¹⁸F-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 ¹⁸F-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 ± SD, 63 ± 11 y) with stage IIIA disease who had undergone whole-body ¹⁸F-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 = 0.46, P = 0.006), whereas hemoglobin levels were inversely correlated with MTV (r = −0.56, P = 0.0001). At follow-up, patients who developed progressive disease (n = 18) showed a significantly higher MTV (74.7 ± 19.3 vs. 29.8 ± 5.1 mL, P = 0.009) than patients without progressive disease (n = 29). Furthermore, patients who died of myeloma (n = 9) had a significantly higher MTV (123.2 ± 30.6 vs. 28.9 ± 4.2 mL, P = 0.0001) than survivors (n = 38). No differences in age, plasma cell infiltration, M protein, albumin, β2-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 (χ² = 3.9, P = 0.04, and χ² = 56.3, P < 0.0001, respectively). Conclusion: The direct measurement of tumor burden obtained by calculating MTV on ¹⁸F-FDG PET/CT images may be used in the prediction of progression-free and overall survival in myeloma patients.

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. 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. (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). 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.

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 18F-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. Clin Cancer Res; 21(22); 5110–20. ©2015 AACR.

PURPOSE: Since we have previously shown that the efflux rate of technetium 99m (99mTc) sestamibi, a transport substrate of P-glycoprotein (Pgp), is directly correlated with Pgp levels in untreated breast carcinoma, we tested whether tumor clearance of 9mTc-sestamibi may be predictive of therapeutic response to neoadjuvant chemotherapy in patients with locally advanced breast cancer. PATIENTS AND METHODS: Thirty-nine patients with stage III disease, median tumor diameter 5.8 cm (range, 3 to 10) were enrolled onto this prospective clinical trial and underwent 99mTc-sestamibi scan before neoadjuvant chemotherapy. Patients were injected intravenously (i.v.) with 740 MBq of 99mTc-sestamibi; a 15-minute dynamic study was performed, and static planar images were obtained at 0.5, 1, 2, and 4 hours. The time to half clearance of 99mTc-sestamibi was calculated in each patient from decay corrected time-activity curves using a monoexponential fitting. Patients were treated with epirubicin 150 mg/m2 i.v. every 2 weeks for three courses and then underwent surgery within 3 weeks from the completion of chemotherapy. Residual tumor was assessed by pathologic examination of mastectomy specimens. RESULTS: Seventeen of 39 patients showed a rapid tumor clearance of 9mTc-sestamibi (time to half clearance [t1/2] < or = 204 minutes) and 15 of these 17 (88%) showed a highly cellular macroscopic residual tumor at histology that indicated lack of tumor response to neoadjuvant chemotherapy. In contrast, only eight of 22 (36%) with prolonged retention of 99mTc-sestamibi (t1/2 > 204 minutes) showed residual macroscopic tumor at histology (Fisher's exact test, P < .01). CONCLUSION: A rapid tumor clearance of 99mTc-sestamibi may predict lack of tumor response to neoadjuvant chemotherapy with drugs affected by the multidrug-resistant phenotype in patients with locally advanced breast carcinoma.