Mitsuaki Tatsumi

Dynamic Imaging of Allogeneic Mesenchymal Stem Cells Trafficking to Myocardial Infarction

Background—Recent results from animal studies suggest that stem cells may be able to home to sites of myocardial injury to assist in tissue regeneration. However, the histological interpretation of postmortem tissue, on which many of these studies are based, has recently been widely debated. Methods and Results—With the use of the high sensitivity of a combined single-photon emission CT (SPECT)/CT scanner, the in vivo trafficking of allogeneic mesenchymal stem cells (MSCs) colabeled with a radiotracer and MR contrast agent to acute myocardial infarction was dynamically determined. Redistribution of the labeled MSCs after intravenous injection from initial localization in the lungs to nontarget organs such as the liver, kidney, and spleen was observed within 24 to 48 hours after injection. Focal and diffuse uptake of MSCs in the infarcted myocardium was already visible in SPECT/CT images in the first 24 hours after injection and persisted until 7 days after injection and was validated by tissue counts of radioactivity. In contrast, MRI was unable to demonstrate targeted cardiac localization of MSCs in part because of the lower sensitivity of MRI. Conclusions—Noninvasive radionuclide imaging is well suited to dynamically track the biodistribution and trafficking of mesenchymal stem cells to both target and nontarget organs.

Hepatocellular Carcinoma: Hepatocyte-selective Enhancement at Gadoxetic Acid–enhanced MR Imaging—Correlation with Expression of Sinusoidal and Canalicular Transporters and Bile Accumulation

PURPOSE To investigate the mechanism of enhancement of hepatocellular carcinoma (HCC) on gadoxetic acid-enhanced hepatobiliary phase magnetic resonance (MR) images and to characterize HCC thus enhanced. MATERIALS AND METHODS This retrospective study was approved by the institutional review board, and patient informed consent for research use of the resected specimen was obtained. MR images in 25 patients (20 men, five women; mean age, 68 years; range, 49-82 years) with 27 resected hypervascular HCCs (one well, 13 moderately, 13 poorly differentiated) that demonstrated hepatocyte-selective enhancement on gadoxetic acid-enhanced MR images, were quantitatively studied, and findings were correlated with results of immunohistochemical staining for a sinusoidal transporter, organic anion transporting polypeptide (OATP) 1B1 (OATP1B1) and/or OATP1B3 (OATP1B1 and/or -1B3), and a canalicular transporter, multidrug resistance-associated protein 2 (MRP2), and also with bile accumulation in tumors. Statistical analysis was performed with the Student t test and Scheffé post hoc test. RESULTS Combined with positive OATP1B1 and/or -1B3 expression (O+), two patterns of MRP2 expression contributed to high enhancement: decreased expression (M-, n = 3) and increased expression at the luminal membrane of pseudoglands (M+[P], n = 3). Nodules without OATP1B1 and/or -1B3 expression (O-, n = 13) and nodules with O+ associated with increased MRP2 expression only at the canaliculi (M+[C], n = 8) induced significantly lower enhancement than those with the two expression patterns described before (O+/M- group vs O- group, P = .002; O+/M- group vs O+/M+[C] group, P = .047; O+/M+[P] group vs O- group, P < .001; O+/M+[P] group vs O+/M+[C] group, P < .001). Nodules with bile pigment (n = 12) showed significantly higher enhancement (P = .004); all five nodules (one well differentiated HCC, four moderately differentiated HCCs), which were enhanced more than adjacent liver parenchyma, contained bile pigment. CONCLUSION High hepatocyte-selective enhancement is induced by expression patterns of transporters, which may result in accumulation of gadoxetic acid in cytoplasm of tumor cells or in lumina of pseudoglands. An HCC with gadoxetic acid enhancement is characterized by bile accumulation in tumors.

Initial experience with FDG-PET/CT in the evaluation of breast cancer

PurposeWe retrospectively reviewed FDG-PET/CT images in patients with breast cancer to determine whether PET/CT improved the level of diagnostic confidence as compared with PET and to compare PET/CT and CT findings at the location of suspected malignancies.MethodsThe study included 75 patients with known breast cancer. The initial PET/CT study for each patient was retrospectively reviewed to determine whether improved diagnostic confidence (IDC) regarding lesion localization and characterization was observed with PET/CT as compared with PET alone. PET/CT and CT findings were compared regarding lesion characterization and staging in 69 of the 75 patients, and in the case of discordant findings, comparison with histological or informative follow-up results was also performed.ResultsFifty of the 75 patients exhibited increased FDG uptake in a total of 95 regions. In the comparison of PET/CT and PET, PET/CT resulted in IDC in 30 (60%) of these 50 patients and in 52 (55%) of the 95 regions. In the comparison between PET/CT and CT in 69 patients, PET/CT demonstrated a significantly better accuracy than CT (P<0.05). PET/CT showed definitely positive findings in 60 regions with malignancies, among which CT exhibited positive findings in 43 (72%). PET/CT and CT accurately staged 59 (86%) and 53 (77%) of the 69 patients, respectively.ConclusionsPET/CT added incremental diagnostic confidence to PET in more than 50% of patients and regions with increased FDG uptake. PET/CT accurately detected more regions with malignancies than did CT. This initial evaluation suggests that PET/CT is preferable to PET or CT in the diagnosis of breast cancer.

Comparison of FDG-PET with MIBI-SPECT in the detection of breast cancer and axillary lymph node metastasis.

PURPOSE The purpose of this work was to compare [18F]2-deoxy-2-fluoro-D-glucose (FDG) PET and 99mTc-methoxyisobutylisonitrile (MIBI) SPECT in the detection of breast cancer and axillary lymph node metastasis in the same patients. METHOD FDG-PET and MIBI-SPECT were performed within 3 days for 40 women (age range 25-86 years old) with suspected breast cancer, in whom biopsies and/or mastectomies were performed. Both images were visually assessed, and the count ratio between tumor and normal tissue (T/N ratio) was calculated. RESULTS Thirty-eight patients had breast cancer, and the remaining two had benign breast lesions. The sensitivities of FDG-PET and MIBI-SPECT were 78.9 and 76.3% for breast cancer and 50.0 and 37.5% for axillary lymph node metastasis, respectively. The T/N ratio of breast cancer was significantly higher in FDG-PET (6.01 +/- 3.08 mean +/- SD) than that in MIBI-SPECT (3.48 +/- 1.21) (p = 0.01). Nonmalignant diffuse uptake of FDG in the breasts and the accumulation of MIBI in heart and liver occasionally obscured tumor uptake. CONCLUSION These results indicate that MIBI-SPECT is comparable with FDG-PET in detecting breast cancer. Neither FDG-PET nor MIBI-SPECT is sufficiently sensitive to rule out axillary lymph node metastasis.

Multicenter Phase II Study of Bendamustine Plus Rituximab in Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma

PURPOSE Effective and less aggressive therapies are required for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who are not eligible for or have undergone autologous stem-cell transplantation (ASCT). The present phase II study assessed the efficacy and safety of bendamustine plus rituximab (BR) in this population. PATIENTS AND METHODS Patients with relapsed or refractory DLBCL treated with one to three prior chemotherapy regimens received rituximab 375 mg/m(2) intravenous (IV) infusion on day 1 and bendamustine 120 mg/m(2) by IV infusion on days 2 and 3 of each 21-day cycle for up to six cycles. The primary end point was overall response rate (ORR), and the secondary end points were complete response (CR) rate, progression-free survival (PFS), and safety. RESULTS Sixty-three patients were enrolled, and 59 received BR. The median age was 67 years (range, 36 to 75 years), and 62.7% of patients were 65 years of age or older. Fifty-seven patients (96.6%) were previously treated with rituximab-containing chemotherapy. The ORR was 62.7% (95% CI, 49.1% to 75.0%), with a CR rate of 37.3% (95% CI, 25.0% to 50.9%). The ORRs were comparable between patients ≥ 65 years of age and less than 65 years (62.2% and 63.6%, respectively). The median PFS was 6.7 months (95% CI, 3.6 to 13.7 months). The most frequently observed grade 3 or 4 adverse events were hematologic: lymphopenia (78.0%), neutropenia (76.3%), leukopenia (72.9%), CD4 lymphopenia (66.1%), and thrombocytopenia (22.0%). CONCLUSION BR is a promising salvage regimen for patients with relapsed or refractory DLBCL after rituximab-containing chemotherapy, warranting further investigation.

Correlation of GLUT-1 Overexpression, Tumor Size, and Depth of Invasion with 18F-2-fluoro-2-deoxy-d-glucose Uptake by Positron Emission Tomography in Colorectal Cancer

We investigated the wide variability of 18F-2-fluoro-2-deoxy-d-glucose (FDG) uptake, semiquantified as standardized uptake value (SUV), in positron emission tomography (PET) scanning, in 20 patients with colorectal cancer (CRC), including 1 with synchronous hepatic metastasis. The sensitivity of PET in CRC diagnosis was 100%, with a mean SUV of 8.0 (3.1–11.9). Tumor size and depth of invasion were associated with higher SUVs (P=.0004, .042, respectively). Strong glucose transporter-1 (GLUT-1) expression had significantly positive correlation with the SUV (r=.619, P=.003). GLUT-1 expression revealed positive staining in 17 (85%) of the 20 primary lesions. The central part of the tumor, thought to be relatively hypoxic, had stronger GLUT-1 expression and a higher SUV than the periphery, in both the primary tumor and hepatic metastatic foci. Our data suggest that the SUVs of FDG uptake in PET may be a noninvasive biomarker for advanced CRC, indicative of a large hypoxic tumor with deep invasion.

Evaluation of Response to Neoadjuvant Chemotherapy for Esophageal Cancer: PET Response Criteria in Solid Tumors Versus Response Evaluation Criteria in Solid Tumors

Recently, PET response criteria in solid tumors (PERCIST) have been proposed as a new standardized method to assess chemotherapeutic response metabolically and quantitatively. The aim of this study was to evaluate therapeutic response to neoadjuvant chemotherapy for locally advanced esophageal cancer, comparing PERCIST with the currently widely used response evaluation criteria in solid tumors (RECIST). Methods: Fifty-one patients with locally advanced esophageal cancer who received neoadjuvant chemotherapy (5-fluorouracil, adriamycin, and cisplatin), followed by surgery were studied. Chemotherapeutic lesion responses were evaluated using 18F-FDG PET and CT according to the RECIST and PERCIST methods. The PET/CT scans were obtained before chemotherapy and about 2 wk after completion of chemotherapy. Associations were statistically analyzed between survival (overall and disease-free survival) and clinicopathologic results (histology [well-, moderately, and poorly differentiated squamous cell carcinoma], lymphatic invasion, venous invasion, clinical stage, pathologic stage, resection level, reduction rate of tumor diameter, reduction rate of tumor uptake, chemotherapeutic responses in RECIST and PERCIST, and pathologic response). Results: There was a significant difference in response classification between RECIST and PERCIST (Wilcoxon signed-rank test, P < 0.0001). Univariate analysis showed that lymphatic invasion, venous invasion, resection level, pathologic stage, and PERCIST were significant factors associated with disease-free or overall survival in this study. Although multivariate analysis demonstrated that venous invasion (disease-free survival: hazard ratio [HR] = 4.519, P = 0.002; overall survival: HR = 5.591, P = 0.003) and resection level (disease-free survival: HR = 11.078, P = 0.001) were the significant predictors, PERCIST was also significant in noninvasive therapy response assessment before surgery (disease-free survival: HR = 4.060, P = 0.025; overall survival: HR = 8.953, P = 0.034). Conclusion: RECIST based on the anatomic size reduction rate did not demonstrate the correlation between therapeutic responses and prognosis in patients with esophageal cancer receiving neoadjuvant chemotherapy. However, PERCIST was found to be the strongest independent predictor of outcomes. Given the significance of noninvasive radiologic imaging in formulating clinical treatment strategies, PERCIST might be considered more suitable for evaluation of chemotherapeutic response to esophageal cancer than RECIST.

Hypervascular hepatocellular carcinomas: detection with gadoxetate disodium-enhanced MR imaging and multiphasic multidetector CT

ObjectivesTo retrospectively compare the accuracy of detection of hypervascular hepatocellular carcinoma (HCC) by multiphasic multidetector CT and by gadoxetate disodium-enhanced MR imaging.MethodsAfter ethical approval, we analysed a total of 73 hypervascular HCC lesions from 31 patients suspected of having HCC, who underwent both gadoxetate disodium-enhanced MR imaging and multiphasic multidetector CT. Five blinded observers independently reviewed CT images, as well as dynamic MR images alone and combined with hepatobiliary phase MR images. Diagnostic accuracy (Az values), sensitivities and positive predictive values were compared by using the Scheffe post hoc test.ResultsThe mean Az value for dynamic and hepatobiliary phase MR combined (0.81) or dynamic MR images alone (0.78) was significantly higher than that for CT images (0.67, P < 0.001, 0.005, respectively). The mean sensitivity of the combined MR images (0.67) was significantly higher than that of dynamic MR alone (0.52, P < 0.05) or CT images (0.44, P < 0.05). The mean positive predictive values were 0.96, 0.95 and 0.94, for CT, dynamic MR alone and combined MR images, respectively.ConclusionsCompared with multiphasic multidetector CT, gadoxetate disodium-enhanced MR imaging combining dynamic and hepatobiliary phase images results in significantly improved sensitivity and diagnostic accuracy for detection of hypervascular HCC.Key Points• Gadoxetate disodium is a new liver-specific MR imaging contrast agent. Gadoxetate disodium-enhanced MRI helps the assessment of patients with liver disease.• It showed high diagnostic accuracy for the detection of hepatocellular carcinoma.

Effect of Nicotine and Ephedrine on the Accumulation of 18F-FDG in Brown Adipose Tissue

This study evaluated the effect of various β-adrenergic agonists on 18F-FDG uptake in brown adipose tissue (BAT) in rats using ex vivo biodistribution studies. Methods: Caffeine (10 mg/kg of body weight, n = 4), ephedrine (5 mg/kg of body weight, n = 4), nicotine (0.8 mg/kg of body weight, n = 9), or a mixture of nicotine and ephedrine (0.8 mg/kg of body weight and 5 mg/kg of body weight, respectively, n = 9) was injected into the peritoneal cavity of female Lewis rats 30 min before intravenous 18F-FDG injection. One hour after injection of 18F-FDG, the animals were sacrificed, and BAT, other major organs, and blood were extracted. The biodistribution results were compared with body temperature data. Results: In the rats injected with nicotine or ephedrine, the mean uptake of 18F-FDG, in percentage injected dose (%ID)/(g of interscapular BAT) × (kg of body weight), was significantly increased (7.9-fold for nicotine and 3.7-fold for ephedrine), compared to the control rats. Nicotine had the strongest effect on 18F-FDG uptake in BAT. Caffeine increased BAT uptake slightly, but this increase did not reach statistical significance. The combination of nicotine and ephedrine increased the uptake 12.0-fold, compared with control rats; more than either nicotine or ephedrine alone. Uptake of 18F-FDG in most other major organs did not change significantly. The effect of nicotine was blocked by prior injection of β-adrenergic antagonists. A transient decrease in body temperature was observed in the nicotine-injected group, and this effect was canceled by prior injection of β-adrenergic antagonists. No significant change in baseline temperature was seen before or after β-adrenergic agonist injection. Conclusion: Nicotine caused a greater increase in 18F-FDG uptake in BAT than did other interventions, and the effect was increased when nicotine was combined with ephedrine. The effect of nicotine was completely blocked by prior injection of β-adrenergic antagonists, indicating that β-adrenergic agonists increase the metabolism of BAT. These preclinical data suggest that patients should avoid nicotine and ephedrine before undergoing 18F-FDG PET to minimize 18F-FDG uptake in BAT.

18F-FDG PET/MRI fusion in characterizing pancreatic tumors: comparison to PET/CT

ObjectiveTo demonstrate that positron emission tomography (PET)/magnetic resonance imaging (MRI) fusion was feasible in characterizing pancreatic tumors (PTs), comparing MRI and computed tomography (CT) as mapping images for fusion with PET as well as fused PET/MRI and PET/CT.MethodsWe retrospectively reviewed 47 sets of 18F-fluorodeoxyglucose (18F -FDG) PET/CT and MRI examinations to evaluate suspected or known pancreatic cancer. To assess the ability of mapping images for fusion with PET, CT (of PET/CT), T1- and T2-weighted (w) MR images (all non-contrast) were graded regarding the visibility of PT (5-point confidence scale). Fused PET/CT, PET/T1-w or T2-w MR images of the upper abdomen were evaluated to determine whether mapping images provided additional diagnostic information to PET alone (3-point scale). The overall quality of PET/CT or PET/MRI sets in diagnosis was also assessed (3-point scale). These PET/MRI-related scores were compared to PET/CT-related scores and the accuracy in characterizing PTs was compared.ResultsForty-three PTs were visualized on CT or MRI, including 30 with abnormal FDG uptake and 13 without. The confidence score for the visibility of PT was significantly higher on T1-w MRI than CT. The scores for additional diagnostic information to PET and overall quality of each image set in diagnosis were significantly higher on the PET/T1-w MRI set than the PET/CT set. The diagnostic accuracy was higher on PET/T1-w or PET/T2-w MRI (93.0 and 90.7%, respectively) than PET/CT (88.4%), but statistical significance was not obtained.ConclusionPET/MRI fusion, especially PET with T1-w MRI, was demonstrated to be superior to PET/CT in characterizing PTs, offering better mapping and fusion image quality.