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W Becker

Publications and source records attributed to W Becker.

At least 145 records · Page 8Linked to original sources
PubMed1999

Cholecystokinin-B/gastrin receptor binding peptides: preclinical development and evaluation of their diagnostic and therapeutic potential.

The high sensitivity of pentagastrin stimulation in detecting primary or metastatic medullary thyroid cancer (MTC) suggests widespread expression of the corresponding receptor type on human MTC. Indeed, autoradiographic studies demonstrated cholecystokinin (CCK)-B/gastrin receptors not only in >90% of MTCs but in a high percentage of small cell lung cancers and potentially a variety of gastrointestinal adenocarcinomas. In a pilot study, we have demonstrated the feasibility of radiolabeled gastrin-I to target CCK-B receptor-expressing tissues in vivo in animals and patients (T. M. Behr et al., Eur. J. Nucl. Med., 25: 424-430, 1998). The aim of the present study was to systematically optimize, in a preclinical model, suitable radioligands for targeting CCK-B receptors in vivo. For this purpose, a variety of CCK/gastrin-related peptides, all having in common the COOH-terminal CCK-receptor binding tetrapeptide sequence Trp-Met-Asp-PheNH2 or derivatives thereof, were studied. They were radioiodinated by the Iodogen or Bolton-Hunter procedures. The peptides tested were members of the gastrin- or cholecystokinin families or possessed characteristics of both, which differ by the intramolecular position of a tyrosyl moiety (occurring in native or sulfated form). Their stability and affinity were studied in vitro and in vivo; their biodistribution and therapeutic efficacy were tested in nude mice bearing s.c. human MTC xenografts. Diethylene-triamine-pentaacetate derivatives of suitable peptides were synthesized, evaluated, and labeled with (111)In. All members of the CCK or gastrin family were stable in serum (with t(1/2)s of several hours at 37 degrees C); nevertheless, the stability of those peptides was highest that bore the NH2-terminal pGlu residues (e.g., big gastrin, gastrin-I, caerulein, and others) or D-amino acids. In accordance to their comparably low affinity, nonsulfated members of the CCK family showed fairly low uptake in the tumor and other CCK-B receptor-expressing tissues (e.g., the stomach). Sulfated CCK derivatives performed significantly better but additionally displayed a high uptake in normal, CCK-A receptor-expressing tissues (such as the liver/gallbladder, pancreas, and bowel). Best tumor uptake and tumor:nontumor ratios were obtained with members of the gastrin family, probably because of their selectivity and affinity for the CCK-B receptor subtype. Pilot therapy experiments in MTC bearing animals showed significant antitumor efficacy as compared with untreated controls. (111)In-Labeled diethylene-triamine-pentaacetate derivatives of minigastrin showed excellent targeting of CCK-B receptor-expressing tissues in animals and a normal human volunteer. These data suggest that CCK/gastrin analogues may be a useful new class of receptor binding peptides for diagnosis and therapy of CCK-B receptor-expressing tumors, such as MTC or small cell lung cancer. Nonsulfated gastrin derivatives may be preferable because of their CCK-B receptor selectivity, and hence, lower accretion in normal CCK-A receptor-expressing organs. Further preclinical as well as clinical studies are ongoing.

Amino Acid Sequence↗
PubMed1999

Radioimmunotherapy of small volume disease of colorectal cancer metastatic to the liver: preclinical evaluation in comparison to standard chemotherapy and initial results of a phase I clinical study.

At the time of surgery, occult metastases (micrometastases) are present in more than 50% of colorectal cancer patients, and the liver is the most frequent site of apparent metastatic disease. Frequently, adjuvant chemotherapy is unable to prevent tumor recurrence. Thus, novel therapeutic strategies are warranted. The aim of this study was to establish a model of human colon cancer metastatic to the liver of nude mice, to assess, in this setting, the therapeutic efficacy of radioimmunotherapy (RAIT) compared to standard chemotherapy and to evaluate, in a Phase I/II trial, the toxicity and therapeutic efficacy of RAIT in colorectal cancer patients with small volume disease metastatic to the liver. Multiple liver metastases of the human colon cancer cell line GW-39 were induced by intrasplenic injection of a 10% tumor cell suspension. Whereas controls were left untreated, therapy was initiated on day 10 or 20 after tumor inoculation with the 131I-labeled, low affinity anticarcinoembryonic antigen (anti-CEA) monoclonal antibody (MAb), F023C5 (Ka = 10(7) liters/mol), or the high-affinity anti-CEA MAb, MN-14 (Ka = 10(9) liters/mol), or chemotherapy (5-fluorouracil/leucovorin (folinic acid) versus irinotecan) at their respective maximum tolerated doses (MTDs). Twelve colorectal cancer patients with small volume disease metastatic to the liver (all lesions < or = 2.5 cm) were entered into a mCi/m2-based Phase I dose escalation study with 131I-labeled humanized version of MN-14, hMN-14. The patients were given single injections, starting at 50 mCi/m2 and escalating in 10-mCi/m2 increments. The MTD was defined as the dose level at which < or = 1 of 6 patients develop grade 4 myelotoxicity. In the mice, untreated controls died from rapidly progressing hepatic metastases at 6-8 weeks after tumor inoculation. The life span of mice treated with 5-fluorouracil/leucovorin was prolonged for only 1-3 weeks, whereas irinotecan led to a 5-8-week prolongation. In contrast, at their respective MTDs, the 131I-labeled low-affinity anti-CEA MAb, F023C5, led to a 20% permanent cure rate, and the high affinity MAb, MN-14, led to an 80% permanent cure rate, when therapy was initiated at 10 days after tumor inoculation. In the 20-day-old tumor stage, although it prolonged life, 131I-F023C5 was unable to achieve cures, whereas 131I-MN-14 was still successful in 20%. Histologically, no remaining viable tumor cells could be demonstrated in these animals surviving > 6 months. In patients, the MTD was reached at 60 mCi/m2 of hMN-14 (at 70 mCi/m2, two of three grade 4 myelotoxicities). Of 11 assessable patients, 2 had partial remissions (corresponding to an objective response rate of 18%), and 5 (45%) had minor/mixed responses or experienced stabilization of previously rapidly progressing disease. These data suggest that in small volume disease, RAIT may be superior to conventional chemotherapy. Antibodies of higher affinity seem to be clearly superior. The clinical response rates in patients with small volume disease are encouraging, being comparable to the response rates of conventional chemotherapeutic regimens but with fewer side effects. Ongoing studies will show whether treatment at the MTD will further improve therapeutic results.

Adult↗
PubMed1999

Low- versus high-dose radioimmunotherapy with humanized anti-CD22 or chimeric anti-CD20 antibodies in a broad spectrum of B cell-associated malignancies.

Both CD22 and CD20 have been used successfully as target molecules for radioimmunotherapy (RAIT) of low-grade B cell non-Hodgkin's lymphoma. Because both CD20 and CD22 are highly expressed relatively early in the course of B cell maturation, and because its expression is maintained up to relatively mature stages, we studied the potential of the humanized anti-CD22 antibody, hLL2, as well as of the chimeric anti-CD20 (chCD20) antibody, rituximab (IDEC-C2B8), for low- or high-dose (myeloablative) RAIT of a broad range of B cell-associated hematological malignancies. A total of 10 patients with chemorefractory malignant neoplasms of B cell origin were studied with diagnostic (n = 5) and/or potentially therapeutic doses (n = 9) of hLL2 (n = 4; 0.5 mg/kg, 8-315 mCi of 131I) or chCD20 (n = 5; 2.5 mg/kg, 15-495 mCi of 131I). The diagnostic doses were given to establish the patients' eligibility for RAIT and to estimate the individual radiation dosimetry. One patient suffered of Waldenström's macroglobulinemia, eight patients had low- (n = 4), intermediate- (n = 2) or high- (n = 2) grade non-Hodgkin's lymphoma, and one patient had a chemorefractory acute lymphatic leukemia, after having failed five heterologous bone marrow or stem cell transplantations. Three of these 10 patients were scheduled for treatment with conventional (30-63 mCi, cumulated doses of up to 90 mCi of 131I) and 7 with potentially myeloablative (225-495 mCi of 131I) activities of 131I-labeled hLL2 or chCD20 (0.5 and 2.5 mg/kg, respectively); homologous (n = 6) or heterologous (n = 1) stem cell support was provided in these cases. Good tumor targeting was observed in all diagnostic as well as posttherapeutic scans of all patients. In myeloablative therapies, the therapeutic activities were calculated based on the diagnostic radiation dosimetry, aiming at lung and kidney doses < or = 20 Gy. Stem cells were reinfused when the whole-body activity retention fell below 20 mCi. In eight assessable patients, five had complete remissions, two experienced partial remissions (corresponding to an overall response rate of 87%), and one (low-dose) patient had progressive disease despite therapy. In the five assessable, actually stem-cell grafted patients, the complete response rate was 100%. Both CD20 and CD22 seem to be suitable target molecules for high-dose RAIT in a broad spectrum of hematological malignancies of B cell origin with a broad range of maturation stages (from acute lymphatic leukemia to Waldenström's macroglobulinemia). The better therapeutic outcome of patients undergoing high-dose, myeloablative RAIT favors this treatment concept over conventional, low-dose regimens.

Adolescent↗
PubMed1999

Scintigraphy with 99mTc-pertechnetate in the evaluation of functional thyroidal autonomy.

Iodine deficiency and iodine deficiency disorders are still present in several parts of Europe. Sonography is neither specific in the diagnosis nor sensitive in the evaluation of the amount of autonomous thyroid tissue. Thyroidal autonomy is defined as a functional state of the thyroid and therefore only functional scintigraphic imaging, preferably performed with 99mTc-pertechnetate (99mTcO4-), will offer both high sensitivity and specificity in its diagnosis. Recently the cloning and characterisation of the Na+/I- symporter (NIS) offered a deeper understanding of iodine and pertechnetate uptake in the thyroid gland. Overexpression of the Na+/I- symporter following activation of the adenylate-cyclase-cAMP-cascade has been demonstrated in hot nodules, which gives for the first time an explanation for the enhanced iodine clearance of autonomous thyroidal tissue on a molecular level. The scintigraphic evaluation of thyroidal autonomy is performed both as a quantitative and qualitative thyroid scintigraphy, using a gamma camera fitted with an on-line computer system. A strong and linear correlation between the global 99mTc-pertechnetate thyroid uptake (TCTU) and 123I clearance has been recognised. Therefore TCTU-values can be used as a reliable equivalent of the iodine clearance in the evaluation of actual thyroid function. The clinical value of the TCTU in the diagnosis of thyroidal autonomy is limited because it represents iodine clearance of both normal and autonomous tissue. As a consequence scintigraphic diagnosis and quantification of autonomy can only be established if the global 99mTc-pertechnetate thyroid uptake under suppression (TCTUs) is determined. This method is sensitive in risk stratification of spontaneous or iodine induced hyperthyroidism, in the estimation of the target volume prior to radioiodine therapy independently of its distribution and in the evaluation of therapeutic success after definitive therapy.

Humans↗
PubMed1999

Diagnostic applications of radiolabeled peptides in nuclear endocrinology.

Regulatory peptides are small, readily diffusable and potent natural substances with a wide spectrum of receptor-mediated actions in humans. High affinity receptors for these peptides are (over-) expressed in many neoplasms, and these receptors may represent, therefore, new molecular targets for cancer diagnosis and therapy. This review intends to give an overview of the peptide-based radiopharmaceuticals which are presently already commercially available or which are in advanced stages of their clinical testing so that their broader availability is anticipated soon. Physiologically, these peptides bind to and act through G protein-coupled receptors in the cell membrane. Historically, somatostatin analogs are the first class of receptor binding peptides having gained clinical application. 111In-DTPA-[D-Phe1]-octreotide is the first and only radiopeptide which has obtained regulatory approval in Europe and the United States to date. Extensive clinical studies involving several thousands of patients have shown that the major clinical application of somatostatin receptor scintigraphy is the detection and the staging of gastroenteropancreatic neuroendocrine tumors (carcinoids). In these tumors, octreotide scintigraphy is superior to any other staging method. However, its sensitivity and accuracy in other, more frequent neoplasms is limited. Radiolabeled vasoactive intestinal peptide (VIP) has been shown to visualize the majority of gastrointestinal adenocarcinomas, as well as some neuroendocrine tumors, including insulinomas (the latter being often missed by somatostatin receptor scintigraphy). Due to the outstanding diagnostic accuracy of the pentagastrin test in detecting the presence, persistence, or recurrence of medullary thyroid cancer (MTC), we postulated the expression of the corresponding [i.e., cholecystokinin (CCK-)-B] receptor type in human MTC. This receptor is also widely expressed on human small-cell lung cancer. Indeed, 111In-labeled DTPA derivatives of gastrin showed excellent targeting of CCK-B receptor expressing tissues in animals and patients. A variety of further peptide-based radioligands is currently under development. Summarizing, radiolabeled regulatory peptides have opened new horizons in nuclear oncology for diagnosis (and potential internal radionuclide therapy). Further work will probably reveal a multitude of novel potentially clinically useful peptide-based radioligands.

Humans↗
PubMed1998

The mouse ADP-ribosylation factor-like 4 gene: two separate promoters direct specific transcription in tissues and testicular germ cell.

ADP-ribosylation factor-like protein 4 (ARL4) is a Ras-related GTPase that has been cloned from the 3T3-L1 preadipocyte cell line as an adipocyte-specific cDNA [Schürmann, Breiner, Becker, Huppertz, Kainulainen, Kentrup and Joost (1994) J. Biol. Chem. 269, 15683-15688]. The Arl4 gene maps to the proximal region of mouse chromosome 12 linked to Lamb1-1, Hfhbf1 and Sos2. Compared with all other known genes of Ras-related GTPases, the genomic organization of Arl4 is unusual in that its entire coding region, the 3' untranslated region (UTR) and most of the 5' UTR are located on a single exon. This structure suggests that Arl4 has evolved by retroposition of an Arf (ADP-ribosylation factor) or Arf-like gene. Isolation of the 5' UTR by rapid amplification of cDNA ends (RACE)-PCR revealed heterogeneous transcription initiation sites in alternative exons 1. Both 5'-flanking regions exhibited promoter activity when expressed in COS-7 cells, indicating that the expression of Arl4 is directed by two separate promoters. mRNA transcribed under the control of the downstream promoter was isolated by RACE-PCR from all investigated tissues. In contrast, the upstream promoter seems to drive specifically the expression of Arl4 in adult testis. Hybridization of rat testis in situ indicated that Arl4 is expressed in germ cells of puberal and adult testis, but not in prepuberal testis, suggesting that Arl4 is involved in sperm production.

5' Untranslated Regions↗
PubMed1998

Sequence characteristics, subcellular localization, and substrate specificity of DYRK-related kinases, a novel family of dual specificity protein kinases.

DYRK1 is a dual specificity protein kinase presumably involved in brain development. Here we show that the kinase belongs to a new family of protein kinases comprising at least seven mammalian isoforms (DYRK1A, DYRK1B, DYRK1C, DYRK2, DYRK3, DYRK4A, and DYRK4B), the yeast homolog Yak1p, and the Drosophila kinase minibrain (MNB). In rat tissues, DYRK1A is expressed ubiquitously, whereas transcripts for DYRK1B, DYRK2, DYRK3, and DYRK4 were detected predominantly in testes of adult but not prepuberal rats. By fluorescence microscopy and subcellular fractionation, a green fluorescent protein (GFP) fusion protein of DYRK1A was found to accumulate in the nucleus of transfected COS-7 and HEK293 cells, whereas GFP-DYRK2 was predominantly detected in the cytoplasm. DYRK1A exhibited a punctate pattern of GFP fluorescence inside the nucleus and was co-purified with the nuclear matrix. Analysis of GFP-DYRK1A deletion constructs showed that the nuclear localization of DYRK1A was mediated by its nuclear targeting signal (amino acids 105-139) but that its characteristic subnuclear distribution depended on additional N-terminal elements (amino acids 1-104). When expressed in Escherichia coli, DYRK1A, DYRK2, DYRK3, MNB, and Yak1p catalyzed their autophosphorylation on tyrosine residues. The kinases differed in their substrate specificity in that DYRK2 and DYRK3, but not DYRK1A and MNB, catalyzed phosphorylation of histone H2B. The heterogeneity of their subcellular localization and substrate specificity suggests that the kinases are involved in different cellular functions.

Amino Acid Sequence↗
PubMed1998

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 (131)I-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 (131)I-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 (131)I-labeled immunoconjugates [IgG, F(ab')2 and Fab], the red marrow was the only dose-limiting organ; MTDs were 260 microCi for IgG, 1,200 microCi 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.

Animals↗
PubMed1998

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 beta-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 C017-1A 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 microCi and 3 mCi, respectively. Myelotoxicity was dose-limiting; bone marrow transplantation allowed for an increase of the MTD to 400 microCi 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 C017-1A, 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 beta-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).

Animals↗
PubMed1998

Eye-head coordination in labyrinthine-defective humans.

Eye-head coordination during saccadic gaze shifts normally relies on vestibular information. A vestibulo-saccadic reflex (VSR) is thought to reduce the eye-in-head saccade to account for current head movement, and the vestibulo-ocular reflex (VOR) stabilizes postsaccadic gaze while the head movement is still going on. Acute bilateral loss of vestibular function is known to cause overshoot of gaze saccades and postsaccadic instability. We asked how patients suffering from chronic vestibular loss adapt to this situation. Eye and head movements were recorded from six patients and six normal control subjects. Subjects tracked a random sequence of horizontal target steps, with their heads (1) fixed in primary position, (2) free to move, or (3) preadjusted to different head-to-target offsets (to provoke head movements of different amplitudes). Patients made later and smaller head movements than normals and accepted correspondingly larger eye eccentricities. Targeting accuracy, in terms of the mean of the signed gaze error, was better in patients than in normals. However, unlike in normals, the errors of patients exhibited a large scatter and included many overshoots. These overshoots cannot be attributed to the loss of VSR because they also occurred when the head was not moving and were diminished when large head movements were provoked. Patients' postsaccadic stability was, on average, almost as good as that of normals, but the individual responses again showed a large scatter. Also, there were many cases of inappropriate postsaccadic slow eye movements, e.g., in the absence of concurrent head movements, and correction saccades, e.g., although gaze was already on target. Performance in patients was affected only marginally when large head movements were provoked. Except for the larger lag of the head upon the eye, the temporal coupling of eye and head movements in patients was similar to that in normals. Our findings show that patients with chronic vestibular loss regain the ability to make functionally appropriate gaze saccades. We assume, in line with previous work, three main compensatory mechanisms: a head movement efference copy, an active cervico-ocular reflex (COR), and a preprogrammed backsliding of the eyes. However, the large trial-to-trial variability of targeting accuracy and postsaccadic stability indicates that the saccadic gaze system of patients does not regain the high precision that is observed in normals and which appears to require a vestibular head-in-space signal. Moreover, this variability also permeates their gaze performance in the absence of head movements.

Adaptation, Physiological↗
PubMed1998

Reducing the renal uptake of radiolabeled antibody fragments and peptides for diagnosis and therapy: present status, future prospects and limitations.

Elevated renal uptake and prolonged retention of radiolabeled antibody fragments and peptides is a problem in the therapeutic application of such agents. Over recent years, one of the focuses of research has therefore been to develop suitable methods to reduce this renal uptake, and to evaluate whether the resulting methodology will benefit therapy with antibody fragments and peptides. In these studies it has been shown that the kidney uptake of antibody fragments in animals can be reduced in a dose-dependent manner by almost one order of magnitude by the systemic administration of cationic amino acids and their derivatives, whereas the uptake in all other organs, as well as the tumor, remains unaffected. A similar reduction in renal retention is achieved for all intracellularly retained radionuclides (e.g., radiometals) or radioiodinated immunoconjugates, as well as for smaller peptides. Lysine is usually the preferred agent, and its d- and l-isomers are equally effective whether given intraperitoneally or orally. Amino sugars are effective, but their N-acetyl derivatives, lacking the positive charge, are not. Basic polypeptides are also effective, and their potency increases with increasing molecular weight (i.e., the amount of positive charges per molecule). Urine analysis of treated individuals shows the excretion of unmetabolized, intact fragments or peptides, in contrast to mostly low-molecular-weight metabolites in untreated controls. In therapy studies using radiometal-conjugated Fab fragments, the kidney is the first dose-limiting organ. Administration of cationic amino acids results in a substantial increase in the maximum tolerated dose of such Fab fragments. No biochemical or histological evidence of renal damage has been observed under these conditions. As was the case in animal studies, in pilot clinical trials the renal uptake in patients injected with Fab' fragments and given amino acids could be decreased significantly, whereas the uptake by all other organs remained unaffected. These recent studies indicate that a variety of basic compounds are capable of inhibiting the tubular reabsorption of peptides and proteins, thus significantly lowering the renal uptake of antibody fragments or peptides in both animals and patients. On a molecular basis, the effect seems to rely essentially on the presence of a positively charged amino group. Thus, radiation nephrotoxicity of antibody fragments and peptides can be overcome successfully; this may provide new prospects for cancer therapy with radiolabeled antibody fragments and peptides.

Amino Acids↗
PubMed1998

Intraindividual comparison of 99mTc-labelled anti-SSEA-1 antigranulocyte antibody and 99mTc-HMPAO labelled white blood cells for the imaging of infection.

Technetium-99m labelled antigranulocyte antibodies are ready to use and are sensitive and specific in the diagnosis of infectious diseases. 99mTc-SSEA antigranulocyte antibodies have a very high affinity constant (Kd 10(-12) M) for human neutrophils (PMNs), and excellent imaging qualities with high target/background ratios. The aim of this study was to compare the diagnostic accuracy of the 99mTc-anti-SSEA-1 monoclonal antibody (Mab) with that of 99mTc-hexamethylpropylene amine oxime (HMPAO)-labelled white blood cells (WBCs). To this end, 17 patients with 23 proven infectious foci were examined with 555 MBq 99mTc-anti-SSEA-1 MAb and with 370 MBq 99mTc-HMPAO labelled autologous leucocytes within a period of 7 days. All the infections were confirmed by culture, biopsy, surgery and follow-up. Whole-body images and planar spot views with the antibody were performed at 1-h, 4-h and 24-h post injection; the biodistribution of the antibody was quantified, absorbed radiation doses were calculated and the diagnostic results were compared with the 99mTc-HMPAO WBC images. Human anti-mouse antibody (HAMA) evaluation was performed in all patients before and 3 months after antibody injection. Blood was drawn at different times after 99mTc-anti-SSEA-1 MAb injection to determine the amount of granulocyte-associated radioactivity and to calculate recovery. 99mTc-anti-SSEA-1 MAb scintigraphy detected all 23 lesions, while 21 were detected with 99mTc-HMPAO WBC scan. In this small group of patients, the sensitivity and specificity of 99mTc-anti-SSEA-1 MAb scintigraphy were 95% and 96% respectively, as compared with 91% and 82% respectively for 99mTc-HMPAO WBC scan. An increasing uptake of the injected activity in the lesion at different time points was indicative of high affinity and of specific PMN binding. There was no HAMA formation. In four of five patients investigated, a transient mild leukopenia was found at 15 min p.i.. There was increased uptake of the antibody in liver and spleen and normal uptake in kidneys and bone marrow. The estimated radiation doses for the whole body and the red bone marrow were 1.1x10(-2) cGy/37 MBq and 5.3x10(-2) cGy/37 MBq, respectively. The activity associated to the PMNs in vivo was 33.5%, 30.6%, 21.3% and 9% at 5, 15, 30 and 45 min. post-injection, respectively. It is councluded that use of 99mTc-anti-SSEA-1 antigranulocyte antibodies demonstrates promising results comparable to those obtained with 99mTc-labelled autologous WBCs. The 99mTc-labelled MAb is ready to use, has excellent image qualities and a high target/background ratio.

Adult↗
PubMed1998

Targeting of cholecystokinin-B/gastrin receptors in vivo: preclinical and initial clinical evaluation of the diagnostic and therapeutic potential of radiolabelled gastrin.

The outstanding sensitivity of pentagastrin in detecting the presence of primary, recurrent or metastatic medullary thyroid cancer (MTC) suggests widespread expression of the corresponding receptor type in human MTC. Indeed, recent autoradiographic studies have demonstrated the presence of cholecystokinin (CCK)-B (= gastrin) receptors not only in more than 90% of MTCs but also in a high percentage of small cell lung cancers, stromal ovarian cancers, astrocytomas and several other tumour types. The aim of this study was to evaluate whether radiolabelled gastrin may be suitable for targeting CCK-B receptor-expressing tumours in vivo. For this purpose, the biodistribution of the radioiodinated human heptadecapeptide gastrin-I was studied in nude mice bearing subcutaneous xenografts of the human MTC cell line, TT. Initial therapy experiments were undertaken. Finally, the biodistribution of iodine-131- labelled gastrin-I was studied in a patient with metastatic MTC. At a peptide amount of approximately 1 microg, maximum tumour uptake (8.9+/-2.9%ID/g) was observed in animals at 1 h post injection, with tumour-to-blood ratios as high as 6.3+/-1.9. Physiological CCK-B receptors in the stomach, gallbladder and pancreas of the mice were targeted as well. The major route of excretion was renal, but strong evidence for a biliary excretion pathway also exists. Pilot therapy studies with 131I-labelled gastrin showed significant anti-tumour efficacy as compared with untreated controls. In accordance with the preclinical data, good receptor targeting was observed in the tumour sites, stomach, gallbladder and pancreas of a patient with metastatic MTC. These data suggest that gastrin and its analogues may represent a useful new class of receptor binding peptides for diagnosis and therapy of a variety of tumour types, including MTC and small cell lung cancer. Future preclinical and clinical studies will address in more detail the molecular features that render CCK-B receptor binding agents potentially useful candidates for in vivo scintigraphy and radionuclide therapy.

Aged↗
PubMed1998

Localisation of epileptic foci with electric, magnetic and combined electromagnetic models.

We compare the localisation of epileptic foci by means of (1) EEG, (2) magnetoencephalography (MEG) and (3) combined EEG/MEG data in a group of patients suffering from pharmaco-resistant focal epilepsy. Individual epileptic events were localised by means of a moving dipole model in a 4-shell spherical head approximation. A patient's epileptic activity was summarised by calculating the spatial density distribution (DD) of all localised events, and the centre of gravity of DD was considered the most likely locus of seizure generation. To verify these loci a subgroup of 6 patients was selected, in which seizures could be related to a clearly identifiable lesion in MRI. On average, the combined EEG/MEG approach resulted in the smallest error (1.8 cm distance between calculated locus and the nearest lesion border); using only MEG yielded the largest error (2.4 cm), while EEG resulted in an intermediate value (2.2 cm). In the individual patients, EEG/MEG would also rank intermediate, but never worst. In summary, combining EEG/MEG appears to be a more robust approach to localisation than using only EEG or only MEG. Finally, we also report on the use of the barbiturate methohexital as a safe method of increasing the number of spike events during an EEG/MEG recording session.

Algorithms↗
PubMed1998

Scintigraphic evaluation of functional thyroidal autonomy.

The scintigraphic evaluation of thyroidal autonomy is performed both as a quantitative and qualitative thyroid scintigraphy with 99m-Tc-pertechnetate (99m-TcO4-), using a gamma camera fitted with an on-line computer system. A strong and linear correlation between the global 99m-Tc-pertechnetate thyroid uptake (TCTU) and I-123 clearance has been recognised. Therefore TCTU-values can be used as an reliable equivalent of the iodine clearance in the evaluation of actual thyroid function. The clinical value of the TCTU in the diagnosis of thyroidal autonomy is limited because it represents iodine clearance of both normal and autonomous tissue. As a consequence scintigraphic diagnosis and quantification of autonomy can only be established if the global 99m-Tc-pertechnetate thyroid uptake under suppression (TCTUs) is determined. This method is valuable in risk stratification of spontaneous or iodine induced hyperthyroidism, in the estimation of the target volume prior to radioiodine therapy and in the evaluation of therapeutic success after definitive therapy.

Gamma Cameras↗
PubMed1998

[Radiotherapy only in severe, progressive endocrine orbitopathy: long-term results and comparison of various classification systems].

BACKGROUND: Therapeutic results after radiotherapy in thyroid associated orbitopathy (TAO) often are not comparable, because either different therapeutic methods at the same time or different scores were used in the evaluation. This study focuses on radiotherapy alone by means of different evaluation scores. PATIENTS AND METHODS: 60 patients (49 women, 11 men) received standard external beam radiotherapy (20 Gy: 10 fractions of each 2 Gy) as ultima ratio after failing different other therapies of thyroid associated orbitopathy. The mean interval from beginning of the symptoms to the radiotherapy was 17 +/- 36 months (between 6 and 240 months). The follow up was documented--classified by means of 4 different scores--before radiotherapy, 6-12 weeks, 1 year after radiotherapy and at last follow up. The changes of symptom categories or grades of the different scores were analysed. RESULTS: Significant changes of the ophthalmic scores were observed when comparing the endpoints at 6-12 weeks, and at 1-year follow up after radiotherapy. The "classical" Werner score at 12 months follow up did not correlate well with the other TAO scores: American thyroid association (ATA) scoring system, Stanford scoring system, International ophthalmopathy index, while all other TAO scores revealed a high correlation among each other. According to the Orbitopathy Index (OI) of Grussendorf an improvement from 14.2 points to 6.0 points was achieved. Soft tissue involvement and corneal involvement demonstrated the highest response rate (83/87%), extraocular muscle involvement and proptosis a good response rate (69/70%). No long-term complications were observed. CONCLUSION: According to this study there are indications that external beam radiotherapy is a suitable therapy even after pretreatment and a longer course of TAO. The OI, the ATA and the Stanford scoring systems lead to similar results in the assessment of thyroid orbitopathy.

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