Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer.

Improvement in the clinical outcome of lung cancer is likely to be achieved by identification of the molecular events that underlie its pathogenesis. Here we show that a small inversion within chromosome 2p results in the formation of a fusion gene comprising portions of the echinoderm microtubule-associated protein-like 4 (EML4) gene and the anaplastic lymphoma kinase (ALK) gene in non-small-cell lung cancer (NSCLC) cells. Mouse 3T3 fibroblasts forced to express this human fusion tyrosine kinase generated transformed foci in culture and subcutaneous tumours in nude mice. The EML4-ALK fusion transcript was detected in 6.7% (5 out of 75) of NSCLC patients examined; these individuals were distinct from those harbouring mutations in the epidermal growth factor receptor gene. Our data demonstrate that a subset of NSCLC patients may express a transforming fusion kinase that is a promising candidate for a therapeutic target as well as for a diagnostic molecular marker in NSCLC.

Torque teno virus DNA titre elevated in idiopathic pulmonary fibrosis with primary lung cancer.

BACKGROUND AND OBJECTIVE: IPF is an independent risk factor for lung cancer, but the mechanism of this association has not fully been elucidated. The role of Torque teno virus (TTV) in respiratory disease is poorly understood, although it has been shown that infection with TTV is associated with the activity and prognosis of IPF. This study aimed to investigate the prevalence and titre of TTV DNA among patients with IPF and lung cancer. METHODS: The presence of TTV DNA was determined by PCR in the sera of patients with both lung cancer and IPF (n = 22), patients with IPF only (n = 35), and patients with lung cancer only (n = 142). RESULTS: TTV DNA was detectable in all patients with both IPF and lung cancer, in 94.3% of the patients with IPF only and 97.2% of the patients with lung cancer only. The TTV DNA titre in the patients with IPF and lung cancer was significantly higher than that in the patients with IPF only or lung cancer only. The percentage of TTV-positive patients with a high TTV titre in the IPF and lung cancer group was significantly higher than that in the IPF only group. CONCLUSIONS: These findings are the first report on the association between TTV and the complication of lung cancer in IPF and suggest that TTV infection might be associated with the development of lung cancer in IPF.

Preventive effects of edaravone, a free radical scavenger, on lipopolysaccharide-induced lung injury in mice.

BACKGROUND AND OBJECTIVE: Reactive oxygen species (ROS) play an important role in the pathogenesis of acute lung injury (ALI) and pulmonary fibrosis. It was hypothesized that edaravone, a free radical scavenger, would be able to attenuate LPS-induced lung injury in mice by decreasing oxidative stress. METHODS: For the in vivo experiments, lung injury was induced in female BALB/c mice by the intranasal instillation of LPS. Edaravone was given by intraperitoneal administration 1 h before the LPS challenge. For the in vitro experiments, MH-S cells (murine alveolar macrophage cell line) were exposed to edaravone, followed by stimulation with LPS. RESULTS: In the LPS-induced ALI mouse model, the administration of edaravone attenuated cellular infiltration into and the concentrations of albumin, IL-6, tumour necrosis factor-alpha, keratinocyte-derived chemokine and macrophage inflammatory protein-2 in BAL fluid. In addition, the in vitro studies showed that the elevated IL-6 secretion from MH-S cells in response to LPS was significantly attenuated by co-incubation with edaravone. CONCLUSIONS: In an experimental murine model, a free radical scavenger may prevent ALI via repression of pro-inflammatory cytokine production by lung macrophages.

Drug-induced pneumonitis associated with imatinib mesylate in a patient with idiopathic pulmonary fibrosis.

A 74-year-old man with idiopathic pulmonary fibrosis (IPF) developed severe dyspnea on exertion after the readministration of imatinib mesylate for chronic myeloid leukemia. Chest X-ray and CT showed ground-glass opacities in both lungs in addition to preexisting honeycombing. Discontinuation of imatinib and methylprednisolone pulse therapy followed by administration of oral prednisolone resulted in improvement in both symptoms and radiographic findings. Imatinib-induced pneumonitis was diagnosed based on the clinical course and findings. Only five previous reports of imatinib-induced pneumonitis have been published in the literature, and this is the first case reported in a patient with IPF.

[A case of paraneoplastic cerebellar degeneration associated with small cell lung cancer showing marked response to intravenous immunoglobulin].

BACKGROUND: Paraneoplastic cerebellar degeneration (PCD), one of the paraneoplastic neurological syndromes (PNS), develops a subacute cerebellar dysfunction and its neurological prognosis is poor in most cases. Because it is considered to be immune-mediated, immunosuppressive therapy may be effective, but its past outcomes are not constant. CASE: A 59-year-old woman presented with deteriorating cerebellar manifestations such as ataxic gait, nausea, and dysarthria. Chest CT revealed a nodule in the upper lobe of the right lung, and small cell lung cancer was diagnosed by transbronchoscopic lung biopsy and sputum cytology. Although known antineuronal antibodies were not detected, no other causative diseases were recognized, so PCD associated with SCLC was diagnosed. The cerebellar manifestations improved remarkably with immediate intravenous immunoglobulin (IVIG) therapy. SCLC showed complete response (CR) after chemoradiotherapy, and the neurological symptoms have not worsened at present. CONCLUSION: Treatment with IVIG at the early stage may lead to the improvement of PCD and is worth attempting.

[A case of drug-induced pneumonia caused by propiverine: follow-up drug lymphocyte stimulation test useful for identification of the suspected drug].

A 75-year-old woman presented with general malaise and exertional dyspnea one week after the administration of propiverine, a urination-improving drug, with a diagnosis of neurogenic bladder. Her chest X-ray film and high-resolution computed tomography (HRCT) revealed bilateral, non-segmental, ground-glass opacities with partial consolidation and cord-shaped shadows. Bronchoalveolar lavage (BAL) fluid suggested an increase in the ratio of lymphocytes. A drug lymphocyte stimulation test (DLST) for propiverine showed a negative reaction 2 weeks after onset; however, a positive reaction was noted after a further 2 weeks. After the discontinuation of propiverine, the symptoms and imaging findings markedly improved. The clinical course suggested drug-induced pneumonia caused by propiverine. Considering the risk of additional administration and the necessity of subsequent prescription, drug provocation test was not performed. No study has reported propiverine-related lung injuries; however, as this agent is frequently prescribed in elderly patients, the possibility of drug-induced pneumonia must be considered.

[Case of minocycline-induced acute eosinophilic pneumonia accompanied by marked neutrophilia in the peripheral blood].

A 37-year-old woman presenting with high fever, dry cough and progressive dyspnea was admitted to our hospital. She took 100 mg of minocycline hydrochloride orally because of a common cold one day prior to her admission. A chest CT scan showed diffuse ground-glass opacities with interlobular septal thickening and thickening of bronchovascular bundles. An analysis of bronchoalveolar lavage fluid showed an increase in both the total cell counts and the number of eosinophils. The result of a lymphocyte stimulation test performed on peripheral blood lymphocytes was positive for minocycline. This patient had a history of pneumonia with similar clinical and radiographic findings, which had developed while receiving minocycline. As a result, we made a diagnosis of minocycline-induced acute eosinophilic pneumonia. Her symptoms and radiographic findings improved within a few days after admission. Corticosteroid therapy was effective. A marked increase of peripheral blood neutrophils were noted on admission. The serum levels of IL-8 and G-CSF increased at the early phase of the disease, but thereafter decreased in association with neutrophils, thus suggesting the contribution of these cytokines to the early phase neutrophilia in this case.

[Case of pneumothorax due to pulmonary metastases from uterine leiomyosarcoma].

A 44-year-old woman who had undergone hystero-oophorectomy for uterine sarcoma presented to our hospital with palindromic pneumothorax and her chest CT revealed multiple cystic lesions. After admission video-assisted thoracoscopic surgery (VATS) showed the pulmonary lesions to be primarily leiomyoma, however, further examination revealed that her uterine sarcoma resected in 2000 exhibited not only mitosis but also venous invasion. We therefore considered her lung tumors as metastases from uterine leiomyosarcoma. Cases of secondary spontaneous pneumothorax (SSP) due to pulmonary metastases are rare and almost half are from mesenchymal tumors. Thin-wall cavities and cysts are formed by a check-valve mechanism in the process of pulmonary metastases formation. When multiple thin-wall cavities and cysts are found in the lung, pulmonary metastases should be considered as one of the causes, and pathological specimens obtained in past illness should be re-examined in detail.

[Our clinical experiences of amrubicin hydrochloride monotherapy in extensive-disease small cell lung cancer].

We retrospectively investigated monotherapy of amrubicin hydrochloride in patients with extensive-disease small cell lung cancer (ED-SCLC) and assessed its efficacy and safety. Twenty-two patients were enrolled. The response rate of total, previously untreated, sensitive relapsed, and refractory relapsed cases were 59%, 50%, 100% and 46%, respectively. As for the dose of amrubicin, the response rates of 30 mg/m(2), 35 mg/m(2), 40 mg/m(2), and 45 mg/m(2) were 50%, 33%, 69% and 100%, respectively. Severe myelosuppression was frequently observed as the adverse event, but significant differences among several dosages were not recognized. Median survival time was 230 days in relapsed cases. Monotherapy of amrubicin might be effective in ED-SCLC not only as first-line but also as second-line treatment in relapsed cases. The recommended dose was above 40 mg/m(2) because of its higher response rate.

[Nationwide epidemiological survey of patients with idiopathic interstitial pneumonias using clinical personal records].

A nationwide epidemiological survey of idiopathic interstitial pneumonias (IIPs) in 2005 was performed using clinical personal records. According to the data from the Japan Intractable Diseases Information Center, 4,396 patients with IIPs were covered by public insurance. The prevalence of IIPs in Japan was estimated to be 3.44 per 100,000. The forms of 1543 patients (new: 658, recurrent: 885) were collected. Of 1543 cases, 1322 cases (85.7%) had idiopathic pulmonary fibrosis (IPF), therefore details were investigated in patients with IPF. The mean age at onset was 65.4 years and men were more frequent than women (878 in men, 444 in women). The severity, diagnostic method, symptoms, imaging findings, and pulmonary function tests were analyzed in the new forms. Severity levels of I, II, III and IV were seen in 32, 28, 177, and 287 cases, respectively. A pathological diagnosis was made in 67 cases (12%). The positive rates of fine crackles, dry cough, exertional dyspnea, and finger clubbing were 98%, 94%, 98%, and 53%, respectively. On HRCT, honeycomb was noted in the subpleural lung lesions in more than 90% of the cases. As for pulmonary function tests, restrictive and diffusing capacity impairment were noted in 86% and 92%, respectively, and SpO2 was below than 90% in 91% on a 6-minute walking test. The serum KL-6 level was elevated in 95%. Most of the IPF analyzed cases were at a severity level of III or IV because the analysis aimed at those coverage by public insurance. Since this was only the initial nationwide epidemiological survey in Japan, the current situation should be investigated.

[Evaluation of the drug lymphocyte stimulation test (DLST) with shosaikoto].

BACKGROUND: Our aim is to evaluate the significance of DLST by Shosaikoto. METHODS: We clinically evaluated 3 cases of drug-induced pneumonia assumed to be caused by Shosaikoto, and we performed DLST of Shosaikoto for healthy controls, and compared the data with drug-induced pneumonia cases of Shosaikoto. RESULTS: As clinical characteristics of 3 cases, 2 cases were positive for hepatitis C virus antibody, and 1 case was positive for DLST of Shosaikoto. The observed chest high-resolution CT (HRCT) findings showed hypersensitivity pneumonia (HP) pattern in all 3 cases. Prognosis was good in all 3 cases. DLST of Shosaikoto was positive in 27.5% of healthy controls. Stimulation index (S.I.) of DLST in drug-induced pneumonia cases increased depending on drug dilution density, compared to that of healthy controls. CONCLUSION: DLST of Shosaikoto showed high false-positive rate. However, we may be able to distinguish the true-positive cases with the false-positive cases by comparing the S.I. of DLST according to drug dilution density.

[Sjögren's syndrome with multiple bullae due to pulmonary nodular amyloidosis].

We reported a case of Sjögren's syndrome with pulmonary involvement diagnosed by video-assisted thoracoscopic lung biopsy. The patient was a 54-year-old woman with antiphospholipid syndrome. Her chest radiograph and CT scan showed multiple nodules with or within cystic lesions. The thoracoscopic lung biopsy specimens revealed nodular amyloid deposits associated with bronchiolitis. The mechanism of bulla formation appeared to be a check-valve mechanism caused by the narrowing of the airway due to bronchiolitis with mononuclear cell infiltration. She has no symptoms without respiratory failure or functional impairment, therefore we are following her closely without therapy.

[Case of small cell lung cancer complicated with diabetes insipidus and Cushing syndrome due to ectopic adrenocorticotropic hormone secretion].

A 54-year-old woman had been given a diagnosis with scleroderma and interstitial pneumonia due to scleroderma when she was 45 years old. Thirst, with resulting polydipsia and polyuria (about 7 liters/day) were present since May, 2004, and bloody sputum appeared in June of 2004. The patient was admitted to our hospital. Chest CT examination showed multiple nodules in the bilateral lower lung field and multiple movable subcutaneous nodules on the abdomen. Small-cell lung cancer (metastases in the pituitary, subcutaneous tissue, and lungs) was diagnosed by transbronchial lung biopsy and subcutaneous nodule biopsy of the abdomen. The final diagnosis was diabetes insipidus and Cushing syndrome. Chemotherapy was done with CDDP and VP-16, which resulted in reduction of the tumor and improvement in endocrinological findings. Nevertheless, chemotherapy could not be continued because of infected bullae. The patient died of deteriorating illness after 91 sickness days. We concluded that this case was Cushing syndrome caused by ectopic adrenocorticotropic hormone-producing small cell lung cancer, and that it presented with diabetes insipidus because of pituitary metastasis. Therefore, when drastic endocrinological changes are found, it is important to examine for cancer, including lung cancer, as soon as possible.

[Case of myeloperoxidase-antineutrophil cytoplasmic antibody-associated pulmonary alveolar hemorrhage caused by propylthiouracil].

We reported the case of pulmonary alveolar hemorrhage caused by propylthiouracil (PTU) with severe respiratory failure and anemia, who improved with PTU discontinuance and steroid therapy. A 35-year-old woman presented with pyrexia, shortness of breath, and arthralgia. Her chest radiograph and CT showed diffuse ground-glass opacities, and her arterial blood gas analysis revealed severe respiratory failure. Laboratory results included a hemoglobin level of 5.2 g/dl, and a myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA) level of 203 EU (normal range <9.0 EU). As bronchoalveolar lavage (BAL) fluid showed fresh blood-like fluid containing hemosiderin-laden macrophages, pulmonary alveolar hemorrhage was diagnosed. Since she had been taking PTU for 4 years, PTU was immediately discontinued. Steroid pulse therapy was performed, followed by oral prednisolone 30 mg per day, and her symptoms and chest radiograph findings rapidly improved. Based on the time-course changes, MPO-ANCA may have been involved in the development of pulmonary alveolar hemorrhage.

[A case of juvenile lung cancer with suspected progeroid syndrome and mental retardation].

A 28-year old woman developed juvenile lung cancer. Cockayne syndrome, one of the progeroid syndromes, was suspected because of mental retardation, renal disfunction, photosensitivity, and the characteristic physical appearance such as low set ears, microcephaly, senile face, short stature, and cachectic habitus. We tried chemotherapy with gefitinib and docetaxel, but they were ineffective and she was found to have multiple extraocular muscle metastasis. CT scan showed carcinomatous lymphangiosis findings, her respiratory condition worsened gradually and she died about 7 months after the diagnosis of lung cancer. Some progeroid syndromes are known for their high incidence of juvenile cancres, and the responsible genes are gradually coming to light. However, concerning the relationship between lung cancer and progeroid syndromes, our investigations revealed only one case report of Werner syndrome, one of the progeroid syndromes, accompanied by lung cancer. Progeroid syndromes with lung cancer are thought to be very rare. We expect collection of data on cases like the present case will help to clarify the mechanism of aging and carcinogenesis.

[A case of HLA-B54 positive silicosis with rheumatoid arthritis and lung cancer].

In the same environment or workplace, some people contract pneumoconiosis, including silicosis, and some do not. This suggests the important role of constitutional predisposition. In Japanese cases with silicosis, the frequency of HLA-B54 was increased and disease susceptibility gene (s) may exist near the HLA-B locus. It is well known that silicosis is frequently accompanied with rheumatoid arthritis, probably due to the effects of silica on the immunological system. We encountered a case of silicosis with rheumatoid arthritis and lung cancer, who was found to have HLA-B54.

[An autopsy case of myelodysplastic syndrome complicated by recurrent organizing pneumonia].

We reported an autopsy case of a 58-year-old-man, who developed intractable organizing pneumonia accompanying myelodysplastic syndrome with neutrophil hypofunction. Slight clinical improvement was obtained by steroid pulse therapy, but re-exacerbation occurred during steroid tapering. Infection was suspected, and we administered antibiotics and antifungal agents, while holding steroid administration. However, both the clinical findings and images deteriorated. By both steroid and cyclosporine treatment, a slight improvement was temporarily obtained, but he died. The findings of lung tissue on autopsy showed extensive old and new organized pneumonia, and, as for the etiology of the intractable pneumonia, the likelihood of the lung infectious disease was considered most likely. In addition, invasive pulmonary aspergillosis led directly to death.

[A case of primary fibrosarcoma of the pulmonary artery].

A 38-year-old-man was admitted to our hospital complaining of exertional dyspnea. Chest radiography and CT showed a huge mass that completely occluded the left main pulmonary artery and spread into the right main pulmonary artery. The tumor was diagnosed as sarcoma by transbronchial biopsy. Radiation therapy obtained temporary partial response. He died of respiratory insufficiency after 14 months. The autopsy revealed primary pulmonary artery sarcoma: fibrosarcoma arising from the left pulmonary artery. To our knowledge, this is the first case report of fibrosarcoma of the pulmonary artery in Japan.

Reassessment of the classification of the severity in idiopathic pulmonary fibrosis using SF-36 questionnaire.

OBJECTIVE: To investigate whether or not the newly revised classification of the severity of idiopathic interstitial pneumonia (IIP) is appropriate with respect to quality of life (QOL). METHODS: The association between the subscale of Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) and pulmonary function or serum marker was analyzed using Pearson's correlation coefficient. The association between the subscale of SF-36 and the previous or newly revised classification of the severity of IIP was analyzed using Spearman's rank correlation test. PATIENTS: Forty patients with idiopathic pulmonary fibrosis (IPF) were enrolled. RESULTS: The mean deviation value scores for 7 items, excluding bodily pain (BP) in SF-36 were below the national reference values. % vital capacity (VC) was correlated with the 7 items excluding BP. However, neither serum LDH nor KL-6 values were correlated with any item in SF-36. According to the new or previous classification of the severity, severity was correlated with physical function, limitation of role functioning related physical problems and general health (GH); the correlation coefficient with the new one was slightly higher than the previous one. Based on these results, we established a unique draft on the classification of the severity. %VC <70% was added as an item for the newly revised classification in our draft. In our draft, there was rank correlation between the 7 items, excluding BP, in SF-36 and severity. CONCLUSION: With respect to QOL, the newly revised classification of the severity of IIP was not satisfactory, but the hypoxemia during exercise in patients with resting PaO(2) >80 Torr and reduction of VC were found to be important factors.

Inhaled corticosteroid rapidly improved pulmonary sarcoidosis.

We report two cases in whom inhaled corticosteroid rapidly improved pulmonary sarcoidosis. In the first case, fluticasone at 400 microg/day was initiated, because dry cough and small nodular shadows on chest X-ray persisted for six months. But her cough and the nodular shadows were persisted, therefore the treatment was replaced with budesonide at 800 microg/day. Two months later, her dry cough subsided and pulmonary shadows improved. Serum angiotensin-converting enzyme (ACE) level was decreased and pulmonary function improved. In the second case, bumethasone was already administered at a local clinic. Budesonide at 400 microg/day was combined with oral steroid, because pulmonary shadows continued for eight years. Also two months later, the serum ACE level was decreased and the pulmonary shadows slightly improved. Inhaled corticosteroid therapy for two to three months is tolerable, and may be a useful treatment option in some patients with sarcoidosis.