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Aldosterone is thought to regulate cardiac work independently of sodium retention, though the mechanisms remain to be known. In the present study, we have demonstrated that aldosterone reinforces endothelin-mediated cardiac hypertrophy with the increase in cell surface area and upregulation of the transcripts characteristic of hypertrophy. We have also shown that aldosterone augments c-Jun N-terminal kinase activation induced by endothelin-1. Taken together, it is suggested that aldosterone modulates cardiac hypertrophy, at least partially, synergistically with extracellular signals that have been shown to be involved in cardiac remodeling.

Expression of the Wilms' tumor gene WT1 in de novo lung cancer was examined using quantitative real-time RT-PCR and immunohistochemistry. Overexpression of the WT1 gene was detected by RT-PCR in 54/56 (96%) de novo non-small cell lung cancers examined and confirmed by detection of WT1 protein with an anti-WT1 antibody. Overexpression of the WT1 gene was also demonstrated in 5/6 (83%) de novo small cell lung cancers by immunohistochemistry. Furthermore, when the WT1 gene was examined for mutations by direct sequencing of genomic DNA in 7 lung cancers, no mutations were found. These results suggest that the nonmutated, wild-type WT1 gene plays an important role in tumorigenesis of de novo lung cancers and may provide us with the rationale for new therapeutic strategies for lung cancer targeting the WT1 gene and its products., (Copyright 2002 Wiley-Liss, Inc.)

Objective: To determine the incidence, etiology, prognosis, and treatment of vocal cord paralysis (VCP) after surgery for thoracic aortic aneurysm (TAA)., Study Design: Retrospective study performed between 1989 and 1995., Setting: Academic, tertiary care, referral medical center., Patients: Seventy-one TAA patients underwent surgery at the Kameda Medical Center between 1989 and 1995., Results: Sixty-two of 71 patients were examined postoperatively for voice quality. Twenty patients (32%) had hoarseness develop caused by VCP, as confirmed by laryngoscopy. The left recurrent laryngeal nerve had been sacrificed in 1 patient during surgery, but it was preserved in the remaining 19 patients. Unilateral left VCP was noted in 19 patients, and bilateral VCP occurred in 1 patient. The incidence of VCP was higher in those patients who underwent surgery for type I aneurysms (9 of 14 patients, 64%). In 16 of the 19 patients (84%) who received follow-up for > 6 months, vocal cord movement did not return to normal. Surgery to improve voice quality, arytenoid adduction in five patients and intracordal injection in two patients, was performed with success., Conclusions: Our results indicate that surgery for TAA is associated with a relatively high incidence of VCP. VCP occurred despite preservation of the recurrent laryngeal nerve, and the paralysis did not show a spontaneous recovery even 6 months after surgery.

Objective: To investigate the role of bone marrow cells (BMC) in the induction of antigen induced arthritis (AIA), the expression of 3 major proinflammatory cytokines, interleukin 1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), and IL-6, was examined in the bone marrow (BM) of mice with AIA. We also examined whether AIA could be transferred by bone marrow transplantation (BMT)., Methods: Expression of IL-1beta, TNF-alpha, and IL-6 in BMC was assessed by immunohistochemistry throughout the course of AIA. BMT experiments were performed using 2 different mouse genotypes, wild type (IL-6+/+) and IL-6 deficient (IL-6-/-) mice, as a donor. The gradation of AIA was evaluated histologically., Results: IL-6 was highly expressed in the BM at induction as well as during progression of AIA, while TNF-alpha showed a marginal expression, and no significant expression of IL-1beta was detected throughout the course of AIA. In BMT experiments, all irradiated IL-6+/+ mice developed typical AIA by transplantation of BMC from immunized IL-6+/+ mice, whereas almost no irradiated IL- 6+/+ mice transplanted with BMC from the immunized IL-6-/- mice developed definite arthritis., Conclusion: These results suggest that BMC play a critical role and IL-6 is a key cytokine for the induction and progression of AIA. There may be clinical benefits in the blockade of IL-6 and BMT in the treatment of rheumatoid arthritis.

A 51-year-old man with recurrent episodes of angioedema was diagnosed as having autoimmune acquired angioedema, based on adult onset, lack of apparent family history, decreased activity of C1 esterase inhibitor (C1 INH) and CH50, decreased levels of serum C4 and Clq and the presence of autoantibodies to C1 INH. The danazol treatment relieved the symptoms of angioedema and increased the C1 INH activity and concentration with the normalization of CH50, C1q and C4 levels. To our knowledge, this is the first case of autoimmune acquired angioedema in Japan.

Signal transducer and activator of transcription 3 (STAT3) functions in cell proliferation, differentiation, and cell survival. Previously, we have demonstrated that the activation of STAT3 is required for glycoprotein 130-mediated induction of VEGF in cardiac myocytes, but the functional importance of STAT3 as an angiogenic mediator remains to be determined. To address this issue, we first generated the adenoviral vector expressing constitutively active STAT3 (caSTAT3). Adenoviral gene transfer of caSTAT3 induced an increase in the expression of VEGF in cultured cardiomyocytes. The conditioned medium from caSTAT3-transfected cardiomyocyte culture promoted endothelial tubule formation, which was inhibited by anti-VEGF antibody. Next, we generated the transgenic (TG) mice with cardiac-specific overexpression of caSTAT3 and demonstrated that caSTAT3 TG mice showed evidence of VEGF induction in the hearts. The caSTAT3 TG hearts also demonstrated increased capillary density accompanied by an increase in the expression of VE-cadherin, an endothelial-specific component. These data indicate that caSTAT3 TG hearts exhibit an enriched vascular structure compared with non-transgenic hearts. The study presented here provides the first evidence that activation of STAT3 controls vessel growth in vivo and suggests that STAT3 contributes to cardiac adaptation by regulating vascular function under the conditions of stress.

To examine the correlation between telomerase activity and clinical features in patients with lung cancer, we examined 86 patients with endoscopically visible lung cancer including 61 with non-small cell lung cancer (NSCLC) and 25 with small cell lung cancer (SCLC). Telomerase activity was detected by using Telomerase ELISA Kit (Böhringer Manheim, Germany). The median and interquartile ranges of telomerase activity in normal lung, NSCLC and SCLC were 65 and 51-75, 106 and 58-349 and 285 and 117-2214, respectively. Normal lung, NSCLC and SCLC had significantly different telomerase activity (p < or = 0.0001). Between NSCLC and SCLC, SCLC exhibited higher telomerase activity than did NSCLC (p=0.0029). A cut-off level of absorbance [A450nm-A690nm] of 86 derived from 90% specificity in normal lung was used; sensitivity for overall lung cancer, NSCLC and SCLC was 62.8%, 54.1% and 84.0%, respectively. There was no significant difference in telomerase activity between each stage in NSCLC (p=0.9243). In SCLC, however, the median and interquartile range of telomerase activity in extensive disease (2128 and 292-2681) was significantly higher than those in limited disease (207 and 97-252) (p=0.0285).

Background: Perioperative stroke is one of the most serious complications of cardiac surgery., Methods: Using transesophageal echocardiography, we estimated the intimal thickness of the thoracic aorta as an index of the severity of aortic atherosclerosis to determine the risk of stroke in coronary artery bypass grafting (CABG) patients. The study population comprised 315 consecutive patients who underwent isolated CABG with cardiopulmonary bypass., Results: Five patients (1.6%) had perioperative cerebral stroke or systemic emboli. We compared the mean intimal thicknesses of the ascending aorta, aortic arch, and descending aorta. Mean thicknesses in patients without stroke were 2.07 +/- 0.76, 2.78 +/- 1.15, and 2.32 +/- 1.21 mm, respectively, and mean thicknesses in the stroke patients were 1.94 +/- 0.55, 6.94 +/- 3.79, and 3.39 +/- 1.85 mm, respectively. The patients with an intima of more than 5 mm at the aortic arch had a significantly greater incidence of perioperative stroke (p = 0.007)., Conclusions: These results suggest that patients who have an aortic arch intima thickened to more than 5 mm are at a significantly high risk for perioperative stroke, and thus, the CABG procedure should be carefully evaluated to prevent such complications.

To investigate the prognostic role of hTERT expression in non-small cell lung cancer (NSCLC), we examined the expression of hTERT mRNA in tumor specimens from 68 patients with NSCLC using RT-PCR. The expression of hTERT was detected in 34 (50%) of 68 cancer tissues. There were no correlations between hTERT status and any common clinical features except age. Patients with hTERT expression had shorter survival than those without hTERT expression. Multivariate analysis showed that hTERT expression was an independent negative prognostic factor. These results suggest that expression of hTERT may be an independent prognostic factor for NSCLC patients.

This study was performed to evaluate the prognostic significance of alteration in telomere length in pathological stage (p-stage) I-IIIA non-small cell lung cancer (NSCLC). Paired cancer and normal lung tissues were obtained from 72 patients with histologically confirmed p-stage I-IIIA NSCLC. Terminal restriction fragment (TRF) length, which indicates telomere length, was measured by Southern blot analysis. Tumor telomerase activity was also assayed by non-radioactive PCR-ELISA in 55 patients. TRF length (mean +/- SD) in normal tissue was 6.2 +/- 1.1 Kb. Therefore, upper and lower limits of normal range in TRF length was set at 8.4 (mean + 2SD) Kb and 4.0 (mean-2SD) Kb, respectively. A tumor showing TRF length over normal range was defined as positive for the alteration. In 72 patients, 25 (34.7%) with alteration in TRF length had significantly shorter survival durations than those of the others. Telomerase activity did not correlate with survival duration. In multivariate analysis, alteration in TRF length (P = 0.0033) was second to p-stage (P = 0.0004) in importance among the various parameters.

The mechanisms of radiation pneumonitis have not been established. In a study on multi-field radiation therapy for lung cancer, one patient developed severe radiation pneumonitis even though the target volume was small. Radiation therapy was performed at a dose of 75 Gy in 50 fractions over five weeks. High-density areas conforming to the radiation field were observed by high-resolution CT. They were observed in the irradiated volume at doses under 20 Gy in the contralateral lung as well as in the ipsilateral lung.

Background: GPI-anchored molecule-like protein (GML) has been identified as a new target molecule of p53. In esophageal cancer cell lines, expression of GML mRNA, which was found to be significantly correlated with in vitro anti-cancer drug sensitivity, was observed only in the presence of wild-type p53., Materials and Methods: The relationship between expression of GML mRNA and p53 gene status in 24 non-small cell lung cancer (NSCLC) cell lines was examined using RT-PCR and PCR-SSCP followed by direct DNA sequencing., Results: Expression of GML mRNA was observed in only 3 of 24 cell lines. In contrast to previous studies showing p53-dependent GML expression, of the 3 cell lines expressing GML mRNA, one had a p53 gene mutation (codon 245: Gly to Cys)., Conclusion: These findings suggest that the expression of GML mRNA is infrequent and regulated in a p53-independent manner in NSCLC.

p53 abnormalities appear to play critical roles in human carcinogenesis. Many studies have indicated that p53 alteration is responsible for the differences in clinical characteristics of non-small cell lung cancer (NSCLC). The purpose of this review is to evaluate and summarize the significance of p53 alteration in the diagnosis and therapy of NSCLC. After assessing the principles of each approach to detecting p53 alteration, we reviewed the literature describing the impact of p53 alteration on clinical modalities such as diagnosis, prediction of prognosis, and response to treatment. We also reviewed p53 gene replacement therapy for NSCLC. Although p53 appears to be the most important gene in the development of NSCLC, it is not known whether p53 abnormalities are useful markers for clinicians. A multicenter, prospective study of p53 immunohistochemistry should therefore be performed. Replacement of the p53 gene has been shown to be effective in a clinical trial for patients with NSCLC. In addition to simple gene replacement, combination treatments of gene transfer and chemotherapy are now being tested in clinical trials.

A survey was conducted from April through September, 1997, of 24 hospitalized terminal lung cancer patients connected to IVH and CSC, for whom the possibility of release from hospital was considered, and of their families. A comparative survey was made between patients who accepted HIT and those who did not. No difference was found between the groups by age, sex, or disease stage, nor was there a difference in physical symptoms such as pain and respiratory difficulty. However, the percentage of patients who were told the name of their disease was significantly higher in the group switched to HIT, 3 of whom were even given prognoses. There was no difference in the percentage of patients who lived with their families, although there was a higher percentage in the HIT group whose spouses also lived with the family. Nineteen of the 24 patients wished to return home, but 8 of those patients were not released from hospital for such reasons as the patient not wanting to be a burden on his or her family or the family's lack of ability to provide care. It was found that important factors in urging home care for the terminal cancer patient were whether or not the patient was told the name of his or her disease, and whether or not the patient lived with a healthy spouse.

Between July 1991 and February 1993, CYFRA 21-1 levels of 149 newly diagnosed patients with histologically proven non-small cell lung cancer (NSCLC) at Osaka Prefectural Habikino Hospital were measured with an enzyme immunoassay method developed by Boeringer Mannheim (Enzymun-Test CYFRA 21-1). NSCLC patients with CYFRA 21-1 serum levels over 3.5 ng/ml had a significantly poorer prognosis than did patients with normal CYFRA 21-1 levels (P < 0.001). Univariate analysis revealed that CYFRA 21-1 levels above 3.5 ng/ml, poor PS, advanced stage and serum LDH over 450 U/l strongly correlated with survival period. In multivariate analysis, however, only CYFRA 21-1 was found to be an independent prognostic factor compatible with Stage and PS (P = 0.0040 for CYFRA 21-1, P < 0.001 for PS, P = 0.0052 for Stage).

Purpose: To determine the response rate, survival, and toxicity of irinotecan (CPT-11), a topoisomerase I inhibitor, combined with etoposide, a topoisomerase II inhibitor, in refractory or relapsed small-cell lung cancer (SCLC)., Patients and Methods: Twenty-five patients with refractory or relapsed SCLC were entered onto the trial. All 25 patients had been pretreated with some form of cisplatin-based combination chemotherapy and had also received previous etoposide- or anthracyclinecontaining chemotherapy. The median time off chemotherapy was 6.7 months (range, 0.9 to 23.5). Patients were treated at 4-week intervals using CPT-11 (a starting dose of 70 mg/m2 intravenously on days 1, 8, and 15) plus etoposide (80 mg/m2 intravenously on days 1 to 3), with a subsequent dose based on toxicity. In addition, recombinant human granulocyte colony-stimulating factor (rhG-CSF; 2 microg/kg/d) was given from day 4 to day 21, except on the days of CPT-11 administration., Results: All patients were assessable for toxicity and survival. Twenty-four patients were assessable for response. There were 14 partial responses (PRs) and three complete responses (CRs), for an overall response rate of 71% (95% confidence interval, 53% to 89%). The median response duration was 4.6 months. Median survival was 271 days. Major toxicities were myelosuppression (predominantly leukopenia) and diarrhea. Grade 3 to 4 neutropenia and thrombocytopenia occurred in 56% and 20% of patients, respectively. Grade 3 to 4 diarrhea was observed in 4%. There was one treatment-related death due to severe myelosuppression., Conclusion: A combination of CPT-11 and etoposide with rhG-CSF support is an active therapy against refractory or relapsed SCLC and deserves to be studied more extensively in a phase III trial.

Purpose: To evaluate radiation therapy regimens for improvement in local control in patients with limited-stage small cell lung cancer., Materials and Methods: Radical radiation therapy results in 117 patients with limited-stage small cell lung cancer were retrospectively reviewed. The protocols in 90 patients were 40 Gy in 20 fractions (n = 28), 50 Gy in 25 fractions (n = 32), and 45 Gy in 30 fractions (accelerated hyperfractionation, n = 30). The other 27 patients received thoracic irradiation (dose range, 20-60 Gy; median dose, 54 Gy). All patients underwent systemic chemotherapy., Results: The 5-year Kaplan-Meier survival rates in the patients with N0, N1, N2, and N3 disease were 26%, 34%, 18%, and 0%, respectively; the rates of in-field relapse were 25%, 36%, 26%, and 25%, respectively; and the rates of marginal relapse were 0%, 9%, 15%, and 29%, respectively. In 56% of patients with marginal relapse, the relapse site was at the upper margin. The 4-year in-field control rates for the patients who underwent 40, 50, and 45 Gy were 51%, 70%, and 56%, respectively., Conclusion: Patients with N3 limited-stage small cell lung cancer should undergo a separate protocol, and the upper margin should be extended in patients with N2 or N3 disease.

Purpose: To test the feasibility of a system for intermittent irradiation synchronized with respiratory motion in a clinical setting., Materials and Methods: A newly developed gate pulse controller that starts and stops irradiation at a chosen phase of the respiratory cycle by controlling a linear accelerator was used in six patients with lung cancer. A laser displacement sensor was used for the detection of respiratory motion. Three patients underwent radiation therapy during the cycles between 50% expiration and 50% inspiration (step 1), and three patients underwent radiation therapy during the cycles between 70% expiration and 30% inspiration (step 2)., Results: The system functioned well; irradiation was verified with portal verification radiography in all six patients. The range of the tumor position during synchronized irradiation was detectable with fast portal localization radiography. The treatment times for steps 1 and 2 were 1.38-1.71 and 2.03-2.18 times longer, respectively, than those for conventional irradiation., Conclusion: Synchronized irradiation with the authors' system allowed convenient and reliable reduction of the target volume. Further study is needed to standardize the system for clinical use.

Unlabelled: The purpose of this study was to evaluate the correlation between alteration in telomere length and prognosis in patients with pathological stage I-II non-small cell lung cancer. We measured telomeric repeat length and telomerase activity by use of southern blot analysis of terminal restriction fragments and a non-radioactive ELISA-based assay, respectively., Results: Alterations in TRF lengths were present in 17(29.8%) of 57 patients. Patients with altered TRF length had significantly shorter survival than did patients without (P = 0.0051). In multivariate analysis, only alteration in TRF length independently correlated with shortened survival (P = 0.0033).

To improve the quality of life in cancer patients at a near-terminal stage, we assisted patients to stay home using a system for home infusion therapy (HIT) established at Osaka Prefectural Habikino Hospital in 1994. From April in 1995 to April in 1996, 25 patients were treated at home using the HIT system for longer than 7 days. Thirteen out of 25 patients still stayed at home even at a terminal stage and died in their residences. There was no difference either in the mean age or in the HIT duration between 13 patients who died at home and the remaining 12 patients who were readmitted to their hospitals before death. However, 47% of the patients who died at home had been told their diagnoses by doctors and realized their own prognoses, while only 17% of the patients who died in the hospital knew their diagnoses and prognoses. Seventy-seven percent of the patients who died at home were given home oxygen therapy (HOT), against 33% of the patients who died in the hospital. Furthermore, the patients who died at home were given more intensive care than the patients who died in the hospital, because the former had a larger family than the latter. In conclusion, HIT at a near-terminal stage and death at home may be more readily accepted by patients who know their diagnoses and prognoses and have a large family.

Although p21 WAF1/Cip1 expression has been detected immunohistochemically in non-small cell lung cancer (NSCLC), the associations between p21 expression and clinical characteristics are unknown. To determine the association between p21 expression and clinical features, p21 expression was immunohistochemically analyzed in paraffin-embedded tumor samples from 137 patients with curatively resected NSCLC. p21 expression, indicating normal p21 function, was detected in 48 (35.0%) of the 137 patients with curatively resected NSCLC and was detected more frequently in patients with stage I or II disease (40.2%) than in those with stage IIIA disease (22.5%; P = 0.0483). There was no difference in the positive rate between squamous cell carcinoma [SCC; 15 of 48 (31.3%)] and adenocarcinoma [30 of 77 (39.0%)]. For SCC, patients with tumors expressing p21 survived longer than did those with tumors negative for p21 expression; however, the corresponding survival time was not significant for adenocarcinoma. On the other hand, p53 expression, detected in 58 (42.3%) of these patients, did not act as any predictor for prognosis in either SCC or adenocarcinoma. Our findings suggest that the presence of p21 expression is associated with favorable prognosis in SCC and may be useful in obtaining candidates for adjuvant therapies from among patients with SCC.

Background: The prognostic significance of serum p53-Abs positivity for non-small cell lung cancer (NSCLC) is still unknown., Patients and Methods: To determine the prognostic value of serum p53-Abs status, we determined serum p53-Abs and immunohistochemistry in 140 patients with stage I-IIIA NSCLC., Results: p53-Abs were detected in 12.1% of all patients and in 17.6% of those with squamous cell carcinoma (SCC). Neither p53-Abs nor p53 overexpression alone was correlated with survival for all patients. When these factors were combined for SCC, seronegative patients with tumors overexpressing p53 survived significantly longer than did those with p53-Abs or p53-nonexpressing tumors. In multivariate analysis, p53-Abs status and p53 overexpression were independent prognostic factors for SCC (p = 0.0337)., Conclusions: These findings suggest that the combination of p53Abs seropositivity and p53 overexpression may be a prognostic factor for SCC.

Purpose: To evaluate the usefulness of transcutaneous needle biopsy (TCNB)., Material and Methods: From May 1988 to December 1994, we performed TCNB under fluoroscopic control in 408 patients with mass lesions of the peripheral lung. The Surecut needle (1.5 mm) was selected mainly because of its ability to obtain specimens large enough for histological examination. Of the 408 patients, 286 had had previous bronchofiberscopic examinations but no definite diagnosis had been reached., Results: A definite diagnosis was obtained by TCNB in 305 (74.7%) of 408 cases (251 malignant neoplasms, 54 benign lesions). In malignant neoplasms, the pathological diagnosis based on cytology and histology together was more reliable than that based on cytology alone. Although the complications of this procedure (such as pneumothorax) were within the range of acceptability, care should be taken to avoid air embolism and the seeding of cancer cells along the needle tract., Conclusion: TCNB with the Surecut needle is a useful procedure with relatively low risk.

We investigated the ability of 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin (CPT-11) to increase tumor radio-response in vivo using human lung tumor xenografts. The xenografts were treated with (1) CPT-11 (10 mg/kg) intraperitoneally on days 1, 5 and 9, (2) single dose radiation (10 Gy/leg) on day 1, or (3) a combination regimen of both treatments in which radiation was given 1 h after the first dose of CPT-11. DNA flow cytometry studies were performed to define the cell cycle changes following treatment for 1 to 12 h with 0, 0.5, 2.0 or 8.0 ng/ml SN-38, the major active metabolite of CPT-11. In both small cell lung cancer (MS-1) and small cell/large cell carcinoma (LX-1) xenografts, combination treatment resulted in significant tumor regression compared with the use of CPT-11 (P = 0.0005, 0.0053) or radiation treatment (P = 0.00221, 0.0035) alone. Neither severe body weight loss nor enhanced skin reaction was observed following the combined treatment. In flow cytometry studies, the proportion of cells in G2/M-phase, the most radio-sensitive phase, increased after 1 h exposure to the lowest dose of SN-38 (0.5 ng/ml). These findings suggest that CPT-11 is a potent radiosensitizing agent, and that its activity is related to the cell cycle. This is the first report to indicate that CPT-11 serves as a radiosensitizer in vivo.

Photodynamic therapy (PDT) utilizing Photofrin is proving to be effective for the treatment of early stage lung cancers. The effect of PDT utilizing YAG-OPO laser as new light source was evaluated in 26 patients (29 lesions) with early stage lung cancers. YAG-OPO laser is solid state tunable laser which is easy to change wavelength between 620 and 670 nm exciting various kinds of photosensitizers. Moreover, YAG-OPO laser is more reliable, smaller and has less consumables than argon-dye laser or excimer-dye laser. As the result of PDT with YAG-OPO laser, complete remission (CR) was obtained in 82.6% of the 29 lesions, partial remission (PR) in 13.8% and no change (NC) was obtained in 3.4%. We conclude that PDT utilizing YAG-OPO laser is efficacious in the treatment of early stage lung cancers and can achieve complete remission.

To improve the quality of life in patients with malignant diseases at the near-terminal stage, we established a system for home infusion therapy (HIT) in Osaka Prefectural Habikino Hospital in 1994. Thirty-three patients were taken care of at home using the HIT system from January, 1995 to May, 1996. Their average age was 70 years old. The duration of HIT varied from 1 to 105 days (mean:25.5 days). Twenty-four cases received parenteral nutrition. The others received agents for brain edema (4 cases), morphine hydrochloride (2 cases), and anti-fungal agents (3 case). Additionally, 63% of these patients required home oxygen therapy (HOT) with HIT. Questionnaires to their families revealed that they were afraid of the progress of the disease in patients and their physical burden became heavier after the start of HIT. However, they were quite satisfied with the results of HIT.

In an attempt to examine various factors affecting the short- and long-term results of emergent coronary bypass graft surgery (ECABG) after an acute myocardial infarction (AMI), all patients undergoing ECABG without associated procedures at our institution from January 1987 to July 1995 were reviewed. Forty eight patients underwent ECABG after AMI. The hospital mortality rate was 20.8%. The charts of these patients were reviewed with regard to sex, age, preoperative shock, location of AMI, type of infarction, coronary anatomy, presence of postinfarction angina, technique of myocardial preservation, use of saphenous vein graft (SVG) alone, time from AMI to operation and short and long-term outcome. Univariate analyses showed that three factors were significantly associated with increased hospital death: preoperative shock (p = 0.001), type of infarction (p = 0.01), use of SVG alone (p = 0.003). Follow-up was 100% complete at a mean time of 36.4 +/- 4.8 months. Of all patients 77.0% were alive at 5 years after operation. Univariate comparison of survival curves and coronary event free curves showed that use of SVG alone was associated with decreased survival (p = 0.0009) and event free (p = 0.02) rates. Patients with non-Q-wave infarction and without cardiogenic shock may undergo ECABG relatively safely at any time. The use of internal thoracic artery at ECABG without cardiogenic shock does not increase hospital mortality and improves both long-term survival and freedom from coronary events.

We have operated upon 30 cases of coronary reoperation during the past 12 years. The mean interval between the two operations was 46 months. The mean follow-up after reoperation was 61 months. The major reasons for reoperation were graft failure from technical problems in early and time-related degeneration in graft and native coronary progression in late cases. We aggressively have replaced the stenotic and obstructed vein graft with the arterial graft at reoperation since 1990. Hypoperfusion syndrome is clinical entity reported secondary to inadequate flow via the internal thoracic artery. For patients with atherosclerotic vein grafts to the LAD, the minimal manipulation of the old vein graft, adding the IMA graft to the LAD and leaving the stenotic vein graft intact appear to be safe and better procedure for long-term results. There were no operative and hospital death. Five and 10 years survival rate were 100% and 90% respectively. Five and 10 years event free rate were 92.1% and 82.9% respectively. The outcome of reoperation was satisfactory.

A 74-year-old man underwent standard aortic valve replacement. The aortotomy was closed by use of strips of Teflon felt because of somewhat friable thin aortic wall. After the termination of cardiopulmonary bypass, aortic cannulation site was carefully sutured enforcing with a piece of pericardium, since some bleeding persisted. The intraoperative diagnosis of acute aortic dissection (Stanford type A) was made with transesophageal echocardiography. Since extension of the dissection toward the aortic root was hardly possible due to the Teflon felt enforced aortotomy closure, further surgical intervention was not considered at this time. Thiry-two hours later after admission to CCU, sudden bleeding through the mediastinal tube prompted the patient back to OR for exploration Bleeding was noted from the posterior wall of the ascending aorta. Ascending aorta and transverse arch were significantly enlarged with notable discoloration. With the aid of extracorporeal circulation and selective cerebral perfusion, the total graft replacement of the ascending aorta and aortic arch was performed. The intimal tear located at the aortic cannulation site. The postoperative course was uneventful. Prompt recognition and appropriate surgical management are necessary to improve patient outcome.

Data on 16 potential risk factors for myelosuppression were assessed in 134 patients who received either vindesine and cisplatin (VP) or mitomycin C, vindesine and cisplatin (MVP) for inoperable stage III or IV non-small cell lung cancer in a randomized trial. Determinant factors for myelosuppression were evaluated by using univariate analysis and the logistic regression model. Recursive partitioning and amalgamation (RPA) was also used to define patient subgroups frequently suffering from severe bone marrow toxicity. Overall, 33 (25%) of 134 patients experienced at least one episode of grade 4 leukopenia. In univariate analysis, age, body surface area, serum creatinine, and pretreatment hemoglobin concentration were associated with severe leukopenia. A multivariate analysis using the logistic regression method showed that only raised creatinine level was an independent predictor for grade 4 leukopenia (P = 0.049). The RPA model generated three distinct subgroups based on age, body surface area and regimen. The three subgroups were distinguished by the frequency of severe (grade 4) leukopenia (50%, 25%, and 2.4%, respectively) (P < 0.001). Grade 4 leukopenia occurred more frequently in patients in class 3 (age > or = 65 years and treatment with MVP). The RPA model was useful in identifying the risk factors for myelosuppression induced by cisplatin-based chemotherapy, and in defining patient subgroups with elevated risk of toxicity.

We attempted to clarify whether serum levels of a carboxy-terminal fragment of ProGRP, ProGRP(31-98), could serve as a more accurate tumour marker in patients with SCLC than neuron-specific enolase (NSE). ProGRP(31-98) and NSE were measured retrospectively in 101 newly diagnosed untreated patients with SCLC, 111 with non-small-cell lung cancer (NSCLC) and 114 patients with non-malignant lung diseases. ProGRP(31-98) and NSE levels were determined using a sandwich enzyme-linked immunosorbent assay. Sensitivity in SCLC patients was 72.3% for ProGRP(31-98) and 62.4% for NSE. Comparing the area under curve (AUC) of 'receiver operator characteristics' of ProGRP(31-98) with that of NSE, ProGRP(31-98) was the more powerful marker in the diagnosis of SCLC (P = 0.0001). Serum levels of ProGRP(31-98) were higher in the 40 patients with extensive disease than in the 61 patients with limited disease (P = 0.0082). ProGRP(31-98) was significantly higher in patients with pure small-cell carcinoma than in patients with mixed small-cell/large-cell carcinoma (P = 0.02). In serial measurement in 16 patients responding to treatment, a high degree of correlation was noted between the decrease in serum ProGRP(31-98) levels and clinical response during the second week after treatment (P = 0.0045). These results indicate that the determination of serum ProGRP(31-98) levels plays an important role in the diagnosis and treatment of SCLC patients.

A carcinoembryonic antigen (CEA)-producing human lung cancer cell line (A549), a nonproducing human lung cancer cell line (CADO-LC9), and a human uterine cervical cancer (HeLa) were transfected with the herpes simplex virus thymidine kinase (HSV-TK) gene regulated by 445 nucleotides upstream from the translational start of CEA gene. Fifty % growth inhibitory concentration of ganciclovir (GCV) was 0.57 micron for HSV-TK-transfected A549; relative sensitivity to GCV was more than 1000 times higher compared to the 50% growth inhibitory concentration of the parental cell line. Both CADO-LC9 and HeLa transfected with HSV-TK were still resistant to GCV. There was no difference in either morphology or doubling time between HSV-TK-transfected and parental clones. Injections (i.p.) of GCV resulted in significant regression of HSV-TK-transfected A549 tumors in nude mice. These data show the possibility of gene therapy using the cell type-specific promoter of CEA gene against CEA-producing adenocarcinoma of the lung.

A 47-year-old woman, with a history of recurrent venous thrombosis in her lower limbs (1988 and June, 1992), was admitted because of pulmonary thromboembolism in the right middle lung lobe. She was given anti-coagulant therapy with warfarin. The consolidation in the right middle lobe disappeared within two months. Hematological examinations concerning the coagulation and fibrinolytic system showed a significant decrease in both the serum concentration and the activity of protein C, a vitamin K-dependent hepatic protein which acts as an anticoagulant by shutting off fibrin formation and stimulating fibrinolysis. Since a sister of the patient also has a history of venous thrombosis, several members of her family were tested for protein C deficiency. The familial study revealed that her sister and mother had both a decreased concentration and depressed activity of protein C, indicating that this is a case of congenital protein C deficiency. Warfarin therapy has been continued to reduce the prothrombin time to 70% of the normal control level, resulting in no further episodes of thrombosis.

Experimental workstations for oral reporting and synchronized image filing have been developed and evaluated by radiologists and referring physicians. The file media is a 5.25-inch rewritable magneto-optical disk of 600-Mb capacity whose file format is in accordance with the IS&C specification. The results of evaluation tell that this system is superior to other existing methods of the same kind such as transcribing, dictating, handwriting, typewriting and key selections. The most significant advantage of the system is that images and their interpretation are never separated. The first practical application to the teaching file and the teaching conference is contemplated in the Osaka University Hospital. This system is a complete digital system in terms of images, voices and demographic data, so that on-line transmission, off-line communication or filing to any database will be easily realized in a PACS environment. We are developing an integrated system of a speech recognizer connected to this digitized oral system.

We have examined the deletion of the long arm of chromosome 5 (5q) in 59 cases of advanced lung cancer [39 cases of small cell lung cancer (SCLC), 20 cases of non-SCLC] using 12 restriction fragment length polymorphism markers on 5q. Of 59 lung cancer cases, 48 (81%) exhibited deletion at any portion of the 5q locus (loci). Such a high frequency of 5q deletion has not been reported in surgically resectable non-SCLC. One SCLC case showed a 5q deletion only in metastatic sites but not in the primary cancer. These data suggest that the inactivation of putative tumor-suppressor gene(s) on 5q may be a late event in the progression of lung cancer. There was no significant difference in frequency of 5q deletion between SCLC and non-SCLC. Compared to non-SCLC, however, SCLC usually showed widespread deletion on 5q. While the most frequent target region was estimated to be about 3-5 megabases at 5q21 around the adenomatous polyposis coli (APC) gene locus, some cases showed more telomeric deletion (5q33-35), suggesting that there are at least two different tumor-suppressor genes on 5q associated with the progression of lung cancer.

We constructed a detailed deletion map of the short arm of chromosome 3 (3p) for 55 lung cancer cases by using 17 restriction fragment length polymorphism (RFLP) probes. Initially, we examined 40 small cell lung cancer (SCLC) cases and found three regions of deletion at 3p25-26, 3p21.3 and 3p14-cen, suggesting the possibility of at least three different tumor-suppressor genes on 3p. In order to obtain more detailed deletion area, and to compare the pattern of 3p deletion, we also examined 15 non-small cell lung cancer (NSCLC) cases. Compared to NSCLC cases, most of SCLC cases have widespread deletion on 3p, suggesting multiple tumor-suppressor genes on 3p may be inactivated in this type of cancer. In 3p21.3 area, minimum overlapping area of deletion lays between two probes which are close to each other. These data will be useful to isolate the putative tumor-suppressor genes located on the chromosome 3p.

The neural cell adhesion molecule (N-CAM), a member of the immunoglobulin gene super-family mediating homophilic cell-cell adhesion in a neuroendocrine system, is preferentially expressed in human small cell lung cancer (SCLC). Immunoprecipitation of a panel of SCLC cell lines by monoclonal antibodies (mAbs) specific for N-CAM detects mainly the 145-kDa isoform. This result was correlated with Northern blotting where a single 6.2-kb mRNA was detected in nine SCLC cell lines. To determine cDNA sequence encoding the N-CAM isoform, we selected several cDNA clones encoding N-CAM isolated from OS2-R, a SCLC cell line established in our laboratory. Based on the analysis of the full-length cDNA obtained from two clones, the sequence of this 145-kDa isoform was shown to be essentially identical to that of the 140-kDa N-CAM isoform of neuroblastoma except for a single base pair changed at position 1620 without changing amino acid encoded.

An experimental radiologic reporting system using oral presentations has been developed and tested. The rewritable and compact magneto-optical disk (MOD) is employed to store oral diagnostic reports together with read radiologic images. The MOD is 5.25 inches in diameter, has a 600 MB memory capacity, and is erasable, light and compact. Advantages of the system are simultaneous retrieval of oral reports by a radiologist and the images he or she interpreted, and the capability of media circulation in addition to the function of filing. Thus MOD has a multimedia function of both off-line communication and filing. When medical images are interpreted and oral presentations are registered, automatically digitized oral reports and digitized images are filed in the MOD. Referring physicians can get oral diagnostic reports and can see the images at the same time on a personal computer. Furthermore, integration with voice recognition capability is being tried in our experiment.

A 20-year-old woman with a primary angiosarcoma of the right atrium is reported. The patient had a cardiorespiratory arrest due to cardiac tamponade with bloody pericardial effusion. Magnetic resonance imaging (MRI) revealed a tumor, which was corroborated by selective coronary angiography. Open-heart surgery was performed. The tumor relapsed however, and she died four months after operation. The tumor was undetectable by echocardiography, but MRI demonstrated a heterogeneous mass with focal areas of high- and low-signal intensity in the right atrium, suggesting that MRI may allow characterization of cardiac tumors.

A consecutive series of 30 patients 75 years of age and older who underwent isolated coronary artery bypass graftings during a 6 year period (from 1985 to 1990) was analyzed. This group was compared with a consecutive series of 512 patients under the age of 75 who underwent the same procedure during the same period. The elderly patients had a higher incidence of unstable angina pectoris, left main or triple vessel disease and depression of ejection fraction. There were no deaths in the hospital or within 30 days of operation (0%), but postoperative complication occurred in 26 cases (86.7%) in the elderly patients. Mean postoperative hospital stay was longer in the elderly patients than the younger ones (21.7 +/- 8.7 days, 18.9 +/- 5.9 days, respectively). The factors frequently noted in the elderly cases with major complications were emergency or urgent operation, history of congestive heart failure and diabetes. The factors associated with prolonged postoperative hospital stay in elderly cases were octogenarians, intraoperative blood transfusion, wound complications, perioperative myocardial infarction, pulmonary failure and low cardiac output state. It is concluded that CABG can be performed safely even in elderly patients by the proper postoperative management, in spite of having increased postoperative complications and resulting in a prolonged postoperative hospital stay.

Increasing number of coronary artery bypass surgery has been performed utilizing more arterial grafts because of poor long term patency rate of saphenous vein grafts. The risk of bilateral internal mammary artery grafting was studied in two groups of patients who were matched for recognized risk factors such as year of operation, age, gender, extent of coronary artery disease, left ventricular function, completeness of myocardial revascularization, and history of congestive heart failure. The patient groups differed in the fact that they received on internal mammary artery graft or two internal mammary artery grafts. The operative mortality rate was zero in either group. Analysis of operative and postoperative morbidity demonstrated no significant differences except for a slight increase in transfusion requirement, rate of wound infection and use of catecholamine in the group receiving two internal mammary artery grafts (p = 0.1, 0.1 and 0.05, respectively). We conclude at this moment that bilateral internal mammary artery grafting does not increase surgical mortality but increases the use of catecholamine comparing with the ipsilateral internal mammary artery grafting. Since the cases analysed in this study are limited, definitive conclusion should be deferred.

Three cell lines of small cell lung cancer (SCLC), which were established from specimens of untreated primary tumors biopsied by diagnostic bronchofiberscopy, were analyzed for immunological characteristics. These cell lines showed considerable heterogeneity in chemo-radiosensitivity, which was well correlated with clinical responses of the respective tumors, but their HLA-class I antigen expressions were equally depressed and they were susceptible to peripheral blood lymphocytes (PBL) and lymphokine-activated killer (LAK) cells, irrespective of their diverse chemo-radiosensitivity. Treatment of the cell lines with recombinant immune interferon (rIFN-gamma) increased their HLA-class I antigen expression and conversely depressed PBL sensitivity but not LAK sensitivity. This inverse relationship between HLA-class I expression and PBL susceptibility was also demonstrated using other pairs of autologous PBL and SCLC cell lines. rIFN-gamma changed neither HLA-class II antigen nor SCLC-specific antigen expression under the same experimental conditions. In vitro immunization of allogeneic peripheral blood lymphocytes with rIFN-gamma-treated SCLC cells induced allo-specific killer cells which lysed rIFN-gamma-treated more strongly than non-treated SCLC cells. These results suggest that reduced HLA-class I antigen expression of SCLC could protect the cancer from attack of killer T cells in spite of the higher sensitivity to PBL or LAK cells.

The present study was undertaken to determine whether small cell lung cancer (SCLC) cell lines produce immunosuppressive factors and, if they do, to characterize the factors. The supernatants of SCLC cell lines, H69 and N857, inhibited not only the blastogenic response of human peripheral blood lymphocytes (PBL) to phytohemagglutinin or concanavalin A, but also the cytotoxic activity of lymphokine-activated killer cells. Neither was inhibited by supernatants from non-SCLC cell lines PC9, QG56, and A549. The immunosuppressive activity of H69 supernatant was stable upon heating to 56 degrees C for 60 min, but labile when heated to 70 degrees C for 10 min. The activity was abolished after dialysis at pH 2.0 or pH 11.0, but not at pH 4.5 or pH 9.0. Digestion with trypsin or proteinase eliminated the immunosuppressive activity, whereas treatment with neuraminidase, mixed glycosidase, DNase or RNase had no effect, suggesting that the immunosuppressive activity in H69 supernatant is due to a protein factor. This H69-derived immunosuppressive factor was isolated by ion exchange chromatography using a gradient of 0.04 to 0.08 M NaCl solution. Gel filtration and sodium dodecyl sulfate-polyacrylamide gel electrophoresis showed the factor to have molecular weights of 98 kD and 102 kD, respectively. These results suggest that SCLC cells produce a potent immunosuppressive factor which may account for the immune deficiency in SCLC patients.

Murine IgG1 monoclonal antibodies (mAbs), ITK-2 and ITK-3, were generated against a small-cell lung cancer (SCLC) cell line. Enzyme-linked immunosorbent assay using a variety of established cell lines as substrates, immunoperoxidase staining of freshly frozen tissue sections, and fluorescence-activated cell sorter analysis of peripheral blood leukocytes showed that these mAbs recognize a part of the SCLC-associated cluster 1 antigen. In immunoprecipitation studies, both ITK-2 and ITK-3 bound to a 145-kDa glycoprotein of SCLC cell membrane extracts, as did MOC-1 and NKH-1, which both recognize the cluster 1 antigen. However, because the binding of 125I-labeled ITK-2 to SCLC cells was not inhibited by MOC-1 or NKH-1, the binding site of ITK-2 on SCLC cells appeared to be different from that of either MOC-1 or NKH-1. Unexpectedly, binding of 125I-labeled ITK-2 to SCLC cells increased in the presence of ITK-3. This ITK-3-induced increase in ITK-2 binding was due partly to an increase in the number of binding sites for ITK-2 on SCLC cells. Addition of ITK-3 may, therefore, improve the effectiveness of ITK-2-based tumor detection or therapy.

New cell lines of small cell lung cancer (SCLC) were established from specimens of untreated primary tumors biopsied by diagnostic bronchofiberscopy. The advantage of this method was ease of obtaining specimens from lung tumors. Establishment of cell lines was successful with 4 of 13 specimens (30%). Clinical responses of the tumors showed considerable variation, but were well correlated with the in vitro sensitivity of the respective cell lines to chemotherapeutic drugs and irradiation. One of the cell lines was resistant to all drugs tested and irradiation, while another was sensitive to all of them. Although the acquired resistance of SCLC is the biggest problem in treatment, the natural resistance to therapy is another significant problem. Either acquired or natural, resistance mechanisms of SCLC may be elucidated by the use of such cell lines derived from untreated tumors. This method and these SCLC cell lines are expected to be useful for the serial study of biologic and genetic changes of untreated and pre-treated tumors, or primary and secondary tumors.

A 28 year old man with no underlying disease developed a cavity and multiple nodules in the lung from which Corynebacterium equi was isolated. He experimented with organic solvents and microorganisms including Corynebacterium species for several years. Computed tomography of his pulmonary lesions revealed that these nodules were related to the bronchial tree. Histologically, the lesions were compatible with nonspecific inflammatory changes. The clinician must suspect the pulmonary infections with Corynebacterium species even if the patient has no underlying disease.

The induction of concomitant immunity was studied in Donryu strain rats with Yoshida ascites sarcoma cells. The changes of enzyme activity in spleen lymphocytes were also examined in normal and tumor-bearing rats. The concomitant immunity was detected 1 week after transplantation of tumor cells. Extended metastases were found 2 weeks after transplantation. The enzyme activities of ATPase and acid phosphatase were definitely higher than that of normal rat 1 week after the transplantation but decreased to lower level than normal 2 weeks later. On the other hand, alkaline phosphatase activity increased 3 times at 1 week after the transplantation and remained at the same level even at 2 weeks later.