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Patient with IgA-chain myeloma, stage IIIA. Radiographs revealed multiple lytic lesions in areas that showed positive findings on 18 F-FDG PET imaging (e.g., spine, pelvis, and hips). Plasmacytoma in left lung was confirmed on biopsy. Plasmacytomas were noted in left apex and hilar regions on CT scanning. Splenic myeloma was also suspected but not directly confirmed.
Source publication
The purpose of this study was to evaluate the clinical utility of whole-body PET with (18)F-FDG in patients with multiple myeloma and related monoclonal diseases.
Between July 1, 1996, and July 2000, 98 (18)F-FDG PET scans were obtained for 66 patients, with 25 patients having 2 or more scans. The results were compared with routine clinical and sta...
Context in source publication
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... were also 4 (25%) of 16 patients, already docu- mented to have stage III disease, who were found to have additional foci of extramedullary disease. The nature of the focal uptake was confirmed both by other imaging and by direct biopsy in 2 instances (pulmonary [ Fig. 1] and peri- orbital). The predilection for extramedullary spread was also confirmed by the subsequent development of additional extramedullary disease, including subcutaneous lesions. One patient died with fulminant disease at 4 mo after the study, and another with aggressive relapse after stem cell transplantation died at 23 mo. The other 2 patients with extramedullary disease are still alive and undergoing ther- apy at 6 and 18 mo, although the disease of 1 has already relapsed after ...
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Citations
... The primary application of PET image reconstruction is the diagnosis and staging of disease in various medical fields, e.g. Oncology, Cardiology, and Neurology [Durie et al. 2002;Fiechter et al. 2012;Wolk et al. 2012]. A result of this medical application is the desire for reduced patient scan durations and fast but reliable image reconstruction algorithms. ...
Positron Emission Tomography (PET) is a medical imaging technique that is used to pro- vide functional information regarding physiological processes. Statistical PET reconstruc- tion attempts to estimate the distribution of radiotracer in the body but this methodology is generally computationally demanding because of the use of iterative algorithms. These algorithms are often accelerated by the utilisation of data subsets, which may result in con- vergence to a limit set rather than the unique solution. Methods exist to relax the update step sizes of subset algorithms but they introduce additional heuristic parameters that may result in extended reconstruction times. This work investigates novel methods to modify subset algorithms to converge to the unique solution while maintaining the acceleration benefits of subset methods. This work begins with a study of an automatic method for increasing subset sizes, called AutoSubsets. This algorithm measures the divergence between two distinct data subset update directions and, if significant, the subset size is increased for future updates. The algorithm is evaluated using both projection and list mode data. The algorithm’s use of small initial subsets benefits early reconstruction but unfortunately, at later updates, the subsets size increases too early, which impedes convergence rates. The main part of this work investigates the application of stochastic variance reduction optimisation algorithms to PET image reconstruction. These algorithms reduce variance due to the use of subsets by incorporating previously computed subset gradients into the update direction. The algorithms are adapted for the application to PET reconstruction. This study evaluates the reconstruction performance of these algorithms when applied to various 3D non-TOF PET simulated, phantom and patient data sets. The impact of a number of algorithm parameters are explored, which includes: subset selection methodologies, the number of subsets, step size methodologies and preconditioners. The results indicate that these stochastic variance reduction algorithms demonstrate superior performance after only a few epochs when compared to a standard PET reconstruction algorithm.
... [ 18 F]FDG is the gold standard MM imaging agent for MM patient management largely due to its ability to differentiate between metabolically active and inactive sites [57][58][59]. While used prolifically, [ 18 F]FDG has limitations in therapy response monitoring in MM patients. ...
Background
Multiple myeloma (MM) is a disease of cancerous plasma cells in the bone marrow. Imaging-based timely determination of therapeutic response is critical for improving outcomes in MM patients. Very late antigen-4 (VLA4, CD49d/CD29) is overexpressed in MM cells. Here, we evaluated [ ¹⁸ F]FDG and VLA4 targeted [ ⁶⁴ Cu]Cu-LLP2A for quantitative PET imaging in disseminated MM models of variable VLA4 expression, following bortezomib therapy.
Methods
In vitro and ex vivo VLA4 expression was evaluated by flow cytometry. Human MM cells, MM.1S-CG and U266-CG (C: luciferase and G: green fluorescent protein), were injected intravenously in NOD-SCID gamma mice. Tumor progression was monitored by bioluminescence imaging (BLI). Treatment group received bortezomib (1 mg/kg, twice/week) intraperitoneally. All cohorts (treated, untreated and no tumor) were longitudinally imaged with [ ¹⁸ F]FDG (7.4–8.0 MBq) and [ ⁶⁴ Cu]Cu-LLP2A (2–3 MBq; Molar Activity: 44.14 ± 1.40 MBq/nmol) PET, respectively.
Results
Flow cytometry confirmed high expression of CD49d in U266 cells (> 99%) and moderate expression in MM.1S cells (~ 52%). BLI showed decrease in total body flux in treated mice. In MM.1S-CG untreated versus treated mice, [ ⁶⁴ Cu]Cu-LLP2A localized with a significantly higher SUV mean in spine (0.58 versus 0.31, p < 0.01) and femur (0.72 versus 0.39, p < 0.05) at week 4 post-tumor inoculation. There was a four-fold higher uptake of [ ⁶⁴ Cu]Cu-LLP2A (SUV mean ) in untreated U266-CG mice compared to treated mice at 3 weeks post-treatment. Compared to [ ⁶⁴ Cu]Cu-LLP2A, [ ¹⁸ F]FDG PET detected treatment-related changes at later time points.
Conclusion
[ ⁶⁴ Cu]Cu-LLP2A is a promising tracer for timely in vivo assessment of therapeutic response in disseminated models of MM.
... One of the most commonly used imaging agent for MM is [ 18 F]FDG, that assesses the metabolic activity of myeloma cells [45]. [ 18 F]FDG is the gold standard MM imaging agent for MM patient management largely due to its ability to differentiate between metabolically active and inactive sites of MM [46,47]. ...
Background
Multiple myeloma (MM) is a disease of cancerous plasma cells. Current treatments have improved the survival rate; however, most MM patients relapse. Imaging based timely determination of therapeutic response is critical for improving outcomes in MM patients. Very late antigen-4 (VLA4) is over expressed in MM cells. Here, we evaluated [ ¹⁸ F]FDG and VLA4 targeted [ ⁶⁴ Cu]LLP2A for quantitative PET imaging in MM models of variable VLA4 expression, and following bortezomib therapy.Methods In vitro and ex vivo VLA4 expression was evaluated by flow cytometry. Human MM cells, MM.1S-CG and U266-CG (CG: luciferase and green fluorescent protein), were injected intravenously in NOD-SCID gamma mice. Tumor progression was monitored by bioluminescence imaging (BLI). Treatment group received bortezomib (1mg/kg, twice/week) intraperitoneally. All cohorts (treated, untreated and no-tumor) were longitudinally imaged with [ ⁶⁴ Cu]LLP2A (2-3 MBq; Molar Activity: 44.14±1.40 MBq/nmol) and [ ¹⁸ F]FDG (7.4-8.0 MBq) PET respectively.ResultsFlow cytometry confirmed high expression of CD49d in U266 cells (>99%) and moderate expression in MM.1S cells (~52%). BLI showed decrease in total body flux in treated mice. In MM.1S-CG untreated versus treated mice, [ ⁶⁴ Cu]LLP2A localized with a significantly higher SUV mean in spine (0.58 versus 0.31) and femur (0.72 versus 0.39) at week 4 post tumor inoculation. In U266-CG treated versus untreated mice, there was a 4-time percent [ ⁶⁴ Cu]LLP2A increase in spine at week 3. Compared to [ ⁶⁴ Cu]LLP2A, [ ¹⁸ F]FDG PET detected treatment related changes at later time points.Conclusion[ ⁶⁴ Cu]LLP2A is a promising tracer for in vivo assessment of therapeutic response in disseminated models of MM.
... Skeletal survey using X-rays has long been the method used to identify bone lytic lesions, however, this cannot detect extramedullary disease nor cord involvement with MM and is not sensitive in detecting small lytic lesions 24 . The skeletal survey has essentially been replaced by more sensitive imaging modalities including whole body low-dose CT, MRI and 18 F-uorodeoxyglucose PET/CT which have now been incorporated into diagnostic and response assessment criteria [24][25][26] . CT can detect early destructive bone lesions but is unable to detect active MM in areas of prior destruction nor extramedullary sites of MM 24,27 . ...
... When used in asymptomatic MM, identi cation of at least one lesion, a diffuse in ltrative marrow pattern and 20% or more marrow in ltration predicted progression to symptomatic MM 29 . FDG-PET has similar advantages to MRI however results are obtained in a more reasonable time frame whilst CT shows early bone destruction 25 . ...
New approaches to stratify multiple myeloma patients for informing on prognosis and therapy selection are needed since patients are currently managed in a similar manner regardless of individual risk factors. However, despite new and improved biomarkers for determining the prognosis of patients, there is currently insufficient information to utilise biomarkers to intensify, reduce or altogether change treatment, nor to target patient-specific biology. The ever-increasing number and complexity of drug classes to treat multiple myeloma have improved response rates and so clinically useful biomarkers will need to be relevant in the era of such novel therapies. Therefore, the field of multiple myeloma biomarker development is rapidly progressing, spurred on by new technologies and therapeutic approaches, and underpinned by a deeper understanding of tumour biology with individualised patient management the goal. In this review we describe the main biomarker categories in multiple myeloma and relate these to prognostic and therapeutic applications.
... Vorgehen (Mesguich et al., 2016). Bislang wurde für 18 F-FDG ein prognostischer Wert vor und nach Behandlung publiziert (Derlin & Bannas, 2014;Durie et al., 2002;Lapa et al., 2014;Zamagni et al., 2011), der dem prognostischen Wert der MRT überlegen ist (Bartel et al., 2009;Zamagni et al., 2011 ...
... Systems und der Überarbeitung der Diagnosekriterien des MM durch die IMWG mit Einführung erweiterter bildgebender Modalitäten stellt die planare Ganzkörperröntgenaufnahme weiterhin den Goldstandard in der Bildgebung des MM zur Detektion von Osteolysen dar(Caers et al., 2014; Dimopoulos et al.der Anpassung therapeutischer Ansätze könnte der funktionellen Bildgebung eine entscheidende Rolle einräumen(Mihailovic & Goldsmith, 2015). 18 F-FDG als Glukoseanalogon in der Anwendung bei der PET/CT stellt dabei unter anderem einen Ansatz der neuen molekularen Bildgebungsverfahren dar(Durie et al., 2002).Die hohe Sensitivität in der Detektion extramedullärer MM-Manifestationen wird jedoch durch Limitationen in der Spezifität überschattet (Shortt et al., 2009; Zamagni et al., 2007). Trotz signifikanter Verbesserungen bezüglich des Überlebenszeitraums, führt das MM noch immer in der Mehrzahl der Erkrankungen zu einem Rezidiv und gilt als unheilbar (Barlogie et al., 2014; Brioli et al., 2014). ...
Das Multiple Myelom ist eine hämatologische Erkrankung, die durch die Proliferation von Plasmazellen und die Produktion von Antikörpern oder deren Leichtketten gekennzeichnet ist. Eine frühe Diagnosestellung durch Detektion sowohl intra- als auch extramedullärer Manifestationen ist für die Einleitung einer effektiven Therapie von entscheidender Bedeutung. Ebenso bedeutsam ist ein wirksames Therapiemonitoring. Wichtige diagnostische Modalitäten sind bei beiden Fragestellungen tomografische, bildgebende Verfahren. Hierbei wurde die Effektivität der 18F-FDG-PET/CT im Rahmen der Diagnose, des Stagings und der Prognoseabschätzung bereits nachgewiesen. Dennoch ist ihr klinischer Nutzen durch die geringe Sensitivität bei Detektion von diffusem Knochenmarksbefall und Vorliegen sowohl falsch positiver als auch falsch negativer Befunde limitiert. Die vorliegende Arbeit hat untersucht, ob der aminosäurebasierte Tracer 11C-MET über spezifische Eigenschaften verfügt, die eine höhere Sensitivität und Spezifität in der Detektion von Myelomzellen ermöglichen und ob der Radioligand dem etablierten Glukoseanalogon 18F-FDG überlegen ist. Hierfür wurden drei etablierte humane Myelomzelllinien, sowohl nativ als auch nach 48-stündiger Therapie mit dem Proteasominhibitor Carfilzomib, mit 18F-FDG und 11C-MET inkubiert und mithilfe eines Gammastrahlungszählers beurteilt. Zudem wurde untersucht, ob die Traceraufnahme mit spezifischen Charakteristika der Tumorbiologie korreliert. So wurde die Oberflächenexpression von CD138 und CXCR4, die intrazelluläre Expression der Leichtketten κ/λ und die Proliferation der Zelllinien mittels Durchflusszytometrie vor und nach Behandlung mit Carfilzomib eruiert. Die unbehandelten Zellen zeigten, verglichen zu 18F-FDG, bereits nach kürzester Inkubationsdauer eine 3-3,5-fach höhere 11C-MET Retention. Weiterhin zeigte sich die 11C-MET-Aufnahme nach Behandlung aller Zellreihen insgesamt marginal höher als die 18F-FDG-Aufnahme, während die Reduktion der 11C-MET-Anreicherung im prä- zu posttherapeutischen Vergleich für alle drei Zelllinien signifikant war. Eine mögliche Erklärung für diese Beobachtungen liefert die Myelombiologie: eine erhöhte Aufnahme der radioaktiv markierten Aminosäure durch MM-Zellen könnte durch eine Zunahme der Zellproliferation und insbesondere durch eine Steigerung der Proteinsynthese im Rahmen der überschießenden Produktion von M-Protein bedingt sein. In Zusammenschau könnte 11C-MET mit höherer Sensitivität Myelommanifestationen detektieren, wodurch ggf. Läsionen mit geringem Metabolismus dargestellt und eine bessere Beurteilung des Krankheitspogresses erfolgen könnte. Zudem bietet für den klinischen Einsatz die – verglichen zu 18F-FDG – größere Differenz der 11C-MET-Retention zwischen prä- und posttherapeutischer Messung die Möglichkeit einer besseren Beurteilbarkeit des Therapieansprechens. 11C-MET birgt ggf. das Potential auch minimale aktive Restherde zu detektieren und damit Patienten einem individualisierten Therapiekonzept zuzuführen. Ein Zusammenhang zwischen den untersuchten Biomarkern und der 11C-MET Retention bzw. deren Abnahme nach Behandlung konnte nicht gezeigt werden. Somit sollten für 11C-MET andere Biomarker herangezogen werden, um diese mit der Bildgebung zu korrelieren und zu bewerten.
... [62][63][64]. It accurately distinguishes overt myeloma from its precursor conditions [65,66], detects extramedullary disease [67], and determines bone marrow involvement with 85% sensitivity and 92% specificity [68]. Moreover, in treated but newly diagnosed MM patients, the metabolic responses and numbers of focal lesions detected by 18 F-FDG PET/ CT have independent prognostic value [69,70]. ...
In the past decades, considerable progress has been made in our understanding and treatment of multiple myeloma. Several challenges remain including our abilities to longitudinally image tumor responses to treatment, to combine various therapeutic agents with different mechanisms of action but with overlapping toxicities, and to efficiently harness the power of the immune system to augment remission and/or to induce permanent cures. Nanomedicine may help to address many of these outstanding issues, affording novel diagnostic capabilities and offering disruptive technologies that promise to revolutionize treatment. Here, we review recent developments and the future of nanomedicine for multiple myeloma, highlighting new considerations in nanoparticle designs that may help to augment active targeting, to facilitate longitudinal imaging, and to improve drug delivery.
... Only skeletal plain radiography was included in staging systems, but was unsuitable for assessing response to therapy [10]. More recently, MRI was included in staging procedures because of its exceptional sensitivity in the detection of tumour spread, especially in the spine [11][12][13][14]. However, MRI is also insensitive for the interim assessment of therapy response [15]. ...
Materials and methods:
Patients affected by symptomatic MM who had performed an FDG PET/CT at baseline (PET0), after induction (PET-AI), and the end of treatment (PET-EoT) were prospectively enrolled in a multicenter trial (EMN02)(NCT01910987; MMY3033). After anonymization, PET images were uploaded in the web platform WIDEN® and hence distributed to five expert nuclear medicine reviewers for a blinded independent central review according to the IMPeTUs criteria. Consensus among reviewers was measured by the percentage of agreement and the Krippendorff's alpha. Furthermore, on a patient-based analysis, the concordance among all the reviewers in terms of positivity or negativity of the FDG PET/CT scan was tested for different thresholds of positivity (Deauville score (DS 2, 3, 4, 5) for the main parameters (bone marrow, focal score, extra-medullary disease).
Results:
Eighty-six patients (211 FDG PET/CT scans) were included in this analysis. Median patient age was 58 years (range, 35-66 years), 45% were male, 15% of them were in stage ISS (International Staging System) III, and 42% had high-risk cytogenetics. The percentage agreement was superior to 75% for all the time points, reaching 100% of agreement in assessing the presence skull lesions after therapy. Comparable results were obtained when the agreement analysis was performed using the Krippendorff's alpha coefficient, either in every single time point of scanning (PET0, PET-AI or PET-EoT) or overall for all the scans together. DS proved highly reproducible with the highest reproducibility for score 4.
Conclusions:
IMPeTUs criteria proved highly reproducible and could therefore be considered as a base for harmonizing PET interpretation in multiple myeloma. A prospective clinical validation of IMPeTUs criteria is underway.
... PET imaging allows for survey of the whole body in a convenient single imaging session with an added advantage of combined functional assessment of disease with computed tomography (CT) assessment of lytic lesions in bones. Its use in characterizing the high-risk disease is well recognized [1]. For patients undergoing or completing treatment, assessment of residual disease is critical for further management. ...
... Under this, "Imaging plus MRD-negative" criteria requires a complete resolution or disappearance of uptake in lesions or decreased uptake in lesions to lower than mediastinal blood pool or adjacent normal tissue uptake on PET-CT is required along with a negative next generation flow or sequencing assessment. Physiologic changes in tumor burden precede structural changes in lesions; lytic bone lesions may persist and appear unchanged for long period on CT or MR, reported up to 9-12 months with MRI for reversal of abnormalities after therapy [1,4]. Functional assessment is therefore critical in those receiving or completing treatment and imaging modalities that would allow for early and accurate assessment of response and minimal residual disease are needed. ...
... Serial imaging to follow a change in metabolic uptake in lesions is useful for treatment response assessment (Fig. 3); the changes may be seen as early as within first few hours after effective therapy and sustained decreased values are indicative of an ongoing response. On the other hand, persistent uptake in lesion on FDG-PET scan correlates with an earlier relapse and is a poor prognostic factor (Fig. 4); in the post-transplant setting is associated with relapse within 6 months [1]. Several studies have shown usefulness of FDG imaging for response assessment in initial and pretransplant setting [8][9][10]. ...
Imaging plays a key role is assessment of myeloma. Lytic bone lesions are optimally assessed using structural imaging however the structural changes lag in assessment of functional changes in the assessment of disease. Functional imaging with Fluoro Deoxy glucose (FDG) positron emission tomography computerized tomography (PET CT) is useful in assessment of high risk myeloma, provides prognostic information and is helpful in monitoring therapy response. However it is nonspecific and may not be optimal in assessing treatment response to immunotherapeutic agents. Specific targeted imaging may allow for better assessment of changes from therapy that is based on specific mechanism. ImmunoPET imaging is a novel method to assess targeting of specific antigen by therapeutic antibodies. This review summarizes the role of functional imaging and development of novel immunoPET agents for assessment of treatment response and residual disease.
... Tumor cells, including those of the largely fatal plasma cell malignancy multiple myeloma (MM), exhibit elevated glucose uptake [1][2][3], a cancer hallmark that forms the basis for clinical monitoring of myeloma using positron emission tomography (FDG-PET) [3][4][5][6]. Although the fundamental reliance of tumor cells on increased glucose catabolism for survival, proliferation and chemoresistance is well established, therapeutic targeting of this key metabolic phenotype in a tumor-specific manner has not yet been achieved [7][8]. ...
... To enable a rapid and modular approach to new analogs, an efficient 3-step synthesis was developed as shown in Scheme 1. Synthesis began with reductive amination of 4-(aminomethyl) pyridine (1) with 3hydroxybenzaldehyde (2) to provide secondary amine 3 in 68% yield. The reaction was performed in methanol with the addition of Ti(O-i-Pr) 4 , which was found to increase the yield of the reaction. ...
... Leu185. The SAR we observed is consistent with our compounds binding in this manner, which show that R1 groups containing polar functionality are less well tolerated (compounds 4,9,12). In addition, incorporating a single methylene spacer between the amide carbonyl and the R2 aromatic group produced compound 20, which is more potent than our original hit. ...
Cancer cells consume more glucose to fuel metabolic programs fundamental to sustaining their survival, growth and proliferation. Among the fourteen SLC2A family members, GLUTs 1 and 4 are high-affinity glucose transporters. GLUT4 (SLC2A4) is highly expressed in muscle and adipose tissue. Basally retained within the cell, GLUT4 traffics to the plasma membrane (PM) in response to insulin and exercise-stimulation. The plasma cell malignancy multiple myeloma (MM) exhibits increased constitutive expression of GLUT4 on the PM, co-opting use of GLUT4 for survival and proliferation. GLUT4 inhibition by knockdown or treatment with the FDA-approved HIV protease inhibitor ritonavir leads to cytostatic and/or cytotoxic and chemosensitizing effects in tumor cells both in vitro and in vivo. We recently reported our generation of GLUT4 homology models and virtual high-throughput screening (vHTS) to identify multiple series of novel GLUT4 antagonists. In this report, we describe our initial hit-to-lead optimization to synthesize new analogs with improved potency and selectivity for GLUT4, and the biological characterization of these compounds in a variety of assays. We show that our lead compound (compound 20) decreases glucose uptake and cell proliferation as well as inhibits the expression of pro-survival MCL-1 in MM similar to the effect observed via knockdown of GLUT4 expression. Compound 20 is also effective at chemosensitizing multiple myeloma cell lines and patient samples to venetoclax, dexamethasone and melphalan. In sum, we report development of selective GLUT4 inhibitors lacking inhibitory activity against GLUT1 and GLUT8. We show that selective pharmacological inhibition of GLUT4 is feasible and this may represent a novel strategy for the treatment and chemosensitization of multiple myeloma to standard therapeutics.
... Fluoro-deoxy-glucose PET imaging has limited spatial resolution but combining it with CT imaging addresses this issue and enables areas of active disease to be identified with exact anatomical localisation (Zamagni & Cavo, 2012;Agarwal et al, 2013;Nakamoto, 2014). This type of information is valuable in myeloma and FDG PET/CT has a potential role in initial diagnosis (Walker et al, 2012), particularly in extramedullary disease and non secretory myeloma (Durie et al, 2002;Orchard et al, 2002;Dimopoulos et al, 2009;Agarwal et al, 2013). ...
... There is little evidence for a role for FDG PET/CT in stable MGUS patients who are at low risk of progression to multiple myeloma. Durie et al (2002) performed FDG PET/ CT scans in a series of 66 patients with myelomatous and monoclonal disease. Fourteen patients had MGUS. ...
... Fourteen patients had MGUS. All had normal PET/CT scans and only one patient progressed to multiple myeloma after 8 months (Durie et al, 2002). ...
The role of imaging in myeloma has gained increasing importance over the past few years. The recently revised definition of myeloma from the International Myeloma Working Group (IMWG) includes cross sectional imaging as a method to define bone disease and also incorporates its use in the disease definition for patients with suspected smouldering myeloma. The National Institute for Health and Care Excellence myeloma guidelines also recommend cross sectional imaging for patients with suspected myeloma. There is also increasing use of imaging in disease assessments and the International Myeloma Working Group has recently incorporated imaging in defining new response categories of minimal residual disease negativity, with or without imaging-based evidence of disease. Plain X-rays have previously been the standard imaging modality included in a myeloma work up at presentation but evidence is mounting for use of cross-sectional modalities such as computed tomography (CT), magnetic resonance imaging (MRI) and (18) fluoro-deoxyglucose ((18) F-FDG) positron emission tomography (PET)/CT. Funding and therefore availability of newer imaging techniques remains a barrier. Here, we propose an evidence-based approach to the use and technical application of the latest imaging modalities at diagnosis and in the follow-up of patients with myeloma and plasmacytoma.
