SummaryThe AMG implies far-reaching implications for the synthesis of new radiopharmaceuticals for clinical trials. Aim, methods: As a part of the DFG-funded Clinical Research Group (KFO 179) a project designated „Immuno-PET for assessment of early response to radiochemotherapy of advanced rectal cancer“ was initiated. This trial is focused on a trivalent bispecific humanized monoclonal antibody, and a 68Ga-labeled peptide. Following the new regulatory framework we established a GMPcompliant cleanroom laboratory and applied for a manufacturing permission. Results: During the project constructural, personnel and organizational conditions for a successful application were established, including a quality management system. A GMP-conform cleanroom laboratory class C was constructed, equipped with a two-chamber lock. The actual manufacturing is performed in a closed system with subsequent sterile filtration. The manufacturing processes have been automatised and validated as well as the necessary quality controls. The manufacturing permission was granted after an official inspection. Conclusions: The new German Drug Act is considered as a break in the production practice of nuclear medicine. The early involvement and communication with the authorities avoids time-consuming and costly planning errors. It is much to be hoped that the new legal situation in Germany will not cause serious impairments in the realization of clinical trials in German nuclear medicine.

The development of monofunctional DTPA derivatives has been a major breakthrough in the labelling of proteins or peptides with a variety of radiometals. Although this methodology is simple and useful for indium-111 labelling, the stability of these conjugates is too low for most therapeutic nuclides. Cyclic chelators, such as DOTA, have shown excellent kinetic stability with a variety of radiometals, but the labelling procedure is more difficult, requiring ultra-pure reagents and a heating step that sometimes endangers the biomolecule's integrity. The aim of this work was twofold: (a) to develop a novel, open chain chelator which can be easily labelled with various radiometals, displaying higher kinetic stability than monofunctional DTPA, and (b) to evaluate this chelator in vitro and in vivo when conjugated to a CCK-B receptor ligand as a detection modality for receptor-(over-)expressing tumours. DTPA derivatives of Leu1- and dGlu1-minigastrin were synthesised. All conjugates could be labelled with 111In or 88/90Y at high specific activities (8.5–44.4 GBq/μmol) and with high radiochemical purity. Serum stability testing was performed, and the labelled conjugates were compared concerning their stability against DTPA challenge. The biodistribution of the radiolabelled Leu1- and dGlu1-minigastrin derivatives was studied in tumour-bearing nude mice, in one healthy human volunteer and in three patients with metastatic medullary thyroid carcinoma. The transchelation of all tested radiometals to serum proteins was significantly slower with the DTPA-Glu conjugates as compared with their Leu analogues (e.g. transchelation t1/2 of DTPA-dGlu1-minigastrin vs its Leu1 analogue at 37°C in human serum for 111In: 239 h vs 91 h; for 90Y: 130 h vs 53 h). In animals, all labelled CCK-B receptor ligands showed fast and specific uptake in CCK-B-receptor-positive tissues, such as the stomach and tumour, as well as a fast renal clearance pattern. However, DTPA-Leu1-minigastrin showed higher background activity in the whole body and those organs known to accumulate the respective free radiometal (e.g. 88Y-DTPA-Leu1-minigastrin had bone uptake of 22%ID/g as compared to only 1.2%ID/g with its dGlu1 analogue). In humans, fast tumour and stomach uptake was observed for both 111In-labelled compounds, but DTPA-dGlu1-minigastrin lacked the liver, spleen and bone marrow uptake observed with its Leu1 analogue. In conclusion, anionic amino acid derivatives of DTPA may display improved metabolic stability as compared with monofunctional DTPA conjugates. DTPA-dGlu1-minigastrin is preferred to "monofunctional" DTPA-Leu1-minigastrin for diagnostic application with 111In for the in vivo detection of CCK-B receptor-expressing tissues.

SummaryAim: Formal and clinical comparison of a new 3rd-gene-ration-Tg-IRMA (3-G-IRMA; Dynotest®Tg-plus) with a conventional Tg-IRMA (3-G-IRMA; SELco®Tg-assay) for patients with differentiated thyroid carcinoma. In addition we evaluated, if thyroglobulin (Tg) levels above a specific threshold concentration indicate the need for further investigations for residual disease. Patients, methods: Tg concentration of 105 sera of 93 consecutive patients with a differentiated thyroid cancer was determined with both assays and compared at different cut-off values (Dynotest®Tg-plus: 0.2, 1, 2 ng/ml; SELco®Tg-assay: 0.5, 1, 2 ng/ml) with the clinical results in respect to the corresponding TSH concentration. Results: Tg concentration did not show any significant difference (SELco®Tg-assay 0.5 ng/ml, Dynotest® Tg-plus 0.2 ng/ml). The Tg-values of both assays correlated with 97%. However, correlation of recovery in both assays was small (40%). The sensitivities and specificities of both assays at different cut-offs and TSH values did not reveal significant differences. In patients with TSH concentration >30 µU/ml the functional assay sensitivity was superior to arbitrary cut-offs in the decision to start further evaluations. Conclusions: In our study neither formal nor clinical significant differences between two Tg-assays were found. In a hypothyroid patient (TSH >30 µU/ml, Tg concentration exceeding the functional assay sensitivity) further investigations for residual disease are warranted. Higher thresholds are of limited value, due to a inacceptable high rate of false negative results.

BACKGROUND: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 ((131)I)-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 (131)I-labeled humanized anti-CEA antibody in colorectal cancer patients with small-volume disease or in an adjuvant setting.METHODS:Thirty colorectal cancer patients, with small-volume metastatic disease (n = 21; all lesions less-than-or-equal 3.0 cm, and chemorefractory to 5-fluorouracil and folinic acid) or in an adjuvant setting (n = 9), 4-6 weeks after surgical resection of liver metastases with curative intention, were studied. The patients were given a single injection of (131)I-hMN-14 immunoglobulin G at a 60 mCi/m(2) dose level, which was shown to be the maximum tolerated dose in the previous Phase I study. Follow-up was obtained at 3-month intervals for as long as 36 months.RESULTS:At a mean blood-based red marrow dose of 1.8 +/- 0.8 Gy, myelotoxicity was the only toxicity observed, but only 1 of 28 assessable patients developed transient Grade 4 thrombocytopenia. Of the 21 patients with radiologically documented lesions, 19 were assessable. Three experienced partial remission and eight showed minor responses up to 15 months in duration (corresponding to an objective response rate of 16% and an overall response rate of 58%; the mean duration of response was 9 months). At the time this article was written, seven of nine patients in the adjuvant setting had remained free of disease for up to 36 months (one patient relapsed after 6 months and another after 30 months), whereas the relapse rate in a historical control group receiving chemotherapy was 67% over the same time period. Five patients with radiologically documented lesions, having experienced at least disease stabilization as a consequence of RIT, were retreated at the same 60-mCi/m(2) dose level at 8-16 months after the first therapy. No evidence of increased toxicity was observed (no hematologic toxicity was higher than Grade 3). Two of four assessable retreated patients experienced partial remissions; one of these four again experienced disease stabilization as a consequence of the second radioantibody therapy injection.CONCLUSIONS:These data suggest that RIT is a safe and effective form of therapy for small-volume colorectal cancer and has potential as treatment for colorectal cancer in an adjuvant setting. Toxicity is restricted to mild and transient leuko- and thrombocytopenia. Retreatment seems to be a feasible option. A prospective randomized comparison with standard chemotherapy is indicated.

Retraction: “Radioimmunotherapy of small‐volume disease of metastatic colorectal cancer: results of a phase II trial with the iodine‐131–labeled humanized anti–carcinoembryonic antigen antibody hMN‐14,” by Behr TM, Liersch T, Greiner‐Bechert L, Griesinger F, Béhé M, Markus PM, Gratz S, Angerstein C, Brittinger G, Becker H, Goldenberg DM, Becker W.1

BACKGROUND. 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 (I-131)-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 I-131-labeled humanized anti-CEA antibody in colorectal cancer patients with small-volume disease or in an adjuvant setting. METHODS. Thirty colorectal cancer patients, with small-volume metastatic disease (n = 21; all lesions less than or equal to 3.0 cm, and chemorefractory to 5-fluorouracil and folinic acid) or in an adjuvant setting (n = 9), 4-6 weeks after surgical resection of liver metastases with curative intention, were studied. The patients were given a single injection of I-131 -hMN- 14 immunoglobulin G at a 60 mCi/m(2) dose level, which was shown to be the maximum tolerated dose in the previous Phase I study. Follow-up was obtained at 3-month intervals for as long as 36 months. RESULTS. At a mean blood-based red marrow dose of 1.8 +/- 0.8 Gy, myelotoxicity was the only toxicity observed, but only 1 of 28 assessable patients developed transient Grade 4 thrombocytopenia. Of the 21 patients with radiologically documented lesions, 19 were assessable. Three experienced partial remission and eight showed minor responses up to 15 months in duration (corresponding to an objective response rate of 16% and an overall response rate of 58%; the mean duration of response was 9 months). At the time this article was written, seven of nine patients in the adjuvant setting had remained free of disease for up to 36 months (one patient relapsed after 6 months and another after 30 months), whereas the relapse rate in a historical control group receiving chemotherapy was 67% over the same time period. Five patients with radiologically documented lesions, having experienced at least disease stabilization as a consequence of RIT, were retreated at the same 60-mCi/m(2) dose level at 8-16 months after the first therapy. No evidence of increased toxicity was observed (no hematologic toxicity was higher than Grade 3). Two of four assessable retreated patients experienced partial remissions; one of these four again experienced disease stabilization as a consequence of the second radioantibody therapy injection. CONCLUSIONS. These data suggest that RIT is a safe and effective form of therapy for small-volume colorectal cancer and has potential as treatment for colorectal. cancer in an adjuvant setting. Toxicity is restricted to mild and transient leuko- and thrombocytopenia. Retreatment seems to be a feasible option. A prospective randomized comparison with standard chemotherapy is indicated. Cancer 2002; 94:1373-81. (C) 2002 American Cancer Society.

Introduction In the present study, Tc-99m-radiolabelled E-selectin binding peptide (Tc-99m-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 (Tc-99m-IMP-100) to demonstrate specificity.Methods An acute pyogenic osteomyelitis was induced by injecting 0.05 ml of 5% sodium morrhuate and 5 x 10(8) 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 Tc-99m-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, Tc-99m-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 Tc-99m-IMP-178 and 0.30 +/-0.02% ID.g(-1) for Tc-99m-IMP-100), resulting in a higher osteomyelitis-to-healthy collateral ratio with T/B of 2.40 +/-0.65 (Tc-99m-IMP-178) compared with 1.85 +/-0.48 (Tc-99m-IMP-100). No adverse reactions were seen after injection of 99mTc-IMP-178.Conclusions Tc-99m-IMP-178 allows imaging of an acute osteomyelitic lesions, presumably by interaction of Tc-99m-IMP-178 with activated upregulated vascular endothelium. ((C) 2001 Lippincott Williams & Wilkins).

Derivatives of somatostatin (sms) are attracting increasing interest as part of the treatment of several cancer diseases expressing sms receptors (srs). Radiolabeled sms analogs can additionally be used for systemic radiotherapy and for diagnostic investigations.