Frederik L. Giesel

3D printing based on imaging data: review of medical applications

PurposeGeneration of graspable three-dimensional objects applied for surgical planning, prosthetics and related applications using 3D printing or rapid prototyping is summarized and evaluated.Materials and methodsGraspable 3D objects overcome the limitations of 3D visualizations which can only be displayed on flat screens. 3D objects can be produced based on CT or MRI volumetric medical images. Using dedicated post-processing algorithms, a spatial model can be extracted from image data sets and exported to machine-readable data. That spatial model data is utilized by special printers for generating the final rapid prototype model.ResultsPatient–clinician interaction, surgical training, medical research and education may require graspable 3D objects. The limitations of rapid prototyping include cost and complexity, as well as the need for specialized equipment and consumables such as photoresist resins.ConclusionsMedical application of rapid prototyping is feasible for specialized surgical planning and prosthetics applications and has significant potential for development of new medical applications.

Dynamic contrast-enhanced magnetic resonance imaging in oncology.

Dynamic contrast-enhanced MRI (DCE-MRI) is the acquisition of sequential images during the passage of a contrast agent within a tissue of interest. The current gadolinium chelate agents enable visualization of lesion vasculature and, due to their small size, can be used to assess vascular permeability. Recent studies demonstrated that the temporal evolution of gadolinium-induced signal intensity changes within a tumor reflects the angiogenic properties of the tumor. These can be quantified and are related to vascular density and other angiogenic characteristics of lesions, such as the level of vascular endothelial growth factor. DCE-MRI provides noninvasive characterization of antiangiogenic response of tumor during therapeutic intervention to monitor and predict response. This article reviews the fundamental pathophysiological basis of DCE-MRI and the technical aspects necessary for successful implementation DCE-MRI. The role of DCE-MRI in tumor detection, characterization, and therapy monitoring is reviewed.

Diagnostic performance of spectroscopic and perfusion MRI for distinction of brain tumors

Objective: To assess the value of spectroscopic and perfusion MRI for glioma grading and for distinguishing glioblastomas from metastases and from CNS lymphomas. Methods: The authors examined 79 consecutive patients with first detection of a brain neoplasm on nonenhanced CT scans and no therapy prior to evaluation. Spectroscopic MRI; arterial spin-labeling MRI for measuring cerebral blood flow (CBF); first-pass dynamic, susceptibility-weighted, contrast-enhanced MRI for measuring cerebral blood volume; and T1-weighted dynamic contrast-enhanced MRI were performed. Receiver operating characteristic analysis was performed, and optimum thresholds for tumor classification and glioma grading were determined. Results: Perfusion MRI had a higher diagnostic performance than spectroscopic MRI. Because of a significantly higher tumor blood flow in glioblastomas compared with CNS lymphomas, a threshold value of 1.2 for CBF provided sensitivity of 97%, specificity of 80%, positive predictive value (PPV) of 94%, and negative predictive value (NPV) of 89%. Because CBF was significantly higher in peritumoral nonenhancing T2-hyperintense regions of glioblastomas compared with metastases, a threshold value of 0.5 for CBF provided sensitivity, specificity, PPV, and NPV of 100%, 71%, 94%, and 100%. Glioblastomas had the highest tumor blood flow values among all other glioma grades. For discrimination of glioblastomas from grade 3 gliomas, sensitivity was 97%, specificity was 50%, PPV was 84%, and NPV was 86% (CBF threshold value of 1.4), and for discrimination of glioblastomas from grade 2 gliomas, sensitivity was 94%, specificity was 78%, PPV was 94%, and NPV was 78% (CBF threshold value of 1.6). Conclusion: Perfusion MRI is predictive in distinguishing glioblastomas from metastases, CNS lymphomas and other gliomas vs MRI and magnetic resonance spectroscopy.

Influence of human serum albumin on longitudinal and transverse relaxation rates (r1 and r2) of magnetic resonance contrast agents.

Objectives:Exogenous magnetic resonance (MR) contrast media (CM) are used to improve detection and delineation of physiological and pathologic structures. Temporary binding between CM and proteins such as human serum albumin (HSA) may alter the relaxation-enhancing properties of specific contrast agents. In this study, the presence and strength of HSA interaction with different CM was investigated. Material and Methods:Three contrast agents were chosen: Gd-DTPA, Gd-BT-DO3A, and Gd-BOPTA, each of which is known to have a different protein interaction. Samples were prepared using 7 different HSA concentrations, all at a constant CM concentration of 0.5 mmol/L. The relaxation rates, R1 and R2, of each sample were measured at 1.5 T. Virtual docking studies were performed to estimate the number of high affinity-binding sites of Gd-BOPTA and the surface of the HSA dimer. Results:Gd-BOPTA caused the greatest increase in R1 and R2, which followed an exponential dependency with increasing HSA concentration. Between the range of 0 and 7 g/dL of HSA, Gd-DTPA and Gd-BT-DO3A showed a relative change in both relaxation rates of approximately 13% and 22% for R1 and 26% and 30% for R2, respectively. In contrast, Gd-BOPTA demonstrated a relative increase of approximately 108% and 363% for R1 and R2, respectively. Changes of HSA concentration within physiological range (3.5–5.5 g/dL) resulted in an increase of R1 and R2 of approximately 40% when using Gd-BOPTA. The docking study revealed that approximately 10 small hydrophobic pockets exist on the HSA surface where the aromatic tail of Gd-BOPTA can fit in and a stronger noncovalent binding can occur compared with Gd-DTPA and Gd-BT-DO3A. Conclusion:Relaxation rates of Gd-BOPTA showed a strong dependency on HSA. In contrast, Gd-DTPA and Gd-BT-DO3A demonstrated little or no relevant dependency. On the basis of these results, the influence of serum protein concentration should be considered in both research studies and in clinical use.

The Theranostic PSMA Ligand PSMA-617 in the Diagnosis of Prostate Cancer by PET/CT: Biodistribution in Humans, Radiation Dosimetry, and First Evaluation of Tumor Lesions

PET imaging with the prostate-specific membrane antigen (PSMA)–targeted radioligand 68Ga-PSMA-11 is regarded as a significant step forward in the diagnosis of prostate cancer (PCa). More recently, a PSMA ligand was developed that can be labeled with 68Ga, 111In, 177Lu, and 90Y. This ligand, named PSMA-617, therefore enables both diagnosis and therapy of PCa. The aims of this evaluation were to clinically investigate the distribution of 68Ga-PSMA-617 in normal tissues and in PCa lesions as well as to evaluate the radiation exposure by the radioligand in PET imaging. Methods: Nineteen patients, most of them with recurrent PCa, were referred for 68Ga-PSMA-617 PET/CT. The quantitative assessment of tracer uptake of several organs and of 53 representative tumor lesions was performed in 15 patients at 1 and 3 h after injection. In 4 additional patients, the same procedure was conducted at 5 min, 1 h, 2 h, 3 h, 4 h, and 5 h after injection. On the basis of the data for these 4 patients (mean injected dose, 231 MBq), the radiation exposure of a 68Ga-PSMA-617 PET/CT was identified. Results: Intense tracer uptake was observed in the kidneys and salivary glands. In 14 of 19 patients (73.7%), at least 1 lesion suspected of being a tumor was detected at 3 h after injection. Of 53 representative tumor lesions selected at 3 h after injection, 47 lesions were visible at 1 h after injection. The mean tumor-to-background ratio for maximum standardized uptake value was 20.4 ± 17.3 (range, 2.3–84.0) at 1 h after injection and 38.2 ± 38.6 (range, 3.6–154.3) at 3 h after injection. The average radiation exposure (effective dose) was approximately 0.021 mSv/MBq. Conclusion: Within healthy organs, the kidneys and salivary glands showed the highest 68Ga-PSMA-617 uptake. The radiation exposure was relatively low. 68Ga-PSMA-617 shows PCa lesions with high contrast. Images obtained between 2 and 3 h after injection seem to be the best option with regard to radiotracer uptake and tumor contrast. Later images can help to clarify unclear lesions.

Contrast‐enhanced MR angiography of the run‐off vasculature: Intraindividual comparison of gadobenate dimeglumine with gadopentetate dimeglumine

To compare intraindividually gadobenate dimeglumine (Gd‐BOPTA) with gadopentetate dimeglumine (Gd‐DTPA) for multi‐station MR Angiography of the run‐off vessels.

PSMA-Targeted Radionuclide Therapy of Metastatic Castration-Resistant Prostate Cancer with 177Lu-Labeled PSMA-617

Prostate-specific membrane antigen (PSMA) is an excellent target for radionuclide therapy of metastasized castration-resistant prostate cancer (mCRPC). Besides high affinity and long tumor retention, the DOTA-conjugated ligand PSMA-617 has low kidney uptake, making it an excellent choice for therapeutic application. We retrospectively report our experience with 177Lu-PSMA-617–targeted radionuclide therapy in a case series of mCRPC patients resistant to other treatments. Methods: Patients with PSMA-positive tumor phenotypes were selected by molecular imaging. Thirty patients received 1–3 cycles of 177Lu-PSMA-617. During therapy, pharmacokinetics and radiation dosimetry were evaluated. Blood cell count was checked every 2 wk after the first and every 4 wk after succeeding cycles. Prostate-specific antigen (PSA) was determined every 4 wk. Radiologic restaging was performed after 3 cycles. Results: Twenty-one of 30 patients had a PSA response; in 13 of 30 the PSA decreased more than 50%. After 3 cycles, 8 of 11 patients achieved a sustained PSA response (>50%) for over 24 wk, which also correlated with radiologic response (decreased lesion number and size). Normally, acute hematotoxicity was mild. Diffuse bone marrow involvement was a risk factor for higher grade myelosuppression but could be identified by PSMA imaging in advance. Xerostomia, nausea, and fatigue occurred sporadically (<10%). Clearance of non–tumor-bound tracer was predominantly renal and widely completed by 48 h. Safety dosimetry revealed kidney doses of approximately 0.75 Gy/GBq, red marrow doses of 0.03 Gy/GBq, and salivary gland doses of 1.4 Gy/GBq, irrespective of tumor burden and consistent on subsequent cycles. Mean tumor-absorbed dose ranged from 6 to 22 Gy/GBq during cycle 1. Conclusion: 177Lu-PSMA-617 is a promising new option for therapy of mCRPC and deserves more attention in larger prospective trials.

225Ac-PSMA-617 for PSMA-Targeted α-Radiation Therapy of Metastatic Castration-Resistant Prostate Cancer

Prostate-specific membrane antigen (PSMA) is a promising target in prostate cancer. Recently, we started the first-in-human treatment with an α-radionuclide–labeled PSMA ligand. Although the case series is still ongoing, we here report in advance about two patients in highly challenging clinical situations who showed a complete response to 225Ac-PSMA-617 therapy. Methods: 68Ga-PSMA-11 PET/CT validated the presence of the PSMA-positive tumor phenotype. A 100-kBq activity of 225Ac-PSMA-617 per kilogram of body weight was administered bimonthly. Prostate-specific antigen response and hematologic toxicity were measured at least every 4 wk. Restaging was performed with 68Ga-PSMA-11 PET/CT. Results: Both patients experienced a prostate-specific antigen decline to below the measurable level and showed a complete response on imaging. No relevant hematologic toxicity was observed. Xerostomia was the only mentionable clinical side effect. Conclusion: Targeted α-therapy with 225Ac-PSMA-617, although still experimental, obviously has strong potential to significantly benefit advanced-stage prostate cancer patients.

Hippocampal volume and 2-year outcome in depression

Although the hippocampus has been found to be smaller in people with depression, the clinical relevance of this is unclear. We investigated hippocampal volume (using high-resolution magnetic resonance imaging) and 2-year outcome in 57 patients with major depression. The left and right hippocampal volumes of patients with a depression relapse were significantly smaller than those of healthy controls. Our results support the hypothesis that the hippocampus is crucial in the outcome of depression.

[177Lu]Lutetium-labelled PSMA ligand-induced remission in a patient with metastatic prostate cancer

The prostate-specific membrane antigen (PSMA) shows intense overexpression in the majority of prostate cancers (PCa) [1]. A Glu-urea-Lys motif has been found to bind with high affinity to the catalytic domain of PSMA [2]. Following conjugation to the chelator HBED-CC, a Ga-labelled PSMA ligand (Ga-DKFZ-11) has been derived as a novel PET tracer [3]. Since PSMA is internalized after binding of a ligand [4], it is also an excellent target for systemic radionuclide therapy. Consequently, a I-labelled PSMA ligand (I-MIP-1095) demonstrated favourable tumour-targeting properties and promising antitumour efficacy [5]. However, clinical application of I causes a high radiation burden and is hampered by complex regulations in most countries. Therefore, Lu is considered to be preferable for targeted radionuclide therapy. The novel theranostic drug Lu-DKFZ-617 is a DOTA derivative of the Glu-urea-Lys motif. The chelator is conjugated via an aromatic linker that further improves tumour accumulation while simultaneously reducing kidney uptake. The image presented here shows a patient with metastatic PCa. PSMA PET/CT (a) demonstrates a tumour phenotype with strong PSMA expression. The patient was treated with a cumulative activity of 7.4 GBq Lu-DKFZ-617 (b, c). Restaging with PSMA PET/CT (d) reveals a striking radiological response. In addition the PSA level decreased from 38.0 to 4.6 ng/ml. Patient stratification by means of PSMA imaging and subsequent treatment with a therapeutic PSMA-targeted