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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.

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

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.

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.

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.

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

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 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.

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.

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.

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.

Our purpose was to determine whether lipid peroxides are elevated in the plasma of patients with non-insulin dependent diabetes with multiple lacunar infarcts as detected by magnetic resonance imaging (MRI), and to confirm whether peroxide levels correlate with glycemic controls and blood lipid levels. The level of lipid peroxide (measured as thiobarbituric acid reactive substances (TBARS)) was measured in 23 healthy controls and 28 diabetics showing normal MRI findings and 22 diabetics with multiple lacunar infarcts. These groups were age-matched. In patients with multiple lacunar infarcts, systolic blood pressure, diastolic blood pressure and TBARS levels were significantly higher than in diabetics without such infarcts (p < 0.05). When the diabetic patients were divided into two groups according to the presence or absence of hypertriglyceridemia or hyperglycemia, in both groups plasma TBARS levels in patients with multiple lacunar infarcts were significantly higher than in patients without such infarcts. Multivariate analysis showed systolic blood pressure and plasma TBARS levels to be independent predictors of multiple lacunar infarcts. Among diabetics, total plasma TBARS levels were positively correlated with fasting blood glucose, HbA1c and triglyceride levels, but not with total cholesterol levels and age. In conclusion plasma lipid peroxides were elevated in diabetics with multiple lacunar lesions, and are related to the metabolic imbalance of plasma glucose and lipids.

We report a case of mucous gland adenoma of the trachea in a 73-year-old male revealed by bronchoscopy. The tumor was resected with a contact neodymium: yttrium aluminum garnet (Nd-YAG) laser after five years of observation. The tumor was histologically peculiar because it presented numerous cystically dilated, or irregularly shaped mucus-filled glands lined with cuboidal or tall columnar cells. In some parts, the lining cells of the tumor showed papillary proliferation. We diagnosed this tumor as a mucous gland adenoma of the trachea. We review the clinical features of this rare tumor and discuss the usefulness of the laser in the diagnosis and the therapy.

A 47-year-old male was infected with Tsutsugamushi disease showing typical findings after mountain climbing in the Republic of Korea (ROK). Immunoserological examinations suggested that he had been infected in ROK. In this case, detection of the characteristic sting was useful for early diagnosis and treatment. Until now, Tsusugamushi disease has not been reported in Hokkaido. It is the first case registered in Hokkaido. With extensive international intercourse these days, this case suggests that Tsutsugamushi disease can occur potentially all over Japan.

Background. Alterations of the p53 gene are one of the most common genetic changes in various types of cancer, including lung cancer. Abnormalities in the ras genes, including point mutations and overexpression, are another common feature in the molecular biology of lung cancer and are associated with a poorer prognosis. The authors' purpose was to determine expression of the mutated p53 gene in nonsmall cell lung cancer (NSCLC) specimens that were studied for expression of ras p21 and to document whether altered p53 expression was also an important factor for survival. Methods. Ninety-six patients with NSCLC underwent surgical resection between 1977 and 1985, 63 of whom received postoperative combination chemotherapy. None received radiation therapy. Tumor specimens were analyzed for altered p53 expression by immunohistochemistry. Univariate and multivariate analyses were performed to assess the association between p53 expression and survival. Results. Fifty-six (58%) of 96 tumor specimens showed altered p53 expression, and 91 patients were analyzed for survival. Altered p53 expression did not correlate with clinicopathologic characteristics except for postsurgical pathologic tumor (pT) classification. The patients with altered p53 expression survived for a significantly shorter period after surgery than those without p53 expression, including all patients who underwent resection and potentially curative resection (P = 0.02 and P = 0.048, respectively, generalized [Wilcoxon test]. Multivariate analysis showed independent prognostic significance for altered p53 expression (hazard ratio [HR] = 1.72, P = 0.04) and surgical cure (HR = 4.69, P < 0.001). The combined analysis of mutated p53 and ras p21 expression in the same tumor specimens revealed that patients with p53- and ras p21-negative tumors survived the longest among those with different p53 and ras p21 features (P = 0.005, generalized Wilcoxon test). Conclusion. Altered p53 expression is a significant and independent negative prognostic factor for patients with surgically resected NSCLC. Combined immunohistochemical analysis of mutated p53 and ras p21 expression can divide patients with NSCLC into more accurate prognostic groups. If the current findings can be confirmed in larger prospective studies, combined immunohistochemical analysis of mutated p53 and ras p21 expression can be a useful clinical tool for stratifying patients with NSCLC into accurate prognostic groups and for identifying the population with a different risk of recurrence.

Although long-term home oxygen therapy (LTOT) certainly prolongs survival, it is not known whether this advantageous effect is similar for both sexes. In this study, we analyzed sex-related differences in survival based on a very large population that had received LTOT from 1986 to 1993. A total of 9,759 patients with chronic obstructive pulmonary disease (COPD), sequelae of tuberculosis (TBsq), and chronic interstitial pneumonia (IP) were selected in 1,212 medical institutions for analysis of survival rates. The survival rates of both sexes were compared with each other using the Cutler-Ederer Method. Despite higher PaCO2 at the beginning, the survival rate of women was significantly better than that of men in these three disease categories. Cox's proportional hazards analysis further confirmed the gender effect on survival by eliminating the effects of age, PaO2, PaCO2, %VC, and FEV1/FVC. The mean survival periods of the women who died during follow-up periods were also significantly longer than those of men (0.41 yr in COPD, 1.84 yr in TBsq, and 0.78 yr in IP). From these findings, we conclude women have a better prognosis than men when they start receiving LTOT, regardless of the cause of respiratory failure.

Little is known about the role of circulating platelets in PMA-induced lung injury in vivo. We investigated the effects of platelet depletion (PD) on the injury using seven unanesthetized sheep with lung lymph fistulas and eight other sheep for morphological study. PD diminished a decrease in the lymph to plasma concentration ratio (L/P) after 1 microgram/kg PMA treatment (n = 4) and caused more increases in lung lymph flow, L/P and lung lymph clearance after 5 micrograms/kg PMA treatment (n = 3) than in control sheep. The high dose was lethal to platelet-depleted sheep. However, PD had no effects on pulmonary hemodynamics. Morphologically, alveolar hemorrhages and exudate, and bleb formation of type I epithelial cells were more prominent in the platelet-depleted sheep than in the control sheep. We conclude that circulating platelets have protective effects against PMA-induced lung injury but have little involvement in PMA-induced pulmonary hypertension.

A 21-yr-old man with multiple pulmonary AV fistulae presented with moderate hypoxemia with chronic hyperventilation, which continued even after sufficient oxygenation by 100% O2 inhalation. The infusion of aminophylline, an adenosine receptor blocker, not only increased PaCO2 from 35 to 39 mm Hg but also depressed the magnitude of hypoxic ventilatory response (HVR). After a surgical removal of the major fistulae, PaCO2 increased to 42 mm Hg. At this time, aminophylline increased the resting ventilation and slightly augmented the HVR value, which was opposite to the findings of preoperation. Dipyridamole, which potentiates endogenous adenosine by inhibiting its cellular uptake, increased the magnitude of HVR both before and after the operation. We propose that the hyperventilation observed in this case can at least in part be attributed to the ventilatory stimulation by endogenous adenosine, which presumably passed through the fistulae without being metabolized in the pulmonary circulation.

BACKGROUND Hematogenous metastasis requires angiogenesis within the tumor. Previous studies have shown that microvessel counts in histologic sections of the primary tumor, which reflect angiogenesis, are correlated with metastasis in breast, prostate and Stage I nonsmall cell lung carcinoma. In this study, the authors investigated the association between angiogenesis, hematogenous metastasis and lymph node metastasis in all stages of lung adenocarcinoma. METHODS Microvessels were highlighted by immunostaining endothelial cells for factor VIII. We counted microvessels within the tumors of 42 patients who had surgical resection (25 with relapse and 11 without relapse more than 5 years after surgical resection). Without knowledge of patient outcome, microvessels were counted on a 200x field (0.723 mm2) in the most active areas of neovascularization. RESULTS The microvessel counts from patients with relapse after surgical resection (mean +/- standard deviation, 75.4 +/- 64.3) were significantly higher than those without relapse more than 5 years after surgical resection (42.6 +/- 26.0) (P = 0.027). Analysis of regional lymph node metastases (factor N) revealed that the microvessel counts were 62.6 +/- 35.1 for N0 (no regional lymph node metastasis), 51.7 +/- 22.2 for N1 (metastasis in ipsilateral, peribronchial and/or ipsilateral hilar lymph nodes, including direct extension), 75.4 +/- 75.3 for N2 (metastasis in ipsilateral mediastinal and/or subcarinal lymph nodes), and 74.0 for N3 (metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene or supraclavicular lymph node[s]), and these values were not significantly different from each other. CONCLUSIONS Angiogenesis assessed by microvessel counts, correlated positively with relapse after surgical resection and hematogenous metastasis in all stages of lung adenocarcinoma; there was no correlation with lymph node metastasis in lung adenocarcinoma.

We examined the relationship between the retention of thallium-201 (201Tl) on a delayed scan and the metastatic potential of adenocarcinomas of the lung. We studied 43 patients with adenocarcinoma of the lung and divided them into two groups according to the presence or absence of lymph node metastasis. 201Tl single photon emission computerised tomography (SPECT) was conducted twice: 15 min (early scan) and 120 min (delayed scan) after intravenous injection of 3 mCi of 201Tl chloride. We calculated the retention index in order to evaluate the degree of 201Tl retention in the primary tumour. The retention indices were significantly higher in the group that was positive for lymph node metastasis than in the negative group. In adenocarcinomas with high metastatic potential, 201Tl SPECT demonstrated slow washout or increased retention on the delayed scan. The retention index of 201Tl SPECT is a useful indicator of metastatic potential, thereby facilitating the prediction of prognosis, and provides insight into the relationship between 201Tl uptake and malignancy. This is the first report demonstrating a significant relationship between the retention of 201Tl SPECT and lymph node metastasis. Images Figure 1

Many attempts have failed to correlate in vivo airway responsiveness with in vitro airway smooth muscle functions. We have reexamined this relation by taking account of airway epithelial functions in guinea pigs sensitized with inhaled ovalbumin (OA). In vivo responses were assessed by the provocative concentration of acetylcholine (ACh) required to double the airway opening pressure (PC200) under mechanical ventilation. In vitro responses were measured in a perfused whole-tracheal preparation. The negative logarithm of the molar concentration of ACh required to produce a 10% reduction in diameter was calculated both for epithelial-side stimulation (PC10(in)) and for serosal-side stimulation (PC10(out)). OA-sensitized guinea pigs showed significantly smaller log PC200 than control animals (0.51 +/- 0.07 and 0.81 +/- 0.10, respectively, p0.01). In in vitro study, there were variable differences in PC10(in) and PC10(out) in each animal. The difference in sensitivity between epithelial- and serosal-side stimulation (PC10(in-out)) showed a significant correlation in PC10(in) (r = 0.82, n = 9, p0.01) but not to PC10(out) (r = 0.39, p0.1), indicating that the variation in PC10(in-out) resulted from the changes in PC10(in). For in vivo-in vitro correlation, log PC200 correlated significantly with PC10(in) (r = 0.68, n = 9, p0.05) but not with PC10(out) (r = 0.18, p0.1). These results indicate that the sensitization by inhalation of OA produces increased airway responsiveness to ACh in vivo and that this airway responsiveness may be related, at least in part, to the altered airway epithelial functions.

治療を必要とした癌性胸膜炎または心嚢炎患者にAnthracyclines系抗癌剤を局所投与し, 投与後に採取した排液中の癌細胞に対し共焦点レーザー顕微鏡を用いて癌細胞内の薬剤分布パターンを観察した.局所療法により胸水, 心嚢液のコントロールが良好であった群は癌細胞内の薬剤分布パターンは核内に著明な取り込みを示し, 胞体内にもびまん性に分布していた (Diffuse pattern).一方, コントロールが不良であった群は胞体内では斑状の分布を認め, 核辺縁, 核内には不均一にわずかな薬剤分布を示すのみであった (Spot pattern).このように薬剤分布バターンと治療効果の間には関連が見られ, 細胞内分布の観察は癌性胸膜炎または心嚢炎患者における局所療法の効果推定の指標となる可能性が示唆された.また, 共焦点レーザー顕微鏡を用いた抗癌剤の細胞内分布の観察は容易であり, 臨床検体への応用も可能であった.

Following a three-week administration of alpha-interferon (IFN-α), a 62-year-old woman with chronic hepatitis C manifested fever and dyspnea and showed diffuse infiltrative opacities on chest roentgenograms. Her laboratory data included results of anemia with reticulocytosis, a decreased complement level and hepatitis with elevated ALP, LDH and γ-GTP, Because laboratory data also revealed a positive lymphocyte stimulation test for IFN-α, this cytokine was considered to be responsible for the development of interstitial pneumonia, hemolytic anemia and cholestatic liver dysfunction due to its immunomodulatory effects. Although these three disorders have been reported to develop singly after IFN-α therapy, this is the first report of a patient in whom these disorders occurred simultaneously.(Internal Medicine 33: 337-341, 1994)

Multiple bullae have often been observed in the lungs of patients with idiopathic interstitial pneumonia (IIP). The etiology of bullae has been considered to be distinct from that of interstitial pneumonia and honeycomb lesions seen in IIP. The incidence of bullae was evaluated in 27 IIP patients (male; 23 cases, female; 4 cases) and clinical factors which are related to the development of bulla were analyzed. Of the 27 patients, 16 (59%) had bullae. All 16 were male smokers, and had higher smoking indices (p