Alfons H. H. Bongaerts

Comparison of contrast-enhanced magnetic resonance angiography and conventional pulmonary angiography for the diagnosis of pulmonary embolism : a prospective study

BACKGROUND Diagnostic strategies for pulmonary embolism are complex and consist of non-invasive diagnostic tests done to avoid conventional pulmonary angiography as much as possible. We aimed to assess the diagnostic accuracy of magnetic resonance angiography (MRA) for the diagnosis of pulmonary embolism, using conventional pulmonary angiography as a reference method. METHODS In a prospective study, we enrolled 141 patients with suspected pulmonary embolism and an abnormal perfusion scan. Patients underwent MRA before conventional pulmonary angiography. Two reviewers, masked with respect to the results of conventional pulmonary angiography, assessed MRA images independently. Statistical analyses used chi(2) and 95% CI. FINDINGS MRA was contraindicated in 13 patients (9%), and images were not interpretable in eight (6%). MRA was done in two patients in whom conventional pulmonary angiography was contraindicated. Thus, MRA and conventional pulmonary angiography results were available in 118 patients (84%). Prevalence of pulmonary embolism was 30%. Images were read independently in 115 patients, and agreement obtained in 105 (91%), kappa=0.75. MRA identified 27 of 35 patients with proven pulmonary embolism (sensitivity 77%, 95% CI 61-90). Sensitivity of MRA for isolated subsegmental, segmental, and central or lobar pulmonary embolism was 40%, 84%, and 100%, respectively (p<0.01 for isolated subsegmental vs segmental or larger pulmonary embolism). However, subgroups contained small numbers. MRA identified pulmonary embolism in two patients with normal angiogram (98%, 92-100). INTERPRETATION MRA is sensitive and specific for segmental or larger pulmonary embolism. Results are similar to those obtained with helical computed tomography, but MRA has safer contrast agents and does not involve ionising radiation. MRA could become part of the diagnostic strategy for pulmonary embolism.

Oesophageal endoscopic ultrasound with fine needle aspiration improves and simplifies the staging of lung cancer

Background: Positron emission tomography (PET) is accurate for mediastinal staging of lung cancer but has a moderate positive predictive value, necessitating pathological verification. Endoscopic ultrasonography with fine needle aspiration (EUS-FNA) is a technique for tissue verification of mediastinal and upper retroperitoneal abnormalities. The use of EUS-FNA may decrease the number of surgical procedures and thereby staging costs. Methods: EUS-FNA was used prospectively for the cytological assessment of mediastinal and/or upper retroperitoneal PET hot spots in patients with suspected lung cancer. Only if EUS-FNA was positive for malignancy was subsequent mediastinoscopy or exploratory thoracotomy cancelled. The cost effectiveness of EUS-FNA was determined. Results: Of 488 consecutive patients with suspected lung cancer, 81 were enrolled with mediastinal and/or upper retroperitoneal PET hot spots. EUS-FNA was positive in 50 (62%) patients, negative in six, and inconclusive in 25. Of the 31 negative or inconclusive patients, 26 underwent surgical staging (resulting in 14 patients with and 12 without mediastinal malignancy), while five patients had mediastinal metastases during follow up. No EUS-FNA related morbidity or mortality was encountered. The accuracy of the decision to proceed to surgery (or not) on the basis of EUS-FNA was 77% (95% CI 68 to 86). EUS-FNA detected more mediastinal abnormalities than PET except for the upper mediastinal region. Addition of EUS-FNA to conventional lung cancer staging reduced staging costs by 40% per patient, mainly due to a decrease in surgical staging procedures. Conclusion: EUS-FNA can replace more than half of the surgical staging procedures in lung cancer patients with mediastinal and/or upper retroperitoneal PET hot spots, thereby saving 40% of staging costs.

Lung scintigraphy and helical computed tomography for the diagnosis of pulmonary embolism: A meta-analysis

To assess the diagnostic value of lung scintigraphy and helical computed tomography (hCT) in patients with suspected pulmonary embolism (PE), all English-language articles that described lung scintigraphy and hCT in patients with suspected PE were retrieved. Articles were assessed for strength of methodology, based on nine a priori-defined criteria. Parameters of diagnostic accuracy and results of management studies were calculated and evaluated. Lung scintigraphy is diagnostic in approximately 50% of patients with suspected PE. A normal perfusion scan has a chance of recurrent PE in two of 693 patients (0.3%; 95% CI: 0.2-0.4%; fatal in 0.15%). A high-probability lung scan is corrected with angiographically proven PE in 308 of 350 patients (88%; 95% CI: 84-91%). Pulmonary embolism was proven in 385 of 1529 patients (25%; 95% CI: 24-28%) with a nondiagnostic lung scan. Helical CT studies were compared with angiography and lung scintigraphy in 1171 patients, with a prevalence of PE of 39%. The sensitivity and specificity of hCT was 283/320 (88%; 95% CI: 83-91%) and 374/408 (92%; 95% CI:89-94%), respectively. Only one prospective management study using hCT was available. In patients in whom anticoagulants were withheld based on a normal hCT study, recurrent thromboembolic events occurred in six of 109 patients (5.5%; 95% CI: 2-12%), with one fatality (1%; 95% CI: 0.02-4.3%). Lung scintigraphy is evaluated extensively and yields a diagnostic result in 50% of patients. Helical CT has similar positive predictive value to a high-probability lung scan. However, the exact role of hCT in the management of patients with suspected PE needs to be determiined in prospective studies.

Zr-89-trastuzumab and Zr-89-bevacizumab PET to Evaluate the Effect of the HSP90 Inhibitor NVP-AUY922 in Metastatic Breast Cancer Patients

Purpose: HSP90 chaperones have key client proteins that are involved in all hallmarks of breast cancer growth and progression. The primary aim of this clinical trial was to evaluate the feasibility of using 89Zr-trastuzumab PET (for HER2-positive breast cancer) or 89Zr-bevacizumab PET [for estrogen receptor (ER)–positive breast cancer] to determine in vivo degradation of client proteins caused by the novel HSP90 inhibitor NVP-AUY922. Experimental Design: Of note, 70 mg/m2 NVP-AUY922 was administered intravenously in a weekly schedule to patients with advanced HER2 or ER-positive breast cancer. Biomarker analysis consisted of serial PET imaging with 2[18F]fluoro-2-deoxy-D-glucose (FDG), 89Zr-trastuzumab, or 89Zr-bevacizumab. Response evaluation was performed according to RECIST1.0. FDG, 89Zr-trastuzumab, and 89Zr-bevacizumab distributions were scored visually and quantitatively by calculating the maximum standardized uptake values (SUVmax). In blood samples, serial HSP70 levels, extracellular form of HER2 (HER2-ECD), and pharmacokinetic and pharmacodynamic parameters were measured. Results: Sixteen patients (ten HER2-positive and six ER-positive tumors) were included. One partial response was observed; seven patients showed stable disease. SUVmax change in individual tumor lesions on baseline versus 3 weeks 89Zr-trastuzumab PET was heterogeneous and related to size change on CT after 8 weeks treatment (r2 = 0.69; P = 0.006). Tumor response on 89Zr-bevacizumab PET and FDG-PET was not correlated with CT response. Conclusions: NVP-AUY922 showed proof-of-concept clinical response in HER2-amplified metastatic breast cancer. Early change on 89Zr-trastuzumab PET was positively associated with change in size of individual lesions assessed by CT. Clin Cancer Res; 20(15); 3945–54. ©2014 AACR.

89Zr-Bevacizumab PET Visualizes Heterogeneous Tracer Accumulation in Tumor Lesions of Renal Cell Carcinoma Patients and Differential Effects of Antiangiogenic Treatment

No validated predictive biomarkers for antiangiogenic treatment of metastatic renal cell carcinoma (mRCC) exist. Tumor vascular endothelial growth factor A (VEGF-A) level may be useful. We determined tumor uptake of 89Zr-bevacizumab, a VEGF-A–binding PET tracer, in mRCC patients before and during antiangiogenic treatment in a pilot study. Methods: Patients underwent 89Zr-bevacizumab PET scans at baseline and 2 and 6 wk after initiating either bevacizumab (10 mg/kg every 2 wk) with interferon-α (3–9 million IU 3 times/wk) (n = 11) or sunitinib (50 mg daily, 4 of every 6 wk) (n = 11). Standardized uptake values were compared with plasma VEGF-A and time to disease progression. Results: 89Zr-bevacizumab PET scans visualized 125 evaluable tumor lesions in 22 patients, with a median SUVmax (maximum standardized uptake value) of 6.9 (range, 2.3–46.9). Bevacizumab/interferon-α induced a mean change in tumor SUVmax of −47.0% (range, −84.7 to +20.0%; P < 0.0001) at 2 wk and an additional −9.7% (range, −44.8 to +38.9%; P = 0.015) at 6 wk. In the sunitinib group, the mean change in tumor SUVmax was −14.3% at 2 wk (range, −80.4 to +269.9; P = 0.006), but at 6 wk the mean change in tumor SUVmax was +72.6% (range, −46.4 to +236%; P < 0.0001) above baseline. SUVmax was not related to plasma VEGF-A at all scan moments. A baseline mean tumor SUVmax greater than 10.0 in the 3 most intense lesions corresponded with longer time to disease progression (89.7 vs. 23.0 wk; hazard ratio, 0.22; 95% confidence interval, 0.05–1.00). Conclusion: Tumor uptake of 89Zr-bevacizumab is high in mRCC, with remarkable interpatient and intrapatient heterogeneity. Bevacizumab/interferon-α strongly decreases tumor uptake whereas sunitinib results in a modest reduction with an overshoot after 2 drug-free weeks. High baseline tumor SUVmax was associated with longer time to progression.

Everolimus Reduces Zr-89-Bevacizumab Tumor Uptake in Patients with Neuroendocrine Tumors

Everolimus increases progression-free survival in patients with advanced neuroendocrine tumors (NETs). Currently, no biomarkers are available for early selection of patients who will benefit from everolimus. Everolimus can reduce vascular endothelial growth factor A (VEGF-A) production by tumor cells. Therefore, we aimed to investigate the effect of everolimus on tumor uptake of the radioactive-labeled VEGF-A antibody bevacizumab with PET in NET patients. Methods: Patients with advanced progressive well-differentiated NETs underwent 89Zr-bevacizumab PET scans before and at 2 and 12 wk during everolimus treatment. 89Zr-bevacizumab uptake was quantified by the maximum standardized uptake value (SUVmax). Tumor response and the percentage change in the sum of target lesion diameters were determined according to Response Evaluation Criteria in Solid Tumors 1.1 on CT (3 monthly). Results: In 4 of the 14 patients entered, no tumor lesions were visualized with 89Zr-bevacizumab PET. In the remaining patients, 19% of tumor lesions 1 cm or greater known by CT were visualized. Tumor SUVmax decreased during everolimus treatment, with a median of −7% at 2 wk (P = 0.09) and a median of −35% at 12 wk (P < 0.001). The difference in SUVmax at 2 and 12 wk with respect to SUVmax at baseline correlated with percentage change on CT at 6 mo (r2 = 0.51, P < 0.05, and r2 = 0.61, P < 0.01, respectively). Conclusion: This study demonstrates variable 89Zr-bevacizumab PET tumor uptake in NET patients. 89Zr-bevacizumab tumor uptake diminished during everolimus treatment. Serial 89Zr-bevacizumab PET might be useful as an early predictive biomarker of anti–VEGF-directed treatment in NET patients.

Intravenous coronary angiography using electron beam computed tomography

Intravenous coronary angiography with electron beam computed tomography (EBCT) allows for the noninvasive visualisation of coronary arteries. With dedicated computer hardware and software, three-dimensional renderings of the coronary arteries, veins, and other cardiac structures can be constructed from the individual transaxial tomograms. Interest in this technique is growing, and recently a number of clinical studies have been published comparing EBCT coronary angiography with conventional cine-coronary angiography. In this article, image acquisition, postprocessing techniques, and the results of recently published clinical studies are discussed. EBCT coronary angiography is a promising imaging technique of coronary arteries. Currently, it is a reasonably robust technique for the visualization and assessment of the left main and left anterior descending coronary artery. However, at the moment a relatively high proportion of the right and circumflex coronary angiograms are noninterpretable. Improvements in image acquisition and postprocessing techniques are expected to improve visualization and diagnostic accuracy of the technique.

Normal tissue complication probability (NTCP) models for late rectal bleeding, stool frequency and fecal incontinence after radiotherapy in prostate cancer patients.

BACKGROUND AND PURPOSE Curative radiotherapy for prostate cancer may lead to anorectal side effects, including rectal bleeding, fecal incontinence, increased stool frequency and rectal pain. The main objective of this study was to develop multivariable NTCP models for these side effects. MATERIAL AND METHODS The study sample was composed of 262 patients with localized or locally advanced prostate cancer (stage T1-3). Anorectal toxicity was prospectively assessed using a standardized follow-up program. Different anatomical subregions within and around the anorectum were delineated. A LASSO logistic regression analysis was used to analyze dose volume effects on toxicity. RESULTS In the univariable analysis, rectal bleeding, increase in stool frequency and fecal incontinence were significantly associated with a large number of dosimetric parameters. The collinearity between these predictors was high (VIF>5). In the multivariable model, rectal bleeding was associated with the anorectum (V70) and anticoagulant use, fecal incontinence was associated with the external sphincter (V15) and the iliococcygeal muscle (V55). Finally, increase in stool frequency was associated with the iliococcygeal muscle (V45) and the levator ani (V40). No significant associations were found for rectal pain. CONCLUSIONS Different anorectal side effects are associated with different anatomical substructures within and around the anorectum. The dosimetric variables associated with these side effects can be used to optimize radiotherapy treatment planning aiming at prevention of specific side effects and to estimate the benefit of new radiation technologies.

ImmunoPET with Anti-Mesothelin Antibody in Patients with Pancreatic and Ovarian Cancer before Anti-Mesothelin Antibody-Drug Conjugate Treatment

Purpose: Mesothelin (MSLN) is frequently overexpressed in pancreatic and ovarian cancers, making it a potential drug target. We performed an 89Zr-PET imaging study with MMOT0530A, a MSLN antibody, in conjunction with a phase I study with the antibody–drug conjugate DMOT4039A, containing MMOT0530A bound to MMAE. The aim was to study antibody tumor uptake, whole-body distribution, and relation between uptake, response to treatment, and MSLN expression. Experimental Design: Before DMOT4039A treatment, patients received 37 MBq 89Zr-MMOT0530A followed by PET/CT imaging 2, 4, and 7 days postinjection. Tracer uptake was expressed as standardized uptake value (SUV). MSLN expression was determined with immunohistochemistry (IHC) on archival tumor tissue. Results: Eleven patients were included, 7 with pancreatic and 4 with ovarian cancer. IHC MSLN expression varied from absent to strong. Suitable tracer antibody dose was 10 mg MMOT0530A and optimal imaging time was 4 and 7 days postinjection. Tumor tracer uptake occurred in 37 lesions with mean SUVmax of 13.1 (±7.5) on PET 4 days postinjection, with 11.5 (±7.5) in (N = 17) pancreatic and 14.5 (±8.7) in (N = 20) ovarian cancer lesions. Within patients, a mean 2.4-fold (±1.10) difference in uptake between tumor lesions existed. Uptake in blood, liver, kidneys, spleen, and intestine reflected normal antibody distribution. Tracer tumor uptake was correlated to IHC. Best response to DMOT4039A was partial response in one patient. Conclusions: With 89Zr-MMOT0530A-PET, pancreatic and ovarian cancer lesions as well as antibody biodistribution could be visualized. This technique can potentially guide individualized antibody-based treatment. Clin Cancer Res; 22(7); 1642–52. ©2015 AACR.

In vivo assessment of three dimensional coronary anatomy using electron beam computed tomography after intravenous contrast administration

Intravenous coronary angiography with electron beam computed tomography (EBCT) allows for the non-invasive visualisation of coronary arteries. With dedicated computer hardware and software, three dimensional renderings of the coronary arteries can be constructed, starting from the individual transaxial tomograms. This article describes image acquisition, postprocessing techniques, and the results of clinical studies. EBCT coronary angiography is a promising coronary artery imaging technique. Currently it is a reasonably robust technique for the visualisation and assessment of the left main and left anterior descending coronary artery. The right and circumflex coronary arteries can be visualised less consistently. Improvements in image acquisition and postprocessing techniques are expected to improve visualisation and diagnostic accuracy of the technique.