Precise differential diagnosis of acute bone marrow edema and hemorrhage and trabecular microfractures using naïve and gamma correction pinhole bone scans.

OBJECTIVE: To analyze the performance of sequential naïve pinhole bone scan (nPBS) and gamma correction pinhole bone scan (GCPBS), reinforced by ImageJ densitometry and pixelized microfracture measurement, for making specific diagnoses of bone marrow edema (BME), bone marrow hemorrhage (BMH), and trabecular microfractures (TMF). METHODS: We prospectively examined BME, BMH, TMF, and normal trabeculae in 10 patients using sequential nPBS and GCPBS. The intensity of 99mtechnetium-hydroxydiphosphonate (99mTc-HDP) uptake was measured using a pixelized method and calculated using ImageJ densitometry in terms of arbitrary units (AU). This overall method was termed a visuospatial-mathematic assay (VSMA). We analyzed the ability of the calculated AU values to discriminate between the four states using GraphPad Prism software, with reference to previous morphological data. RESULTS: The calculated values were categorized as ≤50 AU for normal trabecula, 51-100 AU for BME, 101-150 AU for BMH, and ≥151 AU for TMF. The difference in uptake between normal trabecula and BME was significant and the differences among BME, BMH, and TMF were highly significant. CONCLUSION: VSMA is a useful technique for refining objective individual diagnoses and for differentiating and quantitating BME, BMH, and TMF.

Clinical Performance of Whole-Body 18F-FDG PET/Dixon-VIBE, T1-Weighted, and T2-Weighted MRI Protocol in Colorectal Cancer.

PURPOSE: The aim of this study was to investigate the clinical performance of whole-body (18)F-FDG PET/Dixon-volume-interpolated breath-hold examination (Dixon-VIBE), T1-weighted, and T2-weighted MRI protocol in patients with colorectal cancer. PATIENTS AND METHODS: A total of 59 patients with colorectal cancer were enrolled in this study. Each patient had one of the following clinical conditions: initial stage before therapy, stage after neoadjuvant therapy, suspicious colorectal liver metastases, and colorectal liver metastases after chemotherapy. Fourteen patients had primary colorectal cancer, whereas 38 patients had a total of 132 hepatic lesions, 53 lesions existed before chemotherapy, and 79 lesions appeared after chemotherapy. The primary stage and metastases images were obtained using our PET/Dixon-VIBE/T1/T2 MRI protocol and were analyzed by 2 nuclear medicine physicians. Diagnostic accuracy was compared with contrast-enhanced MRI images, which were based on surgical pathology results. RESULTS: The sensitivity of our imaging protocol for primary colorectal cancer was 100% (14/14). T and N stage both showed 92.9% (13/14) accuracy. Of all 132 hepatic lesions, 115 metastatic lesions were analyzed, and 17 benign lesions were excluded (6 were during pretreatment cases, and 11 were during posttreatment cases). In pretreatment metastatic lesions (n = 47), the sensitivities of our protocol and dedicated MRI were 95.7% (45/47) and 100% (47/47), respectively. In posttreatment lesions (n = 68), sensitivities of our protocol and dedicated MRI were 75% (51/68) and 91.2% (62/68), respectively. CONCLUSIONS: Whole-body PET/Dixon-VIBE/T1/T2 MRI protocol is clinically useful for TNM staging and chemonaive hepatic metastasis in colorectal cancer.

Prognostic implication of extrarenal metabolic tumor burden in advanced renal cell carcinoma treated with targeted therapy after nephrectomy.

OBJECTIVE: In the era of targeted therapy for advanced renal cell carcinoma (RCC), appropriate prognosis prediction is necessary for optimal therapy with or without cytoreductive surgery. We evaluated prognostic implication of extrarenal metabolic tumor burden in nephrectomized patients with advanced RCC. METHODS: Forty-four patients with advanced RCC who underwent (18)F-fluorodeoxyglucose PET/CT were retrospectively enrolled. The patients were treated with nephrectomy and targeted therapy. On PET/CT image of each patient, maximal standardized uptake value (SUVmax) of lesions were measured, and metabolic tumor burden was measured as total lesion glycolysis (TLG) by multiplying tumor volume and mean SUV. An overall TLG was calculated as the sum of those of all lesions. The prognostic value of PET parameters (SUVmax and TLG), and established major clinical factors (serum hemoglobin and corrected calcium, and number of metastatic sites) were tested with regard to overall survival. RESULTS: Among 44 patients, 8 died during mean follow-up time of 21.9 ± 17.7 months. On FDG PET/CT, a total of 250 lesions were analyzed. In univariate analyses, SUVmax, TLG, number of metastatic sites, serum hemoglobin and corrected calcium were significant prognostic factors. Among them, TLG remained as an independent prognostic factor in a multivariate analysis (P = 0.038). In subgroup analyses, TLG was still a significant prognostic factor in patients treated with sunitinib only and in patients on the first staging as well as restaging. CONCLUSIONS: Extrarenal metabolic tumor burden is a significant prognostic factor in advanced RCC patients treated with targeted therapy. In selection of candidates for cytoreductive surgery, the measurement of metabolic tumor burden may be effective.

Molecular imaging of mesothelioma with (99m)Tc-ECG and (68)Ga-ECG.

We have developed ethylenedicysteine-glucosamine (ECG) as an alternative to (18)F-fluoro-2-deoxy-D-glucose ((18)F-FDG) for cancer imaging. ECG localizes in the nuclear components of cells via the hexosamine biosynthetic pathway. This study was to evaluate the feasibility of imaging mesothelioma with (99m)Tc-ECG and (68)Ga-ECG. ECG was synthesized from thiazolidine-4-carboxylic acid and 1,3,4,6-tetra-O-acetyl-2-amino-D-glucopyranose, followed by reduction in sodium and liquid ammonia to yield ECG (52%). ECG was chelated with (99m)Tc/tin (II) and (68)Ga/(69)Ga chloride for in vitro and in vivo studies in mesothelioma. The highest tumor uptake of (99m)Tc-ECG is 0.47 at 30 min post injection, and declined to 0.08 at 240 min post injection. Tumor uptake (%ID/g), tumor/lung, tumor/blood, and tumor/muscle count density ratios for (99m)Tc-ECG (30-240 min) were 0.47 ± 0.06 to 0.08 ± 0.01; 0.71 ± 0.07 to 0.85 ± 0.04; 0.47 ± 0.03 to 0.51 ± 0.01, and 3.49 ± 0.24 to 5.06 ± 0.25; for (68)Ga-ECG (15-60 min) were 0.70 ± 0.06 to 0.92 ± 0.08; 0.64 ± 0.05 to 1.15 ± 0.08; 0.42 ± 0.03 to 0.67 ± 0.07, and 3.84 ± 0.52 to 7.00 ± 1.42; for (18)F-FDG (30-180 min) were 1.86 ± 0.22 to 1.38 ± 0.35; 3.18 ± 0.44 to 2.92 ± 0.34, 4.19 ± 0.44 to 19.41 ± 2.05 and 5.75 ± 2.55 to 3.33 ± 0.65, respectively. Tumor could be clearly visualized with (99m)Tc-ECG and (68)Ga-ECG in mesothelioma-bearing rats. (99m)Tc-ECG and (68)Ga-ECG showed increased uptake in mesothelioma, suggesting they may be useful in diagnosing mesothelioma and also monitoring therapeutic response.

Sulfonylurea receptor as a target for molecular imaging of pancreas beta cells with (99m)Tc-DTPA-glipizide.

OBJECTIVE: This study was aimed to assess pancreas beta cell activity using (99m)Tc-diethyleneaminepentaacetic acid-glipizide (DTPA-GLP), a sulfonylurea receptor agent. The effect of DTPA-GLP on the blood glucose level in rats was also evaluated. METHODS: DTPA dianhydride was conjugated with GLP in the presence of sodium amide, yielding 60%. Biodistribution and planar images were obtained at 30-120 min after injection of (99m)Tc-DTPA-GLP (1 mg/rat, 0.74 and 11.1 MBq per rat, respectively) in normal female Fischer 344 rats. The control group was given (99m)Tc-DTPA. To demonstrate pancreas beta cell uptake of (99m)Tc-DTPA-GLP via a receptor-mediated process, a group of rats was pretreated with streptozotocin (a beta cell toxin, 55 mg/kg, i.v.) and the images were acquired at immediately-65 min on day 5 post-treatment. The effect on the glucose levels after a single administration (ip) of DTPA-GLP was compared to glipizide (GLP) for up to 6 h. RESULTS: The structure of DTPA-GLP was confirmed by NMR, mass spectrometry and HPLC. Radiochemical purity assessed by ITLC was >96%. (99m)Tc-DTPA-GLP showed increased pancreas-to-muscle ratios, whereas (99m)Tc-DTPA showed decreased ratios at various time points. Pancreas could be visualized with (99m)Tc-DTPA-GLP in normal rat, however, (99m)Tc-DTPA has poor uptake suggesting the specificity of (99m)Tc-DTPA-GLP. Pancreas beta cell uptake could be blocked by pre-treatment with streptozotocin. DTPA-GLP showed an equal or better response in lowering the glucose levels compared to the existing GLP drug. CONCLUSIONS: It is feasible to use (99m)Tc-DTPA-GLP to assess pancreas beta cell receptor recognition. (99m)Tc-DTPA-GLP may be helpful in evaluating patients with diabetes, pancreatitis and pancreatic tumors.

Nodal status of malignant lymphoma in pelvic and retroperitoneal lymphatic pathways: comparison of integrated PET/CT with or without contrast enhancement.

AIM: To determine the diagnostic accuracy of integrated contrast-enhanced positron emission tomography (PET) and computed tomography (CT), as compared with non-contrasted PET/CT, in evaluating nodal status of malignant lymphoma in pelvic and retroperitoneal lymphatic pathways. MATERIALS AND METHODS: Sixty-six patients (33 men and 33 women) with malignant lymphoma underwent staging with integrated CT and fluorine-18-fluorodeoxyglucose ((18)FDG) PET. Tumor types were diffuse large B-cell lymphoma (n=26, 39%), follicular lymphoma (n=20, 30%), Hodgkin disease (n=16, 24%), and marginal zone B-cell lymphoma (n=4, 6%). Both non-contrasted PET/CT and contrast-enhanced PET/CT images were examined separately by two different qualified physicians for each imaging modality, and nodal status of pelvic and retroperitoneal lymphatic pathways was evaluated. Reference standard included follow-up with clinical, laboratory, and conventional CT findings. We compared diagnostic accuracy retrospectively on basis of per-patient and per-lesion analyses between two modalities using McNemar test, respectively. RESULTS: Nodal status of pelvic and retroperitoneal lymphatic pathways was more accurately determined on contrast-enhanced PET/CT (n=52, 79%) compared with non-contrasted PET/CT (n=47, 71%). Difference in the accuracy of nodal staging between non-contrasted PET/CT and contrast-enhanced PET/CT was significant (p=0.048). On basis of per-lesion analysis, contrast-enhanced PET/CT determined more accurately the status of external iliac lymph node (p=0.002), internal iliac lymph node (p<0.0001), and common iliac lymph node (p=0.002) compared with non-contrasted PET/CT. Diagnostic accuracies of paraaortic lymph node, aortocaval lymph node, and paracaval lymph node were similar by either non-contrasted PET/CT or contrast-enhanced PET/CT. CONCLUSION: Integrated contrast-enhanced PET/CT improves the diagnostic accuracy in evaluating nodal status of pelvic and retroperitoneal lymphatic pathways in patients with malignant lymphoma.

Assessment of cyclooxygense-2 expression with 99mTc-labeled celebrex.

Cyclooxygenase-2 (COX-2) plays an important role in angiogenesis and cancer progression. Since many tumor cells exhibit COX-2 expression, functional imaging of COX-2 expression using celebrex (CBX, a COX-2 inhibitor) may provide not only a non-invasive, reproducible, quantifiable alternative to biopsies, but it also greatly complements pharmacokinetic studies by correlating clinical responses with biological effects. Moreover, molecular endpoints of anti-COX-2 therapy could also be assessed effectively. This study aimed at measuring uptake of Tc-EC-CBX in COX-2 expression in tumor-bearing animal models. In vitro Western blot analysis and cellular uptake assays were used to examine the feasibility of using Tc-EC-CBX to measure COX-2 activity. Tissue distribution studies of Tc-EC-CBX were evaluated in tumor-bearing rodents at 0.5-4 h. Dosimetric absorption was then estimated. Planar scintigraphy was performed in mice, rats and rabbits bearing tumors. In vitro cellular uptake indicated that cells with higher COX-2 expression (A549 and 13762) had higher uptake of Tc-EC-CBX than lower COX-2 expression (H226). In vivo biodistribution of Tc-EC-CBX in tumor-bearing rodents showed increased tumor:tissue ratios as a function of time. In vitro and biodistribution studies demonstrated the possibility of using Tc-EC-CBX to assess COX-2 expression. Planar images confirmed that the tumors could be visualized with Tc-EC-CBX from 0.5 to 4 h in tumor-bearing animal models. We conclude that Tc-EC-CBX may be useful to assess tumor COX-2 expression. This may be useful in the future for selecting patients for treatment with anti-COX-2 agents.

Detection of acute postoperative mediastinitis in mice using (99m)Tc-liposomes.

RATIONALE AND OBJECTIVES: To evaluate the usefulness of size-modified (99m)Tc-labeled liposomes for the detection of acute postoperative mediastinitis in a mouse model. METHODS: Fourteen mice underwent low-neck collar incision and had sterile abscesses induced in mediastinum with turpentine. Ten of these animals were injected intravenously with anionic liposomes of 516 +/- 20 nm containing poly(ethylene)glycol labeled with (99m)Tc; the remaining four mice were injected with (67)Ga citrate and used as positive controls. In addition, eight mice either underwent the same surgical procedure but without turpentine (n = 4) or were not operated (n = 4). These were used as negative controls. Therefore, scintigraphy using (99m)Tc-liposomes was performed in eighteen and (67)Ga citrate in four mice. Target area of interest was outlined, and target to background count density ratio and percentage-injected dose were measured. RESULTS: Significant accumulation of radiolabeled liposomes was observed at sites of inflammation within 1 hour in abscess-bearing animals. This correlated well with the findings of the lower quality (contrast) of (67)Ga images at 24 and 48 hours. The radiopharmaceutical did not significantly accumulate in the mediastinum of negative control animals. CONCLUSION: (99m)Tc-liposomes (size modified) may prove useful nonspecific agent for the early diagnosis of postoperative mediastinitis.