Head-to-head comparison of [68Ga]Ga-PSMA-11 and [18F]FDG PET/CT in multiple myeloma.

PURPOSE: The aim of this study was to compare [18F]FDG and [68Ga]Ga-PSMA-11 PET/CT image findings in patients with multiple myeloma (MM). METHODS: Twenty consecutive patients with symptomatic biopsy-proven MM were submitted to whole body [18F]FDG and [68Ga]Ga-PSMA-11 PET/CT with a time interval of 1-8 days between procedures. All lesions were counted and had their maximum SUV (SUVmax) measured. Intra-class correlation (ICC) was used to assess the agreement between [18F]FDG and [68Ga]Ga-PSMA-11 PET/CT findings. RESULTS: A total of 266 lesions were detected in 19/20 patients. [18F]FDG detected 223/266 (84%) lesions in 17 patients and [68Ga]Ga-PSMA-11 190/266 (71%) lesions in 19 patients. Both procedures did not identify any active lesion in 1 patient. Forty-three (16%) lesions were detected only by [68Ga]Ga-PSMA-11 and 76 (29%) only by [18F]FDG. Both tracers identified 147 (55%) lesions. Intralesional mismatch of FDG-PSMA uptake was identified in 25 of these 147 lesions, found in 8 different patients. Different lesions with uptake of only [18F]FDG or [68Ga]Ga-PSMA-11 in the same patient were found in 4 patients. The highest SUVmax of [18F]FDG and [68Ga]Ga-PSMA-11 had a median (min-max) SUVmax of 6.5 (2.0-37.8) and 5.5 (1.7-51.3), respectively. [18F]FDG and [68Ga]Ga-PSMA-11 respectively identified 18 and 19 soft tissue lesions. False-positive [18F]FDG findings had minimal or no uptake of [68Ga]Ga-PSMA-11. Good reliability (ICC ≥ 0.75) was found for number of lesions, number of soft tissue lesions and highest SUVmax in each patient. CONCLUSION: [18F]FDG or [68Ga]Ga-PSMA-11 alone can detect most MM lesions. Almost half of the lesions take up only one of the tracers, reflecting increased glycolysis or angiogenesis in specific lesions, and suggesting their possible complementary role in MM. The marked [68Ga]Ga-PSMA-11 uptake in some cases raises the possibility of a theranostic approach in selected patients.

15d-PGJ2 as an endoplasmic reticulum stress manipulator in multiple myeloma in vitro and in vivo.

Multiple myeloma (MM) is characterised by intense protein folding and, consequently endoplasmic reticulum (ER) stress. The prostaglandin 15d-PGJ2 is able to raise oxidative stress levels within the cell and potentially trigger cell death. The aim of this study was to evaluate the antineoplastic effect of 15d-PGJ2 on MM in vitro and in vivo via ER and oxidative stress pathways. MM.1R and MM.1S cell lines were treated with 15d-PGJ2 at 1-10µM and evaluated with regard to proliferation, mRNA expression of PRDX1, PRDX4, GRP78, GRP94, CHOP, BCL-2 and BAX. Stress data was validated via oxidized glutathione assays. MM.1R cells were inoculated into NOD/SCID mice, which were subsequently treated daily with 15d-PGJ2 at 4mg/kg or vehicle (control), with tumour volume being monitored for 14days. 15d-PGJ2 reduced cell proliferation, induced cell death and apoptosis at 5µM and 10µM and Stress-related genes were upregulated at the same doses. Oxidized glutathione levels were also increased. 15d-PGJ2 at 4mg/kg in vivo halted tumour growth. In conclusion, 15d-PGJ2 induced myeloma cell death via ER stress in vitro. 15d-PGJ2 in vivo also inhibited tumour growth.

Imatinib restores VASP activity and its interaction with Zyxin in BCR-ABL leukemic cells.

Vasodilator-stimulated phosphoprotein (VASP) and Zyxin are interacting proteins involved in cellular adhesion and motility. PKA phosphorylates VASP at serine 157, regulating VASP cellular functions. VASP interacts with ABL and is a substrate of the BCR-ABL oncoprotein. The presence of BCR-ABL protein drives oncogenesis in patients with chronic myeloid leukemia (CML) due to a constitutive activation of tyrosine kinase activity. However, the function of VASP and Zyxin in BCR-ABL pathway and the role of VASP in CML cells remain unknown. In vitro experiments using K562 cells showed the involvement of VASP in BCR-ABL signaling. VASP and Zyxin inhibition decreased the expression of anti-apoptotic proteins, BCL2 and BCL-XL. Imatinib induced an increase in phosphorylation at Ser157 of VASP and decreased VASP and BCR-ABL interaction. VASP did not interact with Zyxin in K562 cells; however, after Imatinib treatment, this interaction was restored. Corroborating our data, we demonstrated the absence of phosphorylation at Ser157 in VASP in the bone marrow of CML patients, in contrast to healthy donors. Phosphorylation of VASP on Ser157 was restored in Imatinib responsive patients though not in the resistant patients. Therefore, we herein identified a possible role of VASP in CML pathogenesis, through the regulation of BCR-ABL effector proteins or the absence of phosphorylation at Ser157 in VASP.

Intensity of bone involvement: a quantitative 18F-FDG PET/CT evaluation for monitoring outcome of multiple myeloma.

PURPOSE: The parameter intensity of bone involvement (IBI) was recently proposed to quantitatively assess patients with multiple myeloma using 18F-fluorodeoxyglucose-PET combined with computed tomography (18F-FDG PET/CT) images. Here, we aimed to calculate IBI variation (ΔIBI) between two consecutive PET/CT of the same patient and verified its relationship with a subjective visual analysis of the images and with clinical outcome. METHODS: Consecutive whole-body 18F-FDG PET/CT performed to assess the outcomes of 29 patients diagnosed with multiple myeloma were retrospectively evaluated. ΔIBI was calculated after bone segmentation, using liver standardized uptake value as a threshold to determine metabolically active volumes in the skeleton. For each pair of consecutive PET/CTs, two nuclear medicine physicians classified visually the most recent image as PET-remission, PET-progression or PET-stable when compared to the previous examination. RESULTS: The lowest ΔIBI was -1.27 and the highest was 0.29. PET-remission was related to ΔIBI <0 (median = -0.10; -1.27 to +0.03), while PET-progression was related to ΔIBI >0 (median = 0.02; -0.07 to +0.29). ΔIBI around zero was found in images classified as PET-stable (median = 0.00; -0.08 to +0.06). Significant difference in ΔIBI was found between the three groups. Multivariate stepwise analysis showed that IBI value at diagnostic PET/CT, serum calcium and percentage of plasma cells in the bone marrow are independent prognostic factors. CONCLUSION: Delta IBI provides quantitative data for variations of 18F-FDG uptake in the bone marrow during the follow-up of the patients. In addition, higher IBI values at diagnosis are associated with a higher risk of patient's death.

Computed tomography-based skeletal segmentation for quantitative PET metrics of bone involvement in multiple myeloma.

PURPOSE: Quantifications in nuclear medicine are occasionally limited by the lack of standardization for defining volumes of interest (VOIs) on functional images. In the present article, we propose the use of computed tomography (CT)-based skeletal segmentation to determine anatomically the VOI in order to calculate quantitative parameters of fluorine 18 fluorodeoxyglucose (F-FDG) PET/CT images from patients with multiple myeloma. METHODS: We evaluated 101 whole-body F-FDG PET/CTs of 58 patients with multiple myeloma. An initial subjective visual analysis of the PET images was used to classify the bone involvement as negative/mild, moderate, or marked. Then, a fully automated CT-based segmentation of the skeleton was performed on PET images. The maximum, mean, and SD of the standardized uptake values (SUVmax, SUVmean, and SDSUV) were calculated for bone tissue and compared with the visual analysis. RESULTS: Forty-five (44.5%), 32 (31.7%), and 24 (23.8%) PET images were, respectively, classified as negative/mild, moderate, or marked bone involvement. All quantitative parameters were significantly related to the visual assessment of bone involvement. This association was stronger for the SUVmean [odds ratio (OR): 10.52 (95% confidence interval (CI), 5.68-19.48); P < 0.0001] and for the SDSUV [OR: 5.58 (95% CI, 3.31-9.42); P < 0.001) than for the SUVmax [OR: 1.01 (95% CI, 1.003-1.022); P = 0.003]. CONCLUSION: CT-based skeletal segmentation allows for automated and therefore reproducible calculation of PET quantitative parameters of bone involvement in patients with multiple myeloma. Using this method, the SUVmean and its respective SD correlated better with the visual analysis of F-FDG PET images than SUVmax. Its value in staging and evaluating therapy response needs to be evaluated.

99mTc-sestamibi SPECT/CT and 18F-FDG-PET/CT have similar performance but different imaging patterns in newly diagnosed multiple myeloma.

PURPOSE: F-fluorodeoxiglucose (F-FDG)-PET/CT has been widely used to evaluate multiple myeloma. Tc-sestamibi (MIBI) scintigraphy has also been proposed for assessing multiple myeloma, but its use with state-of-the-art single-photon emission computed tomography/computed tomography (SPECT/CT) technology has not been fully evaluated.This study aimed to compare these two imaging modalities in multiple myeloma staging. MATERIALS AND METHODS: Sixty-two patients with recently diagnosed multiple myeloma were submitted to whole-body F-FDG-PET/CT and whole-body MIBI scans plus SPECT/CT of the chest and abdomen/pelvis. Number of focal lesions, contiguous soft tissue involvement (CSTI), extramedullary lesions (EMLs) and diffuse bone marrow (BM) involvement were recorded. RESULTS: PET/CT was positive in 59 patients (95%) and MIBI SPECT/CT in 58 (93%) (P = 0.69). MIBI detected more diffuse bone marrow involvement than PET/CT (respectively 78 vs. 58% of the patients), while PET/CT demonstrated more focal lesions than MIBI SPECT/CT (81 vs. 54% of the patients) (P = 0.002). PET/CT detected EMLs in four subjects and MIBI in one subject. CSTI was found in 28 (45%) and 23 (37%) patients on PET/CT and MIBI images, respectively (P = 0.36). Three patients with lytic lesions and no FDG uptake were MIBI positive, and two subjects with lytic lesions without MIBI uptake were FDG positive. CONCLUSION: MIBI SPECT/CT performs similarly to F-FDG-PET/CT in identifying sites of active disease in multiple myeloma staging. MIBI is more efficient than FDG for detecting the diffuse involvement of bone marrow but less efficient for detecting focal lesions. Some patients presented a 'mismatch' pattern of FDG/MIBI uptake.

Proposal for a Quantitative 18F-FDG PET/CT Metabolic Parameter to Assess the Intensity of Bone Involvement in Multiple Myeloma.

Many efforts have been made to standardize the interpretation of 18F-FDG PET/CT in multiple myeloma (MM) with qualitative visual analysis or with quantitative metabolic parameters using various methods for lesion segmentation of PET images. The aim of this study was to propose a quantitative method for bone and bone marrow evaluation of 18F-FDG PET/CT considering the extent and intensity of bone 18F-FDG uptake: Intensity of Bone Involvement (IBI). Whole body 18F-FDG PET/CT of 59 consecutive MM patients were evaluated. Compact bone tissue was segmented in PET images using a global threshold for HU of the registered CT image. A whole skeleton mask was created and the percentage of its volume with 18F-FDG uptake above hepatic uptake was calculated (Percentage of Bone Involvement - PBI). IBI was defined by multiplying PBI by mean SUV above hepatic uptake. IBI was compared with visual analysis performed by two experienced nuclear medicine physicians. IBI calculation was feasible in all images (range:0.00-1.35). Visual analysis categorized PET exams into three groups (negative/mild, moderate and marked bone involvement), that had different ranges of IBI (multi comparison analysis, p < 0.0001). There was an inverse correlation between the patients' hemoglobin values and IBI (r = -0.248;p = 0.02). IBI score is an objective measure of bone and bone marrow involvement in MM, allowing the categorization of patients in different degrees of aggressiveness of the bone disease. The next step is to validate IBI in a larger group of patients, before and after treatment and in a multicentre setting.

Lithium, a classic drug in psychiatry, improves nilotinib-mediated antileukemic effects.

Although Tyrosine kinase inhibitors (TKIs) that target Bcr-Abl play a key role in Chronic Myeloid Leukemia (CML) therapy, they do not eradicate CML-initiating cells, which lead to the emergence of drug resistance. Here we used the lithium, a GSK-3 inhibitor, to attempt to potentiate the effects of nilotinib against leukemia cells. For this purpose, a K562 leukemia cell line and bone marrow cells from untreated Chronic Myeloid Leukemia (CML) patients, prior to any exposure to TKIs, were used as a model. Our results demonstrated that the combination of lithium + nilotinib (L + N) induced K562-cell death and cleaved caspase-3 when compared to lithium or nilotinib alone, accompanied by GSK-3ß phosphorylation and Bcr-Abl oncoprotein levels reduction. Interestingly, these events were related to autophagy induction, expressed by increased LC3II protein levels in the group treated with L + N. Furthermore, the clonogenic capacity of progenitor cells from CML patients was drastically reduced by L + N, as well as lithium and nilotinib when used separately. The number of cell aggregates (clusters), were increased by all treatments (L + N, lithium, and nilotinib). This pioneering research has demonstrated that lithium might be of therapeutic value when targeting Bcr-Abl cells with nilotinib because it triggers cell death in addition to exerting classical antiproliferative effects, opening new perspectives for novel target and therapeutic approaches to eradicate CML.