Reversible myocardial perfusion defects in patients not suffering from obstructive epicardial coronary artery disease as assessed by coronary angiography.

In approximately 10-30% of patients presenting with angina complaints, normal or non-obstructive coronary arteries are found on angiography. In this review paper, available literature on the underlying pathophysiological substrate explaining these discrepancies is reviewed. Both histological studies as well as studies using intravascular ultrasound e.g. the PROSPECT trial, show that epicardial coronary vessel significant lumen stenosis may be delayed until a plaque occupies 40% of the internal elastic lamina area. Limited available data suggest that these angiographically undetectable plaques are associated with an abnormal vasodilation capacity of the coronary circulation and may results in reversible perfusion defects on myocardial perfusion imaging (MPI). Organic non-atherosclerotic causes of epicardial coronary artery disease such as anomalous coronary arteries that course between the aorta and pulmonary artery, myocardial bridging and coronary vasospasm may also contribute to MPI results suggesting the presence of ischemia in the presence of normal coronary arteries on coronary angiography. Additional causes of reversible perfusion defects on MPI in the presence of a normal coronary angiogram are intraventricular conduction disturbances. The existence of reversible perfusion defects in the anteroseptal region in most of the patients suffering from left bundle branch block (LBBB) on MPI following physical exercise as stressor is well documented. As the observed reduced septal uptake of both 201Tl and 99mTc-sestamibi/tetrofosmin in LBBB reflects coronary autoregulation in response to lower oxygen demands, not surprisingly, dipyridamole which uniformly exploits flow reserve, has proven more accurate for the diagnosis of coronary artery disease (CAD) in patients suffering from LBBB. Although patients with a permanent ventricular pacemaker have a similar conduction abnormality as patients presenting with a LBBB, most of the defects found on MPI imaging in this patient population (in up to 78% of patients with a normal coronary angiogram that area continuously paced) are localized in the inferoposterior (71%), apical (50%) and inferoseptal (28%) wall; coronary flow velocities in the left anterior descending (LAD) and dominant coronary artery and coronary flow reserve are also significantly lower when compared to a control group. Contrary to what is seen in LBBB patients, dipyridamole stress does not significantly reduce the incidence of abnormalities found but limits the defects to the inferior wall. Furthermore, the frequency of abnormalities found on MPI increases over time with right ventricular outflow tract pacing. Previous histologic studies have shown that microvessel disease is often accompanied by a slow-flow phenomenon reflecting decreased resting flow velocity. Thus, not surprisingly, MPI reversible abnormalities in the presence of a normal coronary angiogram have been reported in a wide variety of diseases characterized by microvessel disease such as diabetes, systemic lupus erythematosus, Behçet's disease and metabolic syndrome. In these patients, low adiponectin and high lipoprotein(a) levels are found which are known to be associated with endothelial dysfunction, atherosclerosis and coronary artery disease. Furthermore, in these patients, limited available data suggest that reversible perfusion defects on MPI confer a significantly poorer prognosis both in terms of hard event rate (MI and cardiac death) and total event rate (MI, cardiac death or late revascularization). It is thus suggested that MPI could discriminate patients with a more severe prognosis. Finally, physical training in patients with primary microvascular angina appears to be associated with reduction of myocardial perfusion abnormalities.

(99m)Tc-Annexin A5 quantification of apoptotic tumor response: a systematic review and meta-analysis of clinical imaging trials.

PURPOSE: (99m)Tc-Annexin A5 has been used as a molecular imaging probe for the visualization, characterization and measurement of apoptosis. In an effort to define the quantitative (99m)Tc-annexin A5 uptake criteria that best predict tumor response to treatment, we performed a systematic review and meta-analysis of the results of all clinical imaging trials found in the literature or publicly available databases. METHODS: Included in this review were 17 clinical trials investigating quantitative (99m)Tc-annexin A5 (qAnx5) imaging using different parameters in cancer patients before and after the first course of chemotherapy and/or radiation therapy. Qualitative assessment of the clinical studies for diagnostic accuracy was performed using the QUADAS-2 criteria. Of these studies, five prospective single-center clinical trials (92 patients in total) were included in the meta-analysis after exclusion of one multicenter clinical trial due to heterogeneity. Pooled positive predictive values (PPV) and pooled negative predictive values (NPV) (with 95% CI) were calculated using Meta-Disc software version 1.4. RESULTS: Absolute quantification and/or relative quantification of (99m)Tc-annexin A5 uptake were performed at baseline and after the start of treatment. Various quantitative parameters have been used for the calculation of (99m)Tc-annexin A5 tumor uptake and delta (Δ) tumor changes post-treatment compared to baseline including: tumor-to-background ratio (TBR), ΔTBR, tumor-to-noise ratio, relative tumor ratio (TR), ΔTR, standardized tumor uptake ratio (STU), ΔSTU, maximum count per pixel within the tumor volume (Cmax), Cmax%, absolute ΔU and percentage (ΔU%), maximum ΔU counts, semiquantitative visual scoring, percent injected dose (%ID) and %ID/cm(3). Clinical trials investigating qAnx5 imaging have included patients with lung cancer, lymphoma, breast cancer, head and neck cancer and other less common tumor types. In two phase I/II single-center clinical trials, an increase of ≥25% in uptake following treatment was considered a significant threshold for an apoptotic tumor response (partial response, complete response). In three other phase I/II clinical trials, increases of ≥28%, ≥42% and ≥47% in uptake following treatment were found to be the mean cut-off levels in responders. In a phase II/III multicenter clinical trial, an increase of ≥23% in uptake following treatment was found to be the minimum cut-off level for a tumor response. In one clinical trial, no significant difference in (99m)Tc-annexin A5 uptake in terms of %ID was found in healthy tissues after chemotherapy compared to baseline. In two other clinical trials, intraobserver and interobserver measurements of (99m)Tc-annexin A5 tumor uptake were found to be reproducible (mean difference <5%, kappa = 0.90 and 0.82, respectively) and to be highly correlated with treatment outcome (Spearman r = 0.99, p < 0.0001). The meta-analysis demonstrated a pooled positive PPV of 100% (95% CI 92 - 100%) and a pooled NPV of 70% (95% CI 55 - 82%) for prediction of a tumor response after the first course of chemotherapy and/or radiotherapy in terms of ΔU%. In a symmetric sROC analysis, the AUC was 0.919 and the Q* index was 85.21 %. CONCLUSION: Quantitative (99m)Tc-annexin A5 imaging has been investigated in clinical trials for the assessment of apoptotic tumor responses. This meta-analysis showed a high pooled PPV and a moderate pooled NPV with ΔU cut-off values ranging between 20% and 30%. Standardization of quantification and harmonization of results are required for high-quality clinical research. A standardized uptake value score (SUV, ΔSUV) using quantitative SPECT/CT imaging may be a promising approach to the simple, reproducible and semiquantitative assessment of apoptotic tumor changes.

Added-value of SPECT/CT to lymphatic mapping and sentinel lymphadenectomy in gynaecological cancers.

Lymphatic mapping and sentinel lymphadenectomy (LM/SL) have been successfully used in pre-treatment nodal staging of gynaecological cancers. We hypothesised the added-value of LM/SL plus SPECT/CT in patients with early stage of cervical cancer and vulvar cancer. A prospective, single-center, diagnostic, open label, active control, non-randomized clinical trial has been conducted in 7 patients with FIGO IA-IB1 cervical cancer and 7 patients with FIGO stage I-II-IIIcN0 vulvar cancer. All patients underwent LM/SL plus SPECT/low-dose CT and complete lymph node dissection (CLND) according to the standard of care. In case of negative hematoxylin-eosin staining, serial sections of the SLNs were analysed by immunohistochemistry and high molecular weight cytokeratin. Primary outcome measures were the detection rate, the sensitivity (SV), the negative predictive value (NPV), the diagnostic accuracy (DA) for anatomic localisation of SLNs, and the impact on management of SPECT/CT guided LM/SL versus CLND. The secondary outcome measure was the patient tolerability and operating time of LM/SL guided SPECT/CT versus CLND. http://clinicaltrials.gov/show/NCT00773071 All 14 patients were enrolled into the 1-day research protocol with dual-tracer LM/SL and SPECT/CT. Additional SLNs were detected on SPECT/CT compared to conventional planar imaging. Hot and cold > 1cm SLNs were detected on SPECT/CT. Detection rate, SV, NPV, DA were 100% in both groups; false negative rate was 0%. Rate of SLN metastases was 28.5% in cervical cancer and 42.9% in vulvar cancer. Impact on treatment was 28.5% and 14.3% in cervical cancer and vulvar cancer patients, respectively. SPECT/CT was well tolerated by all patients and operating time for LM/SL was within 30 min. No adverse events were reported with a time frame of 1-to-3 years. In early stage of gynaecological cancers, SPECT/low-dose CT is technically feasible and of clinical added-value for LM/SL.

SPECT/CT imaging of the lumbar spine in chronic low back pain: a case report.

Mechanical low back pain is a common indication for Nuclear Medicine imaging. Whole-body bone scan is a very sensitive but poorly specific study for the detection of metabolic bone abnormalities. The accurate localisation of metabolically active bone disease is often difficult in 2D imaging but single photon emission computed tomography/computed tomography (SPECT/CT) allows accurate diagnosis and anatomic localisation of osteoblastic and osteolytic lesions in 3D imaging. We present a clinical case of a patient referred for evaluation of chronic lower back pain with no history of trauma, spinal surgery, or cancer. Planar whole-body scan showed heterogeneous tracer uptake in the lumbar spine with intense localisation to the right lateral aspect of L3. Integrated SPECT/CT of the lumbar spine detected active bone metabolism in the right L3/L4 facet joint in the presence of minimal signs of degenerative osteoarthrosis on CT images, while a segment demonstrating more gross degenerative changes was more quiescent with only mild tracer uptake. The usefulness of integrated SPECT/CT for anatomical and functional assessment of back pain opens promising opportunities both for multi-disciplinary clinical assessment and treatment for manual therapists and for research into the effectiveness of manual therapies.

Transbilayer phospholipids molecular imaging.

Nuclear medicine has become a key part of molecular imaging. In the present review article, we focus on the transbilayer phospholipids as exquisite targets for radiolabelled probes in molecular imaging. Asymmetry of phospholipid distribution is a characteristic of mammalian cell membranes. Phosphatidylcholine and sphyngomyelin cholinophospholipids are primarily located within the external leaflet of the cell membrane. Phosphatidylserine and phosphatidylethanolamine aminophospholipids, and also phosphatidylinositol are primarily located within the internal leaflet of the cell membrane. New radiolabelled tracers have been designed in preclinical and clinical research for PET-CT and SPECT-CT molecular imaging of transbilayer phospholipids.

Small field-of-view cardiac SPECT can be implemented on hybrid SPECT/CT platforms where data acquisition and reconstruction are guided by CT.

INTRODUCTION: Image truncation in nuclear medicine is a common problem that can lead to artifacts in reconstructed images. We evaluate a modified single-photon emission computed tomography/computed tomography (SPECT/CT) acquisition and reconstruction method for truncated SPECT, which is guided by nontruncated CT. The method nearly eliminates truncation errors, and is ideal for cardiac imaging. We demonstrate its application on phantom and clinical cardiac SPECT/CT scans. METHODS: Tc-MIBI (2-methoxy isobutyl isonitrile) SPECT/CT scans were acquired on 14 patients, and on an anthropomorphic cardiac chest phantom. The original 34 x 34 cm field-of-view (FOV) projections were truncated to simulate a small 16 x 16 cm FOV acquisition. Data were reconstructed in three ways: (i) nontruncated and standard reconstruction (NTOSEM), which was our gold standard; (ii) truncated and standard reconstruction (TOSEM); and (iii) truncated and a modified reconstruction (TMOSEM). TMOSEM and TOSEM were both compared with NTOSEM by comparing relative count ratios in the heart, looking at the change in perfusion defect size, and comparing pixel correlation coefficients. RESULTS: Compared with NTOSEM, the use of TOSEM for small FOV clinical imaging incurred an average count ratio error greater than 100%, and decreased the calculated defect size by 17.13%. For TMOSEM, the average count ratio error was only 8.9%, and the defect size was only decreased by 0.19% compared with NTOSEM. When we plotted TOSEM against NTOSEM a correlation coefficient of 0.734 was calculated, and when we plotted TMOSEM against NTOSEM a correlation coefficient of 0.996 was measured. Comparing NTOSEM with TOSEM in the phantom study produced an average count ratio error greater than 100%. TMOSEM produced an error of 4.3% compared with NTOSEM. CONCLUSION: Projection truncation due to small FOV cameras in cardiac SPECT/CT can lead to significant errors. TMOSEM guided by nontruncated CT reconstruction shows promise in reducing these errors.

Complementary roles of low-dose SPECT-CT and high-resolution volume CT for detection of coronary artery disease.

A 70-year-old woman with a high pretest likelihood of coronary artery disease (CAD) underwent a Tc-99m MIBI SPECT-CT study for myocardial perfusion imaging (MPI), which was complemented by a high-resolution volume CT (VCT) study. After attenuation correction, an MPI pattern of ischemia was detected in the lateral wall of the myocardium. The CT calcium score (CTCS) was above the 75th percentile. The CT angiography (CTA) demonstrated a 70% stenosis at the ostial part of the circumflex artery, and incidentally revealed a saccular aneurysm. In today's nuclear cardiology, low-dose SPECT-CT plus high-resolution VCT allows anatofunctional assessment of suspected CAD.

Clinical added-value of 18FDG PET in neuroendocrine-merkel cell carcinoma.

Merkel cell carcinoma (MCC) is a rare and highly malignant skin cancer with neuroendocrine differentiation. We studied the potential value of 18FDG PET in the management of MCC. Eleven patients with MCC were examined by 18FDG PET and PET-CT for staging purpose (n=4) or for detection of recurrence (n=7). Qualitative and quantitative interpretation of PET studies was performed routinely. 18FDG PET observations were compared to clinical and radiological findings. In 6 patients, PET findings were also compared to histology. In 7 patients, the 18FDG tumor uptake was compared to the MCC proliferative activity expressed by the Ki-67 index. 18FDG PET was contributive in 10/11 MCC patients. In 7 patients, 18FDG PET detected focal lesions or a disseminated stage of the disease including dermal, nodal and visceral metastases. In 3 patients, a normal 18FDG PET confirmed complete remission of disease. Most MCC patients exhibited highly 18FDG-avid sites suggestive of increased glucose metabolism. This imaging pattern was related to a high proliferative activity (Ki-67 index >50%). In 1 patient with a weakly proliferative nodal MCC (Ki-67<10%), a false negative result was yielded by metabolic imaging. In 4/11 patients, 18FDG PET revealed an unsuspected second neoplasm in addition to MCC. It is concluded that whole-body 18FDG PET may be useful in the management of MCC patients. However, a normal 18FDG PET aspect cannot rule out MCC with low proliferative activity.

Role of nuclear medicine in the management of cutaneous malignant melanoma.

Malignant melanoma of the skin is one of the most lethal cancers. The disease may spread either locally or regionally and to distant sites through predictable or unpredictable metastatic pathways. Accurate staging and restaging of disease are required for appropriate treatment decision making. Routine protocols based on clinical examinations and traditional radiologic evaluations are not cost-effective for the detection of systemic disease. In the last decade, nuclear medicine techniques, such as lymphoscintigraphy-directed lymphatic mapping and sentinel lymphadenectomy and (18)F-FDG PET, have played key roles in nodal and distant staging of melanoma. More recently, anatomic-functional imaging has been improved with the development of integrated PET/CT devices or combined SPECT/CT systems. (18)F-FDG-sensitive intraoperative probes have been specifically designed to detect small nodal and visceral metastases from melanoma and may become important tools for the cancer surgeon. In this article, we review the role of nuclear medicine in the assessment of malignant melanoma.

18FDG PET in oncology: the best and the worst (Review).

The clinical added-value of 18F-fluoro-2-deoxy-D-glucose positron emission tomography (18FDG PET) in the management of oncology patients is increasingly documented. In the present review, we discuss both the benefits and the limitations of 18FDG PET in different cancers. Considering the literature data and our own experience, we also indicate the best clinical approach to optimize the use of metabolic imaging in oncology.

Novel imaging techniques in melanoma.

Cutaneous melanoma is one of the most deadly malignancies. Although it accounts for approximately 4% of all cancer cases, it ac-counts for approximately 79% of skin cancer-related deaths. In the past few years, the nuclear medicine platform used in the management of melanoma has extended to biochemical and structural imaging. In clinical practice, integrated positron emission tomography/CT devices allow anatomic and metabolic characterization of meta-static disease in a single study. Similarly, more accurate localization of sentinel nodes in a 3-D space now is feasible with hybrid single photon emission CT/CT system. In translational research, [18F]fluorodeoxyglucose probes have been designed to optimize the detection of melanoma tumor sites in vivo.

The imaging of apoptosis with the radiolabelled annexin A5: a new tool in translational research.

Programmed cell death also called apoptosis plays a pivotal role in many physiological and pathological conditions. In the multi-step process of drug development, a number of medications are being designed to target strategic checkpoints of the apoptotic cascade either to induce or to inhibit programmed cell death. Conceptually, the assessment of programmed cell death in response to various therapeutic interventions appears to be critical for evaluating the efficacy of many drugs that act through apoptotic pathways. In the last decade, nuclear medicine techniques provided proofs of principle for the imaging of apoptosis both in vitro and in vivo. The purpose of this article was to review current knowledge on the imaging of apoptosis with radiolabelled annexin A5 in various pre-clinical and clinical models, and beyond that, to assess the potential integration of such a dedicated technology into translational research.

99mTc-Annexin A5 uptake and imaging to monitor chemosensitivity.

Most anticancer agents act by inducing apoptosis in sensitive tumor cells. Hence, in many types of cancers, significant increase of tumor apoptosis after chemotherapy correlates with tumor chemosensitivity. Theoretically, a reliable evaluation of apoptotic changes, postchemotherapy to baseline, may provide valuable insights into the apoptotic competence of cancers. Until now, assessment of chemosensitivity has usually relied upon histological evidence of tumor response (i.e., partial or complete disappearance of tumor cells) or demonstration of tumor shrinkage by means of morphological imaging (i.e., computed tomography or magnetic resonance imaging). In clinical practice, however, these conventional methods are proving ineffective for monitoring tumor chemosensitivity on a daily basis. Recent developments in molecular imaging have allowed the synthesis of a new radiolabeled agent, 99mTc-recombinant human Annexin A5, designed to the assessment of apoptotic response of cancers after a single course of chemotherapy. Such in vivo technique opens promising perspectives for evaluating, noninvasively and early, tumor response to anticancer therapies. Alternative methods for Annexin A5 labeling and imaging may improve the detection of drug-induced apoptosis to monitor chemosensitivity.

Metabolic monitoring of chemosensitivity with 18FDG PET.

Accurate and early evaluation of tumor response to chemotherapy is a growing clinical need for optimal management of oncology patients. This is even more warranted by the lack of appropriate response evaluation criteria to new molecularly targeted anticancer therapies. In the two last decades, new developments in the field of nuclear oncology have allowed the introduction of various radiopharmaceuticals to be used on dedicated imaging devices. In the present chapter, we report the added value that positron emission tomography (PET) with 18F-fluorodeoxyglucose (18FDG) may offer to assess tumor response to treatment. PET is a high-end imaging technology using 18FDG as metabolic tracer that mimics the biochemical behavior of the natural glucose molecule. Because most tumor types exhibit increased glucose metabolism, the imaging of 18FDG uptake within cancer tissues prior to any treatment enables the metabolic technique to follow tumor responsiveness sequentially after one or several courses of chemotherapy. Moreover, metabolic tumor response evaluated by 18FDG PET often precedes morphological tumor changes measured by computed tomography or magnetic resonance imaging. So far, the suboptimal proper ties of 18FDG tracer and the lack of standardized methodology in PET imaging remain objective limitations for qualitative and quantitative assessment of chemosensitivity using the metabolic method.

Nuclear medicine in the era of genomics and proteomics: lessons from annexin V.

In the past decade, genomics and proteomics have begun to develop many new targets for potential diagnostic and therapeutic agents. Among the life sciences, nuclear medicine is also deeply involved in the field of clinical investigation. Experience with radiolabeled annexin V highlights the many steps required to translate a good basic-science concept into the clinical setting. This model also emphasizes the value of synergy between basic and medical specialties in developing and optimizing a clinically useful product initially derived from basic investigation.