Atsuhisa Tamura

Long-Term Low-Dose Administration of Erythromycin to Patients with Diffuse Panbronchiolitis

Although diffuse panbronchiolitis (DPB) has carried a poor prognosis, long-term low-dose administration of erythromycin (EM) is very effective. We administered EM at a daily dose of 400-600 mg to 19 DPB subjects for more than 2 months. Sixteen subjects were relieved from productive cough and dyspnea, and their chest X-ray pictures were improved. We performed a pharmacokinetic study of EM in 11 DPB subjects (8 responders; 3 nonresponders) after the long-term low-dose administration. The maximal serum and sputum levels of EM were below the MICs of clinically pathogenic H. influenzae and P. aeruginosa which were often isolated from the sputum of DPB patients. No difference was observed in the absorption of EM between responders and nonresponders. The results suggested that DPB patients might respond favorably to EM due to mechanisms other than antibacterial activity. Individual variation in the absorption of EM was observed. As EM was effective at very low serum and sputum levels, it was suggested that even 200 mg/day of EM would be effective in DPB patients who had high serum and sputum EM levels and it was necessary to monitor the concentrations of EM in serum and sputum for the treatment of DPB to determine the appropriate dose of EM individually.

Performance Status and Smoking Status Are Independent Favorable Prognostic Factors for Survival in Non-small Cell Lung Cancer: A Comprehensive Analysis of 26,957 Patients with NSCLC

Background: Performance status (PS) is an important factor in determining survival outcome in non-small cell lung cancer (NSCLC) but is generally confounded by stage, age, gender, and smoking status. We investigated the prognostic significance of PS taking into account these important factors. Methods: Retrospective analysis of registry database of the National Hospital Study Group for Lung Cancer (NHSGLC) between1990 and 2005. Univariate analysis was performed using Kaplan-Meier method. Multivariate analysis was performed using Cox proportional hazards model to identify independent prognostic factors. Results: A total of 26,957 patients with NSCLC were analyzed of which 12,613 patients (46.8%) had World Health Organization (WHO) PS = 0, 8,137 patients were never smokers (30.2%), and most of them were females (72.7%). The majority of PS = 0 patients presented with stage I disease (56.9%). Patients with PS = 0 constituted the group with the highest proportion of never smokers (36.7%). There was a significant difference in the median overall survival (OS) between patients with PS = 0 and PS = 1 (51.5 months versus 15.4 months, respectively; p < 0.0001) and among patients with various PS within individual American Joint Committee on Cancer stage (all p values <0.0001). Never smokers had significantly improved median OS than ever smokers (30.0 months versus 19.0 months, respectively; p < 0.0001). Multivariate analysis demonstrated good PS, never smoker (versus ever smoker; hazard ratio = 0.935, 95% confidence interval: 0.884–0.990; p = 0.0205), early stage, female gender, squamous cell carcinoma histology, and treatment were all as independent favorable prognostic factors. Conclusions: PS and smoking status are independent prognostic factors for OS in NSCLC.

Gender, Histology, and Time of Diagnosis Are Important Factors for Prognosis: Analysis of 1499 Never-Smokers with Advanced Non-small Cell Lung Cancer in Japan

Background: There has been a growing interest in lung cancer in never-smokers. Methods: Utilizing a database from the National Hospital Study Group for Lung Cancer, information for never-smokers and ever-smokers with advanced non-small cell lung cancer was obtained from 1990 to 2005, including clinicopathologic characteristics, chemotherapy response, and survival data. Time of diagnosis was classified into two periods: 1990–1999 and 2000–2005. Multivariate analysis was performed using the Cox regression and logistic regression method, including gender, age, performance status, histology, stage, and period of diagnosis. Results: There were 1499 never-smokers and 3455 ever-smokers with advanced stage IIIB and IV diseases who received cytotoxic chemotherapy. Never-smokers generally included more females, were younger, with better performance status and more adenocarcinoma diagnosed (p < 0.0001 for all). Smoking status was a significant prognostic factor (never-smoker versus ever-smoker; hazard ratio [HR] = 0.880, 95% confidence interval [CI]: 0.797–0.970; p = 0.0105). In separate multivariate analysis for never-smokers and ever-smokers, female gender and better performance status (p < 0.0001 for both) were both favorable prognostic factors. However, adenocarcinoma histology (versus squamous cell carcinoma; HR = 0.790, 95% CI: 0.630–0.990; p = 0.0403) and the period after 2000 (versus before 2000; HR = 0.846, 95% CI: 0.731–0.980; p = 0.0254) were significant only in the never-smokers, and younger age (HR = 1.007, 95% CI: 1.003–1.011; p = 0.0010) was significant only in the ever-smokers. In an exploratory analysis, different profiles were observed in predictive factors for chemotherapy response between the two groups. Conclusions: Never-smokers with non-small cell lung cancer lived longer than ever-smokers. Gender, histology, and time of diagnosis are important factors for prognosis in these patients.

Effect of gefitinib re-challenge to initial gefitinib responder with non-small cell lung cancer followed by chemotherapy.

PURPOSE We investigated the efficacy of gefitinib re-challenge for the patients who responded to initial treatment with gefitinib and acquired resistance to gefitinib thereafter. EXPERIMENTAL DESIGN Medical records were retrospectively reviewed in the hospitals of National Hospital Organization from August 2002 to August 2008. Patients histologically or cytologically confirmed NSCLC were eligible if they once responded to initial treatment with gefitinib (CR, PR or SD) and then re-treated with gefitinib following subsequent chemotherapy. RESULT Twenty patients (16 PR, 4 SD) were enrolled in this study. After re-treatment with gefitinib, 5 cases showed PR and 8 cases SD. Overall response rate was 25% (5/20) and disease control rate was 65% (13/20) in the gefitinib re-treated patients. Median survival time from the start of the initial gefitinib and from the start of the re-administration of gefitinib were 34.0 and 10.0 months, respectively. CONCLUSION Re-administration of gefitinib was effective and therefore should be considered as one of the treatment option for the patients with NCLCL who once responded and acquired resistant to gefitinib following subsequent chemotherapy.

Alveolar basement membrane breaks down in diffuse alveolar damage: An immunohistochemical study

Sequential structural changes of the alveoli in diffuse alveolar damage (DAD) were examined by immunohistochemical methods. Lung specimens obtained at autopsy from 52 patients with DAD were stained with antibodies to laminin, 7S collagen (7S) and type IV collagen (type IV) for alveolar basement membrane, to von Willebrand factor, CD‐31 and thrombomodulin (TM) for the alveolar capillary endothelial cell, and to epithelial membrane antigen and surfactant apo‐protein (PE‐10) for the alveolar epithelium. Forty‐two of the patients had the exudative form of DAD; 10 of the patients had the proliferative form of DAD. The results were summarized as follows: (i) laminin was most easily impaired both in the epithelial and capillary basement membrane in the early exudative stage; (ii) following laminin, 7S and type IV in the capillary basement membrane were also injured in the early exudative stage, and recovered in the proliferative stage; (iii) subsequently, 7S and type IV in the epithelial basement membrane were also impaired in the late exudative stage, and remained impaired even in the proliferative stage; and (iv) alveolar epithelium regenerated almost completely in the late exudative stage, but staining for TM in the alveolar capillary recovered in the proliferative stage. Because the alveolar basement membrane must govern the homeostasig of alveolar tissue architecture, it was concluded that its preservation is necessary to avoid the abnormal remodeling of the alveoli in the reparative stage of DAD, if the patient survives the acute episodes of the disease.

Pathological features of the pulmonary artery in Takayasu arteritis

SummaryLittle attention has been paid to the pathological features of the pulmonary artery in Takayasu arteritis. Autopsy specimens of 6 cases of this disease were studied. Lesions were found in the aortic arch and its brachiocephalic branches in all cases and in both the aortic arch and thoracoabdominal aorta in 5 cases. The pathohistologic characters of the pulmonary artery were very similar to those of the systemic artery. Stenosis-recanalization, so-called blood vessels-in-blood vessels, of the pulmonary elastic arteries were found in four cases. These lesions were not observed in the systemic arteries, and most of the newly formed channels in them seemed to be branches of bronchial arteries. Luminal obstruction of pulmonary muscular arteries was observed in 4 cases, cellular arteritis of muscular arteries in 2 cases, and angiomatoid dilatation of small blood vessels in 2 cases. Thus in this study we found peculiar stenosis-recanalization lesions of the pulmonary elastic arteries, and also showed that the pulmonary elastic and muscular arteries are frequently involved in Takayasu arteritis. These findings suggest that pulmonary hypertension could influence morbidity and long-term mortality in this disease.

Assessment of sleep disturbance in lung cancer patients: Relationship between sleep disturbance and pain, fatigue, quality of life, and psychological distress

OBJECTIVE We investigated the prevalence of sleep disturbance and psychological distress in lung cancer patients. We also examined the association between sleep disturbance and psychological distress, pain, fatigue, and quality of life in the same population. METHOD Fifty lung cancer patients were evaluated. Sleep disturbance was assessed using the Athens Sleep Insomnia Scale (AIS) and psychological distress using the Hospital Anxiety and Depression Scale (HADS). Quality of life (QOL), pain, and fatigue were assessed employing the European Organization of Research and Treatment Quality of Life Questionnaire-Cancer 30 (EORTC QLQ-C30). RESULTS We observed that 56% of lung cancer patients had sleep disturbance (AIS score ≥6) and 60% had psychological distress (total HADS score ≥11). Patients with sleep disturbance had a HADS score of 14.6 ± 5.8, a fatigue score of 45.3 ± 22.0, and a pain score of 27.2 ± 26.2. In contrast, patients without sleep disturbance had a lower HADS score of 9.9 ± 8.1 (p < 0.05) and a higher fatigue score of 28.5 ± 18.0 (p < 0.01) and a pain score of 8.7 ± 15.8 (p < 0.01). In addition, we found a lower QOL in patients with sleep disturbance (46.3 ± 20.2) than in those without (65.2 ± 20.7) (p < 0.05). We also observed a significant correlation between the AIS, HADS, fatigue, QOL, and pain scores. SIGNIFICANCE OF RESULTS Lung cancer patients suffered from combined symptoms related to sleep. Sleeping pills improved sleep induction but were not sufficient to provide sleep quality and prevent daytime dysfunction. Daytime dysfunction was specifically associated with psychological distress. Additionally, the type of sleep disturbance was related to other patient factors, including whether or not they received chemotherapy.

Prognostic significance of thrombomodulin expression and vascular invasion in stage I squamous cell carcinoma of the lung

Thrombomodulin (TM) is an important modulator of intravascular coagulation. TM exists on endothelial cells and on several types of tumor cells, especially squamous cell carcinoma cells. Tumor cell TM is thought to be associated with progression and metastasis of the tumor. To evaluate the prognostic significance of TM in lung cancer, we examined TM expression and vascular invasion in surgical specimens obtained from 90 patients with completely resected stage I non-small cell lung cancer (NSCLC). In addition, we correlate these pathologic data to other clinicopathologic data, including the outcome of the patients. Squamous cell carcinomas had a significantly higher incidence (P<0.0001) of TM expression (22/36 cases, 61%) than adenocarcinomas (9/54 cases, 17%). In 36 squamous cell carcinoma patients, both vascular invasion (P=0.0153; risk ratio 6.507) and TM non-expression (P=0.0282; risk ratio 3.584) were significant for a poor prognosis. Univariate analysis of patient survival rates also revealed that vascular invasion and TM expression were significant prognostic factors (P=0.0036 and 0.012, respectively). Further, combination analysis of vascular invasion and TM expression in the squamous cell carcinoma patients showed that the 5-year survival rate was 90% in patients with TM expression and without vascular invasion, but 21% in patients with vascular invasion and without TM expression (P=0.0004). Since our results suggest that vascular invasion and TM expression are independent prognostic factors of stage I squamous cell carcinoma of the lung, and since the two factors play different roles in the metastatic process of cancers (promotion of metastasis by vascular invasion and inhibition of metastasis by TM expression), the combination evaluation of vascular invasion and TM expression may be very significant in evaluating the prognosis of patients with completely resected stage I squamous cell carcinoma.

Nasal biopsy in the early diagnosis of Wegener's (pathergic) granulomatosis

The diagnostic value of the nasal biopsy in the early diagnosis of Wegeners granulomatosis and its value in prognosis were examined in 11 patients with a clinicopathological diagnosis of the disease. The vascular lesions found included microabscess in the vascular walls in 82%, leukocytoclastic capillaritis in 73%, fibrinoid necrosis of blood vessels in 45%, leukocytoclastic endovasculitis in 27%, and palisading granuloma in vascular wall in 9% of cases. The extravascular lesions included palisading granuloma in all cases, microabscess in 91%, and diffuse granulomatous tissues in 82%. Palisading microgranuloma (82%) was more frequent than palisading macrogranuloma (45%). After therapy, complete remission occurred in 8 patients, but 3 patients died of sepsis, diffuse pulmonary haemorrhage, and cerebral haemorrhage. Comparison of the frequency of each finding in the nasal biopsy specimens between patients who achieved remission and those who died showed that leukocytoclastic vasculitis was found more commonly in fatal cases, and leukocytoclastic endovasculitis was observed only in fatal cases. Palisading granuloma as a vascular or extravascular lesion is the primary and most important finding in a histopathological diagnosis of Wegeners granulomatosis, microabscess in vascular walls is a secondary but the next most important finding, and leukocytoclastic vasculitis heralds dissemination of the disease and poor prognosis. It requires aggressive therapy.

Disseminated Mycobacterium avium complex infection in a patient carrying autoantibody to interferon-γ

A 66-year-old man was admitted to our hospital on suspicion of lung cancer with bone metastasis. He suffered multiple joint and muscle pain. 18F-Fluorodeoxy glucose positron emission tomography (FDG–PET) showed multiple accumulations in the lung, bones including the vertebrae, and mediastinal lymph nodes. Anti-human immunodeficiency virus (HIV) antibody was negative. Because Mycobacterium avium complex (MAC) was isolated from bronchial lavage fluid, bronchial wall, peripheral blood, and muscle abscess, he was diagnosed as having disseminated MAC infection. Although multidrug chemotherapy was initiated, his condition rapidly deteriorated at first. After surgical curettage of the musculoskeletal abscess, his condition gradually improved. As for etiology, we suspected that neutralizing factors against interferon-gamma (IFN-γ) might be present in his serum because a whole blood IFN-γ release assay detected low IFN-γ level even with mitogen stimulation. By further investigation, autoantibodies to IFN-γ were detected, suggesting the cause of severe MAC infection. We should consider the presence of autoantibodies to IFN-γ when a patient with disseminated NTM infection does not indicate the presence of HIV infection or other immunosuppressive condition.