An international validation of knowledge-based planning [Meeting Abstract]
Purpose: To carry out a large international validation of how dose prediction quality translates to plan quality in a radiotherapy knowledge-based planning (KBP) process.
Method(s): We collected dose predictions for head-and-neck cancer radiotherapy from 21 different research groups internationally who participated in the OpenKBP Grand Challenge. Each research group used the same training dataset (n=200) and validation dataset (n=40) to develop their methods. These methods predicted dose on a testing dataset (n=100), and those 2100 unique dose predictions were input to a previously published plan optimization method to generate 2100 treatment plans. The predictions and plans were compared to the ground truth dose via: (1)error, the mean absolute voxel-by-voxel difference in dose; and (2) quality, the mean and maximum deviation across 23 dose-volume histogram (DVH) criteria.
Result(s): The range in median prediction error among the top 20 methods was 2.3Gy to 12.0Gy, which was 6.8Gy wider than the range in median plan error of 2.1Gy to 5.0Gy. One method also achieved significantly lower prediction error (P<0.05; one-sided Wilcoxon test) than all the other methods, however, it generated plans with error that was not significantly lower than 28.6% of the other methods. Additionally, predicted dose was consistently lower quality than plan dose. Half (n=1050) of all predictions and plans had an average deviation that was 0.1Gy worse and 0.8Gy better than the ground truth dose, respectively. Similarly, half of all predictions had a maximum deviation that was 3.7Gy worse than the ground truth dose, which was 1.0Gy worse than half of all plans.
Conclusion(s): Many dose prediction methods can achieve low error, however, optimization often improves upon the predictions and eliminates significant differences between prediction methods. Thus, it is critical that we improve the optimization stage in KBP to get better utility out of the existing high-quality dose prediction methods
First-in-kind treatment to block protease function of botulinum neurotoxins inside neurons [Meeting Abstract]
Background: Botulinum neurotoxins (BoNTs) pose serious military and civilian mass casualty threats with potential to rapidly overwhelm medical resources. Currently, the only FDA-approved treatment for botulism is infusion of antibody-based antitoxins to neutralize BoNT that circulates in the bloodstream. Presently, there is no treatment to inactivate the protease activity of BoNTs within the neuron. Here, we describe a first-in-kind treatment approach to block the protease activity of BoNT at the site of intoxication. The technology is based on "atoxic" derivatives of botulinum neurotoxins (serotypes A and C) that can maintain their natural biological trafficking properties and deliver single-chain antibodies to inhibit the protease activity of BoNTs. This report focuses on in vitro and in vivo studies of a treatment candidate for BoNT/A, termed Cyto-111. Method(s): In vitro studies were performed using E18 rat cortical neurons. In vivo studies were performed in: (1) CD-1 female mice (22 to 27 g); (2) Hartley guinea pigs (250 to 350 g); and (3) adult Rhesus macaques (5 to10 kg). Result(s): In vitro, Cyto-111 binds and inhibits the light chain of BoNT/A. When administered intraperitoneally (ip), Cyto-111 traffics to the neuromuscular junction of the diaphragm, where it localizes with presynaptic markers. In a murine postsymptomatic model of BoNT/A toxemia, treatment ip or intravenously with Cyto-111 prevented death at stages of disease that are completely refractory to antitoxin treatment. In an FDA clinical surrogate model of lethal respiratory botulism in guinea pigs, treatment with Cyto-111 provided 55% survival. Currently, we are evaluating the safety and efficacy of Cyto-111 in a Rhesus macaque model of botulism. Conclusion(s): Collectively, these results demonstrate that Cyto-111 reverses clinical symptoms of botulism and prevents mortality following exposure to lethal doses of BoNT/A. Cyto-111 represents a first-in-class, novel therapeutic approach that allows the precise delivery of single-domain function-blocking antibodies to the presynaptic compartment of BoNT/A-intoxicated neurons. Disclaimer: The views expressed in this abstract are those of the authors and do not reflect the official policy of the Department of Army, Department of Defense, or the US Government. The experimental protocol was approved by the Animal Care and Use Committee at the United States Army Medical Research Institute of Chemical Defense, and all procedures were conducted in accordance with the principles stated in the Guide for the Care and Use of Laboratory Animals and the Animal Welfare Act of 1966 (P.L. 89-544), as amended. Funding(s): (1) Defense Threat Reduction Agency (DTRA), (2) NIH; R01-5R01AI093504, (3) ORISE, and (4) Geneva.
Imaging of the placenta with pathologic correlation
The placenta functions to nourish and protect the fetus. Imaging of the placenta can have a profound impact on patient management, owing to the morbidity and mortality associated with various placental conditions. To fully appreciate placental pathology, its physiology, anatomy, and variant anatomy will be outlined. Placental conditions affecting the mother and fetus include molar pregnancies, placental hematoma, abruption, previa, accreta, vasa previa, choriocarcinoma, and retained products of conception. Ultrasonography remains the definitive modality in diagnosing most of these conditions, with magnetic resonance imaging remaining an adjunctive measure. Computed tomography is occasionally used in cases of trauma and tumor staging.
Adnexal masses in pregnancy
Adnexal masses are often seen in the gravid patient. With current advances in technology, an increased number of adnexal masses are incidentally discovered on antenatal screening ultrasonography examinations. Sonography is the first-line imaging modality for any adnexal mass. However, further evaluation with magnetic resonance imaging (MRI) may be critical for diagnosis. For example, MRI can determine whether a mass contains fat, which can be useful in the diagnosis of a teratoma. Characteristic features of nonneoplastic and neoplastic ovarian lesions seen on sonography and MRI will be discussed. Radiologic features that help distinguish benign from malignant neoplasms will be described. Additional lesions specific to the gravid state must be considered in the differential diagnosis when appropriate, such as hyperstimulated ovaries, hyperreactio luteinalis, theca lutein cyst, and luteomas.
Aripiprazole as an adjunct to clozapine therapy in chronic schizophrenia [Meeting Abstract]
A placebo-controlled trial of sibutramine added to patients with olanzapine-induced weight gain [Meeting Abstract]
Initial behavioral health assessment of Asian Americans. Part 1. Key principles
Part 2. Putting principles into practice
In vivo adenovirus-mediated p53 tumor suppressor gene therapy for colorectal cancer
BACKGROUND: The p53 tumor suppressor gene is altered in up to 70% of colorectal cancers. MATERIALS AND METHODS: We infected the colorectal cancer cell lines SW620 and KM12L4, in which p53 is mutated, with the replication-defective adenovirus Ad5/CMV/p53 to evaluate the effects of adenovirus-mediated wild-type p53 gene transfer. Gene transduction was measured by cytochemical staining of cells infected with the Ad5/CMV/beta-gal virus and expression of the wildtype p53 protein in these cells was demonstrated by immunoblotting. RESULTS: Significant suppression of in vitro cell proliferation and induction of apoptosis (as measured by TUNEL assay labeling) were observed following Ad5/CMV/p53 infection. More importantly, similar effects were observed in vivo in an established nude mouse subcutaneous tumor model; significant suppression of tumor growth (60%-70%) and induction of apoptosis were observed following intratumoral injections of Ad5/CMV/p53. CONCLUSION: This form of therapy may provide a novel approach to colorectal cancer.
Adenoviral-mediated wild-type p53 gene expression sensitizes colorectal cancer cells to ionizing radiation
Wild-type p53 gene transfer into the SW620 colorectal carcinoma cell line was performed using the replication-defective adenovirus Ad5/CMV/p53 to evaluate the effect of wild-type p53 expression on radiation sensitivity. The results indicated that infection with Ad5/CMV/p53 sensitized the cells. The survival at 2 Gy was reduced from 55 to 23%. Flow cytometric analysis of terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay-labeled cells and in situ TUNEL staining of xenograft tumors demonstrated an increase in labeled cells with combination treatment, indicating increased apoptosis in cells treated with Ad5/CMV/p53 before irradiation. A significant enhancement of tumor growth suppression by this combination strategy was observed in a s. c. tumor animal model compared to p53 gene therapy alone. The delay in regrowth to control tumor size of 1000 mm3 was 2 days for 5 Gy, 15 days for Ad5/CMV/p53, and 37 days for Ad5/CMV/p53 + 5 Gy, indicating synergistic interactions. These data indicate that the delivery of wild-type p53 to cells with p53 mutations increases their radiation sensitivity, and this may be accomplished by adenoviral-mediated gene therapy.