Birgit Meller

Pelvic lymph node dissection for nodal oligometastatic prostate cancer detected by 68Ga-PSMA-positron emission tomography/computerized tomography.

The first evaluation of pelvic extended lymph node dissection (pLND) in oligometastatic prostate cancer (PCa) detected by 68Ga‐PSMA PET/CT.

Comparative Analysis of the Effects of Neurotrophic Factors CDNF and GDNF in a Nonhuman Primate Model of Parkinson's Disease

Cerebral dopamine neurotrophic factor (CDNF) belongs to a newly discovered family of evolutionarily conserved neurotrophic factors. We demonstrate for the first time a therapeutic effect of CDNF in a unilateral 6-hydroxydopamine (6-OHDA) lesion model of Parkinson’s disease in marmoset monkeys. Furthermore, we tested the impact of high chronic doses of human recombinant CDNF on unlesioned monkeys and analyzed the amino acid sequence of marmoset CDNF. The severity of 6-OHDA lesions and treatment effects were monitored in vivo using 123I-FP-CIT (DaTSCAN) SPECT. Quantitative analysis of 123I-FP-CIT SPECT showed a significant increase of dopamine transporter binding activity in lesioned animals treated with CDNF. Glial cell line-derived neurotrophic factor (GDNF), a well-characterized and potent neurotrophic factor for dopamine neurons, served as a control in a parallel comparison with CDNF. By contrast with CDNF, only single animals responded to the treatment with GDNF, but no statistical difference was observed in the GDNF group. However, increased numbers of tyrosine hydroxylase immunoreactive neurons, observed within the lesioned caudate nucleus of GDNF-treated animals, indicate a strong bioactive potential of GDNF.

Radioactive EGFR Antibody Cetuximab in Multimodal Cancer Treatment: Stability and Synergistic Effects With Radiotherapy

PURPOSE Systemic therapies when added to whole brain radiotherapy have failed to improve the survival of patients with multiple brain metastases. The epidermal growth factor receptor antibody cetuximab is an attractive option, if it is able to cross the blood-brain barrier. This might be proven with molecular imaging if the radiolabeled antibody is stable long enough to be effective. This study investigated the stability of radiolabeled cetuximab (Erbitux) ((131)I-Erbi) and potential synergistic effects with radiotherapy in vitro. METHODS AND MATERIALS Two cell lines were investigated, A431 with numerous epidermal growth factor receptors, and JIMT without epidermal growth factor receptors. We labeled 0.4 mg cetuximab with 50 MBq of [(131)I] iodide. Stability was determined for 72 h. The cell cultures were incubated with (131)I-Erbi or cold cetuximab for 72 h. Uptake and cell proliferation were measured every 24 h after no radiotherapy or irradiation with 2, 4, or 10 Gy. RESULTS The radiolabeling yield of (131)I-Erbi was always >80%. The radiochemical purity was still 93.6% after 72 h. A431 cells showed a (131)I-Erbi uptake about 100-fold greater than the JIMT controls. After 48 h, the A431 cultures showed significantly decreased proliferation. At 72 h after irradiation, (131)I-Erbi resulted in more pronounced inhibition of cell proliferation than the cold antibody in all radiation dose groups. CONCLUSION (131)I-Erbi was stable for <or=72 h. Radiotherapy led to increased tumor cell uptake of (131)I-Erbi. Radiotherapy and (131)I-Erbi synergistically inhibited tumor cell proliferation. These results provide the prerequisite data for a planned in vivo study of whole brain radiotherapy plus cetuximab for brain metastases.

Increased Radioiodine Uptake of Thyroid Cell Cultures after External Irradiation

Background:Radioiodine uptake (RIU) is one of the main prognostic factors for curative results of radioiodine therapy in patients with differentiated thyroid cancer. Some days after application of 131I, the uptake of a subsequent administration of radioiodine was found to be reduced. In contrast, early after irradiation with high-energy photons glucose and amino acid uptake were observed to be increased. Effects of external irradiation on RIU of thyrocytes using high-energy photons have not been investigated so far.Material and Methods:Two different cell lines (FRTL-5 and ML-1 cells) derived from thyroid tissue were studied in vitro. Cell lines were either incubated with 131I only (controls) or additionally irradiated with single doses of 6 or 10 Gy of high-energy photons using a linear accelerator. Cell number and RIU were determined 24–96 h after 131I application. RIU measurements were repeated after application of sodium perchlorate in excess to investigate specificity of the uptake. Statistical analyses were performed using non-parametric tests.Results:Incubation with radioiodine as well as irradiation with high-energy photons slowed down proliferation in investigated cell lines significantly. Irradiation with solely 131I resulted in stable or slightly decreased iodide uptake. Compared to those cells, the RIU increased significantly in externally irradiated cells, i. e., additional irradiation with 10 Gy resulted in an almost threefold increase of RIU in FRTL-5 after 72 h. The increase of RIU after irradiation was dose-dependent in both cell lines and could be blocked by perchlorate excess.Conclusion:It could be demonstrated that external irradiation increases RIU in thyroid cell cultures early after irradiation. The increase was dose-dependent and specific, as it could be blocked by perchlorate. This effect appears to be similar to the increase of other actively transported substances after irradiation with high-energy photons. Therefore, the results of this study may contribute to the knowledge of a generalized irradiation-induced mechanism which causes the activation of different cellular transporters. The clinical impact of these findings on combined therapy concepts has to be investigated in further experiments.Hintergrund:Der Radioiod-Uptake (RIU) ist ein wesentlicher prognostischer Faktor für den kurativen Erfolg der Radioiodtherapie bei Patienten mit differenziertem Schilddrüsenkarzinom. Es konnte gezeigt werden, dass einige Tage nach 131I-Gabe der Uptake bei einer erneuten Radioiodapplikation deutlich vermindert war. Im Gegensatz dazu wurde eine Zunahme des Glukose- und Aminosäure-Uptakes kurz nach der Bestrahlung mit hochenergetischen Photonen beschrieben. Effekte einer externen Bestrahlung mit hochenergetischen Photonen auf den RIU von Thyreozyten sind bisher noch nicht untersucht worden.Material und Methodik:Die Untersuchungen wurden in vitro an zwei unterschiedlichen Zelllinien (FRTL-5- und ML-1-Zellen) thyreoidalen Ursprungs durchgeführt. Die Zellkulturen wurden entweder nur mit Radioiod inkubiert (Kontrollen) oder zusätzlich einzeitig mit Hilfe eines Linearbeschleunigers mit 6 oder 10 Gy bestrahlt. Die Bestimmung der Zellzahl und des RIU erfolgte 24–96 h nach der 131I-Applikation. Die Messungen wurden nach Zugabe von Natriumperchlorat im Überschuss wiederholt. Statistische Analysen erfolgten mittels nichtparametrischer Tests.Ergebnisse:Die Proliferation der untersuchten Zelllinien wurde sowohl durch die Inkubation mit Radioiod als auch durch die Bestrahlung signifikant vermindert. Die Bestrahlung mit 131I allein führte zu gleichbleibendem oder leicht vermindertem Iodid-Uptake. Verglichen mit diesen Zellen erhöhte die externe Bestrahlung den RIU signifikant. So konnte bei FRTL-5-Zellen durch die zusätzliche Bestrahlung mit 10 Gy der RIU nach 72 h beinahe verdreifacht werden. Der Anstieg des RIU nach Bestrahlung war bei beiden Zelllinien dosisabhängig und konnte durch einen Überschuss an Perchlorat blockiert werden.Schlussfolgerung:In dieser Studie konnte gezeigt werden, dass eine externe Bestrahlung mit hochenergetischen Photonen zu einem Anstieg des RIU von Schilddrüsen-Zellkulturen führt. Dieser Anstieg war dosisabhängig und spezifisch, da er durch Perchlorat geblockt werden konnte. Dieser Effekt weist Ähnlichkeiten zum Anstieg anderer aktiv transportierter Substanzen nach Bestrahlung auf. Die Ergebnisse dieser Studie liefern einen Beitrag zur Kenntnis eines generalisierten Mechanismus, welcher auf eine Aktivierung unterschiedlicher zellulärer Transporter nach Bestrahlung mit hochenergetischen Photonen hinweist. Die klinische Relevanz dieser Ergebnisse für kombinierte Therapieverfahren sollte in weiteren Untersuchungen geklärt werden.

Repeated adjuvant anti-CEA radioimmunotherapy after resection of colorectal liver metastases: Safety, feasibility, and long-term efficacy results of a prospective phase 2 study

In previous work, a single administration of anticarcinoembryonic antigen (anti‐CEA) 131I‐labetuzumab radioimmunotherapy (RIT) after complete resection of colorectal liver metastases was well tolerated and significantly improved survival compared with controls. In the current phase 2 trial, the authors studied repeated RIT in the same setting, examining safety, feasibility, and efficacy.

Radioprotective Effect of Lidocaine on Neurotransmitter Agonist-Induced Secretion in Irradiated Salivary Glands

Background Previously we verified the radioprotective effect of lidocaine on the function and ultrastructure of salivary glands in rabbits. However, the underlying mechanism of lidocaines radioprotective effect is unknown. We hypothesized that lidocaine, as a membrane stabilization agent, has a protective effect on intracellular neuroreceptor-mediated signaling and hence can help preserve the secretory function of salivary glands during radiotherapy. Methods and Materials Rabbits were irradiated with or without pretreatment with lidocaine before receiving fractionated radiation to a total dose of 35 Gy. Sialoscintigraphy and saliva total protein assay were performed before radiation and 1 week after the last radiation fraction. Isolated salivary gland acini were stimulated with either carbachol or adrenaline. Ca2+ influx in response to the stimulation with these agonists was measured using laser scanning confocal microscopy. Results The uptake of activity and the excretion fraction of the parotid glands were significantly reduced after radiation, but lidocaine had a protective effect. Saliva total protein concentration was not altered after radiation. For isolated acini, Ca2+ influx in response to stimulation with carbachol, but not adrenaline, was impaired after irradiation; lidocaine pretreatment attenuated this effect. Conclusions Lidocaine has a radioprotective effect on the capacity of muscarinic agonist-induced water secretion in irradiated salivary glands.

Radioprotective Effect of Lidocaine on Function and Ultrastructure of Salivary Glands Receiving Fractionated Radiation

PURPOSE Radiation-induced xerostomia still represents a common side effect after radiotherapy for head-and-neck malignancies. The aim of the present study was to examine the radioprotective effect of lidocaine hydrochloride during fractionated radiation in an experimental animal model. METHODS AND MATERIALS To evaluate the influence of different radiation doses on salivary gland function and the radioprotective effect of lidocaine, rabbits were irradiated with 15, 25, 30, and 35 Gy (equivalent doses in 2-Gy fractions equivalent to 24, 40, 48, and 56 Gy, respectively). Lidocaine hydrochloride (10 and 12 mg/kg) was administered before every radiation fraction in the treatment groups. Salivary gland function was assessed by flow sialometry and sialoscintigraphy, and the morphologic changes were evaluated using transmission electron microscopy. RESULTS Functional impairment was first observed after 35 Gy and pretreatment with lidocaine improved radiation tolerance of both parotid and submandibular glands. The use of 12 mg/kg lidocaine was superior and displayed significant radioprotection with regard to flow sialometry and sialoscintigraphy. The ultrastructure was largely preserved after pretreatment with both lidocaine doses. CONCLUSIONS Lidocaine represents an effective radioprotective agent and a promising approach for clinical application to avoid radiation-induced functional impairment of salivary glands.

See the unseen: Mesorectal lymph node metastases in prostate cancer

Our study is the first evaluation of nodal metastatic prostate cancer (PCa) to mesorectal lymph nodes (MLN) detected by 68Ga‐PSMA‐PET/CT.

68Ga-Pentixafor PET/CT Imaging of Chemokine Receptor CXCR4 in Chronic Infection of the Bone: First Insights

Because of its role in infection and inflammatory processes, the chemokine receptor CXCR4 might be a potent target in imaging of infectious and inflammatory diseases. The aim of this pilot study was to determine whether the CXCR4 ligand 68Ga-pentixafor is suitable for imaging chronic infection of the bone. Methods: The study comprised 14 patients with suspected infection of the skeleton who underwent 68Ga-pentixafor PET/CT between April 2015 and February 2017 in our facility. 68Ga-pentixafor PET/CT results were retrospectively evaluated against a histologic, bacteriologic, and clinical standard. The results were also compared with available bone scintigraphy, white blood cell scintigraphy, and 18F-FDG PET/CT results. Results: 68Ga-pentixafor PET/CT was positive in 9 of 14 patients. Diagnoses included osteitis or osteomyelitis of peripheral bone, osteomyelitis of the maxilla, and infected endoprostheses. Target-to-background ratios were 5.1–15 (mean, 8.7). Eight of 9 cases were true-positive as confirmed by pathology, bacteriology, or clinical observation. All negative cases were confirmed as true-negative by other imaging modalities and follow-up. Conclusion: Imaging of CXCR4 expression with 68Ga-pentixafor PET/CT appears suitable for diagnosing chronic infection of the skeleton. The findings of this study reveal a possible diagnostic gain in suspected chronic infections that are difficult to diagnose by other imaging modalities.

Novel Carcinoembryonic-Antigen-(CEA)-Specific Pretargeting System to Assess Tumor Cell Viability after Irradiation of Colorectal Cancer Cells

AbstractPurpose:To date, no valid imaging modality exists for early response prediction to neoadjuvant radiochemotherapy in carcinoembryonic-antigen-(CEA)-expressing rectal cancers (UICC stages II and III). It is hypothesized that the uptake of an anti-CEA antibody is directly related to the number of viable tumor cells and may be quantified by immuno-positron emission tomography (immuno-PET). Therefore, we evaluated a novel pretargeting system using TF2, a humanized bispecific trivalent monoclonal antibody (mAb), directed against CEA and the IMP-288-peptide, a hapten for binding radiometals for imaging. Uptake and kinetics of the pretargeting system were investigated in vitro prior to and after irradiation.Methods:TF2 was labeled with 131I and IMP-288 with 111InCl3. The colorectal cancer cell lines HT29, SW480, and T84 with known varying CEA expression were incubated (≤72 hours) with 131I-TF2 or the TF2-111In-IMP-288 pretargeting system. Parallel cultures were irradiated with 2–10 Gy high-energy photons. Tracer uptake, proliferation, apoptosis, and CEA-RNA expression of cancer cells were investigated.Results:The uptake of tracers was dependent on CEA expression and cell count of the cell lines (uptake/106 cells: 0.3% in HT29, 1.5% in SW480, and 14% in T84, p < 0.001). The TF2-111In-IMP-288 pretargeting system showed a higher uptake after 4 and 72 hours compared to 131I-TF2 in parallel cultures. Only in one cell line (SW480) an increased apoptosis after irradiation could be detected. Irradiation increased dose dependently both the specific uptake of 131I-TF2 and of the TF2-111In-IMP-288 system (4-fold in HT29 and T84 after 10 Gy (72 hours), p < 0.001). These results were CEA-mRNA independent.Conclusion:This novel pretargeting system allows the quantitative analysis of CEA-expressing colorectal cancer cells and represents a promising tool for evaluation of tumor cell viability after irradiation.ZusammenfassungHintergrund:Derzeit gibt es beim CEA-exprimierenden Rektumkarzinom (der UICC-Stadien II und III) keine valide Diagnostik zur frühzeitigen Response-Beurteilung auf eine neoadjuvante Radiochemotherapie. Allerdings wird vermutet, daß mit einer Immuno-Positronen-Emissions-Tomographie (Immuno-PET) und einem anti-CEA-Antikörper die Anzahl viabler Tumorzellen nach erfolgter Radiatio quantifizierbar ist. Demzufolge wurde von unserer Arbeitsgruppe zur Etablierung eines Immuno-PETs ein neues Pretargeting-System evaluiert. Dieses Pretargeting-System besteht aus dem humanisierten bispezifischen trivalenten monoklonalen Antikörper (TF2), der an CEA sowie an das radioaktiv markierte Hapten-Peptid IMP-288 bindet. Wir untersuchten in vitro die Bindung und Kinetik dieses Pretargeting-Systems vor und nach Radiatio. Methoden:TF2 wurde mit 131I und IMP-288 mit 111InCl3 markiert. Die Inkubation (≤72 h) der kolorektalen Tumorzelllinien HT29, SW480 und T84 mit unterschiedlicher CEA-Expression erfolgte mit 131I-TF2 und dem TF2-111In-IMP-288-Pretargeting-System. Parallelkulturen wurden mit 2–10 Gy hochenergetischer Photonen bestrahlt. Neben der Bindung der markierten Substanzen wurden die Proliferation, Apoptose und CEA-RNA-Expression der Tumorzellen untersucht. Ergebnisse:Der Tracer-Uptake korrelierte sowohl mit der CEA-Expression als auch der Zellzahl der jeweiligen Zelllinie (Uptake/106 Zellen: 0,3% in HT29, 1,5% in SW480 und 14% in T84; p < 0,001). Das Pretargeting-System wurde nach 4 h und 72 h stärker gebunden als 131I-TF2 in Parallelkulturen. Lediglich in einer Zelllinie (SW480) konnte eine erhöhte Apoptoserate nach Bestrahlung nachgewiesen werden. Die Radiatio erhöhte dosisabhängig die spezifische Aufnahme des Pretargeting-Systems (4fach in HT29 und T84 nach 10 Gy (72 h), p < 0,001). Diese Ergebnisse waren CEA-mRNA-unabhängig. Schlussfolgerung:Das neue Pretargeting-System erlaubt eine quantitative Analyse der CEA-Expression kolorektaler Tumorzellen und ist eine vielversprechende Methode zur Evaluation der Tumorzellviabilität nach Radiatio.