Babak Saboury

CD40 Agonists Alter Tumor Stroma and Show Efficacy Against Pancreatic Carcinoma in Mice and Humans

CD40 immunotherapy shows efficacy in treating pancreatic cancer in mice and humans by eliciting antitumor immunity. Immunosuppressive tumor microenvironments can restrain antitumor immunity, particularly in pancreatic ductal adenocarcinoma (PDA). Because CD40 activation can reverse immune suppression and drive antitumor T cell responses, we tested the combination of an agonist CD40 antibody with gemcitabine chemotherapy in a small cohort of patients with surgically incurable PDA and observed tumor regressions in some patients. We reproduced this treatment effect in a genetically engineered mouse model of PDA and found unexpectedly that tumor regression required macrophages but not T cells or gemcitabine. CD40-activated macrophages rapidly infiltrated tumors, became tumoricidal, and facilitated the depletion of tumor stroma. Thus, cancer immune surveillance does not necessarily depend on therapy-induced T cells; rather, our findings demonstrate a CD40-dependent mechanism for targeting tumor stroma in the treatment of cancer.

A phase I study of an agonist CD40 monoclonal antibody (CP-870,893) in combination with gemcitabine in patients with advanced pancreatic ductal adenocarcinoma

Purpose: This phase I study investigated the maximum-tolerated dose (MTD), safety, pharmacodynamics, immunologic correlatives, and antitumor activity of CP-870,893, an agonist CD40 antibody, when administered in combination with gemcitabine in patients with advanced pancreatic ductal adenocarcinoma (PDA). Experimental Design: Twenty-two patients with chemotherapy-naïve advanced PDA were treated with 1,000 mg/m2 gemcitabine once weekly for three weeks with infusion of CP-870,893 at 0.1 or 0.2 mg/kg on day three of each 28-day cycle. Results: CP-870,893 was well-tolerated; one dose-limiting toxicity (grade 4, cerebrovascular accident) occurred at the 0.2 mg/kg dose level, which was estimated as the MTD. The most common adverse event was cytokine release syndrome (grade 1 to 2). CP-870,893 infusion triggered immune activation marked by an increase in inflammatory cytokines, an increase in B-cell expression of costimulatory molecules, and a transient depletion of B cells. Four patients achieved a partial response (PR). 2-[18F]fluoro-2-deoxy-d-glucose-positron emission tomography/computed tomography (FDG-PET/CT) showed more than 25% decrease in FDG uptake within primary pancreatic lesions in six of eight patients; however, responses observed in metastatic lesions were heterogeneous, with some lesions responding with complete loss of FDG uptake, whereas other lesions in the same patient failed to respond. Improved overall survival correlated with a decrease in FDG uptake in hepatic lesions (R = −0.929; P = 0.007). Conclusions: CP-870,893 in combination with gemcitabine was well-tolerated and associated with antitumor activity in patients with PDA. Changes in FDG uptake detected on PET/CT imaging provide insight into therapeutic benefit. Phase II studies are warranted. Clin Cancer Res; 19(22); 6286–95. ©2013 AACR.

PET/MR Imaging : Technical Aspects and Potential Clinical Applications

UNLABELLED Instruments that combine positron emission tomography (PET) and magnetic resonance (MR) imaging have recently been assembled for use in humans, and may have diagnostic performance superior to that of PET/computed tomography (CT) for particular clinical and research applications. MR imaging has major strengths compared with CT, including superior soft-tissue contrast resolution, multiplanar image acquisition, and functional imaging capability through specialized techniques such as diffusion-tensor imaging, diffusion-weighted (DW) imaging, functional MR imaging, MR elastography, MR spectroscopy, perfusion-weighted imaging, MR imaging with very short echo times, and the availability of some targeted MR imaging contrast agents. Furthermore, the lack of ionizing radiation from MR imaging is highly appealing, particularly when pediatric, young adult, or pregnant patients are to be imaged, and the safety profile of MR imaging contrast agents compares very favorably with iodinated CT contrast agents. MR imaging also can be used to guide PET image reconstruction, partial volume correction, and motion compensation for more accurate disease quantification and can improve anatomic localization of sites of radiotracer uptake, improve diagnostic performance, and provide for comprehensive regional and global structural, functional, and molecular assessment of various clinical disorders. In this review, we discuss the historical development, software-based registration, instrumentation and design, quantification issues, potential clinical applications, potential clinical roles of image segmentation and global disease assessment, and challenges related to PET/MR imaging. SUPPLEMENTAL MATERIAL http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.13121038/-/DC1.

Systemic and Vascular Inflammation in Patients With Moderate to Severe Psoriasis as Measured by [18F]-Fluorodeoxyglucose Positron Emission Tomography –Computed Tomography (FDG-PET/CT): A Pilot Study

OBJECTIVE To evaluate the feasibility of using [18F]-fluorodeoxyglucose positron emission tomography-computed tomography (FDG-PET/CT) to detect and quantify systemic inflammation in patients with psoriasis. DESIGN Case series with a nested case-control study. SETTING Referral dermatology and preventive cardiology practices. PARTICIPANTS Six patients with psoriasis affecting more than 10% of their body surface area and 4 controls age and sex matched to 4 of the patients with psoriasis for a nested case-control study. MAIN OUTCOME MEASURES The FDG uptake in the liver, musculoskeletal structures, and aorta measured by mean standardized uptake value, a measure of FDG tracer uptake by macrophages and other inflammatory cells. RESULTS FDG-PET/CT identified numerous foci of inflammation in 6 patients with psoriasis within the skin, liver, joints, tendons, and aorta. Inflammation in the joints was observed in a patient with psoriatic arthritis as well as in 1 patient with no history of joint disease or joint symptoms. In a nested case-control study, FDG-PET/CT imaging demonstrated increased vascular inflammation in multiple segments of the aorta compared with controls. These findings persisted after adjustment for traditional cardiovascular risk factors in multivariate analysis (mean β = 0.33; P < .001). Patients with psoriasis further demonstrated increased hepatic inflammation after adjusting for cardiovascular risk factors (β = 0.18; P < .001), but the association was no longer significant when adjusted for alcohol intake (β = -0.25; P = .07). CONCLUSION FDG-PET/CT is a sensitive tool for identifying inflammation and can be used to identify clinically observed inflammation in the skin and subclinical inflammation in the blood vessels, joints, and liver of patients with psoriasis.

Direct comparison of fluorodeoxyglucose positron emission tomography and arterial spin labeling magnetic resonance imaging in Alzheimer's disease

The utility of fluorodeoxyglucose positron emission tomography (FDG‐PET) imaging in Alzheimers disease (AD) diagnosis has been well established. Recently, measurement of cerebral blood flow using arterial spin labeling magnetic resonance imaging (ASL‐MRI) has shown diagnostic potential in AD, although it has never been directly compared with FDG‐PET.

Emerging role of radiolabeled nanoparticles as an effective diagnostic technique

Nanomedicine is emerging as a promising approach for diagnostic applications. Nanoparticles are structures in the nanometer size range, which can present different shapes, compositions, charges, surface modifications, in vitro and in vivo stabilities, and in vivo performances. Nanoparticles can be made of materials of diverse chemical nature, the most common being metals, metal oxides, silicates, polymers, carbon, lipids, and biomolecules. Nanoparticles exist in various morphologies, such as spheres, cylinders, platelets, and tubes. Radiolabeled nanoparticles represent a new class of agent with great potential for clinical applications. This is partly due to their long blood circulation time and plasma stability. In addition, because of the high sensitivity of imaging with radiolabeled compounds, their use has promise of achieving accurate and early diagnosis. This review article focuses on the application of radiolabeled nanoparticles in detecting diseases such as cancer and cardiovascular diseases and also presents an overview about the formulation, stability, and biological properties of the nanoparticles used for diagnostic purposes.

Erectile Dysfunction Severity as a Risk Predictor for Coronary Artery Disease

INTRODUCTION Erectile dysfunction (ED) is now beginning to be considered as an early manifestation of a subclinical systemic vascular disorder and may be an index of subclinical coronary artery disease (CAD). AIM To further evaluate whether ED is a predicting factor for CAD while adjusting for other common risk factors. METHODS One hundred eighty-three patients with newly diagnosed and documented CAD and 134 participants without CAD were enrolled in this case-control study at our referral center. Univariate and multivariate logistic regression analysis were performed to assess the effect of classic risk factors and ED severity on CAD; calculating odds ratio (OR) and 95% confidence interval (CI). Adjustments were made for potential confounding factors including age, hypertension, diabetes, dyslipidemia, obesity, and smoking. MAIN OUTCOME MEASURES The prevalence of ED and the distribution of CAD risk factors (age, smoking, lipid profile, hypertension, obesity, and diabetes mellitus) were evaluated. The 5-item International Index of Erectile Function was used to evaluate the presence and the severity of ED. RESULTS The prevalence of ED in CAD-positive and CAD-negative groups was 88.5% and 64.2%, respectively (P < 0.05). A statistically significant difference was found for all risk factors (except total cholesterol and low-density lipoprotein levels), and also ED prevalence between studied groups. Adjusted OR for age, diabetes, hypertension, hypercholesterolemia, and smoking demonstrated a significant confounding effect. Our results also revealed a significant association between severe ED and CAD (OR: 2.22, 95% CI: 1.11-6.03; P < 0.05). CONCLUSION This study suggests that ED could be considered as a surrogate marker which can predict the occurrence of CAD, and severe ED could be regarded as an independent risk predictor in addition to the established ones.

Evolving role of molecular imaging with PET in detecting and characterizing heterogeneity of cancer tissue at the primary and metastatic sites, a plausible explanation for failed attempts to cure malignant disorders

The diversity in cancer cell characteristics is an area of great interest in the practice of clinical oncology. By now, we know that tumors can be composed of different subpopulations of cells that can harbor very different characteristics (both in terms of genotype and phenotype), thereby exhibiting differential biologies including degrees of differentiation, growth rates, and response to various therapeutic interventions [1]. Intertumor heterogeneity across various malignancies and lesions (i.e., different biological characteristics between various lesions of the same malignancy or between different histological subtypes) has been relatively well described compared to intratumor heterogeneity (i.e., different biological characteristics within the subpopulations of neoplastic and non-neoplastic cells that successively evolve within a tumor mass) which, though recognized, has been relatively less well investigated probably due to paucity of available techniques and methodologies. This regional intratumoral heterogeneity is manifested at the cellular level by multiple subpopulations with different genetic and phenotypic characteristics. Several newer tools (e.g., laser capture microdissection) have been utilized to study this phenomenon on a cellular basis in an apparently homogeneous tumor [2, 3]. There is also tremendous temporal and spatial variation in the environment (and, therefore, environmental selection forces) that drive regional phenotypic evolution, largely as a result of variability of vascular density and blood flow. The prognostic significance of tumor heterogeneity has been emphasized in several malignancies, and in fact, grading systems have evolved in certain tumors based upon this characteristic [4–9]. To cite an example of its importance, in a study designed to determine genetic profiles of breast carcinoma cells, CD44+ cells had an active transforming growth factor beta (TGF-beta) pathway that correlated with decreased patient survival and poor prognosis compared to CD24+ cells [7]. It is important to note that heterogeneity is typically generated prior to clinical detection of the tumor, and that phenotypic diversity probably generally increases with tumor size, in parallel with the potential for genetic mutation to occur with each mitosis and the development of hypoxia, acidosis, ischemia, and necrosis.

A new dimension of FDG-PET interpretation: assessment of tumor biology

Abstract18F-Fluoro-2-deoxy-d-glucose (FDG) positron emission tomography (PET) is increasingly being used for the evaluation of several malignancies. Key to the correct interpretation of oncological FDG-PET studies is awareness of the concept that the degree of FDG uptake reflects the biology of the tumor in many cancers. More specifically, cancers with high FDG uptake are often histologically and clinically more aggressive than those with low or no FDG uptake. Therefore, although a negative FDG-PET scan in a patient with a cancer that has a size above the spatial resolution of PET may be interpreted as false-negative in terms of tumor detectability, it should in fact be regarded as true-negative from the view-point of tumor biology. This nonsystematic review will give examples of several major cancers in which the relationship between FDG avidity and tumor biology is applicable, and emphasizes the need to reconsider the definition of a “false-negative” FDG-PET scan in clinical oncology.

Current Evidence Base of FDG-PET/CT Imaging in the Clinical Management of Malignant Pleural Mesothelioma: Emerging Significance of Image Segmentation and Global Disease Assessment

Increasingly, integrated positron emission tomography-computed tomography (PET/CT) imaging is playing a crucial role in the assessment of patients with known or suspected malignant pleural mesothelioma (MPM). Based on the data reported in the literature, this combined modality is likely to become the instrument of choice for examining patients of MPM. The research on this subject has focused on the following five domains: (1) differentiation of MPM from other benign pleural diseases, (2) preoperative staging for the selection of appropriate candidates for surgery, (3) evaluation for therapy response and post-treatment surveillance for recurrence, (4) prognostication based upon the intensity of 2-deoxy-2-[18F]fluoro-d-glucose (FDG) uptake, and (5) planning of radiotherapy. These represent the bases for critical decision making in the management of mesothelioma, and FDG-PET/CT offers potential advantages over conventional CT imaging and thus can play a pivotal role in this regard. Optimal characterization of this potentially fatal disease with a high negative predictive value for MPM, superior capability for cancer staging initially and at the later course of disease, and ability for measuring therapeutic response and the precise determination of the target volume for radiotherapy planning represent distinct advantages of this promising molecular imaging tool. In this communication, we have explored the promising role of integrated FDG-PET/CT in the overall management of this serious malignancy. From the available data, the major role of PET-CT at present appears to be in the preoperative disease staging, response to treatment assessment, and post-treatment disease surveillance of MPM. In all these three areas, PET-CT convincingly shows better results than conventional anatomical imaging alone and thereby can aid in exploring novel therapeutic approaches. Disease prognosis and radiotherapy planning are evolving areas where this modality has demonstrated significant promise, but this has to be investigated further. The differentiating of MPM from benign pleural disease is a challenging issue; though in limited studies, it has shown promising results, single standardized uptake value (SUV) cutoff technique cannot be the optimal way for this purpose. Dual time point and delayed imaging helps further in this setting; however, more data require to be accrued in this area. We, in this review, have also discussed the feasibility of a new method of image segmentation based on an iterative thresholding algorithm, which permits definition of the boundaries of lesions based on PET images alone to provide lesional metabolically active tumor volumes, lesional partial volume corrected SUV (PVC-SUV) measurements, lesional PVC metabolic burden (PVC-MB) (calculated as the product of lesional MVP and lesional PVC-SUV), and whole body metabolic burden (WBMB) (calculated as the sum of lesional PVC-MB of all lesions). This global disease assessment, we believe, will be the way forward for assessing this malignancy with a non-invasive imaging modality.