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In 1982, we reported a case of retroperitoneal fibrosis (RPF) exhibiting various clinical manifestations. Our current understanding of immunoglobulin G4 (IgG4)-related disease led us to consider it as a possible diagnosis because all of the patient's clinical features could be explained by this disease entity. To confirm our hypothesis, were investigated the histopathological findings of resected specimens that had been stored for 35 years postoperatively. Typical pathological findings together with predominant IgG4+ plasma cell infiltration confirmed a potential diagnosis of IgG4-related RPF. Furthermore, we observed positive immunohistochemical staining for several molecules associated with T regulatory and T follicular helper cells.

Hereditary xanthinuria is an extremely rare purine metabolism disorder caused by a genetic abnormality in xanthine dehydrogenase. A new case of hereditary xanthinuria type 1 accompanied by bilateral renal calculi was encountered. We performed an allopurinol loading test and diagnosed classical type 1 xanthinuria. Through genetic diagnosis, we identified a mutation site in the xanthine dehydrogenase gene. Genetic analysis revealed a homozygous deletion of cytosine 2,567 in the xanthine dehydrogenase gene, and as a result, a stop codon was formed at position 928. Renal failure caused by the deposition of xanthine crystals is a known complication because xanthine is poorly soluble in water. With high fluid intake and low purine diet, no significant increase in calculi has been observed in this patient for 2 years.

Although a number of animal studies have been conducted to investigate the toxic effects of gaseous pollutants on human airways, the anatomical and physiological differences between animals and humans represent a challenge in extrapolating the animal data to humans. The aim of this study was to examine how interspecies anatomical and physiological differences influence the transport of the inhaled gases throughout the airways and alveoli. We designed mathematical airway models of three mammalian species, rats, dogs, and humans, in which interspecies differences in airway dimensions and respiratory patterns were taken into account. We then simulated the bulk flow of three gases (ozone [O(3)], nitrogen dioxide [NO(2)], and sulfur dioxide [SO(2)]) and obtained the intra-airway concentrations of the gases and the amount absorbed using these models. For all three gases, both real-time and mean concentrations in the upper and lower airways were higher in humans when compared with rats and dogs. For example, the mean concentration of O(3) in the 5th bronchi of humans was 3 and 12 times higher than in rats and dogs, respectively. Similarly, the amount of absorbed gases corrected for airway surface area was again higher in the upper and lower airways of humans than the other two species. Sensitivity analysis indicated that tidal volume, respiratory rate, and surface area of the upper and lower airways had significant impact on the results. In conclusion, kinetics of inhaled gaseous substances vary substantially among animals and humans, and such variations are, at least partially, the result of anatomical and physiological differences in their airways.

BACKGROUND The ras oncogene and the p53 tumor suppressor gene play important roles in the carcinogenic process of lung carcinoma. The authors evaluated whether alterations of the ras and p53 proteins may contribute to the development of lung carcinoma in patients with idiopathic pulmonary fibrosis (IPF) and whether such alterations may explain the high incidence of lung carcinoma among patients with IPF. METHODS Lung tissues were obtained from 35 patients who had IPF without complications of lung carcinoma and from 36 patients who had IPF with complications of lung carcinoma. Altered expression of ras and p53 proteins was evaluated by immunohistochemistry, and mutations of both genes were evaluated by polymerase chain reaction-single strand conformation polymorphism and sequencing analyses. RESULTS The frequency of expression of ras protein in type II alveolar pneumocytes was significantly greater in lung tissues from patients with IPF who had lung carcinoma compared with lung tissues from patients with IPF who did not have lung carcinoma (75% vs. 40%, respectively; P < 0.01). K-ras point mutation in codon 12 (GGT to GTT transversion) was detected in lung tissue with interstitial pneumonia, in which ras protein was overexpressed in type II alveolar pneumocytes obtained from 2 of 41 patients with IPF complicated by lung carcinoma, causing amino acid substitution (Gly to Val) in both patients. A p53 mutation was detected in three of six lung tissue samples from patients who had IPF lung with positive p53 immunoreactivity, and multiple mutations were detected in two samples. CONCLUSIONS Expression of ras protein in type II alveolar pneumocytes and mutation in the codon 12 of K-ras gene in lung tissue may contribute to the induction of lung carcinoma in patients with IPF. Furthermore, the presence of multiple mutations in the p53 gene may explain the high incidence lung carcinoma in patients with IPF. Cancer 2002;95:624–33. © 2002 American Cancer Society. DOI 10.1002/cncr.10708

Summary In vitro treatment of thymocytes and splenocytes with rabbit complement (C′) alone induced significant reductions in the proportion of NK-T cells in murine system. The reduction appeared to be prominent in the thymic NK-T cells compared to that in splenic NK-T cells. No reductions were detected in other populations, such as T, B and NK cells. Thus, NK-T cells lineage-specifically showed the enhanced C′ sensitivity. However, NK-T cells in T cell receptor (TCR) transgenic mice of RAG–/– background that lack B cells and antibodies exhibited no C′ sensitivity. On the other hand those from the same TCR transgenic mice of RAG intact background that have a normal population of B cells and antibodies showed the C′ sensitivity similar to that in normal mice. These findings suggest that the enhanced C′ sensitivity observed in the NK-T cell population is associated with the NK-T specific autoantibodies. Indeed, we found that a subset of NK-T cells in the thymus bound mouse immunoglobulins. Similar observations were obtained with several strains of lupus model mice, some of which show a decrease of NK-T cells with aging. Possible roles of the enhanced C′ sensitivity of NK-T cells in pathophysiological conditions in various mouse strains including lupus models are discussed.

Objectives: Few genetic markers for the prognosis of sarcoidosis have been found. Tumor necrosis factor (TNF)-a has been implicated in the pathogenesis of sarcoidosis. Induced TNF-a or TNF-b levels have been shown to be associated with the polymorphisms of the TNF genes. We investigated the roles of such polymorphisms in the development and prolongation of sarcoidosis. Subjects and measurements: One hundred ten Japanese patients with sarcoidosis and 161 control subjects were genotyped for three biallelic polymorphisms in the promoter region of TNF-a gene by direct sequencing of polymerase chain reaction (PCR) products. A polymorphism of the TNF-b gene (TNFB * 1/TNFB * 2) was detected by Nco I restriction fragment length polymorphism analysis of PCR products spanning intron 1 and exon 2 of the TNF-b gene. Results: None of the polymorphisms conferred susceptibility to sarcoidosis. However, our study identified the allele TNFB * 1, detected by the presence of a Nco I restriction site, as a marker of prolonged clinical course, with the resolution of sarcoidosis being defined as the disappearance of all clinical symptoms, physical signs of active lesions, abnormal chest radiograph findings, and abnormal results of pulmonary function and biochemical tests. When the probability of remission in patients homozygous for TNFB * 2 was defined as 1.00, it was 0.48 (95% confidence interval, 0.26 to 0.88; p < 0.05) in patients with TNFB * 1 (genotypes TNFB * 1/1 and TNFB * 1/2). Conclusions: The TNFB * 1 allele is a marker for prolonged clinical course in patients with sarcoidosis. Our study is the first to link a cytokine gene polymorphism to the prognosis of sarcoidosis. (CHEST 2001; 119:753‐761)

A 48-year-old man was admitted because of bloody sputum in whom a chest computed tomography (CT) scan and fiberoptic bronchoscopy demonstrated a polypoid tumor in the left main bronchus. The tumor was surgically resected, and the pathological and immunohistochemical findings led to diagnosis of the tumor as a bronchial glomus tumor.

Early gastric cancer can be macroscopically classified into elevated and depressed types. To clarify the relationship between macroscopic appearance of early gastric cancer and apoptosis or cell proliferation, formalin-fixed paraffin-embedded tissue specimens of 44 intestinal-type early gastric cancers were investigated by the TUNEL method and immunohistochemical techniques. Diffuse type was excluded in this study. When tissue sections of gastric cancer were vertically classified into the 3 compartments of luminar, intermediate and basal, the apoptosis index (%) was significantly higher in the basal compartment of depressed type (1.76 +/- 2.04, mean +/- SD) than in the basal compartment of elevated type (0.63 +/- 0.81, P = 0.01). In depressed type, the apoptosis index (%) was significantly higher in the basal compartment than in the luminar compartment (0.76 +/- 0.85, P = 0.03). Apoptosis-inducing protein, Bax, was expressed more in each of the compartments of depressed type than in those of elevated type, while there were no significant differences in expression of anti-apoptotic protein, Bcl-2, between the two types. Moreover, the apoptosis index (%) of Bax-positive gastric cancer was significantly higher in the basal compartment (P = 0.03), compared to that of Bax-negative gastric cancer, while there were no significant differences in apoptosis index (%) in any compartment between Bcl-2-positive and Bcl-2-negative gastric cancers. There were no significant differences in Ki-67 expression, either between the two types, or among the compartments of depressed type. These results indicate that increased apoptosis with excessive expression of Bax in the basal compartment is involved in the morphogenesis of the depressed type in intestinal-type early gastric cancer.

Susceptibility to asthma and other atopic diseases is known to be associated with elevated total IgE levels. Several investigators have linked the interleukin-4 (IL-4) gene and nearby markers located on chromosome 5q to elevated total IgE levels. A single nucleotide polymorphism in the IL-4 gene promoter region (C+33T) has recently been identified. As part of an effort to identify genetic variants contributing to the susceptibility to elevated total serum IgE levels, an association analysis of a newly identified promoter polymorphism (C+33T) with total serum IgE levels was conducted. The study was conducted using 240 Japanese subjects (120 asthmatics and 120 healthy controls). The IL-4 C+33T polymorphism was genotyped by PCR-restriction fragment length polymorphism analysis. The frequency of the T allele was 0.675 in asthmatic subjects and 0.671 in healthy controls. An anova model adjusted for age, sex and disease status suggested a genetic association of C+33T polymorphism with elevated total serum IgE levels (P

The dysregulation of both c-myc expression and retinoid signaling pathways commonly occurs in small cell lung cancers (SCLC), frequently accompanying tumor relapse, and contributing to the poor prognosis of patients with SCLC. In this study, we investigated whether c-myc antisense oligodeoxynucleoside phosphorothioate (OPT) covering the translational initiation site of c-myc mRNA used in combination with all-trans-retinoic acid (RA) would be more effective than either agent alone in inhibiting the growth of an SCLC cell line, NCI-H82, overexpressing c-myc with amplification of this gene, and whether this combination could be an experimental therapeutic tool against SCLC. c-myc antisense OPT decreased c-myc expression in Northern and Western blot analyses, thus inducing 40% and 20% cell growth inhibition compared with scrambled and sense OPT and with scrambled four guanosine-containing OPT (p0.01, and p0.01, respectively). All-trans-RA also inhibited cell proliferation at the rate of 40% by downregulating c-myc expression. Having obtained these results, we tested the hymothesis that c-myc antisense OPT in combination with all-trans-RA may further reduce c-myc expression and lead to improved cell growth control. This combination showed a greater inhibition of cell proliferation than either agent given alone (p0.01) (60% inhibition of cell growth compared with treatment of control scrambled or sense OPT alone, p0.01) through enhanced downregulation of c-myc expression. In conclusion, c-myc antisense DNA in combination with other modalities for c-myc downregulation may represent an attractive gene regulation-based therapy of SCLC in the future. Further efforts, however, using new oligodeoxynucleotide analogs, specific interventions for DNA delivery into cells, and more potent therapeutic agents are required to increase the potentiation of c-myc downregulation and cell growth inhibition.

Ex-chromate workers are frequently afflicted with lung cancers, especially central-type squamous cell carcinomas (SCCs) of the lung. However, little is known about the molecular and cellular biologic characteristics of chromate-induced lung cancers. We investigated expression of cyclin D1, bcl-2, and p53 proteins in chromate-induced lung cancers by immunohistochemistry, compared with those in lung cancers from nonexposed individuals and those in individuals with pneumoconiosis. Of 19 chromate-induced lung cancers, 16 tumors were SCCs, including 11 central and 5 peripheral types. Eleven (69%) of 16 chromate SCCs showed cyclin D1 expression. In contrast, cyclin D1 expression was observed in only 3 (12%) of 26 SCCs from nonexposed individuals and 6 (16%) of 37 SCCs that developed in patients with pneumoconiosis, respectively. The frequency of cyclin D1 expression proved to be significantly higher in chromate-induced SCCs than in SCCs from nonexposed individuals and from those with pneumoconiosis (P < .001). When comparisons were extended to all histologic types of lung cancer, cyclin D1 expression was observed significantly more often in chromate-induced lung cancers than in lung cancers from nonexposed subjects and those from patients with pneumoconiosis (11 [58%] of 19 v 5 [10%] of 52, P < .001, and 7 [11%] of 63, P < .001, respectively). Frequencies of bcl-2 and p53 expression were not significantly different among lung cancers from ex-chromate workers, nonexposed individuals and those with pneumoconiosis. The current study suggests that cyclin D1 expression may be involved in the development of chromate-induced lung cancers, although its underlying mechanism remains to be determined.

BACKGROUND With the recent development of minimal treatment for early stage gastric carcinoma, identifying specific indicators of the metastatic potential of primary tumors has become more important. Cathepsin B and cathepsin L, both lysosomal cysteine proteases, degrade the extracellular matrix during tumor progression. Although many studies have shown their relation to human cancer progression, little is known about their roles in the early stage. The clinicopathologic significance of cathepsins was therefore studied in early stage gastric carcinoma. METHODS Expression of both cathepsins was studied immunohistochemically in 51 tissue specimens from gastric carcinomas that invaded the submucosal layer or muscularis propria. The relation between their expression and clinicopathologic factors was analyzed. RESULTS Both cathepsins were expressed at higher levels in tumors that invaded the muscularis propria than in those within the submucosa (P < 0.05). In addition, tumors with lymphatic invasion showed higher cathepsin B expression than those without it (P < 0.05), whereas tumors with venous invasion showed higher cathepsin L expression than those without it (P < 0.05). No other clinicopathologic factors correlated with expression of either cathepsin. CONCLUSIONS Tumors with overexpression of cathepsins have powerful potential for invasiveness in the early stage of gastric carcinoma. Moreover, the authors hypothesize that cathepsins may be one of the determinants of the metastatic route. To the authors' knowledge, this is the first report on specific proteases concerning the mode of metastasis, and the results of this study suggest that therapeutic strategies for early stage gastric carcinoma might need to be changed according to the status of cathepsins. Cancer 2000;89:482–7. © 2000 American Cancer Society.

Study objectives: Serum KL-6 (Krebs von den Lungen-6) has been recognized to be a marker for the activity of diffuse interstitial lung diseases. The purpose of the study is to evaluate serum KL-6 measurement as a marker for farmer’s lung disease (FLD). Design: A cross-sectional survey of a cohort of dairy farmers. Retrospective measurement of KL-6 stored serum samples from those dairy farmers previously screened for FLD. Setting: University hospital screening project for FLD within a dairy-farming community in Japan. Participants: Four hundred seventy-two dairy farmers were invited to attend a local clinic. Measurements and results: We examined serum KL-6 concentrations in 272 farmers. Subjects were classified into three groups: (1) 5 farmers with FLD, (2) 30 farmers with positive serum precipitating antibodies to Saccharopolyspora rectivirgula and/or Thermoactinomyces vulgaris without FLD (Ab 1 ), and (3) 237 farmers without these antibodies (Ab 2 ). Serum KL-6 concentrations in the FLD group were significantly higher than those in the Ab 1 and the Ab 2 groups (1,263 6 288 [SEM], 328 6 57, and 207 6 6 U/mL, respectively, p < 0.001). Serum KL-6 concentrations in those with FLD were significantly higher than KL-6 concentrations from stored screening samples from the same individual when FLD was not diagnosed (1,263 6 288 and 419 6 209 U/mL, respectively, p < 0.05). Serum KL-6 concentrations of the Ab 1 group were significantly higher than those of the Ab 2 group (p < 0.001). In the Ab 1 group, farmers with high serum KL-6 concentrations had lower permeability coefficients than farmers with normal serum KL-6 concentrations (p < 0.05). These results may suggest that subclinical FLD can be detected in farmers with high KL-6 concentrations and precipitating antibodies. Conclusion: Serum KL-6 concentration can be a useful marker for assessing the activity of FLD and may be able to be used to detect subclinical disease. (CHEST 2000; 118:445‐ 450)

BACKGROUND Macrophage migration inhibitory factor (MIF) is known to be a proinflammatory cytokine and glucocorticoid-induced immunomodulator as well as a regulator of tumor growth. Although positive and negative effects of MIF on tumor cell growth have been reported, to the authors' knowledge the precise role of MIF in tumorigenesis remains unclear. In the current study the authors assessed expression of MIF protein and mRNA in lung adenocarcinomas with regard to patient prognosis. METHODS Immunohistochemical analysis was performed on tissue specimens surgically obtained from 74 patients with primary lung adenocarcinoma (American Joint Committee on Cancer pathologic Stages I, II, and IIIa). In addition, expression of MIF mRNA in the cancerous tissue was investigated using in situ hybridization. Patient prognosis was evaluated with regard to MIF expression levels and its distribution was analyzed with the Kaplan–Meier method. RESULTS MIF mRNA and MIF protein were observed in the bronchial epithelium, alveolar epithelium, vascular smooth muscle, and alveolar macrophages in the normal lung tissue. In tumor tissue from lung adenocarcinoma specimens, both MIF mRNA and protein were observed at much higher levels than in the normal alveolar epithelium. MIF protein was observed diffusely in the cytoplasm of tumor cells in all tumor specimens examined. MIF protein also was observed in the nuclei of tumor cells from 59 patients (79.7%), whereas it was not observed in the nuclei of tumor cells from 15 patients (20.3%). The patients without nuclear MIF expression had a worse prognosis compared with those patients with MIF expression in the nuclei (P = 0.04). CONCLUSIONS The results of the current study suggest that intracellular MIF distribution predicts patient prognosis in individuals with adenocarcinoma of the lung. Cancer 2000;89:334–41. © 2000 American Cancer Society.

It has been reported that patients with pneumoconiosis occasionally have a diffuse interstitial fibrosis (DIF) that resembles interstitial pneumonia, but little is known about the relation between pneumoconiosis-associated DIF and the risk of lung cancer. In the present study, we evaluated the incidence of DIF by chest CT and its contribution to lung cancer in 563 patients with nonasbestos pneumoconiosis. Fifty-five (10%) of the 563 patients had DIF. Pneumoconiosis with DIF had an exceedingly high concurrence of lung cancers when compared with pneumoconiosis without DIF (29 [53%] of 55 versus 78 [15%] of 508, p < 0.001). Squamous cell carcinomas (SCCs) of the lung from pneumoconiosis with DIF exclusively comprised peripheral-types, as compared with SCCs from pneumoconiosis without DIF (13 [100%] of 13 versus 33 [72%] of 46, p = 0.03). In addition, lung cancers arose frequently from the area of DIF in pneumoconiosis with DIF (20 [74%] of 27). Furthermore, our pathologic examination revealed that dysplasias from pneumoconiosis with DIF were significantly more frequently observed in peripheral bronchioli than were dysplasias from pneumoconiosis without DIF (11 [69%] of 16 versus 20 [30%] of 66, p = 0.01). p53 expression evaluated by immunohistochemistry was frequently observed in dysplasias from pneumoconiosis with DIF, although it was not significantly different compared with that in dysplasias from pneumoconiosis without DIF (5 [50%] of 10 versus 12 [38%] of 32). Taken together, these results may suggest a positive causal relationship between pneumoconiosis and peripheral-type SCCs of the lung, and further indicate a pivotal role of diffuse fibrosis for the excess incidence of lung cancers, especially peripheral-type SCCs, in DIF-type pneumoconiosis.

Genetic factors are important in defining total serum IgE levels. Linkage analyses have localized a gene or genes that influence atopic phenotype at chromosome 11q13. Variants of the FCER1B gene have been identified, which are associated with an increased risk of developing atopy and bronchial asthma. Given uncertain functional consequences and low frequencies of these coding variants of FCER1B, we screened for new mutations using 24 subjects with atopic asthma. A common 109C/T polymorphism at the promoter region of FCER1B was identified, although no variant was found in the entire coding region. We genotyped this promoter polymorphism in 226 healthy control subjects and 226 asthmatic subjects using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. Allele frequencies were 0.697 for 109T and 0.303 for 109C in 226 healthy control subjects. No significant difference in the distribution of 109C/T polymorphism was found between asthmatic subjects and healthy control subjects. A homozygosity for the 109T allele, however, was associated with increased total serum IgE levels in 226 subjects with asthma (p = 0.0015). The strongest evidence for an association between total serum IgE levels and 109C/T polymorphism (p = 0.0004) was obtained when age at onset of asthma was incorporated into the analysis. Our findings may represent genetic heterogeneity and complex interactions between genetic and environmental components involved in the regulation of total IgE levels, providing evidence that the 109C/T polymorphism of the FCER1B promoter region is one of the genetic factors identified thus far, which affects total serum IgE levels in a Japanese population. Hizawa N, Yamaguchi E, Jinushi E, Kawakami Y. A common FCER1B gene promoter polymorphism influences total serum IgE levels in a Japanese population.

Background: The concentration of exhaled nitric oxide ([NO]) has been reported to reflect the inflammatory process of airways in patients with bronchial asthma, particularly when they are steroid naive. However, it is not fully understood whether it equally reflects the degree of airway inflammation in patients receiving inhaled corticosteroids, but whose symptoms are not necessarily well controlled. Objective: To examine whether the exhaled [NO] really reflects airway inflammation in patients with bronchial asthma, regardless of treatment with inhaled steroids. Methods: Exhaled [NO] was measured in patients with bronchial asthma (43 steroid treated and 32 steroid naive), chronic obstructive pulmonary disease (COPD) (n = 36), bronchiectasis (n = 10) and in control subjects (n = 26). We examined in each asthmatic group whether the exhaled [NO] correlated with parameters reflecting airway inflammation. Results: Exhaled [NO] was significantly correlated with symptom score, clinical severity, circulating eosinophil count, and the percentage of eosinophils in induced sputum in the steroid-naive asthmatics, but not in the steroid-treated asthmatics, although airway inflammation in this group was not well controlled, as evidenced by clinical symptoms and the higher percentage of eosinophils in induced sputum. Exhaled [NO] from the patients with COPD (6.2 ± 0.7 ppb) or bronchiectasis (5.4 ± 1.3 ppb) was not significantly increased compared with the controls (6.0 ± 1.0 ppb), and was significantly lower than in the asthmatic patients as a whole (19.0 ± 2.0 ppb). Conclusions: Although exhaled [NO] is a useful marker of airway inflammation for differential diagnosis and evaluation of severity in steroid-naive patients with bronchial asthma, it may not be as useful in steroid-treated patients.

Background: Neutrophil elastase (NE) is thought to be one of the key proteinases in the development of chronic obstructive pulmonary disease (COPD). Previously, we have shown that the NE-α1-proteinase inhibitor (NE-α1PI) complex in bronchoalveolar lavage (BAL) fluid was markedly elevated in asymptomatic smokers who had subclinical emphysema on CT scans. We proposed that excessive NE-α1PI complex in BAL fluid was a factor which might differentiate smokers who were developing emphysema from others. Objective: In this study, we addressed the question of whether elevated levels of the NE-α1PI complex in BAL fluid are linked to the accelerated decline in pulmonary functions in those subjects. Methods: We conducted a follow-up study to analyze the decline in FEV1 for 4.3 years on average for 26 community-based volunteers who had received pulmonary function tests, CT scans and BAL. The levels of the NE-α1PI complex in BAL fluid and in plasma was measured. Results: Neither pulmonary function measurements nor the presence of emphysema on CT scans could predict the decline in FEV1. The number of inflammatory cells in BAL fluid was also not an indicator of progression. By contrast, subjects with higher levels of the NE-α1PI complex in BAL fluid had a significantly accelerated decline in FEV1 compared to those with lower levels. Conclusion: These data seem to support the hypothesis that NE in the lung is related to the onset and/or progression of COPD.

1983年より1998年までに当科に入院した原発性肺癌755例のうち, 先行肺疾患それぞれの合併率と先行肺疾患合併肺癌の臨床的特徴を検討した.最も合併頻度が高かったのは肺結核で125例 (16.6%), 次いで肺気腫81例 (10.7%), 問質性肺炎30例 (4.0%), 気管支喘息14例 (1.9%), 珪肺11例 (1.5%) の順であった.肺気腫は合併率が年々急激に増加したが, 呼吸機能には変化はなかった.肺気腫, 間質性肺炎, 肺結核の合併は男性に多く (P

1983年より1998年までに当科に入院した原発性肺癌755例, 762病変を年齢によって40歳以下, 41～50歳, 51～60歳, 61～70歳, 71～80歳, 81歳以上の6群に分i類し, 各グループの臨床的特徴について検討した.組織型では若年齢であるほど腺癌の比率が高く, 高年齢になるほど扁平上皮癌の比率が増加していた.この傾向は男性, 喫煙者群において明らかであったが, 女性, 非喫煙群では年齢とは無関係に腺癌の比率が高かった.発見動機iでは40歳以下において有症状受診例が約76%と高く, 81歳以上では他疾患治療中の症例が多く見られた (p

1983年より1998年までに当科に入院した原発性肺癌患者755例, 762病変の組織型の変遷とその背景因子について検討した. 便宜的に前半8年間 (1983～1990: 1980年代) と後半8年間 (1991～1998: 1990年代) に分けて比較した. 1980年代と1990年代では, 原発性肺癌総患者数, 男女比, 喫煙率, 発見動機, 臨床病期, 治療法に大きな変化はなかったが, 平均年齢は1990年代が有意に低かった (平均1.5年, p

The predictive value of expression of p16INK4A, retinoblastoma (Rb) and p53 proteins for prognosis was evaluated in 76 patients with non-small-cell lung cancers (NSCLCs) that were potentially curatively resected between 1990 and 1995, using the results of immunostaining analyses of these proteins as reported in our previous study (Kinoshita et al, 1996). Of these NSCLCs, 22 (29%) lacked p16 protein expression and eight (11%) Rb protein, while 30 (39%) showed positive (altered) p53 protein expression. Survival of patients with p16-negative tumours was not significantly different from that of patients with p16-positive tumours (5-year survival rates 67% and 72% respectively, P = 0.8), nor was survival of patients with Rb-negative tumours significantly different from that of patients with Rb-positive tumours (5-year survival rates 42% and 69% respectively, P = 0.9). Moreover, survival of patients with p16/Rb-negative (either p16- or Rb-negative) tumours was not significantly different from that of patients with p16/Rb-positive (both p16- and Rb-positive) tumours (5-year survival rates 67% and 68% respectively, P = 0.7). In contrast, survival of patients with p53-positive (altered) tumours tended to be shorter than that of patients with p53-negative (unaltered) tumours (5-year survival rates 56% and 78% respectively, P = 0.06). In univariate analysis of potential prognostic factors, p16, Rb and p16/Rb proteins were not significant prognostic factors in the present cohort of potentially curatively resected NSCLCs. Altered p53 protein status tended to be a negative prognostic factor (P = 0.06 by the univariate analysis). These results indicate that loss of p16 protein alone, or in combination with loss of Rb protein, does not predict the clinical outcome of patients with resected NSCLCs. © 1999 Cancer Research Campaign

Cyclin D1, like p16INK4 (p16) and retinoblastoma (RB) proteins, participates in the cell cycle control at the G1–S transition. We have previously demonstrated altered p16 and RB protein status in non-small-cell lung cancers (NSCLCs) and their potential synergistic effect with altered p53 protein on proliferative activity (Kinoshita et al (1996) Cancer Res56: 5557–5562). In the present study, cyclin D1 expression was studied by immunohistochemistry in the same cohort of 111 resected NSCLCs as in our previous study, and the amount of the cyclin D1 gene was analysed by Southern blot analysis in 29 NSCLCs. Cyclin D1 expression was analysed in relation to the status of p53, p16 and RB proteins, and proliferative activity determined by the Ki-67 index. It was also analysed in relation to survival of 77 patients with NSCLCs which were potentially curatively resected between 1990 and 1995. We found that: (1) cyclin D1 was expressed in 13 (11.7%) of 111 NSCLCs; (2) the cyclin D1 gene was neither significantly amplified nor rearranged; (3) cyclin D1 expression significantly correlated with altered p53 protein expression (P = 0.04), whereas it did not correlate with p16 and RB protein status; (4) proliferative activity tended to be higher in cyclin D1-positive (+) tumours than in cyclin D1-negative (–) tumours, although this difference was not statistically significant (P = 0.08); and (5) patients with cyclin D1+ tumours survived longer than patients with cyclin D1– tumours (5-year survival rates, 89% and 64% respectively, by the Kaplan–Meier method; P = 0.045 by the log-rank test), and cyclin D1 expression tended to be a favourable prognostic factor (P = 0.08 in univariate analysis). These findings suggest the involvement of cyclin D1 in the development and progression of NSCLCs, their proliferative activity and clinical outcome of NSCLC patients. © 1999 Cancer Research Campaign

Adenosine, a purine nucleoside, plays a variety of roles in cardiovascular and ventilatory control, and may be a marker of tissue hypoxia. There is, however, no direct evidence of an increase in plasma or in tissue levels of adenosine during moderate hypoxia in humans. We measured the plasma concentrations of adenosine in an artery and the median cubital vein simultaneously in 12 normal volunteers, and also in the internal jugular vein in seven of them during normoxia and moderate hypoxia (SaO2 = 80%, 20 min) with or without dipyridamole (0.6 mg/kg) pretreatment. Dipyridamole was expected to block reuptake of adenosine by red blood cells and vascular endothelial cells so that the plasma level of adenosine would more likely reflect the tissue level. Blood was sampled with an appropriate stopping solution, and adenosine was measured with a high-pressure liquid chromatographic (HPLC)-fluorometric technique. The plasma concentration of adenosine did not rise either in the artery or in the vein at any phase of hypoxia without the dipyridamole pretreatment. However, when subjects were pretreated with dipyridamole, the plasma concentration of adenosine increased significantly and markedly in a time-dependent manner during hypoxia in the vein, but not in the artery. The adenosine level rose from 20. 7 +/- 2.5 nM (mean +/- SE) during normoxia to 50.7 +/- 10.7 nM at 20 min of hypoxia, and returned to the baseline level in the recovery phase. The plasma concentration of adenosine in the jugular vein did not change during hypoxia either with or without dipyridamole pretreatment. These data provide evidence that in humans, the local production of adenosine increases during moderate hypoxia in forearm tissue, although this is not reflected in plasma unless the subject is pretreated with dipyridamole.

We isolated six clones of weakly tumorigenic fibrosarcoma (QR) from the tumorigenic clone BMT-11 cl-9. The QR clones were unable to grow in normal C57BL/6 mice when injected s.c. (1 × 105 cells). However, they formed aggressive tumours upon co-implantation with a ‘foreign body’, i.e. a gelatin sponge, and the rate of tumour take ranged from 8% to 58% among QR clones. The enhanced tumorigenicity was due to host cell-mediated reaction to the gelatin sponge (inflammation). Immunoblot analysis and enzyme activity assay revealed a significant inverse correlation between the frequencies of tumour formation by QR clones and the levels of manganese superoxide dismutase (Mn-SOD, P

We report five cases of purple urine bag syndrome (PUBS). All the patients were women and they had been bed-ridden for a long period due to cerebrovascular diseases. They tended to be constipated as a result of habitual use of laxatives. Indicanuria was proven in the all urinary samples from the patients. The four assessable urinary cultures showed Proteus mirabilis contamination. Total days without evacuation per month in patients with PUBS and control subjects (5 catheterized subjects without PUBS) were 16.5 +/- 3.7 and 6.8 +/- 4.8, respectively (mean +/- SD), showing a significant difference (p < 0.05). In each case, this syndrome was not considered to have affected their clinical course. We concluded that it is unnecessary to treat patients with PUBS aggressively. Control of evacuation and urological sanitation are important in these patients.

Abnormal expression of the bcl-2 gene product (Bcl-2) has been found in a wide variety of tumors, including lung cancer. In the present study, a total of 116 tumor specimens from surgically resected non-small cell lung cancer (NSCLC) patients, that were previously studied for p53 protein expression, were analyzed with immunohistochemistry for Bcl-2 expression. Forty (34%) of 116 tumor specimens showed Bcl-2 expression, which was found to occur more frequently in males than females (p = 0.049) and to be associated with smoking (p = 0.047). Bcl-2 expression was more frequently observed in squamous cell carcinomas (27 of 51, 53%) than in adenocarcinomas (12 of 55, 22%; p = 0.002), and in pT1 tumors (11 of 13, 85%) than in pT2 and pT3 tumors (16 of 38, 42%) in squamous cell carcinomas (p = 0.01). Bcl-2 expression did not correlate either with p53 protein status. We compared Bcl-2 expression in primary tumors and metastatic tumors of regional lymph nodes. Of 11 cases with Bcl-2-negative primary tumors, 10 were Bcl-2-negative in metastatic tumors except 1 case. In contrast, of 10 cases with Bcl-2-positive primary tumors, 6 lost Bcl-2 expression in metastatic tumors, while the remaining 4 cases still showed Bcl-2 expression in metastatic tumors. In the 89 potentially curatively treated patients, those with Bcl-2-positive and Bcl-2-negative tumors did not show a significant difference in survival (5-year survival rates, 56 and 42%, respectively, p = 0.2 by the generalized Wilcoxon test). These data indicate that Bcl-2 expression is frequently observed in squamous cell carcinomas with early pT status, and that it does not predict prognosis of patients with NSCLC.

Several cytokines are involved in the pathophysiology of sarcoidosis. Granulocyte-macrophage colony-stimulating factor (GM-CSF) may be one of these cytokines because its mRNA is expressed by inflammatory cells obtained from the sarcoid lung. We thus asked two questions. Is GM-CSF secreted by bronchoalveolar lavage (BAL) cells? What type of cells express GM-CSF? GM-CSF secreted by the cultured BAL cells from 19 untreated sarcoid patients was measured by an enzyme-linked immunosorbent assay. The individual cells expressing GM-CSF mRNA were identified by in situ hybridization in seven patients. Spontaneous release of GM-CSF by BAL cells was demonstrated in one patient. When stimulated, BAL cells secreted GM-CSF in all subjects studied. In situ hybridization with digoxigenin-labelled GM-CSF cRNA probe revealed that the positive cells were round in shape and larger than lymphocytes, but smaller than large alveolar macrophages that are often irregular in shape. These results strongly indicated that small alveolar macrophages secrete GM-CSF in the sarcoid lesion. This phenomenon may contribute to the enhanced immunological activities observed in sarcoidosis.

This study examined the role of cysteine proteinases and their inhibitor in the development of emphysema in comparison with neutrophil elastase (NE) complexed with alpha1-protease inhibitor (NE-alpha1-PI), which was previously demonstrated to be increased in bronchoalveolar lavage (BAL) fluid from subjects with subclinical emphysema. Eight nonsmokers and 31 current smokers with (n=17) and without (n=14) emphysema, as evidenced by lung computed tomographic scans, were studied. The concentrations of immunologically detected cathepsin L and cystatin C, but not cathepsin B, were significantly increased in BAL fluid from the smokers with emphysema compared with those without emphysema, although the activity of cathepsin L, measured using a synthetic substrate and cathepsin L, released from cultured alveolar macrophages at 24 h, did not show any significant difference between the two groups. When comparison was made only for the subjects aged

Pulmonary alveolar proteinosis (PAP) is a disease characterized by the filling of alveolar spaces with periodic acid-Schiff-positive proteinaceous material and by the hypertrophy of type II pneumocytes in the alveolar interstitium. To examine if KL-6, a mucinlike glycoprotein, is useful for the diagnosis of PAP and the estimation of its activity, serum KL-6 levels in patients with PAP were measured by an enzyme-linked immunosorbent assay and compared with those of patients with other lung diseases. Furthermore, to estimate the origin of KL-6 in some patients, measurements of KL-6 levels in bronchoalveolar lavage (BAL) fluid and immunohistochemical staining of the lung tissues with a monoclonal antibody to KL-6 antigen were performed. Serum KL-6 levels in patients with PAP were extremely high and were significantly higher than those in patients with interstitial lung diseases in which elevation of serum KL-6 has been recognized. BAL-fluid KL-6 levels in patients with PAP were higher than serum levels. Both serum and BAL-fluid KL-6 levels in patients with PAP correlated well with the disease activity. Immunohistochemically, positive staining was observed in proliferating type II pneumocytes. These results suggest the usefulness of KL-6 measurement in the diagnosis and estimation of disease activity of PAP.

Macrophage migration inhibitory factor (MIF) is a recently rediscovered pro-inflammatory cytokine that has the unique potential to override the anti-inflammatory action of glucocorticoids. Since recent reports suggest the pivotal role of MIF in acute lung injury, we examined the protective effect of anti-MIF antibody on lipopolysaccharide (LPS)-induced acute lung injury in rats. Rats were injected with LPS (7 mg/kg) intraperitoneally with or without pretreatment with anti-MIF antibody. The anti-MIF antibody significantly attenuated LPS-induced migration of neutrophils to the lungs at 4 and 24 h as demonstrated by observation of the number of neutrophils per alveolus, the activity of myeloperoxidase of the lung tissue, and cell differentiation of neutrophils in bronchoalveolar lavage (BAL) fluid. The increased level of macrophage inflammatory protein-2, a powerful neutrophil chemokine, in BAL fluid was also significantly attenuated by pretreatment with the anti-MIF antibody as compared with the control group. Additionally, positive immunostaining for MIF was observed in bronchial epithelial cells and alveolar macrophages, and Northern blot analysis of lung tissues demonstrated increased MIF mRNA 24 h after LPS injection. These data suggest that the anti-MIF antibody has therapeutic potential for the treatment of acute lung injury by suppressing the level of neutrophil chemokine in the lungs.

Several studies have reported that proliferating cell nuclear antigen (PCNA), nucleolar organizer regions (NOR) and epidermal growth factor receptor (EGF-R) are cellular proliferation parameters in malignant tumours. However, the correlation of EGF-R with PCNA and NOR has not been reported in colon tumours. To clarify this, we investigated the correlation of the expression of EGF-R with PCNA and NOR in colonic epithelial tumours. Using immunohistochemical staining and one-step silver staining techniques, the expressions of EGF-R-, PCNA- and NOR-associated protein were studied in paraffin sections from five normal mucosae, 10 adenomas with mild atypia, 16 adenomas with moderate atypia, 32 adenomas with severe atypia including carcinoma in situ and 47 with invasive colon carcinomas. Significant differences were found among the respective degrees of atypia in Ag-NOR counts, PCNA labelling index (LI), and the expression of EGF-R. However, there were no significant differences among the Ag-NOR counts of the severe atypia and invasive carcinoma. There was a significant positive correlation between Ag-NOR counts and PCNA LI (P < 0.001). The Ag-NOR counts and PCNA LI in EGF-R-positive cases were higher than in EGF-R-negative cases (P < 0.001). These results indicate that each of the parameters increased significantly with the increase in atypia and the progression of cancer. Epidermal growth factor receptor provokes an exacerbation of protein synthesis and the cell cycle in colonic epithelial tumours.

Chronic airway inflammation, one of the pathophysiologic features of bronchial asthma, is suspected to be responsible for irreversible pathological changes of airways, called airway remodeling. To examine the mechanisms of airway remodeling in asthma, we investigated the expression of epidermal growth factor (EGF) and its receptor immunohistochemically in asthmatic human airways. Airway specimens from seven patients with asthma were obtained from autopsied and surgically resected lungs. Control specimens were obtained from lungs of eight subjects without asthma and other pulmonary complications at autopsy. We stained those specimens by the avidin-biotin-peroxidase complex (ABC) method with anti-human polyclonal EGF antibody and monoclonal EGF receptor antibodies. Three different portions of airways-large bronchi (about 1 cm in diameter), small bronchi (about 3 mm in diameter), and peripheral airways (less than 2 mm in diameter)-were examined. The thickness of the bronchial smooth muscle and basement membrane was significantly greater in the asthmatic airways than in controls. Clear immunoreactivities of EGF were widely observed on bronchial epithelium, glands, and smooth muscle in asthmatic airways. In the controls, the bronchial epithelium and the bronchial glands partially expressed faint EGF immunoreactivity. For the EGF receptor, clear immunoreactivities were also observed on bronchial epithelium, glands, smooth muscle, and basement membrane in asthmatic airways. In control airways, only part of the bronchial epithelium and smooth muscle weakly expressed EGF receptor immunoreactivity. These results suggest a possible contribution of EGF to the pathophysiology of bronchial asthma, including airway remodeling.

A 23-year-old man who worked at a hard metal factory from 1988 had developed bronchial asthma in 1990. He was diagnosed as having bronchial asthma by inhalation challenge with cobalt. He never developed a severe attack after that by avoiding inhalation of cobalt. In 1993, he developed iridocyclitis, and his chest radiograph showed bilateral hilar lymph node swelling. He was diagnosed as having sarcoidosis with pathological certainty and an increased serum angiotensin-converting enzyme (ACE) level. On second admission, an inhalational challenge with cobalt resulted in no significant decrease of FEV1. Cobalt is well known to cause occupational asthma and other interstitial lung diseases. Although we could not get clear evidence suggesting an association between the sarcoidosis and his history of cobalt exposure, there is a possibility that changes in the immune reaction to cobalt might explain the improvement of asthma followed by sarcoidosis in this case.

Inductively coupled plasma mass spectrometry (ICP-MS) has been used to detect trace elements in biologic materials. In this study, we evaluated its application for the determination of cisplatin (cis-diamminedichloroplatinum) accumulation in human non-small cell lung cancer cell lines. We used 2 squamous lung cancer cell lines (EBC-1 and LK-2), and 4 adenocarcinoma cell lines (ABC-1, RERF-LC-MS, A549, and its cisplatin-resistant subline A549/CDDP). The cells were incubated in 10 ppb cisplatin for 2 hours. After the incubation, cells were digested with nitric acid at 120°C, diluted with filtered water, and nebulized into an ICP-MS machine. A calibration curve was obtained using 5 standard platinum solutions, and cellular platinum concentrations were corrected by protein. Chemosensitivity to cisplatin was determined using the XTT assay. The cell-number detection limit for the determination of cellular platinum was 5.0×104 cells for 10 ppb cisplatin. No significant correlation was observed between cisplatin sensitivity and cellular platinum accumulation among these 6 cell lines, but an inverse correlation was observed between A549/CDDP and its parental line. This study indicates that ICP-MS can be applied to the determination of platinum accumulation in human non-small cell lung cancer cell lines.

Thallium-201 single-photon emission computerized tomography (SPECT) was used to clarify the relationship between 201Tl uptake and the response in chemotherapy to platinum compounds in 21 patients with small-cell lung cancer. 201Tl-SPECT scans were obtained twice: at 15 min (early scan) and 120 min (delayed scan) after an intravenous injection of 111 MBq (3 mCi) of thallium-201 chloride. We obtained the uptake ratio from each scan and calculated the retention index:uptake ratio = region of interest uptake/contralateral normal lung uptake; retention index = (delayed ratio - early ratio)/early ratio. After 201Tl scintigraphy, 12 patients received chemotherapy consisting of platinum compounds and nine were treated with chemoradiation. Among patients receiving only chemotherapy, the retention index correlated with the responses to chemotherapy. In an in vitro study, ouabain, an inhibitor of the Na,K-ATPase pump, reduced sensitivity to cisplatin and inhibited intracellular thallium uptake in the small-cell lung cancer cell line. These studies suggest that 201Tl-SPECT is a useful indicator of response to chemotherapy with platinum compounds in small-cell lung cancer, and that Na,K-ATPase is commonly involved in transporting both thallium and platinum compounds into cancer cells.

The role of genetic factors was reviewed with respect to the pathophysiology of bronchial asthma, sarcoidosis and cough induced by angiotensin converting enzyme (ACE) inhibitor administration. The so-called 'atopy gene' in 11q13 is not linked to atopy but is associated with serum IgE levels. The beta2-adrenergic receptor gene on 5q32-33 was found to have polymorphism by Ban I and to be related to beta2-receptor function; a defect of a 2.3 kb allele is related to lowered sensitivity to beta2-agonists. This defect is also related to higher prevalence on non-atopic bronchial asthma. The occurrence of amino acid mutation (Arg16 to Gly) of beta2-receptors was lower and Gln27 to Glu mutation is extremely rare in the Japanese population compared with Caucasians. There is polymorphism of ACE genotypes among normal subjects and patients with sarcoidosis, II, ID and DD. The genotype is a significant determinant of serum ACE activity and may determine the prognosis of sarcoid patients. Genotype II has a higher incidence of coughing induced by ACE inhibitors.

The mechanism of hyposensitization in bronchial asthma has not been fully elucidated. We established a hyposensitization model of bronchial asthma in rats and examined airway responses and immunological parameters. Brown Norway rats were sensitized by a subcutaneous injection of ovalbumin (OA) at day 1 and by the inhalation of 2% OA aerosol at day 15. Animals were hyposensitized by intraperitoneal injections of OA from day 17 to day 22. They were challenged with OA or acethylcholine (Ach) aerosol at day 23 and changes in intratracheal pressure were recorded. Lungs were lavaged and OA-induced proliferative responses by blood lymphocytes were examined for animals without aerosol challenge at day 23. OA-specific serum IgE levels were measured by enzyme-linked immunosorbent assay. Hyposensitization significantly reduced the OA-induced immediate airway response, accumulation of CD4+ lymphocytes and eosinophils recovered by bronchoalveolar lavage, and the OA-induced proliferative response by blood lymphocytes. The airway responses to Ach and serum OA-specific IgE levels in hyposensitized group were not significantly different from those in the sensitized group. These results indicate that amelioration of airway inflammation and hyporesponsiveness of lymphocytes against OA are involved in the attenuated immediate antigen-induced airway response following hyposensitization.

We prospectively examined the survival rate of 67 chronic obstructive pulmonary disease (COPD) and 74 late sequelae of pulmonary tuberculosis (TB seq) patients to clarify whether nocturnal oxyhemoglobin desaturation (NOD)could be one of the independent factors determining their mortality. The sleep monitoring of arterial oxygen saturation (SpO2) and pulmonary function tests were assessed in all patients at the time of registration. Forty %of COPD and 24%of TB seq died as the direct result of deterioration of chronic respiratory failure during the 7-year observation period. Cox's proportional hazards analysis showed that NOD was an independent prognostic factor in both groups, and this was especially prominent when evaluated in terms of sleep lowest SpO2 in COPD and 85% desaturation time in TB seq. No significant prognostic factor was observed among age, vital capacity percent predicted (%VC), forced expiratory volume in one second (FEV1.0%)and partial pressure of carbon dioxide (PaCO2). We conclude that the degree of NOD can affect mortality in COPD and TB seq.(Internal Medicine 37: 354-359, 1998)

A mass of 8 cm in diameter was revealed in the right upper lung field of a 46-year-old female patient. The chest X-ray film taken one year previously revealed only a linear shadow in the same position, which was thought to be a vacant cyst. The levels of carbohydrate antigen (CA) 19-9 in cyst fluid and serum were elevated, at 410,000 and 130 U/ml, respectively. After surgical resection, serum CA19-9 returned to normal. Pathologically, the cyst wall was lined with bronchial epithelium with no evidence of malignancy. Immunohistochemical study revealed CA19-9 positivity in the bronchial epithelium of the cyst wall.

BACKGROUND The uptake of thallium-201 (Tl-201) in malignant tumors is associated with malignant potential (metastatic potential and proliferative activity). The grade of accumulation of Tl-201 in malignant tumors may provide information regarding prognosis. METHODS A Tl-201 single photon emission computed tomography was conducted 120 minutes after intravenous injection of 111 megabecquerel of Tl-201 chloride. The authors calculated the uptake ratio to evaluate the degree of Tl-201 uptake in the primary tumor. This ratio was compared with survival time and other prognostic factors. RESULTS The authors studied 152 patients (125 men and 27 women). The group of patients with the low Tl-201 uptake ratio survived longer than the group of patients with the high Tl-201 uptake ratio (median survival, 58 weeks vs. 33 weeks; P = 0.0138 by the log rank test). The multivariate analysis confirmed that the Tl-201 uptake ratio was an independent prognostic factor for survival. CONCLUSIONS These results suggest that the Tl-201 uptake ratio provides independent and objective prognostic information for patients with lung carcinoma. Cancer 1997; 80:198-203. © 1997 American Cancer Society.

Macrophage migration inhibitory factor (MIF) has been rediscovered as a proinflammatory cytokine, pituitary hormone, and glucocorticoid-induced immunoregulator. A survey of tissue distribution revealed that MIF expression is not limited to T lymphocytes, but exists in several other tissues; however, its presence in adipose tissue has never been investigated. In this study, we examined the expression of MIF in adipose tissue using the rat epididymal fat pad and murine 3T3-L1 adipocytes. Northern and Western blot analyses revealed the expression of MIF mRNA and MIF protein, respectively, in both the fat pad and the adipocyte cell line. In immunohistochemistry, a positive staining reaction with an anti-rat MIF antibody was detected largely in the cytosol of adipocytes of the epididymal fat pad. To examine the production and release of MIF by adipocytes, we examined its content in the culture medium of the 3T3-L1 adipocytes. The results showed that MIF content was 1.6 +/- 0.48 ng/ml (mean +/- SD) after 24 hr culture, and the content was increased up to 9.7 +/- 2.8 ng/ml by stimulation with TNF-alpha (50 nM). Since TNF-alpha produced in adipocytes is known to induce insulin resistance, the results suggest the possibility that MIF plays an important role in the mechanism of insulin resistance often observed in obesity and diabetes via regulation of TNF-alpha expression.

The recent progress in molecular biology has led to the elucidation of pathogenesis of lung cancer. The development of a lung cancer requires multiple genetic changes, consisting of the activation of oncogenes, including the K-ras and myc genes, and of inactivation of tumour suppressor genes, including the Rb, p53 and CDKN2 genes. Knowing the specific genes undergoing such changes should be useful as biomarkers for the early detection of cells destined to become malignant. Moreover, such genetic changes could be targets of newly designed drugs and gene-based therapy. Although the angiotensin I-converting enzyme was originally discovered in equine plasma, it has been recognized in various organs and cells other than vascular endothelial cells. This enzyme is also known to have wide substrate specificity to many peptides. The definite roles of angiotensin converting enzyme (ACE) in the respiratory system are largely unknown. Recent progress in molecular biology of the ACE, however, gives us a good chance to look over the significance of ACE in respiratory diseases as well as cardiovascular disorders. In this review, we show the recent advances in the basic studies of the ACE and refer to its clinical application.

BACKGROUND Inactivation of the retinoblastoma (Rb) gene has been documented in various types of cancer, including lung cancer. Alterations of the p53 and ras genes are also common features in the molecular biology of lung carcinoma, and the authors of this article have reported previously on the prognostic significance of both of them. In the present study, the authors evaluated the prognostic significance of the loss of Rb protein expression alone, then performed a combined analysis of Rb protein and ras p21 status (Rb/ras) as well as an analysis of Rb and p53 protein status (Rb/p53) in patients with nonsmall cell lung cancer (NSCLC). METHODS Ninety-one patients with NSCLC underwent potentially curative resection between 1977 and 1988, 65 of whom received postoperative combination chemotherapy. Tumor specimens were analyzed for Rb protein expression by immunohistochemistry. Univariate and multivariate analyses were performed to assess the association between Rb protein expression and survival. RESULTS Nineteen (21%) of the 91 NSCLCs showed negative Rb protein expression. Positive or negative Rb protein expression (Rb+ or Rb-) as an individual factor was not statistically correlated with survival or prognosis in this cohort of NSCLC patients, although a tendency among Rb- patients to do worse was observed. The authors then combined the Rb protein status with previously studied results of ras p21 and p53 protein expression in the same tumor specimens, and compared the prognosis between the individuals with theoretically the best pattern of gene expression in their tumors and those with theoretically the worst pattern of expression, i.e., Rb+/ras- versus Rb-/ras+ and Rb+/p53- versus Rb-/p53+. In patients with adenocarcinoma, those with Rb-/ras+ tumors survived for a significantly shorter period after surgery (13% 5-year survival) than those with Rb+/ras- tumors (82% 5-year survival) (P = 0.01). Similarly, patients with Rb-/p53+ tumors survived for a significantly shorter period (20% 5-year survival) compared with those who had Rb+/p53- tumors (73% 5-year survival) (P = 0.008). Rb/ras status was a significant prognostic factor (P = 0.02 by univariate analysis, P = 0.048 by multivariate analysis), and Rb/p53 status tended to be significant as a prognostic factor (P = 0.04 by univariate analysis, P = 0.08 by multivariate analysis). In patients with squamous cell carcinoma, neither Rb/ras nor Rb/p53 status was a significant prognostic factor in this cohort. CONCLUSIONS These results suggest that combined immunohistochemical analyses of Rb and ras p21 proteins and of Rb and p53 proteins may indicate their potentially synergistic effects on survival and prognosis. These analyses may also be useful for stratifying patients with adenocarcinoma of the lung into different prognostic groups and identifying populations with different risks of recurrence. Larger prospective studies with Stage I NSCLC patients are necessary to confirm the current findings. Cancer 1997; 79:1329-37. © 1997 American Cancer Society.

Atopy defined as high IgE responsiveness has now been subject to genetic studies at the molecular level owing to the development of a great number of DNA markers over the human genome. Either by linkage analysis or by association study strong candidate genes of atopy have been proposed to be located on chromosome 11q13 and 5q31 where high-affinity IgE Fc receptor beta subunit and allergy-associated cytokines, respectively, have been mapped. Meanwhile, we found a novel association between one of alleles of D11S97, an anonymous DNA marker on 11q13, and high total serum IgE in a large number of Japanese general population and atopic family members. However, failure to replicate linkage or association studies by different investigators suggest polygenic nature of atopy. In addition to the genes regulating IgE synthesis, the requirement of local (pulmonary) genetic factors in the development of bronchial asthma have been speculated. Linkage analysis suggested possible existence of gene(s) regulating susceptibility and/or clinical characteristics of bronchial asthma also on chromosome 5q. One of the candidate is beta 2-adrenergic receptor gene polymorphism. Mutated gene transfection studies suggested functional significance of some polymorphisms and clinical evaluations have revealed their contribution to airway responsiveness and severity of asthma.