Successful erlotinib rechallenge after both gefitinib- and erlotinib-induced interstitial lung diseases.

Epidermal growth factor receptor tyrosine kinase inhibitors, gefitnib and erlotinib, are effective for advanced nonsmall-cell lung cancer with epidermal growth factor receptor gene mutation. However, interstitial lung disease induced by these drugs is sometimes fatal, and discontinuation of the medication is the principle approach once this occurs. There are, however, some reports of cases in which rechallenge of gefitinib or erlotinib was successful, and it remains unclear when or how rechallenge should be attempted. We report the first successful case of erlotinib rechallenge after both gefitinib- and erlotinib-induced interstitial lung diseases. Our case suggests that, in interstitial lung disease induced by an epidermal growth factor receptor tyrosine kinase inhibitor, rechallenge with concurrent glucocorticoid administration and gradual increase of dosage could be a clinical option if imaging does not show a diffuse alveolar damage pattern, and if no alternative therapy is available.

Long-term efficacy of inhaled N-acetylcysteine in patients with idiopathic pulmonary fibrosis.

BACKGROUND: Inhalation of N-acetylcysteine (NAC) has been carried out in our department since 1994 for treating interstitial pneumonia such as idiopathic pulmonary fibrosis (IPF). In this study, the clinical efficacy and safety of long-term NAC inhalation monotherapy for IPF was investigated. METHODS: NAC inhalation was carried out in 23 of 34 cases diagnosed as IPF by surgical lung biopsy in our department between 1994 and 2008. The treatment was continued for one year or longer in 14 cases. In these 14 cases and in 11 cases without treatment, the clinical courses, prognosis, lung function (%FVC, %DLco, and %TLC), and changes in serum markers for interstitial pneumonia (KL-6 and SP-D) were examined. RESULTS: There were no significant differences in survival curves between the two groups. Acute exacerbation was observed in 4 of 14 cases (28.6%) receiving NAC inhalation. Compared with the results just before the beginning of NAC inhalation, Δ%FVC and Δ%DLco in the treated cases were -4.7% and -2.9% one year later and -4.0% and -5.8% two years later, respectively. In cases without treatment, Δ%FVC and Δ%DLco were -3.5% and +5.3% one year later and +0.2% and +1.0% two years later, respectively. CONCLUSION: Since this study is an open case-control study in a single institute and the number of cases is not large, its use in evaluating the efficacy of NAC inhalation monotherapy is limited. In addition, the role of NAC inhalation in combination with a steroid, an immunosuppressive agent, and a new anti-fibrosis drug should also be investigated.

Risk of Acute Exacerbation After Video-assisted Thoracoscopic Lung Biopsy for Interstitial Lung Disease.

Biopsy by video-assisted thoracoscopic surgery (VATS) for interstitial pneumonia allows collection of samples sufficient for accurate histologic diagnosis. Although VATS is relatively safe, several reports have suggested that surgical lung biopsy may be a risk factor for acute exacerbation of idiopathic pulmonary fibrosis (IPF). We retrospectively reviewed data on the 113 cases that underwent biopsy by VATS to diagnose diffuse parenchymal lung disease in our department between 1994 and 2006, and analyzed its complications, in particular, risk of acute exacerbation of IPF. As the final diagnosis, idiopathic interstitial pneumonia was most frequent, involving 52 cases, of which IPF was most frequently found followed by nonspecific interstitial pneumonia and cryptogenic organizing pneumonia, in that order. Among our cases, there were 2 deaths after VATS (mortality rate, 1.8%), and both were IPF cases with acute exacerbation. When examining clinical markers in the 2 fatal IPF cases with acute exacerbation, we found that the percentage of predicted forced vital capacity was 55 or lower, percentage of predicted carbon monoxide diffusing capacity was 40 or lower, serum interstitial pneumonia markers KL-6 and SP-D were elevated, intraoperative inhalation of 100% O2 was 80 minutes or longer, and postoperative thoracic drainage was required for 10 days or longer. Although acute exacerbations of IPF seem to occur at any time during the course of disease, it is important to be aware of the possibility of acute exacerbation of IPF after VATS.

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.

[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.

[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.

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.

[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.

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.

[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.

Preventive effect of hochu-ekki-to, a Japanese herbal medicine, on bleomycin-induced lung injury in mice.

OBJECTIVE: Pulmonary fibrosis is thought to be closely associated with the T-helper type-2 (Th2) immune response. Recent studies have shown that hochu-ekki-to (TJ-41), a Japanese herbal medicine, may correct the Th1/Th2 imbalance skewed to Th2. The present study was designed to investigate the preventive effect of TJ-41 on the development of bleomycin (BLM)-induced lung injury in mice. METHODS: Female C57BL/6 mice were divided into a group given ordinary feed and another group given the same feed plus TJ-41 mixed in at a dose of 1 g/kg/day. Both groups were maintained on this diet for 8 weeks before and 5 weeks after administration of 2 mg/kg BLM intratracheally. RESULTS: Mortality after BLM-induced lung injury was significantly lower in the TJ-41-treated mice. The hydroxyproline content and fluid content in the lung on day 35 was significantly lower in the TJ-41-treated mice. Histologically, TJ-41 reduced the number of infiltrating cells, thus ameliorating the destruction of the lung architecture, and attenuated the lung fibrosis score. Furthermore, TJ-41 inhibited the expression of the interleukin-5/interferon-gamma mRNA ratio in the lung on day 7. CONCLUSIONS: Treatment with TJ-41 partially prevented experimental lung fibrosis through the correction of the Th1/Th2 imbalance skewed to Th2.

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.

[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.

ST2 gene induced by type 2 helper T cell (Th2) and proinflammatory cytokine stimuli may modulate lung injury and fibrosis.

The authors have investigated gene expression of ST2 in the lung tissue of a bleomycin (BLM)-induced lung fibrosis model in vivo and in a human lung fibroblast cell line, WI38, and a human type II alveolar epithelial cell line, A549, reacting to proinflammatory and type 2 helper T cell (Th2)-type cytokine stimuli in vitro. The lung mRNA expression of interleukin (IL)-4, IL-5, IL-1beta, and tumor necrosis factor (TNF)-alpha increased significantly at day 7 after instillation of BLM, whereas interferon (IFN)-gamma mRNA expression did not increase. ST2 and transforming growth factor (TGF)-beta1 mRNA expression of the lung increased significantly between days 7 and 21, and increased to maximal levels at day 14 post-BLM challenge. ST2 mRNA expression statistically correlated with TGF-beta 1 mRNA expression. In addition, the combination of IL-1 beta, TNF-alpha, and IL-4 had an additive effect on ST2 mRNA expression from A549 cells and WI38 cells. These findings suggest that soluble ST2 gene may increase, possibly reflecting the development of the inflammatory process and the Th2-type immune response in the fibrotic lung tissue, and may modulate a process of pulmonary fibrosis.

Preventive effect of Hochu-ekki-to on lipopolysaccharide-induced acute lung injury in BALB/c mice.

This study was designed to investigate the effect of Hochu-ekki-to (TJ-41), a Japanese herbal medicine, on the development of lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice. ALI was induced in female BALB/c mice by the intranasal administration of 0.1 mg/kg LPS. The mice were divided into a group receiving normal feed and another group receiving feed mixed with TJ-41 at a dose of 1 g/kg/day for 8 weeks before LPS challenge. In the bronchoalveolar lavage fluid, the preadministration of TJ-41 caused significant reduction in the absolute number of total cells, neutrophils, and macrophages. The preadministration of TJ-41 significantly inhibited increases in the serum level of keratinocyte chemoattractant (KC), which is a murine chemotaxin for neutrophils that corresponds to human interleukin-8, with respect to its concentration at 24 h after LPS challenge. Furthermore, the histopathologic findings indicated that alveolitis with leukocyte infiltration in the alveolar space was less severe in the TJ-41-treated mice than in the control mice. These findings indicated that the preadministration of TJ-41 could show an inhibitory effect on ALI in this experimental murine system associated with the suppression of chemokine production.

[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.

[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.

Intrathoracic sporadic desmoid tumor with the beta-catenin gene mutation in exon 3 and activated cyclin D1.

We report a case of intrathoracic desmoid tumor without familial adenomatous polyposis and demonstrate beta-catenin mutation of exon 3. A 15-year-old male presented with a desmoid tumor after having sustained an assault. In an examination for a mutation of the beta-catenin gene, an activating mutation from ACC (Thr) to GCC (Ala) at codon 41 was found. Immunohistochemical staining showed that accumulated beta-catenin protein was predominantly localized in the nuclei of desmoid cells, and cyclin D1 protein was also overexpressed. These findings might suggest that an activating mutation of the beta-catenin gene affected regulation of the cyclin D1 gene, resulting in the generation of intrathoracic sporadic desmoid tumor, which arose at the site of posttraumatic injury.