Pulmonary Emboli Imaging with 99mTc-labelled Anti-D-dimer (DI-80B3) Fab′ Followed by SPECT

doi:10.1016/j.hlc.2011.03.113

Heart, Lung and Circulation

Volume 20, Issue 8, August 2011, Pages 503-511

https://doi.org/10.1016/j.hlc.2011.03.113 Get rights and content

Objectives

Pre-clinical experiments demonstrated that intravenous ^99mTc labelled DI-DD-3B6/22-80B3 humanised anti-fibrin-D-dimer Fab′ fragments (^99mTc-DI-80B3) allowed scintigraphic imaging of acute pulmonary emboli (PE). The aims of this clinical study were to determine the safety of ^99mTc-DI-80B3 in patients with PE and evaluate the resulting scintigraphic images for the localisation of acute PE.

Materials/patients and methods

^99mTc-DI-80B3 (0.5 mg, 710–850 MBq) was administered intravenously to subjects (n = 14) with segmental or larger PE on recent contrast-enhanced helical CT scans. Thoracic SPECT scans were acquired 15 minutes, 2 hours and 4 hours afterwards. Subjects were followed for 90 days subsequently.

Results

There were no serious adverse events or antibody responses associated with ^99mTc-DI-80B3 administration. Focal accumulations of ^99mTc-DI-80B3 on the SPECT images of the thorax acquired at four hours corresponded to pulmonary emboli detected by CT. Two independent “blinded” SPECT readers identified 79% and 71% (respectively) of the right lung and 79% and 64% (respectively) of the left lung in which CT scans disclosed PE.

Conclusions

^99mTc-DI-80B3 is well-tolerated in patients with acute PE and does not induce an immune response. ^99mTc-DI-80B3 may offer a novel approach to imaging PE in a clinically acceptable timeframe without exposure to potentially nephrotoxic radiographic contrast agents.

Section snippets

Background

Mortality from acute pulmonary embolism (PE) remains a substantial public health care problem [1]. Autopsy series suggest that death from acute PE is at least three-fold higher than the current clinical incidence estimates of PE [2], [3], [4], [5], [6], which suggests that limitations in current diagnostic approaches may leave a proportion of patients with PE undiagnosed and therefore untreated. Improvements in the ability to diagnose PE would be especially beneficial in light of the excellent

Study Population

Adults diagnosed with acute PE at the participating medical centres were considered for enrolment in the study. Inclusion criteria were: (1) ability to give informed consent; (2) onset of PE-related symptoms in the seven days prior to enrolment; (3) presence of PE, defined as intra-luminal filling defects in segmental or larger pulmonary arteries on multi-detector CTPA; (4) ability to receive injection of ^99mTc-DI-80B3 Fab′ within 72 hours of the CTPA; (5) men or non-pregnant women, aged 18

Characteristics of the Subjects

Sixteen subjects with acute pulmonary emboli were enrolled in the study. One subject did not receive ^99mTc-DI-80B3 due to equipment failure on the study day. The remaining 15 received ^99mTc-DI-80B3. One subject withdrew consent prior to imaging and pharmacokinetic analysis, but agreed to continue with safety assessments. The remaining 14 subjects underwent imaging and pharmacokinetic analysis. All 14 subjects had evaluable ^99mTc-DI-80B3 imaging and pharmacokinetic data. One of these subjects

Discussion

The results of this study indicate that intravenous ^99mTc-DI-80B3 administration is safe in patients with acute PE. It was associated with no serious adverse effects and no detectable antibody responses. This is consistent with the results of similar studies in normal volunteers [12] and patients with deep venous thrombosis [15]. Transient and asymptomatic elevations in liver enzymes were observed in three patients in the first week after ^99mTc-DI-80B3 administration, although those patients

Conclusion

The technique of SPECT scanning after administration of ^99mTc-DI-80B3 appeared to be safe in patients with acute PE, and shows promise as an alternative method of PE diagnosis. The imaging data from this study are being used to optimise the image acquisition and interpretation for subsequent Phase II studies.

Competing Interests

This study was funded by a research grant from AGEN Biomedical Ltd. Drs. Gerometta and Ms. Tsui were employees of AGEN Biomedical Ltd., Dr. Eisenberg was a consultant to AGEN Biomedical Ltd. and held 50,000 shares of Agen stock (currently no value) and Dr. Macfarlane was a consultant to AGEN Biomedical Ltd. during the performance of the study. Dr. Morris received research support for this study and other studies concerning the same agent from AGEN Biomedical Ltd. and his travel to the

Authors’ Contributions

TM, MG, PE, RS and DM conceived of and designed the study. DM was the principal coordinating investigator for the enrolment sites. RS, WT and DM reviewed the raw acquisition data. PR, NB, KT and SU contributed to the study design, acted as site principal investigators and assisted in the analysis of the final results. All authors read, edited and approved of the final manuscript.

Authors’ Information

Not applicable.

Acknowledgements

The authors would like to acknowledge the expert image interpretations provided by Dr. Richard Slaughter who reviewed the CT images; Drs. Paul Thomas, Fred Khafagi, and John Hunter who initially reviewed the ^99mTc-DI-80B3 to optimise the imaging parameters and develop the image interpretation guide; as well as Drs. Scott Beuzeville and. Ernest Belezzuoli who reviewed the ^99mTc-DI-80B3 SPECT scans diagnostically. They thank Peter Chiles for assistance with the illustrations for the manuscript

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SPECT Ventilation/Perfusion Imaging for Acute Pulmonary Embolism: Meta-analysis of Diagnostic Test Accuracy
2024, Academic Radiology
This study aimed to evaluate the diagnostic accuracies of ventilation/perfusion-single photon emission computed tomography (V/Q-SPECT) imaging modalities for acute pulmonary embolism (PE). These included, in addition to V/Q-SPECT, V/Q-SPECT with low-dose computed tomography (CT; V/Q-SPECT-CT), Q-SPECT with low-dose CT (Q-SPECT-CT), and Q-SPECT.
PubMed, Embase, CINAHL, and Web of Science databases were searched, and studies included if they studied ≥10 adult participants with acute PE and reported data on the imaging tests’ diagnostic performance. Data were meta-analyzed using bivariate random effects regression model.
Data from participants totaling 4146 from 11 V/Q-SPECT studies, 785 from 7 V/Q-SPECT-CT studies, 1196 from 7 Q-SPECT-CT studies, and 728 from five Q-SPECT studies were separately meta-analyzed. The bivariate weighted mean sensitivity and specificity were 0.94 (95% confidence interval [CI]: 0.88–0.97) and 0.95 (95% CI: 0.87–0.98) for V/Q-SPECT, 0.95 (95% CI: 0.88–0.98) and 0.99 (95% CI: 0.92–1.00) for V/Q-SPECT-CT, 0.92 (95% CI: 0.79–0.97) and 0.92 (95% CI: 0.83–0.96) for Q-SPECT-CT, and 0.89 (95% CI: 0.76–0.95) and 0.86 (95% CI: 0.67–0.95) for Q-SPECT studies. The positive and negative likelihood ratios (+LRs and –LRs) were 17.4 (6.9–44.0) and 0.06 (0.03–0.13), 76.7 (11.8–498.0) and 0.06 (0.02–0.13), 11.0 (5.3–22.9) and 0.09 (0.04–0.23), and 6.4 (2.6–15.8) and 0.13 (0.07–0.27) for V/Q-SPECT, V/Q-SPECT-CT, Q-SPECT-CT, and Q-SPECTs, respectively.
In the diagnosis of acute PE, this meta-analysis showed that V/Q-SPECT-CT had the highest specificity and +LR. Conversely, Q-SPECT showed the lowest specificity and an unfavorably high −LR.
New developments and future challenges of nuclear medicine and molecular imaging for pulmonary embolism
2018, Thrombosis Research
Citation Excerpt :
However, in a phase 3 multicenter trial comparing 99mTc-Apcitide with contrast venography in 280 patients, Taillefer et al. found sensitivity and specificity of only 75% and 73% respectively for imaging acute VTE [46]. Radiolabeled antibody fragment that binds to the D-dimer regions of fibrin (99mTc-DI-80B3) has also successfully completed two US FDA phase II human clinical trials for imaging DVT and PE [47,48]. Although 99mTc-DI-80B3 has shown a potential interest for patients with suspected DVT with a promising accuracy and safety profile, additional clinical development in diagnostic accuracy and clinical management studies are still needed.
Although widely validated, current tests for pulmonary embolism (PE) diagnosis, i.e. computed tomography pulmonary angiography (CTPA) and V/Q planar scintigraphy, have some limitations. Drawbacks of CTPA include the radiation dose, some contra indications and a rising concern about a possible overdiagnosis/overtreatment of PE. On the other hand, V/Q planar scintigraphy has a high rate of non-diagnostic tests responsible for complex diagnostic algorithms.
Since the PIOPED study, imaging equipment and radiopharmaceuticals have greatly evolved allowing the introduction of techniques that improve imaging of lung ventilation and perfusion. Single photon emission computed tomography (SPECT) and SPECT/CT techniques are already largely used in daily practice and have been described to have greater diagnostic performance and much fewer non-diagnostic tests as compared with planar scintigraphy. However, they have not yet been firmly validated in large scale prospective outcome studies. More recently, it has also been proposed to image pulmonary perfusion and ventilation using positron emission tomography (PET), which has an inherent technical superiority as compared to conventional scintigraphy and may provide new insight for pulmonary embolism. Regardless of modality, these new thoracic imaging modalities have to be integrated into diagnostic strategies.
The other major challenge for venous thromboembolism diagnosis may be the potential additional value of molecular imaging allowing specific targeting of thrombi in order, for example, to differentiate venous thromboembolism from tumor or septic thrombus, or acute from residual disease.
In this article, the new imaging procedures of lung ventilation perfusion imaging with SPECT, SPECT/CT and PET/CT are discussed. We also review the current status and future challenge of molecular imaging for the in vivo characterization of venous thromboembolism.
Accuracy and safety of <sup>99m</sup>Tc-labeled anti-D-dimer (DI-80B3) Fab' fragments (ThromboView®) in the diagnosis of deep vein thrombosis: A phase II study
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In summary, 99mTc-DI-80B3 is a novel diagnostic modality for patients with suspected DVT that has a promising accuracy and safety profile. When these findings are combined with comparable findings of this imaging modality in patients with suspected PE [18,19], there is compelling evidence to support further clinical evaluation of 99mTc-DI-80B3 with additional accuracy and, eventually, clinical management studies. All co-authors have declared any potential conflicts of interests.
The assessment of patients with suspected deep vein thrombosis (DVT) remains challenging despite current diagnostic algorithms. ^99mTc-labelled DI-DD3B6/22-80B3 Fab´ fragments (^99mTc-DI-80B3, ThromboView®) is a novel diagnostic test that uses a radiolabelled humanized monoclonal antibody fragment specific for the D-dimer region of cross-linked fibrin to detect DVT. This test has an anatomic component to locate DVT and a functional component to differentiate acute (newly formed) thrombus from inactive (old) thrombus.
In a multi-centre prospective cohort trial we investigated the diagnostic accuracy and safety of ^99mTc-DI-80B3 in consecutive patients with suspected DVT who had the diagnosis confirmed or excluded by venography.
We enrolled 94 patients with suspected DVT of whom 12 did not have ^99mTc-DI-80B3 imaging, leaving 82 patients for the safety analysis. Of these patients, there were 16 with non-evaluable imaging (11 venography, 7 ^99mTc-DI-80B3, both in two patients) leaving 66 patients for the accuracy analysis. ^99mTc-DI-80B3 imaging was well-tolerated: 2 patients developed urticaria; none developed serious adverse events. For proximal DVT, the sensitivity (84.2%; 95% confidence interval [CI]: 62.4–94.5) and specificity (97.6%; CI: 83.3–99.4) were highest when the combined 0.25-hour and 3-hour ^99mTc-DI-80B3 images were used. The accuracy was lower for distal DVT, irrespective of the images used. There were insufficient patients to comment on the accuracy of ^99mTc-DI-80B3 imaging for suspected recurrent DVT.
^99mTc-DI-80B3 (ThromboView®) is a novel diagnostic modality for patients with suspected DVT with a promising accuracy and safety profile that justifies additional clinical development in diagnostic accuracy and clinical management studies.
An unmet clinical need: The history of thrombus imaging
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Pulmonary Embolism: Third Edition
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Original ArticlePulmonary Emboli Imaging with 99mTc-labelled Anti-D-dimer (DI-80B3) Fab′ Followed by SPECT

Objectives

Materials/patients and methods

Results

Conclusions

Section snippets

Background

Study Population

Characteristics of the Subjects

Discussion

Conclusion

Competing Interests

Authors’ Contributions

Authors’ Information

Acknowledgements

Mayo Clin Proc

Chest

Thromb Res

J Immunol Methods JID -1305440

Chest JID-0231335

Thromb Res JID-0326377

Heart disease and stroke statistics – 2008 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee

Circulation

Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study

Arch Intern Med

Fatal pulmonary emboli in hospitalized patients. An autopsy study

Arch Intern Med

Comparison of clinical and postmortem diagnosis of pulmonary embolism

J Clin Pathol

Risk of fatal pulmonary embolism in patients with treated venous thromboembolism

JAMA

Single photon emission computed tomography of pulmonary emboli and venous thrombi using anti-D-dimer

Am J Respir Crit Care Med

Clinical diagnostic imaging of pulmonary emboli using radiolableled anti-crosslinked fibrin antibodies (thromboview)

Chest

Safety, pharmacokinetic and dosimetry evaluation of the proposed thrombus imaging agent 99mTc-DI-DD-3B6/22-80B3 Fab’

Eur J Nucl Med Mol Imaging

Original Article
Pulmonary Emboli Imaging with ^99mTc-labelled Anti-D-dimer (DI-80B3) Fab′ Followed by SPECT

Safety, pharmacokinetic and dosimetry evaluation of the proposed thrombus imaging agent ^99mTc-DI-DD-3B6/22-80B3 Fab’