Effects of hemoglobin on pulmonary arterial pressure and pulmonary vascular resistance in patients with chronic emphysema.

BACKGROUND: The increase in viscosity caused by secondary polycythemia is thought to be one of the major causes of pulmonary hypertension secondary to chronic emphysema. However, very few clinical studies considered the relation between pulmonary hypertension and polycythemia in the case of chronic obstructive pulmonary disease. OBJECTIVE: The purpose of this study is to elucidate the relative contribution of an increase in hemoglobin level (Hb) to mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance (PVR). METHODS: We retrospectively investigated 41 patients with chronic emphysema who had undergone a right heart catheterization. Multiple-regression analysis and F test were performed to investigate both direct effects of Hb and PaO(2) as independent variables on mPAP and PVR as dependent variables. RESULTS: Significant correlations were found between PaO(2) and mPAP (or PVR), or Hb and mPAP (or PVR), indicating that both Hb and PaO(2) are contributory to mPAP and PVR. The F test demonstrated that Hb and PaO(2) could directly affect the level of either mPAP or PVR. CONCLUSIONS: It was concluded that Hb had a direct effect on mPAP and PVR, independently of hypoxia in patients with chronic emphysema.

Short dynamic FDG-PET imaging protocol for patients with lung cancer.

This positron emission tomography (PET) study was designed to compare 2-[fluorine-18]fluoro-2-deoxy-D-glucose (FDG) kinetic parameters of tumours derived from imaging frames of 0-60 min post FDG injection with those derived from shorter imaging frames of 0-30 min. Dynamic FDG-PET scans were performed on 20 patients with primary lung cancers for 1 h after intravenous injection of FDG. Images were reconstructed with attenuation correction using transmission images obtained with a germanium-68 ring source immediately before FDG injection. A region of interest (ROI) was placed on the plane of the maximal tumour FDG uptake. Arterial input function was estimated from an ROI defined in the left atrium. Based on the standard three-compartment metabolic model, we calculated the rate constants (K1-k3) and influx constant Ki = K1k3/(k2+k3) using the imaging frames for 60 min and 30 min post FDG injection. The standardized uptake value (SUV) of tumour was measured using the imaging frame of 50-60 min post injection. High correlations were observed between kinetic parameters (K1, k2, k3 and Ki) derived from imaging frames of 0-60 min and 0-30 min [0.231+/-0.114 vs 0.260+/-0.174 (r=0.958), 1.149+/-1.038 vs 1.565+/-2.027 (r=0.968), 0.259+/-0.154 vs 0.311+/-0.194 (r=0.886) and 0.044+/-0.022 vs 0.048+/-0.023 (r=0.961), respectively, P<0.001]. Ki showed an excellent agreement between the two methods (y=-0.0041+0.9831x). Mean SUV of the lung cancers was 6.58+/-2.85. It is concluded that the briefer 30-min acquisition may yield essentially the same results as the standard 60-min imaging protocol, thus offering a time saving in dynamic PET studies in which the model parameters are desired.

[A case of Bence-Jones protein-lambda positive multiple myeloma complicated by abnormal plasma cells in pleural effusion].

A 53-year-old woman was admitted to this institution with chest pain and dyspnea. Chest roentgenogram showed pleural effusion and multiple tumor shadows, bilaterally which represented extrapleural signs. Numerous atypical plasma cells were found in the pleural effusion. Bone marrow biopsy showed atypical plasma cells. Immunoelectrophoresis revealed monoclonal Bence-Jones protein-lambda in serum and urine. Myeloma was subsequently diagnosed and chemotherapy was started. Multiple myeloma is a plasmacytoma, and myeloma cells proliferate in the bone marrow. The incidence of myeloma associated with malignant pleural effusion is rare with only 33 cases previously reported in Japan, to the best of our knowledge.

[A case of pneumoconiosis (welder's lung) suspected to be lung cancer].

A 60-year-old man, employed as a welder for 25 years, was admitted with an abnormal shadow on chest X-ray. An ill-defined and solitary mass shadow 3 cm in diameter was subsequently detected in the left upper lung field. The mass shadow exhibited high attenuation on chest CT scan. Transbronchial lung biopsy (TBLB) revealed an organized lesion possessing a large quantity of iron. Although pneumoconiosis was suspected, the possibility of lung cancer could not be dismissed. Pneumoconiosis (welder's lung) was diagnosed after thoracotomy and examination of the resected mass. Pneumoconiosis (welder's lung) rarely presents as a solitary mass lesion.

[Allergic bronchopulmonary mycosis caused by Schizophyllum commune].

In December 1989, a 72-year-old woman was hospitalized with atelectasis in the left lower lobe. The atelectasis resolved after bronchoscopic removal of impacted mucous plugs. Histopathological examination showed pulmonary mycosis. Microscopy suggested that a species of Aspergillus was responsible, but no definite diagnosis was made. After treatment with flucytosine and nebulized amphotericin, the patient's condition improved and she was discharged. In the middle of August 1994, she visited a local hospital complaining of fatigue. Eosinophilia (22%) was detected, and a few days later she visited that hospital again due to sudden dyspnea. A chest X-ray examination showed an abnormal shadow, and she was referred to our hospital. Atelectasis was seen in the left upper lobe. This finding, together with eosinophilia, suggested recurrence of pulmonary mycosis, and therefore bronchoscopy was performed. White mucous plugs obstructing the left upper lobe were observed and were bronchoscopically removed. Microscopical examination of the mucous plugs showed marked eosinophil infiltration and hyphae. Cultures of specimens obtained during bronchoscopy showed Schizophyllum commune, and allergic bronchopulmonary mycosis due to this microorganism was diagnosed. Identification of this microorganism as a cause of deep-seated pulmonary mycosis is very rare.

[A case of traumatic hernia of diaphragm showing prolapse of liver with abnormal lobulation into pleural cavity].

A 48-year-old male was admitted to our hospital in 1988 with injury by a traffic accident, resulting in fracture of the right rib, right clavicle, and pelvic. The patient came to us again with a chief complaint of abdominal pain in May, 1991 when digestive tract gas was observed in the right pleural cavity casting a doubt of diaphragmatic hernia. Chest CT scan and liver scintigraphy disclosed prolapse of the colon into the pleural cavity together with a picture on the diaphragm being supposed as parenchyma of the liver. Operation findings showed prolapses of the colon and the omentum through the opening of diaphragm into the pleural cavity and also exhibited prolapse of hepatic parenchyma, supposedly S4, together with gallbladder into the pleural cavity. The case, which had showed no abnormality in the Chest X-ray film before the injury, was conceivably an extremely rate case of traumatic hernia with the right diaphragm showing; abnormality of hepatic lobulation accompanied by diaphragmatic rupture, and prolapse of the liver with abnormal lobulation.

Invasive tumors derived from xenotransplanted, immortalized human cells after in vivo exposure to chemical carcinogens.

Several chemicals that are found in cigarette smoke or diesel oil engine exhausts, such as benzo[a]pyrene (B[a]P) and 1,6-dinitropyrene (DNP) are carcinogenic in experimental animal models. In the present study, we have exposed in vivo the xenotransplanted immortalized human bronchial epithelial cell line BEAS-2B to the ultimate carcinogen of B[a]P, benzo[a]pyrene diolepoxide (BPDE), to DNP or to the benzo[e]pyrene, a less active compound that has tumor-promoting abilities in mouse skin carcinogenesis bioassays. All three compounds were administered using slow-release beeswax pellets. After a 6 month exposure, BPDE produced two tumors in seven transplants, four tumors were seen in 10 transplants treated with DNP and one tumor was observed in five tracheal grafts exposed to B[a]P. All the neoplasms were well-differentiated invasive adenocarcinomas. Tracheal transplants exposed to beeswax without carcinogen did not show any evidence of neoplastic growth, and their luminal surfaces were lined by a single or double layer of cuboidal cells. All lines derived from the adenocarcinomas showed increased in vitro resistance to serum-induced terminal differentiation, gelatinolytic activity, s.c. tumorigenicity and invasive growth in an in vivo assay. When these cell lines were compared with previously described tumor cell lines derived from xenotransplants exposed to cigarette smoke condensate, it became clear that the latter exhibited a more aggressive invasive behavior. Nevertheless treatment with the three chemicals gave rise to tumor cell lines that exhibited a similar invasive behavior in vivo, and were able to penetrate early into the wall of the tracheal transplants in which they were seeded. These data indicate that this system based on xenotransplanted bronchial epithelial cells is a very relevant model to identify human carcinogens and to study mechanisms of bronchogenic cancer pathogenesis.

[Study on local recurrence in patients undergoing curative surgical resection of lung cancer].

Clinical features of recurrence in patients of lung cancer undergoing curative surgical resection were examined with special reference to the local recurrence. Subjects were 308 patients, consisting of 160 adenocarcinomas, 121 squamous cell carcinomas, 15 large cell carcinomas, 12 small cell carcinomas. They underwent curative resection in our department between 1973 and 1987. Local recurrence developed in 54 patients (18%). There was no significant difference in the incidence of local recurrence among the four histological types of carcinoma. According to the pathological stage, the incidence was 9% in stage I, 15% in stage II, and 35% in stages IIIA+IIIB. The local recurrence was subdivided into the following patterns: 1) lymphatic metastases to the hilar, mediastinal, or supraclavicular sites, 2) recurrence at the surgical margin, 3) malignant pleuritis or pericarditis, 4) so-called "endobronchial metastasis". The incidence of recurrence according to the patterns was 15%, 2%, 2% and 1%, respectively. The incidence of recurrence due to lymphatic metastases was correlated significantly with the pN factor but not with the pT factor. Patients with central type lung cancer showed a significantly higher incidence of lymphatic recurrence than patients with the peripheral type. Patients having postoperative radiotherapy to prevent local recurrence showed a lower incidence of lymphatic recurrence than patients having no radiotherapy. In conclusion, lymphatic recurrence was the most frequent pattern in local recurrence after curative resection of lung cancer, and therefore improvements in the operative procedure of lymphatic dissection, as well as in postoperative adjuvant therapy including radiotherapy will be urgently required for the purpose of reducing local recurrence.

A tobacco-specific N-nitrosamine or cigarette smoke condensate causes neoplastic transformation of xenotransplanted human bronchial epithelial cells.

Using a xenotransplantation system in which immortalized nontumorigenic human bronchial epithelial cells (BEAS-2B cells) are grown in deepithelialized rat tracheas that are subcutaneously transplanted into athymic nude mice, we exposed BEAS-2B cells either to cigarette smoke condensate or to the tobacco-specific N-nitrosamine 4-(methylnitrosamine)-1-(3-pyridyl)-1- butanone. After 6 mo the carcinogen-exposed BEAS-2B cells were neoplastically transformed to invasive adenocarcinomas. Cell lines obtained from xenografts exposed in vivo to chemicals exhibited several features typical of malignant lung cancer cells, such as increased in vivo invasiveness that correlated well with enhanced type IV collagenolytic activity, resistance to serum-induced growth inhibition, and increased expression of transforming growth factor alpha and its cellular-membrane receptor. Invasiveness, similar to that seen after exposure to phorbol esters, was also detected after in vitro exposure of BEAS-2B cells to cigarette smoke condensate. Collectively, these data indicate that cigarette smoke condensate and N-nitrosamine 4-(methylnitrosamine)-1-(3-pyridyl)-1-butanone induce in vivo phenotypic changes in BEAS-2B cells similar to the progressive changes that occur during human lung carcinogenesis.

Effects of formaldehyde on xenotransplanted human respiratory epithelium.

A laboratory animal model that permits the exposure of xenotransplanted human respiratory epithelium to formaldehyde was used to study the effects of formaldehyde alone or in combination with the ultimate carcinogenic metabolite of benzo[a]pyrene, benzo[a]pyrene diol epoxide. Epithelial cells obtained from autopsies of full-term human fetuses or infants less than one year old were isolated, amplified in primary cultures, and then inoculated into rat tracheas from which the epithelial layer had been removed. These tracheas then were sealed and transplanted subcutaneously into irradiated athymic nude mice. Four weeks after transplantation, the tracheal lumen was completely covered by epithelium, most of which was of the mucociliary respiratory type. At this stage, tracheal transplants containing tracheobronchial epithelium from 20 different human infant donors were exposed to silastic devices containing 0, 0.5, 1, or 2 mg of formaldehyde. The tracheal transplants were examined histologically 2, 4, 8, or 16 weeks after transplantation. Before being killed, all animals were injected with a single pulse of tritiated thymidine. Important epithelial alterations were seen in the transplants treated with formaldehyde, with a maximum effect visible two weeks after exposure. In most cases, the highest dose of 2 mg produced numerous areas of epithelial erosion and inflammation; however, this effect was not as evident with the lower doses. All doses produced areas of hyperplastic epithelium alternating with areas of atrophic epithelium. Although the differences in predominance of different types of epithelium were not clearly dependent on dose, the labeling index showed dose dependence between two and four weeks after the initiation of exposure. The maximum mean labeling index was three to four times higher than normal, although in some focal hyperplastic-metaplastic lesions the labeling index increased up to 20 times. These studies show that formaldehyde, although toxic at higher doses, is able to elicit at lower doses a proliferative response of the human infant tracheobronchial epithelium that is not preceded by a massive toxic effect. Similar studies were performed using xenotransplanted human adult nasal respiratory epithelium (Study 2). The response pattern was very similar to that of the xenotransplanted human tracheobronchial epithelium from human infants (Study 1). In Study 3, using cells obtained from 11 human infant tracheobronchial epithelia, the formaldehyde applied simultaneously or sequentially with benzo[a]pyrene diol epoxide did not induce epithelial alterations different from those observed with formaldehyde treatments alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Partial suppression of tumorigenicity in a human lung cancer cell line transfected with Krev-1.

A human non-small-cell lung carcinoma cell line, Calu-6 (from an anaplastic carcinoma), was transfected with the Ki-ras-related anti-oncogene Krev-1. Several transfectant lines were obtained that showed a reduced tumorigenicity in nude mice with respect to the parental and control transfected cell lines. This decrease was approximately 50% in tumor incidence at 4 wk after subcutaneous inoculation of the transfected cells. In addition, the volume of the Calu-6 revertant-derived tumors was three to 10 times smaller than that of the equivalent tumors produced by inoculation of the control cell line transfected with the neomycin-resistance gene. Krev-1--transfected cells that exhibited reduced tumorigenicity expressed Krev-1 mRNA and had variable numbers of copies of the Krev-1 gene. Moreover, Krev-1--transfected cells exhibited a more differentiated squamous epithelial morphology than the parental and control cell lines did. Moderately elevated levels of protein kinase C activity were detected in some revertant clones. Such activity correlated with the level of expression of Krev-1 mRNA in most cases. In summary, Krev-1 induced important morphological and biological changes in transfected Calu-6 cells that we interpreted as partial reversion of the malignant phenotype.

[Endoscopic Nd-YAG laser treatment of tracheobronchial lesions].

Eight cases treated with Nd-YAG laser via fiberoptic bronchoscopy were studied. Four of them were primary lung cancer, one was tracheal invasion of thyroid cancer and three were postintubation lesions of trachea. In six cases, Nd-YAG laser treatment was effective for enlargement of the airway lumen and improvement of their symptoms. In the cases of advanced lung cancer, not only local findings of the tumor but also clinical stage and possibility of adjuvant therapy must be considered to apply this procedure. In the cases of postintubation tracheal stenosis (except polypoid lesions), T-tube stenting or surgical reconstruction must be followed after laser treatment. Nd-YAG laser treatment can be useful for the tracheobronchial lesions such as primary tracheal tumors, lung cancer, metastatic tumors, postintubation tracheal stenosis and so on if applied precisely.

Detection of p53 in primary lung tumors and nonsmall cell lung carcinoma cell lines.

Immunohistochemical analysis of p53, a nuclear protein involved in the development of numerous human tumors, was performed in a series of 50 primary nonsmall cell lung carcinomas and in a group of eight lung carcinoma cell lines. Using two mouse monoclonal antibodies, PAb1801 and PAb421, sixteen of thirty-five (45.7%) lung adenocarcinomas and seven of fifteen (46.6%) squamous cell carcinomas showed marked-to-moderate immunoreactivity. In fifty-six percent of the positive tumors more than 40% of all cells were p53 positive, and in only 17% of positive tumors the percentage of immunostained cells was less than ten. Although the number of p53 negative adenocarcinomas without metastasis was larger than the number of p53 positive tumors without metastasis, there were not clear differences between p53 positive and negative tumors with metastasis. Furthermore, six adenocarcinomas that infiltrated the pleura and/or the thoracic wall were p53 positive, whereas only two of these invasive tumors were p53 negative. From eight cell lines studied, six were positive for p53. A good correlation between immunocytochemistry and immunoprecipitation was observed. Two tumorigenic and metastatic cell lines, Calu 1 and Calu 6, that were not immunoreactive also showed lack of protein by immunoprecipitation, as well as absence of mRNA in Northern analysis. In addition, Calu 1 showed an important gene deletion. These observations point to the fact that deletions and alterations in transcription of the p53 gene could coincide with or eventuate in an advanced malignant phenotype that nevertheless results in a p53 negative immunostain. Although this type of change cannot be detected immunohistochemically in primary tumors without further molecular analysis, the results presented herein indicate that p53 can be detected immunohistochemically in a majority of lung tumors and that there is a tendency for more advanced adenocarcinoma stages to exhibit positive p53 immunostain.

Transformation of human breast epithelial cells by c-Ha-ras oncogene.

To determine whether the c-Ha-ras oncogene plays a role in the initiation of mammary carcinogenesis, an immortalized human breast epithelial cell line, MCF-10A, was transfected with the plasmid vector pHo6T1 containing the T24 Ha-ras oncogene and the aminoglycoside phosphotransferase gene, which confers resistance to geneticin. Transfected cells exhibited an altered pattern of growth and tridimensional morphology in collagen gel. They also exhibited anchorage-independent growth and loss of requirement for hormones and epidermal growth factor; in addition, they expressed invasiveness and increased collagenolytic activity in an in vitro system and became tumorigenic in irradiated nude mice, all properties indicative of malignant transformation. Transformed cells contained the mutated c-Ha-ras oncogene and expressed the p21 mutated protein. These data indicate that the c-Ha-ras oncogene is capable of inducing malignant phenotypes in immortalized human breast epithelial cells.

In vivo and in vitro invasiveness of human lung carcinoma cell lines.

Eight cell lines derived from human non-small cell lung carcinomas were used to compare their in vivo invasiveness, in vitro chemoinvasive abilities and type IV collagenase activity. For the evaluation of the in vivo invasive potential, the tumor cells were seeded into deepithelialized rat tracheas and transplanted subcutaneously into nude mice. The invasive behavior of the cells was observed at 4, 8 and 12 weeks and assessed histologically by determination of the levels of penetration of tumor cells into the different layers of the tracheal wall. Except for two cell lines that did not grow at all in vivo, there was a very good correspondence between the levels of in vivo tracheal wall penetration and the in vitro chemoinvasion assay using fibronectin as chemoattractant and Matrigel as barrier. This also correlated very well with the capacity of the cells to secrete type IV collagenase. The in vivo evaluation of invasion using tracheal transplants, although requiring several weeks of experimentation, proved to be very reliable, yielding homogeneous results with little internal variation, and is proposed as a dependable in vivo invasion assay that closely mimics the in vivo human conditions in which most carcinomas develop and eventually invade neighboring tissues.

Enhancement of the invasive ability of a transformed human bronchial epithelial cell line by 12-O-tetradecanoyl-phorbol-13-acetate and diacylglycerol.

The effect of the tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate (TPA) was studied using an immortalized human bronchial epithelial cell line, BEAS-2B, both in vivo and in vitro. The in vivo model consisted of tracheas reconstituted with an epithelium of BEAS-2B cells xenotransplanted into athymic nude mice. Intraluminal TPA treatment caused increased BEAS-2B cell proliferation and downgrowth into the tracheal stroma. In an in vitro invasion assay, TPA enhanced the invasive capacity of BEAS-2B cells 20- to 25-fold. A similar result was observed with diacylglycerol (DAG), an endogenous activator of protein kinase C, and the effects of TPA and DAG were abolished by simultaneous treatment with H-7, a protein kinase C inhibitor. TPA induced type IV collagenolysis, and this effect also was prevented by H-7. These data are consistent with the hypothesis that TPA causes these cells to become invasive by inducing collagenase activity and that this effect is mediated via protein kinase C.

Benzoyl peroxide enhances the invasive ability of a mouse epidermal carcinoma cell line.

The effect of the skin tumor promoter benzoyl peroxide on the invasive potential of a murine squamous carcinoma cell line was investigated using an in vitro assay based on the capacity of cells to migrate through a porous filter coated with matrigel. Pre-treatment of the murine squamous carcinoma cell line CH72 with benzoyl peroxide added to the tissue culture medium increased the invasive capacity of these cells 5-8 times. No effects were observed on cells from primary cultures of normal murine epidermis. The simultaneous treatment of CH72 cells with benzoyl peroxide and the free radical scavengers, superoxide dismutase or CuSO4, prevented the increase and the values did not differ significantly from the baseline invasive potential. This suggests that activated oxygen species participate in the benzoyl peroxide-induced enhancement of the invasive capacity of these carcinoma cells.

[A sensitivity test of UFT and FT-207 against human pulmonary cancer using nude mice].

Transplanted tumors of human pulmonary adenocarcinoma subcutaneously into nude mice were used, to investigate the effect UFT and FT-207. Concentration of 5-FU and uracil in tumors, measured by the gas chromatographic-mass fragment graphic method, was followed. 5-FU concentration in UFT group were higher than other group, and uracil concentration show no significant difference. In one of the lines, tumor growth was stopped in UFT group and regression rate was 68% in comparison with control group, pathologically revealed grade II b in classification of Simosato-Oohoshi. It was also indicated in this experiment, anticancer effect is related with specific anticancer drug sensitivity.