Joji Kawabe

Neuroinflammation in Patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: An 11C-(R)-PK11195 PET Study

Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a disease characterized by chronic, profound, disabling, and unexplained fatigue. Although it is hypothesized that brain inflammation is involved in the pathophysiology of CFS/ME, there is no direct evidence of neuroinflammation in patients with CFS/ME. Activation of microglia or astrocytes is related to neuroinflammation. 11C-(R)-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline-carboxamide (11C-(R)-PK11195) is a ligand of PET for a translocator protein that is expressed by activated microglia or astrocytes. We used 11C-(R)-PK11195 and PET to investigate the existence of neuroinflammation in CFS/ME patients. Methods: Nine CFS/ME patients and 10 healthy controls underwent 11C-(R)-PK11195 PET and completed questionnaires about fatigue, fatigue sensation, cognitive impairments, pain, and depression. To measure the density of translocator protein, nondisplaceable binding potential (BPND) values were determined using linear graphical analysis with the cerebellum as a reference region. Results: The BPND values of 11C-(R)-PK11195 in the cingulate cortex, hippocampus, amygdala, thalamus, midbrain, and pons were 45%–199% higher in CFS/ME patients than in healthy controls. In CFS/ME patients, the BPND values of 11C-(R)-PK11195 in the amygdala, thalamus, and midbrain positively correlated with cognitive impairment score, the BPND values in the cingulate cortex and thalamus positively correlated with pain score, and the BPND value in the hippocampus positively correlated with depression score. Conclusion: Neuroinflammation is present in widespread brain areas in CFS/ME patients and was associated with the severity of neuropsychologic symptoms. Evaluation of neuroinflammation in CFS/ME patients may be essential for understanding the core pathophysiology and for developing objective diagnostic criteria and effective medical treatments.

Diagnostic usefulness of FDG PET for pancreatic mass lesions

The purpose of this study was to investigate the feasibility of [18F]2-deoxy-2-fluoro-d-glucose (FDG) positron emission tomography (PET) in patients with a pancreatic mass by comparing the results with those of X-ray computed tomography (CT) and magnetic resonance (MR) imaging.Methods: Eighty-six patients with pancreatic lesions, included 65 malignant tumors and 21 benign masses (55 masses were proven histologically and the others were diagnosed clinically), were studied. The diagnostic factors of CT and MR imaging were evaluated, and those of FDG PET were also evaluated for malignant and benign masses by visual interpretation and quantitative interpretation with the standardized uptake value (SUV) and SUV gluc which was designed to reduce the effects of a high blood sugar level. Visual interpretations were evaluated only in FDG PET images, and quantitative interpretations were evaluated by referring to CT and/or MR imaging. The correlation between SUV and the degree of histological differentiation in pancreatic ductal adenocarcinoma was investigated.Results: Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy for CT imaging were 91, 62, 88, 68 and 84%, and for MR imaging 78, 70, 88, 54 and 76%, respectively. In visual interpretation of FDG PET images, the sensitivity, specificity, PPV, NPV and accuracy were 82, 81, 93, 59 and 81%, respectively. Significant differences between malignant and benign lesions existed in SUV and SUV gluc (p<0.0001, each). With the cutoff value of SUV as 2.1 and SUV gluc as 2.2, the accuracy of diagnosis was maximal. With that cutoff value, the sensitivity, specificity, PPV, NPV and accuracy for SUV were 89, 76, 92, 70 and 86%, and for SUV gluc 91, 76, 92, 73 and 87%, respectively. The sensitivity and NPV of SUV gluc were higher than those of SUV, which suggests that SUV gluc may be more useful in reducing the number of overlooked malignant tumors. The specificity and PPV of FDG PET were superior to those of CT and MR imaging. There were no significant differences between the SUVs of moderately differentiated adenocarcinomas and those of well differentiated adenocarcinomas.Conclusion: To improve the diagnostic procedure for classifying masses, FDG PET with not only SUV but also SUV corrected by the blood sugar level is required in addition to morphological diagnosis by CT and/or MR imaging.

Clinical usefulness of positron emission tomography with fluorine-18-fluorodeoxyglucose in the diagnosis of liver tumors

We studied various liver tumors by positron emission tomography with fluorine-18 fluorodeoxyglucose (FDG-PET) to examine the diagnostic usefulness of this technique. We also examined the relation between findings on FDG-PET and the characteristics of hepatocellular carcinoma.FDG-PET was performed in 78 patients with liver tumors, including 53 with primary liver cancer [48 hepatocellular carcinomas (HCC) and 5 cholangiocellular carcinomas (CCC)], 20 with metastatic liver cancer, 2 with liver hemangioma, and 3 with focal nodular hyperplasia. For quantitative evaluation, a region of interest (ROI) was placed over the entire tumor region, at the level of the maximum diameter of the tumor. A background ROI was then placed over the non-tumor region of the liver. The average activity within each ROI was subsequently corrected for radioactive decay, and the standardized uptake value (SUV) was calculated by dividing the tissue activity by the injected dose of radioactivity per unit body weight. SUV ratio was expressed as the tumor-to-non-tumor ratio of the SUV.The median SUV was significantly lower in HCC than in metastatic live cancer or CCC, and the median SUV ratio was significantly lower in HCC than in metastatic liver cancer or CCC. The median SUV was not higher in multiple HCC than in single HCC, but the median SUV ratio was significantly higher in multiple HCC than in single HCC. The median SUV and the median SUV ratio were significantly higher in the presence of portal vein thrombosis than in the absence of such thrombosis. The Cancer of the Liver Italian Program score and the α-fetoprotein value correlated significantly with both the SUV and SUV ratio. These results suggest that FDG-PET is clinically useful not only for the differential diagnosis of liver tumors but also for evaluation of the clinical characteristics of HCC.

Evaluation of treatment effects in brain abscess with positron emission tomography: comparison of fluorine-18-fluorodeoxyglucose and carbon-11-methionine.

Positron emission tomography (PET) imaging is in common use preoperatively to clinically evaluate patients who present with central nervous system mass lesions. The usefulness of PET is also recognized as a method to detect intracranial tumorous lesions. A number of papers report that some inflammatory processes also showed the uptake of Fluorine-18-Fluorodeoxyglucose (FDG) and Carbon-11-Methionine (Met) tracers. We performed two PET studies before and after treatment in 4 patients with brain abscess. PET showed the uptake of both tracers to the brain abscess before treatment. The area showing an increased uptake of Met corresponded closely to the enhanced area on both CT and MR images. FDG-PET visually showed an uptake of FDG in a small area corresponding to an enhanced lesion within the CT and MR images. After treatment the area of lesions became small on enhancement CT or MRI and both PET studies showed reduced lesion and decreased uptake. The mechanism of Met uptake in the inflammatory area may be related to the higher metabolic rate and the active transport of amino acids as well as disruption of the blood brain barrier. Furthermore, it appears that the mechanism of FDG uptake is also related to a higher metabolic rate and, in addition, is related to the increased density of inflammatory cells. PET studies, more directly, reflect the degree of inflammatory response in brain abscess than enhancement CT or MRI. Therefore, PET is useful in detecting the inflammatory lesion and assessing the clinical effects of antibiotics treatment on brain abscesses.

Fluorine-18 Fluorodeoxyglucose Positron Emission Tomography Imaging of Parotid Mass Lesions

Using X-ray CT or magnetic resonance imaging (MRI), fluorine-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) studies were performed in 28 patients with parotid lesions. All lesions except two showed higher accumulation of FDG than normal parotid gland. High accumulation was found in all of 5 carcinomas, all of 6 Warthins tumors, and 8 of 12 pleomorphic adenomas, with standardized uptake values (SUVs) over 3.0. The mean SUVs of carcinomas, Warthins tumors, and pleomorphic adenomas were 5.92 +/- 2.05, 7.03 +/- 2.49, and 4.07 +/- 1.55, respectively. On the other hand, all 5 inflammatory lesions demonstrated low accumulation, with mean SUVs of 1.66 +/- 0.89. It is thus difficult to differentiate malignant from benign parotid lesions by SUV on FDG-PET.

Correlation of amino-acid uptake using methionine PET and histological classifications in various gliomas

ObjectiveThe uptake of L-methyl-11C-methionine (MET) by gliomas is greater than that by intact tissue, making methionine very useful for evaluation of tumor extent. If the degree of malignancy of brain tumors can be evaluated by MET-PET, the usefulness of MET-PET as a means of diagnosing brain tumors will increase.MethodsWe performed this study on 67 glioma patients between 3 and 69 years of age (36 males and 31 females). Tumors included diffuse astrocytoma, anaplastic astrocytoma, glioblastoma, ependymoma, oligodendroglioma, medulloblastoma, dysembryoplastic neuroepithelial tumor, choroid plexus papilloma, central neurocytoma, optic glioma, gliomatosis cerebri, pleomorphic xanthoastrocytoma, and ganglioglioma. Tumor activity and degree of malignancy were evaluated using Ki-67LI (LI: labeling index) and Kaplan-Meier survival curves. The correlations between methionine uptake and tumor proliferation (tumor versus contralateral gray matter ratio (T/N) and Ki-67LI) were determined for the group of all subjects. The existence of significant correlations between T/N and KJ-67LI and between SUV and Ki-67LI was determined for astrocytic tumors. Receiver operating characteristics (ROC) analysis of T/N and standardized uptake value (SUV) was performed for the group of astrocytic tumors. We also determined the ROC cut-off levels to ensure high accuracy of the analysis.ResultsFor the 67 cases of glioma, the degree of accumulation was variable. Ki-67LI differed significantly between the high-grade group and low-grade group at T/N levels between 1.5 and 1.8 on analysis using tumor proliferative potential (p - 0.019–0.031). The prognosis differed significantly between the highgrade and low-grade groups when T/N was in the range of 1.6–1.8 (p = 0.028–0.032). The accuracy thus calculated was highest (85.7%) when T/N was 1.5 as determined by ROC analysis.ConclusionsWhen analysis was confined to cases of astrocytic tumor, a correlation was noted between methionine accumulation and Ki-67LI. For the astrocytic tumors, T/N ratio seemed to be more useful as a diagnostic indicator than SUV. The cut-off level of T/N ratio for distinction between high-grade and low-grade astrocytoma appears to lie between 1.5 and 1.6.

Distinguishing benign from malignant gallbladder wall thickening using FDG-PET.

ObjectiveBecause thickening of the gallbladder wall is observed not only in patients with gallbladder cancer but also in those with benign diseases such as chronic cholecystitis and gallbladder adenomyosis, it is difficult to distinguish between benign and malignant gallbladder wall thickening by conventional techniques of diagnostic imaging such as computed tomography (CT), magnetic resonance imaging (MRI), and abdominal ultrasonography (US). In the present study, we attempted to distinguish between benign and malignant gallbladder wall thickening by means of fluorine- 18-fluorodeoxyglucose (FDG)- Positron emission tomography (PET).MethodsFDG-PET was performed in 12 patients with gallbladder wall thickening detected by CT or US, to determine whether it was benign or malignant. Emission scans were taken, beginning 45 minutes after intravenous administration of FDG, and SUV was calculated as an indicator of glucose metabolism.ResultsOf the 12 patients, 4 showed positive uptake of FDG in the gallbladder wall. Of these 4 patients, 3 had gallbladder cancer. The remaining one, who had chronic cholecystitis, had false-positive findings. The other 8 patients had negative uptake of FDG in the gallbladder wall. Two of these 8 underwent surgical resection, which yielded a diagnosis of chronic cholecystitis. The other 6 patients exhibited no sign of gallbladder malignancy and have been followed without active treatment.ConclusionsFDG-PET appears able to distinguish between benign and malignant gallbladder wall thickening.

Monitoring of Response to Radiotherapy with Fluorine-18 Deoxyglucose PET of Head and Neck Squamous Cell Carcinomas

We examined the usefulness of positron emission tomography (PET) using fluorine-18 deoxyglucose (FDG) in determining the therapeutic effects of irradiation and chemotherapy on head and neck malignant tumors. Twenty-two patients with head and neck lesions who underwent histological examinations were studied. Squamous cell carcinoma was histologically diagnosed in all cases. Sixteen of them underwent radiotherapy with approximately 40 Gy in combination with carboplatin therapy. The remaining 6 patients underwent radiotherapy alone. After these treatments, 11 underwent surgery. For PET study, each patient was injected with intravenous FDG 185-370 MBq. We evaluated the degree of FDG accumulation using scanned images taken 40-55 min after the injection. We measured the standardized uptake value (SUV), a semiquantative evaluation, ROI activity divided by the dosage per weight of each patient. FDG-PET, CT and MRI were performed twice for each patient, before and after treatment. FDG uptake, but not the tumor size in CT or MRI, was significantly reduced in each patient after the treatment. Therefore, our findings have clearly demonstrated that FDG-PET provides for more valuable therapeutic outcomes than conventional imaging such as CT and MRI. FDG-PET should thus provide a new dimension in the management of head and neck malignant tumors.

A Randomized Pilot Trial of Oral Branched-Chain Amino Acids in Early Cirrhosis: Validation Using Prognostic Markers for Pre-Liver Transplant Status

Because of the chronic shortage of liver donors, hepatologists are required to prolong the liver transplant waiting period by preserving the hepatic reserve of scheduled recipients. This study examined the effectiveness of oral branched‐chain amino acids (BCAAs), using outcome markers indicating pretransplant hepatic reserve. Fifty‐six consecutive eligible patients with Child class A cirrhosis without major complications were randomly assigned to receive oral BCAA granules (12.45 g/day) for least 1 year or no BCAAs. Differences between groups in the Model for End‐Stage Liver Disease (MELD) score, Child‐Turcotte‐Pugh (CTP) score, asialoscintigraphic clearance index (CI), and complications were examined. Of 50 remaining patients, 27 received BCAAs, and 23 received no BCAAs (mean duration, 3.2 years). The mean annual changes in the MELD score, CTP score, and asialoscintigraphic CI were smaller in the BCAA group than in the control group (−0.06 ± 0.23 versus 0.10 ± 0.40, P = 0.024, 0.06 ± 0.30 versus 0.30 ± 0.48, P = 0.037, and 0.00 ± 0.02 versus 0.02 ± 0.04, P = 0.040, respectively). The mean annual changes in the serum total bilirubin and the serum albumin in the BCAA group were better preserved than those in the control group (−0.07 ± 0.20 versus 0.12 ± 0.18 mg/dL, P < 0.001, and 0.07 ± 0.13 versus −0.02 ± 0.19 g/dL, P = 0.005, respectively); other laboratory variables were not significant. The incidence of overall major cirrhotic complications was lower in the BCAA group than in the control group [14.8% (4 of 27 patients) versus 30.4% (7 of 23 patients) at 3 years, P = 0.043]; only ascites was significant individually. In conclusion, early interventional oral BCAAs might prolong the liver transplant waiting period by preserving hepatic reserve in cirrhosis. Liver Transpl 15:790–797, 2009.

A case of hepatic inflammatory pseudotumor identified by FDG-PET

A 53-year-old man with a history of nausea and elevated liver functions presented to our clinic. A CT scan showed a small tumor in the right lobe of the liver. Fluorine-18-fluorodeoxyglucose (18F-FDG) positron emission tomography confirm abnormal metabolic activity with a high standardized uptake value of 7.3 in the lesion. These findings could indicate a malignancy such as well-differentiated hepatocellular carcinoma or cholangiocarcinoma, or a benign lesion such as hepatic abscess. He was diagnosed by histopathological examination as having an epithelioid granuloma with many inflammatory cells. This is the rare report of hepatic inflammatory pseudotumor featuring markedly increased18F-FDG uptake.