Pirfenidone attenuates lung fibrotic fibroblast responses to transforming growth factor-ß1.

BACKGROUND: Pirfenidone, an antifibrotic agent used for the treatment of idiopathic pulmonary fibrosis (IPF), functions by inhibiting myofibroblast differentiation, which is involved in transforming growth factor (TGF)-ß1-induced IPF pathogenesis. However, unlike normal lung fibroblasts, the relationship between pirfenidone responses of TGF-ß1-induced human fibrotic lung fibroblasts and lung fibrosis has not been elucidated. METHODS: The effects of pirfenidone were evaluated in lung fibroblasts isolated from fibrotic human lung tissues after TGF-ß1 exposure. The ability of two new pharmacological targets of pirfenidone, collagen triple helix repeat containing protein 1(CTHRC1) and four-and-a-half LIM domain protein 2 (FHL2), to mediate contraction of collagen gels and migration toward fibronectin were assessed in vitro. RESULTS: Compared to control lung fibroblasts, pirfenidone significantly restored TGF-ß1-stimulated fibroblast-mediated collagen gel contraction, migration, and CTHRC1 release in lung fibrotic fibroblasts. Furthermore, pirfenidone attenuated TGF-ß1- and CTHRC1-induced fibroblast activity, upregulation of bone morphogenic protein-4(BMP-4)/Gremlin1, and downregulation of α-smooth muscle actin, fibronectin, and FHL2, similar to that observed post-CTHRC1 inhibition. In contrast, FHL2 inhibition suppressed migration and fibronectin expression, but did not downregulate CTHRC1. CONCLUSIONS: Overall, pirfenidone suppressed fibrotic fibroblast-mediated fibrotic processes via inverse regulation of CTHRC1-induced lung fibroblast activity. Thus, CTHRC1 can be used for predicting pirfenidone response and developing new therapeutic targets for lung fibrosis.

Development of interstitial pneumonia during treatment with eribulin: a case report.

BACKGROUND: Eribulin is typically used to treat patients with advanced breast cancer, and anti-cancer agents often cause the development of interstitial pneumonia in Japanese patients with advanced cancer. However, few case reports have addressed eribulin-induced interstitial pneumonia. Herein, we report a rare case of interstitial pneumonia-specifically, organized pneumonia-during treatment with eribulin in a patient with advanced breast cancer. CASE PRESENTATION: A 52-year-old Japanese woman was diagnosed as having advanced breast cancer 3 years before the admission described in the present report. She had received eribulin as third-line chemotherapy. Five days after her second treatment with eribulin, she was admitted to our hospital with dyspnea and dry cough. Upon admission, a chest computed tomography scan showed consolidation, with air bronchograms along the bronchovascular bundle of both lower lobes. The patient's serum levels of sialylated carbohydrate antigen Krebs von den Lungen-6 were high, as were her surfactant protein-D levels. There was no evidence of heart failure, renal failure, or infection. Based on the clinical cause, as well as on the findings of organized pneumonia, the patient was diagnosed as having interstitial pneumonia and treated with corticosteroids. After the initiation of steroid treatment, her respiratory condition and chest radiological findings improved. CONCLUSIONS: This case reveals an association between eribulin treatment and interstitial pneumonia. To our knowledge, this is the first case report to describe eribulin-induced organized pneumonia. Clinicians should be aware that interstitial pneumonia can develop during treatment with anti-cancer agents.

Expression of thymidylate synthase predicts clinical outcomes of S-1-based chemotherapy in squamous cell lung cancer.

Non-small cell lung cancer (NSCLC) patients with squamous cell carcinoma (SCC) histology have limited chemotherapeutic options. Treatment with S-1 combined with carboplatin (CBDCA) has been shown to provide a significant survival benefit in SCC patients compared with treatment with combined CBDCA and paclitaxel. The aim of the present study was to investigate the association between the expression of molecular markers related to the pharmacological action of S-1, including thymidylate synthase (TS), orotate phosphoribosyltransferase (OPRT) and dihydropyrimidine dehydrogenase (DPD), and the clinical efficacy of S-1-based chemotherapy in SCC patients. The immunohistochemical expression of TS, OPRT and DPD were retrospectively analyzed in tumor biopsy and resection specimens from patients with advanced SCC (n=32). Immunohistochemical H-scores were calculated and their association with S-1/CBDCA response was evaluated. Median progression-free survival time was significantly longer in patients with low TS H-scores than in those with high TS H-scores (162.5 vs. 97 days; P=0.004); by contrast, overall survival time was not observed to differ significantly between these groups (P=0.185). In the multivariate analysis, low TS expression was a significant positive factor for progression-free survival rate (hazard ratio, 0.40; P=0.021). A low TS H-score was also associated with an increased response to S-1-based chemotherapy compared with a high TS H-score (P=0.002). This indicates that SCC patients with low TS expression can benefit significantly from S-1-based chemotherapy, and that H-score measurement of intratumoral TS expression may represent a useful predictive biomarker for response to S-1-based chemotherapy by patients with SCC-type NSCLC.

Lung metastases from cutaneous adenoid cystic carcinoma 23 years after initial treatment.

Cutaneous adenoid cystic carcinoma (CACC) is an extremely rare neoplasm of head and neck region, and is characterized by propensity for local recurrence and perineural invasion. Late distant metastases occur usually to lungs. Although patients with lung metastases from CACC cannot be cured, long-term survival may be possible due to its slow-growing malignancy. We report a case of a 69-year-old female with lung metastases from CACC 23 years after initial surgery of scalp nodule.

Serious injury prediction algorithm based on large-scale data and under-triage control.

The present study was undertaken to construct an algorithm for an advanced automatic collision notification system based on national traffic accident data compiled by Japanese police. While US research into the development of a serious-injury prediction algorithm is based on a logistic regression algorithm using the National Automotive Sampling System/Crashworthiness Data System, the present injury prediction algorithm was based on comprehensive police data covering all accidents that occurred across Japan. The particular focus of this research is to improve the rescue of injured vehicle occupants in traffic accidents, and the present algorithm assumes the use of an onboard event data recorder data from which risk factors such as pseudo delta-V, vehicle impact location, seatbelt wearing or non-wearing, involvement in a single impact or multiple impact crash and the occupant's age can be derived. As a result, a simple and handy algorithm suited for onboard vehicle installation was constructed from a sample of half of the available police data. The other half of the police data was applied to the validation testing of this new algorithm using receiver operating characteristic analysis. An additional validation was conducted using in-depth investigation of accident injuries in collaboration with prospective host emergency care institutes. The validated algorithm, named the TOYOTA-Nihon University algorithm, proved to be as useful as the US URGENCY and other existing algorithms. Furthermore, an under-triage control analysis found that the present algorithm could achieve an under-triage rate of less than 10% by setting a threshold of 8.3%.

Development of diffuse alveolar damage after initiation of Nijutsuto.

Chinese traditional medicine, Nijutsuto, is used to treat patients with frozen shoulder and osteoarthritis. Herbal medicine is often linked to the development of interstitial lung disease. An 83-year-old Japanese man with osteoarthritis who was on Nijutsuto was admitted to our hospital with dyspnoea and severe cough after 2 weeks from initiation of Nijutsuto. A chest computed tomography scan on admission showed diffuse ground glass opacity with traction bronchiectasis. Thus, he was diagnosed with Nijutsuto-induced interstitial lung disease, and was treated with a high dose of methylprednisolone and cyclophosphamide. However, the patient died of respiratory failure 2 weeks after admission. The patient was definitively diagnosed with diffuse alveolar damage by pathological autopsy. Nijutsuto contains Radix Scutellariae, which is considered to be the cause of interstitial lung disease. Chinese traditional medicine containing both Radix Scutellariae and Licorice should be carefully used because of its potential role in the development of diffuse alveolar damage.

Loxoprofen-induced interstitial pneumonia: a case report.

BACKGROUND: Loxoprofen is a nonsteroidal anti-inflammatory drug used in the treatment of many diseases. However, there are no case reports about loxoprofen-induced pneumonia. We have encountered a rare case of loxoprofen-induced pneumonia. CASE PRESENTATION: We report the case of a 71-year-old Japanese woman who was initially treated with loxoprofen for fever. She was admitted to our hospital because of worsening of her symptoms, including fever and dyspnea. Her symptoms improved after treatment with ceftriaxone. Seven days after admission, she again developed high fever. She was again treated with loxoprofen and levofloxacin. However, acute respiratory failure developed after initiation of loxoprofen treatment. Chest computed tomography showed peribronchovascular consolidation. She was diagnosed with loxoprofen-induced pneumonia for which she was administered steroids. After treatment, her dyspnea and radiological findings improved. CONCLUSIONS: The findings in this case report reveal an association between treatment with a nonsteroidal anti-inflammatory drug and pneumonia. This rare case was diagnosed after accidental retreatment with loxoprofen. This is the first report of loxoprofen-induced pneumonia.

Diagnostic significance of cerebrospinal fluid EGFR mutation analysis for leptomeningeal metastasis in non-small-cell lung cancer patients harboring an active EGFR mutation following gefitinib therapy failure.

BACKGROUND: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been successfully used to treat patients with non-small cell lung cancer (NSCLC) harboring EGFR mutations. However, despite an initial excellent response, recurrence within one or two years is common. Diagnosis and treatment of leptomeningeal metastasis (LM), a form of NSCLC recurrence, remains particularly difficult. Here, we analyzed the EGFR mutation status of cerebrospinal fluid (CSF) directly using real-time polymerase chain reaction (PCR) and evaluated the efficacy of therapy with erlotinib, an EGFR TKI. PATIENTS AND METHODS: Seven NSCLC patients harboring activating EGFR mutations who had developed LM during or after therapy with gefitinib, an EGFR TKI, were retrospectively analyzed. CSF was obtained and subjected to cytological examination and EGFR mutation analysis, including detection of the resistance-associated T790M mutation, using real-time PCR. RESULTS: In all seven cases, the EGFR mutation detected in the CSF was the same as that detected in the primary tumor (sensitivity, 100%). Conversely, cytology results were positive in only two patients (sensitivity, 28.6%). No additional T790M mutations were detected. Erlotinib was efficacious in all cases, and improved performance status was achieved for five of the seven patients. The effect of erlotinib treatment was temporary, however, with time to treatment failure (TTF) ranging from 29 to 278 days (median, 65 days) and the interval between commencement of erlotinib treatment and death ranging from 45 to 347 days (median, 168 days). CONCLUSIONS: Analysis of EGFR mutations in CSF using a highly sensitive real-time PCR assay is a potentially powerful diagnostic method for LM.

High prevalence of gene abnormalities in young patients with lung cancer.

BACKGROUND: Recently, driver oncogenes in adenocarcinoma of the lung were identified, and several molecular target agents were introduced in the clinical setting. However, there are few reports on the frequency of gene abnormalities in young patients with lung cancer. MATERIALS AND METHODS: Twelve patients with lung adenocarcinoma aged 40 or younger at Juntendo University Urayasu Hospital or Juntendo University Hospital from July 2004 to March 2010 were analyzed for driver oncogene status including EGFR activating mutation, EML4-ALK fusion gene, and K-ras mutation. RESULTS: Four patients showed EGFR gene mutation. Five out of 7 EGFR mutation-negative patients showed positive results for EML4-ALK gene fusion. One case whose EGFR mutation was indeterminate. CONCLUSIONS: Driver oncogene including EGFR mutation and EML4-ALK fusion gene was identified in 9 of 12 cases (75%). Examination of gene abnormalities is essential in young patients with non-small cell lung cancer to provide the best treatment.

A feasibility study of zoledronic acid combined with carboplatin/nedaplatin plus paclitaxel in patients with non-small cell lung cancer with bone metastases.

AIMS AND BACKGROUND: Although zoledronic acid (ZOL) has been reported to inhibit bone metastasis from lung cancer, the optimum chemotherapy regimen in combination with ZOL has not yet been determined. METHODS AND STUDY DESIGN: Eighteen patients having non-small cell lung cancer (NSCLC) with bone metastasis who received carboplatin/nedaplatin plus paclitaxel combined with ZOL (4 mg every 28 days) were enrolled to investigate the feasibility of this treatment. The efficacy was evaluated by the percentage of patients at 9 months who were receiving radiation therapy, the time to first radiation treatment, and quality of life. Adverse effects were also evaluated. RESULTS: Only 3 among 18 patients received radiation therapy for bone metastases during the 9 months of the study. ZOL seems to prolong the median time to the first radiation treatment and maintain the quality of life regarding pain and activity status. No patients discontinued the treatment, although grade 3 or 4 treatment-related adverse effects occurred in 8 patients. CONCLUSIONS: ZOL combined with carboplatin/nedaplatin plus paclitaxel is an effective and tolerable treatment for NSCLC with bone metastases.

[Evaluation of clinical effectiveness of Pazufloxacin Mesilate in acute exacerbation of chronic respiratory diseases].

Patients with chronic respiratory disease have increased susceptibility to infection, because of impairment of the local immunologic defense mechanism in the airway system, which often results in acute exacerbation. Acute exacerbation of chronic respiratory disease is one of the most important predictors of increased morbidity and mortality, and thus the management in the acute phase is essential for better prognosis. Although the clinical guidelines for the management of respiratory tract infections published by the Japanese Respiratory Society recommend administering fluoroquinolones intravenously in case of hospitalized patients, the clinical evidence is still limited. In this study, we evaluated the efficacy of Pazufloxacin Mesilate (PZFX). an intravenous fluoroquinolone. in patients with chronic respiratory diseases complicated with acute exacerbation caused by acute respiratory infections. As a result, 16 out of 18 cases were successfully treated with PZFX. No adverse event was observed during this study. These results may support the validity of administering intravenous fluoroquinolone in hospitalized patients with acute exacerbation caused by infections, as recommended by the Japanese Respiratory Society.

Isolated congenital spleen agenesis: a rare cause of chronic thromboembolic pulmonary hypertension in an adult.

This report describes a case of isolated congenital spleen agenesis complicated by chronic thromboembolic pulmonary hypertension (CTPH) in a 44-year-old female patient. The patient had increasing exertional dyspnoea and thrombocytosis. An echocardiogram showed severe pulmonary hypertension and right ventricular hypertrophy, and contrast-enhanced chest CT revealed multiple thromboemboli within both pulmonary arteries. A perfusion lung scan demonstrated multiple segmental defects and no spleen was detected by abdominal CT, ultrasonography or scintigraphy. Comprehensive clinical examinations disclosed no evidence of a thrombus elsewhere or of an associated malformation such as a cardiac anomaly. Anticoagulation therapy was started, and a perfusion lung scan revealed partial improvement of the hypoperfusion in the right lower lobe. However, repeat echocardiography showed the pulmonary hypertension persisting for 1 year. The multiple segmental defects in the perfusion lung scans were also persistent. Collectively, a diagnosis of CTPH with isolated congenital spleen agenesis was established. This is the first documented case of CTPH in an adult with isolated congenital asplenia. Although congenital spleen agenesis is a rare condition, this case report suggests that this possibility should be considered when a diagnosis of CTPH and thrombocytosis is made.

Successful resection of dermatomyositis associated with thymic carcinoma: report of a case.

We report a case of thymic carcinoma associated with dermatomyositis (DM) in a 53-year-old man. The patient presented with the characteristic features of a skin rash with Gottron's papules, proximal muscle weakness, and increased serum levels of the muscle-associated enzymes. Comprehensive clinical examinations revealed an anterior mediastinal tumor. We resected the tumor and histological examination confirmed squamous cell carcinoma of the thymus. Thereafter, his clinical symptoms improved dramatically and his serum levels of muscle-associated enzymes dropped, indicating that the DM was a paraneoplastic phenomenon. Our search of the literature found only one other case report of DM accompanied by thymic carcinoma, and to our knowledge, this is the fi rst documented case of dramatic improvement of DM after resection of thymic carcinoma. We propose that thymic carcinoma should be added to the list of malignancies that can complicate DM as a paraneoplastic disease.

Mutations of the Birt Hogg Dube gene in patients with multiple lung cysts and recurrent pneumothorax.

RATIONALE: Birt-Hogg-Dubé (BHD) syndrome, a rare inherited autosomal genodermatosis first recognised in 1977, is characterised by fibrofolliculomas of the skin, an increased risk of renal tumours and multiple lung cysts with spontaneous pneumothorax. The BHD gene, a tumour suppressor gene located at chromosome 17p11.2, has recently been shown to be defective. Recent genetic studies revealed that clinical pictures of the disease may be variable and may not always present the full expression of the phenotypes. OBJECTIVES: We hypothesised that mutations of the BHD gene are responsible for patients who have multiple lung cysts of which the underlying causes have not yet been elucidated. METHODS: We studied eight patients with lung cysts, without skin and renal disease; seven of these patients have a history of spontaneous pneumothorax and five have a family history of pneumothorax. The BHD gene was examined using PCR, denaturing high-performance liquid chromatography and direct sequencing. MAIN RESULTS: We found that five of the eight patients had a BHD germline mutation. All mutations were unique and four of them were novel, including three different deletions or insertions detected in exons 6, 12 and 13, respectively and one splice acceptor site mutation in intron 5 resulting in an in-frame deletion of exon 6. CONCLUSIONS: We found that germline mutations of the BHD gene are involved in some patients with multiple lung cysts and pneumothorax. Pulmonologists should be aware that BHD syndrome can occur as an isolated phenotype with pulmonary involvement.

Abrogation of the interaction between osteopontin and alphavbeta3 integrin reduces tumor growth of human lung cancer cells in mice.

Osteopontin (OPN) is a multifunctional cytokine involved in cell signaling by interacting with alphavbeta3 integrins. Recent clinical studies have indicated that OPN expression is associated with tumor progression and poor prognosis among patients with lung cancer. However, the biological role of OPN in human lung cancer has not yet been well-defined. The purpose of this study is to investigate and provide evidence for the causal role of OPN regarding tumor growth and angiogenesis in human lung cancer. In this study, we developed a stable OPN transfectant from human lung cancer cell line SBC-3 which does not express the intrinsic OPN mRNA. To reveal the in vivo effect of OPN on tumor growth of human lung cancer, we subcutaneously injected OPN-overexpressing SBC-3 cells (SBC-3/OPN) and control cells (SBC-3/NEO) into the nude mice. Transfection with the OPN gene significantly increased in vivo tumor growth and neovascularization of SBC-3 cells in mice. These in vivo effects of OPN were markedly suppressed with administration of anti-alphavbeta3 integrin monoclonal antibody or anti-angiogenic agent, TNP-470. Furthermore, recombinant OPN protein enhanced human umbilical vein endothelial cell (HUVEC) proliferation in vitro, and this enhancement was significantly inhibited with the addition of anti-alphavbeta3 integrin antibody. Taken together, these results suggest that OPN plays a crucial role for tumor growth and angiogenesis of human lung cancer cells in vivo by interacting with alphavbeta3 integrin. Targeting the interaction between OPN and alphavbeta3 integrin could be effective for future development of anti-angiogenic therapeutic agents for patients with lung cancer.

Signal transduction mediated by endostatin directly modulates cellular function of lung cancer cells in vitro.

Endostatin (ED) is a carboxyl-terminal fragment of collagen XVIII with strong antiangiogenic activity. ED has been considered as a highly specific inhibitor of endothelial cell proliferation and migration through interaction with its receptor on the surface of endothelial cells. Recently, direct antitumor effects of ED in colon cancer cells and head and neck squamous cell carcinoma cells has been reported. However, its effect on lung cancer cells has not been clarified. The purpose of the present study was to determine the effect of ED on in vitro lung cancer cell function and to identify its receptor on lung cancer cells. We revealed that alpha5 integrin is capable of being a functional ED receptor among several integrins that are expressed on murine lung cancer (Lewis lung cancer [LLC]) cells. We further demonstrated that the ED-integrin interaction modulates various in vitro biological functions of LLC cells as we revealed that immobilized ED helps in LLC cell adhesion and migration in an integrin-dependent manner. Furthermore, ED inhibited LLC cell proliferation and induced apoptosis. Interestingly, ED did not demonstrate any antiproliferative activity against the other murine lung cancer cell line, KLN205, that lacks alpha5 integrin but binds to immobilized ED through the beta1 integrin. In addition, the binding of ED to alpha5 integrin on LLC cells induced phosphorylation of focal adhesion kinase. Taken together, these results suggest that the interaction between ED and alpha5 integrin may play an important role in lung cancer cell function.

Interaction between CD44 and hyaluronate induces chemoresistance in non-small cell lung cancer cell.

CD44s is a principle hyaluronate (HA) receptor and has been reported to play an important role in cancer cell invasion and metastasis. The aim of our study is to determine if the interaction between HA and CD44s influences in vitro chemosensitivity of non-small cell lung cancer (NSCLC). NSCLC cell line, H322 cells, transfected with the CD44s gene (H322/CD44s) cultured on HA coated plates were more resistant to cisplatin (CDDP) than that on bovine serum albumin. Multidrug resistance protein2 (MRP2) expression was induced in H322/CD44s cells cultured on HA. MRP2 inhibitor, MK571, not only suppressed MRP2 expression but also reversed CDDP resistance. These results suggest that the interaction between CD44s and HA play a pivotal role in acquired resistance to CDDP in NSCLC and MRP2 could be involved in this potential mechanism.

Pulmonary sarcoidosis and antiphospholipid syndrome.

Various autoimmune diseases have been reported to occur in patients with sarcoidosis. However, coexistence of sarcoidosis and antiphospholipid syndrome (APS) is extremely rare. We describe a 59-year-old female patient with pulmonary sarcoidosis who had preceding APS. Her previous medical history consisted of a miscarriage and ischemic colitis. She was diagnosed as APS during the onset of a brainstem infarction with positive reaction to beta2-glycoprotein I-dependent anticardiolipin antibody. Two years later, chest CT revealed enlargement of the hilar and mediastinal lymph nodes and small nodules in the lung fields. Transbronchial lung biopsy demonstrated non-caseating epithelioid cell granuloma leading to the diagnosis of definite pulmonary sarcoidosis. This is the first APS case where pulmonary involvement with sarcoidosis has been confirmed through lung biopsy. Our case report suggests that APS should be recognized as an accompanying disorder of sarcoidosis.