Arthur Adams

Cardiac Magnetic Resonance Imaging Findings and the Risk of Cardiovascular Events in Patients With Recent Myocardial Infarction or Suspected or Known Coronary Artery Disease

The goal of this study was to review the prognostic value of cardiac magnetic resonance (CMR) imaging findings for future cardiovascular events in patients with a recent myocardial infarction (MI) and patients with suspected or known coronary artery disease (CAD). Although the diagnostic value of CMR findings is established, the independent prognostic association with future cardiovascular events remains largely unclear. Studies published by February 2013, identified by systematic MEDLINE and EMBASE searches, were reviewed for associations between CMR findings (left ventricular ejection fraction [LVEF], wall motion abnormalities [WMA], abnormal myocardial perfusion, microvascular obstruction, late gadolinium enhancement, edema, and intramyocardial hemorrhage) and hard events (all-cause mortality, cardiac death, cardiac transplantation, and MI) or major adverse cardiovascular events (MACE) (hard events and other cardiovascular events defined by the authors of the evaluated papers). Fifty-six studies (n = 25,497) were evaluated. For patients with recent MI, too few patients were evaluated to establish associations between CMR findings and hard events. LVEF (range of adjusted hazard ratios [HRs]: 1.03 to 1.05 per % decrease) was independently associated with MACE. In patients with suspected or known CAD, WMA (adjusted HRs: 1.87 to 2.99), inducible perfusion defects (adjusted HRs: 3.02 to 7.77), LVEF (adjusted HRs: 0.72 to 0.82 per 10% increase), and infarction (adjusted HRs: 2.82 to 9.43) were independently associated with hard events, and the presence of inducible perfusion defects was associated with MACE (adjusted HRs: 1.76 to 3.21). The independent predictor of future cardiovascular events for patients with a recent MI was LVEF, and the predictors for patients with suspected or known CAD were WMA, inducible perfusion defects, LVEF, and presence of infarction.

Tumor-specific uptake of fluorescent bevacizumab-IRDye800CW microdosing in patients with primary breast cancer: a phase I feasibility study

Purpose: To provide proof of principle of safety, breast tumor–specific uptake, and positive tumor margin assessment of the systemically administered near-infrared fluorescent tracer bevacizumab–IRDye800CW targeting VEGF-A in patients with breast cancer. Experimental Design: Twenty patients with primary invasive breast cancer eligible for primary surgery received 4.5 mg bevacizumab–IRDye800CW as intravenous bolus injection. Safety aspects were assessed as well as tracer uptake and tumor delineation during surgery and ex vivo in surgical specimens using an optical imaging system. Ex vivo multiplexed histopathology analyses were performed for evaluation of biodistribution of tracer uptake and coregistration of tumor tissue and healthy tissue. Results: None of the patients experienced adverse events. Tracer levels in primary tumor tissue were higher compared with those in the tumor margin (P < 0.05) and healthy tissue (P < 0.0001). VEGF-A tumor levels also correlated with tracer levels (r = 0.63, P < 0.0002). All but one tumor showed specific tracer uptake. Two of 20 surgically excised lumps contained microscopic positive margins detected ex vivo by fluorescent macro- and microscopy and confirmed at the cellular level. Conclusions: Our study shows that systemic administration of the bevacizumab–IRDye800CW tracer is safe for breast cancer guidance and confirms tumor and tumor margin uptake as evaluated by a systematic validation methodology. The findings are a step toward a phase II dose-finding study aimed at in vivo margin assessment and point to a novel drug assessment tool that provides a detailed picture of drug distribution in the tumor tissue. Clin Cancer Res; 23(11); 2730–41. ©2016 AACR.

Imaging Features of HER2 Overexpression in Breast Cancer: A Systematic Review and Meta-analysis

Breast cancer imaging phenotype is diverse and may relate to molecular alterations driving cancer behavior. We systematically reviewed and meta-analyzed relations between breast cancer imaging features and human epidermal growth factor receptor type 2 (HER2) overexpression as a marker of breast cancer aggressiveness. MEDLINE and EMBASE were searched for mammography, breast ultrasound, magnetic resonance imaging (MRI), and/or [18F]fluorodeoxyglucose positron emission tomography studies through February 2013. Of 68 imaging features that could be pooled (85 articles, 23,255 cancers; random-effects meta-analysis), 11 significantly related to HER2 overexpression. Results based on five or more studies and robustness in subgroup analyses were as follows: the presence of microcalcifications on mammography [pooled odds ratio (pOR), 3.14; 95% confidence interval (CI), 2.46–4.00] or ultrasound (mass-associated pOR, 2.95; 95% CI, 2.34–3.71), branching or fine linear microcalcifications (pOR, 2.11; 95% CI, 1.07–4.14) or extremely dense breasts on mammography (pOR, 1.37; 95% CI, 1.07–1.76), and washout (pOR, 1.57; 95% CI, 1.11–2.21) or fast initial kinetics (pOR, 2.60; 95% CI, 1.43–4.73) on MRI all increased the chance of HER2 overexpression. Maximum [18F]fluorodeoxyglucose standardized uptake value (SUVmax) was higher upon HER2 overexpression (pooled mean difference, +0.76; 95% CI, 0.10–1.42). These results show that several imaging features relate to HER2 overexpression, lending credibility to the hypothesis that imaging phenotype reflects cancer behavior. This implies prognostic relevance, which is especially relevant as imaging is readily available during diagnostic work-up. Cancer Epidemiol Biomarkers Prev; 23(8); 1464–83. ©2014 AACR.

Threshold Analysis and Biodistribution of Fluorescently Labeled Bevacizumab in Human Breast Cancer.

In vivo tumor labeling with fluorescent agents may assist endoscopic and surgical guidance for cancer therapy as well as create opportunities to directly observe cancer biology in patients. However, malignant and nonmalignant tissues are usually distinguished on fluorescence images by applying empirically determined fluorescence intensity thresholds. Here, we report the development of fSTREAM, a set of analytic methods designed to streamline the analysis of surgically excised breast tissues by collecting and statistically processing hybrid multiscale fluorescence, color, and histology readouts toward precision fluorescence imaging. fSTREAM addresses core questions of how to relate fluorescence intensity to tumor tissue and how to quantitatively assign a normalized threshold that sufficiently differentiates tumor tissue from healthy tissue. Using fSTREAM we assessed human breast tumors stained in vivo with fluorescent bevacizumab at microdose levels. Showing that detection of such levels is achievable, we validated fSTREAM for high-resolution mapping of the spatial pattern of labeled antibody and its relation to the underlying cancer pathophysiology and tumor border on a per patient basis. We demonstrated a 98% sensitivity and 79% specificity when using labeled bevacizumab to outline the tumor mass. Overall, our results illustrate a quantitative approach to relate fluorescence signals to malignant tissues and improve the theranostic application of fluorescence molecular imaging. Cancer Res; 77(3); 623-31. ©2016 AACR.

The potential of hypoxia markers as target for breast molecular imaging – a systematic review and meta-analysis of human marker expression

BackgroundMolecular imaging of breast cancer is a promising emerging technology, potentially able to improve clinical care. Valid imaging targets for molecular imaging tracer development are membrane-bound hypoxia-related proteins, expressed when tumor growth outpaces neo-angiogenesis. We performed a systematic literature review and meta-analysis of such hypoxia marker expression rates in human breast cancer to evaluate their potential as clinically relevant molecular imaging targets.MethodsWe searched MEDLINE and EMBASE for articles describing membrane-bound proteins that are related to hypoxia inducible factor 1α (HIF-1α), the key regulator of the hypoxia response. We extracted expression rates of carbonic anhydrase-IX (CAIX), glucose transporter-1 (GLUT1), C-X-C chemokine receptor type-4 (CXCR4), or insulin-like growth factor-1 receptor (IGF1R) in human breast disease, evaluated by immunohistochemistry. We pooled study results using random-effects models and applied meta-regression to identify associations with clinicopathological variables.ResultsOf 1,705 identified articles, 117 matched our selection criteria, totaling 30,216 immunohistochemistry results. We found substantial between-study variability in expression rates. Invasive cancer showed pooled expression rates of 35% for CAIX (95% confidence interval (CI): 26-46%), 51% for GLUT1 (CI: 40-61%), 46% for CXCR4 (CI: 33-59%), and 46% for IGF1R (CI: 35-70%). Expression rates increased with tumor grade for GLUT1, CAIX, and CXCR4 (all p < 0.001), but decreased for IGF1R (p < 0.001). GLUT1 showed the highest expression rate in grade III cancers with 58% (45-69%). CXCR4 showed the highest expression rate in small T1 tumors with 48% (CI: 28-69%), but associations with size were only significant for CAIX (p < 0.001; positive association) and IGF1R (p = 0.047; negative association). Although based on few studies, CAIX, GLUT1, and CXCR4 showed profound lower expression rates in normal breast tissue and benign breast disease (p < 0.001), and high rates in carcinoma in situ. Invasive lobular carcinoma consistently showed lower expression rates (p < 0.001).ConclusionsOur results support the potential of hypoxia-related markers as breast cancer molecular imaging targets. Although specificity is promising, combining targets would be necessary for optimal sensitivity. These data could help guide the choice of imaging targets for tracer development depending on the envisioned clinical application.

Mono- and multimodal registration of optical breast images

Optical breast imaging offers the possibility of noninvasive, low cost, and high sensitivity imaging of breast cancers. Poor spatial resolution and a lack of anatomical landmarks in optical images of the breast make interpretation difficult and motivate registration and fusion of these data with subsequent optical images and other breast imaging modalities. Methods used for registration and fusion of optical breast images are reviewed. Imaging concerns relevant to the registration problem are first highlighted, followed by a focus on both monomodal and multimodal registration of optical breast imaging. Where relevant, methods pertaining to other imaging modalities or imaged anatomies are presented. The multimodal registration discussion concerns digital x-ray mammography, ultrasound, magnetic resonance imaging, and positron emission tomography.

Estimation of detection limits of a clinical fluorescence optical mammography system for the near-infrared fluorophore IRDye800CW: phantom experiments

To evaluate if clinical fluorescence imaging of IRDye800CW is feasible on our fluorescence optical mammography system by estimating detection limits assessed by breast-cancer-simulating phantom experiments. Phantoms (2.1 cm(3), 0.9 cm(3)) with IRDye800CW concentrations of 0.5 to 120 nM were suspended in a 550 cm(3) measurement cup containing 507 surface-mounted source and detector fibers. The cup was filled with optical matching fluid containing IRDye800CW concentrations of 0, 5, 10, or 20 nM. Tomographic fluorescence images were acquired by exciting IRDye800CW at 730 nm; wavelengths above 750 nm were filtered. Signal intensities were calculated over a volume of interest corresponding to the size and location of the phantom in the reconstructed images. Correlations (R(2)) were calculated, and detection limits with associated upper 95% prediction interval were estimated. Between-day reproducibility was assessed with intraclass correlation coefficients (ICC). Fluorescent intensities were strongly correlated with phantom IRDye800CW concentrations (R(2)0.983 to 0.999). IRDye800CW detection limits ranged from 0.14 to 2.46 nM (upper 95% prediction limit 4.63 to 18.63 nM). ICC ranged from 0.88 to 1.00. The estimated detection limits for IRDye800CW were in the low-nanomolar range. These results support the start of clinical trials to evaluate the fluorescence optical mammography system using IRDye800CW labeled breast cancer targeting ligands.

Fluorescently labeled bevacizumab in human breast cancer: defining the classification threshold

In-vivo fluorescently labelled drug (bevacizumab) breast cancer specimen where obtained from patients. We propose a new structured method to determine the optimal classification threshold in targeted fluorescence intra-operative imaging.

Abstract 4935: Hypoxia targeting fluorescent nanobodies for optical molecular imaging of preinvasive breast cancer

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Introduction: Optical molecular imaging is a novel strategy in diagnosis and therapy of breast cancer. Essential for succesful implementation of this technology is a high tumor-to-normal tissue ratio (TNR), which requires tumor-specific probes/tracers. However, most tumor markers are expressed in a minority of tumors only. Therefore, we have developed a novel probe binding to the membrane-bound protein carbonic anhydrase IX (CAIX), which is commonly expressed in solid tumors as a result of hypoxic conditions. The probe is based on nanobodies (15 kDa, variable domains obtained from heavy-chain antibodies present in animals from the Camelidae family), that has a faster tumor uptake and body clearance than conventional (monoclonal) antibodies, and can be applied for molecular imaging of pre-invasive breast cancer. Methods: High affinity CAIX-specific nanobodies were selected using a modified phage display technology and site-directed conjugated to IRDye800CW. Mice bearing orthotopically transplanted MCF10DCIS (DCIS) and CAIX-overexpressing MCF10DCIS (DCIS+CAIX) xenografts were injected with fluorescent CAIX-specific nanobody (B9-IR), or non-specific control nanobody (R2-IR) and imaged up to 48 hours non-invasively. Tumors were resected under image-guidance. Nanobody uptake was assessed in tissue sections and quantified using a biodistribution assay. Results: A highly specific nanobody for CAIX was obtained. In DCIS+CAIX xenografts, mean TNR was 4.3±0.6 (8 mice) already two hours after injection. In DCIS tumors, mean TNR was 1.8±0.1 (8 mice), which was higher than TNR obtained after injection with R2-IR (1.4±0.2, 4 mice). After three hours, probe accumulation was sufficient to allow imag-guided tumor resection. Biodistribution studies showed that B9-IR uptake was 4.6±0.8% of injected dose per gram in DCIS tumor tissue (%I.D./g), while 2.0±0.2 %I.D./g was found with R2-IR. Upon fluorescence imaging of tissue sections, B9-IR was present in perinecrotic areas, while R2-IR showed no accumulation in these regions. Conclusion: We have developed a novel IRDye800CW-labeled anti-CAIX-nanobody that can be used for rapid optical molecular imaging of (pre-)invasive breast cancer before and during surgery. Furthermore, the stability of the conjugate allowed for ‘molecular fluorescence pathology’, which might results in better contrast than conventional chromagen based immunohistochemistry at the pathology department. Acknowledgement: This research was supported by the Center for Translational Molecular Medicine (MAMMOTH). Citation Format: Aram SA van Brussel, Arthur Adams, Sabrina Oliveira, Mohamed El Khatabbi, Jeroen F. Vermeulen, Elsken Van der Wall, Willem PThM Mali, Patrick WB Derksen, Paul J. Van Diest, Paul MP Van Bergen en Henegouwen. Hypoxia targeting fluorescent nanobodies for optical molecular imaging of preinvasive breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4935. doi:10.1158/1538-7445.AM2014-4935

Abstract 3005: Vascular endothelial growth factor A - a systematic review and meta-analysis of expression patterns in breast cancer

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Background Vascular Endothelial Growth Factor-A (VEGF-A), pivotal for neo-angiogenesis, is an interesting target for breast cancer molecular imaging. To assess its potential clinical value, we performed a systematic review and meta-analysis of VEGF-A expression rates in normal breast tissue, benign and (pre-)invasive breast disease, and investigated associations with clinicopathological characteristics. Methods We systematically searched EMBASE and MEDLINE for articles describing VEGF-A expression in breast disease assessed by immunohistochemistry (IHC) or Enzyme-Linked Immunosorbent Assay (ELISA). We pooled IHC expression rates with random-effects models and applied meta-regression to identify associations with clinicopathological characteristics. We summarized findings for ELISA results. Results Of 2,711 unique articles retrieved, 157 studies described IHC results (16,046 tissue samples). Pooled expression rates were lower in studies applying antibody clone VG1 (-21%, p=0.018) or C-1 (-24%, p=0.016), compared to A-20. Expression compared to invasive carcinoma was lower in normal tissue (-51%, p<0.001) and benign breast diseases (-34%, p<0.001), but comparable for carcinoma in situ (+5%, p=0.289). Expression rates increased with tumour grade (II: +14%, p<0.001; III: +25%, p<0.001), stage (II: +11%, p<0.001; III: +22%, p<0.001), size (T3/4: +11%, p=0.004), HER2-positivity (+14%, p<0.001), lymph node positivity(+11%, p<0.001), and decreased in hormone receptor positive (PR-positive: -7%, p<0.001; ER-positive:-8%, p<0.001) and lobular cancers (-14%, p<0.001). Substantial heterogeneity was observed in study results. Furthermore, expression rates strongly depended on VEGF-A positivity threshold. VEGF-A levels assessed by ELISA (42 studies, 8,498 samples) were highly variable. Conclusion Although reported VEGF-A expression rates in breast cancer were variable, we found significant correlations with clinicopathological characteristics indicating aggressive disease. Also, expression rates were low in normal breast tissue and benign breast disease. As expression rates strongly depended on VEGF-A positivity - arguing against an on/off phenomenon - applicability of VEGF-A for molecular imaging purposes will depend on sensitivity of the molecular imaging modality, target population, and envisioned applications. Acknowledgment This research was supported by the Center for Translational Molecular Medicine (MAMMOTH). Citation Format: Arthur Adams, Jeroen Vermeulen, Peter Zuithoff, Elsken Van der Wall, Laetitia Lamberts, Elisabeth de Vries, Johannes de Jong, Gooitzen Van Dam, Paul J. van Diest, Willem P.Th.M. Mali, Sjoerd G. Elias. Vascular endothelial growth factor A - a systematic review and meta-analysis of expression patterns in breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3005. doi:10.1158/1538-7445.AM2014-3005