low-grade (Grades II and III) glioma (LGG) and high-grade (grade IV) glioma (HGG) on conventional MRI images by using deep convolutional neural networks (CNNs). Methods All MRI images have been preprocessed first by rigid image registration and intensity inhomogeneity correction. Both proposed methods consist of two steps: (a) three-dimensional (3D) brain tumor segmentation based on a modification of the popular U-Net model; (b) tumor classification on segmented brain tumor. In the first method, the slice with largest area of tumor is determined and the state-of-the-art mask R-CNN model is employed for tumor grading. To improve the performance of the grading model, a two-dimensional (2D) data augmentation has been implemented to increase both the amount and the diversity of the training images. In the second method, denoted as 3DConvNet, a 3D volumetric CNNs is applied directly on bounding image regions of segmented tumor for classification, which can fully leverage the 3D spatial contextual information of volumetric image data. Results The proposed schemes were evaluated on The Cancer Imaging Archive (TCIA) low grade glioma (LGG) data, and the Multimodal Brain Tumor Image Segmentation (BraTS) Benchmark 2018 training datasets with fivefold cross validation. All data are divided into training, validation, and test sets. Based on biopsy-proven ground truth, the performance metrics of sensitivity, specificity, and accuracy are measured on the test sets. The results are 0.935 (sensitivity), 0.972 (specificity), and 0.963 (accuracy) for the 2D Mask R-CNN based method, and 0.947 (sensitivity), 0.968 (specificity), and 0.971 (accuracy) for the 3DConvNet method, respectively. In regard to efficiency, for 3D brain tumor segmentation, the program takes around ten and a half hours for training with 300 epochs on BraTS 2018 dataset and takes only around 50 s for testing of a typical image with a size of 160 × 216 × 176. For 2D Mask R-CNN based tumor grading, the program takes around 4 h for training with around 60 000 iterations, and around 1 s for testing of a 2D slice image with size of 128 × 128. For 3DConvNet based tumor grading, the program takes around 2 h for training with 10 000 iterations, and 0.25 s for testing of a 3D cropped image with size of 64 × 64 × 64, using a DELL PRECISION Tower T7910, with two NVIDIA Titan Xp GPUs. Conclusions Two effective glioma grading methods on conventional MRI images using deep convolutional neural networks have been developed. Our methods are fully automated without manual specification of region-of-interests and selection of slices for model training, which are common in traditional machine learning based brain tumor grading methods. This methodology may play a crucial role in selecting effective treatment options and survival predictions without the need for surgical biopsy.

Despite the growth of photoredox methods in academia, application of photoredox at scale in the pharmaceutical and fine chemical industries has been slow. In this report, a photoredox trifluoromethylation of a thiophenol was modified from the original literature report and the mechanism was investigated to define key scale-up parameters. The mechanistic insight was leveraged in the design and execution of two different reactor designs: an LED-based plug flow photoreactor as well as a laser-based continuous stirred tank photoreactor. In one of the first examples of commercial scale photoredox chemistry, the process was scaled to provide over 500 kilograms of the desired intermediate and amended to fully continuous manufacturing.

ABT-450 (8), a potent hepatitis C (HCV) NS3/4A protease inhibitor, was approved as part of AbbVie's first generation HCV treatment for the United States in December 2014. A series of process optimizations were developed over six years to support the program starting with recycling of a previous protease inhibitor candidate through route development and final process. This discussion will focus on optimization of the final six steps starting from dipeptide 12 and amino acid 13 and highlights the use of a large scale ring closing metathesis (RCM), reactive crystallizations for isolation of intermediates, and detailed process understanding of the final sulfonamide coupling. The process provides ABT-450 (8) in 72% overall yield for the final 6 steps.

1.1 Biomedical Imaging of Multimodality Three-dimensional (3D) biomedical imaging starts from computed tomography (CT) in 1960’s-1970’s (Cormack, 1963, Hounsfield, 1973) followed by magnetic resonance imaging (MRI) in 1970’s (Lauterbur, 1973, Garroway et al, 1974, Mansfield & Maudsley, 1977). These anatomical imaging techniques are based on physical features of a patient’s anatomy, such as linear attenuation coefficient or electromagnetic interaction and relaxation. 3D biological imaging (molecular imaging or functional imaging), such as positron emission tomography (PET) and single photon emission computed tomography (SPECT), was also developed in mid 1970’s (Ter-Pogossian, et al, 1975, Phelps, et al, 1975). They detect biological features using a molecular probe, labelled with either a positron emitter or a gamma emitter, to target a molecular, cellular or physiological event, process or product. So, the x-ray/γ-ray intensity from a particular anatomical site is directly related to the concentration of the radio-labelled molecular marker. Therefore, a biological event will be imaged in 3D space. Since the concept of hybrid PET/CT scanner was introduced (Beyer, et al, 2000), the coregistration of biological image with anatomical image offers both biological and anatomical information in space, assuming that there is no patient’s motion between and during the two image acquisitions. Other combined scanners, such as SPECT/CT and PET/MRI, have also been developed (Cho, et al, 2007, Bybel, et al, 2008, Chowdhury & Scarsbrook, 2008). Registration of biological and anatomical images at acquisition or post acquisition provides multi-dimensional information on patient’s disease stage (Ling, et al, 2000), facilitating lesion identification for diagnosis and target delineation for treatment.

Working memory (WM) is the ability to temporarily store and retrieve a limited amount of information during complex cognitive activities, especially in the face of distraction. The dual-component model describes WM as including active maintenance in primary memory (PM) and cue-dependent search and retrieval from secondary memory (SM). Previously, researchers have found that WM training (WMT) fails to enhance SM capacity, a component that mediates the relationship between WM and fluid reasoning (gF). Thus, a double-blinded, placebo-controlled, randomized trial was conducted to elucidate whether retrieval from SM could be targeted using a two-component WMT regimen versus two control conditions: adaptive one-component WMT targeting solely PM capacity and non-adaptive one-component WMT. Participants were 174 adolescents, aged 10 to 13 years, who were assessed before, after, and 6 months following training. Retrieval from SM was measured using delayed free recall tasks, far transfer to gF was assessed with matrix reasoning and verbal inference tests, and far transfer to academic performance was assessed with reading and math tests. It was predicted that solely two-component WMT would enhance retrieval from SM and result in far transfer. ANCOVAs with pre-test scores as the covariate indicated that two-component participants increased total errors over controls. There were no significant differences between the groups on recall latency, total correct, or gF measures. The non-adaptive one-component group significantly improved on reading, although a drop in the other two groups drove the effect. Additional research is needed to elucidate whether theoretically motivated WMT can positively impact higher-level cognition through SM retrieval mechanisms.

Objective. The goal of the current study was to examine the impact of maternal attention-deficit hyperactivity disorder and oppositional defiant disorder symptoms on several dimensions of parenting...

Functionalized derivatives of the saddle-shaped molecule tetrabenzo[8]circulene were successfully synthesized through a Diels-Alder/oxidative cyclodehydrogenation approach. This methodology improves on our previously reported synthesis, affording products containing both electron-rich and electron-poor functional groups from readily available starting materials in a more efficient manner. The optoelectronic effects that result from the introduction of this functionality are presented and briefly discussed.

A long-term research study in Milwaukee, Wisconsin, USA investigated how construction (i.e., repairs to streets, curbs, and sidewalks) affected tree condition, survival, and growth compared to control trees outside construction zones and effects of a tree preservation program on reducing construction impacts. This study is divided into three periods: (1) a limited implementation period (1979–1989) prior to a formal tree preservation program, (2) an intermediate implementation period (1989–2005) during the development and refinement of a tree preservation program, and (3) a full implementation period (2005–2018) after comprehensive execution of the tree preservation program. During the initial limited preservation period, baseline measurements from 1989 showed trees in construction zones died at a higher annual rate (4.1% actual) and had a lower tree condition rating (5.7% actual) in the limited implementation period (1979–1989) as compared to the other two periods. During the intermediate implementation period (i.e. program under development), construction activities resulted in a reduced effect on tree condition (2.4% actual) as measured in 2005. Tree survival and condition in the full implementation period were similar between trees associated with construction zones and non-impacted control trees measured in 2018. Results demonstrate the effect of a tree preservation program on promoting healthy trees in construction zones. Significant findings also show the importance of growing space with trees farther away from curbs and sidewalks having a higher tree condition and survival rate in all three periods. Findings from this study can encourage city-wide-preservation programs elsewhere to protect public street trees from construction.

Gliomas are the most frequent primary brain tumors in adults. Improved quantification of the various aspects of a glioma requires accurate segmentation of the tumor in magnetic resonance images (MRI). Since the manual segmentation is time-consuming and subject to human error and irreproducibility, automatic segmentation has received a lot of attention in recent years. This paper presents a fully automated segmentation method which is capable of automatic segmentation of brain tumor from multi-modal MRI scans. The proposed method is comprised of a deeply-supervised neural network based on Holistically-Nested Edge Detection (HED) network. The HED method, which is originally developed for the binary classification task of image edge detection, is extended for multiple-class segmentation. The classes of interest include the whole tumor, tumor core, and enhancing tumor. The dataset provided by 2017 Multimodal Brain Tumor Image Segmentation Benchmark (BraTS) challenge is used in this work for training the neural network and performance evaluations. Experiments on BraTS 2017 challenge datasets demonstrate that the method performs well compared to the existing works. The assessments revealed the Dice scores of 0.86, 0.60, and 0.69 for whole tumor, tumor core, and enhancing tumor classes, respectively.

2,5-Diarylthiophene-1-oxides have been prepared from readily available arylacetylene precursors via zirconacyclopentadiene intermediates. The isolated yields of the desired thiophene-1-oxides are comparable to those obtained from the oxidation of thiophene derivatives while avoiding the formation of over-oxidation products. Furthermore, this route offers broader versatility than commonly used methods by providing products outfitted with electron-donating or electron-withdrawing groups with very little variation in isolated product yields. Finally, this strategy provides access to products containing functional groups that are not compatible with oxidation conditions.

Purpose Gliomas are rapidly progressive, neurologically devastating, largely fatal brain tumors. Magnetic Resonance Imaging (MRI) is a widely used technique employed in the diagnosis and management of gliomas in clinical practice. MRI is also the standard imaging modality used to delineate the brain tumor target as part of treatment planning for the administration of radiation therapy. Despite more than 20 years of research and development, computational brain tumor segmentation in MRI images remains a challenging task. We are presenting a novel method of automatic image segmentation based on holistically-nested neural networks that could be employed for brain tumor segmentation of MRI images. Methods Two preprocessing techniques were applied to MRI images. The N4ITK method was employed for correction of bias field distortion. A novel landmark-based intensity normalization method was developed so that tissue types have a similar intensity scale in images of different subjects for the same MRI protocol. The holistically-nested neural networks (HNN), which extend from the convolutional neural networks (CNN) with a deep supervision through an additional weighted-fusion output layer, was trained to learn the multi-scale and multi-level hierarchical appearance representation of the brain tumor in MRI images and was subsequently applied to produce a prediction map of the brain tumor on test images. Finally, the brain tumor was obtained through an optimum thresholding on the prediction map. Results The proposed method was evaluated on both the Multimodal Brain Tumor Image Segmentation (BRATS) Benchmark 2013 training data sets, and clinical data from our institute. A dice similarity coefficient (DSC) and sensitivity of 0.78 and 0.81 were achieved on 20 BRATS 2013 training data sets with High Grade Gliomas (HGG), based on a two-fold cross-validation. The HNN model built on the BRATS 2013 training data was applied to 10 clinical data sets with HGG from a locally developed database. DSC and sensitivity of 0.83 and 0.85 were achieved. A quantitative comparison indicated that the proposed method outperforms the popular fully convolutional network (FCN) method. In terms of efficiency, the proposed method took around 10 hours for training with 50,000 iterations, and approximately 30 seconds for testing of a typical MRI image in the BRATS 2013 data set with a size of 160×216×176, using a DELL PRECISION workstation T7400, with an NVIDIA Tesla K20c GPU. Conclusions An effective brain tumor segmentation method for MRI images based on a HNN has been developed. The high level of accuracy and efficiency make this method practical in brain tumor segmentation. It may play a crucial role in both brain tumor diagnostic analysis and in the treatment planning of radiation therapy. This article is protected by copyright. All rights reserved.

N,N-Carbonyldiimidazole (CDI) is known to be sensitive to degradation by atmospheric moisture. This work details some mechanistic aspects of CDI degradation by atmospheric moisture along with the m...

Stereotactic body radiation therapy (SBRT) is being applied more widely for oligometastatic disease. This technique is now being used for non-spine bony metastases in addition to liver, spine, and lung. However, there are few studies examining the toxicity and outcomes of SBRT for non-spine bone metastases.Between 2008 and 2012, 74 subjects with oligometastatic non-spine bony metastases of varying histologies were treated at the Mayo Clinic with SBRT. A total of 85 non-spine bony sites were treated. Median local control, overall survival, and progression-free survival were described. Acute toxicity (defined as toxicity90 days) and late toxicity (defined as toxicity ≥90 days) were reported and graded as per standardized Common Toxicity Criteria for Adverse Events 4.0 criteria.The median age of patients treated was 60 years. The most common histology was prostate cancer (31%) and most patients had fewer than 3 sites of disease at the time of simulation (64%). Most of the non-spine bony sites lay within the pelvis (65%). Dose and fractionation varied but the most common prescription was 24 Gy/1 fraction. Local recurrence occurred in 7 patients with a median time to failure of 2.8 months. Local control was 91.8% at 1 year. With a median follow-up of 7.6 months, median SBRT specific overall survival and progression-free survival were 9.3 months and 9.7 months, respectively. Eighteen patients developed acute toxicity (mostly grade 1 and 2 fatigue and acute pain flare); 9 patients developed grade 1-2 late toxicities. Two patients developed pathologic fractures but both were asymptomatic. There were no late grade 3 or 4 toxicities.Stereotactic body radiation therapy is a feasible and tolerable treatment for non-spine bony metastases. Longer follow-up will be needed to accurately determine late effects.

In 1976, the first attempted synthesis of the saddle-shaped molecule [8]circulene was reported. The next 37 years produced no advancement towards the construction of this complicated molecule. Remarkably, however, over the last six months a flurry of progress has been made with two groups reporting independent and strikingly different strategies for the synthesis of [8]circulene derivatives. Herein, we present a third synthetic method in which we target tetrabenzo[8]circulene. Our approach employs a Diels-Alder reaction and a palladium-catalyzed arylation reaction as the key steps. Despite calculations describing the instability of [8]circulene, coupled with the reported instability of synthesized derivatives of the parent molecule, the addition of four fused benzenoid rings around the periphery of the molecule provides a highly stable structure. This increased stability over the parent [8]circulene was predicted using Clar’s theory of aromatic sextets and is a result of the compound becoming fully benzenoid upon incorporation of these additional rings. The synthesized compound exhibits remarkable stability under ambient conditions – even at elevated temperatures – with no signs of decomposition over several months. The solid-state structure of this compound is significantly twisted compared to the calculated structure primarily as a result of crystal packing forces in the solid state. Despite this contortion from the lowest energy structure, a range of structural data is presented confirming the presence of localized aromaticity in this large polycyclic aromatic hydrocarbon.

2,5-Diarylthiophene-1-oxides have been prepared from readily available arylacetylene precursors via zirconacyclopentadiene intermediates. The isolated yields of the desired thiophene-1-oxides are comparable to those obtained from the oxidation of thiophene derivatives while avoiding the formation of over-oxidation products. Furthermore, this route offers broader versatility than commonly used methods by providing products outfitted with electron-donating or electron-withdrawing groups with very little variation in isolated product yields. Finally, this strategy provides access to products containing functional groups that are not compatible with oxidation conditions.

Various radiotherapy planning methods for locally advanced squamous cell carcinoma of the head and neck (SCCHN) have been proposed to decrease normal tissue toxicity. We compare IMRT, adaptive IMRT, proton therapy (IMPT), and adaptive IMPT for SCCHN.Initial and re-simulation CT images from 10 consecutive patients with SCCHN were used to quantify dosimetric differences between photon and proton therapy. Contouring was performed on both CTs, and plans (n=40 plans) and dose-volume histograms were generated.The mean GTV volume decreased 53.4% with re-simulation. All plans provided comparable PTV coverage. Compared with IMRT, adaptive IMRT significantly reduced the maximum dose to the mandible (p=0.020) and mean doses to the contralateral parotid gland (p=0.049) and larynx (p=0.049). Compared with IMRT and adaptive IMRT, IMPT significantly lowered the maximum doses to the spinal cord (p0.002 for both) and brainstem (p0.002 for both) and mean doses to the larynx (p0.002 for both) and ipsilateral (p=0.004 IMRT, p=0.050 adaptive) and contralateral (p0.002 IMRT, p=0.010 adaptive) parotid glands. Adaptive IMPT significantly reduced doses to all critical structures compared with IMRT and adaptive IMRT and several critical structures compared with non-adaptive IMPT.Although adaptive IMRT reduced dose to several normal structures compared with standard IMRT, non-adaptive proton therapy had a more favorable dosimetric profile than IMRT or adaptive IMRT and may obviate the need for adaptive planning. Protons allowed significant sparing of the spinal cord, parotid glands, larynx, and brainstem and should be considered for SCCHN to decrease normal tissue toxicity while still providing optimal tumor coverage.

Current estimation of radiation dose from computed tomography (CT) scans on patients has relied on the measurement of Computed Tomography Dose Index (CTDI) in standard cylindrical phantoms, and calculations based on mathematical representations of “standard man”. Radiation dose to both adult and pediatric patients from a CT scan has been a concern, as noted in recent reports. The purpose of this study was to investigate the feasibility of adapting a radiation treatment planning system (RTPS) to provide patient‐specific CT dosimetry. A radiation treatment planning system was modified to calculate patient‐specific CT dose distributions, which can be represented by dose at specific points within an organ of interest, as well as organ dose‐volumes (after image segmentation) for a GE Light Speed Ultra Plus CT scanner. The RTPS calculation algorithm is based on a semi‐empirical, measured correction‐based algorithm, which has been well established in the radiotherapy community. Digital representations of the physical phantoms (virtual phantom) were acquired with the GE CT scanner in axial mode. Thermoluminescent dosimeter (TLDs) measurements in pediatric anthropomorphic phantoms were utilized to validate the dose at specific points within organs of interest relative to RTPS calculations and Monte Carlo simulations of the same virtual phantoms (digital representation). Congruence of the calculated and measured point doses for the same physical anthropomorphic phantom geometry was used to verify the feasibility of the method. The RTPS algorithm can be extended to calculate the organ dose by calculating a dose distribution point‐by‐point for a designated volume. Electron Gamma Shower (EGSnrc) codes for radiation transport calculations developed by National Research Council of Canada (NRCC) were utilized to perform the Monte Carlo (MC) simulation. In general, the RTPS and MC dose calculations are within 10% of the TLD measurements for the infant and child chest scans. With respect to the dose comparisons for the head, the RTPS dose calculations are slightly higher (10%–20%) than the TLD measurements, while the MC results were within 10% of the TLD measurements. The advantage of the algebraic dose calculation engine of the RTPS is a substantially reduced computation time (minutes vs. days) relative to Monte Carlo calculations, as well as providing patient‐specific dose estimation. It also provides the basis for a more elaborate reporting of dosimetric results, such as patient specific organ dose volumes after image segmentation. PACS numbers: 87.55.D‐, 87.57.Q‐, 87.53.Bn, 87.55.K‐

Purpose: Image segmentation techniques using fuzzy connectedness (FC) principles have shown their effectiveness in segmenting a variety of objects in several large applications. However, one challenge in these algorithms has been their excessive computational requirements when processing large image datasets. Nowadays, commodity graphics hardware provides a highly parallel computing environment. In this paper, the authors present a parallel fuzzy connected image segmentation algorithm implementation on NVIDIA’s compute unified device Architecture (cuda) platform for segmenting medical imagedata sets. Methods: In the FC algorithm, there are two major computational tasks: (i) computing the fuzzy affinity relations and (ii) computing the fuzzy connectedness relations. These two tasks are implemented ascuda kernels and executed on GPU. A dramatic improvement in speed for both tasks is achieved as a result. Results: Our experiments based on three data sets of small, medium, and large data size demonstrate the efficiency of the parallel algorithm, which achieves a speed-up factor of 24.4x, 18.1x, and 10.3x, correspondingly, for the three data sets on the NVIDIA Tesla C1060 over the implementation of the algorithm on CPU, and takes 0.25, 0.72, and 15.04 s, correspondingly, for the three data sets. Conclusions: The authors developed a parallel algorithm of the widely used fuzzy connected image segmentation method on the NVIDIA GPUs, which are far more cost- and speed-effective than both cluster of workstations and multiprocessing systems. A near-interactive speed of segmentation has been achieved, even for the large data set.

The purpose was to evaluate and correct the co‐registration of diagnostic PET/CT and MRI/MRI images for stereotactic radiosurgery (SRS) using 3D volumetric image registration (3DVIR). The 3DVIR utilizes the homogeneity of color distribution over a volumetric anatomical landmark as the registration criterion with submillimeter accuracy. Fifty‐three PET/CT and MRI (T1, T2 and FLAIR) image sets of patients with brain lesions were acquired sequentially from a hybrid PET/CT or an MRI scanner with common diagnostic head holding devices. Twenty‐five sets of head 18F−FDG−PET/CT images were scanned over a 10‐minute interval and 14 whole‐body sets were scanned over a 30‐minute interval. Fourteen sets of MRI images were acquired, and each 3‐modal image set (T1, T2 and FLAIR) was scanned in sequence at time 0, ~5 and ~20 minutes. The misalignments in these “co‐registered” images were evaluated and corrected using the 3DVIR. Using the head immobilization devices commonly found in diagnostic PET/CT and MRI/MRI imaging, 80%–100% of these “co‐registered” images were identified as misaligned. For PET/CT, the magnitude of misalignment was 0.4°±0.5° and 0.7±0.4mm for 10‐minute scans, and 0.8°±1.2° and 2.7±1.7mm for 30‐minute scans. For MRI/MRI, the magnitude was 0.2°±0.4° and 0.3±0.2mm for 5‐minute scan intervals, and 1.1°±0.7° and 1.2±1.4mm for 20‐minute intervals. Small, but significant, misalignment is present in the co‐registered diagnostic PET/CT and MRI/MRI images and can be corrected in SRS treatment planning using the volumetric image registration for improved target localization within the clinical error tolerance. PACS numbers: 87.53.Ly, 87.57.nj, 87.57.uk, 87.57.Q‐, 87.61.jc, 87.19.xc Conflict of Interest Statement: The authors do not have any conflict of interest on this research report.

Registration is critical for image‐based treatment planning and image‐guided treatment delivery. Although automatic registration is available, manual, visual‐based image fusion using three orthogonal planar views (3P) is always employed clinically to verify and adjust an automatic registration result. However, the 3P fusion can be time consuming, observer dependent, as well as prone to errors, owing to the incomplete 3‐dimensional (3D) volumetric image representations. It is also limited to single‐pixel precision (the screen resolution). The 3D volumetric image registration (3DVIR) technique was developed to overcome these shortcomings. This technique introduces a 4th dimension in the registration criteria beyond the image volume, offering both visual and quantitative correlation of corresponding anatomic landmarks within the two registration images, facilitating a volumetric image alignment, and minimizing potential registration errors. The 3DVIR combines image classification in real‐time to select and visualize a reliable anatomic landmark, rather than using all voxels for alignment. To determine the detection limit of the visual and quantitative 3DVIR criteria, slightly misaligned images were simulated and presented to eight clinical personnel for interpretation. Both of the criteria produce a detection limit of 0.1 mm and 0.1°. To determine the accuracy of the 3DVIR method, three imaging modalities (CT, MR and PET/CT) were used to acquire multiple phantom images with known spatial shifts. Lateral shifts were applied to these phantoms with displacement intervals of 5.0±0.1mm. The accuracy of the 3DVIR technique was determined by comparing the image shifts determined through registration to the physical shifts made experimentally. The registration accuracy, together with precision, was found to be: 0.02±0.09mm for CT/CT images, 0.03±0.07mm for MR/MR images, and 0.03±0.35mm for PET/CT images. This accuracy is consistent with the detection limit, suggesting an absence of detectable systematic error. This 3DVIR technique provides a superior alternative to the 3P fusion method for clinical applications. PACS numbers: 87.57.nj, 87.57.nm, 87.57.‐N, 87.57.‐s

The dose measurements of the small field sizes, such as conical collimators used in stereotactic radiosurgery (SRS), are a significant challenge due to many factors including source occlusion, detector size limitation, and lack of lateral electronic equilibrium. One useful tool in dealing with the small field effect is Monte Carlo (MC) simulation. In this study, we report a comparison of Monte Carlo simulations and measurements of output factors for the Varian SRS system with conical collimators for energies of 6 MV flattening filter‐free (6 MV) and 10 MV flattening filter‐free (10 MV) on the TrueBeam accelerator. Monte Carlo simulations of Varian's SRS system for 6 MV and 10 MV photon energies with cones sizes of 17.5 mm, 15.0 mm, 12.5 mm, 10.0 mm, 7.5 mm, 5.0 mm, and 4.0 mm were performed using EGSnrc (release V4 2.4.0) codes. Varian's version‐2 phase‐space files for 6 MV and 10 MV of TrueBeam accelerator were utilized in the Monte Carlo simulations. Two small diode detectors Edge (Sun Nuclear) and Small Field Detector (SFD) (IBA Dosimetry) were applied to measure the output factors. Significant errors may result if detector correction factors are not applied to small field dosimetric measurements. Although it lacked the machine‐specific kQclin,Qmsrfclin,fmsr correction factors for diode detectors in this study, correction factors were applied utilizing published studies conducted under similar conditions. For cone diameters greater than or equal to 12.5 mm, the differences between output factors for the Edge detector, SFD detector, and MC simulations are within 3.0% for both energies. For cone diameters below 12.5 mm, output factors differences exhibit greater variations. PACS number(s): 87.55.k, 87.55.Qr

In a series of 574 individuals with the Rubinstein-Taybi syndrome, 28 had keloids, and 19 had one or more neoplasms. The array of malignant neoplasms does not suggest an etiology or pathogenesis in common. One possible exception is that four cases of leukemia were observed. When the data for malignant and benign neoplasms were combined, at least nine of the 22 could have arisen from developmental errors. The apparent excess of keloid formation indicates overreaction to mild injury, with no known relevance to neoplasia but of potential interest in future studies of scar formation.

An optical fibre point dosemeter based on the gated detection of the luminescence from a Cu(1+)-doped fused quartz detector effectively eliminated errors due to Cerenkov radiation and native fibre fluorescence. The gated optical fibre dosemeter overcomes serious problems faced by scintillation and optically stimulated luminescence approaches to optical fibre point dosimetry. The dosemeter was tested using an external beam radiotherapy machine that provided pulses of 6 MV X rays. Gated detection was used to discriminate the signal collected during the radiation pulses, which included contributions from Cerenkov radiation and native fibre fluorescence, from the signal collected between the radiation pulses, which contained only the long-lived luminescence from the Cu(1+)-doped fused quartz detector. Gated detection of the luminescence provided accurate, real-time dose measurements that were linear with absorbed dose, independent of dose rate and that were accurate for all field sizes studied.

Vaccination with autologous tumor cells genetically modified to express costimulatory molecules has shown utility for cancer immunotherapy in preclinical and limited clinical settings. Given the complicated nature of gene therapy, a practical alternative approach has been designed that relies on modification of the cell membrane with biotin and its "decoration" with a chimeric protein composed of the functional portion of human CD80 and core streptavidin (CD80-SA). We tested whether primary tumor cells resected from cancer patients can be decorated with CD80-SA and whether such cells serve as antigen-presenting cells (APCs) to generate autologous T cell responses ex vivo. Tumors and peripheral blood lymphocytes (PBLs) were collected from 14 lung, 9 colon, and 2 breast "treatment-naive" cancer patients presenting various clinical stages of the disease. Tumors were mechanically processed, irradiated, decorated with CD80-SA or control streptavidin (SA) protein, and used as APCs in ex vivo autologous T cell-proliferative and cytotoxicity assays. All tumor samples were modified with CD80-SA, albeit with various degrees of decoration ranging from 21.8 to 100%. CD80- SA-decorated cells generated significant proliferative responses in autologous T cells from 9 of 16 evaluable patients (p < 0.05). Proliferative responses were CD80-SA specific and heterogeneous, with stimulation indices ranging from 0.25 to 45. In 15 of 15 evaluable patients, CD80-SA-specific cytotoxic T cell responses against autologous tumors were generated, 11 of which were significant, with specific killing ranging from 5 to 70%. Taken together, these data demonstrate that primary tumor cells can be effectively decorated with CD80-SA and that such cells serve as APCs to induce autologous antitumor T cell responses.

Purpose: To develop and optimize a technique for inverse treatment planning based solely on magnetic resonance imaging (MRI) during high-dose-rate brachytherapy for prostate cancer. Methods and Materials: Phantom studies were performed to verify the spatial integrity of treatment planning based on MRI. Data were evaluated from 10 patients with clinically localized prostate cancer who had undergone two high-dose-rate prostate brachytherapy boosts under MRI guidance before and after pelvic radiotherapy. Treatment planning MRI scans were systematically evaluated to derive a class solution for inverse planning constraints that would reproducibly result in acceptable target and normal tissue dosimetry. Results: We verified the spatial integrity of MRI for treatment planning. MRI anatomic evaluation revealed no significant displacement of the prostate in the left lateral decubitus position, a mean distance of 14.47 mm from the prostatic apex to the penile bulb, and clear demarcation of the neurovascular bundles on postcontrast imaging. Derivation of a class solution for inverse planning constraints resulted in a mean target volume receiving 100% of the prescribed dose of 95.69%, while maintaining a rectal volume receiving 75% of the prescribed dose of

A technique for transperineal high-dose-rate (HDR) prostate brachytherapy and needle biopsy in a standard 1.5 T MRI scanner is demonstrated. In each of eight procedures (in four patients with intermediate to high risk localized prostate cancer), four MRI-guided transperineal prostate biopsies were obtained followed by placement of 14-15 hollow transperineal catheters for HDR brachytherapy. Mean needle-placement accuracy was 2.1 mm, 95% of needle-placement errors were less than 4.0 mm, and the maximum needle-placement error was 4.4 mm. In addition to guiding the placement of biopsy needles and brachytherapy catheters, MR images were also used for brachytherapy treatment planning and optimization. Because 1.5 T MR images are directly acquired during the interventional procedure, dependence on deformable registration is reduced and online image quality is maximized.

Optical fibers offer a unique capability for remote monitoring of radiation in difficult-to-access and/or hazardous locations. Optical fiber sensors can be located in radiation hazardous areas and optically interrogated from a safe distance. A variety of remote optical fiber radiation dosimetry methods have been developed. All of the methods take advantage of some form of radiation-induced change in the optical properties of materials such as: radiation-induced darkening due to defect formation in glasses, luminescence from native defects or radiation-induced defects, or population of metastable charge trapping centers. Optical attenuation techniques are used to measure radiation-induced darkening in fibers. Luminescence techniques include the direct measurement of scintillation or optical excitation of radiation-induced luminescent defects. Optical fiber radiation dosimeters have also been constructed using charge trapping materials that exhibit thermoluminescence or optically stimulated luminescence (OSL).

A U.S.-Japan Seminar on was held in Tokyo on November 1–5, 1965 on “Epidemiological Studies into the Etiology of Congenital Malformations and Cancer.” It was convened by Dr. Hideo Nishimura of Kyoto University and Dr. Robert W. Miller of the National Cancer Institute (NCI). The main purposes were to introduce teratologists from the two countries to one another and to seek new areas of research. Among the assets for research in Japan were 1) Dr. Nishimura's collection of embryos for studies of normal intrauterine growth and for studies of congenital malformations among spontaneous miscarriages; 2) the availability of standard occupational records for information related to reproductive performance; 3) the family registry (koseki), useful for follow-up studies, vital events and evidence of consanguinity; 4) the Metropolitan Tokyo Children's Cancer Registry which soon after was extended to 5 more metropolitan areas; 5) the annual publication of autopsy summaries; 6) data from the (U.S.-Japan) Atomic Bomb Casualty Commission in Hiroshima and Nagasaki; 6) death-certificate diagnoses for migrants from Japan to the U.S. among whom studies of changes in cancer rates had been initiated at the NCI. Also in Japan 7% of marital partners were second-cousins or closer, of interest in studying genetic effects on the occurrence of cancer or congenital malformations. The seminar was followed by a workshop on methods in teratology held in Kyoto in 1968. These meetings led to progressive increases in the exchange of scientists and information.

Background. Excesses of various childhood cancers have been reported after retinoblastoma, including a trickle of Ewing sarcoma (ES) and perhaps histologically similar olfactory neuroblastoma, both of which are neural tumors. To update and advance this information, case reports were sought by an extensive review of the literature. Procedure. The search was made through the use of PubMed, and the Web of Science (Citation Index Expanded), keying on primary references. Three sinonasal cancers diagnosed as ES were immunohistochemically stained for MIC-2 protein (positive in ES). Results. Retinoblastoma occurred before ES in ten cases (seven bilateral). In four others, retinoblastoma (three bilateral) developed before sinonasal neural tumors (poorly differentiated). ES also occurred after 14 cancers other than retinoblastoma (five lymphomas, four leukemias, and one each of five miscellaneous cancers). The predominance of retinoblastoma prior to ES differs markedly from the low-frequency of retinoblastoma among childhood cancers in the general population. On the contrary, cancers other than retinoblastoma were proportionate to those in the general population. Previously, retinoblastoma followed by excesses of osteosarcoma and soft tissue sarcomas has been attributed to the action of the inherited RB-1 gene. The sinonasal tumors stained negative for MIC-2 protein. Conclusions. Heritable retinoblastoma may predispose to ES and perhaps to a subset of poorly differentiated neuroectodermal tumors in the sinonasal region that may be related to olfactory neuroblastoma.

There is an increasing threat that chemical and biological weapons will be used on a civilian population in an act of domestic terrorism. Casualties among adults and children could be significant in such an event. Federal, state, and local authorities have begun extensive planning to meet a chemical-biological incident by developing methods of rapid identification of potential agents and protocols for management of victims without injury to health care personnel. Because children would be disproportionately affected by a chemical or biological weapons release, pediatricians must assist in planning for a domestic chemical-biological incident. Government agencies should seek input from pediatricians and pediatric subspecialists to ensure that the situations created by multiple pediatric casualties after a chemical-biological incident are considered. This statement reviews key aspects of chemical-biological agents, the consequences of their use, the potential impact of a chemical-biological attack on children, and issues to consider in disaster planning and management for pediatric patients.

Werner syndrome (WS), adult progeria, is more common in Japan than elsewhere. It predisposes to osteosarcoma (OS) and five other rare tumors. To determine if and how OS is atypical in this genetic disorder, we studied the characteristics of ten Japanese cases with respect to clinical features, pathology, and radiographs, and compared them with a hospital series of 36 skeletal OS with the same atypical age-range, 35 - 57 years. The anatomic sites were also atypical: seven ankle / foot, two radius and one patella compared with only one at the ankle in the hospital series. The osteoblastic cell-type was about equally frequent in both series, but, among others than the three major subtypes, there was only one in WS as compared with 14 (39%) in the hospital series. The types of mutations were sought in five WS cases with OS. One showed no mutation at any of the ten known loci for Japanese, two were of type 4 / 4 and two of type 6 / 6. The mutations 4 and 6 have been found in 66% of alleles of WS cases in Japan. The increased frequency and unusual age and site distributions of OS in WS may be due to increased susceptibility, related to later-life leg ulcers, and weight-bearing on spindly ankles weakened by severe loss of lower limb subcutaneous tissue.