Evaluation Of New Therapies Research Articles

Abstract 1567: Use of humanized NOG mice within the pre-clinical development of new human specific therapies.

Abstract Immune cells within the tumor microenvironment are now well recognized as to be targets of interest for cancer treatment. However there are no available pre-clinical models that will accurately support the pre-clinical development of such therapeutic approaches. Humanized NOG (NOD/shi-scid/IL-2Rγnull) mice, bearing human immune cells with or without human target tumor cells, are relevant models to test various therapeutic strategies (e.g. antibody dependent cell cytotoxicity, Treg targeting antibodies, TLR agonists, vaccines, adoptive T cells transfer, …) in various pathologies (e.g. oncology, autoimmune disease, inflammation, transplantation, …). Humanization of NOG mice was already characterized and validated using freshly collected human PBMCs or hematopoietic stem cells (HSCs) in both newborn and adult NOG mice. The complete characterization of the reconstituted NOG mice was done in peripheral blood as well as central lymphoid organs such as bone marrow, spleen and thymus, using FACS analysis. Moreover, the human immune reconstitution and function in NOG mice was also evidenced with human cytokine and immunoglobulin quantification in mouse plasma samples. The injection of mature human PBMC in adult NOG mice leads to the consistent development of a xenogeneic graft-versus-host disease (GvHD), which mimics human GvHD (modification of CD4/CD8 ratio, expression of T cells activation markers and cytokine production). Growth characteristics of human tumors models on humanized mice will be presented either as subcutaneous or as disseminated intravenous model. Randomization parameters were selected regarding both tumor and immune cell sides. Required readouts to understand immune cell modulation (Cell phenotyping and functionality) and related antitumor efficacy will be described. Finally, such models, i.e. humanized NOG mice bearing or not human tumor cells in the context of evaluation of new therapies will be detailed in various pathologies. Citation Format: Caroline Mignard, Jean-Francois Mirjolet, Holger Kissel, Francis Bichat, Olivier Duchamp. Use of humanized NOG mice within the pre-clinical development of new human specific therapies. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1567. doi:10.1158/1538-7445.AM2013-1567

The Utility of Micro-CT and MRI in the Assessment of Longitudinal Growth of Liver Metastases in a Preclinical Model of Colon Carcinoma

Liver is a common site for distal metastases in colon and rectal cancer. Numerous clinical studies have analyzed the relative merits of different imaging modalities for detection of liver metastases. Several exciting new therapies are being investigated in preclinical models. But, technical challenges in preclinical imaging make it difficult to translate conclusions from clinical studies to the preclinical environment. This study addresses the technical challenges of preclinical magnetic resonance imaging (MRI) and micro-computed tomography (CT) to enable comparison of state-of-the-art methods for following metastatic liver disease. We optimized two promising preclinical protocols to enable a parallel longitudinal study tracking metastatic human colon carcinoma growth in a mouse model: T2-weighted MRI using two-shot PROPELLER (Periodically Rotated Overlapping ParallEL Lines with Enhanced Reconstruction) and contrast-enhanced micro-CT using a liposomal contrast agent. Both methods were tailored for high throughput with attention to animal support and anesthesia to limit biological stress. Each modality has its strengths. Micro-CT permitted more rapid acquisition (<10 minutes) with the highest spatial resolution (88-micron isotropic resolution). But detection of metastatic lesions requires the use of a blood pool contrast agent, which could introduce a confound in the evaluation of new therapies. MRI was slower (30 minutes) and had lower anisotropic spatial resolution. But MRI eliminates the need for a contrast agent and the contrast-to-noise between tumor and normal parenchyma was higher, making earlier detection of small lesions possible. Both methods supported a relatively high-throughput, longitudinal study of the development of metastatic lesions.

Different Wording of the Patient Global Visual Analogue Scale (PG‐VAS) Affects Rheumatoid Arthritis Patients’ Scoring and the Overall Disease Activity Score (DAS28): A Cross‐Sectional Study

The Disease Activity Score in 28 joints (DAS28) is a key measure in clinical practice and clinical trials. There are at least five different versions of the 'Patient Global' Visual Analogue Scale (PG-VAS) being used in the DAS28. The developers suggested that the PG-VAS can be an assessment of global health or disease activity, but did not specify the wording of the question. There is no consensus on what the PG-VAS is intended to capture, and the different words and phrases have not been evaluated. The aim of this study was to test if phrasing affects PG-VAS scores and hence yields different results for the DAS28. Fifty patients with rheumatoid arthritis taking biologic agents in a rheumatology outpatient department completed a self-administered questionnaire containing five versions of the 100 mm PG-VAS. All PG-VAS versions correlated strongly with each other (rho = 0.67-0.87, p < 0.0001). However, individual scores for each PG-VAS, when compared with the comparator on a Bland-Altman chart had wide limits of agreement--the largest being -42 mm to +45 mm. The five overall DAS28 scores were calculated for each patient using the five different PG-VAS. The largest difference in DAS28 scores was 0.63. Different phrasing of the PG-VAS gives different DAS28 results. As the DAS28 is a key outcome measure, such differences have the potential to influence clinical decisions relating to eligibility for biologic agents and evaluation of new therapies. We urgently need to decide on the concept to be measured and the phrasing required to capture this. The PG-VAS phrasing should then be standardized and validated.

Importance of proper patient selection and endpoint selection in evaluation of new therapies in acute stroke: further analysis of the SENTIS trial

BackgroundThe magnitude of treatment effect in acute stroke depends on several factors, including time from symptom onset (TFSO) to treatment and severity of the initial insult.ObjectiveTo report further evaluation of...

Importance of proper patient selection and endpoint selection in evaluation of new therapies in acute stroke: further analysis of the SENTIS trial: Table 1

Importance of proper patient selection and endpoint selection in evaluation of new therapies in acute stroke: further analysis of the SENTIS trial: Table 1

Drug Development: Neoadjuvant Opportunities in Breast Cancer

Preoperative therapy allows for a higher rate of breast conserving surgery and has been shown equivalent to adjuvant therapy. Preoperative therapy provides an opportunity to obtain insights into breast cancer biology and to accelerate the evaluation of new therapies. Clinical trials have shown that women who achieve a pathologic complete response (pCR) have substantially improved outcomes compared with those who do not achieve a pCR. The U.S. Food and Drug Administration (FDA) meta-analysis demonstrated that the association of pCR and long-term outcomes is greater in women with aggressive breast cancer subtypes. In patients with HER2+ breast cancer, the addition of trastuzumab to chemotherapy in the neoadjuvant setting has doubled pCR and correlated with improved outcomes. Clinical trials will evaluate tailoring the use of radiation therapy in patients who have received neoadjuvant therapy. Trials have established neoadjuvant endocrine therapy as a valid treatment and research option for ER-rich breast cancer. The neoadjuvant setting allows for evaluation of endocrine therapies in combination with newer targeted therapies in the appropriate patient populations. The neoadjuvant setting provides opportunity to accelerate the evaluation of new agents, improve pCR rates, and identify predictive biomarkers for response. This setting provides the opportunity for screening new agents in combination with chemotherapy while obtaining serial biopsies to understand biology of response and resistance. Although current standard therapies provide substantial benefits for patients with a pCR, patients with residual disease are at substantial risk for disease recurrence. New agents are being evaluated in patients with high-risk residual disease following standard treatment regimens.

An Overview of Models, Methods, and Reagents Developed for Translational Autoimmunity Research in the Common Marmoset (&lt;i&gt;Callithrix jacchus&lt;/i&gt;)

The common marmoset (Callithrix jacchus) is a small-bodied Neotropical primate and a useful preclinical animal model for translational research into autoimmune-mediated inflammatory diseases (AIMID), such as rheumatoid arthritis (RA) and multiple sclerosis (MS). The animal model for MS established in marmosets has proven their value for exploratory research into (etio) pathogenic mechanisms and for the evaluation of new therapies that cannot be tested in lower species because of their specificity for humans. Effective usage of the marmoset in preclinical immunological research has been hampered by the limited availability of blood for immunological studies and of reagents for profiling of cellular and humoral immune reactions. In this paper, we give a concise overview of the procedures and reagents that were developed over the years in our laboratory in marmoset models of the above-mentioned diseases.

Results From a Carotid Intima-Media Thickness Trial as a Decision Tool for Launching a Large-Scale Morbidity and Mortality Trial

Trials with carotid intima-media thickness (CIMT) as primary end point may improve the efficiency of the evaluation of new therapies targeting atherosclerosis considerably, and the results of CIMT trials may be used as a decision tool to help in the choice to launch or not to launch a large-scale morbidity and mortality (M&M) trial. We evaluated the literature to provide evidence to support or refute this proposition. PubMed Medline was systematically searched on May 1, 2012, for randomized double-blind controlled CIMT trials. The agreement between the results from CIMT and M&M trials was assessed, and positive and negative predictive values were calculated. Forty-eight CIMT trials were included. CIMT trials (n=20) on lipid-level modifying therapies are all, except one, in agreement with the M&M trial findings. For blood pressure-lowering trials (n=13), 3 were not congruent with the M&M trial. The positive and negative predictive value (95% confidence interval) of a CIMT trial to predict the outcome of a M&M trial are 96% (80-99%) and 83% (64-93%), respectively. The predictive values are higher for lipid-level modifying therapies than for other therapies. A CIMT trial positioned before an M&M trial may considerably improve the efficiency of the evaluation of new drug therapies on atherosclerosis and cardiovascular disease risk. Hence, the results of a CIMT trial should be seen as a decision tool to support or refute the start of a large-scale M&M trial on drugs targeting atherosclerosis.

Cardiovascular Effects of Noninsulin, Glucose-Lowering Agents: Need for More Outcomes Data

Macrovascular complications of type 2 diabetes mellitus (DM) are primarily driven by the combination of underlying atherosclerosis and propensity for thrombosis. Prevention of macrovascular complications in DM relies on therapies directed at multiple coexisting intermediary pathophysiologies that contribute to cardiovascular events, including hyperglycemia, lipoprotein abnormalities, hypertension, inflammation, and propensity for thrombosis. Multiple noninsulin, glucose-lowering agents have been developed that effectively lower blood glucose levels. This review explores the literature on the cardiovascular benefits and harms associated with these therapies, with an emphasis on cardiovascular outcomes when available. The lack of long-term data on cardiovascular outcomes regarding safety and efficacy of available traditional glucose-lowering agents has led to recommendations for more thorough evaluations of new therapies before approval. Furthermore, recent data suggest harm from intensive hemoglobin A(1c) reductions. Accordingly, there are multiple, large, cardiovascular-event driven phase 3-4 trials of therapies from the incretin axis currently enrolling. Recommendations for a therapeutic approach with noninsulin, glucose-lowering agents for the prevention of cardiovascular events in patients with type 2 DM are provided based on current data. Ultimately, multifactorial risk interventions, including lifestyle modifications, antihyperglycemic agents, antihypertensives, statins, and aspirin remain the primary focus to prevent macrovascular complications in patients with type 2 DM.

O1-011 - Introduction and Current Status of the Development Program for a Japanese Version of the NCI PRO-CTCAE

ABSTRACT Background The U.S. National Cancer Institute (NCI)-Common Toxicity Criteria for Adverse Events (CTCAE) is a long-standing empirically developed ‘dictionary’ or lexicon, designed for the use in clinical trials to aid clinicians in detecting and documenting an array of adverse events (AEs) commonly encountered in oncology. There is growing awareness that collecting symptom data directly from patients using patient-reported outcome (PRO) tools can improve the accuracy and efficiency of symptomatic AE data collection. The purpose of the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) project is to develop an electronic-based system for patient self-reporting of symptom adverse events listed in the CTCAE in an effort to improve the accuracy and precision of grading of this class of AEs. The accurate reporting of AEs that in clinical trials is a federal requirement that facilitates evaluation of new therapies. To develop a translation of the PRO-CTCAE to Japanese would serve important role to collect subjective symptom in the clinical oncology setting. Methods and Results Forward and back translations were carried out and an independent review was carried out by the Japan Clinical Oncology Group (JCOG) Executive Committee. These items were designated as PRO-CTCAE-Japanese Version 1.0 by Tohoku University/The University of Tokyo/JCOG. We are now conducting cognitive interviews in a range of treatment settings among diverse groups of cancer patients. Participants are asked to self-complete the PRO-CTCAE and then are interviewed to determine when items are difficult to comprehend and/or not relevant to their symptoms. Conclusion and next steps We developed a Japanese version of the PRO-CTCAE and will now assess the level of comprehension and cognitive equivalence of the translation via cognitive interviews. In 2012, we will perform a validation study and examine the reliability and validity of the Japanese version. In addition, in a multicenter clinical trial, JCOG1018, a subset of PRO-CTCAE items related to the expected adverse events in this trial, will be administered. An electronic-based system will be developed to provide interfaces to investigators, clinicians, and patients to collect and report patient-reported symptom data.

Cuban research in current international journals

direct observations and interviews. Results The total economic cost per inhabitant (p.i.) per month. (p.m.) increased from 2.76 USD in months without dengue transmission to 6.05 USD during an outbreak. In months without transmission, the routine Aedes control programme cost 1.67 USD p.i. p.m. Incremental costs during the outbreak were mainly incurred by the population and the primary/secondary level of the healthcare system, hardly by the vector control programme (1.64, 1.44 and 0.21 UDS increment p.i. p.m., respectively). The total cost for managing a hospitalized suspected dengue case was 296.60 USD (62.0% direct medical, 9.0% direct non-medical and 29.0% indirect costs). In both periods, the main cost drivers for the Aedes control programme, the healthcare system and the community were the value of personnel and volunteer time or productivity losses. Conclusions Intensive efforts to keep A. aegypti infestation low entail important economic costs for society. When a dengue outbreak does occur eventually, costs increase sharply. In-depth studies should assess which mix of activities and actors could maximize the effectiveness and cost-effectiveness of routine Aedes control and dengue prevention. Effectiveness of adaptive designs for phase II cancer trials. Lopez MF, Dupuy JF, Gonzalez CV. Contemp Clin Trials. 2011 Oct 7. [Epub ahead of print]. Background Evaluation of new therapies for cancer has suffered a paradigm shift in the last years. The use of innovative and more effi cient designs is a priority for the scientifi c community; nevertheless, the use of this kind of design is not yet wide spread. Purpose In this paper will examine the effectiveness of adaptive designs compared with traditional designs in phase II clinical trials. Methods We reviewed a group of abstracts records between 1980 and 2008 and extracted data regarding statistical design, year of publication, kind of evaluated product, localization, sample size and results of the trials. Results Nine hundred and eighty-nine clinical trials were identifi ed and from them 333 traditional designs and 19 adaptive designs were included in the review. Two hundred statistical papers were located and 16 were included in the review. The most frequent designs were Standard up and down designs, continual reassessment methods and its variation and designs

Combination Radiotherapy in an Orthotopic Mouse Brain Tumor Model

Glioblastoma multiforme (GBM) are the most common and aggressive adult primary brain tumors. In recent years there has been substantial progress in the understanding of the mechanics of tumor invasion, and direct intracerebral inoculation of tumor provides the opportunity of observing the invasive process in a physiologically appropriate environment. As far as human brain tumors are concerned, the orthotopic models currently available are established either by stereotaxic injection of cell suspensions or implantation of a solid piece of tumor through a complicated craniotomy procedure. In our technique we harvest cells from tissue culture to create a cell suspension used to implant directly into the brain. The duration of the surgery is approximately 30 minutes, and as the mouse needs to be in a constant surgical plane, an injectable anesthetic is used. The mouse is placed in a stereotaxic jig made by Stoetling (figure 1). After the surgical area is cleaned and prepared, an incision is made; and the bregma is located to determine the location of the craniotomy. The location of the craniotomy is 2 mm to the right and 1 mm rostral to the bregma. The depth is 3 mm from the surface of the skull, and cells are injected at a rate of 2 μl every 2 minutes. The skin is sutured with 5-0 PDS, and the mouse is allowed to wake up on a heating pad. From our experience, depending on the cell line, treatment can take place from 7-10 days after surgery. Drug delivery is dependent on the drug composition. For radiation treatment the mice are anesthetized, and put into a custom made jig. Lead covers the mouse's body and exposes only the brain of the mouse. The study of tumorigenesis and the evaluation of new therapies for GBM require accurate and reproducible brain tumor animal models. Thus we use this orthotopic brain model to study the interaction of the microenvironment of the brain and the tumor, to test the effectiveness of different therapeutic agents with and without radiation.

Combination Radiotherapy in an Orthotopic Mouse Brain Tumor Model

Glioblastoma multiforme (GBM) are the most common and aggressive adult primary brain tumors1. In recent years there has been substantial progress in the understanding of the mechanics of tumor invasion, and direct intracerebral inoculation of tumor provides the opportunity of observing the invasive process in a physiologically appropriate environment2. As far as human brain tumors are concerned, the orthotopic models currently available are established either by stereotaxic injection of cell suspensions or implantation of a solid piece of tumor through a complicated craniotomy procedure3. In our technique we harvest cells from tissue culture to create a cell suspension used to implant directly into the brain. The duration of the surgery is approximately 30 minutes, and as the mouse needs to be in a constant surgical plane, an injectable anesthetic is used. The mouse is placed in a stereotaxic jig made by Stoetling (figure 1). After the surgical area is cleaned and prepared, an incision is made; and the bregma is located to determine the location of the craniotomy. The location of the craniotomy is 2 mm to the right and 1 mm rostral to the bregma. The depth is 3 mm from the surface of the skull, and cells are injected at a rate of 2 μl every 2 minutes. The skin is sutured with 5-0 PDS, and the mouse is allowed to wake up on a heating pad. From our experience, depending on the cell line, treatment can take place from 7-10 days after surgery. Drug delivery is dependent on the drug composition. For radiation treatment the mice are anesthetized, and put into a custom made jig. Lead covers the mouse's body and exposes only the brain of the mouse. The study of tumorigenesis and the evaluation of new therapies for GBM require accurate and reproducible brain tumor animal models. Thus we use this orthotopic brain model to study the interaction of the microenvironment of the brain and the tumor, to test the effectiveness of different therapeutic agents with and without radiation.

Effectiveness of adaptive designs for phase II cancer trials

Background Evaluation of new therapies for cancer has suffered a paradigm shift in the last years. The use of innovative and more efficient designs is a priority for the scientific community; nevertheless, the use of this kind of design is not yet wide spread. Purpose In this paper will examine the effectiveness of adaptive designs compared with traditional designs in phase II clinical trials. Methods We reviewed a group of abstracts records between 1980 and 2008 and extracted data regarding statistical design, year of publication, kind of evaluated product, localization, sample size and results of the trials. Results Nine hundred and eighty-nine clinical trials were identified and from them 333 traditional designs and 19 adaptive designs were included in the review. Two hundred statistical papers were located and 16 were included in the review. The most frequent designs were Standard up and down designs, continual reassessment methods and its variation and designs with Bayesian approaches. More than 80% of the studies evaluated different schemes of chemotherapy. Adaptive designs evaluated only drugs and not any kind of treatment combination and the most often localizations evaluated in both designs were lung, haematology malignancies, and colon cancers. Conclusions Adaptive designs are more efficient from the statistical point of view but they are not yet widely used because of complex and computationally intensive methods needed, substantial effort for planning the trials and lack of regulatory guidance.

Bayesian Meta‐Experimental Design: Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes

Recent guidance from the Food and Drug Administration for the evaluation of new therapies in the treatment of type 2 diabetes (T2DM) calls for a program-wide meta-analysis of cardiovascular (CV) outcomes. In this context, we develop a new Bayesian meta-analysis approach using survival regression models to assess whether the size of a clinical development program is adequate to evaluate a particular safety endpoint. We propose a Bayesian sample size determination methodology for meta-analysis clinical trial design with a focus on controlling the type I error and power. We also propose the partial borrowing power prior to incorporate the historical survival meta data into the statistical design. Various properties of the proposed methodology are examined and an efficient Markov chain Monte Carlo sampling algorithm is developed to sample from the posterior distributions. In addition, we develop a simulation-based algorithm for computing various quantities, such as the power and the type I error in the Bayesian meta-analysis trial design. The proposed methodology is applied to the design of a phase 2/3 development program including a noninferiority clinical trial for CV risk assessment in T2DM studies.

Tracking human multiple myeloma xenografts in NOD-Rag-1/IL-2 receptor gamma chain-null mice with the novel biomarker AKAP-4

BackgroundMultiple myeloma (MM) is a fatal malignancy ranking second in prevalence among hematological tumors. Continuous efforts are being made to develop innovative and more effective treatments. The preclinical evaluation of new therapies relies on the use of murine models of the disease.MethodsHere we describe a new MM animal model in NOD-Rag1null IL2rgnull (NRG) mice that supports the engraftment of cell lines and primary MM cells that can be tracked with the tumor antigen, AKAP-4.ResultsHuman MM cell lines, U266 and H929, and primary MM cells were successfully engrafted in NRG mice after intravenous administration, and were found in the bone marrow, blood and spleen of tumor-challenged animals. The AKAP-4 expression pattern was similar to that of known MM markers, such as paraproteins, CD38 and CD45.ConclusionsWe developed for the first time a murine model allowing for the growth of both MM cell lines and primary cells in multifocal sites, thus mimicking the disease seen in patients. Additionally, we validated the use of AKAP-4 antigen to track tumor growth in vivo and to specifically identify MM cells in mouse tissues. We expect that our model will significantly improve the pre-clinical evaluation of new anti-myeloma therapies.

Abstract C8: Endogenous mouse models of pancreatic adenocarcinoma as a preclinical trial platform characterized by multiparametric magnetic resonance imaging

Abstract Development of strategies for early tumor detection and evaluation of new therapies in preclinical models is one of the main goals of current cancer research. Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with no effective treatment plan. PDAC progression can be very well mimicked by established genetically engineered mouse models (GEMMs), representing an excellent platform for preclinical studies. Therefore, tumor physiology, including growth kinetics, tumor perfusion and tumor composition, were characterized in several GEMM. In addition, tumor response to the standard therapeutic agent gemcitabine was monitored by multiparametric MRI. Ptf1a+/Cre mice were crossed to Kras+/LSL-G12D (K)Tgfα(T), K;p53(P)+/fl, K;Pfl/fl, K;P+/R172H; T and K;P+/fl;T GEMMs to generate conditional endogenous PDAC models. Animals were subjected to serial T2-weighted (T2w) MRI from 4–6 weeks of age onwards using 1,5 T clinical scanner. Upon detection of solid tumor, longitudinal diffusion-weighted imaging (DWI) and dynamic contrast enhanced-MRI (DCE-MRI with Gd-DTPA) protocols were applied. For the evaluation of therapy response monitoring, K;Pfl/fl mice were injected twice a week with 120 mg/kg body weight with gemcitabine or 0.9% NaCl solution. MRI data were correlated with survival analysis, vascular staining, and histopathology of tumor specimens. Volume analysis was performed using semiautomatic segmentation of solid and cystic compartments. K;Pfl/fl, and K;P+/fl; T models showed 100% tumor incidence, detected by MRI and verified by histology. Moreover, K;P+/fl; T animals often presented with metastatic disease to lung and liver, easily identified on T2w scans, while no metastases were observed in K;Pfl/fl mice. The final tumor volume ranged between 800 and 4500 mm3. Characterization of solid tumor tissue composition by DWI correlated well (R=72%) with the histopathology. K;Pfl/fl, K;P+/R172H; T, K;P+/fl; T, and K; T models mostly developed highly fibrotic, well-differentiated PDAC (apparent diffusion coefficient, ADC=1.03-1.14), whereas cancers observed in K;Pfl/+ animals revealed an anaplastic phenotype with significantly lower ADC values (0.8843 ± 0.05056). Spontaneous necrosis was detectable by DWI and DCE analysis. Intraductal mucinous papillary neoplasms (mIPMN) appeared hypointense on T2w MRI and were better perfused compared to hyperintense PDAC. Interestingly, the calculated ADC values of mIPMN lesions were similar to those of solid tumors (1.03 ± 0.012). Gemcitabine-treated K;Pfl/fl animals showed an increased overall survival as well as tumor volume reduction in individual cases. Although selected animals revealed changes in tumor perfusion, no differences in tissue composition, reflected by the ADC values and histology, were noticed in vehicle- or gemcitabine-treated animals. In summary, based on tumor incidence, growth kinetic and overall survival criteria, we propose two very suitable models for preclinical therapy studies: K;Pfl/fl and K;P+/fl; T. The validated multimodal MRI-based methods are feasible for correct interpretation of spontaneous and drug-induced changes in tumor physiology when conducting preclinical therapy studies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr C8.

Abstract C14: Optical imaging of integrin αVβ3 detects pancreatic cancer in endogenous mouse models.

Abstract Pancreatic ductal adenocarcinoma remains one of the most lethal malignacies in the Western World with a 5-year survival rate lower then 4%. Late diagnosis and poor response to all available chemotherapies are main causes for the devastating clinical course. Development of methods for early detection and evaluation of new therapies is of great importance. Here, we used optical imaging for detection of αVβ3 integrin in pancreatic cancer in endogenous mouse models. To model stages of PDAC development in humans, following genetically engineered animal models (GEMM) were used: mice with pancreas specific activation of oncogenic Kras (p48+/Cre Kras+/LSL-G12D, CK) that develop preneoplastic lesions preceding the cancer and mice with concomitant deletion of p53 (p48+/Cre Kras+/LSL-G12D p53Lox/Lox, CKP) that develop PDAC already at 6–8 weeks of age. Pancreatic αVβ3 integrin expression was analysed by immunohistochemistry and Western blot. For optical imaging, animals were injected with Integrisense680, Near Infrared fluorochrome labelled agent that specifically binds to αVβ3. After 24h, animals were subjected to intraoperative epi-illumination optical imaging procedure. Sacrificed animals were whole-mount frozen for analysis of Integrisense intra-tissue distribution via multispectral cryoslicing optical imaging. For comparison, T2 weighted (T2w) images of the abdomen were generated with 1,5T clinical MRI scanner and a dedicated surface coil. β3 protein expression was dramatically increased in CKP pancreatic tumors compared to CK pancreata. β3 positive cells were found among malignant cells and in the reactive stroma. In CK animals, β3 expression was specifically limited to ductal and preneoplastic lesions and surrounding stroma with no expression in normal tissue. Intraoperative optical imaging of Integrisense correlated well with the high β3 expression in the tumor and demonstrated very strong and specific fluorescence signals at the tumor surface with excellent demarcation of tumor borders and good contrast to surrounding tissues. CK pancreas was well visualized and spotty fluorescence pattern of Integrisense was observed. Cryoslicing imaging of the animals confirmed that Integrisense680 penetrated well into all parts of the tumor and accumulated very specifically in cancer tissue in CKP animals. In CK pancreata, spots of fluorescence were also observed throughout the tissue confirming intraoperative imaging. Spots of fluorescence correlated well with the foci of ductal and preneoplastic lesions embedded in healthy tissue as confirmed by histopathological analysis. In contrast, preneoplastic lesions were difficult to differentiate on T2w-MRI images due to low spatial resolution. Tumors appeared relative homogenously hyperintense on T2w images and tumor borders were in certain cases difficult to identify, when adjacent structures, i.e. gut, were of similar signal intensity. We demonstrated increased expression of αVβ3 integrin in pancreatic tumors in GEM models and ability to detect this integrin via optical imaging procedures. We were able to specifically identify the cancer, demarcate its borders and differentiate between pancreatic tissue with preneoplastic lesions and cancer. We suggest that optical imaging of αVβ3 integrin is a promising future approach for clinical practice. αVβ3 fluorescence guided surgery can assist the surgeon in precise demarcation of surgical margins and minimisation of residual tissue. Additionally, targeted Integrisense optical imaging would allow early evaluation αVβ3 targeted therapies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr C14.

Conditionally Funded Field Evaluations—A Solution to the Economic Barriers Limiting Evidence Generation in Dialysis?

Evaluation of new therapies after licensing is usually a binary decision by payers; to fund or not to fund. In the real world, many therapies fall into a gray zone of incomplete evaluation. Many clinical and economic issues in nephrology have combined to create a long list of such promising but incompletely evaluated therapies. This article focuses on the economic challenges that limit evidence generation in nephrology. Conditionally funded field evaluations such as coverage with evidence development can allow both earlier access to new treatments and rigorous evaluation. The authors propose that field evaluations will stimulate an environment that promotes pivotal renal care advances. Certainly, the evidence challenge faced by nephrology requires urgent discussions on creating conditions that catalyze and accelerate innovation, and improve patient outcomes.

Update in Asthma 2010

The prevalence of asthma has been increasing, especially in children (1). An article reported that in Canada one in three patients would have a physician diagnosis of asthma in their lifetime (2). Work in the field of asthma this year included evaluation of new therapies, reevaluation of the benefits and risks of available therapy, and research into clinical and biomarker patterns that might allow us to differentiate among different phenotypes of asthma. There were also reports on advances in the understanding of potential immune, cellular, and biochemical mechanisms that might contribute to asthma pathobiology, work in defining genetic contributors to asthma, and elucidation of environmental factors that can influence the development or expression of the disease.