Stefan Gratz

Radioimmunotherapy of small-volume disease of metastatic colorectal cancer.

Whereas radioimmunotherapy (RIT) has shown disappointing results in bulky, solid tumors, preclinical results in small‐volume disease and in an adjuvant setting are promising. In a previous Phase I study, the authors had encouraging results with the iodine‐131 (131I)–labeled humanized anti–carcinoembryonic antigen (anti‐CEA) antibody (MAb) hMN‐14 in small‐volume disease of colorectal cancer. The aim of this study was to evaluate, in a subsequent Phase II trial, the therapeutic efficacy of this 131I‐labeled humanized anti‐CEA antibody in colorectal cancer patients with small‐volume disease or in an adjuvant setting.

Experimental studies on the role of antibody fragments in cancer radio-immunotherapy: Influence of radiation dose and dose rate on toxicity and anti-tumor efficacy

Whereas bivalent fragments have been widely used for radio‐immunotherapy, no systematic study has been published on the therapeutic performance of monovalent conjugates in vivo. The aim of our study was, therefore, to determine the therapeutic performance of 131I‐labeled Fab as compared to bivalent conjugates and to analyze factors that influence dose‐limiting organ toxicity and anti‐tumor efficacy. The maximum tolerated doses (MTDs) and dose‐limiting organ toxicities of the 131I‐labeled anti‐CEA antibody MN‐14 [IgG, F(ab′)2 and Fab] were determined in nude mice bearing s.c. human colon cancer xenografts. Mice were treated with or without bone marrow transplantation (BMT) or inhibition of the renal accretion of antibody fragments by D‐lysine or combinations thereof. Toxicity and tumor growth were monitored. Radiation dosimetry was calculated from biodistribution data. With all 3 131I‐labeled immunoconjugates [IgG, F(ab′)2 and Fab], the red marrow was the only dose‐limiting organ; MTDs were 260 μCi for IgG, 1,200 μCi for F(ab′)2 and 3 mCi for Fab, corresponding to blood doses of 17 Gy, 9 Gy and 4 Gy, respectively. However, initial dose rates were 10 times higher with Fab as compared to IgG and 3 times higher as compared to F(ab′)2. The MTD of all 3 immunoconjugates was increased by BMT by approximately 30%. In accordance with renal doses below 10 Gy, no signs of nephrotoxicity were observed. Despite lower absorbed tumor doses, at equitoxic dosing, Fab fragments were more effective at controlling tumor growth than the respective bivalent fragment or IgG, probably due to higher intratumoral dose rates. Our data indicate that the improved anti‐tumor effectiveness of antibody fragments as compared to IgG and the higher myelotoxicity at comparably lower red marrow doses are most likely due to the higher initial dose rates observed with antibody fragments. Int. J. Cancer 77:787–795, 1998.

18F-FDG PET, somatostatin receptor scintigraphy, and CT in metastatic medullary thyroid carcinoma: a clinical study and an analysis of the literature.

AimTo determine the clinical potential of 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography (18F-FDG PET) in patients with medullary thyroid carcinoma (MTC), we compared it to computed tomography (CT), and somatostatin receptor scintigraphy (SRS). Patients and methodsBlinded evaluation of PET, CT and SRS images obtained from 26 patients with histologically proven metastatic MTC was done by nuclear medicine and radiology specialists. Sites of tumour involvement were classified as ‘sure’ or ‘suspicious’. The data were analysed in comparison to two different standards. Either those sites classified as ‘sure’ by at least one of the methods were defined as the standard or those sites of involvement which were classified as ‘sure’ by at least two methods. ResultsDependent on the type of data analysis performed, PET was able to demonstrate 56.8%/80.6% of the tumour sites, CT showed 64.5%/79.6%, and SRS showed 47.5%/69.9% of the tumour sites. ConclusionOverall, CT is similar or better than PET in our patients (dependent on the standard) while SRS is inferior to both other techniques. Our data are in agreement with publications that consider CT superior to PET in the diagnosis of metastatic MTC while other studies show superiority of PET. However, a combination of CT and PET seems to be the most appropriate non-invasive diagnostic approach in patients with MTC.

Therapeutic efficacy and dose-limiting toxicity of auger-electron vs. beta emitters in radioimmunotherapy with internalizing antibodies: Evaluation of 125I- vs. 131I-labeled CO17-1A in a human colorectal cancer model

Recent clinical results suggest that higher anti‐tumor efficacy may be achieved with internalizing monoclonal antibodies (MAbs) at lower toxicity when labeled with Auger‐electron, as compared to conventional β‐emitters. The aim of our study was to compare the toxicity and anti‐tumor efficacy of the 125I‐labeled internalizing MAb, CO17‐1A, with its 131I‐labeled form in a human colon cancer model in nude mice. Biodistribution studies were performed in nude mice bearing s.c. human colon cancer xenografts. For therapy, the mice were injected either with unlabeled 125I‐ or 131I‐labeled CO17‐1A at equitoxic doses. Control groups were left untreated, were given a radiolabeled isotype‐matched irrelevant antibody or a tumor‐specific, but noninternalizing antibody. The maximum tolerated activities (MTD) of 131I‐ and 125I‐CO17‐1A without artificial support were 300 μCi and 3 mCi, respectively. Myelotoxicity was dose‐limiting; bone marrow transplantation allowed for an increase of the MTD to 400 μCi of 131I‐17‐1A, whereas the MTD of 125I‐17‐1A with bone marrow support had not been reached at 5 mCi. Whereas no significant therapeutic effects were seen with unlabeled CO17‐1A, tumor growth was retarded with 131I‐CO17‐1A. With the 125I‐label, however, therapeutic results were clearly superior. In contrast, no significant difference was observed in the therapeutic efficacy of the 131I‐ vs. 125I‐labeled, noninternalizing antibodies. Our data indicate a superiority of Auger‐electron emitters, such as 125I, as compared to therapy with conventional β‐emitters with internalizing antibodies. The lower toxicity of Auger emitters may be due to the short path length of their low‐energy electrons, which can reach the nuclear DNA only if the antibody is internalized (as is the case in antigen‐expressing tumor tissue, but not in the stem cells of the red marrow). Int. J. Cancer 76:738–748, 1998.© 1998 Wiley‐Liss, Inc.

Enhanced bilateral somatostatin receptor expression in mediastinal lymph nodes (“chimney sign”) in occult metastatic medullary thyroid cancer: A typical site of tumour manifestation?

In medullary thyroid cancer (MTC), post-surgically elevated plasma calcitonin and/or carcinoembryonic antigen levels frequently indicate persisting metastatic disease, although conventional diagnostic procedures fail to localize the responsible lesions (occult disease). Somatostatin analogues have been used successfully in disease localization, but recently concerns have been raised that increased thoracic uptake of indium-111 pentetreotide in patients with previous external beam irradiation may represent a false-positive finding, caused by post-irradiation pulmonary fibrosis. We recently examined seven patients with metastatic MTC by somatostatin receptor scintigraphy (six with occult and one with established disease). In four patients, all of whom had stable or slowly rising tumour marker levels over several years, a chimney-like bilateral mediastinal uptake of indium-111 penetreotide was found. In two patients with persisting hypercalcitonaemia immediately after primary surgery, supraclavicular lymph node metastases were identified as the responsible lesions. None of these seven patients had prior external beam radiation therapy. In two cases, histological confirmation was obtained. In one patient, disease progression could be shown during follow-up. These data suggest that bilateral mediastinal lymph node involvement is a typical site of disease in slowly progressing occult metastatic MTC; the “chimney sign” may represent a typical finding with somatostatin analogues in such cases. Therefore, we believe that even in the case of prior external beam irradiation, mediastinal uptake of octreotide might represent metastatic MTC rather than radiation fibrosis.

(99m)Tc-E-selectin binding peptide for imaging acute osteomyelitis in a novel rat model.

Introduction In the present study, 99mTc-radiolabelled E-selectin binding peptide (99mTc-IMP-178) was investigated for its potential to image acutem pyogenic osteomyelitis in a new animal model. Intraindividual comparisons were performed using an irrelevant peptide (99mTc-IMP-100) to demonstrate specificity. Methods An acute pyogenic osteomyelitis was induced by injecting 0.05 ml of 5% sodium morrhuate and 5×108 CFU of Staphylococcus aureus into the medullary cavity of the right tibia in 16 rats. Sixteen additional rats served as untreated controls. Whole-body imaging of pyogenic (n = 4) and untreated (n = 4) animals was performed continously during the first 8 h (12 MBq i.v. of 99mTc-IMP-178 and 99mTc-IMP-100 for control), and one further single image was acquired after 16 h p.i. Tissue biodistribution studies were performed in 12 rats with an acute pyogenic osteomyelitis and in 12 untreated rats 1, 4 and 24 h after injection. Data of the histological/radiological and haematological investigations were obtained in all animals. Results Histopathologically, 15 of 16 treated rats (93%) developed an acute pyogenic osteomyelitis showing a major infiltration of the bone marrow by polymorphonuclear leukocytes as well as the formation of sequestra. Haematologically, the number of leukocytes increased by 100%, the lymphocytes by 11% and the granulocytes decreased by 39%. After i.v. injection, 99mTc-IMP-178 rapidly cleared from the body resulting in good scintigraphic target-to-background (T/B) ratios. The highest uptake of the tracer in the pyogenic bone was observed at 60 min p.i. (0.43±0.02% ID·g−1 for 99mTc-IMP-178 and 0.30±0.02% ID·g−1 for 99mTc-IMP-100), resulting in a higher osteomyelitis-to-healthy collateral ratio with T/B of 2.40±0.65 (99mTc-IMP-178) compared with 1.85±0.48 (99mTc-IMP-100). No adverse reactions were seen after injection of 99mTc-IMP-178. Conclusions 99mTc-IMP-178 allows imaging of an acute osteomyelitic lesions, presumably by interaction of 99mTc-IMP-178 with activated upregulated vascular endothelium.

Nuclear medical imaging in case of painful knee arthroplasty

ZusammenfassungHintergrundZiel der vorliegenden Studie war die Bewertung der diagnostischen Treffsicherheit nuklearmedizinischer Untersuchungstechniken bei Patienten mit schmerzhafter Knieprothese.Material und MethodenZwischen 2003 und 2007 wurden 87 Patienten mit schmerzhafter Knieprothese sowohl mit der 99mTc-Dreiphasenskelettszintigraphie (99mTc-Dreiphasen-DPD; n=120) als auch mit 99mTc-anti-Granulozyten-Antikörpern (Behring-Werke 250/183; n=20) untersucht.ErgebnisseAusgewertet wurden 87 Patienten mit 94 Knieprothesen mit Verdacht auf septische Prothesenlockerung. Sensitivität, Spezifität, positiver und negativer prädiktiver Wert sowie die diagnostische Genauigkeit mit der 99mTc-Dreiphasen-DPD zur Unterscheidung zwischen septischer und aseptischer Knieprothesenlockerung betrugen 100, 85, 55, 100, 73 und bei BW 250/183 91, 66, 76, 85, 80%. Ein signifikanter Zugewinn an diagnostischer Genauigkeit mit entsprechend 94, 88, 89, 95 und 89% (p <0,001) konnte erreicht werden, wenn beide Methoden kombiniert ausgewertet wurden.SchlussfolgerungBeide Methoden alleine haben einen hohen negativen prädiktiven Aussagewert, aber die Kombination beider Methoden ergänzen sich, sodass ein signifikanter Zugewinn an diagnostischer Genauigkeit und positivem prädiktivem Aussagewert zum spezifischen Nachweis einer Knieprothesenlockerung erreicht werden kann.AbstractRationaleThe aim of the present study was to calculate the overall diagnostic accuracy of nuclear medical imaging in patients with painful knee arthroplasty.Material and methodsThis retrospective study of all patients (n=87) where a 99mTc-triple phase bone scintigraphy (TPBS; n=120) and 99mTc-anti-granulocyte scintigraphy (BW 250/183; n=20) for a painful knee arthroplasty was performed between 2003 and 2007.ResultsA total of 87 patients with 94 knee arthroplasties were examined to detect septic and aseptic loosening and to differentiate between them. The sensitivity, specificity, the positive and negative predictive value and accuracy of TPBS for the detection of septic knee arthroplasty loosening was 100%, 85%, 55%, 100%, 73% and for BW 250/183 was 91%, 66%, 76%, 85%, 80% for sepsis, respectively. A significant increase in diagnostic accuracy with 94%, 88%, 89%, 95% und 89% (p <0.001) could be achieved when both methods were used in combination.ConclusionBoth methods alone have high negative predictive values, but the combination of both is complementary and significantly increases the diagnostic accuracy and positive predictive value for final diagnosis of knee arthroplasty loosening.RATIONALE The aim of the present study was to calculate the overall diagnostic accuracy of nuclear medical imaging in patients with painful knee arthroplasty. MATERIAL AND METHODS This retrospective study of all patients (n=87) where a (99m)Tc-triple phase bone scintigraphy (TPBS; n=120) and (99m)Tc-anti-granulocyte scintigraphy (BW 250/183; n=20) for a painful knee arthroplasty was performed between 2003 and 2007. RESULTS A total of 87 patients with 94 knee arthroplasties were examined to detect septic and aseptic loosening and to differentiate between them. The sensitivity, specificity, the positive and negative predictive value and accuracy of TPBS for the detection of septic knee arthroplasty loosening was 100%, 85%, 55%, 100%, 73% and for BW 250/183 was 91%, 66%, 76%, 85%, 80% for sepsis, respectively. A significant increase in diagnostic accuracy with 94%, 88%, 89%, 95% und 89% (p <0.001) could be achieved when both methods were used in combination. CONCLUSION Both methods alone have high negative predictive values, but the combination of both is complementary and significantly increases the diagnostic accuracy and positive predictive value for final diagnosis of knee arthroplasty loosening.

Unexpected 99mTc-tetrofosmin findings during myocardial perfusion scintigraphy: intraindividual comparison with PET/computed tomography.

Objective99mTc-tetrofosmin single photon emission computed tomography (SPECT) is routinely used in the evaluation of coronary artery disease. A variety of different tumors, however, also demonstrate 99mTc-tetrofosmin uptake. We report six patients found with unexpected mediastinal and thoracic tumor uptake during 99mTc-tetrofosmin myocardial perfusion scintigraphy (MPS). Materials and methodsWe investigated 2155 patients with 99mTc-tetrofosmin MPS during 2006–2007. One thousand four hundred and eighty-six of these patients had no coronary history and were sent to our department due to newly developed thoracic complaint such as chest pain, dyspnea and others. Six hundred and sixty-nine patients had coronary history. All patients underwent 99mTc-tetrofosmin exercise study. Patients with unexpected extracardiac 99mTc-tetrofosmin findings during MPS were referred to PET/CT for further diagnostic investigation. Region of interest (ROI; 99mTc-tetrofosmin) and SUVmax (2-[18F]fluoro-2-deoxy-D-glucose, 18F-FDG) were estimated and the results were compared with histological findings. ResultsAbnormal mediastinal and/or thoracic activities were visualized in six of the 2155 patients with 99mTc-tetrofosmin images. Subsequently, the patients underwent resection of a thymoma (n=2), nonsmall cell lung cancer (n=1) and breast cancer (n=3). In the patients with breast cancer one was a male patient with ductal, invasive breast cancer. Benign thymomas showed high 99mTc-tetrofosmin ROI >4.0 and low 18F-FDG SUVmax <2.0, whereas low 99mTc-tetrofosmin ROI <2.0 were found in nonsmall cell lung cancer and breast cancer and high 18F-FDG SUVmax >2.5 in these malignant tumors. ConclusionDuring 99mTc-tetrofosmin SPECT exercise stress tests performed in patients with suspected coronary artery disease, much more attention must be given to unexpected extracardiac uptakes. With 99mTc-tetrofosmin a large variety of different unknown tumors can be detected during MPS.

Follow-up of perfusion defects in pulmonary perfusion scanning after pulmonary embolism: are we too careless?

Persisting perfusion defects may still be found in pulmonary perfusion scintigraphy months or years after pulmonary embolism. The aim of this study was to investigate the rate of persisting perfusion defects and the pattern of scintigraphic follow-up of patients after pulmonary embolism. Only those patients were included into our study who received pulmonary perfusion scintigraphy between 1991 and 1999, and who had perfusion defects including at least one whole segment. These perfusion defects were considered as persisting perfusion defects if unchanged over at least 1 year. From 3640 patients examined, 451 (12.4%) had perfusion defects meeting the criteria of this study. Of those, 129 (28.6%) received a scintigraphic follow-up. In 62 patients (48.1%), a reperfusion of the defects was found. In 38 patients (29.5%), the defects persisted within a follow-up period of up to 12 weeks. However, no pulmonary perfusion scintigraphy was performed thereafter. Out of the 129 patients receiving a scintigraphic follow-up, only 29 (22.5%) had a follow-up over more than 1 year, 19 of those had persisting perfusion defects. It is concluded that our data show an inadequate scintigraphic follow-up of patients with pulmonary embolism which may lead to unnecessary anticoagulant treatment if persisting perfusion defects are misinterpreted as fresh pulomary embolism. In many cases, there was no further follow-up even if reperfusion of the defects was lacking in early follow-up.

Is there Still Enough Diagnostic Confidence with Bone Spect Scintigraphy Alone: A Retrospective Evaluation and Extended Review of the Literature

Aim: Single photon emission computed tomography (SPECT) dramatically increases the sensitivity of bone scanning for detection of spinal abnormalities. However, the level of specificity obtained by SPECT remains controversial and increased diagnostic confidence can be obtained with new imaging modalities such as fused PET/CT and SPECT/CT. Patients and Methods: Between 7/2005 and 7/2007 ninety one patients with different malignant primary tumors were in- vestigated. Following injection of 555 MBq 99m Tc - MDP planar and SPECT images were performed in all patients. Re- sults: Out of a total of 145 spinal lesions was confirmed by radiography, SPECT detected 133 (91%). In contrast, planar scintigraphy detected only 99/145 (68%) lesions. SPECT uptake pattern including the vertebral body and an adjacent pedicle was seen in 9/28 (32%) of metastatic lesions and in 1/2 (50%) cases of spondylitis. SPECT uptake pattern includ- ing the pedicle alone was seen in 45/115 (39%) of degenerative alterations. Focal lesions limited to the lateral part of the vertebral body, especially to the pars interarticularis (n=8), facet joints (n=14) and costotransversal joints (n=6), were cor- rectly diagnosed as spondylarthrosis and costotransversalarthrosis in all cases. Furthermore, SPECT uptake pattern of spondylitis was biconcave, whereas metastatic lesions showed focal or linear uptakes. Conclusion: SPECT without image fusion still gives sufficient diagnostic confidence for the differentiation of benign and malignant spine lesions. Uptake pat- terns localized at the facet joints or localized at the pedicles are indicative for benign lesions, whereas continuous uptake patterns of the vertebral body and adjacent pedicle remain suspicious for malignancy.