Yutaro Nakamura

Cumulative incidence of and predictive factors for lung cancer in IPF.

Background and objective:  Previous studies have indicated a high incidence of lung cancer in IPF, and some have identified its risk factors. However, those studies were retrospective and the clinical characteristics of IPF patients developing lung cancer were evaluated only when those patients had developed the cancer. The true cumulative incidence of lung cancer after the diagnosis of IPF and its predictive factors at the initial diagnosis of IPF remain unknown. The present study was conducted to elucidate the cumulative incidence and risk factors for lung cancer in IPF patients by retrospective longitudinal cohort analysis.

Higher Sensitivity and Specificity for Diffusion-weighted Imaging of Malignant Lung Lesions without Apparent Diffusion Coefficient Quantification

PURPOSE To compare the performance of apparent diffusion coefficient (ADC) with that of signal intensity of the lesion-to-spinal cord ratio (LSR) in differentiating lung cancer from benign lesions on high-b value diffusion-weighted (DW) magnetic resonance (MR) images. MATERIALS AND METHODS This study received institutional review board approval; written informed consent was provided by all patients. Twenty-eight patients (six women, 22 men; mean age, 64.2 years) with pulmonary nodules seen at chest computed tomography were prospectively reviewed. Two DW images with different motion-probing gradient strengths (b(h) = 1000 sec/mm(2) and b(l) = 0 sec/mm(2)) were analyzed semiquantitatively by measuring the signal intensities of the lesions and the spinal cord. ADC was calculated by using linear regression analysis of the natural logarithm of mean signal intensity versus the gradient factor. For reference, LSR was also measured on the same image with a diffusion gradient of b(h) = 1000 sec/mm(2). RESULTS The LSR of cancer nodules was significantly higher than that of benign lesions, while there were no significant differences between them in relation to ADC. In the receiver operating characteristic curve analysis, LSR had a higher area under the curve than did ADC (0.911 vs 0.600). By using a cutoff value of 1.135, LSR had a positive predictive value of 86.7% a negative predictive value of 90%, and an accuracy of 85.7% for the detection of lung cancer with LSR. CONCLUSION LSR measurement on high-b value DW imaging may be useful for differentiating between benign and malignant lung nodules.

Increased serum kynurenine/tryptophan ratio correlates with disease progression in lung cancer

BACKGROUND Indoleamine 2,3-dioxygenase (IDO) catalyzes the rate-limiting step of tryptophan (Trp) degradation along the kynurenine (Kyn) pathway. By depleting tryptophan, IDO is considered to be a fundamental immune escape mechanism for tumor cells. However, IDO expression in lung cancer has not been explored thoroughly. Thus, the present study investigated IDO activity determined by serum Trp and Kyn concentrations in lung cancer and the correlation between the IDO activity and clinical parameters. METHOD The concentrations of Trp and Kyn were measured simultaneously by liquid chromatography/electrospray ionization tandem mass spectrometry (LC-ESI/MS/MS) in the sera of 123 patients with lung cancer and 45 healthy controls. The IDO activity was estimated by calculating the serum Kyn-to-Trp ratio (Kyn/Trp ratio). RESULTS Trp concentrations were significantly lower in patients with lung cancer than in healthy controls (62.6+/-15.8microM vs. 71.1+/-11.8microM, respectively; p=0.0007), while Kyn concentrations were significantly higher in patients compared with the controls (2.82+/-1.17microM vs. 2.30+/-0.56microM, respectively; p=0.0036). The IDO activity determined by the Kyn/Trp ratio was significantly higher in the patients than in the controls (47.1+/-21.3 vs. 32.9+/-9.10, respectively; p<0.0001). In addition, patients in the advanced stages of lung cancer had significantly lower Trp concentrations and higher IDO activity than those in the early stages (p=0.0058 and p=0.0209, respectively). CONCLUSIONS IDO activity was increased in lung cancer patients, and higher IDO activity was associated with more advanced stages. These results suggest that increased IDO activity is involved in disease progression of lung cancer, possibly through its immunosuppressive effect.

Interstitial lung diseases associated with amyopathic dermatomyositis

The aim of the present study was to clarify the clinical characteristics and prognosis of patients with interstitial lung disease (ILD) associated with amyopathic dermatomyositis (ILD-ADM). The study consisted of 14 consecutive patients with ILD-ADM. Patients were classified into two categories, acute/subacute and chronic forms, according to the clinical presentation of ILD. The clinical features, responsiveness to therapy, and prognosis between the two forms were compared. Nine ILD-ADM patients were categorised as the acute/subacute form, and five as the chronic form. Arterial oxygen tension was significantly lower in the acute/subacute ILD than chronic ILD patients. On high-resolution computed tomography, ground-glass opacities were frequently found in the two forms, but consolidation was more common in acute/subacute ILD than chronic ILD. Bronchoalveolar lavage analysis showed higher numbers of total cells and lymphocytes in acute/subacute ILD than chronic ILD. Histologically, the most common finding was nonspecific interstitial pneumonia in the two forms, while diffuse alveolar damage was only found in acute/subacute ILD. Acute/subacute ILD was generally resistant to therapy, while chronic ILD responded well. Notably, the mortality of acute/subacute ILD was much higher than that of chronic ILD (67 versus 0%, respectively). In conclusion, interstitial lung disease associated with amyopathic dermatomyositis includes two different forms, the acute/subacute and chronic forms, with distinct prognoses.

Alterations in Smoking Habits Are Associated With Acute Eosinophilic Pneumonia

BACKGROUND Acute eosinophilic pneumonia (AEP) is characterized by a febrile illness, diffuse pulmonary infiltrates, and pulmonary eosinophilia. The etiology of AEP remains unknown, but several studies have proposed a relationship between cigarette smoking and AEP. However, most studies showing this possibility are single-case reports, and cigarette smoke has not been fully validated as a causative agent of AEP in a large series of patients. The present study was conducted to clarify the etiologic role of cigarette smoking in AEP, with special reference to alterations in smoking habits. METHODS We took a detailed history of smoking habits before AEP onset in 33 patients with AEP, and performed a cigarette smoke provocation test. RESULTS Of our AEP patients, all but one (97%) were current smokers. Interestingly, 21 of these were new-onset smokers, and 2 had restarted smoking after a 1- to 2-year cessation of smoking. The duration between starting smoking and AEP onset was within 1 month (0.67 +/- 0.53 months). Additionally, six of the remaining smokers had increased the quantity of cigarettes smoked daily, fourfold to fivefold, mostly within the month before AEP onset (0.81 +/- 0.58 months). Only three smokers had not changed their smoking habits before AEP onset. Cigarette smoke provocation tests revealed positive results in all nine patients tested. CONCLUSION These data suggest that recent alterations in smoking habits, not only beginning to smoke, but also restarting to smoke and increasing daily smoking doses, are associated with the development of AEP.

Increased expression of YKL-40, a chitinase-like protein, in serum and lung of patients with idiopathic pulmonary fibrosis

BACKGROUND YKL-40, a mammalian member of chitinase-like proteins, has been shown to play a role in pathological conditions leading to tissue remodeling and fibrosis. Recently, YKL-40 was found to be increased in severe asthma, suggesting that YKL-40 contributes to airway remodeling; however, no data are available about YKL-40 expression in idiopathic pulmonary fibrosis (IPF). The present study was conducted to investigate YKL-40 expression in the serum and lung of IPF patients, and to determine its clinical significance. METHODS Using an enzyme-linked immunosorbent assay, we measured YKL-40 levels in the serum of 63 IPF patients and in bronchoalveolar lavage fluid (BALF) of 18 IPF patients. YKL-40 levels were also assessed in the serum and BALF of healthy subjects. We further investigated the relationship between serum YKL-40 levels and clinical parameters. Additionally, immunohistochemical staining for YKL-40 was performed in lung specimens of IPF patients and control subjects. RESULTS Serum and BALF YKL-40 levels were significantly higher in IPF than in controls (serum: 245.8+/-180.2ng/ml vs. 116.0+/-58.3ng/ml; BALF: 17.8+/-19.1ng/ml vs. 0.3+/-0.9ng/ml, respectively). Serum YKL-40 levels significantly correlated positively with serum KL-6 levels and AaDO(2), and negatively with DLco and PaO(2). Immunohistochemical study revealed enhanced YKL-40 expression in alveolar macrophages and bronchiolar epithelia adjacent to fibrotic lesions in IPF, but not in controls. CONCLUSIONS These data suggest that YKL-40 is increased in the circulation and lungs of IPF patients, suggesting that this glycoprotein is associated with the pathophysiology of IPF.

Mouse Lung CD103+ and CD11bhigh Dendritic Cells Preferentially Induce Distinct CD4+ T-Cell Responses

Mouse lung dendritic cells (LDCs) have been recently shown to contain two major subpopulations: CD103(+) CD11b(low or negative) (CD103(+) LDCs) and CD103(-) CD11b(high) LDCs (CD11b(high) LDCs). Although several studies have demonstrated functional differences between them, it is unclear whether the subpopulations induce distinct T helper (Th) cell responses. The present study was conducted to examine whether CD103(+) and CD11b(high) LDCs preferentially generate different Th responses. Naive DO11.10 CD4(+) T cells were primed with CD103(+) or CD11b(high) LDCs obtained from normal BALB/c mice. The primed CD4(+) T cells were restimulated, and their cytokine secretions were assessed. The expression of intracellular cytokines and the mRNA levels of chemokine receptors were also measured. We found that the CD4(+) T cells primed with CD103(+) LDCs secreted significantly larger amounts of IFN-γ and IL-17A, whereas those primed with CD11b(high) LDCs released significantly higher levels of IL-4, IL-6, and IL-10. Intracellular cytokine assay showed that CD103(+) LDCs induced greater frequencies of CD4(+) T cells producing IFN-γ and IL-17A, whereas CD11b(high) LDCs were more efficient at inducing CD4(+) T cells producing IL-4 and IL-10. The mRNA levels of CXCR3 and CCR5, which are expressed preferentially in Th1 cells, were significantly higher in CD4(+) T cells primed with CD103(+) LDCs. The mRNA levels of CXCR4 and CCR4, which are expressed primarily in Th2 cells, were significantly greater in those primed with CD11b(high) LDCs. These data suggest that mouse CD103(+) LDCs predominantly elicit Th1 and Th17 responses, whereas CD11b(high) LDCs primarily provoke a Th2 response under the steady state.

Type-1 polarized dendritic cells primed for high IL-12 production show enhanced activity as cancer vaccines.

While multiple pathways of dendritic cell (DC) maturation result in transient production of IL-12, fully mature DCs show reduced ability to produce IL-12p70 upon a subsequent interaction with Ag-specific T cells, limiting their in vivo performance as vaccines. Such “DC exhaustion” can be prevented by the presence of IFNγ during the maturation of human DCs (type-1-polarization), resulting in improved induction of tumor-specific Th1 and CTL responses in vitro. Here, we show that type-1 polarization of mouse DCs strongly enhances their ability to induce CTL responses against a model tumor antigen, OVA, in vivo, promoting the induction of protective immunity against OVA-expressing EG7 lymphoma. Interestingly, in contrast to the human system, the induction of mouse DC1s requires the participation of IL-4, a nominal Th2-inducing cytokine. The current data help to explain the previously reported Th1-driving and anti-tumor activities of IL-4, and demonstrate that type-1 polarization increases in vivo activity of DC-based vaccines.

Helper roles of NK and CD8+ T cells in the induction of tumor immunity. Polarized dendritic cells as cancer vaccines.

The work in our laboratory addresses two interrelated areas of dendritic cell (DC) biology: (1) the role of DCs as mediators of feedback interactions between NK cells, CD8+ and CD4+ T cells; and (2) the possibility to use such feedback and the paradigms derived from anti-viral responses, to promote the induction of therapeutic immunity against cancer. We observed that CD8+ T cells and NK cells, the classical “effector” cells, also play “helper” roles, regulating ability of DCs to induce type-1 immune immunity, critical for fighting tumors and intracellular pathogens. Our work aims to delineate which pathways of NK and CD8+ T cell activation result in their helper activity, and to identify the molecular mechanisms allowing them to induce type-1 polarized DCs (DC1s) with selectively enhanced ability to promote type-1 responses and anti-cancer immunity. The results of these studies allowed us and our colleagues to design phase I/II clinical trials incorporating the paradigms of DC polarization and helper activity of effector cells in cancer immunotherapy.

Idiopathic pleuroparenchymal fibroelastosis: consideration of a clinicopathological entity in a series of Japanese patients

BackgroundIdiopathic pleuroparenchymal fibroelastosis (IPPFE) is a recently reported group of disorders characterized by fibrotic thickening of the pleural and subpleural parenchyma predominantly in the upper lobes. We report five Japanese cases fulfilling the criteria of IPPFE and address whether it should be considered a separate clinicopathologic entity. And this study was an attempt to identify features in common between IPPFE and previously described idiopathic upper lobe fibrosis (IPUF), allowing IPPFE to be considered as a distinct entity in our Japanese series.MethodsFive consecutive cases of idiopathic interstitial lung disease confirmed as IPPFE by surgical lung biopsy were studied.ResultsThere were four males and one female, aged 70±2.76 yr. No associated disorder or presumed cause was found in any case. Lung function tests found a restrictive ventilatory defect (4/5) and/or impairment of DLco (4/5). Chest X-ray showed marked apical pleural thickening in all cases. Computed tomography of the chest in all cases mainly showed intense pleural thickening and volume loss associated with evidence of fibrosis, predominantly in the upper lobes. In all cases in this study, markedly thickened visceral pleura and prominent subpleural fibrosis characterized by both elastic tissue and dense collagen were clearly shown. All cases were alive at the last follow-up, 17.6±13.59 months after diagnosis; however, all had deteriorated both clinically and radiologically.ConclusionsIPPFE deserves to be defined as a separate, original clinicopathologic entity owing to its uniformity and IPPFE has some features in common with previously described idiopathic upper lobe fibrosis (IPUF). Our limited experience with a cohort of 5 subjects suggests that IPPFE can be rapidly progressive.