Dose-response Outcomes Research Articles

Micellar solution of [223Ra]RaCl2: Reaching renal excretion, potent efficacy in osteoblastic osteosarcoma in PDX model, biochemistry alterations and pharmacokinetics

Despite the successful use of the radiopharmaceutical radium-223 dichloride ([223Ra]RaCl2) for targeted alpha therapy of castration-resistant prostate cancer patients with bone metastases, some short-term side effects, such as diarrhea and vomiting, have been documented, causing patient discomfort. Hence, we prepared a nanosized micellar solution of [223Ra]RaCl2 and evaluated its biodistribution, pharmacokinetics, and induced biochemical changes in healthy mice up to 96 h after intraperitoneal administration as an alternative to overcome the previous limitations. In addition, we evaluated the bone specificity of micellar [223Ra]RaCl2 in patient-derived xenografts in the osteosarcoma model. The biodistribution studies revealed the high bone-targeting properties of the micellar [223Ra]RaCl2. Interestingly, the liver uptake remained significantly low (%ID/g = 0.1–0.02) from 24 to 96 h after administration. In addition, the micellar [223Ra]RaCl2 exhibited a significantly higher uptake in left (%ID/g = 0.85–0.23) and right (%ID/g = 0.76–0.24) kidneys than in small (%ID/g = 0.43–0.06) and large intestines (%ID/g = 0.24–0.09) over time, suggesting its excretion pathway is primarily through the kidneys into the urine, in contrast to the non-micellar [223Ra]RaCl2. The micellar [223Ra]RaCl2 also had low distribution volume (0.055 ± 0.003 L) and longer elimination half-life (28 ± 12 days). This nanosystem was unable to change the enzymatic activities of alanine aminotransferase, aspartate aminotransferase, gamma GT, glucose, and liquiform lipase in the treated mice. Finally, microscopic examination of the animals' osteosarcoma tumors treated with micellar [223Ra]RaCl2 indicated regression of the tumor, with large areas of necrosis. In contrast, in the control group, we observed tumor cellularity and cell anaplasia, mitotic figures and formation of neoplastic extracellular bone matrix, which are typical features of osteosarcoma. Therefore, our findings demonstrated the efficiency and safety of nanosized micellar formulations to minimize the gastrointestinal excretion pathway of the clinical radiopharmaceutical [223Ra]RaCl2, in addition to promoting regression of the osteosarcoma. Further studies must be performed to assess dose–response outcomes and organ/tissue dosimetry for clinical translation.

Nitrogen Critical Loads: Critical Reflections on Past Experiments, Ecological Endpoints, and Uncertainties.

Nitrogen Critical Loads (NCL), as purported ecological dose-response outcomes for nitrogen deposition from anthropogenic sources, play a central role in environmental policies around the world. In the Netherlands, these NCL are used to assess, via calculations using the model AERIUS, to what extent NCL are exceeded for different habitats as a result of different sources such as industry, agriculture, traffic. NCL are, however, not well defined, and are subject to hitherto unrecognized forms of uncertainty. We will address this with reference to a number of key studies that forms the basis for several NCL. We will subsequently propose amendments that could be applicable to future nitrogen studies and their enhanced relevancy in decision making.

The effect of dose uncertainty on community noise dose-response outcomes

Recent simulations have been performed to determine the effects of dose uncertainty (estimated participant sound levels) on community noise dose-response outcomes. This paper presents a number simulations that illustrate how dose estimation uncertainty, dose range and the frequency distribution of doses across that range combine to modify an underlying true dose-response relationship. It further shows how each combination creates a unique distortion to the underlying curve in the observed results. The complexity of compensating for these uncertainties is discussed, and the paper recommends the formation of standardized data collection practices to enable compensation for them in the analysis.

Current Pharmacological Treatments for Childhood Onset OCD

Obsessive-compulsive disorder (OCD) is a chronic condition associated with substantial morbidity, comorbidity, and functional impairment in affected youths. Fortunately, efficacy has been established for multiple pharmacotherapies; however, treatment response remains neither universal nor complete; hence, treatment development efforts continue. This review aims to examine evidence for recent trials examining augmentation strategies for partial responders to serotonin reuptake inhibitors (SRIs), the efficacy of adding D-cycloserine (DCS) to cognitive behavioral therapy (CBT), interventions for OCD symptoms associated with infection, and a meta-analytic view of SRI efficacy and dose-response outcomes. Augmentative treatment with SRIs or additional CBT confers additional benefit in CBT partial responders; however, DCS augmentation does not enhance CBT outcomes. Further treatment development is needed to establish effective interventions for infection-related OCD symptoms, and an SRI dose-response curve does not appear to be evident when examining across multiple SRI trials. Implications of these finding for next-stage research efforts and clinical practice are considered.

Augmenting Treatment for Posttraumatic Stress Disorder and Co-Occurring Conditions with Oxytocin

The goal of this manuscript is to review the extant literature examining the neurobiological and behavioral mechanisms underlying the potential utility of intranasal oxytocin as a novel pharmacologic intervention for the treatment of posttraumatic stress disorder (PTSD), and for the treatment of co-morbid PTSD and alcohol and substance use disorders. Research indicates that intranasal oxytocin is a low-cost and easily accessible medication with an excellent safety profile. Oxytocin holds promise for facilitating more effective PTSD treatment, particularly when used in combination with evidence-supported psychotherapy interventions. There is still a significant need to identify the mechanisms of action underlying oxytocin treatment of PTSD, and to maximize methods of nasal spray delivery, examine dose-response outcomes, and clarify the characteristics of individuals and populations that are most likely to benefit from adjunctive oxytocin treatment. Collectively, preclinical and human laboratory research suggest that oxytocin may be an effective mechanism by which treatment outcomes for PTSD and common comorbidities can be enhanced. Adequately powered randomized controlled trials are needed to address efficacy, identify predictors of treatment outcome, and to assess the use of intranasal oxytocin within appropriate PTSD populations.

Advancing risk assessment: mechanistic dose-response modelling of Listeria monocytogenes infection in human populations.

The utility of characterizing the effects of strain variation and individual/subgroup susceptibility on dose–response outcomes has motivated the search for new approaches beyond the popular use of the exponential dose–response model for listeriosis. While descriptive models can account for such variation, they have limited power to extrapolate beyond the details of particular outbreaks. By contrast, this study exhibits dose–response relationships from a mechanistic basis, quantifying key biological factors involved in pathogen–host dynamics. An efficient computational algorithm and geometric interpretation of the infection pathway are developed to connect dose–response relationships with the underlying bistable dynamics of the model. Relying on in vitro experiments as well as outbreak data, we estimate plausible parameters for the human context. Despite the presence of uncertainty in such parameters, sensitivity analysis reveals that the host response is most influenced by the pathogen–immune system interaction. In particular, we show how variation in this interaction across a subgroup of the population dictates the shape of dose–response curves. Finally, in terms of future experimentation, our model results provide guidelines and highlight vital aspects of the interplay between immune cells and particular strains of Listeria monocytogenes that should be examined.

Pharmacokinetically guided optimum adaptive dose selection in early phase clinical trials

A new statistical method is introduced for dose finding in phase IB/IIA trials, which, along with efficacy and toxicity as endpoints, also considers pharmacokinetic information in the dose-selection procedure. Following the assignment of a current best dose to a cohort of patients, the concentration of a drug in the blood is measured at the locally D-optimal time points. The dose–response outcomes are also observed for each patient. Based on the updated information, a new dose is selected for the next cohort so that the estimated probability of efficacy is maximum, subject to the condition that the estimated probability of toxicity is not more than a chosen constant. Another condition for the dose selection is related to the total exposure of the drug in the body, expressed by the area under the concentration curve over time, so that the curative purpose is likely to be achieved in the population without overdosing. Simultaneously to the maximisation of the estimated probability of efficacy, the mean area under the concentration curve for a chosen dose is not allowed to be more than a target value taking into account its inter-patient variability. The purpose is to investigate the gain in efficiency of using pharmacokinetic measures in the dose escalation. The proposed method is found to identify the optimal dose accurately without exposing many patients to toxic doses.

Dose-Response Outcomes Associated with Different Forms of Locomotor Training in Persons with Chronic Motor-Incomplete Spinal Cord Injury.

Outcomes of training are thought to be related to the amount of training (training dose). Although various approaches to locomotor training have been used to improve walking function in persons with spinal cord injury (SCI), little is known about the relationship between dose of locomotor training and walking outcomes. This secondary analysis aimed to identify the relationship between training dose and improvement in walking distance and speed associated with locomotor training in participants with chronic motor-incomplete spinal cord injury (MISCI). We compared the dose-response relationships associated with each of four different locomotor training approaches. Participants were randomized to either: treadmill-based training with manual assistance (TM = 17), treadmill-based training with stimulation (TS = 18), overground training with stimulation (OG = 15), and treadmill-based training with locomotor robotic device assistance (LR = 14). Subjects trained 5 days/week for 12 weeks, with a target of 60 training sessions. The distance-dose and time-dose were calculated based on the total distance and total time, respectively, participants engaged in walking over all sessions combined. Primary outcome measures included walking distance (traversed in 2 min) and walking speed (over 10 m). Only OG training showed a good correlation between distance-dose and change in walking distance and speed walked over ground (r = 0.61, p = 0.02; r = 0.62, p = 0.01). None of the treadmill-based training approaches were associated with significant correlations between training dose and improvement of functional walking outcome. The findings suggest that greater distance achieved over the course of OG training is associated with better walking outcomes in the studied population. Further investigation to identify the essential elements that determine outcomes would be valuable for guiding rehabilitation.

Unraveling the dose-response puzzle of L. monocytogenes: A mechanistic approach

Food-borne disease outbreaks caused by Listeria monocytogenes continue to impose heavy burdens on public health in North America and globally. To explore the threat L. monocytogenes presents to the elderly, pregnant woman and immuno-compromised individuals, many studies have focused on in-host infection mechanisms and risk evaluation in terms of dose-response outcomes. However, the connection of these two foci has received little attention, leaving risk prediction with an insufficient mechanistic basis. Consequently, there is a critical need to quantifiably link in-host infection pathways with the dose-response paradigm. To better understand these relationships, we propose a new mathematical model to describe the gastro-intestinal pathway of L. monocytogenes within the host. The model dynamics are shown to be sensitive to inoculation doses and exhibit bi-stability phenomena. Applying the model to guinea pigs, we show how it provides useful tools to identify key parameters and to inform critical values of these parameters that are pivotal in risk evaluation. Our preliminary analysis shows that the effect of gastro-environmental stress, the role of commensal microbiota and immune cells are critical for successful infection of L. monocytogenes and for dictating the shape of the dose-response curves.

Optimal unified combination rule in application of Dempster-Shafer theory to lung cancer radiotherapy dose response outcome analysis.

Our previous study demonstrated the application of the Dempster‐Shafer theory of evidence to dose/volume/outcome data analysis. Specifically, it provided Yager's rule to fuse data from different institutions pertaining to radiotherapy pneumonitis versus mean lung dose. The present work is a follow‐on study that employs the optimal unified combination rule, which optimizes data similarity among independent sources. Specifically, we construct belief and plausibility functions on the lung cancer radiotherapy dose outcome datasets, and then apply the optimal unified combination rule to obtain combined belief and plausibility, which bound the probabilities of pneumonitis incidence. To estimate the incidence of pneumonitis at any value of mean lung dose, we use the Lyman‐Kutcher‐Burman (LKB) model to fit the combined belief and plausibility curves. The results show that the optimal unified combination rule yields a narrower uncertainty range (as represented by the belief–plausibility range) than Yager's rule, which is also theoretically proven.PACS numbers: 87.55.dh, 87.55.dk

Relationships between dose to the gastro-intestinal tract and patient-reported symptom domains after radiotherapy for localized prostate cancer

ABSTRACTBackground. Gastrointestinal (GI) morbidity after radiotherapy (RT) for prostate cancer is typically addressed by studying specific single symptoms. The aim of this study was to explore the interplay between domains of patient- reported outcomes (PROs) on GI morbidity, and to what extent these are explained by RT dose to the GI tract.Material and methods. The study included men from two Scandinavian studies (N = 211/277) who had undergone primary external beam radiotherapy (EBRT) for localized prostate cancer to 70–78 Gy (2 Gy/fraction). Factor analysis was applied to previously identified PRO-based symptom domains from two study-specific questionnaires. Number of questions: 43; median time to follow-up: 3.6–6.4 years) and dose-response outcome variables were defined from these domains. Dose/volume parameters of the anal sphincter (AS) or the rectum were tested as predictors for each outcome variable using logistic regression with 10-fold cross-validation. Performance was assessed using area under the receiver operating characteristic curve (Az) and model frequency.Results. Outcome variables from Defecation urgency (number of symptoms: 2–3), Fecal leakage (4–6), Mucous (4), and Pain (3–6) were defined. In both cohorts, intermediate rectal doses predicted Defecation urgency (mean Az: 0.53–0.54; Frequency: 70–75%), and near minimum and low AS doses predicted Fecal leakage (mean Az: 0.63–0.67; Frequency: 83–99%). In one cohort, high AS doses predicted Mucous (mean Az: 0.54; Frequency: 96%), whereas in the other, low AS doses and intermediate rectal doses predicted Pain (mean Az: 0.69; Frequency: 28–82%).Conclusion. We have demonstrated that Defecation urgency, Fecal leakage, Mucous, and Pain following primary EBRT for localized prostate cancer primarily are predicted by intermediate rectal doses, low AS doses, high AS doses, or a combination of low AS and intermediate rectal doses, respectively. This suggests that there is a domain-specific dose-response for the GI tract. To reduce risk of GI morbidity, dose distributions of both the AS region and the rectum should, therefore, be considered when prescribing prostate cancer RT.

Evaluation of Toxicity Ranking for Metal Oxide Nanoparticles via an in Vitro Dosimetry Model.

It has been argued that in vitro toxicity testing of engineered nanoparticles (NPs) should consider delivered dose (i.e., NP mass settled per suspension volume) rather than relying exclusively on administered dose (initial NP mass concentration). Delivered dose calculations require quantification of NP sedimentation in tissue cell culture media, taking into consideration fundamental suspension properties. In this article, we calculate delivered dose using a first-principles "particles in a box" sedimentation model, which accounts for the particle size distribution, fractal dimension, and permeability of agglomerated NPs. The sedimentation model was evaluated against external and our own experimental sedimentation data for metal oxide NPs. We then utilized the model to construct delivered dose-response analysis for a library of metal oxide NPs (previously used for hazard ranking and prediction making) in different cell culture media. Hierarchical hazard ranking of the seven (out of 24) toxic metal oxide NPs in our library, using EC50 calculated on the basis of delivered dose, did not measurably differ from our ranking based on administered dose. In contrast, simplified sedimentation calculations based on the assumption of impermeable NP agglomerates of a single average size significantly underestimated the settled NPs' mass, resulting in misinterpretation of toxicity ranking. It is acknowledged that in vitro dose-response outcomes are likely to be shaped by complex toxicodynamics, which include NP/cellular association, triggering of dynamic cell response pathways involved in NP uptake, and multiple physicochemical parameters that influence NP sedimentation and internalization.

Accumulated Delivered Dose Response of Stereotactic Body Radiation Therapy for Liver Metastases

To determine whether the accumulated dose using image guided radiation therapy is a stronger predictor of clinical outcomes than the planned dose in stereotactic body radiation therapy (SBRT) for liver metastases. From 2003 to 2009, 81 patients with 142 metastases were treated in institutional review board-approved SBRT studies (5-10 fractions). Patients were treated during free breathing (with or without abdominal compression) or with controlled exhale breath-holding. SBRT was planned on a static exhale computed tomography (CT) scan, and the minimum planning target volume dose to 0.5 cm(3) (minPTV) was recorded. The accumulated minimum dose to the 0.5 cm(3) gross tumor volume (accGTV) was calculated after performing dose accumulation from exported image guided radiation therapy data sets registered to the planning CT using rigid (2-dimensional MV/kV orthogonal) or deformable (3-dimensional/4-dimensional cone beam CT) image registration. Univariate and multivariate Cox regression models assessed the factors influencing the time to local progression (TTLP). Hazard ratios for accGTV and minPTV were compared using model goodness-of-fit and bootstrapping. Overall, the accGTV dose exceeded the minPTV dose in 98% of the lesions. For 5 to 6 fractions, accGTV doses of >45 Gy were associated with 1-year local control of 86%. On univariate analysis, the cancer subtype (breast), smaller tumor volume, and increased dose were significant predictors for improved TTLP. The dose and volume were uncorrelated; the accGTV dose and minPTV dose were correlated and were tested separately on multivariate models. Breast cancer subtype, accGTV dose (P<.001), and minPTV dose (P=.02) retained significance in the multivariate models. The univariate hazard ratio for TTLP for 5-Gy increases in accGTV versus minPTV was 0.67 versus 0.74 (all patients; 95% confidence interval of difference 0.03-0.14). Goodness-of-fit testing confirmed the accGTV dose as a stronger dose-response predictor than the minPTV dose. The accGTV dose is a better predictor of TTLP than the minPTV dose for liver metastasis SBRT. The use of modern image guided radiation therapy in future analyses of dose-response outcomes should increase the concordance between the planned and delivered doses.

End of the road: confounding results of the CORE trial terminate the arduous journey of cilengitide for glioblastoma

End of the road: confounding results of the CORE trial terminate the arduous journey of cilengitide for glioblastoma

PD-0188: Assessing the uncertainty in clinical dose-response outcomes with a bootstrap analysis

PD-0188: Assessing the uncertainty in clinical dose-response outcomes with a bootstrap analysis

Application of Dempster–Shafer theory in dose response outcome analysis

The Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) reviews summarize the currently available three-dimensional dose/volume/outcome data from multi-institutions and numerous articles to update and refine the normal tissue dose/volume tolerance guidelines. As pointed out in the review, the data have limitations and even some inconsistency. However, with the help of new physical and statistical techniques, the information in the review could be updated so that patient care can be continually improved. The purpose of this work is to demonstrate the application of a mathematical theory, the Dempster–Shafer theory, in dose/volume/outcome data analysis. We applied this theory to the original data obtained from published clinical studies describing dose response for radiation pneumonitis. Belief and plausibility concepts were introduced for dose response evaluation. We were also able to consider the uncertainty and inconsistency of the data from these studies with Yager's combination rule, a special methodology of Dempster–Shafer theory, to fuse the data at several specific doses. The values of belief and plausibility functions were obtained at the corresponding doses. Then we applied the Lyman–Kutcher–Burman (LKB) model to fit these values and a belief–plausibility range was obtained. This range could be considered as a probability range to assist physicians and treatment planners in determining acceptable dose–volume constraints. Finally, the parameters obtained from the LKB model fitting were compared with those in Emami and Burman's papers and those from other frequentist statistics methods. We found that Emami and Burman's parameters are within the belief–plausibility range we calculated by the Dempster–Shafer theory.

Helical tomotherapy for anal cancer: Initial clinical outcomes and organ motion.

530 Background: Helical tomotherapy (HT) delivers rotational IMRT with megavoltage CT (MVCT) guidance for patient positioning, offering improved dose conformality and accuracy. We report preliminary clinical outcomes using HT in patients with anal cancer with estimated organ motion and delivered doses. Methods: From 9/2005-8/2009, 15 patients with anal cancer were treated with HT and concurrent chemotherapy (MMC 10 mg/m2 IV bolus d1 and 29; 5FU 1,000 mg/m2/day CI d1-4 and 29-32). Median doses for primary tumor, involved lymph nodes and uninvolved lymph nodes were 50.5, 50.4 and 45 Gy. Dose specifications and target definitions were per RTOG 0529 for the majority. Treatment plans, daily MVCT, and initial clinical outcomes and toxicity were retrospectively analyzed. Center-of-mass (COM) locations and volumes of the targets and OAR with daily shifts were analyzed on selected patients. Doses actually delivered daily were reconstructed. Results: At median follow-up of 15 months, all patients were alive without any evidence of recurrence. There were 40% male, 27% HIV+, 13% T3/4, and 47% lymph node positive. Four patients required treatment break of ≤ 1 week. There were no non-hematologic grade 4/5 toxicities. Overall non-hematologic grade 3 toxicity was 33.3% (GI and skin). All other patients had ≤ grade 2 GI or skin toxicity that completely resolved with aggressive supportive care. There was 40% overall hematologic grade 4 toxicity. Overall hematologic grade 3 toxicity was 60%. Daily shifts were 0.6 ± 3.3, 0.4 ± 3.0, and 0.5 ± 2.2 (SD) mm in lateral, longitudinal and vertical directions. Average daily displacements of the COM from their locations on the planning CT were 9 ± 3, 7 ± 4, 9 ± 2, and 7 ± 2 (SD) mm, for anus, rectum, bladder and vulva. Interfractional organ motion and deformation resulted in variations in the dose delivered in each fraction.For example, daily dose covering 95% of PTV varied by 4%, and vulva volume covered by 50 Gy changed by 23% daily. Conclusions: HT with concurrent chemotherapy is well-tolerated compared to historical reports. Interfractional organ motion is significant and can result in deviations in dose delivery to the target and OAR. Such deviations should be considered in analyzing dose response outcome. No significant financial relationships to disclose.

Application of the Hazard Quotient Method in Remedial Decisions: A Comparison of Human and Ecological Risk Assessments

This paper evaluates the relative roles of the human health hazard index (HI) and the ecological risk assessment hazard quotient (HQ) in remedial decision-making. Through an analysis of HI outcomes drawn from Superfund Records of Decision, the reduced importance of the HI statistic in human health risk assessments is demonstrated, and the high visibility of the ecological risk assessment (ERA) HQ for terrestrial receptors (birds and mammals) is underscored. Three HQ method limitations common to both HHRA and ERA, deriving either from the mathematical construct of the HQ (a simple binary measure, indicating that an animal's exposure either exceeds its toxicity value or does not) or from dose-response outcomes in animal trials, are reviewed. Two additional HQ limitations unique to ERA (i.e., a propensity for the HQ to easily exceed its threshold value, and a propensity for it to assume values that are unreasonably high), and deriving from the complexities of estimating bird and mammal dietary intakes of contaminants and the availability of toxicological effects information, are also identified. The paper cautions of the potential to err in concluding that terrestrial site receptors are at risk when the HQ threshold is exceeded, and regardless of the toxicological information (NOAELs, LOAELs, etc.) used. It recognizes that because other methods of terrestrial assessment are presently unavailable, HQs are sometimes, out of necessity, used to justify a remedial action. The analysis and discussion are intended to remind ecological risk assessors that the HQ is a measure of a level of concern only and not a measure of risk