Leucine-rich diet induces a shift in tumour metabolism from glycolytic towards oxidative phosphorylation, reducing glucose consumption and metastasis in Walker-256 tumour-bearing rats

Leucine can stimulate protein synthesis in skeletal muscle, and recent studies have shown an increase in leucine-related mitochondria! biogenesis and oxidative phosphorylation capacity in muscle cells. However, leucine-related effects in tumour tissues are still poorly understood. Thus, we described the effects of leucine in both in vivo and in vitro models of a Walker-256 tumour. Tumour-bearing Wistar rats were randomly distributed into a control group (W; normoprotein diet) and leucine group (LW; leucine-rich diet [normoprotein +3% leucine]). After 20 days of tumour evolution, the animals underwent (18)-fludeoxyglucose positron emission computed tomography (F-18-FDG PET-CT) imaging, and after euthanasia, fresh tumour biopsy samples were taken for oxygen consumption rate measurements (Oroboros Oxygraph), electron microscopy analysis and RNA and protein extraction. Our main results from the LW group showed no tumour size change, lower tumour glucose (F-18-FDG) uptake, and reduced metastatic sites. Furthermore, leucine stimulated a shift in tumour metabolism from glycolytic towards oxidative phosphorylation, higher mRNA and protein expression of oxidative phosphorylation components, and enhanced mitochondria! density/area even though the leucine-treated tumour had a higher number of apoptotic nuclei with increased oxidative stress. In summary, a leucine-rich diet directed Walker-256 tumour metabolism to a less glycolytic phenotype profile in which these metabolic alterations were associated with a decrease in tumour aggressiveness and reduction in the number of metastatic sites in rats fed a diet supplemented with this branched-chain amino acid.9CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQCOORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIOR - CAPESFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESPSem informação302863/2013-3; 302425/2016-92012/06955-0; 2014/13334-7; 2015/21890-0; 2017/02739-

TREATMENT OF REFRACTORY MULTIPLE MYELOMA WITH PSMA-177LU: A CASE REPORT

Introduction/Justification: Triple-refractory multiple myeloma (MM) has a poor prognosis. It is a neoplasm with marked genomic heterogeneity, and recently, our group demonstrated marked uptake of 68Ga-PSMA-11 in some patients, suggesting the potential theranostic use of PSMA in selected cases (1). Herein, we report the initial treatment with 177Lu-PSMA in a patient with refractory MM. Report: A 76-year-old male patient with IgA/Kappa MM refractory to 6 therapeutic lines, including daratumumab, lenalidomide, and bortezomib, underwent PET/CT with 18F-PSMA-1007, showing marked tracer uptake in multiple osteolytic lesions, several with extensive soft tissue components. A PET/CT with 18F-FDG was also performed, revealing similar findings. A first dose of 7,400 MBq (200 mCi) of 177Lu-PSMA-I&T was administered. The procedure was well tolerated, with slight clinical improvement observed in the week following the infusion. Visual analysis of whole-body scans performed at 21h, 30h, and 7 days demonstrated moderate tracer uptake, lower than that observed with 18F-PSMA-1007. There was slight washout between images at 21h and 30h and moderate/significant washout after 7 days. After 4 weeks, PET/CTs with 18F-PSMA and 18F-FDG were repeated, showing similar findings to the initial scans, with a slight reduction in tracer uptake in some lesions. There was also an increase in the volume of some soft tissue lesions, attributed to post-treatment inflammation. The patient received a second dose of 7,400 MBq (200 mCi) of 177Lu-PSMA-I&T after 6 weeks, and whole-body scans were performed at 2h and 24h, also showing visually lower uptake compared to 18F-PSMA-1007. The patient experienced an intercurrent femoral fracture, limiting mobility for clinical evaluation and subsequent procedures, ultimately leading to their passing after a few days. Conclusion: This preliminary report suggests that treatment of MM with 177Lu-PSMA is feasible and well tolerated after 2 initial doses. The uptake of 177Lu-PSMA-I&T was visually lower than that of 18F-PSMA-1007, which does not seem to be solely explained by the different resolution of images obtained from different tracers and equipment. There was a slight clinical and imaging response after the first dose, out of a total of 6 planned. A fracture complication and the severity of the case prevented imaging evaluation after the 2nd dose and further treatment continuation. PSMA-177Lu therapy in MM treatment appears to be safe with an initial favorable response, albeit slight. Studies with complete treatments (6 cycles) and in clinically less severe patients are needed to assess the effectiveness of the procedure

DUAL-TRACER PET/CT IN MYELOFIBROSIS: A CASE SERIES ANALYSIS USING 18F-FDG AND 18F-PSMA PET/CT

Introduction/Justification: Myelofibrosis, a clonal disorder of hematopoietic stem cells, is characterized by chronic bone marrow inflammation and progressive fibrosis, resulting in hypocellularity and the displacement of neoplastic cells to extramedullary organs such as the spleen and liver, leading to splenomegaly and hepatomegaly. Hematopoietic stem cell transplantation is currently the only curative treatment, with five-year survival rates ranging between 51% and 61%, underscoring the need for novel diagnostic and therapeutic strategies. In recent years, positron emission tomography combined with computed tomography (PET/CT) using 18F-fluorodeoxyglucose (18F-FDG) has emerged as a valuable tool for assessing the glycolytic activity of various neoplasms, although there are limited reports on its utility in myelofibrosis. Concurrently, interest has grown in using the prostate-specific membrane antigen (PSMA) tracer to evaluate the neoangiogenic activity of diverse neoplasms. This study aims to compare glycolytic activity and neoangiogenic activity, assessed through 18F-FDG and 18F-PSMA PET/CT imaging, respectively, in patients with myelofibrosis. Report: Three patients diagnosed with myelofibrosis, aged 69, 71, and 74 years, underwent PET/CT scans on consecutive days, acquired 60 minutes after intravenous administration of 0.1 mCi/kg of 18F-FDG and 90 minutes after intravenous injection of 0.1 mCi/kg of 18F-PSMA. The images were analyzed by two nuclear medicine physicians and a radiologist. The maximum standardized uptake value (SUV) of the bone marrow, as well as the SUV and dimensions of the liver and spleen, were measured. Two patients exhibited mild to moderate diffuse increased uptake of both 18F-FDG and 18F-PSMA in the bone marrow (SUV-FDG: 6.4 and 3.5; SUV-PSMA: 3.5 and 1.7). One of them displayed mild hepatomegaly (18.7 cm), and both had marked splenomegaly (21.5 and 30.3 cm). Liver and spleen uptake of 18F-FDG was close to normal in both patients (SUV-FDG: 2.4 to 3.1), while moderate uptake of 18F-PSMA was observed in these organs (SUV-PSMA: 5.6 to 8.4), at least partially physiological and expected for this radiopharmaceutical. The third patient, who had undergone splenectomy, did not exhibit significant uptake of either tracer in the bone marrow but displayed marked uptake of 18F-PSMA in the liver (SUV-PSMA = 14.8), possibly physiological, with normal 18F-FDG uptake (SUV-FDG = 3.9). Conclusion: Patients with myelofibrosis appear to exhibit variable degrees of glycolytic activity and neoangiogenesis in the bone marrow, as detected by PET/CT imaging with 18F-FDG and 18F-PSMA. The moderate to marked uptake of 18F-PSMA in the liver and spleen, at least partly physiological, along with the uptake in the bone marrow in some cases, may suggest a theranostic potential of this radiopharmaceutical in myelofibrosis

Proposal for a quantitative F-18-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 F-18-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 F-18-FDG PET/CT considering the extent and intensity of bone F-18-FDG uptake: Intensity of Bone Involvement (IBI). Whole body F-18-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 F-18-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.9CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQCOORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIOR - CAPESFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESPSem informação305110/2018-7; 311841/2018-02009/54065-0; 2018/00654-