Kohshi Gotoh

Anti-tumor effect of gallic acid on LL-2 lung cancer cells transplanted in mice

We previously reported that gallic acid (3,4,5-trihydroxybenzoic acid), a naturally occurring plant phenol, can induce apoptosis in four kinds of human lung cancer cell lines in vitro. The present study further investigated the in vivo anti-tumor effects of orally administered gallic acid. Gallic acid reduced cell viability of LL-2 mouse lung cancer cells in vitro dose dependently, with a 50% inhibitory concentration (IC50) value of around 200 μM. C57Black mice were transplanted with LL-2 cells, and administered gallic acid (1 mg/ml in drinking water, ad libitum) and/or cisplatin (4 mg/kg i.p. injection, once a week). The average weight of the transplanted tumors, obtained at 29 days after transplantation, in the mice of control, gallic acid-treated cisplatin-treated and cisplatin plus gallic acid-treated groups was 4.02, 3.65, 3.19 and 1.72 g, respectively. The average tumor weight of the mice treated with cisplatin combined with gallic acid was significantly smaller than that of the control group (p<0.05). The amount of apoptotic cells in the tumor tissues of mice treated with gallic acid and/or cisplatin was significantly higher than those of the control mice. Combination of gallic acid and cisplatin increased the tumor cell apoptosis compared with the treatment with cisplatin alone. The present findings suggest that the combination of gallic acid with an anti-cancer drug, including cisplatin, may be an effective protocol for lung cancer therapy.

An increase of soluble Fas, an inhibitor of apoptosis, associated with progression of COPD

In chronic obstructive pulmonary disease (COPD) which consists of emphysema and chronic bronchitis, alveolar tissue and/or bronchiolar walls are progressively destroyed. This suggests cell death by necrosis and/or apoptosis although no direct evidence of apoptosis has been reported. It was speculated that the apoptosis-related factors are associated with the progression of COPD. Fas/Apo-1 receptor (Fas), Fas ligand (Fas-L) and soluble Fas ligand (sFas-L) are inducers, while soluble Fas (sFas) is an inhibitor of apoptosis. In this study, plasma sFas and sFas-L were measured in 19 COPD patients receiving supplemental O2 (severe COPD) and 20 COPD patients not receiving supplemental O2 (mild/moderate COPD). Twenty-two age- and sex-matched healthy volunteers (healthy controls) and 20 patients receiving supplemental O2 and with level of hypoxaemia similar to severe COPD due to other pulmonary diseases (disease controls) were also examined. Plasma sFas-L was within normal limits in all groups. Plasma sFas levels were similar among healthy controls, disease controls, and mild/moderate COPD patients, but significantly increased in severe COPD (2.6 +/- 1.1, 2.6 +/- 0.2, 2.8 +/- 0.2 and 4.8 +/- 1.0 ng ml-1, respectively). Although PaO2 was lower in severe COPD than in mild/moderate COPD, and PaCO2 was higher in severe COPD than in mild/moderate COPD, they were close between severe COPD and disease controls. Tumour necrosis factor-alpha (TNF-alpha), interleukin 6 (IL-6) and C-reactive protein (CRP) were increased in patients with COPD, but were similar in both severe and mild/moderate COPD patients. We conclude that increased plasma sFas, which is independent of hypoxaemia, and increases in PaCO2, TNF-alpha, IL-6 and inflammation, may be associated with progression of COPD.

Relationship between thallium-201 myocardial SPECT and findings of endomyocardial biopsy specimens in dilated cardiomyopathy.

The purpose of this study was to clarify which myocardial histological findings associated with dilated cardiomyopathy (DCM) are reflected in quantitative201Tl myocardial SPECT. We obtained studied SPECT images from 21 patients with DCM 10 minutes and 2 hours after they received an injection of 111 MBq201Tl at rest. We calculated the percent coefficient of variation of myocardial201Tl counts [%CV(Tl)], the washout rate (WR), standard deviation of WR [SD(WR)], extent score (ES) and severity score (SS). We used image analysis to measure % fibrosis, % myocytes, the ratio of fibrous tissue to myocyte tissue (F/My), myocyte size and standard deviation of myocyte size [SD(My)] in left ventricular endomyocardial biopsy specimens. The %CV(Tl) was correlated with % fibrosis and F/My. The ES and SS also correlated with F/My. The correlation between SD(WR) and SD(My) was significant. The present findings suggest that %CV(Tl), ES and SS of rest201Tl SPECT reflect myocardial fibrosis and that the standard deviation of washout reflects the distribution of myocyte size.

Mechanism of Posturally Induced Crackles as Predictor of Latent Congestive Heart Failure

We investigated the role of changes in pulmonary function in posturally induced crackles (PIC) in 76 patients with various heart diseases. Regional ventilation was evaluated by spirometric gated ventilation scanning using 133Xe in 23 of these patients and its relationship to PIC was analyzed. A change from the sitting to the supine position was associated with a significant decrease in the percent functional residual capacity (FRC, p < 0.01) and significant increases in closing volume (CV), CV/vital capacity (VC) and closing capacity (CC)/FRC (p < 0.01) in the PIC-positive subjects. CV, CV/VC and CC/FRC did not differ significantly between PIC-positive (n = 37) and PIC-negative (n = 39) subjects in the sitting position, but in the supine position, these values were significantly higher in the PIC-positive group than in the PIC-negative group (CV: p < 0.05, CV/VC and CC/FRC: p < 0.01). These results suggest that airway closure was markedly increased in PIC-positive subjects in the supine position compared with PIC-negative subjects. Regional ventilation (V) was assessed in the sitting and the supine position from right lateral images divided into 9 segments from the base to the apex of the lung using spirometric gated ventilation scanning. There was no significant difference in regional ventilation in the sitting position between PIC-negative (n = 11) and PIC-positive (n = 12) subjects; in the supine position, regional ventilation decreased significantly at the base in the PIC-positive group. Findings suggest that PIC at the base of the lungs may be related to airway closure at the base of the lungs in the supine position in PIC-positive subjects.

Thallium-201 myocardial SPECT findings at rest in sarcoidosis

In 41 patients with sarcoidosis (diagnosed according to criteria recommended by the Committee on Diffuse Pulmonary Disease, Ministry of Health and Welfare, Japan 1988), thallium-201 (201Tl) myocardial SPECT was performed to investigate: (1) the ability of201Tl SPECT to detect cardiac involvement of sarcoidosis with images recorded at rest and 2 hours later, and (2) the relationships between201Tl myocardial SPECT findings and the activity of sarcoidosis or endomyocardial biopsy findings. As to the abnormal findings in201Tl myocardial SPECT, (1) a low density area was seen in 13 of 41 cases (31.7%) and non-uniform uptake was found in 17 cases (41.5%), (2) the mean washout ratio (n=39) was 16.5±7.4%, which is significantly (p < 0.05) lower than that found in normal subjects, 23.9±7.5 % (n=10). Of the 19 patients judged visually to be normal, 5 patients had a reduced mean washout ratio less than 12%. Thus, the incidence of abnormal findings including all types of abnormality, on201Tl myocardial SPECT in sarcoidosis was 63.4% (26/41 cases). In studying the relationship between201Tl myocardial SPECT findings and the activity of sarcoidosis (as measured by the serum ACE (angiotensin converting enzyme) or lysozyme level, or the presence of more than 30% symphocyte fraction in BALF (broncho-alveolar lavage fluid)), 20 (80%) of 25 cases with201Tl abnormality were judged to be active sarcoidosis, while only 6 (37.5%) of 16 cases with normal findings on201Tl SPECT were judged to be active. This suggests that there is a significant (p < 0.01) relationship between the presence or absence of an abnormal finding on201Tl myocardial SPECT and the activity of sarcoidosis. Among 13 patients examined by endomyocardial biopsy, 10 patients had abnormal findings on201Tl myocardial SPECT and 7 of these 10 patients had no histological evidence of cardiac sarcoidosis. In all of these 7 patients, however, sarcoidosis was judged to be active. This suggest that endomyocardial biopsy is of limited value in the diagnosis of cardiac sarcoidosis.

Usefulness of resting thallium-201 delayed imaging for detecting myocardial viability in patients with previous myocardial infarction

To test the feasibility of resting thallium-201 (201Tl) initial and delayed scintigraphy for detecting the area of viable myocardium, we performed single photon emission computed tomography (SPECT) in 57 patients with previous myocardial infarction (MI). All had received coronary arteriography (CAG) and left ventriculography (LVG). Initial and delayed myocardial imagings were carried out 10 min and 2 hours, respectively, after the injection of201Tl at rest. Redistribution was judged by visual interpretation and/or the circumferential profile curve, and found in the infarcted or its adjacent area in 40 of the 57 cases (70.2%). A negative washout (net increase of201Tl uptake in delayed image) was detected in 17 of these 40 cases. In 10 of the 57 patients, both exercise and rest-injected201Tl myocardial images were obtained at exercise and rest, and compared visually. The areas of abnormal perfusion were smaller in the resting delayed images than those seen after exercise in 9 of the 10 cases, and were equal in one case. Thus, resting201Tl delayed myocardial scintigraphy appears to reduce the underestimation of the size of the viable myocardium by the usual201Tl images obtained after exercise or by single initial images obtained at rest in patients with previous MI.

Extravascular lung water measured with99mTc-RBC and99mTc-DTPA is increased in left-sided heart failure

Extravascular lung water (EVLW) was quantitatively measured in 81 patients consisting of 10 subjects with normal cardiac function and 71 patients with left-sided heart diseases, using99mTc-RBC as a non-diffusible indicator and99mTc-DTPA as a diffusible indicator in the equilibrium phase. EVLW averaged 3.0±1.4 (ml/kg, mean±SD) in subjects with normal cardiac function (n=10), 4.3±1.7 in New York Heart Association functional class I patients (n=30), 4.8±2.4 in NYHA functional class II patients (n=33) and 9.4±5.4 in NYHA functional class III (n=8) patients. EVLW was greater in NYHA class III than in normal controls or NYHA classes I or II (p < 0.01).Lung thermal volume (LTV) was also measured in 31 of the 81 patients using a double indicator dilution technique with sodium and heat. LTV averaged 6.0±1.2 (ml/kg) in normal subjects (n=4), 8.6±2.0 in NYHA functional class I patients (n=11), 9.7±3.0 in NYHA functional class II patients (n=13), and 15.9±8.2 in NYHA functional class III patients (n=3). The correlation between EVLW and LTV was significant (EVLW=0.79×LTV-72.8, r=0.80, p < 0.01). There were significant differences in EVLW/LTV ratio between NYHA class III (0.93±0.16) and NYHA class I (0.62±0.22) or class II (0.60±0.23). Thus, it was shown that EVLW was increased in left-sided heart failure and that LTV overestimated the EVLW.

P-690 Comparative study of prophylactic Shakuyaku-Kanzou-To for myalgia/arthralgia following carboplatin and paclitaxel combination chemotherapy for non-small cell lung cancer

Nl ANC cl000 and ~500 was experienced by 33% and 20% of SCLC respectively compared to 8% each for NSCLC patients. Cl Hgb decrease >l g occurred in 52% of patients. By Cycle 2, 21% of patients experienced a dose decrease of at least one drug, 22% were placed on antibiotics, 22% were placed on colony stimulating factors, and 33% were placed on erythropoietin. Conclusions: This prospective registry holds promise for further identifying high-risk patients for the targeted application of supportive care approaches.

Human Pulmonary Venous Return Curve: Effect of Dopamine

Pulmonary “venous” compliance (Cp“v”) and pulmonary arterial compliance (Cpa) were determined using radionuclide angiocardiography and a floating catheter in patients with various cardiac diseases. A pulmonary venous return curve was constructed from these measurements, and the effect of dopamine on the pulmonary venous return curve was evaluated. At the same time the pulmonary “venous” volume—pressure relationship and its response to dopamine was documented.

Increase in serum cardiac myosin light chain I associated with elective percutaneous transluminal coronary angioplasty in patients with ischemic heart disease.

Changes in serum myosin light chain I (MLCI) due to elective percutaneous transluminal coronary angioplasty (PTCA) were studied after PTCA (0, 8 and 48 hours) in 57 patients with old myocardial infarction (MI group) and 20 patients with angina pectoris (AP group). The AP group showed no increase after PTCA. In contrast, in the MI group there were 16 patients in whom MLCI at 48 hours was increased by 1.0 ng/m/ or more (MI1 group) and another group of 41 patients who showed no increase in MLCI (MI2 group). The MI1 group had a significantly higher incidence of (1) non-Q wave myocardial infarction (62.5% vs. 17.1%, p< 0.01), (2) 99% stenosis of a coronary artery (50.0% vs. 12.2%, p< 0.01), and (3) redistribution in a hypoperfusion area found in the delayed image of resting thallium-201 (201Tl) myocardial scintigraphy (85.7% vs. 15.8%, p< 0.01). The left ventricular ejection fraction (LVEF) was significantly improved in the MI1 group, 3 to 4 months later (from 0.49±0.12 to 0.58±0.l 1, p< 0.01), in contrast to the patient of MI2 group who did not show any improvement. The AP group was not considered to have a bulk of myocardium impaired enough to show a release of MLCI due to PTCA-associated transient coronary occlusion. In the MI1 group, however, MLCI was probably released from the chronically underperfused, but still salvageable, portion of the myocardium. This is consistent with the improvement in LVEF observed 3 to 4 months after the relief of severe coronary stenosis. These findings suggest that the MI1 group had a large amount of “hibernating myocardium.”