Evaluation of sentinel lymph node localization in malignant melanoma by preoperative semiconductor gamma camera and planar lymphoscintigraphy.

INTRODUCTION: Performing lymphoscintigraphy in a separate room, frees up the conventional gamma camera, coupled with the desire to directly localize sentinel lymph nodes (SLN) in the operating theatre has led to the development of high-resolution semiconductor-detector based handheld gamma-cameras, CrystalCam. METHODS: This work consists of phantom and clinical studies. For the first part, a Jaszczak phantom with hollow spheres of various volumes were filled with the 99m Tc and the camera's sensitivity was measured at various distances to assess the possibilities and limitations of the device. The clinical study evaluates the effectiveness of CrystalCam in localizing SLN in 40 consecutive malignant melanoma patients compared to both conventional planar lymphoscintigraphy and hybrid SPECT/CT. SLNs detected by planar lymphoscintigraphy were marked on the patients' skin using a UV-marker. CrystalCam images were acquired in another room by another examiner and the SLNs were marked with a felt pen. The detected nodes by both camera systems were evaluated using UV-lamp and normal light to visualize the UV- and felt pen marks respectively. The concordance rate of the SLNs and higher-echelon nodes localized by both planar scintigraphy and CrystalCam imaging with respect to the total SLNs and higher-echelon nodes detected by SPECT/CT imaging are compared and statistically analyzed. RESULTS: The results of the phantom study show a good correlation between activity and count-rates for all distancesSPECT/CT, CrystalCamm, and planar lymphoscintigraphy detected 69, 58, and 61 SLNs respectively. The concordance rate of 95.65% by the CrystalCam and planar scintigraphy implies both cameras are statistically coequal in preoperative SLN detection of malignant melanoma. For the higher-echelon nodes, SPECT/CT, planar and CrystalCam imaging systems identified 82, 48, and 13 respectively; thus, CrystalCam was statistically inferior to planar imaging. CONCLUSION: The handheld CrystalCam is a reliable instrument for localizing SLNs in surgical centers without an on-site nuclear medicine department.

The future of radiosynoviorthesis: bright or bleak?

Radiosynoviorthesis (RSO) is a decades known, effective intra-articular nuclear medicine local therapy, with few rare side-effects, in which inflamed synovial membrane is treated by means of colloidal beta-emitters. There are major variations worldwide in terms of acceptance, frequency of use and approved indications for this procedure. Thus, reliable figures that reflect reality are only available for a few countries. A Europe-wide survey revealed that RSO is carried out most frequently in Germany, where RSO is the most common nuclear medicine therapy with about 70,000 joints treated per year. The main indications include synovitis due to rheumatoid arthritis, hemophilia and pigmented villonodular synovitis (PVNS), and depending on national approvals, osteoarthritis. Despite the many indications, there are very few published scientific studies and therefore, RSO evidence is lacking. Reliable data on the clinical usage of RSO and demographics of RSO specialists are only available in Germany, thus we discuss the future challenges of RSO mainly from a German perspective. In the German healthcare system, RSO is performed primarily on an outpatient basis and plays only a minor role in the university setting. The necessary expertise for RSO is therefore lacking, for the most part, at university training centers. Currently, nearly more than three quarters of the German RSO experts are over fifty years old, illustrating a shortage of young talent. In the future, RSO providers from the non-university or private sector will have to cooperate with universities through networks and will have to intensify their cooperation with referring physicians, such as rheumatologist and orthopedic surgeons, and patients in order to maintain a timely and beneficial exchange of information. In networks of RSO experts, the participants must jointly develop and establish training concepts and facilities for future talents, elaborate on guidelines, if clinically useful expand the range of indications, initiate studies to generate further evidence and finally make the procedure more public. In addition, it is worthwhile to apply this process beyond human medicine to other fields, such as medical physics and veterinary medicine. If these points are implemented, the future of RSO will be bright, if it fails, it looks bleak.

Pre- and intratherapeutic predictors of overall survival in patients with advanced metastasized castration-resistant prostate cancer receiving Lu-177-PSMA-617 radioligand therapy.

BACKGROUND: Systemic Lutetium-177 prostate-specific membrane antigen-617 radioligand therapy (Lu-177-PSMA-617-RLT) is a novel treatment approach in patients suffering from metastasized castration-resistant prostate cancer. Nonetheless, a therapeutic response may fail to appear in a proportion of patients. This study aims to identify routinely obtainable pre- and intratherapeutic parameters to allow a prediction of overall survival in patients receiving Lu-177-PSMA-617 radioligand therapy. METHODS: Between January 2015 and December 2020 52 patients treated with a total of 146 cycles Lu-177-PSMA-617-RLT were retrospectively analysed in a single-center trial. The median overall survival time (OS) was compared to pre-therapeutic serological parameters, the extend of metastatic spread and previously performed therapies using Kaplan-Meier estimators and multivariate Cox-regression. Bonferroni-Holm correction was performed on all statistical tests. RESULTS: The median OS of all patients was 55.6 weeks. Multivariate Cox-regression revealed significant lower survival for decreased pretherapeutic hemoglobin levels (HR 0.698 per g/dl; 95%-CI 0.560-0.872; p = 0.001), increased lactate dehydrogenase (LDH) levels (HR 1.073 per 25 U/l; 95%-CI 1.024-1.125; p = 0.003) and the presence of hepatic metastasis (HR 6.981; 95%-CI 2.583-18.863; p < 0.001). Increased pretherapeutic c-reactive protein (CRP), alkaline phosphatase (ALP) and gamma-glutamyltransferase (GGT) levels were also associated with a shorter survival. A prostate-specific antigen decline after one therapy cycle did not significantly correlate with an increased survival. No significant relations were observed between overall survival time and other serological parameters or previously performed therapies. CONCLUSION: Pre-therapeutic hemoglobin and LDH levels, as well as the presence of hepatic metastasis are independent predictors of overall survival in patients receiving Lu-177-PSMA-617-RLT. CRP, ALP and GGT levels cloud be utilized as additional decision aids when a Lu-177-PSMA-617-RLT is intended. Trial Registration Not applicable (retrospective observational study).

Photopharmacological Applications for Cherenkov Radiation Generated by Clinically Used Radionuclides.

Translational photopharmacological applications are limited through irradiation by light showing wavelengths within the bio-optical window. To achieve sufficient tissue penetration, using wavelengths >500 nm is mandatory. Nevertheless, the majority of photopharmacological compounds respond to irradiation with more energetic UV light, which shows only a minor depth of tissue penetration in the µm range. Thus, we became interested in UV light containing Cherenkov radiation (CR) induced as a by-product by clinically employed radionuclides labeling specific tissues. Therefore, CR may be applicable in novel photopharmacological approaches. To provide evidence for the hypothesis, we verified the clinically established radionuclides 68Ga and 90Y but not 18F in clinically used activities to be capable of generating CR in aqueous solutions. We then investigated whether the generated CR was able to photoactivate the caged kinase inhibitor cagedAZD5438 as a photoresponsive model system. Herein, 21% uncaging of the model system cagedAZD5438 occurred by incubation with 90Y, along with a non-specific compound decomposition for 68Ga and partly for 90Y. The findings suggest that the combination of a clinically employed radionuclide with an optimized photoresponsive agent could be beneficial for highly focused photopharmacological therapies.

Vedolizumab is associated with changes in innate rather than adaptive immunity in patients with inflammatory bowel disease.

OBJECTIVE: Vedolizumab, a monoclonal antibody directed against the integrin heterodimer α4ß7, is approved for the treatment of Crohn's disease and ulcerative colitis. The efficacy of vedolizumab has been suggested to result from inhibition of intestinal T cell trafficking although human data to support this conclusion are scarce. We therefore performed a comprehensive analysis of vedolizumab-induced alterations in mucosal and systemic immunity in patients with inflammatory bowel disease (IBD), using anti-inflammatory therapy with the TNFα antibody infliximab as control. DESIGN: Immunophenotyping, immunohistochemistry, T cell receptor profiling and RNA sequencing were performed using blood and colonic biopsies from patients with IBD before and during treatment with vedolizumab (n=18) or, as control, the anti-TNFα antibody infliximab (n=20). Leucocyte trafficking in vivo was assessed using single photon emission computed tomography and endomicroscopy. RESULTS: Vedolizumab was not associated with alterations in the abundance or phenotype of lamina propria T cells and did not affect the mucosal T cell repertoire or leucocyte trafficking in vivo. Surprisingly, however, α4ß7 antibody treatment was associated with substantial effects on innate immunity including changes in macrophage populations and pronounced alterations in the expression of molecules involved in microbial sensing, chemoattraction and regulation of the innate effector response. These effects were specific to vedolizumab, not observed in response to the TNFα antibody infliximab, and associated with inhibition of intestinal inflammation. CONCLUSION: Our findings suggest that modulation of innate immunity contributes to the therapeutic efficacy of vedolizumab in IBD. TRIAL REGISTRATION NUMBER: NCT02694588.

The Hypothalamic-Pituitary-Adrenal Axis and Serotonin Metabolism in Individual Brain Nuclei of Mice with Genetic Disruption of the NK1 Receptor Exposed to Acute Stress.

Mice lacking the substance P (SP) neurokinin-1 (NK1) receptor (NK1R-/-mice) were used to investigate whether SP affects serotonin (5-HT) function in the brain and to assess the effects of acute immobilisation stress on the hypothalamic-pituitary-adrenocortical (HPA) axis and 5-HT turnover in individual brain nuclei. Basal HPA activity and the expression of hypothalamic corticotropin-releasing hormone (CRH) in wild-type (WT)- and NK1R-/- mice were identical. Stress-induced increases in plasma ACTH concentration were considerably higher in NK1R-/- mice than in WT mice while corticosterone concentrations were equally elevated in both mouse lines. Acute stress did not alter the expression of CRH. In the dorsal raphe nucleus (DRN), basal 5-HT turnover was increased in NK1R-/- mice and a 15 min stress further magnified 5-HT utilisation in this region. In the frontoparietal cortex, medial prefrontal cortex, central nucleus of amygdala, and the hippocampal CA1 region, stress increased 5-HT and/or 5-hydroxyindoleacetic acid (5-HIAA) concentrations to a similar extent in WT and NK1R-/- mice. 5-HT turnover in the hypothalamic paraventricular nucleus was not affected by stress, but stress induced similar increases in 5-HT and 5-HIAA in the ventromedial and dorsomedial hypothalamic nuclei in WT and NK1R-/- mice. Our findings indicate that NK1 receptor activation suppresses ACTH release during acute stress but does not exert sustained inhibition of the HPA axis. Genetic deletion of the NK1 receptor accelerates 5-HT turnover in DRN under basal and stress conditions. No differences between the responses of serotonergic system to acute stress in WT and NK1R-/- mice occur in forebrain nuclei linked to the regulation of anxiety and neuroendocrine stress responses.

Value and efficiency of sentinel lymph node diagnostics in patients with penile carcinoma with palpable inguinal lymph nodes as a new multimodal, minimally invasive approach.

PURPOSE: The international guidelines recommend sentinel lymph node biopsy (SLNB) for lymph node staging in penile cancer with non-palpable inguinal lymph nodes (LN) but it is not recommended with palpable inguinal LN. The aim of this study was to evaluate the reliability and morbidity of SLNB in combination with an ultrasound-guided resection of suspect inguinal LNs as a new multimodal, minimally invasive staging approach in these patients. METHODS: We performed SLNB in 26 penile cancer patients with 42 palpable inguinal LNs. Prior to the combined staging procedures the patients underwent an ultrasound examination of the groins as well as planar lymphatic drainage scintigraphy and SPECT/CT scans. During the surgical procedure, the radioactive-labelled sentinel lymph nodes and, in addition, sonographically suspect LNs, were resected under ultrasound guidance. Follow-up screening was done by ultrasound examination of the groins according to the guidelines of the European Association of Urology. RESULTS: Nineteen groins of 42 preoperatively palpable inguinal findings were histologically tumor-positive. SLNB alone showed lymphogenic metastases in 14 groins. Sonography revealed five further metastatic groins, which would not have been detected during SLNB due to a tumor-related blockage of lymphatic drainage or a so-called re-routing of the tracer. During follow-up, none of the 28 groins with tumor-negative LN status showed any LN recurrence in this combined investigation technique. The median follow-up period was 46 (24 to 92) months. Morbidity of this procedure was low at 4.76 % in relation to the number of groins resp. 7.69 % in relation to the number of patients. CONCLUSIONS: The results show that this combined procedure is a reliable multimodal diagnostic approach for treatment of penile cancer patients with palpable inguinal LNs. It is associated with low morbidity rates. SLNB alone would lead to a significantly higher false-negative rate in these patients. The encouraging results of this work can extend the range of indications for nuclear medicine in the form of SLNB using radioactive tracers in this patient group.

10-Year experience regarding the reliability and morbidity of radio guided lymph node biopsy in penile cancer patients and the associated radiation exposure of medical staff in this procedure.

BACKGROUND: The guidelines of the European Association of Urologists (EAU), of the German Society of Nuclear Medicine (DGN), and the European Society for Medical Oncology (ESMO) recommend sentinel lymph node biopsy (SLNB) for lymph node staging in penile cancer with non-palpable inguinal lymph nodes as one diagnostic method. Despite this, the method is neither widely nor regularly applied in Germany - the same applies to many other countries, which may be due to insecurity in dealing with open radioactive tracers. This study aims to assess the reliability and morbidity of this method, as well as the associated radioactive burden for clinical staff. METHODS: Between 2006 and 2016, 34 patients with an invasive penile carcinoma and inconspicuous inguinal lymph node status underwent SLNB in 57 groins after application of a radiotracer (Tc-99 m nanocolloid). We collected the results prospectively. The reliability of the method was assessed by determining the false-negative rate. In addition, we evaluated complication rates and determined the radioactive burden for the clinical staff both pre- and intraoperatively. RESULTS: SLNB was performed in 34 patients with penile cancer with non-palpable inguinal lymph nodes in 57 groins. In two patients inguinal lymph node metastases were detected by means of SLNB. In one patient recurrent inguinal lymph node disease was found after negative SLNB in both groins. Thus, the false negative rate was 3.13 % per patient (1/32 patients) and 3.51 % per groin (2/57 groins). The morbidity rate was 2.94 % per patient (1/34 patients) and 1.75 % per groin (1/57 groins). Radiation exposure for the clinical staff during this procedure was low at a maximum of ca. four µSV per intervention. CONCLUSIONS: SLNB is a reliable method with low morbidity that is associated with a low radiation burden for clinical staff. Due to the enhanced methodological and logistic demands, this intervention should be performed in specialized centres and in an interdisciplinary approach.

Effective method of measuring the radioactivity of [ 131I]-capsule prior to radioiodine therapy with significant reduction of the radiation exposure to the medical staff.

Radiation Protection in Radiology, Nuclear Medicine and Radio Oncology is of the utmost importance. Radioiodine therapy is a frequently used and effective method for the treatment of thyroid disease. Prior to each therapy the radioactivity of the [131I]-capsule must be determined to prevent misadministration. This leads to a significant radiation exposure to the staff. We describe an alternative method, allowing a considerable reduction of the radiation exposure. Two [131I]-capsules (A01 = 2818.5; A02 = 7355.0 MBq) were measured multiple times in their own delivery lead containers - that is to say, [131I]-capsules remain inside the containers during the measurements (shielded measurement) using a dose calibrator and a well-type and a thyroid uptake probe. The results of the shielded measurements were correlated linearly with the [131I]-capsules radioactivity to create calibration curves for the used devices. Additional radioactivity measurements of 50 [131I]-capsules of different radioactivities were done to validate the shielded measuring method. The personal skin dose rate (HP(0.07)) was determined using calibrated thermo luminescent dosimeters. The determination coefficients for the calibration curves were R2 > 0.9980 for all devices. The relative uncertainty of the shielded measurement was < 6.8%. At a distance of 10 cm from the unshielded capsule the HP(0.07) was 46.18 µSv/(GBq•s), and on the surface of the lead container containing the [131I]-capsule the HP(0.07) was 2.99 and 0.27 µSv/(GBq•s) for the two used container sizes. The calculated reduction of the effective dose by using the shielded measuring method was, depending on the used container size, 74.0% and 97.4%, compared to the measurement of the unshielded [131I]-capsule using a dose calibrator. The measured reduction of the effective radiation dose in the practice was 56.6% and 94.9 for size I and size II containers. The shielded [131I]-capsule measurement reduces the radiation exposure to the staff significantly and offers the same accuracy of the unshielded measurement in the same amount of time. In order to maintain the consistency of the measuring method, monthly tests have to be done by measuring a [131I]-capsule with known radioactivity.

Activation of intracellular angiotensin AT2 receptors induces rapid cell death in human uterine leiomyosarcoma cells.

The presence of angiotensin type 2 (AT2) receptors in mitochondria and their role in NO generation and cell aging were recently demonstrated in various human and mouse non-tumour cells. We investigated the intracellular distribution of AT2 receptors including their presence in mitochondria and their role in the induction of apoptosis and cell death in cultured human uterine leiomyosarcoma (SK-UT-1) cells and control human uterine smooth muscle cells (HutSMC). The intracellular levels of the AT2 receptor are low in proliferating SK-UT-1 cells but the receptor is substantially up-regulated in quiescent SK-UT-1 cells with high densities in mitochondria. Activation of the cell membrane AT2 receptors by a concomitant treatment with angiotensin II and the AT1 receptor antagonist, losartan, induces apoptosis but does not affect the rate of cell death. We demonstrate for the first time that the high-affinity, non-peptide AT2 receptor agonist, Compound 21 (C21), penetrates the cell membrane of quiescent SK-UT-1 cells, activates intracellular AT2 receptors and induces rapid cell death; approximately 70% of cells died within 24 h. The cells, which escaped cell death, displayed activation of the mitochondrial apoptotic pathway, i.e. down-regulation of the Bcl-2 protein, induction of the Bax protein and activation of caspase-3. All quiescent SK-UT-1 cells died within 5 days after treatment with a single dose of C21. C21 was devoid of cytotoxic effects in proliferating SK-UT-1 cells and in quiescent HutSMC. Our results point to a new, unique approach enabling the elimination non-cycling uterine leiomyosarcoma cells providing that they over-express the AT2 receptor.

Cutting Edge: Immunological consequences and trafficking of human regulatory macrophages administered to renal transplant recipients.

Regulatory macrophages (M regs) were administered to two living-donor renal transplant recipients. Both patients were minimized to low-dose tacrolimus monotherapy within 24 wk of transplantation and subsequently maintained excellent graft function. After central venous administration, most M regs remained viable and were seen to traffic from the pulmonary vasculature via the blood to liver, spleen, and bone marrow. By 1 y posttransplantation, both patients displayed patterns of peripheral blood gene expression converging upon the IOT-RISET signature. Furthermore, both patients maintained levels of peripheral blood FOXP3 and TOAG-1 mRNA expression within the range consistent with nonrejection. It is concluded that M regs warrant further study as a potential immune-conditioning therapy for use in solid-organ transplantation. The results of this work are being used to inform the design of The ONE Study, a multinational clinical trial of immunomodulatory cell therapy in renal transplantation.

PSMA-617 inhibits proliferation and potentiates the 177Lu-PSMA-617-induced death of human prostate cancer cells.

The human prostate-specific membrane antigen (PSMA) is substantially up-regulated in metastatic prostate cancer (PCa) cells. PSMA can be targeted by 177Lu conjugated to PSMA-617, a high-affinity ligand for the PSMA. The binding of the radioligand, 177Lu-PSMA-617, results in its internalisation and delivery of ß-radiation into the cancer cells. However, PSMA-617, a component of the final product in the synthesis of the radioligand, may also play a role in the pathophysiology of PCa cells. The present study aimed to clarify the effects of PSMA-617 (10, 50 and 100 nM) on the expression of PSMA in PSMA-positive LNCaP cells, their proliferation, 177Lu-PSMA-617-induced cell death by WST-1 and lactate dehydrogenase assays, immunohistochemistry, western blotting, immunofluorescence staining and uptake of 177Lu-PSMA-617. PSMA-617 at 100 nM concentration induced cell-growth arrest, down-regulated cyclin D1 and cyclin E1 (by 43 and 36%, respectively) and up-regulated the cyclin-dependent kinase inhibitor p21Waf1/Cip1 (by 48%). Immunofluorescence staining demonstrated reduced content of DNA, pointing to a lower rate of cell division. PSMA-617 (up to 100 nM) did not alter the uptake of 177Lu-PSMA-617 into the LNCaP cells. Interestingly, simultaneous treatment with 177Lu-PSMA-617 and PSMA-617 for 24 and 48 h substantially potentiated the cell-death promoting effects of the radioligand. In conclusion, the combination of impeding tumour cell proliferation by PSMA-617 and its potentiation of the radiation-induced cell death brought about by 177Lu-PSMA-617 in PCa cells may considerably improve the outcome of the radiation therapy with 177Lu-PSMA-617, especially in patients with decreased radiosensitivity of PCa cells to the radioligand.

Automated synthesis of [68Ga]Ga-FAPI-46 without pre-purification of the generator eluate on three common synthesis modules and two generator types.

BACKGROUND: The recent development of quinoline-based radiotracers, which act as fibroblast activation protein inhibitors (FAPIs), has shown promising preclinical and clinical advantages. [68Ga]Ga-FAPI-46 is a new radiotracer for in vivo detection of the fibroblast activation protein by positron emission tomography (PET). Recently, the automated synthesis of [68Ga]Ga-FAPI-46 was reported based on pre-concentration and purification of the generator eluate by using a cation exchange-cartridge. Our aim was to simplify the synthesis and shorten the automated synthesis of [68Ga]Ga-FAPI-46 to make it accessible and thus even more attractive to a broader clinical and scientific community. RESULTS: We developed and evaluated the GMP compliant automatic synthesis of [68Ga]Ga-FAPI-46 using two different 68Ge/68Ga generators (an Eckert & Ziegler, GalliaPharm generator, 1.85 GBq/50 mCi and an iThemba generator, 1.85 GBq/50 mCi) Somerset West, South Africa) and three different commercial and customized systems: the EasyOne module from Trasis; the GaSy module from Synthra with a customized synthesis template and a customized single use cassette. Additionally, the automatic synthesis of [68Ga]Ga-FAPI-46 was established on a GallElut synthesis module from Scintomics with fixed tubing. CONCLUSIONS: Independent of the synthesis modules or the generators employed we were able to complete the synthesis of [68Ga]Ga-FAPI-46 in 12 min including the process of purification and formulation. In all cases, the final products showed more than 99.5% chemical purity and the radiochemical yield reached around 92.5% (decay corrected). All quality control parameters (e.g. sterility, stability and radiochemical purity) were conform to the European Pharmacopoeia.

A simple, reliable and accurate approach for assessing [131I]-capsule activity leading to significant reduction of radiation exposure of medical staff during radioiodine therapy.

PURPOSE: According to German law, the [131I]-capsule activity has to be checked in the context of radioiodine therapy (RIT) immediately before application. The measurement leads to significant radiation exposure of the medical personnel, especially of their hands. We aimed to establish a method for estimating [131I]-capsule activity by measuring the dose rate (DR) at contact of the delivered lead closed container carrying the [131I]-capsules and to evaluate radiation exposure in comparison to conventional [131I]-capsule measurement using a dose calibrator. METHODS: DR on the surface of the closed lead container was measured at two locations and correlated linearly with the [131I]-capsule activity measured in a dose calibrator to create calibrating curves. The hand and whole body (effective) doses were determined with official dose meters during validation of our method in clinical practice. RESULTS: The determination coefficients (R2) of linear calibration curves were greater than 0.9974. The total relative uncertainty for estimating [131I]-capsule activity with our method was <±7.5% which is lower than the uncertainty of the nominal activity and quite close to the threshold limit for the maximum allowed uncertainty of ± 5% for measuring activity in radioactive drugs. The reduction of the hand dose caused by our method was 97% compared with the conventional measurements of the [131I]-capsules in a dose calibrator. CONCLUSION: Measuring DR on the surface of the closed lead containers enables the [131I]-capsules activity to be estimated simply, reliably and with sufficient accuracy leading to significant reduction of the radiation exposure for the medical staff.

[Noninvasive functional lung imaging with hyperpolarized xenon : Breakthrough for diagnostics?] / Nichtinvasive funktionelle Lungenbildgebung mit hyperpolarisiertem Xenon : Durchbruch für die Diagnostik?

BACKGROUND: Magnetic resonance imaging (MRI) is a noninvasive technique that provides excellent contrast for soft tissue organs. However, due to the low density of protons and many air-tissue junctions, its application in the lung is limited. Thus, X­ray-based methods are often used here (with the well-known disadvantages of ionizing radiation). OBJECTIVES: In this review, we discuss pulmonary MRI with hyperpolarized xenon-129 (Xe-MRI). Xe-MRI provides unique valuable insights into lung microstructure and function, including gas exchange with red blood cells-parameters not accessible by any standard clinical methods. METHODS: By magnetic labelling, i.e. hyperpolarization, the signal from xenon-129 is amplified by up to 100,000 times. In this process, electrons from rubidium are first polarized to 100% using laser light and then transferred to xenon by collisions. Then the hyperpolarized gas is brought to the patient in a bag and inhaled shortly before the MRI scan. RESULTS: Using special programming (sequences) of the MRI, the ventilation, microstructure, or gas exchange of the lungs, can be displayed in 3D. This allows, for example, quantitative visualization of ventilation defects, alveolar size, tissue gas uptake and gas transfer to the blood. CONCLUSIONS: Xe-MRI provides unique information about the state of the lung-noninvasively, in vivo and in less than a minute.

[Hyperpolarized 13C magnetic resonance imaging-a window into metabolism : High-resolution images of human metabolism]. / Hyperpolarisierte 13C­Magnetresonanztomographie ­ ein Fenster in den Stoffwechsel : Hochauflösende Darstellung des humanen Metabolismus.

CLINICAL ISSUE: Despite being one of the main pillars of modern diagnostics, magnetic resonance imaging (MRI) uses only a tiny fraction of its potential: no more than a millionth of all nuclear spins contribute to the MRI signal. In order to increase this fraction, called polarization, MRI scanners with stronger magnetic fields are being developed. However, even the most modern scanners do not exploit the potential of MRI. METHODOLOGICAL INNOVATIONS: To make full use of this potential, hyperpolarized MRI (HP-MRI) is an excellent tool: quantum mechanical tricks can be used to generate contrast agents whose nuclear spins can deliver a MRI signal that is up to a 100,000 times stronger. This signal enhancement allows imaging of in vivo processes that would be otherwise impossible to measure. It is particularly interesting to introduce these magnetically labeled nuclei into metabolic processes so that the metabolism can be investigated non-invasively and in vivo. PERFORMANCE: Small but diagnostically important changes in metabolism could be found before macroscopic tissue changes were otherwise visible. High-resolution images can be acquired within a few 100 ms, enabling metabolic monitoring in real-time. Heart, brain, and prostate are among the organs that have already been investigated in over 90 clinical trials using this emerging technology. ACHIEVEMENTS: So far, displaying tissue in a similar manner was only possible using nuclear medicine, e.g., positron emission tomography (PET) utilizing radionuclides and without resolution of various metabolic steps. A change in tumor metabolism following treatment was shown within hours in HP-MRI. These applications coupled with background information about the technology are the subject of this review.

Case Report: Arterial Wall Inflammation in Atherosclerotic Cardiovascular Disease is Reduced by Olamkicept (sgp130Fc).

Inflammation is a strong driver of atherosclerotic cardiovascular disease (ASCVD). There is a large unmet need for therapies that prevent or reduce excessive inflammation while avoiding systemic immunosuppression. We showed previously that selective inhibition of pro-inflammatory interleukin-6 (IL-6) trans-signalling by the fusion protein olamkicept (sgp130Fc) prevented and reduced experimental murine atherosclerosis in low-density lipoprotein receptor-deficient (Ldlr -/-) mice on a high-fat, high-cholesterol diet independently of low-density lipoprotein (LDL) cholesterol metabolism. Therefore, we allowed compassionate use of olamkicept (600 mg intravenously biweekly for 10 weeks) in a patient with very-high-risk ASCVD. Despite optimal LDL cholesterol under maximum tolerated lipid-lowering treatment, the patient had a remaining very high risk for future cardiovascular events related to significant arterial wall inflammation with lipoprotein (a) [Lp(a)]-cholesterol as the main contributor. 18Fluorodeoxyglucose positron emission tomography/computed tomography (18FDG PET/CT) measurements were performed before and after the treatment period. Olamkicept reduced arterial wall inflammation in this patient without interfering with lipoprotein metabolism. No clinical or laboratory side effects were observed during or after treatment with olamkicept. Our findings in this patient matched the results from our mechanistic study in Ldlr -/- mice, which were extended by additional analyses on vascular inflammation. Olamkicept may be a promising option for treating ASCVD independently of LDL cholesterol metabolism. A Phase II trial of olamkicept in ASCVD is currently being prepared.

Pulmonary functional imaging: qualitative comparison of Fourier decomposition MR imaging with SPECT/CT in porcine lung.

PURPOSE: To compare unenhanced lung ventilation-weighted (VW) and perfusion-weighted (QW) imaging based on Fourier decomposition (FD) magnetic resonance (MR) imaging with the clinical reference standard single photon emission computed tomography (SPECT)/computed tomography (CT) in an animal experiment. MATERIALS AND METHODS: The study was approved by the local animal care committee. Lung ventilation and perfusion was assessed in seven anesthetized pigs by using a 1.5-T MR imager and SPECT/CT. For time-resolved FD MR imaging, sets of lung images were acquired by using an untriggered two-dimensional balanced steady-state free precession sequence (repetition time, 1.9 msec; echo time, 0.8 msec; acquisition time per image, 118 msec; acquisition rate, 3.33 images per second; flip angle, 75°; section thickness, 12 mm; matrix, 128 × 128). Breathing displacement was corrected with nonrigid image registration. Parenchymal signal intensity was analyzed pixelwise with FD to separate periodic changes of proton density induced by respiration and periodic changes of blood flow. Spectral lines representing respiratory and cardiac frequencies were integrated to calculate VW and QW images. Ventilation and perfusion SPECT was performed after inhalation of dispersed technetium 99m ((99m)Tc) and injection of (99m)Tc-labeled macroaggregated albumin. FD MR imaging and SPECT data were independently analyzed by two physicians in consensus. A regional statistical analysis of homogeneity and pathologic signal changes was performed. RESULTS: Images acquired in healthy animals by using FD MR imaging and SPECT showed a homogeneous distribution of VW and QW imaging and pulmonary ventilation and perfusion, respectively. The gravitation-dependent signal distribution of ventilation and perfusion in all animals was similarly observed at FD MR imaging and SPECT. Incidental ventilation and perfusion defects were identically visualized by using both modalities. CONCLUSION: This animal experiment demonstrated qualitative agreement in the assessment of regional lung ventilation and perfusion between contrast media-free and radiation-free FD MR imaging and conventional SPECT/CT.

Neuroprotective and antioxidative effects of pioglitazone in brain tissue adjacent to the ischemic core are mediated by PI3K/Akt and Nrf2/ARE pathways.

The present study elucidates the neuroprotective mechanisms of the PPARγ (peroxisome proliferator-activated receptor γ) agonist pioglitazone in survival of ischemic neurons following middle cerebral artery occlusion with reperfusion (MCAO). Intracerebroventricular infusion of pioglitazone over 5 days before and 24 or 48 h after MCAO alleviated neurological impairments, inhibited apoptosis 24 h, and activated the PI3K/Akt pathway along with increased phosphorylation of Akt (ser473) and GSK-3ß (ser9) in the peri-infarct cortical areas 48 h after MCAO. In primary cortical neurons, pioglitazone suppressed the glutamate-induced release of lactate dehydrogenase by a PPARγ-dependent mechanism. This protective effect was reversed after co-treatment with PI3K and Akt inhibitors, LY294002 and SH-6, respectively. Pioglitazone enhanced the expression of the antioxidative transcription factor Nrf2 and its target gene protein, heme oxidase-1, in the peri-infarct area. Pioglitazone also increased activation of the antioxidant response element (ARE) in neuronal PC12 cells transfected with the pNQO1-rARE plasmid. We demonstrate in primary cortical neurons from Nrf2 knockout mice that the lack of Nrf2 completely abolished the neuroprotective effects of pioglitazone against oxidative and excitotoxic damage. Our results strongly suggest that the neuroprotective effects of PPARγ in peri-infarct brain tissues comprise the concomitant activation of the PI3K/Akt and Nrf2/ARE pathways. KEY MESSAGES: Pioglitazone inhibits apoptosis in ischemic brain tissue.  Pioglitazone acting on PPARγ activates PI3K/Akt pathway in ischemic brain tissue. Pioglitazone activates via Nrf2 the antioxidant defense pathway in injured neurons. Pioglitazone activates the antioxidant response element in neuronal PC12 cells. Pioglitazone fails to protect primary neurons lacking Nrf2 against oxidative damage. Activation of PPARγ supports the survival of viable neurons in peri-infarct regions.

Experimental 177Lu-PSMA-617 radioligand therapy in a patient with extended metastasized leiomyosarcoma.

Systemic radionuclide therapy with 177Lu-PSMA-617 is a novel treatment option in patients with metastasized and castration-resistant prostate cancer 4. The molecular target of the 177Lu-PSMA-617 radioligand therapy is the prostate-specific membrane antigen (PSMA) highly expressed on prostate cancer cells. Beyond the enhanced accumulation of PSMA on prostate cancer cells, PSMA expression is also found on the molecular surface or in the tumor-associated neovasculature of various tumor tissues including sarcomas of the soft tissue 2. Thus, PSMA has theoretically been discussed as a possible future target for systemic radioligand therapy with 177Lu-PSMA-617 even in non-prostate malignancies 1.Here we report on a female patient with extended metastasized leiomyosarcoma experimentally treated with one application of 177Lu-PSMA-617 radioligand therapy.