The usefulness of pleural fluid presepsin, C-reactive protein, and procalcitonin in distinguishing different causes of pleural effusions.

BACKGROUND: We aimed to determine the presepsin concentration in pleural fluid from patients with pleural effusions of different aetiologies and to compare its diagnostic value with that of pleural fluid C-reactive protein (CRP) and procalcitonin (PCT). METHODS: We enrolled 132 patients with pleural effusion who underwent diagnostic evaluation, and we classified them into six categories: empyema, parapneumonic effusion, tuberculous effusion, malignant effusion, paramalignant effusion, and transudate effusion. Additionally, all pleural effusions were categorised as infectious or non-infectious effusions. RESULTS: Receiver operating characteristic analysis was used to evaluate diagnostic performance. When diagnosing empyema, the marker with the highest sensitivity was pleural fluid presepsin (cut-off: 754 pg/mL; sensitivity: 90.9%, specificity: 74.4%) and that with the highest specificity was pleural fluid CRP (cut-off: 4.91 mg/dL; sensitivity: 63.6%, specificity: 89.3%). Pleural fluid PCT tended to be lower in patients with empyema than in those with parapneumonic effusion, but this was not useful for the diagnosis of empyema. When diagnosing infectious pleural effusion, a combination of pleural fluid CRP (cut-off: 2.59 mg/dL) and presepsin (cut-off: 680 pg/mL) produced the highest diagnostic accuracy (83.3%). CONCLUSIONS: Pleural fluid presepsin was found at high levels in patients with empyema and parapneumonic effusion. This pattern closely resembles the previously reported pattern of pleural fluid CRP. Some combinations of pleural fluid inflammatory markers may be more clinically useful than these markers in isolation.

Clinical features of patients with lung cancer accompanied by thromboembolism or disseminated intravascular coagulation.

PURPOSE: Thromboembolism (TE) and disseminated intravascular coagulation (DIC) are often present concomitantly. This study aimed to investigate the clinical features of patients with lung cancer and TE and/or DIC. PATIENTS AND METHODS: Data on 716 patients with pathologically confirmed diagnoses of lung cancer were retrospectively analyzed for TE/DIC. RESULTS: TE was identified in 16 patients (2.2%) and DIC was identified in 5 (0.7%) during the diagnosis of cancer. TE was more often observed in adenocarcinoma (4.0%). Both TE and DIC were more often observed in stage IV (4.7% and 1.5%, respectively). In patients with stage IV adenocarcinoma who received some systemic treatment, overall survival (OS) was significantly shorter in patients with TE (median 280 days) and with DIC (72 days) than in non-TE/DIC patients (538 days). Multivariate analysis showed that older age, poor performance status, greater number of metastatic organs, no EGFR mutation/ALK fusion, presence of interstitial lung disease, and DIC were poor prognostic factors for OS. In 339 patients in stage IV, 25 (7.4%) and 21 (6.2%) patients had TE and DIC, respectively, during the course. Six patients exhibited both TE and DIC. TE was more often observed in adenocarcinoma (20 of 196 patients; 10.2%). Patients with DIC had extremely shorter survival (median 13 days) after onset. Cancer control by systemic therapy, such as chemotherapy and molecular-targeted therapy, contributed to long survival. CONCLUSION: Patients with TE/DIC had shorter OS than patients without TE/DIC. Control of lung cancer by systemic therapy was important for longer survival after the onset of events.

Impact of idiopathic pulmonary fibrosis on advanced non-small cell lung cancer survival.

PURPOSE: The clinical features of patients with advanced non-small cell lung cancer (NSCLC) and interstitial lung disease (ILD) have not fully been elucidated. This study aimed to investigate the clinical features of these patients, particularly with idiopathic pulmonary fibrosis (IPF). METHODS: Data on 218 patients with pathologically confirmed diagnoses of NSCLC who had been treated with chemotherapy and/or molecular targeted therapy were retrospectively analyzed for progression-free survival (PFS), overall survival (OS), responses to first-line therapy, and incidence of acute exacerbations (AEs). RESULTS: Fifty-three of the 218 patients were diagnosed with ILD, and 34 of them with IPF. The frequency of epidermal growth factor receptor (EGFR) mutation was significantly lower in ILD and IPF patients than in non-ILD patients (2 or 0 vs. 32 %, respectively). Median PFS and OS were significantly shorter in both ILD and IPF patients than in non-ILD patients (118, 92, and 196 days for PFS, and 267, 223, and 539 days for OS, respectively). Multivariate analysis showed that poor performance status, absence of EGFR mutation, and presence of IPF were poor prognostic factors for PFS and OS. Disease control rate (DCR) was significantly lower in ILD and IPF patients than in non-ILD patients regardless of the presence of EGFR mutation (67 or 53 vs. 85 %, respectively). The incidence of AEs of ILD was significantly higher during chemotherapy with docetaxel-containing regimens (seven of 38; 18.4 %). CONCLUSIONS: Both IPF and ILD were associated with lower EGFR positivity, lower DCR, and shorter PFS and OS in advanced NSCLC patients.

Full-length cytokeratin 8 is released and circulates in patients with non-small cell lung cancer.

BACKGROUND/AIM: Cytokeratin 8 (CK8) is a type II intermediate filament protein that is persistently expressed in most epithelial malignancies. Circulating CK-related polypeptides have commonly been used as tumor markers. While apoptosis is a mechanism of CK release, the molecular nature of circulating CKs is poorly understood. The aim is to clarify the dynamics of CK8 during apoptosis in vitro and the nature of circulating CK8 in patients with lung cancer. METHODS: Extracellular release of CK8 was examined using A549 human non-small cell lung cancer (NSCLC) cells after apoptosis induction by etoposide. Serum samples from NSCLC patients were examined for circulating CK8 by ELISA (n = 60) and by immunoprecipitation (n = 9). RESULTS: CK8 is released predominantly in full length from A549 cells undergoing apoptosis and is resistant to intracellular cleavage by caspases, unlike type I CK18, which is readily cleaved during apoptosis. Full-length CK8 is shown to constitute a considerable fraction of circulating CK8 in the serum of lung cancer patients. CONCLUSION: Apoptosis causes extracellular release of full-length CK8 in NSCLC cells. CK8 circulates predominantly in full length in patients with NSCLC, illustrating the fundamental differences in protein processing between type I and type II CKs.

A 3-year prospective study of a urinary antigen-detection test for Streptococcus pneumoniae in community-acquired pneumonia: utility and clinical impact on the reported etiology.

To evaluate the efficacy of a rapid immunochromatographic membrane test (ICT) for the detection of Streptococcus pneumoniae urinary antigen for diagnosing S. pneumoniae pneumonia, ICT was performed with urine samples using the Binax NOW Streptococcus pneumoniae kit at the time of admission. The results were compared with those from conventional microbiological studies. Three hundred and forty-nine adult patients with CAP who were admitted to the hospital were studied prospectively between February 2001 and January 2004. The ICT test was positive in 115 (33.0%) of 349 patients enrolled into the study and in 63 (75.9%) of 83 patients with pneumococcal pneumonia confirmed by conventional methods. The test revealed a sensitivity of 75.9% and a specificity of 94.0% with conventional microbiological criteria used as the reference standard. The positive predictive value was 91.3%, and the negative predictive value was 82.6%. The clinical features of 53 patients in whom ICT was positive and no pathogen was identified showed no significant difference from those of 83 patients who had pneumococcal pneumonia identified by conventional methods. The diagnostic yield of pneumococcal pneumonia was increased up to 38.9% using ICT combined with conventional methods. The Binax NOW ICT to detect S. pneumoniae urinary antigen is therefore a rapid and useful method for diagnosing pneumococcal pneumonia. Induction of ICT will prove the predominance of S. pneumoniae in the etiology of CAP.

A case of lung cancer associated with pneumoconiosis diagnosed by fluorine-18 fluorodeoxyglucose positron emission tomography.

We report a case of lung cancer arising from progressive massive fibrosis (PMF) associated with pneumoconiosis. In this case, fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) was able to clearly distinguish the lung cancer from PMF, suggesting a potential usefulness of FDG-PET in cancer screening in patients with pneumoconiosis. To our knowledge, this is the first description of an FDG-PET image of lung cancer arising from PMF.

[A case of the limited from of Wegener's granulomatosis without c-ANCA].

A 46-year-old woman was admitted to our hospital because of fever, cough and headache in December 2001. Although she had been treated for nasal obstruction and epistaxis by an otorhinolaryngologist in our hospital since 1996, no accurate diagnosis had been made despite repeated biopsies of the nasal mucosa. A chest CT taken in 1999 showed ground-glass opacities in both upper lobes. On admission, chest radiography and CT showed mass shadows without cavitation, corresponding to the lesions causing the ground-glass opacities. In addition, paranasal sinus MRI showed a deformity of the nasal septum accompanied by a space-occupying lesion, suggesting Wegener's granulomatosis. However, the cytoplasmic-antineutrophil cytoplasmic antibody (c-ANCA) test was negative. To achieve a definitive diagnosis, we performed an open lung biopsy. The specimen, obtained from the right upper lobe, showed the typical findings of a Wegener's granulomatosis including necrotizing vasculitis. Oral prednisolone treatment initiated at 20 mg daily, combined with oral cyclophosphamide at 50 mg daily markedly improved not only the clinical symptoms, but also the mass shadows in the left upper lobe. Patients with the limited form of Wegener's granulomatosis are occasionally seronegative and respond well to therapy. However, the natural course and the changes in chest radiographs are not understood well in such cases. In this paper, we report a case of the limited form of Wegener's granulomatosis that progressed slowly over a period of 6 years.

Diagnostic accuracy and safety of flexible bronchoscopy with multiplanar reconstruction images and ultrafast Papanicolaou stain: evaluating solitary pulmonary nodules.

STUDY OBJECTIVES: To assess the diagnostic accuracy and safety of flexible bronchoscopy with multiplanar reconstruction (MPR) images and ultrafast Papanicolaou (UFP) stain in evaluating solitary pulmonary nodules (SPNs). DESIGN: Prospective study of bronchoscopies performed between June 2000 and June 2002. PATIENTS: One hundred consecutive patients with SPNs underwent bronchoscopy with MPR and UFP (MPR and UFP group). The data on historical control were collected in a retrospective fashion, between July 1997 and June 2000. METHOD: All information obtained from MPR regarding the leading bronchus of the SPNs was used to guide biopsy. Samples obtained by curette biopsies were stained with UFP and evaluated by a cytopathologist during the bronchoscopy procedure. RESULTS: There were 88 malignant and 12 benign lesions in the MPR and UFP group, and 97 malignant and 3 benign lesions in the historical control group. The total diagnostic accuracy of bronchoscopy in the MPR and UFP group (91%) was significantly higher compared with the historical control group (58%) [p < 0.05]. Although the yield of bronchoscopy was significantly related to the lesion size in the historical control group (p < 0.05), there was no significant association between the diagnostic yield and lesion size in the MPR and UFP group. The diagnostic yield for SPNs < 4.0 cm in the MPR and UFP group was significantly higher compared with the historical control group (p < 0.05). In addition, the diagnostic yield in both upper lobes in the MPR and UFP group was significantly higher compared with the historical control group (p < 0.05). On the contrary, the complication rate was significantly lower in the MPR and UFP group (2%) compared with the historical control group (13%) [p < 0.05]. CONCLUSION: Combined use of the MPR image and UFP during flexible bronchoscopy improved diagnostic accuracy and safety in evaluating SPNs using a double-hinged curette.

Aberrant messenger RNA splicing of the cytokeratin 8 in lung cancer.

Cytokeratin 8 (CK8) is one of the cytoskeletal components and shows caspase-mediated degradation when cells undergo apoptosis. We previously reported that CK8 is highly expressed in non-small cell lung cancer (NSCLC) cell lines and increasing values of serum CK8 are significantly associated with tumor progression in patients with NSCLC. In this investigation, reverse transcriptase-polymerase chain reaction (RT-PCR) analysis in lung cancer cell lines, revealed a shorter PCR product, which differed from the wild-type product of CK8. The nucleotide sequence of the shorter PCR products and genomic DNA for CK8 demonstrated that the shorter product was an aberrantly spliced form of CK8 (AS-CK8) which lacked a caspases cleavage site within the linker lesion in exon 5. The putative protein products predicted by the mRNA of AS-CK8 were demonstrated by Western blotting with monoclonal antibodies for CK8. In addition, AS-CK8 mRNA and its protein products were highly expressed in NSCLC cell lines compared with small-cell lung cancer (SCLC) cell lines. Tissue samples obtained from NSCLC patients also expressed mRNA of AS-CK8. In conclusion, we identified aberrantly spliced CK8 (AS-CK8) which lacked a caspases cleavage site in lung cancer cell lines and primary tumors of NSCLC. AS-CK8 was preferentially expressed in NSCLC, rather than SCLC. These findings lead to speculation that cancer cells expressing AS-CK8 may have a resistance to apoptosis and may perturb keratin network formation.

[A case of synchronous primary lung cancer with hamartoma].

We present a case of a synchronous primary lung cancer adjacent to a hamartoma. In a 48-year-old man, a nodular shadow was found in the right middle lung field in 1990, and had grown slowly for 10 years. Another mass shadow was detected in the right upper lung field in 2000. The patient was admitted to our hospital for further examination of these abnormal shadows. Bronchoscopic examination revealed, in the right upper lobe, a poorly differentiated adenocarcinoma of clinical stage IIIB. Neoadjuvant chemotherapy followed by pneumonectomy was performed. The microscopic findings for the tumor resected from the right S2 showed poorly differentiated adenocarcinoma and those for the other, in the right S3, showed chondromatous hamartoma. Some 50 reports of lung cancer in parents with a chondromatous hamartoma have appeared in the literature. Most of these cases have some common features as follows: 1) men past middle age, 2) adenocarcinoma, and 3) lung cancer and chondromatous hamartoma present in the same lobe. The present case had all of these features, and may assist in the understanding of the process of development of lung cancer adjacent to a hamartoma.

Uptake of fluorine-18-fluorodeoxyglucose in pulmonary Mycobacterium avium complex infection.

Two patients showing abnormal fluorine-18-fluorodeoxyglucose (FDG) uptake due to Mycobacterium avium complex (MAC) infection are presented. Intense focal FDG uptake in the lung field could have been caused by an infectious disease such as MAC. This should be considered as a possibility when FDG whole-body scans of patients with pulmonary nodules are interpreted. To our knowledge, this is the first description of an FDG-positron emission tomography (FDG-PET) image of MAC infection of the lung.

Lung cancer with focal lymphocytic interstitial pneumonia.

A 65-year-old man was found to have a mass lesion surrounded by ground-glass attenuation in the left upper lobe on chest radiography. He was diagnosed with stage IA adenocarcinoma of the lung. The resected lung specimen revealed papillary adenocarcinoma associated with infiltralion of numerous lymphocytes in the alveolar septa, which was consistent with focal lymphocytic interstitial pneumonia (LIP). However, it was not associated with Sjögren's syndrome or any other immunologic abnormalities. Immunohistochemical study disclosed that CD8 positive T-cells constituted the major element of the infiltrated lymphocytes in the tumor, and were also found in the enlarged alveolar septa, suggesting an association between lung cancer and LIP. To our knowledge, this is the first description of an association between LIP and lung cancer. In addition, the focal LIP in this case probably reflected local immune response to an antigenic stimulus caused by lung cancer.

[A case of pneumoconiosis in a dental technician].

We report a case of pneumoconiosis in a dental technician. He was a 33-year-old man who had worked in a dental clinic as a dental technician for 12 years. In October 1999, he visited to the National Zentsuji Hospital complaining of progressive cough and sputum over a three-year period. Although he received medication, his condition did not improve. He visited the same hospital again on May 8, 2000. His chest radiographs and CT films showed massive shadows in both upper lung lobes. Pneumoconiosis was diagnosed from the pathological findings in a lung specimen obtained by video-assisted thoracic surgery (VATS). There are few reports of pneumoconiosis of dental technicians diagnosed by VATS.

Expression of cytokeratin 8 in lung cancer cell lines and measurement of serum cytokeratin 8 in lung cancer patients.

It has been reported that cytokeratin 8 (CK8) can be expressed in several cancers and expression of CK8 is correlated with increased invasiveness of the tumor in vitro and in vivo. In the present study, we investigated expressions of CK8 in human lung cancer cell lines. In addition, we also evaluated the clinical significance of CK8 measurements in sera of patients with lung cancer. Expression of mRNA for CK8 was semi-quantitatively evaluated by the competitive reverse transcriptase-polymerase chain reaction (competitive RT-PCR), using human lung cancer cell lines. The level of CK8 protein in culture supernatants of lung cancer cell lines and 70 sera of patients with lung cancer was measured by enzyme-linked immunosorbent assay (ELISA). Levels of serum CK8 according to clinical parameters were also examined. The level of expression of CK8 mRNA in non-small cell lung cancer (NSCLC) cell lines was significantly high compared with that of small cell lung cancer (SCLC) cell lines (P<0.05). The level of CK8 in culture supernatants in NSCLC was significantly high compared with that of SCLC. The level of serum CK8 in patients with NSCLC was significantly high compared with that of normal non-smokers and compared with that of SCLC (P<0.05). Patients with a CK8 value of 50.0 ng/ml, or higher, had a statistically significant diminished survival compared with those patients whose CK8 values were lower. In conclusion, CK8 was preferentially expressed in NSCLC. Increasing values of CK8 were significantly associated with tumor progression and decreased survival in patients with NSCLC. Therefore, CK8 in sera may become a novel tumor marker in patients with lung cancer.

Corticosteroid refractory radiation pneumonitis that remarkably responded to cyclosporin A.

Radiation therapy is commonly used for the treatment of lung cancer. However, radiation pneumonitis frequently occurs as a complication of the radiation therapy. Although corticosteroids are widely used for the treatment of radiation pneumonitis, they are not always effective. In this report, we used cyclosporin A in the treatment of a patient suffering from steroid-refractory radiation pneumonitis. To our knowledge, this is the first report in which cyclosporin A was successfully used in the treatment of radiation pneumonitis.

Bronchioloalveolar carcinoma masked by gravity-dependent gradient on computed tomography.

A 78-year-old woman was found to have a small bronchioloalveolar carcinoma with ground-glass attenuation in the gravity-dependent gradient in the left lower lobe during a preoperative chest computed tomography (CT) evaluation, which was performed for previously-diagnosed adenocarcinoma of the right upper lobe. To remove the gravitational effect of the CT, the patient underwent a thin section CT in the prone position. Then, a ground-glass attenuation was revealed clearly in the left lower lobe. Postoperative pathological diagnosis was synchronous multiple bronchioloalveolar carcinomas, stage IA. This case suggests that focal areas of ground-glass attenuations on a thin-section CT in patients with BAC would be considered to be multicentric development of BAC. CT with the patient in the prone position helps to exclude the gravitational effect and narrow the differential diagnosis of ground-glass opacity, including localized forms of BAC.