Johannes Schwenck

In vivo visualization of prostate-specific membrane antigen in glioblastoma

The expansion of nutrient vessels is an important factor in the growth of glioblastomas (GBM), which is one of the most vascularized tumours [1]. Therefore, new treatment concepts that include tumour vasculature targets are currently under investigation. Prostate-specific membrane antigen (PSMA) is overexpressed in the tumour vasculature of GBM, which therefore might be considered as a potential endothelial target for treatment with PSMA-based agents [2, 3]. However, according to the limited data so far available, PSMA expression in brain tumours varies with glioma grade [4]. PSMAexpressionwas evaluated in a patient suffering fromGBM prior to surgery by simultaneous PET/MR with [Ga]

Preclinical and Translational PET/MR Imaging

Combined PET and MR imaging (PET/MR imaging) has progressed tremendously in recent years. The focus of current research has shifted from technologic challenges to the application of this new multimodal imaging technology in the areas of oncology, cardiology, neurology, and infectious diseases. This article reviews studies in preclinical and clinical translation. The common theme of these initial results is the complementary nature of combined PET/MR imaging that often provides additional insights into biologic systems that were not clearly feasible with just one modality alone. However, in vivo findings require ex vivo validation. Combined PET/MR imaging also triggers a multitude of new developments in image analysis that are aimed at merging and using multimodal information that ranges from better tumor characterization to analysis of metabolic brain networks. The combination of connectomics information that maps brain networks derived from multiparametric MR data with metabolic information from PET can even lead to the formation of a new research field that we would call cometomics that would map functional and metabolic brain networks. These new methodologic developments also call for more multidisciplinarity in the field of molecular imaging, in which close interaction and training among clinicians and a variety of scientists is needed.

Decoding Intratumoral Heterogeneity of Breast Cancer by Multiparametric In Vivo Imaging: A Translational Study

Differential diagnosis and therapy of heterogeneous breast tumors poses a major clinical challenge. To address the need for a comprehensive, noninvasive strategy to define the molecular and functional profiles of tumors in vivo, we investigated a novel combination of metabolic PET and diffusion-weighted (DW)-MRI in the polyoma virus middle T antigen transgenic mouse model of breast cancer. The implementation of a voxelwise analysis for the clustering of intra- and intertumoral heterogeneity in this model resulted in a multiparametric profile based on [(18)F]Fluorodeoxyglucose ([(18)F]FDG)-PET and DW-MRI, which identified three distinct tumor phenotypes in vivo, including solid acinar, and solid nodular malignancies as well as cystic hyperplasia. To evaluate the feasibility of this approach for clinical use, we examined estrogen receptor-positive and progesterone receptor-positive breast tumors from five patient cases using DW-MRI and [(18)F]FDG-PET in a simultaneous PET/MRI system. The postsurgical in vivo PET/MRI data were correlated to whole-slide histology using the latter traditional diagnostic standard to define phenotype. By this approach, we showed how molecular, structural (microscopic, anatomic), and functional information could be simultaneously obtained noninvasively to identify precancerous and malignant subtypes within heterogeneous tumors. Combined with an automatized analysis, our results suggest that multiparametric molecular and functional imaging may be capable of providing comprehensive tumor profiling for noninvasive cancer diagnostics. Cancer Res; 76(18); 5512-22. ©2016 AACR.

PET/MRI Hybrid Systems

Over the last decade, the combination of PET and MRI in one system has proven to be highly successful in basic preclinical research, as well as in clinical research. Nowadays, PET/MRI systems are well established in preclinical imaging and are progressing into clinical applications to provide further insights into specific diseases, therapeutic assessments, and biological pathways. Certain challenges in terms of hardware had to be resolved concurrently with the development of new techniques to be able to reach the full potential of both combined techniques. This review provides an overview of these challenges and describes the opportunities that simultaneous PET/MRI systems can exploit in comparison with stand-alone or other combined hybrid systems. New approaches were developed for simultaneous PET/MRI systems to correct for attenuation of 511 keV photons because MRI does not provide direct information on gamma photon attenuation properties. Furthermore, new algorithms to correct for motion were developed, because MRI can accurately detect motion with high temporal resolution. The additional information gained by the MRI can be employed to correct for partial volume effects as well. The development of new detector designs in combination with fast-decaying scintillator crystal materials enabled time-of-flight detection and incorporation in the reconstruction algorithms. Furthermore, this review lists the currently commercially available systems both for preclinical and clinical imaging and provides an overview of applications in both fields. In this regard, special emphasis has been placed on data analysis and the potential for both modalities to evolve with advanced image analysis tools, such as cluster analysis and machine learning.

Non-invasive In Vivo Fluorescence Optical Imaging of Inflammatory MMP Activity Using an Activatable Fluorescent Imaging Agent

This paper describes a non-invasive method for imaging matrix metalloproteinases (MMP)-activity by an activatable fluorescent probe, via in vivo fluorescence optical imaging (OI), in two different mouse models of inflammation: a rheumatoid arthritis (RA) and a contact hypersensitivity reaction (CHR) model. Light with a wavelength in the near infrared (NIR) window (650 - 950 nm) allows a deeper tissue penetration and minimal signal absorption compared to wavelengths below 650 nm. The major advantages using fluorescence OI is that it is cheap, fast and easy to implement in different animal models. Activatable fluorescent probes are optically silent in their inactivated states, but become highly fluorescent when activated by a protease. Activated MMPs lead to tissue destruction and play an important role for disease progression in delayed-type hypersensitivity reactions (DTHRs) such as RA and CHR. Furthermore, MMPs are the key proteases for cartilage and bone degradation and are induced by macrophages, fibroblasts and chondrocytes in response to pro-inflammatory cytokines. Here we use a probe that is activated by the key MMPs like MMP-2, -3, -9 and -13 and describe an imaging protocol for near infrared fluorescence OI of MMP activity in RA and control mice 6 days after disease induction as well as in mice with acute (1x challenge) and chronic (5x challenge) CHR on the right ear compared to healthy ears.

In Vivo Optical Imaging of Matrix Metalloproteinase Activity Detects Acute and Chronic Contact Hypersensitivity Reactions and Enables Monitoring of the Antiinflammatory Effects of N-Acetylcysteine

The aim of this study was to determine whether the severity of contact hypersensitivity reactions (CHSRs) can be observed by noninvasive in vivo optical imaging of matrix metalloproteinase (MMP) activity and whether this is an appropriate tool for monitoring an antiinflammatory effect. Acute and chronic CHSRs were elicited by application of a 1% trinitrochlorobenzene (TNCB) solution for up to five times on the right ear of TNCB-sensitized mice. N-Acetylcysteine (NAC)-treated and sham-treated mice were monitored by measuring ear swelling and optical imaging of MMP activity. In addition, we performed hematoxylin-eosin staining and CD31 immunohistochemistry for histopathologic analysis of the antiinflammatory effects of NAC. The ear thickness and the MMP activity increased in line with the increasing severity of the CHSR. MMP activity was enhanced 2.5- to 2.7-fold during acute CHSR and 3.1- to 4.1-fold during chronic CHSR. NAC suppressed ear swelling and MMP signal intensity in mice with acute and chronic CHSR. During chronic CHSR, the vessel density was significantly reduced in ear sections derived from NAC-treated compared to sham-treated mice. In vivo optical imaging of MMP activity measures acute and chronic CHSR and is useful to monitor antiinflammatory effects.The aim of this study was to determine whether the severity of contact hypersensitivity reactions (CHSRs) can be observed by noninvasive in vivo optical imaging of matrix metalloproteinase (MMP) activity and whether this is an appropriate tool for monitoring an antiinflammatory effect. Acute and chronic CHSRs were elicited by application of a 1% trinitrochlorobenzene (TNCB) solution for up to five times on the right ear of TNCB-sensitized mice. N-Acetylcysteine (NAC)-treated and sham-treated mice were monitored by measuring ear swelling and optical imaging of MMP activity. In addition, we performed hematoxylin-eosin staining and CD31 immunohistochemistry for histopathologic analysis of the antiinflammatory effects of NAC. The ear thickness and the MMP activity increased in line with the increasing severity of the CHSR. MMP activity was enhanced 2.5- to 2.7-fold during acute CHSR and 3.1- to 4.1-fold during chronic CHSR. NAC suppressed ear swelling and MMP signal intensity in mice with acute and chronic CHSR. During chronic CHSR, the vessel density was significantly reduced in ear sections derived from NAC-treated compared to sham-treated mice. In vivo optical imaging of MMP activity measures acute and chronic CHSR and is useful to monitor antiinflammatory effects.

Comparative immuno-Cerenkov luminescence and -PET imaging enables detection of PSMA+ tumors in mice using 64Cu-radiolabeled monoclonal antibodies

Here, we describe immuno-Cerenkov luminescence imaging (immuno-CLI) with a specific monoclonal antibody-based tracer for the detection of prostate tumors, which is used in preclinical positron emission tomography (PET) imaging. As PET isotopes generate a continuous spectrum of light in the ultraviolet/visible (UV/vis) wavelength range (Cerenkov luminescence, CL) in dielectric materials and consequently inside living tissues, these isotopes can also be detected by luminescence imaging performed with optical imaging (OI) systems. Imaging tumors with tracers that are specifically binding to a tumor-associated antigen can increase diagnostic accuracy, enables monitoring of treatment efficacy, and can be advantageous compared to radiolabeled small molecules used in PET-oncology such as 2-deoxy-2-[18F]-fluoro-D-glucose ([18F]FDG; glucose metabolism) or [11C]choline (membrane synthesis) which was used to image prostate cancer. In this study, we compared on three consecutive days immuno-CLI and -PET of the applied 64Cu-labeled and well described monoclonal antibody 3/F11 in prostate-specific membrane antigen (PSMA)-positive (C4-2, PSMA+) and -negative (DU 145, PSMA-) prostate tumor xenografts, inoculated in SCID mice. In vivo immuno-CLI and -PET measurements demonstrated linear correlation of both modalities, in line with ex vivo analysis performed with CLI and γ-counting. As CLI is also able to trace radioisotopes used for theranostic approaches, immuno-CLI could be an interesting, low-cost imaging alternative to immuno-PET.

Therapy response assessment with quantitative PET: evaluation of a shortened acquisition protocol with dynamic PET/CT

Purpose The results of SUV quantification for prediction of histopathological response in patients with oesophageal carcinoma show high variations with different accuracy. However, the routine use of a full dynamic PET is limited because of long acquisition times. We tested a shortened acquisition protocol for quantitative PET to overcome that limitation. Material and methods 13 patients with histopathologically proven oesophageal adenocarcinoma underwent a combined dynamic and static 18 F-FDG PET/CT including CT tumour perfusion (Siemens, Biograph mCT). Dynamic PET (listmode) was acquired for 60 min resulting in 38 frames from 10 to 600 sec duration for the full dynamic dataset and 2 frames each with 600 sec duration (20-30 min and 50-60 min p.i.) for dual time point PET (DTP). We evaluated the metabolic rate Ki using different models: 2-compartment irreversible model (Fit), Patlak plot and DTP (van den Hoff et al). The CT tumour perfusion protocol included the parameters blood flow, blood volume and permeability. Results