Pulmonary vein isolation under direct visual identification of the left atrium-pulmonary vein junction using intra-cardiac echography.

INTRODUCTION: Intra-cardiac echocardiography (ICE) which has some benefits, can be used to obtain detailed anatomy of the heart chambers or large vessels, and the catheter positions, and it has been considered useful for improving the outcome of the ablation. In the present study, we performed pulmonary vein isolation (PVI) under real time monitoring of ICE imaging utilizing an ICE catheter placed at the junction of the left atrium (LA) and PVs (LA-PV junction). METHODS: PVI for atrial fibrillation (AF) was performed in 30 cases with drug-resistant AF (mean age: 66-years-old; including 22 males). An ICE catheter utilizing a 9 MHz frequency was inserted into the LA via the atrial septum, and placed at the LA-PV junction. Circumferential ablation was performed in the LA outside of the PV ostium, encircling both the superior and inferior ostia together under ICE imaging. RESULTS: The anatomy of the LA to the PVs and catheter sites were clearly identified by the ICE during the procedure, which enabled a precise and safe catheter manipulation with minimal fluoroscopy. Further, the wall thickness of the PV and LA, and position of the esophagus could be obtained by ICE, facilitating care in adjusting the power and/or duration of the current delivery. CONCLUSION: ICE imaging of the LA-PV junction permitted real time monitoring of the target sites for PVI during the ablation procedure, and was considered a useful technique for performing PVI.

[Primary pineal embryonal carcinoma occurring in a middle aged man].

A case of a primary pineal embryonal carcinoma occurring in a middle aged man is reported. A 42-year-old man suffering from headache and nausea was referred to our department. A neurological examination revealed that he had Parinaud's sign. Head CT and MRI showed a tumor in the pineal region. He was operated on using the occipital trans-tentorial approach. The tumor was partially removed and an intra-operative specimen was used to diagnose a kind of germ cell line tumor. However, the tumor was diagnosed afterwards as a pure embryonal carcinoma. Three courses of PE chemotherapy followed by 30 Gy of whole craniospinal irradiation and 30 Gy of extended local irradiation were completed. An MRI showed the tumor to be in complete remission. Despite careful follow-up with chemotherapy every three months, a re-operation and linac radio-surgery, the tumor recurred, and disseminated. The patient died due to an intra-tumoral hemorrhage. A pure primary pineal embryonal carcinoma occurring in a middle-aged person has never been reported previously in detail.

Possible mechanism of ECG features in patients with idiopathic ventricular fibrillation studied by heart model and computer simulation.

The possible contribution of localized conduction delay and abnormal action potentials to ventricular fibrillation (VF) was studied by applying an anisotropic cardiac computer model to clinical cases of the Brugada-type electrocardiogram (ECG), which shows right bundle branch block (RBBB), a normal QT interval, ST-segment elevation, and late r' in leads V1 and V2. The anisotropic heart model was composed of 50,000 discrete units with a spatial resolution of 1.5 mm and was mounted in a human torso model. The longitudinal/transverse conduction velocity ratio was 3:1. For the normal ECG, a conduction velocity of 0.75 m/s was required. In the abnormal area of the right anterior epicardial wall, the conduction velocity was set at 0.2 m/s, with decreasing action potential amplitude and 10% prolonged action potential duration. The ECG features of ST-segment elevation and Brugada-type right bundle branch block pattern were simulated. The action potential duration was able to change dynamically with coupling interval of stimulation, with a ratio of 9% for normal ventricular muscle and 50% for Purkinje fibers. Five successive stimuli were applied to the left lateral epicardium 300 ms after the first sinus excitation, and sustained VF was induced with the transmural conduction delay at the right anterior ventricle as a block increasing the vulnerability. At the initiation of VF, reentry circuits were shown around the border zone of the right epicardium and were very heterogeneous around the conduction delayed area and septal area. In an area with the characteristics of nontransmural conduction delay, sustained VF was prevented, and the pattern of transient right bundle branch block appeared on the simulated ECG and body surface potential maps. The late r' wave was calculated in the precordial leads and right anterior site on the body surface potential maps. These results suggest that increased multipolarity in the border zone between the Purkinje fibers and delayed conduction area in the right ventricle might play an important role as a functional block for the persistence of VF.

Usefulness of MRA in the Treatment of Dural AVM.

SUMMARY: We report 5 cases of dural AVMs, in which MRA images were considered very useful for evaluating the effectiveness of treatments, such as transvenous embolization therapy. MRA by time of flight method (TOF) with contrast medium for dural AVMs involving the cavernous sinus (dural CCFs) is necessary to assess the caliber of superior ophthalmic veins (SOVs) prior to treatment as well as immediately after treatment and during follow-up. MRA for dural AVM at the transverse-sigmoid sinus is useful for verifying thrombosed sinus in the dural AVM prior to transvenous embolization therapy and necessary to determine the approach to the nidus of the dural AVM(2).

Human glioma-derived interleukin-10 inhibits antitumor immune responses in vitro.

Intracranial malignant gliomas are sequestered from the immune system yet are associated with broad suppression of host immunocompetence. Immune system dysfunction in patients with gliomas seems to be related to inhibitory mediators produced by glioma cells. We investigated the physiological roles of glioma-derived interleukin (IL)-10 in Class II expression of monocytes, cytokine secretion from lymphocytes, and T cell proliferation in vitro. We could detect the messenger ribonucleic acid transcript of IL-10 in four gliomas by the reverse-transcribed polymerase chain reaction. Glioma-derived IL-10 greatly down-regulated human lymphocyte antigens-DR expression on monocytes. The inhibitory effect of IL-10 on interferon-gamma and tumor necrosis factor-alpha was neutralized by the anti-IL-10 monoclonal antibody; however, the inhibitory effect on IL-2 was not neutralized. Next, supernatants of glioma cells remarkably suppressed T cell proliferation in a dose-dependent fashion; however, this inhibitory effect was not restored by adding anti-IL-10 monoclonal antibodies. The supernatant also inhibited the allocytolytic activity of lymphocytes that were not neutralized by anti-IL-10 monoclonal antibody. IL-10 plays an important role in cytokine synthesis; nevertheless, impaired T cell responsiveness cannot be solely explained by glioma-derived IL-10.

Effects of early coronary reperfusion on the time course of signal-averaged electrocardiogram after myocardial infarction and its relation to late arrhythmic events, effects of early coronary reperfusion on signal-averaged ECGs.

The effect of early reperfusion on the time course of signal-averaged ECG was examined in 90 patients with myocardial infarction. Abnormal signal-averaged ECG disappeared more frequently (p < 0.05) and earlier in cases with early reperfusion than in those without. Serious arrhythmic events in the late phase (> 7 days) occurred in patients with abnormal signal-averaged ECG, but not in cases with early reperfusion. These results indicate that dynamic changes in tissue structure and the physiological state of viable muscles after early reperfusion produce different time courses for signal-averaged ECG. The risk of arrhythmic events among patients with abnormal signal-averaged ECG seems to be lower in cases with early reperfusion than in those without.

[Spectro-temporal mapping (STM)].

In recent years, various kinds of time-varying spectral analysis which estimate the frequency content of a signal as a function of time have been proposed. Spectro-temporal mapping (STM) is one of such methods with elaborate modification of a simple fixed period analysis. Merits and demerits of this method in clinical application are described in this chapter. Certain technical aspects pertinent to the interpretation of STM were also discussed. In conclusion, STM in present form is inferior to time domain analysis for the prediction of serious ventricular arrhythmias. But it has some usefulness to supplement time domain analysis in noise detection and application to patients with broad QRS complex.

Primary peripheral-postthymic T-cell lymphoma in the central nervous system: immunological and molecular approaches to diagnosis.

Primary intracranial T-cell lymphoma is a very rare clinical entity, and only limited biological studies of this disease have been undertaken. A tumor specimen from a patient with a primary leptomeningeal and perivascular presentation of a T-cell lymphoma was analyzed using cellular and molecular techniques. Frozen sections of the sample were examined by immunohistochemical techniques using monoclonal antibodies to phenotypic marker antigens expressed on human lymphoid cells. Intercellular adhesion molecules expressed on the tumor were studied, as was expression of messenger ribonucleic acid (mRNA) transcripts of the T-cell receptor variable alpha and beta chain genes. The immunophenotypical analysis of lymphoma revealed that the tumor expressed CD2, CD3, CD4, CD5, CD25 and HLA-DR. In addition, all of the adhesion molecules studied (ICAM-1, LFA-3, VLA-1, CD11a, CD11b, and CD11c) were detected on the cell surface. Polymerase chain reaction amplification of mRNA from the tumor demonstrated 10 V alpha and three V beta T-cell receptor subfamilies, indicating that this tumor was a low-grade well-differentiated helper type of peripheral T-cell lymphoma of the central nervous system. In addition, the tumor was derived from multiple T-cell lineages.

Shared amino acid sequences in the ND beta N and N alpha regions of the T cell receptors of tumor-infiltrating lymphocytes within malignant glioma.

The purpose of this study was to assess the V-(D)-J junctional region of the T cell receptor (TCR), the CDR3 region, which is responsible for glioma-specific antigen contact in alpha beta TCR-mediated recognition. We sequenced the TCR alpha and beta chains of V alpha 7, and V beta 13.1 cDNA derived from tumor-infiltrating lymphocytes (TIL) of 12 glioma patients and also the corresponding clones from the patients' peripheral blood lymphocytes (PBL). A shared V beta 13.1 DJ sequence of the CDR3 region, ND beta N, was demonstrated in 49 of 66 V beta 13.1+ clones (74.2%) from the glioma TIL, whereas only 4 of 33 clones (12.1%) were observed in the V beta 13.1+ clones from the PBL (p < 0.001). A common VDJ sequence, FCASS (V beta 13.1)-YRLPWGTSDS (ND beta N)-GELFF (J beta 2.2), was observed not only in the gliomas from each patient, but also among all the patients with a preference for V beta 13.1. In contrast, the amino acid sequences of the V beta 13.1+ PBL clones were diverse and random. Next, we sequenced subclones from other V beta subfamilies randomly selected to compare their VDJ region rearrangements (V beta 3 and V beta 5.1). In contrast to V beta 13.1, the amino acid sequences of these junctional regions were completely different in these subclones. The V-J junctional region of the alpha chain is dominated by a few clones in some patients, and no shared amino acid sequences were detected in the TCR V alpha junctional region. However, in the N alpha region of the V alpha 7-bearing TIL clones, arginine was used in 27 of 44 clones (61.4%) compared to only 3 of 12 clones from the PBL (p < 0.05). These results are consistent with the hypothesis that a clonal expansion/accumulation of glioma lineage-specific T cells occurred in vivo at the tumor site and that these T cells may be recognizing glioma-specific antigens.

Targeting therapy for glioma by LAK cells coupled with bispecific antibodies.

Targeting of T cells or natural killer (NK) cells to tumours by using bispecific antibodies has attracted increasing interest in the past few years. We treated 31 patients with malignant glioma using adoptive transfer of lymphokine-activated killer (LAK) cells coupled to a bispecific antibody (anti-CD3+anti-glioma) as post-operative adjuvant therapy. Although this study excluded patients with deeply-seated tumours or a poor performance status, approximately 50% of the patients remained alive after 3 years, and 40% were free of recurrence. Serial CT scans revealed disappearance of remnant tumours in some patients. In addition, CT-guided stereotactic biopsy of the tumour in 3 patients showed extensive necrosis and degeneration after specific targeting therapy (STT). Five patients developed acute infection, and one of them died of bacterial meningitis. Our results suggest that antibody-targeted LAK therapy can achieve a higher response rate in patients with standard LAK therapy or any type of conventional treatment.

Interleukin regulation of prolactin and corticotropin from pituitary adenoma.

Recent findings indicate that lymphokines, leukocyte-derived hormones, interact with the hypothalamic-pituitary axis. We examined the role of neurotrophic lymphokines in the neuroendocrine system. Specifically, the action of Interleukin (IL)-1b, IL-2 and IL-6 upon the anterior pituitary hormones, growth hormone (GH), prolactin (PRL) and adrenocoticotropic hormone (ACTH) were studied in rodent pituitary adenoma cell lines. Hormone release by GH and PRL-producing rat adenoma cells (GH3) and ACTH-producing mouse adenoma cells (AtT-20) was analyzed by radioimmunoassay (RIA). Recombinant (r) IL-1beta decreased PRL release from GH3 in a dose-dependent fashion. IL-1 inhibition of PRL production occurred in parallel with IL-1 inhibition of DNA synthesis in GH3 as measured by [(3)H] thymidine incorporation. This result strongly indicates that IL-1 alters PRL production by adenoma cells at the translational level. Low dose IL-2 (10 U/ml) enhanced ACTH production from AtT-20, but higher concentrations of IL-2 failed to affect the release of ACTH. IL-2 did not change the incorporation of [(3)H] thymidine in AtT-20. Previous studies showed that IL-1 and IL-6 induce a significant secretion of ACTH via the hypothalamic-pituitary axis. However, IL-1 and IL-6 failed to affect ACTH secretion by AtT-20. Blood-derived cytokines have direct effects on hormone secretion by pituitary adenoma cells in vitro.

Expression of tumour necrosis factor-alpha, -beta and interferon-gamma genes within human neuroglial tumour cells and brain specimens.

Expression of cytokine genes, TNF-alpha, TNF-beta and IFN-gamma, in human astroglial cell lines and in fresh brain specimens was studied by PCR. mRNA transcripts of TNF-alpha could be detected in three out of five astrocytomas and neuroblastoma cell lines, and after stimulation with IL-1 beta/IFN-gamma or LPS/IFN-gamma all these cell lines expressed TNF-alpha genes. TNF-beta genes could not be detected in these cell lines. We were able to detect expression of IFN-gamma genes within two astrocytoma cell lines, which interestingly did not show TNF-alpha activity. In addition to the cultured cells, we also examined gene expression of these cytokines within four human malignant astrocytoma specimens, two peritumoral brain and two autopsied normal brains. The results show that tumour and surrounding reactive lesions express TNF-alpha genes (four of six) but not normal brains. The concentration of these cytokines in the supernatant of cultured cells was measured quantitatively by TNF-alpha, -beta or IFN-gamma ELISA. The combined stimulation of these neuroglial cell lines with IL-1 beta and LPS or IFN-gamma, revealed a high level of TNF-alpha activity. This was especially evident with a neuroblastoma cell line. The concentration of TNF-alpha in the supernatant of the IMR32 neuroblastoma cell line increased markedly upon stimulation with IL-1 beta in both a time- and dose-dependent fashion in the presence of LPS or IFN-gamma. Next, we examined expression of IL-1 beta and IFN-gamma genes in the brain specimens. The result shows that four in six tumour and peritumoral regions expressed IFN-gamma genes and one specimen showed IL-beta gene by PCR. From these experiments it is suspected that neuroglial cell-derived TNF-alpha induced by IL-1 beta of IFN-gamma may participate in local immune reactions of the brain in an autocrine and paracrine fashion.

Association of malignant glioma with the human leukocyte antigen, HLA-A24(9).

Many immune responses are controlled by genes of the major histocompatibility complex (MHC). In humans these include the loci encoding the HLA-A, -B, -C, -DR, -DQ, and -DP antigens, and many diseases have been linked with these. However, little information is available about any connection between malignant tumors and HLA. In this study the possible association of HLA-A, -B, -C and -DR specificities with susceptibilities to malignant glioma was investigated in 42 patients with malignant glioma and 42 controls with non-glial intracranial tumors using the Terasaki-NIH standard method. The data were also compared with those of the 11th International HLA Workshop. The result showed that a high frequency of HLA-24(9) was observed in patients with intracranial malignant gliomas, which was not common in other, non-glial patient groups. In animals the MHC acts in defense against virally induced tumors, but until now there has been no evidence that they do so in human gliomas. Our discovery of its association with an HLA antigen is important for understanding the immunogenetic basis of susceptibility to glioma.

Skewed distribution of TCR V alpha 7-bearing T cells within tumor-infiltrating lymphocytes of HLA-A24(9)-positive patients with malignant glioma.

The identification and propagation of T cells with anti-tumor reactivity is critical for understanding the human immune response to tumors, which may possibly be useful in the successful implementation of adoptive immunotherapy against cancer. In order to address this question, we examined the diversity of mRNA transcripts of T-cell receptor (TCR) V alpha and V beta genes in tumor-infiltrating lymphocytes (TIL) of 12 glioma specimens obtained at surgery. Using the polymerase chain reaction (PCR) method and primers for 18 different human TCR V alpha and 22 V beta families to analyze TCR V-(D)-J-C gene rearrangements, we detected a limited expression of TCR variable region, V alpha genes and predominant usage of V alpha 7 within glioma TIL. TCR V beta gene usage was more diverse than that for V alpha, but TCR V beta 13.1 was dominantly expressed in 9 out of 12 patients. In addition, we analyzed the percentage of each V alpha- and V beta-bearing T-cell subpopulation in TIL as well as in peripheral blood lymphocytes (PBL) quantitatively. The distribution of T-cell subpopulation bearing each V alpha or V beta subfamily was variable and uneven in all cases. In 3 cases, the distribution of V alpha 7-bearing T cells in TIL was far higher than in PBL. This phenomenon was not found in T cells bearing TCR V beta 13.1. We also performed human leukocyte antigen (HLA) typing in these patients, and A24(9) was observed in 8 out of 11 patients. Among them all 3 patients who showed a skewed distribution of V alpha 7-bearing T cells in TIL expressed HLA-A24(9). There was no correlation between particular class I or II type and TCR V beta gene usage. From these results, it was strongly suggested that T cells bearing TCR V alpha 7 might be targeted to antigenic determinants on glioma cells, and such T-cell population may be useful as effector cells for cancer immunotherapy.

[A case of selective short-term memory disturbance due to a glioma in the left temporo-parietal lobe].

We report a patient with selective short-term memory disturbance caused by a glioma in the left temporal-parietal lobe. The patient was a 40-year-old right-handed housewife who complained of difficulty in memorizing series of numbers. She was working as a car dealer. She was well until 6 months prior to the present admission when she noted a difficulty in memorizing series of numbers such when telephone numbers and car registration numbers. She had to write them down as her customers told them to her. On admission, she was alert and oriented to all spheres. She was mentally sound without dementia. She did not show aphasia, apraxia, or agnosia, except for brief periods of seizures in which she became unable to speech. Neuropsychological examination revealed that she had difficulty in repeating and dictating series of numbers and meaningless kana words. However, she could easily pick up the correct series of numbers or kana words among multiple choices presented visually. Thus it was clear that her problem was not the disturbance of auditory input nor expression, but a selective impairment of short-term memory. She could memorize the same stimuli when visually presented. Therefore, her problem was thought to be a disturbance of auditory short-term memory of meaningless words. After resection of her tumor, she developed transient amnesic aphasia, which improved a year later. She was examined again in her memory function. In the task of visual stimuli, we presented her a card in which a series of numbers or a nonsense syllable was written for 5 seconds and asked her to remember them.(ABSTRACT TRUNCATED AT 250 WORDS)