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Biomedical subjects

M Shinoda

Publications and source records attributed to M Shinoda.

At least 55 records · Page 3Linked to original sources
PubMed1999

Interleukin-6 and soluble interleukin-6 receptor in the colonic mucosa of inflammatory bowel disease.

BACKGROUND: Interleukin-6 (IL-6) has multiple immunological effects on a wide variety of cells and tissues. The expression of IL-6 and IL-6 receptor (IL-6R) may be important to the pathogenesis of inflammatory bowel disease (IBD). METHODS: In the present study, we examined whether mucosal IL-6 and soluble IL-6R were associated with the pathophysiology of IBD using the colonic mucosal specimens obtained from patients with IBD. Enzyme-linked immunosorbent assay was used to measure the levels of IL-6 and sIL-6R in organ cultures of mucosal tissues and in cell cultures of fractionated mucosal cells as well as in the serum. Expression of IL-6 and IL-6R was analysed by reverse transcription-polymerase chain reaction analysis using freshly isolated lamina propria mononuclear cells (LPMC). RESULTS: The levels of IL-6 and sIL-6R in organ cultures were substantially elevated in patients with IBD, especially in those with histologically active inflammation. In contrast, considerably higher levels of sIL-6R were detected in patients with other types of colonic inflammation who were included as inflammatory controls, but elevation of IL-6 was less prominent in such patients. The positivity for expression of IL-6 and IL-6R mRNA in LPMC was in parallel with the results obtained in organ cultures. In cell cultures, mucosal macrophages were the main cell type producing both IL-6 and sIL-6R on a per cell basis and other cell fractions including colonic epithelial cells and lymphocytes produced substantially lower amounts of these molecules. The levels of IL-6 and sIL-6R in organ cultures, but not those in the serum, showed a significantly positive correlation with the degree of clinical disease activity in patients with IBD. CONCLUSIONS: Enhanced IL-6/sIL-6R-mediated immune and inflammatory responses may be implicated, at least partly, in the continuation of intestinal inflammation in patients with IBD.

Adolescent↗
PubMed1999

Inhibition of human aldehyde reductase by drugs for testing the function of liver and kidney.

Drugs for testing the function of liver and kidney (sulfobromophthalein, phenolsulfonphthalein, indigo carmine and indocyanine green) and other organic anions (rose bengal and haematin) were found to potently inhibit human liver aldehyde reductase that is involved in the detoxification of 3-deoxyglucosone and methylglyoxal, reactive intermediates, during the formation of advanced glycation end products. The inhibition patterns by the compounds were non-competitive with respect to both coenzyme (NADPH) and substrate (D-glucuronate). The kinetics of the inhibition by a mixture of the 2 inhibitors suggests that all the inhibitory compounds bind to overlapping sites on the enzyme. The binding of rose bengal, sulfobromophthalein and phenylsulfonphthalein to the free enzyme was detected by ultrafiltration assay. However, in the reverse reaction, the enzyme was inhibited competitively with respect to the alcohol substrate by rose bengal, haematin, phenolsulfonphthalein, sulfobromophthalein, indigo carmine and indocyanine green, which showed Ki values of 0.1, 1, 3, 4, 4 and 10 microM, respectively. The results suggest that these potent inhibitors bind weakly to the free enzyme and tightly to the enzyme-NADP binary complex.

Aldehyde Reductase↗
PubMed1999

Specific targeting immunotherapy of cancer with bispecific antibodies.

In order to enhance cell mediated cytotoxicity, bispecific antibodies (BsAbs), molecules combining two or more antibodies with different antigenic specificities, have been developed as new agents for immunotherapy. Our recent studies revealed that simultaneous administration of two kinds of BsAbs (anti-tumor x anti-CD3 plus anti-tumor x anti-CD28) together with lymphokine activated killer cells with a T cell phenotype (T-LAK cells) inhibited growth of human xenotransplanted tumors in severe combined immunodeficient (SCID) mice, while single BsAb was without effect. Three kinds of BsAbs (anti-tumor x anti-CD3, anti-tumor x anti-CD28, anti-tumor x anti-CD2) showed the highest cytotoxicity against tumor cells when given simultaneously with T-LAK cells or peripheral blood mononuclear cells in vitro and in vivo. BsAbs can be preserved for immediate application, while cytotoxic T lymphocytes (CTLs) must be made-to-order, and are time-consuming to prepare. Tumor associated antigens, such as MAGE antigens, SART antigens, MUC1 antigen, c-erbB 2 antigen or cancer/testis antigens can be served to target antigens for BsAb production. By conjugation with antibodies to effector cells (anti-CD3, anti-CD28, anti-CD16, anti-CD64, anti-CD89 or anti-CD2), many kinds of BsAbs can be produced to cover most types of cancers from different organs. Therefore this strategy might be ubiquitously applicable to most malignancies.

Animals↗
PubMed1998

Enhanced secretion of insulin plays a role in the development of atherosclerosis and restenosis of coronary arteries: elective percutaneous transluminal coronary angioplasty in patients with effort angina.

OBJECTIVES: We investigated the relation between insulin and coronary atherosclerosis and restenosis of the coronary arteries, by performing elective percutaneous transluminal coronary angioplasty (PTCA). BACKGROUND: Insulin is known to promote atherosclerosis of the arteries and has been implicated in the development of restenosis after PTCA. METHODS: Of 210 angina patients who underwent PTCA, newly detected lesions in 35 consecutive nondiabetic subjects without previous intervention on the same main coronary arteries were analyzed after a 75-g oral glucose tolerance test (OGTT) and follow-up coronary angiography. Atherosclerotic lesions were evaluated by pattern, severity and extent. Restenosis was defined as loss of gain, the percentage of loss of the initial gain in the coronary diameter achieved by PTCA > or = 50%. RESULTS: Patients with restenosis had a significantly higher extent index (a marker of atherosclerosis), insulin area, ratio of insulin area to glucose area, insulinogenic index and minimal lumen diameter after PTCA than those without restenosis (p=0.001, 0.011, 0.002, 0.016 and 0.041, respectively). Simple regression analysis revealed that only the ratio of insulin area to glucose area (a relative marker of enhanced insulin secretion) significantly correlated with the extent index (p=0.035). Extent index, insulin area, the ratio of insulin area to glucose area and insulinogenic index significantly correlated with loss of gain (p=0.001, 0.010, 0.002 and 0.032, respectively). Stepwise multiple regression analyses revealed that extent index and the ratio of insulin area to glucose area significantly correlated with loss of gain. CONCLUSIONS: Enhanced secretion of insulin during the OGTT might be useful as a predictor of coronary atherosclerosis and of restenosis after elective PTCA in nondiabetic patients with effort angina.

Aged↗
PubMed1998

Clinical implications of p53 autoantibodies in the sera of patients with non-small-cell lung cancer.

BACKGROUND: The presence of autoantibodies to p53 protein has been associated with the presence of p53 (also known as TP53) gene mutations in primary tumors and with poor prognosis. This study was undertaken to determine the clinical significance of p53 autoantibodies in patients with non-small-cell lung cancer (NSCLC). METHODS: We studied 188 consecutive patients with NSCLC who underwent pulmonary resection and for whom preoperative serum was available. The presence of p53 autoantibodies, detected by use of two amino-terminal and two carboxy-terminal peptides (20-30 mers) as antigens and an enzyme-linked immunosorbent assay, was related to various clinicopathologic parameters and to overexpression of p53 protein in the primary tumor. For 22 patients who had p53 autoantibodies before surgery, we also examined sera taken during postoperative follow-up. Reported P values are two-sided. RESULTS: Autoantibodies to p53 protein were detected in 38 patients. Patients with squamous cell carcinoma, those with more advanced disease (stage III-IV), and those with tumors that overexpressed p53 had a significantly higher incidence of p53 autoantibodies (P = .05,.0079, and .02, respectively). In all but one of the patients with postoperative serum samples, the antibody titer declined after surgery; however, there was no relationship between clinical course and this change in antibody titer. In addition, there was no relationship between the presence of p53 autoantibodies and overall survival in 171 patients who underwent potentially curative resection (P = .28); however, 13 patients with autoantibodies to amino-terminal peptides had a worse overall survival (P = .02). CONCLUSIONS: In NSCLC, the incidence of p53 autoantibodies is associated with histologic type, stage, and p53 overexpression--but not with patient survival. Our data do not support the clinical utility of p53 autoantibodies as diagnostic or prognostic markers in patients with NSCLC.

Adult↗
PubMed1998

Methylation of the 5' CpG island of the FHIT gene is closely associated with transcriptional inactivation in esophageal squamous cell carcinomas.

Previous studies suggested that the FHIT (fragile histidine triad) gene on 3p14.2 might be involved in the development of esophageal squamous cell carcinomas, but the mechanisms for inactivating the gene have not been fully revealed. In the present study, we examined aberrations of the FHIT gene in 23 esophageal squamous cell carcinoma cell lines and 35 primary tumors. We detected aberrant expression in seven cell lines (30%), including a shorter transcript in two cell lines and loss of apparent transcript in five cell lines. Genomic PCR or cDNA sequencing analysis revealed a single exon deletion in two cell lines with a shorter transcript and one cell line without expression, but no structural alterations were found in the other 20 cell lines, including transcriptionally repressed four cell lines. Next we examined methylation of the 5' CpG island of the FHIT gene by bisulfite genomic sequencing. Hypermethylation of the 5' CpG island of the FHIT gene was observed in three of four structurally unaltered but transcriptionally repressed cell lines. The remaining cell line harbored a point mutation upstream of exon 1. All methylated cell lines exhibit re-expression of the FHIT gene and demethylation in the CpG island after treatment with demethylating agent 5-aza-2'-deoxycytidine. Hypermethylation was also found in 5 of 35 (14%) primary tumors, whereas corresponding normal tissue shows no methylation. These findings suggest that methylation of the 5' CpG island of the FHIT gene is closely associated with transcriptional inactivation and might be involved in tumor development of the esophagus.

Acid Anhydride Hydrolases↗
PubMed1998

Effective adoptive immunotherapy by T-LAK cells retargeted with bacterial superantigen-conjugated antibody to MUC1 in xenografted severe combined immunodeficient mice.

To reinforce cytotoxic activity and the targeting ability of lymphokine-activated killer cells with a T-cell phenotype (T-LAK) for adoptive immunotherapy against human bile duct carcinoma (BDC), staphylococcal enterotoxin A (SEA) was conjugated chemically with MUSE11 monoclonal antibody (MUSE11 mAb), directed to the MUC1 antigen, using N-succinimidyl 3-(2-pyridyldithio) propionate and 2-iminothiolane HCl. Both SEA-conjugated MUSE11 mAb (SEA-MUSE11) and the F(ab')2 of MUSE11 mAb (SEA-F(ab')2) showed significant enhancement of T-LAK cell tumor neutralization for MUC1 positive-target tumor cells, even with a concentration of 0.01 microg/ml at an E:T ratio of 5:1 in vitro. In this in vitro test, MUC1-positive BDC cells were observed to attach to surrounding T-LAK cells in the presence of SEA-MUSE11 or SEA-F(ab')2. Remarkable tumor growth inhibition was observed in BDC-grafted severe combined immunodeficient mice to which 2 x 10(7) T-LAK cells preincubated with 2 microg of SEA-MUSE11 or SEA-F(ab')2, together with recombinant interleukin 2 (500 IU), were administered i.v. for 4 consecutive days, when tumor size was 5 mm in diameter. These results point to a promising adoptive immunotherapy for patients with BDC.

Animals↗
PubMed1998

Usefulness of enhanced insulin secretion during an oral glucose tolerance test as a predictor of restenosis after direct percutaneous transluminal coronary angioplasty during acute myocardial infarction in patients without diabetes mellitus.

To determine predictive factors of the development of restenosis after percutaneous transluminal coronary angioplasty (PTCA), 25 nondiabetic nonobese patients aged <80 years old and 57 consecutive patients with successful direct PTCA with acute myocardial infarction were subjected to a 75-g oral glucose tolerance test (OGTT) and underwent follow-up coronary angiography 4 months later. The relation between the development of restenosis (late loss index: the decrease in the absolute minimal lumen diameter [MLD] at follow-up coronary angiography divided by MLD measured 1 day after PTCA) and the results of OGTT together with basic patient characteristics like age, body mass index, plasma levels of cholesterol, triglycerides, and high-density lipoprotein cholesterol were analyzed. Spearman's rank correlation analysis revealed that neither age, body mass index, nor plasma lipids correlated with late loss index, but only insulin area (p = 0.041) and insulin area/glucose area (p = 0.038) significantly correlated with the development of restenosis; a stepwise multiple regression analysis revealed that the insulin area was the only independent predictor of restenosis (p = 0.019). These results suggest that enhanced insulin secretion in response to glucose plays an important role in the development of restenosis after direct PTCA in non-diabetic patients, which may be through the direct action of insulin on smooth muscle cells of the coronary artery. This study also suggests the importance of performing OGTT for patients undergoing PTCA for the prediction of the development of restenosis.

Aged↗
PubMed1998

ER-34122, a novel dual 5-lipoxygenase/cyclooxygenase inhibitor with potent anti-inflammatory activity in an arachidonic acid-induced ear inflammation model.

OBJECTIVE AND DESIGN: To investigate the effect of ER-34122, a novel pyrazole derivative, on 5-lipoxygenase (LOX) and cyclooxygenase (COX) metabolite production in vitro, ex vivo and in vivo. MATERIAL: In vitro, lysate of rat basophilic leukemia cells, the microsome fraction of sheep seminal vesicles, human polymorphonuclear leukocytes, human synovial cells, and human monocytes. Ex vivo and in vivo, male Balb/c mice or SD rats. TREATMENT: In ex vivo study, ER-34122 (0.03-1 mg/kg) was orally administered 1 h before withdrawal of blood samples. In carrageenin-induced paw edema, ER-34122 (3-100 mg/kg) and indomethacin (1-10mg/kg) were orally administered 1 h before carrageenin injection. In arachidonic acid-induced ear inflammation, ER-34122 (0.3-10mg/kg), zileuton (10-100mg/kg) and indomethacin (0.3-3mg/kg) were orally administered 1 h before arachidonic acid application. METHODS: 5-Hydroxyeicosatetraenoic acid and other eicosanoids were determined by using an HPLC method and enzyme immunoassay, respectively. Rat hind paw edema and mouse ear edema were assessed by measuring paw volume and ear thickness, respectively. Myeloperoxidase (MPO) activity and eicosanoid content of the ear tissue were also determined. RESULTS: ER-34122 inhibited both LOX and COX product generation in vitro, and ex vivo. ER-34122 and indomethacin inhibited carrageenin-induced paw edema formation. In the arachidonic acid-induced ear inflammation, ER-34122 inhibited inflammatory responses (edema formation and MPO accumulation) as well as eicosanoids (LTB4, LTC4 and PGE2) generation. A representative LOX inhibitor, zileuton, also inhibited these inflammatory responses, while a COX inhibitor, indomethacin, did not suppress them though it completely inhibited PGE2 generation. CONCLUSIONS: The anti-inflammatory characteristics of ER-34122 are considered to be superior to those of COX inhibitors such as indomethacin, because in addition to its inhibitory activity on the COX pathway, ER-34122 inhibits LOX products generation, as revealed by the inhibition of edema formation or polymorphonuclear leukocyte infiltration in the arachidonic acid-induced ear inflammation model.

Animals↗
PubMed1998

Cold pressor stimulus temperature and resting masseter muscle haemodynamics in normal humans.

Cold pressor stimulation reportedly increases sympathetic nerve activity in human skeletal muscles. This study examined the effect of cold pressor stimulation on the resting haemodynamics of the right masseter muscle in normal individuals, using near-infrared spectroscopy. Nine healthy non-smoking males with no history of chronic muscle pain or vascular headaches participated. Their right hand was immersed in a water bath (4, 10, 15 degrees C) for exactly 1 min. Each trial lasted 7 min (1 min before, 1 min during, 5 min after stimulation) and a strictly random order was utilized for the three test temperatures and the mock trial. Masseter muscle haemoglobin concentration and oxygen saturation, as well as heart rate and blood pressure, were continuously recorded in each trial. After completing the four trials, each participant produced and sustained a 30-s maximum voluntary clench in the intercuspal position. Data across the four trials were baseline-corrected and then magnitude-normalized to the individual's highest absolute haemoglobin and oxygen signal during the 30-s maximal clenching effort. Haemoglobin and oxygen saturation increased progressively during cold pressor stimulation as the water temperature decreased (Hb, p < 0.0001; O2, p = 0.0327); very little effect was seen during the mock trial. Heart rate and blood pressure also increased progressively during the stimulation as the temperature decreased (heart rate, p = 0.0013; systolic blood pressure, p = 0.0042; diastolic blood pressure, p = 0.0156). These data suggest that cold pressor, stimulation induces a strong increase in intramuscular blood volume which appears to be due to both a local vasodilative response and increased cardiac output.

Adult↗
PubMed1998

Differential normalization of mucosal interleukin-8 and interleukin-6 activity after Helicobacter pylori eradication.

There is differential resolution of mucosal infiltration with neutrophils and mononuclear cells following successful Helicobacter pylori eradication. We investigated the effects of H. pylori eradication on mucosal interleukin-8 (IL-8) and IL-6 activity in relation to the resolution of H. pylori-associated gastritis. Eighty-one duodenal ulcer patients with H. pylori infection received dual- or triple-treatment eradication therapy, and mucosal biopsy specimens obtained at the initial and follow-up endoscopic examinations were cultured in vitro for 24 h. The levels of IL-8 and IL-6 were measured by enzyme-linked immunosorbent assays. In the 42 patients in whom H. pylori eradication failed, there was little change in the numbers of neutrophils and mononuclear cells infiltrating the mucosa and in IL-8 and IL-6 activity. In the 39 patients in whom H. pylori was eradicated, there was normalization both in the numbers of infiltrating neutrophils and in mucosal IL-8 activity, which was evident within 1 month following therapy. In contrast, there was a gradual resolution of mononuclear cell infiltration over a 6-month period, accompanied by a gradual normalization in IL-6 levels. Addition of H. pylori to cultures of mucosal tissues induced a significant increase in IL-8 activity in both uninfected control subjects and patients from whom H. pylori was eradicated. However, this introduction yielded a significant increase in IL-6 activity only in the latter group. This study indicates a dichotomy in the changes of mucosal IL-8 and IL-6 activity after H. pylori eradication. The rapid normalization of IL-8 after H. pylori eradication and the ability of H. pylori cells to stimulate IL-8 in control tissues indicate that IL-8 induction is a part of the innate (nonimmune) responses to this organism. In contrast, the results of experiments analyzing IL-6 activity in cultured mucosal tissues suggest that the gradual resolution of mucosal IL-6 activity and mononuclear infiltration after successful eradication observed in vivo may reflect gradually diminishing residual immune responses against H. pylori.

Adult↗
PubMed1998

Metabolic and hormonal responses to exercise in partially hepatectomised rats.

To characterise how the liver affects metabolic and hormonal exercise responses, hepatectomised (70%; HX) rats were submitted to a 30- or 50-min treadmill exercise (26 m/min, 0% slope) 48 hr or 7 days after surgery (reduced or normal liver mass, respectively). To determine whether metabolic effects of liver mass reduction during exercise were caused by reduced capacity of the liver to produce glucose, metabolic and hormonal responses to the same exercise protocol were measured in 48-hr HX rats. Euglycemia, maintained by exogenous glucose infusion, produced attenuated lactate, insulin, and glucagon values in 48-hr HX rats but did not affect FFA, glycerol, and plasma catecholamine responses. Results indicate that metabolic and hormonal exercise responses are amplified in 48-hr HX rats. Maintaining euglycemia in 48-hr HX rats during exercise does not reduce all responses. Intrahepatic events, similar to those in a short-term (48-hr) HX liver, may influence metabolic and hormonal exercise responses.

Animals↗
PubMed1998

A novel prolyl endopeptidase inhibitor, JTP-4819--its behavioral and neurochemical properties for the treatment of Alzheimer's disease.

Formation of beta-amyloid and neurofibrillary tangles in the brain due to genetic or other factors is the most frequent cause of Alzheimer's disease. In addition, marked reduction of certain brain neuropeptide levels is a consistent finding in patients with Alzheimer's disease, together with the deterioration of cholinergic neurons. Currently, there is great demand for the development of new drugs to improve memory deficits or to delay the neurodegenerative process in conditions such as Alzheimer's disease. In this report, the pharmacological actions of JTP-4819, a novel specific prolyl endopeptidase (PEP) inhibitor devised for the treatment of Alzheimer's disease, are reviewed with respect to its effects on PEP activity, neuropeptidergic and cholinergic neurons, and memory-related behavior in rats. We also discuss the possible beneficial effect of JTP-4819 on beta-amyloid metabolism and its potential neuroprotective properties.

Alzheimer Disease↗
PubMed1998

[Severe late effects of esophageal cancer treated by simultaneous intraluminal hyperthermo-brachytherapy: a case report].

Severe late effects occurred after the treatment of esophageal cancer by external irradiation and simultaneous intraluminal hyperthermo-brachytherapy. This is the first case report on late side effects. A 73-year-old man was treated with radiotherapy alone according to his decision. The stage was T2N0M0 according to the 1987 UICC. External irradiation of 40 Gy/20 fr was delivered followed by simultaneous intraluminal hyperthermo-brachytherapy once weekly for four weeks (16 Gy/4 fr). Complete response was achieved. Eight months later, local recurrence and ulcer were found, and surgery was performed. The specimen showed healing of an ulcer acknowledged before surgery and another deep ulcer next to the tumor that penetrated the adventitia, which was close to perforation. The histopathologic specimen showed severe stenosis of muscular arteries in the adventitia, which was caused by fibrosis of the endothelium. The findings suggested that enhancement might be occurred with this combined therapy.

Aged↗
PubMed1997

Specific inhibitor for prolyl endopeptidase suppresses the generation of amyloid beta protein in NG108-15 cells.

A potent and specific prolyl endopeptidase inhibitor, JTP-4819, was used to investigate the role of prolyl endopeptidase in the generation of amyloid beta protein (A beta) from APP by NG108-15 cells. Synthetic substrates, 7-(succinyl-Ile-Ala)-4-methylcoumarinamide and Z(Val-Lys-Met)-4-methylcoumarinamide, respectively, corresponding to the C-terminal and N-terminal portions of A beta, were cleaved by NG108-15 cell lysates. Cleavage of the C-terminal portion, but not the N-terminal, was inhibited by JTP-4819 (IC50 = 0.6 nM). Western blot analysis showed that the A beta level in the culture medium of NG108-15 cells was increased by serum deprivation. JTP-4819 caused concentration (>10(-9) M)- and time-dependent inhibition of this serum deprivation-induced increase of A beta without having any effect on the level of the secretory form of APP. Using both specific anti-A beta (1-40) and anti-A beta (1-42) antisera, the A beta that increased with serum deprivation was confirmed to be A beta (1-40), suggesting that it might be produced by conversion of A beta (1-42) to A beta (1-40). These findings indicate that prolyl endopeptidase may be a key enzyme in the production of A beta by NG108-15 cells and that A beta secretion can be modulated by a prolyl endopeptidase inhibitor.

Amyloid beta-Peptides↗
PubMed1997

A randomized trial of surgery with and without chemotherapy for localized squamous carcinoma of the thoracic esophagus: the Japan Clinical Oncology Group Study.

OBJECTIVE: To determine whether postoperative adjuvant chemotherapy confers a survival benefit on patients with esophageal squamous cell carcinoma undergoing radical surgery, we undertook a cooperative, prospective randomized controlled trial. METHODS: A total of 205 patients underwent transthoracic esophagectomy with lymphadenectomy at eleven institutions between December 1988 and July 1991. These patients were prospectively randomized into two groups (100 patients underwent surgery alone and 105 patients had additional two courses of combination chemotherapy with cisplatin (70 mg/m2) and vindesine (3 mg/m2). The two groups did not differ with respect to sex, age, location of tumor, and distributions of pT, pN, pM, or p stage. RESULTS: The 5-year survival was 44.9% in the surgery alone group and 48.1% in the surgery plus chemotherapy group. The relative risk was estimated to be 0.89 (95% confidence interval, 0.61 to 1.31) in the surgery plus chemotherapy group compared with the surgery alone group. No significant differences in survival were detected between the two groups, even with lymph node stratification. CONCLUSION: Postoperative adjuvant chemotherapy with cisplatin and vindesine has no additive effect on survival in patients with esophageal cancer compared with surgery alone.

Adult↗
PubMed1997

Mutations of the P53 tumor suppressor gene as clonal marker for multiple primary lung cancers.

OBJECTIVES: Second primary lung cancers are prevalent after treatment for initial lung cancer, and the lung is also one of the most frequent sites for recurrence after removal of early-stage lung cancer. The objective of the present study is to clarify the clonal origin of the second tumor with the p53 gene mutation used as a clonal marker. METHODS: Of 794 consecutive patients who underwent pulmonary resection for primary lung cancer from 1980 to 1993, 22 required second pulmonary resection during the follow-up period, with a median interval of 38 months. We examined 16 of these patients for mutations of the p53 gene occurring in exons 5 through 8 by the polymerase chain reaction/single strand conformation polymorphism method. Differential diagnosis was also made on a morphologic basis, considering the degree of cellular differentiation and cytologic subtypes. RESULTS: Nine of the 16 patients analyzed had at least one p53 mutation in their tumors. We were thus able to make molecular diagnoses for these patients. The mutational status of the p53 gene was discordant in all nine patients, suggesting a different clonal origin despite the fact that six of them had almost identical histologic features. CONCLUSIONS: Analysis of p53 gene mutations was thus useful in distinguishing second primary lung cancers from recurrent tumors. The observed heterogeneity of p53 status was also in line with the "field cancerization" concept.

Adenocarcinoma↗