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Small cell lung cancer with interstitial lung disease (ILD-SCLC) is difficult to treat because of the risk of fatal pneumonitis. Our study aims to evaluate the validity of topotecan (TOP) as chemotherapy for patients with relapsed ILD-SCLC. Overall survival was compared between TOP and other drugs as second-line treatments for ILD-SCLC patients. Forty-seven patients began chemotherapy and second-line treatment was administered in 48.5% of relapsed cases. The response rate of TOP for second-line therapy was 16.7%. Hematologic toxicities were grade 4 anemia, grade 3 neutropenia and grade 3 thrombocytopenia. Mild pulmonary toxicity was observed in 1 case. Patients receiving TOP as second-line treatment showed no significant difference in survival when compared to patients who underwent other regimens (median survival time 179 vs. 76 days; p =0.76). TOP is a well tolerated drug and is a viable candidate for second-line treatment of ILD-SCLC patients.

To evaluate radiation therapy regimens for improvement in local control in patients with limited-stage small cell lung cancer.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.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.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.

To test the feasibility of a system for intermittent irradiation synchronized with respiratory motion in a clinical setting.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).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.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.

The operative repair of Ebstein's anomaly is performed usually during the younger age. On the other hand, the operative indication of asymptomatic Ebstein's anomaly in adult patients has not been clearly defined. We encountered a 71-year-old female patient with asymptomatic Ebstein's anomaly. Because of severe tricuspid regurgitation (TR) and right ventricular dilatation, we repaired the tricuspid valve configuration. The operation was successful and medium term result was excellent. We believe that severe TR with moderate right ventricular dysfunction can be the operative indication in adult patients with asymptomatic Ebstein's anomaly especially when tricuspid valve repair is possible.

We recently demonstrated that the WT1 gene was overexpressed in the majority of de novo lung cancers regardless of cancer subtypes. Here, we examined WT1 genomic DNA in 38 cases of de novo non-small cell lung cancers (NSCLC) for mutations using direct sequencing. The sequencing analysis showed no mutations of WT1 genomic DNA in any of 38 de novo non-small cell lung cancers examined. These results indicated that the non-mutated, wild-type WT1 gene played an important role in de novo NSCLC.

IL-18 has been shown to exert anti-allergic or allergy-promoting activities, but the existence of genetic polymorphisms in the coding regions of IL-18 gene has not been demonstrated.The aim of this study was to investigate whether polymorphism is present in the coding regions of the IL-18 gene and, if so, to further analyse the association between polymorphism and asthma in a case-control study.We screened the coding regions of the IL-18 gene for polymorphisms by using PCRsingle-stranded conformation polymorphism and direct sequencing of PCR products, followed by analysis of the association between polymorphism and asthma.We identified one polymorphism (105A/C) in the coding regions. The frequency of the 105A allele was significantly higher in asthmatic patients than in controls (P0.01; odds ratio (OR)=1.83 (1.37-2.26)). Significant linkage disequilibrium was observed between the 105A/C and -137G/C polymorphisms in the 5' flanking region of the IL-18 gene (D=0.58, P0.0001). However, in asthmatic patients the 105A allele was not associated with either total serum IgE or IL-18 levels.The 105A/C polymorphism of the IL-18 gene may be associated with the pathogenesis of asthma.

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 (por = 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).

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.

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.

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.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.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).These findings suggest that the expression of GML mRNA is infrequent and regulated in a p53-independent manner in NSCLC.

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 (P0.001). 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, P0.001 for PS, P = 0.0052 for Stage).

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.

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 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.

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.

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.

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.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.

The prognostic significance of serum p53-Abs positivity for non-small cell lung cancer (NSCLC) is still unknown.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.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).These findings suggest that the combination of p53Abs seropositivity and p53 overexpression may be a prognostic factor for SCC.

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.

Background The prognosis of gastric cancer with peritoneal metastasis is extremely poor. Neither systemic chemotherapy nor surgery alone prolongs survival of patients significantly. Methods Patients diagnosed with advanced gastric cancer underwent staging laparoscopy and received chemotherapy when peritoneal dissemination and/or cancer cells on peritoneal cytology were confirmed. The chemotherapy regimen consisted of S-1, weekly intravenous and intraperitoneal paclitaxel, which was verified in our phase II trial (Ann Oncol 2009). S-1 was administered at 80 mg/m2/day for 14 consecutive days, followed by 7 days rest. Paclitaxel was administered intravenously at 50 mg/m2 and intraperitoneally at 20 mg/m2 on days 1 and 8. Clinical response of chemotherapy was assessed by computed tomography, gastroendoscopy, peritoneal cytology and second-look laparoscopy. Radical gastrectomy was carried out when macroscopic curative resection was made achievable by chemotherapy. Chemotherapy was restarted after operation as soon as possible. Overall survival, relapse free survival, morbidity and mortality of gastrectomy were evaluated. Results Out of 100 patients with peritoneal metastasis who received chemotherapy, 60 patients underwent gastrectomy after response to chemotherapy, including 54 with macroscopic metastasis and 6 with positive peritoneal cytology only. A median of three courses were administered preoperatively (range 1–16). Total or distal gastrectomy with lymphnode dissection was carried out in 54 or 6 patients, respectively. The median survival time was 34.5 months. The median relapse-free survival was 16.7 months. The first site of relapse was the peritoneum in 24 patients and the other organ site in 17 patients. Postoperative complications included anastomotic leakage and pancreatic fistula in two patients each, which were healed conservatively. There were no treatment-related deaths. Conclusions Gastrectomy combined with S-1, intravenous and intraperitoneal paclitaxel is safe and active for gastric cancer patients with peritoneal metastasis.

SRPX2 (Sushi repeat-containing protein, X-linked 2) has recently emerged as a multifunctional protein that is involved in seizure disorders, angiogenesis and cellular adhesion. Here, we analyzed this protein biochemically. SRPX2 protein was secreted with a highly post-translational modification. Chondroitinase ABC treatment completely decreased the molecular mass of purified SRPX2 protein to its predicted size, whereas heparitinase, keratanase and hyaluroinidase did not. Secreted SRPX2 protein was also detected using an anti-chondroitin sulfate antibody. These results indicate that SRPX2 is a novel chondroitin sulfate proteoglycan (CSPG). Furthermore, a binding assay revealed that hepatocyte growth factor dose-dependently binds to SRPX2 protein, and a ligand–glycosaminoglycans interaction was speculated to be likely in proteoglycans. Regarding its molecular architecture, SRPX2 has sushi repeat modules similar to four other CSPGs/lecticans; however, the molecular architecture of SRPX2 seems to be quite different from that of the lecticans. Taken together, we found that SRPX2 is a novel CSPG that is overexpressed in gastrointestinal cancer cells. Our findings provide key glycobiological insight into SRPX2 in cancer cells and demonstrate that SRPX2 is a new member of the cancer-related proteoglycan family.

The clinical significance of the serum crosslinked N-telopeptide of type I collagen (NTx) as a prognostic marker for non-small-cell lung cancer (NSCLC) was evaluated. We have revealed that a high serum NTx level (>22 nmol bone collagen equivalents (BCE)/L) appears to be a risk factor for a reduction in overall survival in patients with NSCLC. Introduction: Lung cancer is the leading cause of cancer-related death. Many patients with lung cancer are in its advanced stages at the time of diagnosis. The 5-year survival rate for lung cancer is 10% to 20%, and the prognosis for patients with lung cancer is still poor. The crosslinked N-terminal telopeptide of type I collagen (NTx) is a metabolite of type I collagen, the main constituent of bone matrix. Patients and Methods: We measured serum NTx levels in patients who underwent staging during hospitalization for the initial treatment of lung cancer in our department. We examined whether serum NTx levels would be relevant to the prognosis of non-small-cell lung cancer (NSCLC). Results: This study included 176 patients with lung cancer (125 men and 51 women), including 109 with adenocarcinoma, 53 with squamous cell carcinoma, 6 with large-cell carcinoma, and 8 with other cancer types. Univariate and multivariate analysis using the Cox proportional hazards model revealed a particularly close associ- ation between sex, performance status, disease stage, and serum NTx levels and overall survival (OS). A median OS of 368 days was observed for patients with a serum NTx level 22 nmol BCE/L, which was significantly longer than the 197 days for patients with a serum NTx level 22 nmol BCE/L (hazard ratio (HR), 2.02; 95% confidence interval (CI), 1.36-2.99; log-rank P.00037). Conclusions: We have revealed that a high serum NTx level ( 22 nmol BCE/L) appears to be a risk factor for a reduction in OS in patients with NSCLC.

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.

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.

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 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.

Interleukin 2 (IL 2) has been shown to be a potent stimulator of natural killer (NK) cells. In the present studies, partially purified mouse and human IL 2 preparations were also found to induce interferon (IFN) from mouse spleen cells. By the criteria of sensitivity to treatment at pH 2 and failure to be neutralized by a potent anti-alpha, beta IFN serum, the species of IFN produced was of type gamma. Cooperation between two types of cell, a macrophage and an NK-like cell, was required for IFN production by murine spleen cells treated with IL 2. The requirement for macrophages could be replaced with supernatant obtained by incubating macrophages for 24 hr with lymphokine preparations containing IL 2. Interestingly, mature T cells apparently played no role in the process. Furthermore, the beige (bg/bg) mutation, which severely impairs NK cell lytic activity, had no effect on the ability of NK-like cells to participate in IFN production. Cell fractionation experiments revealed no dissociation between the requirements for augmentation of NK cytotoxic activity and for IFN production, and it is concluded that at least a portion of the NK boosting induced by IL 2-containing preparations is mediated through gamma-IFN.

The ability of lymphokine-activated killer (LAK) cells to mediate antibody-dependent cellular cytotoxicity and its efficacy against a LAK-resistant tumor were investigated. Cells of the MH134 murine hepatoma line are scarcely lysed by LAK cells generated in vitro by incubation of C3H/HeN mouse spleen cells with human recombinant interleukin 2 (rIL 2). However, the splenic LAK cells potently lysed the LAK-resistant tumor cells in the presence of 11G2, a monoclonal antibody (MAb) of the IgG1 isotype reactive with a part of MM antigen. Peritoneal cells induced by daily i.p. injections of rIL 2 not only exhibited LAK activity but also mediated antibody-dependent cellular cytotoxicity against MH134 tumor cells in the presence of 11G2. The peritoneal cells exhibiting these cytotoxic activities were found to be nonadherent and nonphagocytic mononuclear cells possessing a similar cell surface phenotype as that of splenic LAK cells, that is Thy-1.2+ approximately -, Lyt-1.1-, Lyt-2.1-, and asialo GM1+. Treatment of spleen cells with antibodies and complement before culture with rIL 2 revealed that the phenotype of splenic LAK precursors is Thy-1.2- and asialo GM1+. The in vivo induction of peritoneal LAK cells in response to i.p. injections of rIL 2 was markedly depressed in C57BL/6 beige mice but was normally accomplished in BALB/c nude mice. Combined therapy of C3H/HeN mice bearing MH134 ascitic tumor with i.p. injection of rIL 2 and 11G2 brought about potent suppression of the tumor growth, resulting in the significant increase in the number of tumor-free mice, whereas neither rIL 2 nor the MAb could exhibit such a potent antitumor effect when used alone. Injection (i.v.) of anti-asialo GM1 antibody not only blocked the induction of peritoneal LAK cells by rIL 2 but also abrogated the development of the antitumor effect of the combined therapy. These results strongly suggest that combination of antitumor MAbs capable of inducing antibody-dependent cellular cytotoxicity with rIL 2 therapy could result in the generation of potent antitumor effects against LAK-resistant tumors and that asialo GM1-positive non-T-cell populations including cells of the natural killer cell lineage are essential, at least in part, for development of the antitumor effects of the combined therapy with rIL 2 and MAbs.

Four monoclonal antibodies to MH134 murine syngeneic hepatoma cells, 3H1, 7C2, 11G2, and 12A2, were produced by hybridomas constructed by fusing P3-X63-Ag8-U1 murine myeloma cells with spleen cells of a C3H/HeN mouse immunized with the syngeneic tumor cells. Immunodiffusion analysis with rabbit anti-mouse immunoglobulin antisera showed that 3H1, 7C2, 11G2, and 12A2 are IgG2a, IgM, IgG1, and IgG2a, respectively. Enzyme-linked immunosorbent assay using cells of five syngeneic tumor lines, MH134, MM102, MM46, MM48, and X5563, and lymph node cells of C3H/HeN and C57BL/6 mice showed that 3H1 specifically bound to MH134 tumor cells, whereas 7C2, 11G2, and 12A2 reacted not only with MH134 but also with MM102 and MM46 tumor cells. None of these monoclonal antibodies bound either to cells of MM48 or X5563 tumor lines or to normal lymph node cells. These results strongly suggest that MH134 tumor cells display at least two kinds of tumor-associated antigens on their cell surfaces: one is expressed uniquely by MH134 tumor cells, which are recognized by 3H1; the other is commonly shared by MH134, MM102, and MM46 tumor cells, which are determined by the other three antibodies. 3H1, 11G2, and 12A2 but not 7C2 were found to be able to induce antibody-dependent cellular cytotoxicity (ADCC) against MH134 tumor cells. Target specificity of ADCC induced by these monoclonal antibodies was identical with that seen in enzyme-linked immunosorbent assay. 3H1, 7C2, and 12A2 but not 11G2 exhibited complement-dependent cytotoxicity, showing the same specificity in target cell lysis as that seen in enzyme-linked immunosorbent assay or ADCC. Pretreatment of MH134 tumor cells with 7C2 inhibited ADCC of both 11G2 and 12A2. Pretreatment of the tumor cells with 11G2 inhibited complement-dependent cytotoxicity of both 7C2 and 12A2. Neither ADCC nor complement-dependent cytotoxicity of 3H1 was inhibited by the pretreatment of the cells with 7C2 or 11G2. These results strongly suggest that tumor-associated antigens recognized by 3H1 are located apart from that recognized by 7C2, 11G2, and 12A2 and that the binding sites of the latter three antibodies are closely associated with, or identical with, each other in the tumor-associated antigen. The ability of 12A2 to induce ADCC against MH134 tumor cells was significantly stronger than that of 3H1 or 11G2.(ABSTRACT TRUNCATED AT 400 WORDS)

Effect of the additional treatment with coenzyme Q10 on immunorestoration with Mycobacterium bovis BCG in tumor-bearing mice was investigated. Cell-mediated cytotoxicity in tumor-bearing mice against alloantigenic tumor cells was determined by 51Cr release assay using spleen cells of C57BL/6N mice which had been inoculated subcutaneously with syngeneic melanoma-B16 and immunized intraperitoneally with alloantigenic mastocytoma P815-X2 cells. The cell-mediated cytotoxicity against mastocytoma P815-X2 cells was gradually depressed with the growth of melanoma-B16. The depressed, cell-mediated cytotoxicity in tumor-bearing mice recovered slightly by the treatment with BCG. The recovery effect of BCG on the depressed, cell-mediated cytotoxicity was significantly enhanced by the additional treatment with coenzyme Q10. Coenzyme Q10 did not have an apparent effect on the depressed, cell-mediated cytotoxicity in tumor-bearing mice. These results show that coenzyme Q10 enhances the immunorestoration with BCG in tumor-bearing mice.

Cell-mediated cytotoxicity against syngeneic MC104 fibrosarcoma cells was detected in C57BL/6N mice 7 days after tumor inoculation in the hind foot. This cytotoxicity was undetectable by Day 14 in the Winn test using spleen and draining popliteal lymph node (DPLN) cells. Similar results were obtained with the 51Cr release assay following in vitro activation of these lymphoid cells with mitomycin C-treated tumor cells. The antitumor cytotoxicity was shown to be mediated by T-cells. Spleen but not DPLN cells from 14-day tumor bearers enhanced tumor growth in the Winn test, suggesting the presence of immunosuppressor cells in the spleen. Two intralesional injections of 50 microgram of cell wall skeleton (CWS) of Nocardia rubra on Days 2 and 7 resulted in apparent tumor growth inhibition and prolongation of the survival period of tumor bearers. DPLN cells from tumor bearers treated with N. rubra CWS exhibited significant recovery in the cytotoxicity tested on Day 14, whereas the recovery in that of spleen cells was not apparent. The cytotoxicity augmented by N. rubra CWS was specific to MC104 tumor cells and was shown to be mediated by T-cells. These cytotoxic T-cells were shown to be able to localize not only in DPLN but also in the spleen and tumor in mice receiving the intralesional immunotherapy with N. rubra CWS. These results suggest that T-cell-mediated cytotoxicity against syngeneic tumor can be augmented by N. rubra CWS and might play an important role in the systemic development of its antitumor effect, although the effector cell increase in the spleen might be suppressed by splenic suppressor cells during tumor growth.

The in vivo antitumor effect of i.p. injection of allogeneic spleen cells was investigated. ACl rats were inoculated i.p. with 10(4) AMC-60 syngeneic fibrosarcoma cells and given injections i.p. of 4 X 10(7) Wistar spleen cells once a week for 3 wk from 1 day after tumor inoculation. This treatment significantly prolonged the survival period of the tumor-bearing rats. A similar effect was obtained by i.p. injections of Lewis spleen cells. Injection i.p. into ACl rats of spleen cells of these rat strains resulted in the apparent augmentation of cytolytic activity of peritoneal adherent but not of nonadherent cells against AMC-60 tumor cells. The cytotoxicity was exhibited nonspecifically to cells of a variety of tumor lines but not to concanavalin A blasts of ACl spleen cells and was inhibited by the addition of carrageenan. Irradiation (2000 R) of Lewis spleen cells or fractionation of the allogeneic spleen cells using nylon wool columns revealed that a radiosensitive and nylon wool-passed cell population, presumably a T-cell population, of the allogeneic spleen cells is responsible for the augmentation of peritoneal macrophage tumoricidal activity in ACl rats. Further, Lewis spleen cells irradiated at 2000 R neither augmented peritoneal macrophage cytotoxicity nor prolonged the survival period of ACl rats bearing AMC-60 tumor, suggesting that the augmentation of peritoneal macrophage cytotoxicity plays a major role in the in vivo antitumor effect of the allogeneic spleen cell transfer. ACl rats were given injections i.p. of 4 X 10(7) Lewis spleen cells. Two days after injection, cells including peritoneal cells of the ACl rats and Lewis spleen cells remaining in the peritoneal cavities were obtained by peritoneal lavages and then incubated for 5 days. Significant blastogenic proliferation was observed, and the supernatant of the culture was shown to be able to render thioglycollate-induced peritoneal macrophages of ACl rats cytotoxic to AMC-60 tumor cells, indicating that a certain cell population of the cell mixture produced a lymphokine(s) resembling macrophage activating factor (MAF) during the incubation. When ACl rats were given injections i.p. of irradiated Lewis spleen cells, neither the blastogenic proliferation nor the generation of MAF activity in the culture supernatant was observed. Indirect immunofluorescence analysis using rabbit anti-ACl and anti-Lewis antisera revealed that as many irradiated Lewis spleen cells were remaining in the peritoneal cavities as normal Lewis spleen cells 2 days after injection into ACl rats.(ABSTRACT TRUNCATED AT 400 WORDS)