Publications by authors named "Gerd Wunderlich"

54 Publications

Third generation radioimmunoassay (RIA) for TSH receptor autoantibodies (TRAb) - one step less, similar results?

Nuklearmedizin 2021 Feb 3;60(1):38-46. Epub 2021 Feb 3.

Department of Nuclear Medicine, University Hospital Carl Gustav Carus, TU Dresden, Germany.

Aim:  TSH-receptor (TSHR)-autoantibody (TRAb) is the serological hallmark of Graves' disease (GD). Recently, 3-generation radioimmunoassays (RIA) employing monoclonal TRAb such as M22 or T7 instead of TSH for the inhibition of human TRAb binding with solid-phase TSHR (coated tubes) have been introduced into laboratory routine.

Methods:  As current assays typically employ a consecutive incubation of patient serum and labelled monoclonal TRAb, automation of TRAb RIA is a challenge. Thus, the assay procedure using human TSHR-coated tubes and the mouse monoclonal TRAb T7 was modified by combining both steps. The novel one-step method was compared with its corresponding consecutive 3-generation RIA by investigating 304 individuals encompassing 102 patients with active GD (GD), 43 patients with GD after successful therapy (GD), 31 with Hashimoto's disease (HD), 28 with non-autoimmune thyroid diseases (NAITD) and 100 healthy subjects (HS).

Results:  With the new method, the incubation time was shortened by approximately one hour. Both 3-generation RIAs did not reveal a significantly different assay performance by comparing areas under the curve (AUC) with receiver operating characteristics curve analysis (AUC one-step: 0.94, AUC two-step: 0.96, p > 0.05, respectively). The two-step TRAb RIA demonstrated sensitivity and specificity values of 87.5 % and 96.2 %, respectively, whereas the one-step revealed 84.6 % and 96.2 %, respectively.

Conclusion:  One-step 3-generation RIA may be used for the reliable detection of TRAb. The shorter and easier assay design may improve its use and enable automation in routine nuclear medicine laboratories.
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http://dx.doi.org/10.1055/a-1277-5972DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857932PMC
February 2021

The effect of hypoxia on the induction of strand breaks in plasmid DNA by alpha-, beta- and Auger electron-emitters Ra, Re, Tc and DNA-binding Tc-labeled pyrene.

Nucl Med Biol 2020 Jan - Feb;80-81:65-70. Epub 2020 Jan 18.

University Hospital, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Department of Nuclear Medicine, Dresden, Germany. Electronic address:

Introduction: Radiation-induced DNA damage occurs from direct and indirect effects. The induction is influenced by the physical characteristics of the radionuclide, especially its linear energy transfer. Hypoxia reduces the effect of irradiation treatment in tumor cells and leads to poor patient outcomes. High linear energy transfer emitters can overcome this obstacle. Our aim is to demonstrate the influence of hypoxia on the interaction of different radiation qualities with isolated DNA.

Methods: PuC19 Plasmid DNA was irradiated with Ra, Re, Tc and Tc-labeled pyrene with and without DMSO under hypoxia or normoxic conditions. DNA damages in form of single-(SSB) and double-strand breaks (DSB) were analyzed by gel electrophoresis.

Results: Radiation doses up to 200 Gy of Ra, Re and Tc led to maximal yields of 80% SSB and 30%, 28% and 32% DSB, respectively. Hypoxia had minor effects on damages from Ra, but caused a small enhancement in DSB for Re and Tc. DMSO prevented DSB completely and reduced SSB from the "free" radionuclides to comparable levels. DNA-binding Tc-labeled pyrene induced less SSB and DSB compared to [Tc]TcO. However, the incubation with DMSO could prevent the SSB and DSB induction only to a minor extent.

Conclusions: Hypoxia does not limit DNA damage induced by Ra, Re, Tc and Tc-labeled pyrene. Dose-dependent radiation effects were comparable for alpha-emitters and both high- and low-energy electron emitters. The radioprotection by DMSO was not influenced by hypoxia. The results indicate the contribution of mainly indirect radiation effects for Tc, Re and Ra. Tc-labeled pyrene caused direct DNA damages and Auger-electrons from Tc-labeled pyrene are more effective than high-energy electrons or alpha particles.

Advances In Knowledge: Without the consideration of DNA repair mechanisms, oxygen has no direct influence in radiation-induced DNA damages by different radiation qualities.

Implications For Patient Care: The short-time stimulation with oxygen during patient radiation could have minor influence compared to constant oxygen flooding to overcome hypoxic barriers.
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http://dx.doi.org/10.1016/j.nucmedbio.2020.01.003DOI Listing
January 2021

[Radiation Exposition of preparations of radiopharmaceuticals in routinely use, measured with optical-stimulated luminescence (OSL) dosimeters].

Nuklearmedizin 2019 Dec 13;58(6):470-473. Epub 2019 Nov 13.

Klinik und Poliklinik für Nuklearmedizin, Universitätsklinikum Carl Gustav Carus, Dresden, Germany.

Aim:  Because of the new regulation of the radiation protection in Germany in 2018 (Strahlenschutzverordnung) it was meaningful to calculate an overview of the radiation exposition of the personal in the radiopharmaceutical "Hotlab". The regulation demands that the radiation exposition must be minimized, documented and reduced to an optimized level. In the Klinik und Poliklinik für Nuklearmedizin at the University Hospital of Dresden measurements were done with optical-stimulated luminescence (OSL) dosimeters.

Materials And Methods:  Light protected OSL dosimeters were positioned on the fingertips (thumb, forefinger and middle finger) of both hands and on the forehead. Before use the OSL dosimeters were calibrated. The exposition of the hands was measured at three different days in the preparation lab: Tc preparation in the daily routine, syringes application for radiosynoviorthesis (RSO) and Y Sirtex particles and for preparation of Lu and Ga radiopharmaceuticals.

Results:  A relatively high exposition was seen after Tc preparations because of the quantity of preparations and syringes. Handling of syringes for RSO lead to an likewise raised exposition. The radiation exposition at preparation of Lu and Ga radiopharma-ceuticals depends on handling and use of modules. The exposition of the eye lenses was 0.02 mGy or lower and therefore not critical. But an appropriate radiation protection is necessary and a requirement for the most slightly radiation exposition.

Conclusion:  An optimized number of personal is necessary for preparation of radiopharmaceuticals in a "Hotlab" in nuclear medical facility. Therefore, the individual radiation exposition will be limited.
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http://dx.doi.org/10.1055/a-1031-9251DOI Listing
December 2019

A theranostic PSMA ligand for PET imaging and retargeting of T cells expressing the universal chimeric antigen receptor UniCAR.

Oncoimmunology 2019;8(11):1659095. Epub 2019 Sep 7.

Department of Radioimmunology, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany.

Chimeric antigen receptor (CAR) T cells have shown impressive therapeutic potential. Due to the lack of direct control mechanisms, therapy-related adverse reactions including cytokine release- and tumor lysis syndrome can even become life-threatening. In case of target antigen expression on non-malignant cells, CAR T cells can also attack healthy tissues. To overcome such side effects, we have established a modular CAR platform termed UniCAR: UniCAR T cells per se are inert as they recognize a peptide epitope (UniCAR epitope) that is not accessible on the surface of living cells. Bifunctional adapter molecules termed target modules (TM) can cross-link UniCAR T cells with target cells. In the absence of TMs, UniCAR T cells automatically turn off. Until now, all UniCAR TMs were constructed by fusion of the UniCAR epitope to an antibody domain. To open up the wide field of low-molecular-weight compounds for retargeting of UniCAR T cells to tumor cells, and to follow in parallel the progress of UniCAR T cell therapy by PET imaging we challenged the idea to convert a PET tracer into a UniCAR-TM. For proof of concept, we selected the clinically used PET tracer PSMA-11, which binds to the prostate-specific membrane antigen overexpressed in prostate carcinoma. Here we show that fusion of the UniCAR epitope to PSMA-11 results in a low-molecular-weight theranostic compound that can be used for both retargeting of UniCAR T cells to tumor cells, and for non-invasive PET imaging and thus represents a member of a novel class of theranostics.
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http://dx.doi.org/10.1080/2162402X.2019.1659095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6791425PMC
September 2019

68Ga-RM2 PET in PSMA- positive and -negative prostate cancer patients.

Nuklearmedizin 2019 Sep 23;58(5):352-362. Epub 2019 Aug 23.

Department of Nuclear Medicine, Faculty of Medicine and University Hospital Carl Gustav Carus, TU Dresden, Germany.

AIM:  Ga-PSMA-11 is the gold standard for molecular imaging of prostate cancer. However, recurrent tumor manifestations or metastases cannot be detected in every case. Therefore, we investigated if there is an additive value of the gastrin-releasing peptide receptor (GRP-R) ligand Ga-RM2 compared to the well-established Ga-PSMA-11 in patients with (Group 1) and without (Group 2) pathologic PSMA-expression in different tumor stages.

Patients And Methods:  Sixteen men (median age: 74 years, range 50-80 years) with prostate cancer in different stages who had a recent negative (n = 8) or pathologic (n = 8) PSMA PET underwent a subsequent Ga-RM2 PET. Both examinations were analyzed qualitatively and quantitatively and compared in terms of pathologic and physiologic tracer distribution.

Results:  None of the PSMA-negative patients showed any pathological RM2-accumulation. Pathologic PSMA-uptake was observed in 8 patients of whom 5 had pathologic RM2-uptake. The number of patients with a local recurrence was equal in both scans (n = 3). Bone metastases and lymph node metastases were detected in less patients in RM2 PET compared to PSMA PET (n = 4 vs. 7 and n = 2 vs. 5, respectively). In one patient, PSMA-positive liver metastases were not detected in RM2. RM2 PET revealed two additional lesions indicative for bone metastases in two patients with multiple PSMA-positive bone metastases, which had no therapeutic consequence.

Conclusion:  At least in our small and heterogeneous patient population, Ga-RM2 showed no clinically relevant, additional benefit compared to Ga-PSMA-11 PET.
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http://dx.doi.org/10.1055/a-0990-8898DOI Listing
September 2019

[Radio- and photosensitization of plasmid DNA by DNA binding ligand propidium iodide: Investigation of Auger electron induction and detection of Cherenkov-emission].

Nuklearmedizin 2019 Aug 27;58(4):319-327. Epub 2019 Jun 27.

Klinik und Poliklinik für Nuklearmedizin, Universitätsklinikum Carl Gustav Carus, Dresden.

Purpose: We investigated whether propidium iodide (PI) enhances DNA damaging effects of ionizing and non-ionizing radiation species (X-rays, alpha-, beta-, auger electron emission and light of various wavelengths, respectively). This biophysical experimental setting allowed us, furthermore, to investigate whether Cherenkov emission can be detected by photodynamic effects and increased DNA damage.

Material And Methods: Conformation changes of plasmid DNA were detected and quantified by gelelectrophoresis and fluorescence imaging. Hydrogen peroxide, stannous dichloride, and dimethylsulfoxide were used as chemical modulators, Tc-99m, Re-188, Ra-223, and x-ray (32 kV and 200 kV) reflected radiotoxicity and light (λ = 254 nm, 366 nm and 530-575 nm) induced phototoxicity.

Results: Radiotracers and x-rays induced dose dependent DNA damage. PI did not serve as radiosensitizer in radioisotopes, while a low effect was detected in X-rays. The phototoxicity was dependent on the wavelengths of light. Light with a wavelength range of 530-575 nm in combination with PI resulted in direct DNA damage. The yield of Cherenkov emission was far below the photon emission of light irradiation and not distinguishable from general radiotoxicity.

Conclusions: PI binds to plasmid DNA, is not chemotoxic, and increases radiotoxicity only to minor extent. Phototoxicity and its stimulation by PI is dependent on the wavelength of the light. No kind of energy deposition was capable of inducing an Auger electron cascade. Furthermore, no increase in DNA damage induced by photodynamic effects from Cherenkov emission was detectable.
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http://dx.doi.org/10.1055/a-0953-1157DOI Listing
August 2019

Dual-time-point Cu-PSMA-617-PET/CT in patients suffering from prostate cancer.

J Labelled Comp Radiopharm 2019 Jun 17;62(8):523-532. Epub 2019 Jun 17.

Department of Nuclear Medicine, Faculty of Medicine, University Hospital Carl Gustav Carus, TU Dresden, Dresden, Germany.

Regardless of its high positron energy, Ga-labeled PSMA ligands have become standard of care in metabolic prostate cancer imaging. Cu, a radionuclide with a much longer half-life (12.7 h), is available for PSMA labeling allowing imaging much later than Ga. In this study, the diagnostic performance of Cu-labeled PSMA was compared between early and late scans. Sixteen men (median age: 70 y) with prostate cancer in different stages underwent Cu-PSMA-617-PET/CT 2 and 22 hours post tracer injection. Pathologic and physiologic uptakes were analyzed for both points of time. Pathologic tracer accumulations occurred in 12 patients. Five patients presented with pathologic uptake in 17 different lymph nodes, two patients showed pathologic bone uptake in nine lesions, and seven patients had pathologic PSMA uptake in eight prostatic lesions. Physiologic uptake of the renal parenchyma, urine bladder, and salivary glands decreased over time, while the physiologic uptake of liver and bowel increased. In the present study, Cu-PSMA-617-PET demonstrated to be feasible for imaging prostate cancer for both the primary tumor site and metastases. Later imaging showed no additional, clinically relevant benefit compared with the early scans. At least the investigated time points we chose did not vindicate the additional expenditure.
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http://dx.doi.org/10.1002/jlcr.3745DOI Listing
June 2019

A novel third-generation TSH receptor antibody (TRAb) enzyme-linked immunosorbent assay based on a murine monoclonal TSH receptor-binding antibody.

Immunol Res 2018 12;66(6):768-776

Department of Nuclear Medicine, University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstr 74, 01307, Dresden, Germany.

TSH receptor (TSHR) autoantibody (TRAb) is the serological hallmark of Graves' disease (GD). Third-generation enzyme-linked immunosorbent assays (ELISAs) using monoclonal TRAbs instead of TSH have been found useful for TRAb analysis recently. For the first time, a mouse monoclonal antibody (mAb) against TSHR was analyzed for TRAb detection and compared with human mAb M22 and TSH by the same competitive binding assay technique. A mouse monoclonal antibody (T7) binding to the TSH receptor and inhibiting TSH binding was generated and used for TRAb analysis in a third-generation ELISA. Obtained TRAb levels were compared with a second-generation TRAb assay employing bovine TSH and a third-generation assay with human mAb M22 as TSHR-binding reagents by investigating 89 patients with GD, 56 with Hashimoto's thyroiditis (HT), 73 with non-autoimmune thyroid diseases, 17 with rheumatoid arthritis, and 100 healthy subjects. The T7-based TRAb ELISA did not reveal a significantly different assay performance (area under the curve [AUC]) in contrast to the TSH and M22-based TRAb ELISAs by receiver operating characteristic (ROC) curve analysis (AUC-T7 0.967, AUC-TSH 0.972, AUC-M22 0.958, p > 0.05, respectively). After adjustment of cutoffs by ROC, all three TRAb ELISAs demonstrated sensitivities and specificities above 89.9% and 96.0%, respectively. Both third-generation TRAb ELISAs showed a tendency for a higher prevalence of TRAb positives in HT in contrast to the second-generation ELISA. Mouse mAbs against the TSHR may be used for the reliable detection of TRAb by third-generation TRAb ELISA. The earlier reported higher sensitivity of third-generation TRAb ELISA in GD needs to be considered in the context of a slightly lower specificity regarding HT.
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http://dx.doi.org/10.1007/s12026-018-9062-zDOI Listing
December 2018

Different Radionuclides in DOTA-EB-TATE Effect Different Uptake in Somatostatin Receptor-Positive HEK293 Cells.

J Nucl Med 2019 03 15;60(3):436. Epub 2018 Nov 15.

Universitätsklinikum Dresden Fetscherstrasse 74 01307 Dresden, Germany E-mail:

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http://dx.doi.org/10.2967/jnumed.118.220707DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6910628PMC
March 2019

[Combined internal-external radiotherapy (CIERT) in a cell model].

Nuklearmedizin 2018 Jun 5;57(3):108-116. Epub 2018 Jun 5.

Aim: Combined internal-external radiotherapy (CIERT) requires a unified assessment of biologic radiation effects in addition to the total dose. The concept of biological effective dose (BED) was evaluated in a cell model.

Methods: The thyroid NIS-positive cell line FRTL-5 was irradiated with X-ray and the radiotracer Tc-99m pertechnetate either alone or in combination. The cellular uptake of the radionuclide during the incubation time of 24 h was controlled by the presence or absence of perchlorate. Dose calculation was performed based on measured uptake values. Cell specific radiobiologic parameters were derived from dose effect curves using the colony forming assay as biological endpoint. For the combination of the radiation qualities the sequence and time difference were varied. Cell survival was compared with the prediction of the BED model.

Results: The radiobiologic parameters from X-ray dose response were α = (0.22 ± 0.02) Gy and β = (0.021 ± 0.001) Gy. The half life for repair was (1.51 ± 0.21) h. These values could also explain the dose response curves for Tc-99m-irradiation with exponential decreasing dose rate. CIERT experiments showed no significant differences in cell survival regarding sequence and irradiation break. When the radionuclide uptake was not prevented the cell survival for the combination of X-ray and Tc-99m was lower than the prediction by BED calculations.

Conclusions: The validity of the BED formalism for different dose rates and radiation qualities was verified. Supraaddive effects measured in the combination of X-ray and intracellular Tc-99m might be caused by Auger and conversion electrons, however further experiments are necessary.
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http://dx.doi.org/10.3413/Nukmed-0954-17-12DOI Listing
June 2018

Feasibility of CXCR4-Directed Radioligand Therapy in Advanced Diffuse Large B-Cell Lymphoma.

J Nucl Med 2019 01 18;60(1):60-64. Epub 2018 May 18.

Division of Hematology and Medical Oncology, Department of Internal Medicine II, Universitätsklinikum Würzburg, Würzburg, Germany; and.

We have recently reported on our experience with C-X-C-motif chemokine receptor 4 (CXCR4)-directed radioligand therapy (RLT) in multiple myeloma and acute leukemia. Six patients with heavily pretreated relapsed diffuse large B-cell lymphoma (3 men, 3 women; aged, 54 ± 8 y) underwent CXCR4-directed RLT in combination with conditioning chemotherapy and allogeneic stem cell transplantation. In 2 patients, radioimmunotherapy targeting CD20 or CD66 was added to enhance antilymphoma activity. Endpoints were incidence and severity of adverse events, progression-free survival, and overall survival. RLT and additional radioimmunotherapy were well tolerated, without any acute adverse events or changes in vital signs. Successful engraftment was recorded after a median of 11 d (range, 9-13 d). Of the 4 patients who were available for follow-up (one patient died of CNS aspergillosis 29 d after RLT and another of sepsis in aplasia 34 d after RLT), CXCR4-directed RLT resulted in a partial response in two (both treated with additional radioimmunotherapy) and a mixed response in the remaining two. The response duration was rather short-lived, with a median progression-free survival of 62 d (range, 29-110 d) and a median overall survival of 76 d (range, 29-334 d). CXCR4-directed RLT (in combination with additional radioimmunotherapy) is feasible as a conditioning regimen before allogeneic stem cell transplantation in diffuse large B-cell lymphoma.
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http://dx.doi.org/10.2967/jnumed.118.210997DOI Listing
January 2019

Twins in spirit part IV - [Lu] high affinity DOTATATE. A promising new tracer for peptide receptor radiotherapy?

Nuklearmedizin 2017 Feb 31;56(1):1-8. Epub 2017 Jan 31.

Claudia Brogsitter, Fetscherstr. 74, 01307 Dresden, Germany, Tel. +49-351-458 4160, Fax. +49-351-458 5347, E-Mail:

Aim: Besides the use of somatostatin analogues, small molecules like sunitinib and everolimus as well as conventional chemotherapy, peptide receptor radiotherapy (PRRT) using radiolabelled somatostatin analogues has gained an important role in the treatment of inoperable, metastasized neuroendocrine tumours (NET). There are various radiotracers in use. Based on our experience with the PET tracer [Ga]DOTA-3-iodo-Tyr-octreotate ([Ga]HA-DOTATATE), a DOTATATE derivative with an increased binding affinity to hsst5, the current retrospective analysis is exploring the therapeutic potential of [Lu]HA-DOTATATE.

Methods: Eighteen patients with metastatic NET (G1/G2) were treated using [Lu]DOTATATE and/or [Lu]HA-DOTATATE, and dosimetric results of both tracers were compared.

Results: Using [Lu]HA-DOTATATE, a mean tumour dose of 5.34 Gy/GBq (median 2.53 Gy/GBq; range 0.89-33.3 Gy/GBq) was achieved, while [Lu]DOTATATE delivered a tumour dose of 5.53 Gy/GBq (median 2.70 Gy/GBq; range 0.44-15.3 Gy/GBq). Organ doses for [Lu]HA-DOTATATE vs. [Lu]DOTATATE were as follows: kidney 2.31 ± 0.85 vs. 2.03 ± 0.96 Gy/GBq, liver 1.06 ± 0.79 vs. 1.67 ± 1.73 Gy/GBq, spleen 3.89 ± 4.04 vs. 4.50 ± 3.69 Gy/GBq and whole body 0.16 ± 0.10 Gy/GBq vs. 0.15 ± 0.08 Gy/GBq. Tumour-to-kidney dose ratio was slightly higher for [Lu]DOTATATE (2.4 ± 5.6) compared to [Lu]HA-DOTATATE (1.5 ± 3.6).

Conclusion: Both tracers showed marked inter-patient variation in their dosimetry, and no significant differences in dosimetry of [Lu]HA-DOTATATE and [Lu]DOTATATE were observed when taking all patients into account. Thus, [Lu]HA-DOTATATE appears viable for PRRT, although it was marginally inferior regarding kidney dose and tumour-to-kidney dose ratio compared to the established [Lu]DOTATATE.
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http://dx.doi.org/10.3413/Nukmed-0860-16-11DOI Listing
February 2017

Direct and Auger Electron-Induced, Single- and Double-Strand Breaks on Plasmid DNA Caused by 99mTc-Labeled Pyrene Derivatives and the Effect of Bonding Distance.

PLoS One 2016 1;11(9):e0161973. Epub 2016 Sep 1.

University Hospital/ Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Department of Nuclear Medicine, Dresden, Germany.

It is evident that 99mTc causes radical-mediated DNA damage due to Auger electrons, which were emitted simultaneously with the known γ-emission of 99mTc. We have synthesized a series of new 99mTc-labeled pyrene derivatives with varied distances between the pyrene moiety and the radionuclide. The pyrene motif is a common DNA intercalator and allowed us to test the influence of the radionuclide distance on damages of the DNA helix. In general, pUC 19 plasmid DNA enables the investigation of the unprotected interactions between the radiotracers and DNA that results in single-strand breaks (SSB) or double-strand breaks (DSB). The resulting DNA fragments were separated by gel electrophoresis and quantified by fluorescent staining. Direct DNA damage and radical-induced indirect DNA damage by radiolysis products of water were evaluated in the presence or absence of the radical scavenger DMSO. We demonstrated that Auger electrons directly induced both SSB and DSB in high efficiency when 99mTc was tightly bound to the plasmid DNA and this damage could not be completely prevented by DMSO, a free radical scavenger. For the first time, we were able to minimize this effect by increasing the carbon chain lengths between the pyrene moiety and the 99mTc nuclide. However, a critical distance between the 99mTc atom and the DNA helix could not be determined due to the significantly lowered DSB generation resulting from the interaction which is dependent on the type of the 99mTc binding motif. The effect of variable DNA damage caused by the different chain length between the pyrene residue and the Tc-core as well as the possible conformations of the applied Tc-complexes was supplemented with molecular dynamics (MD) calculations. The effectiveness of the DNA-binding 99mTc-labeled pyrene derivatives was demonstrated by comparison to non-DNA-binding 99mTcO4-, since nearly all DNA damage caused by 99mTcO4- was prevented by incubating with DMSO.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0161973PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5008623PMC
August 2017

Comparison of the radiotoxicity of the Tc-labeled compounds Tc-pertechnetate, Tc-HMPAO and Tc-MIBI.

Int J Radiat Biol 2016 11 27;92(11):698-706. Epub 2016 Apr 27.

a University Hospital/Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden , Department of Nuclear Medicine , Dresden , Germany.

Purpose: In addition to gamma radiation, Tc emits low-energy Auger electrons with path-lengths of nanometers to micrometers that cannot be utilized for diagnostic procedures; however, they have frequently been discussed for therapeutic applications. We compared radiotoxicity of three Tc-labeled radiopharmaceuticals with differences in the subcellular distribution.

Materials And Methods: The intracellular radionuclide uptake and subcellular distribution of [Tc]-pertechnetate (Tc-pertechnetate), [Tc]Tc-hexamethyl-propylene-aminoxime (Tc-HMPAO) and [Tc]Tc-hexakis-2-methoxyisobutylisonitrile (Tc-MIBI) were quantified in rat thyroid FRTL-5 cells. Radiotoxicity was compared using late phosphorylated histone H2AX (γH2AX) foci as a marker for unrepaired DNA double-strand breaks (DNA-DSB) and clonogenic cell survival.

Results: Tc-HMPAO showed a substantially higher uptake into the nucleus and the membrane/organelles than Tc-pertechnetate or Tc-MIBI. The colony-forming assay showed that Tc-pertechnetate and Tc-HMPAO caused a similar reduction in cell survival. Tc-MIBI is less radiotoxic in terms of the estimated nucleus dose and induced the fewest number of γH2AX foci compared with the other Tc-tracers, and Tc-HMPAO induced a fewer number of γH2AX foci than Tc-pertechnetate.

Conclusions: Our findings reveal that clonogenic cellular survival is not solely determined by the DNA-DSB response. This finding may suggest the involvement of extra-nuclear radiosensitive targets in cell inactivation. For example, the mitochondria or the cell membrane could be affected by Tc-HMPAO.
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http://dx.doi.org/10.3109/09553002.2016.1168533DOI Listing
November 2016

Reduced-Intensity Conditioning Combined with (188)Rhenium Radioimmunotherapy before Allogeneic Hematopoietic Stem Cell Transplantation in Elderly Patients with Acute Myeloid Leukemia: The Role of In Vivo T Cell Depletion.

Biol Blood Marrow Transplant 2015 Oct 19;21(10):1754-60. Epub 2015 May 19.

Department of Medicine I, University Hospital Carl Gustav Carus at Dresden University of Technology, Dresden, Germany; German Consortium for Translational Cancer Research, Dresden, Germany. Electronic address:

The combination of reduced-intensity conditioning, (188)rhenium anti-CD66 radioimmunotherapy, and in vivo T cell depletion was successfully applied in elderly patients with acute myeloid leukemia or myelodysplastic syndrome. Within a prospective phase II protocol, we investigated whether a dose reduction of alemtuzumab (from 75 mg to 50 mg MabCampath) would improve leukemia-free survival by reducing the incidence of relapse. Fifty-eight patients (median age, 67 years; range, 54 to 76) received radioimmunotherapy followed by fludarabine 150 mg/m(2) and busulfan 8 mg/kg combined with either 75 mg (n = 26) or 50 mg (n = 32) alemtuzumab. Although we observed a trend towards a shorter duration of neutropenia in the 50 mg group (median, 19 versus 21 days; P = .07), the time from transplantation to neutrophil and platelet engraftment as well as the overall incidence of engraftment did not differ. The incidence of severe acute graft-versus-host disease tended to be higher after the lower alemtuzumab dose (17% versus 4%; P = .15). No significant differences in the cumulative incidences of relapse (38% versus 35%; P = .81) or nonrelapse mortality (46% versus 27%; P = .31) were observed. Accordingly, disease-free and overall survival were not significantly different between groups. Although the feasibility of radioimmunotherapy plus reduced-intensity conditioning could be demonstrated in elderly patients, the dose reduction of alemtuzumab had no positive impact on overall outcome.
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http://dx.doi.org/10.1016/j.bbmt.2015.05.012DOI Listing
October 2015

Theranostic mercury: (197(m))Hg with high specific activity for imaging and therapy.

Appl Radiat Isot 2015 Mar 5;97:177-181. Epub 2015 Jan 5.

Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Bautzner Landstrasse 400, 01328 Dresden, Germany.

The no carrier added (NCA) radionuclide (197(m))Hg is accessible through proton induced nuclear reactions on gold. The decay properties of both simultaneous produced nuclear isomers (197m)Hg and (197)Hg like convenient half life, low energy gamma radiations for imaging, Auger and conversion electrons for therapy are combined with unique chemical and physical properties of mercury and its compounds. Gold as a monoisotopic element has a natural abundance of 100% (197)Au superseding expensive enrichment for the target material. Additionally, the high thermal conductivity of gold enables high beam current irradiations. For separation of target material a liquid-liquid extraction method was applied.
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http://dx.doi.org/10.1016/j.apradiso.2015.01.001DOI Listing
March 2015

99mTc-labeled HYNIC-DAPI causes plasmid DNA damage with high efficiency.

PLoS One 2014 6;9(8):e104653. Epub 2014 Aug 6.

University Hospital/Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Department of Nuclear Medicine, Dresden, Germany.

(99m)Tc is the standard radionuclide used for nuclear medicine imaging. In addition to gamma irradiation, (99m)Tc emits low-energy Auger and conversion electrons that deposit their energy within nanometers of the decay site. To study the potential for DNA damage, direct DNA binding is required. Plasmid DNA enables the investigation of the unprotected interactions between molecules and DNA that result in single-strand breaks (SSBs) or double-strand breaks (DSBs); the resulting DNA fragments can be separated by gel electrophoresis and quantified by fluorescent staining. This study aimed to compare the plasmid DNA damage potential of a (99m)Tc-labeled HYNIC-DAPI compound with that of (99m)Tc pertechnetate ((99m)TcO4(-)). pUC19 plasmid DNA was irradiated for 2 or 24 hours. Direct and radical-induced DNA damage were evaluated in the presence or absence of the radical scavenger DMSO. For both compounds, an increase in applied activity enhanced plasmid DNA damage, which was evidenced by an increase in the open circular and linear DNA fractions and a reduction in the supercoiled DNA fraction. The number of SSBs elicited by 99mTc-HYNIC-DAPI (1.03) was twice that caused by (99m)TcO4(-) (0.51), and the number of DSBs increased fivefold in the (99m)Tc-HYNIC-DAPI-treated sample compared with the (99m)TcO4(-) treated sample (0.02 to 0.10). In the presence of DMSO, the numbers of SSBs and DSBs decreased to 0.03 and 0.00, respectively, in the (99m)TcO4(-) treated samples, whereas the numbers of SSBs and DSBs were slightly reduced to 0.95 and 0.06, respectively, in the (99m)Tc-HYNIC-DAPI-treated samples. These results indicated that (99m)Tc-HYNIC-DAPI induced SSBs and DSBs via a direct interaction of the (99m)Tc-labeled compound with DNA. In contrast to these results, (99m)TcO4(-) induced SSBs via radical formation, and DSBs were formed by two nearby SSBs. The biological effectiveness of (99m)Tc-HYNIC-DAPI increased by approximately 4-fold in terms of inducing SSBs and by approximately 10-fold in terms of inducing DSBs.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0104653PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4123991PMC
November 2015

Quantitative analysis of regional lung ventilation and perfusion PET with (68)Ga-labelled tracers.

Nucl Med Commun 2014 May;35(5):501-10

aDepartment of Nuclear Medicine bDepartment of Radiology cPulmonary Engineering Group, Department of Anesthesiology and Intensive Care Medicine, Medical Faculty, University Hospital Carl Gustav Carus, TU Dresden, Dresden, Germany.

Introduction: The aims of this study were to determine the quantitative parameters of ventilation (V) and perfusion (Q) PET scans assessing V/Q quotients in patients with various lung pathologies, as well as the influence of patient position on regional perfusion patterns.

Methods: Fifty-three patients (24 male and 29 female) underwent lung scintigraphy with (68)Ga-labelled radiopharmaceuticals. (68)Ga Galligas and B20 microspheres used for V and Q imaging were produced in-house. Images were acquired under a standard setup with two emission scans of the whole lung in the supine (S) position (acquisition time 3 min/bed position) on a PET/CT scanner combined with low-dose computed tomography (CT) for attenuation correction. In 27 patients the Q scan was repeated in the prone (P) position. Parametric images were calculated (V/Q, P/S when applicable) for each patient. Patients were grouped according to diagnostic findings, and V/Q ratio distributions were further analysed. Gradients of the regional blood flow in both the supine and prone position were calculated.

Results: The results from visual interpretation could be confirmed with parametric images. Voxel-wise V/Q analysis revealed significant differences in descriptive parameters such as median, mean and SD between normal patients and patients with acute and previous pulmonary embolism. Skewness and kurtosis were not significantly different. The effect of gravitation could be demonstrated by significant position-dependent changes of the gradients in the ventral-dorsal and apical-basal directions.

Conclusion: PET/CT using (68)Ga-labelled tracers allows the application of quantitative procedures to improve functional pulmonary imaging in clinical diagnosis and research.
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http://dx.doi.org/10.1097/MNM.0000000000000084DOI Listing
May 2014

Higher levels of spontaneous breathing induce lung recruitment and reduce global stress/strain in experimental lung injury.

Anesthesiology 2014 Mar;120(3):673-82

From the Pulmonary Engineering Group, Department of Anesthesiology and Intensive Care Medicine, University Hospital Dresden, Technische Universität Dresden, Dresden, Germany (A.G., A.B., N.C., A.B., S.Z., C.U., P.M.S., T.K., and M.G.d.A.); Department of Electric Engineering, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil (A.B.); Institute of Informatics and Biometry, Dresden, Germany (B.W.); Institute of Nuclear Medicine, University Hospital Dresden, Dresden, Germany (G.W., M.A., and J.K.); and IRCCS San Martino Hospital, Department of Surgical Sciences and Integrated Diagnostics, University of Genoa, Genoa, Italy (P.P.).

Background: Spontaneous breathing (SB) in the early phase of the acute respiratory distress syndrome is controversial. Biphasic positive airway pressure/airway pressure release ventilation (BIPAP/APRV) is commonly used, but the level of SB necessary to maximize potential beneficial effects is unknown.

Methods: Experimental acute respiratory distress syndrome was induced by saline lung lavage in anesthetized and mechanically ventilated pigs (n = 12). By using a Latin square and crossover design, animals were ventilated with BIPAP/APRV at four different levels of SB in total minute ventilation (60 min each): (1) 0% (BIPAP/APRV0%); (2) greater than 0 to 30% (BIPAP/APRV>0-30%); (3) greater than 30 to 60% (BIPAP/APRV>30-60%); and (4) greater than 60% (BIPAP/APRV>60%). Gas exchange, hemodynamics, and respiratory variables were measured. Lung aeration was assessed by high-resolution computed tomography. The distribution of perfusion was marked with Ga-labeled microspheres and evaluated by positron emission tomography.

Results: The authors found that higher levels of SB during BIPAP/APRV (1) improved oxygenation; (2) decreased mean transpulmonary pressure (stress) despite increased inspiratory effort; (3) reduced nonaerated lung tissue, with minimal changes in the distribution of perfusion, resulting in decreased low aeration/perfusion zones; and (4) decreased global strain (mean ± SD) (BIPAP/APRV0%: 1.39 ± 0.08; BIPAP/APRV0-30%: 1.33 ± 0.03; BIPAP/APRV30-60%: 1.27 ± 0.06; BIPAP/APRV>60%: 1.25 ± 0.04, P < 0.05 all vs. BIPAP/APRV0%, and BIPAP/APRV>60% vs. BIPAP/APRV0-30%).

Conclusions: In a saline lung lavage model of experimental acute respiratory distress syndrome in pigs, levels of SB during BIPAP/APRV higher than currently recommended for clinical practice, that is, 10 to 30%, improve oxygenation by increasing aeration in dependent lung zones without relevant redistribution of perfusion. In presence of lung recruitment, higher levels of SB reduce global stress and strain despite an increase in inspiratory effort.
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http://dx.doi.org/10.1097/ALN.0000000000000124DOI Listing
March 2014

Dose-dependent histological alterations in the rat lung following intravenous application of Re-188-labeled microspheres.

Int J Radiat Biol 2013 Oct 14;89(10):863-9. Epub 2013 May 14.

Department of Pediatic Surgery.

Purpose: The objective of this study was to determine the dose-effect correlation of pneumopathy after application of Rhenium-188 microspheres (Re-188 MS) in an animal model using histological changes as an end-point.

Methods And Materials: Wistar rats received an intravenous injection of Re-188 MS yielding doses that ranged from ˜ 2 to ˜ 55 Gy. Lungs were removed after ˜ 25 weeks and prepared for histology. Sections were evaluated using a semi-quantitative 5-tiered score. Dose groups of 10 Gy intervals were statistically analyzed using the Chi-square test with respect to grade and extent of connective tissue accumulation, thickness of vessel walls and accumulation of alveolar macrophages (AM).

Results: There was a statistically significant increase in connective tissue content and extent in all dose groups compared to control lungs and at least between each other dose group. The steepest increase in connective tissue was at doses higher than 40 Gy. Starting from that dose, a statistically significant increase of AM accumulation and vessel wall thickness occurred.

Conclusions: There was a clear dose-effect correlation between radiation dose and histological changes. These findings allow an estimation of potential normal tissue damage especially during tumor treatments of liver lesions with radioactive particles in patients with significant liver-to-lung shunts.
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http://dx.doi.org/10.3109/09553002.2013.794320DOI Listing
October 2013

Comparison between F-18 fluorodeoxyglucose and Ga-68 DOTATOC in metastasized melanoma.

Nucl Med Commun 2013 Jan;34(1):47-9

Department of Nuclear Medicine, University of Dresden, Dresden, Germany.

Purpose: Somatostatin binding to somatostatin receptors (SSTRs) is known to have an antiproliferative effect in neuroendocrine tumours. Melanoma cells are derived from the neural crest and thus express SSTR. Treatment options in metastasized melanomas are limited. Therefore, we aimed to investigate whether there is a relevant uptake of the SSTR analogue DOTATOC in metastasized melanoma patients, which could be used for therapy with radiolabelled SSTR analogues.

Materials And Methods: We investigated 18 patients (nine men and nine women; mean age 61 years) with metastasized melanoma using PET/CT, first with F-18 fluorodeoxyglucose ((18)F-FDG) and then with Ga-68 DOTATOC. The number of (18)F-FDG-positive or DOTATOC-positive lesions and the maximum standardized uptake value (SUV(max)) for an index lesion were determined for each patient.

Results: DOTATOC could reveal metastatic lesions in 11 of 18 patients (61%). However, on a lesion-by-lesion basis only 59 of 263 (22%) (18)F-FDG-avid metastases were seen with DOTATOC. Further, DOTATOC uptake was only faint. The mean SUV(max) was 3.1 (range, 1.2-4.2) for DOTATOC, in contrast to 28.2 (range, 2.3-115) for (18)F-FDG.

Conclusion: Radiolabelled DOTATOC does not seem to be a promising agent for treatment of metastasized melanoma.
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http://dx.doi.org/10.1097/MNM.0b013e32835ae4edDOI Listing
January 2013

Reduction in clonogenic survival of sodium-iodide symporter (NIS)-positive cells following intracellular uptake of (99m)Tc versus (188)Re.

Int J Radiat Biol 2012 Dec 9;88(12):991-7. Epub 2012 Oct 9.

University Hospital/Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Department of Nuclear Medicine, Dresden, Germany.

Purpose: Cellular radionuclide uptake increases the heterogeneity of absorbed dose to biological structures. Dose increase depends on uptake yield and emission characteristics of radioisotopes. We used an in vitro model to compare the impact of cellular uptake of (188)Re-perrhenate and (99m)Tc-pertechnetate on cellular survival.

Materials And Methods: Rat thyroid PC Cl3 cells in culture were incubated with (188)Re or (99m)Tc in the presence or absence of perchlorate for 1 hour. Clonogenic cell survival was measured by colony formation. In addition, intracellular radionuclide uptake was quantified.

Results: Dose effect curves were established for (188)Re and (99m)Tc for various extra- and intracellular distributions of the radioactivity. In the presence of perchlorate, no uptake of radionuclides was detected and (188)Re reduced cell survival more efficiently than (99m)Tc. A(37), the activity that is necessary to yield 37% cell survival was 14 MBq/ml for (188)Re and 480 MBq/ml for (99m)Tc. In the absence of perchlorate, both radionuclides showed similar uptakes; however, A(37) was reduced by 30% for the beta-emitter and by 95% for (99m)Tc. The dose D(37) that yields 37% cell survival was between 2.3 and 2.8 Gy for both radionuclides.

Conclusions: Uptake of (188)Re and (99m)Tc decreased cell survival. Intracellular (99m)Tc yielded a dose increase that was higher compared to (188)Re due to emitted Auger and internal conversion-electrons. Up to 5 Gy there was no difference in radiotoxicity of (188)Re and (99m)Tc. At doses higher than 5 Gy intracellular (99m)Tc became less radiotoxic than (188)Re, probably due to a non-uniform lognormal radionuclide uptake.
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http://dx.doi.org/10.3109/09553002.2012.728303DOI Listing
December 2012

Fully automated interpretation of ionizing radiation-induced γH2AX foci by the novel pattern recognition system AKLIDES®.

Int J Radiat Biol 2012 May 26;88(5):439-47. Epub 2012 Mar 26.

Department of Nuclear Medicine, Medical Faculty Carl Gustav Carus, Technische Universität Dresden.

Purpose: Assessment of phosphorylated histone H2AX (γH2AX) foci as a measure for double-strand breaks (DSB) is a common technique. Since visual interpretation is time-consuming and influenced by subjective factors, we adapted the pattern recognition algorithms of autoantibodies to automated reading of γH2AX foci.

Materials And Methods: DSB formation was assessed by detection of γH2AX foci after exposition of thyreocyte rat cell line to (188)Re. We used pattern recognition algorithms of the automated fluorescence interpretation system AKLIDES(®) for evaluation of γH2AX foci. Manual investigation was performed by three laboratories involving five observers. The results were compared by determining correlation and inter-laboratory variability.

Results: The study confirmed the adaptation of automated interpretation system AKLIDES® to automated assessment of γH2AX foci in irradiated cells. Both manual and automated quantification resulted in increasing focus numbers depending on dose. Comparison of automated reading with visual assessment for five manual observers resulted in a determination coefficient of R(2) = 0.889. The inter-laboratory variability for five manual investigators of three laboratories was 38.4 %.

Conclusion: The interpretation system AKLIDES(®) demonstrated a high correlation with visually observed results. High inter-laboratory variability found for manual investigations revealed the usefulness for a standardized technique for evaluation of γH2AX foci.
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http://dx.doi.org/10.3109/09553002.2012.658468DOI Listing
May 2012

Radiation pneumopathy in the rat after intravenous application of (188)Re-labeled microspheres.

Int J Radiat Oncol Biol Phys 2011 Oct 12;81(2):529-36. Epub 2011 Jun 12.

Department of Nuclear Medicine, University Hospital and Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.

Purpose: To determine the dose dependence and kinetics of pneumopathy after systemic administration of rhenium-188 ((188)Re)-labeled microspheres in a rat model.

Methods And Materials: (188)Re-microspheres were injected intravenously into adult Wistar rats (n = 54, age, 8 ± 2 months). The rats were divided into 6 groups according to the intended absorbed dose in the lung (maximum 60 Gy). Gamma camera scans were used to estimate the individual whole lung doses. One control group (n = 5) received nonlabeled microspheres. The breathing rate was measured before and weekly after the treatment using whole body plethysmography until 24 weeks. An increase in the breathing rate by 20% compared with the individual pretreatment control value was defined as the quantal endpoint for dose-effect analyses.

Results: A biphasic increase in the breathing rate was observed. The first impairment of lung function occurred in Weeks 3-6. For late changes, the interval to onset was clearly dose dependent and was 17 weeks (10-30 Gy) and 10 weeks (50-60 Gy), respectively. The incidence of the response was highly dependent on the estimated lung dose. The median effective dose for an early and late response was virtually identical (19.9 ± 0.6 Gy and 20.4 ± 3.1 Gy, respectively). A significant correlation was found between the occurrence of an early and a late effect in the same rat, suggesting a strong consequential component.

Conclusions: The effects of radiolabeled microspheres can be studied longitudinally in a rat model, using changes in the breathing rate as the functional, clinically relevant response. The isoeffective doses from the present study using radionuclide administration and those from published investigations of homogeneous external beam radiotherapy are almost similar.
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http://dx.doi.org/10.1016/j.ijrobp.2010.08.025DOI Listing
October 2011

Comparison of the stability of Y-90-, Lu-177- and Ga-68- labeled human serum albumin microspheres (DOTA-HSAM).

Nucl Med Biol 2010 Nov 24;37(8):861-7. Epub 2010 Jul 24.

Department of Nuclear Medicine, University Hospital, 01307 Dresden, Germany.

Introduction: Microparticles derived from denatured human serum albumin (DOTA-derivatized human serum albumin microspheres, or DOTA-HSAM) are attractive carriers of radionuclides for both therapeutic and diagnostic purposes. In this article, we describe a labeling procedure for diagnostic (Ga-68) and therapeutic (Y-90, Lu-177) radionuclides and report on the results of stability studies of these products.

Methods: DOTA-HSAM was labeled in 0.5 M ammonium acetate buffer, pH 5.0, containing 0.02 mg/ml detergent. After adding the radionuclide, the mixture was shaken for 15 min at 90°C. Labeling yields and in vitro stability were determined by thin-layer chromatography. For determination of the in vivo stability of Ga-68 and Y-90 DOTA-HSAM, the particles were injected intravenously in Wistar rats.

Results: Labeling yields up to 95% in the case of Ga-68 and Lu-177 were achieved. Ga-68-labeled DOTA-HSAM showed high in vitro and in vivo stability. The amount of particle-bound radioactivity of Lu-177 DOTA-HSAM declines slowly in a linear manner to approximately 72% after 13 days. For Y-90, the labeling yield decreased with increasing radioactivity level. We presume radiolysis as the reason for these findings.

Conclusion: The labeling of DOTA-HSAM with different radionuclides is easy to perform. The radiation-induced cleavage of the labeled chelator together with the rather short half-life of radioactivity fixation in vivo (3.7 days) is, in our opinion, opposed to therapeutic applications of DOTA-HSAM. On the other hand, the high stability of Ga-68 DOTA-HSAM makes them an attractive candidate for the measurement of regional perfusion by PET.
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http://dx.doi.org/10.1016/j.nucmedbio.2010.05.004DOI Listing
November 2010

Radioprotection of thyroid cells mediated by methimazole.

Int J Radiat Biol 2010 Oct;86(10):811-6

Department of Nuclear Medicine, University Hospital, Technische Universität Dresden, Germany.

Purpose: The radioprotective effect of antithyroid drugs on radioiodine treatment is a controversial issue. However, it is of clinical relevance whether antithyroid medication has to be interrupted for therapy and when antithyroid medication can be continued after radioiodine treatment. We investigated DNA damage caused by internal or external radiation using thyroid cells (sodium iodine symporter [NIS] positive).

Materials And Methods: Adherent thyroid cells were irradiated following incubation with the mediators methimazole and perchlorate using either X-ray tube or Re-188-perrhenate. DNA damage was quantified by OTM (Olive's tail moment) of the alkaline comet assay.

Results: Following external irradiation of 15 Gy OTM was 4.3 ± 4.2 compared to 0.5 ± 1.4 in controls. DNA damage was reduced by methimazole to 70%. Incubation with Re-188 showed effects depending on presence of the mediators. Non-irradiated controls had a mean OTM < 1, internal irradiation increased OTM to 25.5 ± 9.1 in cells without mediators. OTM decreased to 60% after pre-incubation with methimazole and to 15% with perchlorate. Re-188 uptake was modified by both perchlorate and, to a lesser extent, methimazole.

Conclusions: Methimazole was shown to have a radioprotective effect not only by its scavenger capacity but also by interaction with NIS. Perchlorate acted by competitive inhibition of NIS mediated Re-188 uptake.
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http://dx.doi.org/10.3109/09553002.2010.488276DOI Listing
October 2010

188Re anti-CD66 radioimmunotherapy combined with reduced-intensity conditioning and in-vivo T cell depletion in elderly patients undergoing allogeneic haematopoietic cell transplantation.

Br J Haematol 2010 Mar 7;148(6):910-7. Epub 2009 Dec 7.

Medizinische Klinik und Poliklinik I, University Hospital Carl Gustav Carus, Fetscherstrasse 74, Dresden, Germany.

The addition of radioimmunotherapy to conventional and reduced-intensity conditioning has been shown to be feasible and effective. Within an ongoing prospective phase II trial, 22 patients with advanced myeloid malignancies and a median age of 65 years (range 54-76) received anti-CD66 Rhenium radioimmunotherapy followed by fludarabine (150 mg/m(2)), busulfan (8 mg/kg) and alemtuzumab (75 mg) before allogeneic haematopoietic stem cell transplantation from matched sibling (n = 7) and unrelated donors (n = 15). The extramedullary toxicity in the first 100 d post-transplantation was limited and all patients engrafted with complete donor chimaerism. The incidence of non-relapse mortality at day 100 and after 2 years was 4.5% and 23%, respectively. The probability of overall survival at 2 years was 40%. A comparison with a younger historical cohort (median age 57 years) having received the same dose of fludarabine and busulfan but neither radioimmunotherapy nor alemtuzumab showed no difference in outcome. Although the use of alemtuzumab reduced the incidence of acute graft-versus-host-disease, it was associated with a relapse incidence of 40% despite the incorporation of radioimmmunotherapy. In summary, we confirmed the feasibility of combined radioimmunotherapy and reduced-intensity conditioning in elderly patients. Further optimisation, probably involving less T cell depletion, is necessary before a randomized comparison with standard conditioning can be planned.
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http://dx.doi.org/10.1111/j.1365-2141.2009.08025.xDOI Listing
March 2010

PET aerosol lung scintigraphy using Galligas.

Eur J Nucl Med Mol Imaging 2010 Jan;37(1):175-7

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http://dx.doi.org/10.1007/s00259-009-1304-9DOI Listing
January 2010

Validation of (99m)Tc-labeled "4+1" fatty acids for myocardial metabolism and flow imaging: Part 2. Subcellular distribution.

Nucl Med Biol 2009 Oct;36(7):845-52

Institute of Physiology, Medical Faculty Carl Gustav Carus, Technical University Dresden, 01307 Dresden, Germany.

Introduction: Our group has synthesized technetium-labeled fatty acids (FA) that are extracted into the myocardium and sequestered due to heart-type fatty acid binding protein (H-FABP) binding. In this article, we further address the detailed subcellular distribution and potential myocardial metabolism of [(99m)Tc]"4+1" FA.

Methods: Experiments were conducted using isolated hearts of Wistar rats, as well as of wild-type and H-FABP(-/-) mice. Myocardium samples underwent subcellular fractionation [subsarcolemmal mitochondria (SM), intermyofibrillar mitochondria (IM), cytosol with microsomes, and nuclei and crude membranes] and analysis by thin-layer chromatography and high-performance liquid chromatography.

Results: The largest fraction of tissue radioactivity was associated with cytosol [79.69+/-8.88% of infused dose]. About 9.07+/-0.95% and 3.43+/-1.38% of the infused dose were associated with SM and IM fractions, respectively. In the rat heart, etomoxir, an inhibitor of carnitin-palmitoyl transferase I, did not significantly decrease radioactivity associated with mitochondrial fractions, whereas myocardial extraction of [(123)I]-labeled 15-(p-iodophenyl)-pentadecanoic acid (13.26% vs. 49.49% in controls) and the radioactivity associated with the SM and IM fractions were blunted. The percentage of the infused dose in the mitochondrial and crude fractions increased with the number of NH-amide groups of the FA derivative. Absence of H-FABP significantly decreased radioactivity count in the cytosolic fraction (P<.001). No metabolic product of [(99m)Tc]"4+1" FA could be detected in any isolated heart.

Conclusions: Myocardial [(99m)Tc]"4+1" FA extraction reflects binding to H-FABP and membrane structures (including the mitochondrial membrane). However, the compounds do not undergo mitochondrial metabolism because they do not reach the mitochondrial matrix.
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http://dx.doi.org/10.1016/j.nucmedbio.2009.06.003DOI Listing
October 2009