18 F-FDG PET/CT allows the direct measurement of metabolic tumor burden in a variety of different malignancies. The aim of this study was to assess whether metabolic tumor volume (MTV) determined by 18 F-FDG PET/CT could be used in the prediction of progression-free and overall survival in multiple myeloma patients. Methods: Forty-seven patients (18 women, 29 men; mean age 6 SD, 63 6 11 y) with stage IIIA disease who had undergone whole-body 18 F-FDG PET/CT were retrospectively evaluated. Images underwent a 3-dimensional region-of-interest analysis including all focal lesions with a maximum standardized uptake value . 2.5. The MTV of each lesion was calculated using an automated contouring program based on the standardized uptake value and developed with a threshold of 40% of the maximum standardized uptake value. The total MTV of each patient was defined as the sum of metabolic volume of all focal lesions. Patients were treated and then subjected to a mean follow-up period of 24 mo. Results: In the 47 patients studied, MTV range was 1.3-316.3 mL, with a median of 23.7 mL. A direct, significant correlation was found between MTV and the percentage of diffuse infiltration of bone marrow by plasma cells (r 5 0.46, P 5 0.006), whereas hemoglobin levels were inversely correlated with MTV (r 5 20.56, P 5 0.0001). At follow-up, patients who developed progressive disease (n 5 18) showed a significantly higher MTV (74.7 6 19.3 vs. 29.8 6 5.1 mL, P 5 0.009) than patients without progressive disease (n 5 29). Furthermore, patients who died of myeloma (n 5 9) had a significantly higher MTV (123.2 6 30.6 vs. 28.9 6 4.2 mL, P 5 0.0001) than survivors (n 5 38). No differences in age, plasma cell infiltration, M protein, albumin, b2-microglobulin, performance status, International Staging System score, and presence or absence of a bone marrow transplant were found between groups. The MTV cutoff level was determined by receiver-operating-characteristic curve analysis, and the best discriminative value found for predicting progression-free and overall survival was 42.2 and 77.6 mL, respectively. By Kaplan-Meier analysis and log-rank testing, progression-free and overall survival at follow-up were significantly better in patients showing an MTV lower than the cutoff than in those having an MTV higher than the cutoff (x 2 5 3.9, P 5 0.04, and x 2 5 56.3, P , 0.0001, respectively). Conclusion: The direct measurement of tumor burden obtained by calculating MTV on 18 F-FDG PET/CT images may be used in the prediction of progression-free and overall survival in myeloma patients.

Purpose: One of the hallmarks of cancer cells is the excessive conversion of glucose to lactate under normoxic conditions, also known as the Warburg effect. Here, we tested whether the targeted inhibition of EGFR may revert this effect and reactivate mitochondrial oxidative phosphorylation in non-small cell lung cancer (NSCLC).Experimental Design: Sensitive (HCC827) and resistant (H1975 and H1993) NSCLC cells were treated with a panel of EGFR or MET inhibitors, and then tested for changes of EGFR signaling, glycolytic cascade, and mitochondrial function. Silencing of key glycolytic enzymes was then performed with targeted siRNAs. Furthermore, tumor-bearing nude mice treated with EGFR inhibitors were evaluated with 18 F-FDG PET/CT and tumors were analyzed for glycolytic and mitochondrial proteins.Results: Effective inhibition of EGFR signaling in NSCLC cells induced a dramatic reduction of hexokinase II (HKII) and phospho-pyruvate kinase M2 (p-PKM2, Tyr105) levels as well as an upregulation of mitochondrial complexes subunits (OXPHOS). Accordingly, a decreased lactate secretion and increased intracellular ATP levels were also observed in response to EGFR inhibitors. Downregulation of HKII and PKM2 by targeted siRNA transfection did not cause upregulation of OXPHOS but enhanced the effects of EGFR TKIs. Conversely, selective inhibition of AKT and ERK1/2 caused OXPHOS upregulation and glycolysis inhibition, respectively. Similar findings were obtained in tumors from animals treated with appropriate EGFR inhibitors.Conclusions: Our findings indicate that EGFR inhibitors may reactivate oxidative phosphorylation of cancer cells and provide a mechanistic clue for the rational combination of agents targeting EGFR-dependent proliferation and glucose metabolism in cancer therapy.

Multiple endocrine neoplasia type 1 (MEN1) is a hereditary syndrome predisposing to many endocrine and neuroendocrine tumors (NET). Conventional imaging (CI) cannot provide satisfactory results for all the different types of MEN1-related tumors. Objective of this prospective observational study was to evaluate the role of (68)Ga-DOTATATE PET/CT in MEN1 compared to CI. Diagnostic performance of (68)Ga-DOTATATE PET/CT for the detection of NET was evaluated as well as the prognostic role of SUVmax. Eighteen patients with genetically confirmed MEN1 were evaluated by (68)Ga-DOTATATE PET/CT, endoscopic ultrasounds, multidetector-row computed tomography, magnetic resonance imaging, and hormone/markers serum measurements. Four MEN1-related tumor sites (pancreas, pituitary, parathyroids, adrenals) were considered. Sensitivity and specificity of (68)Ga-DOTATATE PET/CT for the detection of NET were calculated. There was (68)Ga-DOTATATE PET/CT uptake in 11/11 patients with pancreatic lesions, in 9/12 with pituitary adenoma, in 5/15 with parathyroid enlargements, and in 5/7 with adrenal lesions. (68)Ga-DOTATATE PET/CT showed sensitivity and specificity of 100 and 100 % in pancreas, 75 and 83 % in pituitary, 28 and 100 % in parathyroids, and 62.5 and 100 % in adrenals, respectively. Compared with CI, no significant difference in sensitivity for pancreas, pituitary, and adrenals was found, while CI had a better sensitivity for parathyroids (p = 0.002). On the ROC analysis, progression of pancreatic lesions was significantly associated to SUVmax <12.3 (p < 0.05). (68)Ga-DOTATATE PET/CT is greatly helpful in the work-up of MEN1 providing a panoramic view of MEN1-related lesions. There is also a prognostic role of (68)Ga-PET in patients with MEN1-pancreatic lesions.

New imaging techniques have been introduced to assess the extent and severity of disease in multiple myeloma (MM) patients. The aim of our study was to compare newer imaging modalities-such as 18 F-FDG PET/CT, 99m Tc-methoxyisobutylisonitrile ( 99m Tc-MIBI) scintigraphy, and MRI-to assess their relative contribution in the evaluation of MM patients at diagnosis. Methods: Thirty-three newly diagnosed patients with MM were prospectively studied. Diagnosis and staging were made according to standard criteria. All patients underwent whole-body 18 F-FDG PET/CT, whole-body 99m Tc-MIBI, and MRI of the spine and pelvis within 10 d, and imaging findings were compared. Results: 18 F-FDG PET/CT was positive in 32 patients (16 focal uptake, 3 diffuse uptake, 13 focal and diffuse uptake), 99m Tc-MIBI was positive in 30 patients (6 focal, 11 diffuse, 13 focal and diffuse uptake), and MRI of the spine and pelvis was positive in 27 patients (6 focal, 13 diffuse, 8 focal and diffuse uptake). 18 F-FDG PET/CT showed a total of 196 focal lesions (178 in bones and 18 in soft tissues), of which 121 were in districts other than the spine and pelvis, whereas 99m Tc-MIBI visualized 63 focal lesions (60 in bones and 3 in soft tissues), of which 53 were in districts other than the spine and pelvis. In the spinal and pelvic regions, 18 F-FDG PET/CT detected 75 focal lesions (35 in spine and 40 in pelvis), 99m Tc-MIBI visualized 10 focal lesions (1 in spine and 9 in pelvis), and MRI detected 51 focal lesions (40 in spine and 11 in pelvis). Conclusion: In whole-body analysis, 18 F-FDG PET/ CT performed better than 99m Tc-MIBI in the detection of focal lesions, whereas 99m Tc-MIBI was superior in the visualization of diffuse disease. In the spine and pelvis, MRI was comparable to 18 F-FDG PET/CT and 99m Tc-MIBI in the detection of focal and diffuse disease, respectively. Because myelomatous lesions may often occur out of spinal and pelvic regions, MRI should be reserved to the evaluation of bone marrow involvement of these districts, whereas 18 F-FDG PET/CT can significantly contribute to an accurate whole-body evaluation of MM patients. Finally, whole-body 99m Tc-MIBI, despite its limited capacity in detecting focal lesions, may be an alternative option when a PET facility is not available.

Sorafenib allows morphological disease control in the majority of patients with iodine-refractory DTC. Progression-free survival and overall survival were lower than in previous studies as a consequence of the worse clinical condition of our patients. Sorafenib is mostly well tolerated but could have been responsible for the reported fatal events. Baseline Tg and the Tg response to treatment could be useful for predicting morphological response and clinical outcome. Early FDG-PET response could be helpful for the timely identification of nonresponding patients.

No abstract

Neutrophil extracellular traps (NETs), in addition to their function as a host defense mechanism, play a relevant role in thrombus formation and metastatic dissemination of cancer cells. Here we screened different cancer cell lines endogenously expressing a variety of integrins for their ability to bind to NETs. To this end, we used NETs isolated from neutrophil-like cells as a substrate for adhesion assays of HT1080, U-87 MG, H1975, DU 145, PC-3 and A-431 cells. Levels of α5, αIIb, αv, β1, β3 and β5 chains were determined by western blot analysis in all cell lines and levels of whole integrins on the plasma membrane were assessed by fluorescence-activated cell sorting (FACS) analysis. We found that high levels of α5β1, αvβ3 and αvβ5 enhance cell adhesion to NETs, whereas low expression of α5β1 prevents cell attachment to NETs. Excess of cyclic RGD peptide inhibited cell adhesion to NETs by competing with fibronectin within NETs. The maximal reduction of such adhesion was similar to that obtained by DNase 1 treatment causing DNA degradation. Our findings indicate that NETs from neutrophil-like cells may be used as a substrate for large screening of the adhesion properties of cancer cells expressing a variety of RGD-binding integrins.

BAT activity has been shown in CL in resting thermoneutral conditions and may exert a role against adipose tissue deposition.