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Diabetic foot infection is a preventable complication of diabetes mellitus. It is an essential component of diabetic foot disease, which is characterised by a triad of neuropathy, ischaemia and infection. These factors may lead to foot ulceration, sepsis and amputation resulting in increased morbidity and poor quality of life. Confirming or excluding infection can be difficult especially when routine laboratory tests and plain radiographs are inconclusive. Early diagnosis and localization of diabetic foot infection is extremely important to institute timely, appropriate therapy. Structural imaging using computed tomography and magnetic resonance imaging all have individual applications towards the diagnostic workup of this condition but have their own limitations. Scintigraphic detection is based on physiochemical changes and hence provides a functional evaluation of bone pathology. We describe the evolution of functional nuclear medicine imaging including immunoscintigraphy in diabetic foot infection and highlight current applications of physiological 18-Fluoro-deoxyglucose positron emission tomography (18-FDG-PET) and computed tomography (18-FDG-PET/CT) in such patients. 18-FDG-PET/CT is a promising modality for imaging diabetic foot infection. Future studies will allow standardisation of technological details and options of 18-FDG-PET/CT interpretation in diabetic foot infection. [ABSTRACT FROM AUTHOR]

Abstract Background Oncological pretargeting has been implemented and tested in several different ways in preclinical models and clinical trials over more than 30 years. Despite highly promising results, pretargeting has not achieved market approval even though it could be considered the ultimate theranostic, combining PET imaging with short-lived positron emitters and therapy with radionuclides emitting beta or alpha particles. Results We have reviewed the pretargeting approaches proposed over the years, discussing their suitability for imaging, particularly PET imaging, and therapy, as well as their limitations. The reviewed pretargeting modalities are the avidin-biotin system, bispecific anti-tumour x anti-hapten antibodies and bivalent haptens, antibody-oligonucleotide conjugates and radiolabelled complementary oligonucleotides, and approaches using click chemistry. Finally, we discuss recent developments, such as the use of small binding proteins for pretargeting that may offer new perspectives to cancer pretargeting. Conclusions While pretargeting has shown promise and demonstrated preclinical and clinical proof of principle, full-scale clinical development programs are needed to translate pretargeting into a clinical reality that could ideally fit into current theranostic and precision medicine perspectives.

Background: Oncological pretargeting has been implemented and tested in several different ways in preclinical models and clinical trials over more than 30 years. Despite highly promising results, pretargeting has not achieved market approval even though it could be considered the ultimate theranostic, combining PET imaging with short-lived positron emitters and therapy with radionuclides emitting beta or alpha particles. Results: We have reviewed the pretargeting approaches proposed over the years, discussing their suitability for imaging, particularly PET imaging, and therapy, as well as their limitations. The reviewed pretargeting modalities are the avidin-biotin system, bispecific anti-tumour x anti-hapten antibodies and bivalent haptens, antibody-oligonucleotide conjugates and radiolabelled complementary oligonucleotides, and approaches using click chemistry. Finally, we discuss recent developments, such as the use of small binding proteins for pretargeting that may offer new perspectives to cancer pretargeting. Conclusions: While pretargeting has shown promise and demonstrated preclinical and clinical proof of principle, full-scale clinical development programs are needed to translate pretargeting into a clinical reality that could ideally fit into current theranostic and precision medicine perspectives. [ABSTRACT FROM AUTHOR]

Labeled antibodies, as well as their fragments and antibody-derived recombinant constructs, have long been proposed as general vectors to target radionuclides to tumor lesions for imaging and therapy. They have indeed shown promise in both imaging and therapeutic applications, but they have not fulfilled the original expectations of achieving sufficient image contrast for tumor detection or sufficient radiation dose delivered to tumors for therapy. Pretargeting was originally developed for tumor immunoscintigraphy. It was assumed that directly-radiolabled antibodies could be replaced by an unlabeled immunoconjugate capable of binding both a tumor-specific antigen and a small molecular weight molecule. The small molecular weight molecule would carry the radioactive payload and would be injected after the bispecific immunoconjugate. It has been demonstrated that this approach does allow for both antibody-specific recognition and fast clearance of the radioactive molecule, thus resulting in improved tumor-to-normal tissue contrast ratios. It was subsequently shown that pretargeting also held promise for tumor therapy, translating improved tumor-to-normal tissue contrast ratios into more specific delivery of absorbed radiation doses. Many technical approaches have been proposed to implement pretargeting, and two have been extensively documented. One is based on the avidin-biotin system, and the other on bispecific antibodies binding a tumor-specific antigen and a hapten. Both have been studied in preclinical models, as well as in several clinical studies, and have shown improved targeting efficiency. This article reviews the historical and recent preclinical and clinical advances in the use of bispecific-antibody-based pretargeting for radioimmunodetection and radioimmunotherapy of cancer. The results of recent evaluation of pretargeting in PET imaging also are discussed.

Labeled antibodies, as well as their fragments and antibody-derived recombinant constructs, have long been proposed as general vectors to target radionuclides to tumor lesions for imaging and therapy. They have indeed shown promise in both imaging and therapeutic applications, but they have not fulfilled the original expectations of achieving sufficient image contrast for tumor detection or sufficient radiation dose delivered to tumors for therapy. Pretargeting was originally developed for tumor immunoscintigraphy. It was assumed that directly-radiolabled antibodies could be replaced by an unlabeled immunoconjugate capable of binding both a tumor-specific antigen and a small molecular weight molecule. The small molecular weight molecule would carry the radioactive payload and would be injected after the bispecific immunoconjugate. It has been demonstrated that this approach does allow for both antibody-specific recognition and fast clearance of the radioactive molecule, thus resulting in improved tumor-to-normal tissue contrast ratios. It was subsequently shown that pretargeting also held promise for tumor therapy, translating improved tumor-to-normal tissue contrast ratios into more specific delivery of absorbed radiation doses. Many technical approaches have been proposed to implement pretargeting, and two have been extensively documented. One is based on the avidin-biotin system, and the other on bispecific antibodies binding a tumor-specific antigen and a hapten. Both have been studied in preclinical models, as well as in several clinical studies, and have shown improved targeting efficiency. This article reviews the historical and recent preclinical and clinical advances in the use of bispecific-antibody-based pretargeting for radioimmunodetection and radioimmunotherapy of cancer. The results of recent evaluation of pretargeting in PET imaging also are discussed. [ABSTRACT FROM AUTHOR]

An anti-carcinoembryonic antigen (CEA) monoclonal antibody (mAb 6D1.1) was evaluated in vitro and in vivo to determine its suitability as a tracer for immunoscintigraphy of colorectal carcinomas. Determination of mAb affinity for CEA showed a constant of association of 0.63 ± 0.11 x 109 M-1. Binding of technetium-99m (99mTc)-6D1.1, labeled by a direct method, to human cultured lineages was highly specific. Binding to only CEA-positive LS-174T cells resulted in a saturable curve inhibited by pre-incubation with unlabeled mAb. No binding at all was observed for the human lineages MeWo (melanoma) or ZR75-30 (breast carcinoma), neither of them expressing CEA cells. Intravenous injection of 99mTc-6D1.1 into nude mice xenografted with human LS-174T tumors resulted in planar images of excellent quality. Localization of an irrelevant mAb labeled with either 99mTc or iodine-125 was never observed in tumor masses. Biodistribution studies on excised tumoral tissue showed retention of 28.48% of the injected dose per gram of LS-174T tumor. The tumor-to-blood ratio was 3.46. The same analysis performed on the other three human xenografted tumors studied demonstrated that only the CEA-producing HT-29 (colorectal adenocarcinoma) retained 99mTc-6D1.1 while the other two (ZR75-30 and MeWo) did not. These data demonstrate that this mAb is an adequate tool for targeting CEA-expressing tumors in experimental models.

IntroducTION The availability of monoclonal antibodies in Cuba has facilitated development and application of innovative techniques (immunoscintigraphy and radioimmunotherapy) for cancer diagnosis and treatment. Objective Review immunoscintigraphy and radioimmunotherapy techniques and analyze their use in Cuba, based on the published literature. In this context, we describe the experience of Havana’s Clinical Research Center with labeled monoclonal antibodies for cancer diagnosis and treatment during the period 1993-2013. evidence ACQUISITION Basic concepts concerning cancer and monoclonal antibodies were reviewed, as well as relevant international and Cuban data. Forty-nine documents were reviewed, among them 2 textbooks, 34 articles by Cuban authors and 13 by international authors. All works published by the Clinical Research Center from 1993 through 2013 were included. Bibliography was obtained from the library of the Clinical Research Center and Infomed, Cuba’s national health telematics network, using the following keywords: monoclonal antibodies, immunoscintigraphy and radioimmunotherapy. Results Labeling the antibodies (ior t3, ior t1, ior cea 1, ior egf/ r3, ior c5, h-R3, 14F7 and rituximab) with radioactive isotopes was a basic line of research in Cuba and has fostered their use as diagnostic and therapeutic tools. The studies conducted demonstrated the good sensitivity and diagnostic precision of immunoscintigraphy for detecting various types of tumors (head and neck, ovarian, colon, breast, lymphoma, brain). Obtaining different radioimmune conjugates with radioactive isotopes such as 99mTc and 188Re made it possible to administer radioimmunotherapy to patients with several types of cancer (brain, lymphoma, breast). The objective of 60% of the clinical trials was to determine pharmacokinetics, internal dosimetry and adverse effects of monoclonal antibodies, as well as tumor response; there were few adverse effects, no damage to vital organs, and a positive tumor response in a substantial percentage of patients. Conclusions Cuba has experience with production and radiolabeling of monoclonal antibodies, which facilitates use of these agents. Studies in Cuba conducted by the Clinical Research Center over the past 20 years have yielded satisfactory results. Evidence obtained suggests promising potential of monoclonal antibodies and nuclear medicine, with immunoscintigraphy and radioimmunotherapy techniques providing alternatives for cancer diagnosis and treatment in Cuba. [ABSTRACT FROM AUTHOR]

Molecular imaging comprises a series of diagnostic modalities that provide information on the physiology and molecular composition of cells and tissues. One of these modalities, radioimmunodetection, uses radiolabeled monoclonal antibodies (mAbs) to image tissues. Two radioimmunodetection modalities are described in this article: immunoscintigraphy and radioimmunoguided surgery (RIGS). In immunoscintigraphy, the radioactivity is measured with the use of an external gamma camera and used to create images. In RIGS, the radioactivity is detected intraoperatively with the use of a handheld gamma probe to help the surgeon detect foci of otherwise occult disease. Both techniques have the potential to improve the preoperative and intraoperative localization of cancer. Multiple studies have been performed on the efficacy of RIGS on different malignancies, especially colorectal cancer. Despite the good sensitivity of the technique, some concerns revolve around the high rate of false positives and the real significance of leaving RIGS-positive tissue behind in terms of long-term outcomes and survival. More studies are warranted to further develop the technique and determine the specific role it will play on the diagnosis and management of surgical disease. Surgeons should actively participate in these studies and in expanding the applications of this promising technology. [ABSTRACT FROM AUTHOR]

Copyright of IBS, Immuno-analyse & Biologie Specialisee is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Immunoscintigraphy with the use of the antigranulocyte antibody BW 250/183 is a reliable method for detecting infection, especially in septic loosening of hip prostheses, for which purpose quantitative interpretation of the time-activity course is employed. Therefore, we retrospectively studied whether similar results could be achieved in knee prostheses. We verified 28 scintigraphic examinations in 26 patients by histology. Scintigraphy was performed during an early (4–6 h post injection) and a late phase (23–25 h post injection). Infection was diagnosed when activity around the knee prosthesis increased by more than 10% compared with bone marrow. We found a sensitivity and a negative predictive value of 100%, a specificity of 80%, a positive predictive value of 81% and an accuracy of 89%. Specificity and accuracy are lower than in the evaluation of hip prostheses; however, in comparison to other scintigraphic modalities, scintigraphy with the antigranulocyte antibody BW 250/183 is superior in excluding infection and has better specificity and accuracy. Therefore, as in the case of hip prostheses, the described methodology appears to be the scintigraphic modality of choice for knee prostheses. [ABSTRACT FROM AUTHOR]

Aim: Diagnostic delay for inflammatory bowel disease (IBD) is frequent, especially in paediatric patients. Scintigraphy with labelled leucocytes has been proposed as a very sensitive diagnostic tool for detecting bowel inflammation. The aim of this study was to evaluate the sensitivity and specificity of immunoscintigraphy in the diagnosis and follow-up of children with IBD and to compare this technique with other diagnostic techniques.Methods: Sixty-six children with histologically confirmed IBD were enrolled in the study. Twenty-one children in whom IBD was suspected but subsequently not confirmed were used as controls. A total of 138 immunoscintigraphies were performed using 99mTechnetium-labelled monoclonal anti-granulocyte antibodies. Immunoscintigraphy was also compared with other diagnostic techniques.Results: Overall sensitivity of monoclonal antibody immunoscintigraphy (MoAb-IS) in patients with clinically active disease was 94% for Crohn's disease (CD) and 85% for ulcerative colitis (UC). Ultrasonography, endoscopy and radiology were carried out at the same time in 29 patients with CD and in 6 patients with UC: sensitivity of IS was 90% compared with 76% of colonoscopy, 75% for enemas, and 55% for sonography. IS was negative (specificity) in 24% of patients with CD and in 67% of patients with UC during remission, and in 64% of controls with other causes of intestinal inflammation. Diagnostic delay was significantly shorter when compared with a historical cohort of patients.Conclusion: Immunoscintigraphy is a highly sensitive detector of intestinal inflammation in young patients with IBD and can be useful for reducing diagnostic delay. However, its specificity is low and all positive cases must be confirmed histologically. [ABSTRACT FROM AUTHOR]

PurposeIntra-operative radioimmunodetection of malignant involved lymph nodes follows the pre-operative immunoscintigraphy in the treatment of patients with colorectal carcinoma. The aims of this clinical study were to determine the sensitivity of the method, to compare the results in study when using Oncoscint and CEA-Scan and to evaluate the importance of the method of surgery and postoperative adjuvant therapy. Patients and methods121 patients with colorectal tumours (106 primary and 15 recurrent) were operated on using radioimmunoguided surgery (RIGS). The study compared results of pre-operative immunoscintigraphy, intra-operative radioimmunodetection and postoperative histological examination. Histological investigation used classical H&E staining. In histologically negative and RIGS positive cases the immunohistochemical investigation was supplemented. Two radiopharmaceuticals were used Oncoscint CR 103 (MAb B72.3, Satumomab Pendetide), labelled with 111In in 56 patients and CEA-Scan (IMMU 4-Fab′ fragments MAb against CEA, Arcitumomab), labelled with 99mTc in 65 patients. ResultsThe relationship between RIGS positive results and histological examination was statistically assessed after 38 operations and the most acceptable RIGS evaluating index was determined. All subsequent results were evaluated by this index. Immunoscintigraphy of tumour was positive in 112 cases (92.6%). Fifty-five RIGS positive cases of malignant infiltrated lymph nodes were confirmed by 43 histologically positive examinations (78%). In this group 9 cases were discovered only by immunohistochemistry. Sixty-six remaining RIGS negative results were confirmed in 62 (94%) cases by negative histology. ConclusionsBoth immunoscintigraphy and RIGS enable one to make a more accurate diagnosis. While treating the primary disease the use of RIGS may help in assessment of necessary extent of operation performance and in staging of the disease by revealing occult... [ABSTRACT FROM AUTHOR]

Current radiological techniques for staging bladder cancer are inaccurate, especially in the identification of pelvic lymph node metastases. Immunoscintigraphy has the potential to offer improved staging for bladder cancer. The aim of this study was to label the anti-MUC1 monoclonal antibody C595 with 99mtechnetium (Tc), the most widely used diagnostic radionuclide, and assess the potential of the resultant conjugate for intravenous immunoscintigraphy of bladder cancer. A direct, reduction-mediated technique was used to label the antibody. The resultant conjugate was shown to be highly immunoreactive, stable and bound specifically to MUC1. The ability of the conjugate to bind to bladder tumours was demonstrated in an ex vivo model where the mean tumour:normal urothelial uptake was 5.7:1 and by intravesical administration in patients with bladder cancer where the mean tumour:normal urothelial uptake was 20.4:1. The ability of the conjugate to localise MUC1-expressing tumours was demonstrated in a nude mouse xenograft model. A conjugate of 99mTc-C595 has been produced and characterised, and it may be suitable for intravenous immunoscintigraphy, a potential novel staging tool for bladder cancer. [ABSTRACT FROM AUTHOR]

Objective: A retrospective study of the validity of combined bone scintigraphy (BS) and immunoscintigraphy (IS) using (99m)Tc-labelled murine antigranulocyte antibodies (MAB) and magnetic resonance imaging (MRI) in chronic posttraumatic osteomyelitis.Design and Patients: The results of MRI and combined BS/IS of 19 lesions in 18 patients (13 men, 5 women; mean age 45 years, range 27-65 years) were independently evaluated by two radiologists and one nuclear medicine physician with regard to bone infection activity and extent. The patient group was a highly selective collection of clinical cases: the average number of operations conducted because of relapsing infection was eight (range 2-27), the average time interval between the last surgical intervention and the present study was 6.5 years (range 3 months to 39 years), and from the first operation was 14 years (range 1.5-42 years). Interobserver agreement on MRI was measured by kappa statistics. Sensitivity, specificity, accuracy, positive predictive value (PPV) and negative predictive value (NPV) were calculated for MRI and the nuclear medicine studies.Results: For MRI/nuclear medicine, a sensitivity of 100%/77%, a specificity of 60%/50%, an accuracy of 79%/61%, a PPV of 69%/58% and a NPV of 100%/71% were calculated. Four MR examinations were false positives because of postsurgical granulation tissue. A high degree of interobserver agreement was found on MRI (kappa=0.88). A low-grade infection was missed on two scintigrams, while four were false positive because of ectopic haematopoietic bone marrow, and in one examination the anatomical distortion resulted in an inaccurate assignment of the uptake leading to false positive findings. Image analysis was frequently hindered by susceptibility artefacts due to residual abrasions of metallic implants after removal of orthopaedic devices (15/18 patients); this led to limited assessment in 17% (3/18 patients).Conclusion: Acute activity in a chronic osteomyelitis can be excluded with high probability if the MRI findings are negative. In the first postoperative year fibrovascular scar cannot be distinguished accurately from reactivated infection on MRI and scintigraphy may improve the accuracy of diagnosis. MRI is more sensitive in low-grade infection during the later course than combined BS/IS. Scintigraphic errors due to ectopic, peripheral, haematopoietic bone marrow can be corrected by MRI. [ABSTRACT FROM AUTHOR]

Copyright of Colo-Proctology is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Diagnosis of hydatid disease in man is frequently dependent on the imaging of cysts in situ by techniques such as ultrasonography and CAT scans. Such methods are useful but are not specific and can lead to errors in diagnosis. The present work reports preliminary experiments on the development of a specific imaging technique for hydatid cysts using radiolabelled antibodies. A purified preparation of antigen B of hydatid fluid was used to raise polyclonal antisera in rabbits and the resulting affinity-purified IgG labelled with 131I . Gerbils with an established Echinococcus granulosus infection were injected intraperitoneally with the labelled antibody and imaged 48 h later with a gamma camera. Hydatid cysts could be identified within the peritoneal cavity and post-mortem assessment of activity showed the cysts to contain approximately four times as much activity as the surrounding organs thereby indicating successful targeting of the antibody to the cysts. [ABSTRACT FROM AUTHOR]

The ability to effectively define disease status in ovarian cancer after initial therapy or to selectively screen high-risk populations remains a major challenge for in vivo monoclonal antibody (mAb)-targeted approaches. Antitumour murine mAbs (HMFG1, HMFG2, H317, and H17E2) and the reshaped human antibody Hu2PLAP (against placental alkaline phosphatase; PLAP), labelled with indium-111 and iodine-123, were evaluated for their ability to localise ovarian tumours in sequential studies of our group. Thirty patients with ovarian cancer, aged 40–78 years (median 60 years) were studied with HMFG1/G2: 11, and H317/H17E2: 19 murine mAbs. Six patients with ovarian cancer aged between 36 and 65 years (median 49 years) were studied with the reshaped human Hu2PLAP mAb (5 patients) or the murine H17E2 mAb (2 patients) labelled with [sup 111] In via a new macrocyclic chelating agent (DOTA). One of these was imaged twice, with H17E2- and Hu2PLAP-DOTA-[sup 111] In, respectively. In 20 out of 22 patients with radiologically measurable ovarian cancer, the presence of tumour was confirmed by the murine mAb scan and correlated well with the findings of conventional radiology diagnostic methods. One of these patients with a negative H17E2 scan and a large abdominal mass at laparotomy was found to have a PLAP-negative tumour on immunohistochemistry. Additionally, the antibody scan revealed the presence of active disease, confirmed at laparotomy/laparoscopy, in 6 out of 8 patients considered to be in clinical complete remission. Best images were obtained at 24 and 48 h after the [sup 123] I and [sup 111] In mAbs, respectively. Successful imaging with the reshaped human antibody, Hu2PLAP, was seen in 2 patients with PLAP-positive tumours. Antibodies to DOTA developed in 2 patients. In conclusion, immunolocalisation of ovarian tumours is feasible with both murine and reshaped human mAbs. The sensitivity and specificity of the method appear very high in this pilot study, and in view of the absence of toxicity, the diagnostic contribution of this approach should be evaluated prospectively. Given the low number of patients without surgically detectable disease in the present study, future investigations should include more patients with no evidence of disease in order to provide more meaningful estimates of specificity. [ABSTRACT FROM AUTHOR]

The influence of human anti-OC125 antibodies formed after multiple infusions of OC125 F(ab')2 fragments on the apparent levels of CA 125 measured with four different tests were examined in two ovarian cancer patients. With the homologous Assay 1, involving only OC125 antibodies, false increases of CA 125 values were observed after infusion of OC125 fragments, which completely covered real CA 125. In contrast, with Assay 2, 3 and 4, which involve no OC125 antibodies as capture antibodies, only slight false increases occurred in the presence of very high anti-OC125 antibody concentrations. Interference was eliminated by addition of non-specific murine IgG in Assay 2 and 4, but not in Assay 1 and 3 indicating that the false increases in Assay 1 and 3 were caused by anti-idiotypic anti-OC125 antibodies. In the presence of elevated real CA 125, with Assay 2 and to a considerably lesser degree with Assay 4, an inhibitory effect of anti-OC125 antibodies became evident leading to false decreases of CA 125 values. In Assay 4 reduction of assay response was eliminated by addition of nonspecific murine IgG. The results confirm that all available CA 125 tests are influenced by interference with human anti-OC125 antibodies. Thus, CA 125 levels in patients who have been treated with OC125 fragments should be interpreted with care. [ABSTRACT FROM AUTHOR]

Radioimmundetection (RID) using anti-CA 125 antibodies proved to be a valuable tool in the follow-up of metastasizing ovarian cancer. Sensitivity, specificity, and accuracy were high. RID had no clinical side effects. But some patients formed antibodies which interfered a) with the evaluation of the scintigram and b) with further measurement of CA 125 levels. We found 2 cm diameter metastases that were not detected by computed tomography. However, the heterogeneity of tumor metastases limits the sensitivity of this method. CA 125 serum levels, immunohistochemistry, and immunoscintigraphy did not always correlate. Monitoring serum levels of CA 125 was most valuable in clinical management of tumor spread and in the optimal use of RID. [ABSTRACT FROM AUTHOR]

Septic sacroiliitis in childhood is a relatively rare condition. We describe a case of septic sacroiliitis occurring in an 11-year-old girl in whom the diagnosis was suspected on clinical findings and bone scan. Immunoscintigraphy withTc-labelled antigranulocyte antibodies further supported the hypothesis for a septic origin of the disease. The clinical evolution cliniched the diagnosis. [ABSTRACT FROM AUTHOR]

Immunoscintigraphy with technetium-99m labelled BW 250/183, a murine monoclonal antibody specific for granulocytes, yielded a false-positive result in a patient suspected of having an abscess in his renal graft. To substantiate the presumption that diathesis and unspecific accumulation of the antibody may have caused this result, ten selected patients were investigated who presented with chronic vascular graft rejection but without signs of bacterial infection. Scintiscans were recorded 4 and 24 h after administration ofTc-labelled BW 250/183. Graft-background ratios (GBRs) were calculated for each transplant. These were compared with the mean of physiological kidney-background ratios (KBRs) and with bone marrow-background ratios (BMBRs). After removal, the grafts were examined with pathological and immunohistological methods. Seven transplants demonstrated 4-h GBRs (mean: 3.9±1.1, P <0.001) significantly outside the range of normal KBRs while three were within the normal range (mean: 1.8±0.4). The relation between 4-h and 24-h GBRs varied. After 24 h five GBRs still remained increased (mean: 3.2±1.4, P <0.05). By contrast the BMBRs decreased uniformly by 18%±5%. After graft removal, histopathology demonstrated no dominant granulocyte accumulations but various degrees of chronic vascular and tubulo-interstitial rejection. Immunohistochemical studies did not indicate cross-reactivity of BW 250/183. Increased GBRs of longstanding renal allografts indicate the passage of the antibody through injured vascular walls rather than the presence of granulocyte accumulations. Therefore, variability of GBRs with time reflects changes in transitory concentrations ofTc-labelled BW 250/183 in the tissues. [ABSTRACT FROM AUTHOR]

The initial enthusiasm for the development of diagnostic and therapeutic studies involving the use of monoclonal antibodies was replaced by scepticism as hopes remained unfulfilled. Against this background one needs to ask whether immunoscintigraphy (IS) serves clinical needs effectively and whether radioimmunotherapy (RIT) has a future. The current review considers these questions by reference to relevant studies. Taking colorectal cancer as an example, an appraisal is offered of the ability of IS to detect disease at an early stage and thereby to reduce mortality, and of the influence of the results of IS on patient management. It is concluded that in a limited number of cases of colorectal cancer and other solid tumors, IS will allow surgery to be performed at a stage where cure is still possible because of its ability to detect early recurrence. Turning to RIT, the results of studies in respect of various tumour types are reviewed, with due attention to reported toxicity. As regards colorectal cancer, no consistent therapeutic effects have been achieved, and myelotoxicity is typically the dose-limiting factor. Thus many questions remain to be answered, regarding antigens to be targeted, fractionation schedule, the use of 'humanised' antibodies, choice of radionuclide and the use of intact immunoglobulins or fragments. These questions are considered. Overall it is concluded that the most promising application of RIT is as adjuvant therapy in patients with minimal residual disease, and a controlled multicentre trial is recommended. The development of more potent radioimmunoconjugates for therapeutic and ultimately diagnostic purposes will contribute to the improvement and development of IS by increasing its potential to influence prognosis. [ABSTRACT FROM AUTHOR]

Iodine-131 3F8, a murine IgG monoclonal antibody that targets to G-bearing tumors, was administered intravenously to 12 patients with brain tumors. Six patients received 2 mCi (0.74 Bq) ofI-3F8, five patients 10 mCi (3.7 Bq)/1.73 m ofI-3F8, and one patient 2.6 mCi (0.96 Bq) ofI-3F8, with no side-effects. Nine of 11 malignant gliomas and the single metastatic melanoma showed antibody localization, with the best tumor delineation on single-photon emission tomography (SPET) following 10 mCi (3.7 Bq)/1.73 m dose. No nonspecific uptake in the normal craniospinal axis was detected. There was no difference in the pharmacokinetics of low-dose versus the higher-dose antibody groups; plasma and total-body half-lives were 18 h and 49 h, respectively. Surgical sampling and time-activity curves based on quantitative imaging showed peak uptake in high-grade glioma at 39 h, with a half-life of 62 h. Tumor uptake at time of surgery averaged 3.5×10 %ID/g and peak activity by the conjugate view method averaged 9.2×10 %ID/g (3.5-17.8). Mean radiation absorption dose was 3.9 rad per mCi injected (range 0.7-9.6) or 10.5 cGy/Bq (range 1.9-26). There was agreement on positive sites when immunoscintigraphy was compared with technetium-99m glucoheptonate/diethylene triamine penta-acetic acid planar imaging, thallium-201 SPET, and fluorine-18 fluorodeoxyglucose positron emission tomography. Taken together, these data suggest that quantitative estimates of antibody targeting to intracranial tumors can be made using the modified conjugate view method. [ABSTRACT FROM AUTHOR]

To determine the value of immunoscintigraphy (IS) with antigranulocyte monoclonal antibodies (Mab) in the diagnosis of subacute or chronic infection of hip prostheses, we prospectively studied 57 patients (23 women and 34 men; age 29-92 years, mean 72.7 years) sent to our institution in the past 6 years for clinical suspicion of septic loosening of a hip prosthesis. Nineteen patients had bilateral prostheses and one of them was studied twice. A total of 78 prostheses were examined. All patients had three-phase bone scans followed by IS with technetium-99m antigranulocyte Mab BW 250/183. Intervals between bone scans and IS varied from 2 days to 4 weeks. Final diagnosis was assessed by culture in 48 cases (articular puncture or intraoperative sampling) and by clinical follow-up of at least 8 months in 30 cases. Twelve prostheses were considered septic and 66 non-septic. The overall sensitivity and specificity were 92% and 64% respectively for bone scans, 67% and 75% for IS and 67% and 84% for both modalities together. In three cases, IS was doubtful and the final clinical diagnosis was negative for infection. False-positive results were observed in the presence of massive loosening of the prosthesis or in association with metaplastic peri-articular bone formation. In three of the four false-negative results, infection was proven only after enrichment of the culture, and the bacterium was Staphylococcus epidermidis. In 12/33 (36%) positive bone scans IS allowed the diagnosis of infection to be excluded. Overall accuracy of both modalities together was 81% and the negative predictive value was 93%, which compares favourably with the results reported for other non-invasive methods. [ABSTRACT FROM AUTHOR]

Scintigraphy with indium-111 labelled antimyosin has an established role in the evaluation of cardiac muscle damage. This antibody has been shown to cross-react with myosin in skeletal muscle. We therefore studied the usefulness of this method for the detection of skeletal muscle lesions in rhabdomyolysis, myositis and hereditary muscular dystrophies. All nine patients with rhabdomyolysis had focal uptake of antimyosin antibody which correlated with the clinical findings of soft tissue damage. However, a number of symptomless lesions were also detected by immunoscintigraphy. In rhabdomyolysis the target to non-target uptake ratios varied from 1.3 to 7.6. Diffuse uptake of antibody in skeletal muscle was observed in all three patients with polymyositis-dermatomyositis and in 12 out of 13 patients with muscular dystrophies. In myositis the intensity of antibody accumulation correlated reasonably well with the magnitude of oedema detected by magnetic resonance imaging (MRI). Most patients with Becker type or non-X-chromosomal muscular dystrophies showed slight or moderate uptake of antibody, mainly in the lower extremities. In these patients more antibody accumulated in the calves than in the thighs, whereas the findings on MRI were more prominent in the thighs than in the calves, presumably because of the better preserved muscle bulk in the calves. We conclude that antimyosin scintigraphy can be used for the detection of muscle lesions not only in acquired muscle diseases but also in hereditary muscular disorders, and that immunoscintigraphy provides information on muscle disease activity not obtainable with MRI. [ABSTRACT FROM AUTHOR]

A direct comparison of the joint-imaging properties of inflammation-specific- and non-specific monoclonal antibodies (Mabs) was possible in a patient suffering from long-standing, severe rheumatoid arthritis (RA). This patient received an anti-CD4 and an anti-carcinoembryonic antigen (anti-CEA) Mab, both labelled with technetium-99m, 9 days apart from each other. The anti-CD4 Mab was superior to the isotype-matched anti-CEA Mab in imaging inflamed joints. In the knee joint, the target-to-background ratio of the synovial membrane (SM) activity in comparison to that of adjacent large vessels was 1.22 (SM/muscle 1.55) for the anti-CD4 Mab and 0.53 (SM/muscle 0.92) for the anti-CEA Mab, in both cases 4 h after injection of the immunoglobulin. Since the CD4 antigen is present on the surface of T-helper lymphocytes and macrophages infiltrating the inflamed synovial membrane, imaging with the anti-CD4 Mab may allow more specific detection of inflammatory infiltrates in RA. [ABSTRACT FROM AUTHOR]

Fever of unknown origin (FUO) has been defined as an elevation in temperature (38°C) for at least 2-3 weeks despite intensive investigation. The value of immunoscintigraphy with the technetium-99m-labelled anti-granulocyte antibody anti-NCA-95 (BW 250/183, IgG1) was studied retrospectively in 34 consecutive patients with FUO. Every effort was made to confirm a diagnosis, including methods such as ultrasonography, computed tomography, magnetic resonance imaging, bacteriological tests, surgical intervention and clinical follow-up. In 58.8% of the patients, an infectious cause for the fever was found, in 30.2% of the patients, a benign or malignant haematological disease, pancreatitis or thyrotoxicosis was found. No cause for fever could be found in 11%. The overall diagnostic sensitivity and specificity of immunoscintigraphy for infection were 40% and 92% respectively. The positive predictive value was calculated to be 88% and the negative predictive value was calculated to be 52%. False-negative scans were especially noted in patients with endocarditis, pneumonia and small brain abscesses, where the lesions did not exceed a diameter of 0.5 cm. If patients with endocarditis were excluded, the imaging sensitivity and specificity were increased to 57% and 95%. This study demonstrates that 99mTc-anti-NCA-95 scanning is able to localize infectious causes of FUO, other than endocarditis. [ABSTRACT FROM AUTHOR]

Immunoscintigraphy with radiolabelled monoclonal antibodies is widely used to detect solid tumours, but only a few trials have been carried out concerning the specific in vivo localization of an inflammatory process. The purpose of this study was to investigate the detectability of tuberculous foci utilizing this method with radiolabelled bacillus Calmette-Guérin (BCG)-specific F(ab′) in rabbits. All of the tuberculous lesions ( n=8) were clearly visualized on serial scintigraphy for up to 48 h after injection of the antibody. Immunohistochemical and Ziel-Neelson staining of the tuberculous lesions confirmed the presence of the tuberculous antigens and bacilli. It failed to demonstrate any sustained retention of the BCG-specific antibody fragment in the control group with syphilitic orchitis ( n=2). Therefore, the specific in vivo localization of tuberculosis is feasible by immunoscintigraphy. [ABSTRACT FROM AUTHOR]

A correlative imaging study was carried out in 61 female patients previously treated for ovarian carcinoma. Upon suspicion of recurrence, abdominopelvic immunoscintigraphy (IS) using F(ab′)2 fragments of indium-111-labelled OC 125 monoclonal antibody was performed in all patients, Ultrasonography (US) and computed tomography (CT) were performed 53 and 37 times, respectively. The diagnostic accuracy of the different imaging techniques was studied per site (abdomen and pelvis) and per patient. The diagnostic accuracy of planar scintigraphy (PS) was slightly lower than that of emission computed tomography (ECT): 66% vs 73% for abdomen, 65% vs 72% for pelvis, and 78% vs 84% in analysis per patient. The accuracy of IS (PS and ECT combined) was markedly better than that of US and CT for abdomen (IS=73%; US=30%; CT=47%), pelvis (IS=73%; US=37%; CT=52%) and analysis per patient (IS=85%; US=43%; CT =59%). The results of IS and morphological imaging techniques (MIT: US and/or CT) were correlatively analysed with the frequency of recurrence. When IS and MIT were both negative, the frequency of non-recurrence was 14/23 for abdomen, 7/12 for pelvis and 8/13 in analysis per patient. On the other hand, when both IS and MIT were positive, the frequency of recurrence was high (9/9 for abdomen, 17/21 for pelvis and 24/26 for analysis per patient). It was also found that a positive IS associated with a negative MIT was still highly suggestive of recurrence (17/21 for abdomen, 16/22 for pelvis and 17/19 for analysis per patient). The results of this study strongly suggest that in-labelled OC 125 IS is accurate for the diagnosis of recurrence of ovarian cancer and provides complementary data to those obtained by MIT. [ABSTRACT FROM AUTHOR]

The effects of diethylene triamine penta-acetic acid (DTPA) on indium-111 monoclonal antibody (MoAb) metabolism were examined. Sequential analysis of In-MoAb incubated in serum at 37°C by high performance liquid chromatography (HPLC) and electrophoresis revealed that the radioactivity gradually moved from the MoAb to a 70-90 kDa molecular weight fraction. DTPA inhibited the transchelation of In to this fraction. It also decreased In uptake by isolated rat heptocytes but did not remove In incorporated in hepatocytes. The daily in vivo administration of DTPA (0.5-2.0 mg/mouse daily) to athymic mice after In-MoAb injection significantly reduced the In uptake in the liver and kidney. The tumour uptake was decreased somewhat but not significantly. The serum radioactivity in the 70-90 kDa fraction was also decreased. Scintigraphic examination demonstrated a decreased liver uptake in the DTPA-treated group of mice. Our results show that In released from the DTPA-MoAb conjugate in serum binds to molecules of 70-90 kDa and that DTPA decreases the In uptake in this fraction, which induces a decrease of In accmulation in normal tissues. [ABSTRACT FROM AUTHOR]

Combining the volume rendering and bicolour visualization tehniques is proposed as an aid in interpreting single photon emission tomography (SPET) immunoscintigraphy (IS) recorded simultaneously with SPET bone landmarking (BL). The combination helps in localizing abnormal monoclonal uptake and in differentiating it from a physiological radioactivity distribution. The so-called rendered images (RIs) are obtained in both IS and BL studies according to a depth- weighted maximum activity projection algorithm. Fused BL and IS RIs are constructed by a simple, pixel by pixel addition. They are displayed using a bicolour grey-red scale, which makes it possible to visualize both studies by a transparency effect. This method was applied to patients suspected of suffering colorectal or ovarian cancer recurrences, in whom monoclonal antibodies against carci-noembryonic antigen, B72-3 or OC125 labelled with indium-111 were used. [ABSTRACT FROM AUTHOR]

A method of superimposing computed tomography (CT) and immunoscintigraphic (IS) single photon emission tomography (SPET) slices is presented and has been applied to 10 patients with suspected cancer recurrence. IS was performed with carcinoembryonic antigen (CEA)-specific indium-111 monoclonal antibodies (MoAbs) in 5 patients with colorectal cancer, and with OC125 In-MoAbs in 5 patients with ovarian cancer. All patients had an abnormal CT image result in the pelvis, which was interpreted 5 times as recurrence, once as doubtful and four times as scar fibrosis. Recurrence was subsequently proven in all patients. Bone scintigraphy (BS) SPET was recorded at the same time as IS. No special technique was used during BS, IS or CT acquisition. CT images were fed into a computer using a CCD camera. Using the internal anatomical landmarks provided by the pelvic bone structures seen on CT and BS, an operator had to select corresponding fiducial points, which were used by the software to register the images. The final results were CT-BS and CT-IS superimposed images. CT-BS images were used for quality control. In all patients, the inspection of CT-BS and CT-IS showed that the registration process is accurate and assists in the co-interpretation of CT and IS images. [ABSTRACT FROM AUTHOR]

Since 1980, immunoscintigraphy has been performed in thousands of patients, and its clinical value has been demonstrated for selective indications in malignant (early detection of recurrences of colorectal and ovarian carcinomas) and non-malignant (cardiovascular and inflammatory) pathology. However, many clinicians are not yet very convinced of its efficiency. Opinions range between favourable interest and marked scepticism. The causes of this inconclusive verdict include an often moderate target-to-background ratio in images, the immunogenicity of injected murine antibodies and the fact that a true benefit for the patient has not yet been clearly demonstrated in large series of patients. Future prospects could significantly improve this and involve the reduction of non-specific activity in normal tissues (to improve disease target contrast and thus make image interpretation easier) and the decreased immunogenicity of injected immunoconjugates (to permit repetition of examinations). Radioimmunotherapy, an innovative and promising approach, is still limited by numerous problems. The results of clinical studies are still inconclusive, being encouraging only for specific indications. In the future, pre-targetting techniques should allow the rapid elimination of radioactivity from normal tissues, resulting in a significant increase in tumour-to-normal tissue ratios. Progress is also required in the choice of radionuclides and labelling techniques and in methods for dosimetric estimations. The clinical indications of radioimmunotherapy after systemic injection will concern mainly radiosensitive tumours such as lymphomas, small-cell lung cancers and neuroblastomas. After endocavitary injection, radioimmunotherapy could prove efficient in the treatment of micrometastases of ovarian carcinomas. For all indications, this new approach should be combined with other therapeutic modalities. [ABSTRACT FROM AUTHOR]

The immunoscintigraphic detection of tumour foci < 1 cm in diameter fails even with single photon emission tomography (SPET) owing to low contrast against background activity. In an attempt to improve detection of macroscopically invisible tumour spread, intraoperative scintimetry (IOSM) with a hand-held gamma-probe was performed in addition to SPET 24-30 and 41-48 h after injection of the technetium-99m carcinoembryonic antigen (CEA MoA) on 12 patients with colorectal carcinoma and 3 patients with different neoplastic and inflammatory diseases. Tumour specimens were measured in vitro in a gamma well counter. For comparison, the presence and amount of CEA in the tumour cells were evaluated immunohistochemically. After modification, the gamma-probe originally designed for iodine-131 was 20 times more sensitive; activities of Tc located close to the collimator hole were measured with absolute sensitivity of 100 cps = 2.5 kBq Tc. The unfavourably high background activity affected both the in vitro and in vivo analysis: SPET results had been considered positive in 8 of 15 cases. In vitro tumour/non-tumour (t/nt) ratios > 2.0 were found in 4 cases. In vivo IOSM resulted in t/nt ratios >2.0 in only 3 patients. In most cases, there was no coincidence of elevated t/nt ratios from the different methods. A correlation was derived between positive immunoscintimetric in vitro findings and immunohistochemically proven interstitial localization of CEA in tumor cells. In conclusion, the measurement technique of IOSM seems adequate, but clinical success will depend on a more specific enrichment of MoA in tumour tissue. Future in vivo studies should be performed mainly in cases with a positive immunohistochemistry (interstitial CEA localization) result for the primary tumour. [ABSTRACT FROM AUTHOR]

Immunoscintigraphy with a technetium-99m murine monoclonal IgG antibody directed against non-specific cross-reacting antigen (NCA-95) and carcinoembryonic antigen was performed with 20 patients with suspected subacute infective endocarditis (SIE) and 6 controls with suspected inflammatory/infectious disease elsewhere in the body. Immunoscintigraphy and echocardiography localised SIE in 11 of 15 patients in whom the disease could be confirmed. In 4 patients with validated SIE, the immunoscan was abnormal, and the echocardiogram was normal. In another 4 patients, the result was exactly the opposite. These findings suggest that the combination of immunoscintigraphy and echocardiography improves diagnostic efficacy in patients with suspected SIE. [ABSTRACT FROM AUTHOR]

The administration of a radiolabelled monoclonal antibody against tissue plasminogen activator allows detection of areas with increased fibrinolytic activity, i. e. those with an active thrombotic lesion. Eight patients with phlebographically verified deep venous thrombosis were examined. At the time of immunoscintigraphy study they were examined receiving anticoagulant therapy. Some 75-85 MBq indium 111-labelled antibody were injected, and scintigrams were obtained after 30 min and after 24 h. The precise site of the thrombus could not be visualized after 30 min due to high background activity, whereas after 24 h it was detectable in all patients. The thrombus/background ratios achieved are twice as high as those observed in a human antifibrin antibody study. These preliminary data suggest a high sensitivity of our t-PA-specific antibody for the detection of active deep venous thrombosis in man, and our antibody seems to offer theoretical advantages over both platelet and fibrin-specific antibodies. [ABSTRACT FROM AUTHOR]

Interest in bone marrow scanning has been renewed as the result of the development of radiopharmaceuticals for evaluating specific aspects of bone marrow anatomy, physiology and pathology. This article provides a brief review of bone marrow structure, blood flow and function essential to the understanding of basic principles of bone marrow radionuclide imaging. The prospects and limitations of imaging haematopoietic bone marrow in man using indium 111 chloride, technetium-99m (Tc)-labelled microcolloid orTc-labelled monoclonal antigranulocytic and antimyelocytic antibodies are discussed in more detail. The technical aspects of bone marrow scintigraphy are presented. Results of more recent studies evaluating bone marrow scanning in circulatory, inflammatory and in systemic haematological disorders are summarized. Special attention is paid to the concept of bone marrow micrometastases and its implications for the follow-up of patients with malignant tumours. Recent results suggest that immunoscintigraphy of bone marrow may provide a novel and sensitive approach for establishing the presence and extent of bone marrow infiltration. [ABSTRACT FROM AUTHOR]

The imaging of small abdominal tumours with indium 111 labelled monoclonal antibodies (MAbs) is often obscured by the uptake of activity into the hepto cytes of normal liver tissue. A model has therefore been developed to analyse reagents which may inhibit the he patocyte uptake ofIn-MAb whilst preserving tumour uptake. Primary rat hepatocyte cultures and an epithelial membrane antigen (EMA) expressing tumour cell line (MCF7), recognised by the EMA-specific MAb ICR2, were obtained in tissue culture. Monolayers of both cells were incubated with theIn-MAb with or without the additional reagents and the cell uptake then measured and expressed per milligram of cell protein using a Lowry protein assay. No preferential reduction in hepatocyte uptake was noted by incubating cells with either saturated or unsaturated transferrin. The chelating agent, diethylene triamine penta-acetic acid (DTPA), however, significantly reduced the uptake of activity in hepatocytes but not the tumour cell line ( TP<0.05). An optimum concentration and time period for incubating DTPA with labelled MAb was established. The mean hepatocyte uptake was reduced by 80% with a 1 h incubation with 1 mM DTPA. These results suggest that DTPA may have a role in reducing the liver uptake of radioactivity in patient studies usingIn-MAb. [ABSTRACT FROM AUTHOR]

As a model for human mouse-specific antibody responses in patients undergoing immunoscintigraphy, we have investigated in rats the production of mouse-specific antibodies (MA) to the mouse monoclonal antibody 791T/36. At intervals of between 5 and 16 weeks the rats were given repeated cycles of intravenous (IV) injections of antibody with or without a simultaneous intradermal (ID) injection. The IV dose was 60 gmg/kg, a dose similar to that used in many clinical immunoscintigraphy studies. The ID injection was 2 μg, which mimicks the skin test dose often given in clinical imaging protocols. The study was carried out with bothI-labelled antibody and with antibody labelled withIn by diethylenetriamine-penta-acetic acid (DTPA) chelation. MA was measured with a passive haemagglutination assay using sheep red blood cells coated with the monoclonal antibody. Of rats given ID injections of unlabelled antibody at the same time as the IV imaging doses, 9/20 produced MA during 4 cycles of injections. In contrast, only 2/16 rats given only the IV dose produced MA. BothI- andIn-labelled antibody appeared equally immunogenic with 5/18 and 6/18 overall responders, respectively. The production of MA was associated with a significant perturbation in the biodistribution of the IV dose of labelled antibody as seen by gamma-camera imaging of the rats givenIn-labelled antibody. There was clearance of immune complexes to the liver, this organ accumulating up to 90% of the whole body count rate of radiolabel. MA titres of between 1/100 and 1/78000 caused equal perturbation of biodistribution, although below 1/100 the effect was more variable. [ABSTRACT FROM AUTHOR]

CD expressing T-lymphocytes are involved in the pathogenesis of rheumatoid arthritis, so the possibility of using radiolabelled CD-specific antibodies to localise diseased joints was studied. Prospectively six patients with rheumatoid arthritis were investigated. Five of them received 200-300 μg of a 555 MBq technetium 99m CD-specific antibody (MAX.16H5) and were examined with three phase bone scans. Max.16H5 (IgG1) was labelled according to the mercaptoethanol (Schwarz) method. Lymphocytes of one patient were isolated on a Ficoll-Hypaque gradient and labelled with the antibody in vitro. Scans were performed 1.5 h, 4 and 24 h post injection in anterior and posterior views. In all patients, diseased joints could be clearly imaged at as early as 1.5 h. The localisation of the diseased joints correlated ( P<0.01) with the clinical signs, with the early methylene diphosphonate (MDP) scan ( P > 0.01) and only weakly with the late bone scan ( P > 0.05). According to these data we conclude thatTc-labelled CD-specific antibodies specifically image actively diseased joints in rheumatoid arthritis. [ABSTRACT FROM AUTHOR]