Hideki Suganuma

Rheumatoid lung disease: Prognostic analysis of 54 biopsy-proven cases

OBJECTIVE To investigate the prognostic significance of histopathological characteristics in patients with biopsy-proven rheumatoid lung disease (RLD). MATERIALS AND METHODS Retrospective analysis was conducted on samples from 54 RLD patients who underwent surgical lung biopsies (SLBs) at Hamamatsu University Hospital and affiliated hospitals between 1980 and 2009. The overall survival rate, the spectrum of histopathological diagnosis and their associated prognostic significance were investigated. RESULTS The study group consisted of 30 men and 24 women with a median age of 60.3 years. Histopathological analysis revealed the following: usual interstitial pneumonia (UIP), 15 cases; nonspecific interstitial pneumonia/fibrosis, 16 cases; organizing pneumonia, 4 cases; unclassifiable, 2 cases; desquamative interstitial pneumonia, 1 case; and bronchiolar disease, 16 cases. In survival outcome, 10 yr survival rate was 76.6%. Patients with UIP had significantly worse prognosis than those with non-UIP (RLD cases except those with UIP) (p = 0.0452). CONCLUSION RLD includes several histopathological groups. Patients with UIP have worse survival than those with other types of RLD. Histopathological diagnosis may have a major impact on prognostication in patients with RLD.

Distinct prognosis of idiopathic nonspecific interstitial pneumonia (NSIP) fulfilling criteria for undifferentiated connective tissue disease (UCTD)

BACKGROUND Although idiopathic nonspecific interstitial pneumonia (NSIP) was initially identified as a provisional diagnosis, the 2008 American Thoracic Society Project concluded that idiopathic NSIP is a distinct form of idiopathic interstitial pneumonia. However, an association between idiopathic NSIP and autoimmune diseases still attracts interest. In this context, a recent study proposed an intriguing concept that idiopathic NSIP is the pulmonary manifestation of undifferentiated connective tissue disease (UCTD). However, this has not been confirmed in a large number of patients with idiopathic NSIP. The present study was conducted to investigate the proportion and characteristics of patients with idiopathic NSIP who meet the criteria for UCTD. METHODS We reviewed 47 consecutive patients with idiopathic NSIP and examined whether they met prespecified criteria for UCTD. Furthermore, we compared the clinical characteristics between patients fulfilling the UCTD criteria (UCTD-NSIP) and those not meeting them (Non-UCTD-NSIP). RESULTS Of 47 patients with idiopathic NSIP, 22 (47%) met the UCTD criteria. Common symptoms associated with connective tissue diseases (CTDs) were skin change (50%) and Raynauds phenomenon (41%) in UCTD-NSIP. UCTD-NSIP showed a female predominance and significantly higher percentages of lymphocytes with a lower CD4/CD8 ratio in bronchoalveolar lavage than Non-UCTD-NSIP. Interestingly, UCTD-NSIP had a significantly better survival than Non-UCTD-NSIP. CONCLUSIONS Idiopathic NSIP included subjects who fulfilled the UCTD criteria, and these subjects had different clinical characteristics with significantly better outcome than those who did not meet the criteria. These data suggest that a part, but not all, of patients with idiopathic NSIP show CTD-like features with a distinct prognosis.

Phase II Study of Erlotinib as Third-line Monotherapy in Patients with Advanced Non-small-cell Lung Cancer without Epidermal Growth Factor Receptor Mutations

OBJECTIVE There are few standard therapeutic options beyond second-line treatment. We aimed to evaluate the efficacy and safety of erlotinib monotherapy as third-line chemotherapy in patients with advanced non-small-cell lung cancer without epidermal growth factor receptor mutations. METHODS In this phase II trial, patients who did not have epidermal growth factor receptor mutations and who had previously received two cytotoxic chemotherapy regimens containing platinum were treated with erlotinib (150 mg, per os) until disease progression or unacceptable toxicity. RESULTS Twenty patients were eligible for the assessment of efficacy and safety. Three cases showed a partial response, and eight cases showed stable disease with an overall response rate of 15.0% (95% confidence interval: 5.2-36.0%) and a disease control rate of 55.0% (95% confidence interval: 34.2-74.2%). Median progression-free survival and overall survival time were 2.1 and 6.7 months, respectively. Although dose reduction was required in one patient because of skin toxicity, grade 3/4 toxicity or pulmonary disease was not observed. CONCLUSIONS Erlotinib as third-line therapy showed an acceptable response rate, survival time and toxicity. It could be a potential third-line therapy for patients without epidermal growth factor receptor mutations.

Phase II study of combination chemotherapy with S-1 and weekly cisplatin in patients with previously untreated advanced non-small cell lung cancer

We aimed to evaluate the efficacy and safety of combination chemotherapy with S-1 and low-dose weekly cisplatin in patients with advanced non-small cell lung cancer (NSCLC). In this phase II trial, previously untreated patients with stage IIIB/IV NSCLC were treated with oral administration of S-1 at 80 mg/m(2) for 21 days and three consecutive weekly low doses of cisplatin (25 mg/m(2)) followed by a 2-week rest period. Twenty-six patients were eligible for the assessment of efficacy and safety. Six partial responses were observed with an overall response rate of 23.1% (95% confidence interval: 12.3-31.6%). The median survival time and median progression-free survival were 13.4 months and 5.4 months, respectively. Grade 3/4 hematologic toxicities were observed in 9 patients (34.6%), including one grade 4 neutropenia and thrombocytopenia. As for non-hematologic adverse reactions, although grade 3 events were observed in 4 patients (15.3%), no severe renal toxicity or vomiting was found. S-1 and weekly low-dose cisplatin combination chemotherapy in patients with advanced NSCLC showed an acceptable response rate, overall survival time, and toxicity. Because this regimen can be performed in an outpatient setting, it might be an alternative useful and convenient option. Further investigations with a large population are required to confirm our results.

Effects of interferon-alfa and the herbal medicine Sho-saiko-to on cytokine production and lung fibroblast proliferation

Abstract Since interferon-alfa (IFN-α) and Sho-saiko-to (SST) are known to modulate immune responses, their immunological effects may be responsible for the induction of interstitial pneumonia. Additionally, fibroblasts play an important role in lung fibrosis. Therefore, the in vitro effects of IFN-α and/or SST on cytokine production of fibroblasts were examined. No difference in cytokine production was shown among natural IFN-α, IFN-α-2a, and IFN-α-2b. Fibroblasts from three control subjects and four patients with idiopathic pulmonary fibrosis (IPF) were used. Cells from the control and IPF groups produced interleukin-6 (IL-6) dose-dependently with either IFN-α or SST treatment. Combined administration of these agents produced greater IL-6 production. In all controls, interleukin-8 (IL-8) production by fibroblasts was increased with SST but suppressed with IFN-α. In contrast, in 2 of 4 IPF patients, IL-8 production was increased with IFN-α. More importantly, there was a greater production of IL-8 when stimulated with both IFN-α and SST in the IPF group. Proliferation of control and IPF fibroblasts was inhibited equally by each drug. These results suggest that fibroblast cytokine production, augmented by IFN-α and/or SST, may play a role in the development or exacerbation of interstitial pneumonia.

Nonspecific interstitial pneumonia: Prognostic significance of high-resolution computed tomography in 59 patients

Objective: To retrospectively analyze the prognostic implications of high-resolution computed tomography (HRCT) findings for patients with biopsy-proven nonspecific interstitial pneumonia (NSIP). Methods: Fifty-nine patients with NSIP (25 idiopathic NSIP, 34 collagen-vascular disease-associated NSIP) were included. Two chest radiologists independently evaluated the extent, presence, and distribution of various HRCT findings. Cox hazards analysis was used to evaluate the relationship between HRCT findings and prognosis. Results: The 5-year survival rate was 83% and the 10-year survival rate was 66%. Univariate analysis revealed that the extent of areas with ground-glass attenuation without traction bronchi-bronchiolectasis and that of airs-pace consolidation were associated with favorable outcome, whereas that of intralobular reticular opacities was associated with worse prognosis. Multivariate analysis showed that the extent of air-space consolidation was an independent factor of favorable outcome. Conclusion: In NSIP, the extent of areas with ground-glass attenuation without traction bronchi-bronchiolectasis, air-space consolidation, and intralobular reticular opacities correlate with survival.

Effect of Switching from Salmeterol Fluticasone to Formoterol Budesonide Combinations in Patients with Uncontrolled Asthma

BACKGROUND Combination therapy with an inhaled corticosteroid (ICS) and a long-acting β(2)-agonist (LABA) in a single inhaler is the mainstay of asthma management and salmeterol/fluticasone combination (SFC) and fixed-dose formoterol/budesonide combination (FBC) are currently available in Japan; however, there is nothing to choose between the two. The purpose of this study was to clarify the effect of switching from SFC to FBC in patients with asthma not adequately controlled under the former treatment regimen. METHODS This was a prospective, multicenter, open-label, uncontrolled longitudinal study in 87 adult patients with an Asthma Control Questionnaire, 5-item version (ACQ5) score of greater than 0.75 under treatment with SFC 50/250μg one inhalation twice daily (bid). SFC was switched to FBC 4.5/160μg two inhalations bid. Study outcomes included ACQ5 score, peak expiratory flow (PEF), FEV(1), and fractional exhaled nitric oxide (FeNO) at the end of treatment period. RESULTS Eighty-three patients completed the study. ACQ5 scores improved and exceeded the clinically meaningful difference after 12 weeks of treatment and well-controlled asthma (ACQ5 score ≤0.75) was attained in 37 (44.6%) patients. Minimum and maximum PEF and FEV(1) values improved significantly, but not FeNO values, after switching from SFC to FBC. CONCLUSIONS Switching ICS/LABA combination therapy is a useful option in the management of asthma that is not optimally controlled.

Fibroblasts as Target and Effector Cells in Japanese Patients with Sarcoidosis

Abstract. Fibroblasts play a crucial role in progressive lung fibrosis, acting not only as target cells but also as effector cells. To clarify these functions in sarcoidosis, lung fibroblasts from Japanese sarcoid patients were studied for their proliferative capacity and cytokine productivity. Fibroblasts were cultured from transbronchial lung biopsy specimens from seven patients with sarcoidosis. As a comparison, fibroblasts from open lung biopsy specimens of four patients with idiopathic pulmonary fibrosis (IPF) were studied. For controls, fibroblasts were cultured from specimens of normal resected lung tissue of five patients with localized lung cancer. The proliferative activity of cultured fibroblasts from patients with sarcoidosis was highest among the three groups (p < 0.05). However, the proliferative capacity in all groups was suppressed when fibroblasts were cultured with interleukin-1β (IL-1β). No significant differences were noted in the degree of inhibition among the three groups. Addition of interferon-γ (IFN-γ) also resulted in inhibition of fibroblast growth in all groups, but the degree of inhibition was significantly greater in both the sarcoid and IPF groups than in controls (p < 0.05). The amount of interleukin-6 (IL-6) in the culture supernatants from sarcoid fibroblasts cocultured with IL-1β was significantly higher than in controls. Sarcoid fibroblasts are not only proliferatively active but also possess effector cell function to produce cytokines. IL-6 may enhance the immunologic reaction to sarcoidosis and cause the disease to become chronic. IFN-γ suppresses proliferation of sarcoid fibroblasts and may prevent fibrotic changes of the lungs in the Japanese sarcoid patients.