A novel tract imaging technique of the brainstem using phase difference enhanced imaging: normal anatomy and initial experience in multiple system atrophy

Objectives

To develop a new tract imaging technique for visualising small fibre tracts of the brainstem and for detecting the abnormalities in multiple system atrophy of the cerebellar type (MSA-C) using a phase difference enhanced (PADRE) imaging technique, in which the phase difference between the target and surrounding tissue is selectively enhanced.

Methods

Two neuroradiologists compared the high-spatial-resolution PADRE imaging, which was acquired from six healthy volunteers, three patients with MSA-C, and 7 patients with other types of neurodegenerative diseases involving the brainstem or cerebellum.

Results

Various fine fibre tracts in the brainstem, the superior and inferior cerebellar peduncles, medial lemniscus, spinothalamic tract, medial longitudinal fasciculus, central tegmental tract, corticospinal tract and transverse pontine fibres, were identified on PADRE imaging. PADRE imaging from MSA-C demonstrated the disappearance of transverse pontine fibres and significant atrophy of the inferior cerebellar peduncles, while the superior cerebellar peduncles were intact. PADRE imaging also demonstrated that the transverse pontine fibres and inferior cerebellar peduncle were not involved in the other neurodegenerative diseases.

Conclusion

PADRE imaging can offer a new form of tract imaging of the brainstem and may have the potential to reinforce the clinical utility of MRI in differentiating MSA from other conditions.     

Uncommon cases of immature-type CD56+ natural killer (NK)-cell neoplasms, characterized by expression of myeloid antigen of blastic NK-cell lymphoma

Immature-type CD56⁺ natural killer (NK)-cell neoplasms are classified as either myeloid/NK-cell precursor acute leukemia or blastic NK-cell lymphoma. We identified two cases of immature-type CD56⁺ NK-cell neoplasms that were not categorizable as either of these entities. The first case involved a 74-year-old woman presenting with skin eruptions and pancytopenia due to bone marrow necrosis. Skin biopsy specimen revealed CD4⁺, CD7⁻, CD34⁻, CD43⁺, CD56⁺, CD68⁺, muramidase (lysozyme)⁺, and myeloperoxidase (MPO)⁻, and immunophenotyping of peripheral blood showed CD4⁺, CD7⁻, CD13⁺, CD33⁺, CD34⁻, CD43⁺, CD56⁺, cytoplasmic (cy)CD68⁺, CD123⁺, and HLA-DR⁺. The second case involved a 62-year-old man who had bilateral optic nerve tumor and presented with malignant cells in peripheral blood. Cell surface markers of malignant cells showed CD4⁺, CD7⁻, CD13⁺, CD33⁺, CD34⁻, CD43⁺, CD56⁺, cyCD68⁺, and HLA-DR⁺. The phenotypes of tumor cells in both cases were compatible with blastic NK-cell lymphoma, except for the expression of myeloid antigen. Clinical presentations of these cases showed characteristics of both blastic NK-cell lymphoma and myeloid/NK-cell precursor acute leukemia.     

Adult T-cell leukemia/lymphoma in a 21-year-old man

Adult T-cell leukemia/lymphoma (ATL) is malignancy of mature T cells that caused by infection with human T-cell leukemia virus type I (HTLV-I). Leukemogenesis of ATL cells considered to involve a multistep oncogenic process, resulting in a very long latency period. But, we report here the case of a 21-year-old man having suffered from recurrent stomatititis who has already developed acute-type ATL. ATL generally occurs after a long latency period, and the present case in a young man is thus very rare.     

Bortezomib, doxorubicin and intermediate-dose dexamethasone (iPAD) therapy for relapsed or refractory multiple myeloma: a multicenter phase 2 study

We previously conducted a phase 1 study of bortezomib, doxorubicin and intermediate-dose dexamethasone (iPAD) therapy and determined the optimal dose of bortezomib to be 1.0 mg/m². We then conducted a multicenter phase 2 study in patients with relapsed or refractory myeloma. Bortezomib 1.0 mg/m² was administered intravenously on days 1, 4, 8 and 11, in combination with intravenous doxorubicin 9 mg/m² on days 1–4, and dexamethasone 20 mg orally on days 1–2, 4–5, 8–9 and 11–12 at a 3-week interval for six cycles. The primary endpoint of this study was the complete remission (CR) rate, and the secondary endpoints were progression-free survival (PFS), overall survival (OS) and toxicity. Twenty-seven patients, median age of 63, were enrolled. An overall response rate was 89 % with CR rate of 30 %. The median PFS time was 12.1 months, and the median OS time was not reached. One patient died of pneumonia. Although the incidence of hematological toxicities was high, these were transient and manageable. The most common non-hematological toxicity was sensory neuropathy; grade 3 toxicity was observed in six patients (22 %) and treatment was discontinued in four. We conclude that iPAD therapy is feasible, and shows efficacy by inducing high response rates and long response duration.     

ROC Analysis of Detection of Metastatic Pulmonary Nodules on Digital Chest Radiographs with Temporal Subtraction

RATIONALE AND OBJECTIVES: The authors' purpose was to evaluate the effect of temporal subtraction on digital chest radiographs in the detection of metastatic pulmonary nodules. MATERIALS AND METHODS: The study included 21 cases with metastatic pulmonary nodule and 21 cases without metastatic nodule. Eleven radiologists, including eight residents and three certified radiologists, provided their confidence levels for the presence or absence of pulmonary nodules without and with temporal subtraction. Their performances without and with temporal subtraction were evaluated by means of receiver operating characteristic analysis with both independent and sequential tests. RESULTS: For the independent test, the radiologists' Az (area under the receiver operating characteristic curve) values were 0.871 without and 0.954 with temporal subtraction, compared with 0.882 and 0.955, respectively, for the sequential test. Diagnosis accuracy was significantly improved with the use of temporal subtraction. There was no significant difference in Az values between the independent and sequential tests. CONCLUSION: Temporal subtraction is useful in the detection of metastatic pulmonary nodules, and this technique augments the value of digital chest radiography.     

Clinicopathological studies of the gastrointestinal tract in adult T-cell leukemia patients

We analysed the digestive symptoms and the gastrointestinal (GI) tract lesions in 61 patients with adult T cell leukemia (ATL). Digestive symptoms were found in 36 patients (59.0%) at the onset of leukemia, and in 45 patients (73.8%) at the first medical examination. X-ray examination of the GI tract was made in 22 patients, and abnormal stomach mucosa patterns were found in 20 patients (90.9%). Endoscopic examination of the GI tract was carried out in 18 patients, and it revealed that most of the stomach mucosa was accompanied by edema and redness. Erosions and ulcers also were found in many patients. A granular shadow, which was noted during the x-ray examination, could not be confirmed by endoscopy. A pathological examination of biopsied specimens was made in 13 patients, and infiltration of leukemic cells into the stomach was observed in 10 of the 13 cases. These findings suggest that leukemic infiltration into digestive tracts is related to the development of digestive symptoms in ATL patients.     

Interim decision-making strategies in adaptive designs for population selection using time-to-event endpoints

Adaptive designs in oncology clinical trials with interim analyses for population selection could be used in the development of targeted therapies if a predefined biomarker hypothesis exists. In this article, we consider an interim analysis using overall survival (OS), progression-free survival (PFS), and both OS and PFS, to determine whether the whole population or only the biomarker-positive population should continue into the subsequent stage of the trial, whereas the final decision is made based on OS data only. In order to increase the probability of selecting the most appropriate population at the interim analysis, we propose an interim decision-making strategy in adaptive designs with correlated endpoints considering the post-progression survival (PPS) magnitudes. In our approach, the interim decision is made on the basis of predictive power by incorporating information on OS as well as PFS to supplement the incomplete OS data. Simulation studies assuming a targeted therapy demonstrated that our interim decision-making procedure performs well in terms of selecting the proper population, especially under a scenario in which PPS affects the correlation between OS and PFS.     

Inhibition of cytosolic phospholipase A(2) suppresses production of cholesteryl ester through the reesterification of free cholesterol but not formation of foam cells in oxidized LDL-stimulated macrophages

Macrophage-derived foam cells are formed as a result of the accumulation of cholesteryl ester (CE) not only in cytoplasm where CE is produced by the reesterification of free cholesterol derived from oxidized low density lipoprotein (OxLDL) undergoing hydrolysis, but also in lysosomes where the remaining CE of OxLDL is deposited. We examined the possible involvement of cytosolic phospholipase A(2)s (cPLA(2)s) in the production of CE through the reesterification and in the formation of foam cells. In [(3)H]oleic acid-labeled human acute monocytic leukemia (THP-1) cell-derived macrophages (THP-M) and mouse peritoneal macrophages (MPM), which possessed at least cPLA(2)alpha and cPLA(2)gamma, stimulation with OxLDL induced the production of [(3)H]cholesteryl oleate ([(3)H]CE).The production was suppressed by an inhibitor of cPLA(2)s. However, the inhibitor tended to slightly decrease total intracellular levels of CE, and did not affect the formation of foam cells, as estimated by staining with Oil Red O. In cPLA(2)alpha-knockout MPM, OxLDL-induced increases in [(3)H]CE and total CE did not differ from those in wild-type MPM. Our results suggest that cPLA(2)s other than cPLA(2)alpha contribute to the supply of fatty acids, which are utilized for the production of CE through the reesterification, in OxLDL-stimulated macrophages. However, the formation of foam cells could not be inhibited only by the suppression of cPLA(2)-mediated CE production.     

Negative myoclonus in Creutzfeldt-Jakob disease.

OBJECTIVE: To describe electrophysiological findings in a patient with Creutzfeldt-Jakob disease (CJD) showing negative myoclonus. METHODS AND RESULTS: We studied this CJD patient electrophysiologically, in comparison with two patients with cortical reflex positive myoclonus due to benign adult familial myoclonic epilepsy (BAFME). Spontaneous negative myoclonus was associated with periodic synchronous discharges (PSDs) on the electroencephalogram, but negative myoclonus could also be induced by electrical stimulation of the median nerve in the CJD patient. This patient showed giant somatosensory evoked potentials (SEPs) and enhanced C reflexes, and the duration of the induced EMG silences was found to be significantly correlated with the amplitude of cortical SEPs. The duration of silent periods (SPs) produced by magnetic stimulation of the motor cortex was extremely long. The study of recovery function of SEPs suggested that the excitability of the somatosensory cortex was decreased during a long post-stimulus period. These findings were clearly different from those of patients with BAFME. CONCLUSIONS: This CJD patient had two types of negative myoclonus; one was associated with PSDs and the other was cortical reflex negative myoclonus. The long-lasting decrease in excitability of the sensorimotor cortices after stimulation could be related to the occurrence of both types of negative myoclonus.