[Surgical Treatment for Pneumothorax with Granulomatosis with Polyangiitis].

A 42-year-old man had been treated for granulomatosis with polyangiitis for eight years. He was referred to our department with the diagnosis of right pneumothorax on chest radiograph. After chest drainage, the surgical treatment was performed because of continuing air leak from chest tube. Under thoracoscopic approach, the pleural adhesions were carefully dissected and the air leak site was sutured and enforced by a polyglycolic acid sheet with fibrin glue. No recurrence of pneumothorax was observed six months after surgery.

Phanerochaete sordida as a cause of pulmonary nodule in an immunocompromised patient: a case report.

BACKGROUND: Phanerochaete sordida is a species of wood rotting fungus, which can degrade lignin, cellulose and hemicellulose contained in wood and other hard-to-biodegrade organic substances. However, to date, there have been no other reports demonstrating that P. sordida can infect humans. CASE PRESENTATION: A 66-year-old Japanese man presented for a mass increasing in size on his left thigh. He had been suffering from rheumatoid arthritis for 18 years and chronic obstructive pulmonary disease for 20 years, for which he was being treated with 5 mg/day prednisolone and 8 mg/week methotrexate. The mass resection was performed two months later, and was diagnosed as malignant fibrous histiocytosis. However, a computed tomography examination for tumor recurrence after surgery showed a newly emergent pulmonary nodule. We therefore decided to resect the nodule by thoracoscopic procedure. Histopathological examination of the excised specimen showed that the lesion was a granuloma, with necrotic tissue and clumping of Aspergillus-like hyphae. Therefore, the nodule was diagnosed as a fungal infection and tissue specimens were cultured microbiologically. However, fungal growth was not observed. We consequently performed genetic analysis using a broad-range polymerase chain reaction. The 28S rRNA sequence demonstrated 100% homology with P. sordida using the NCBI BLAST program against the GenBank DNA databases. CONCLUSIONS: Using broad-range polymerase chain reaction, we identified P. sordida as the causative agent of a pulmonary nodule. These findings indicate that P. sordida may be an additional opportunistic causative organism of pulmonary infection in immunocompromised patients.

A Clear Difference Between the Outcomes After a Major Hepatectomy With and Without an Extrahepatic Bile Duct Resection.

BACKGROUND: The procedure of a simple hepatectomy and a hepatectomy with an extrahepatic bile duct resection and subsequent choledocho-jejunostomy is largely different. However, these two procedures are sometimes included in the same category. There are no studies comparing postoperative course and liver regeneration rate after a major hepatectomy with and without an extrahepatic bile duct resection. METHODS: We retrospectively reviewed medical records of 245 patients who underwent a right hepatectomy (RH, n = 55) or RH with an extrahepatic bile duct resection (RHEBR, n = 190). Postoperative complications, including incidence of posthepatectomy liver failure (PHLF) and hepatic regeneration rates after surgery, were evaluated. RESULTS: The incidence of PHLF was considerably higher in the RHEBR group than in the RH group (39.5 vs. 16.4 %, p = 0.001). The percentage of newly regenerated liver volume after the hepatectomies on postoperative days 6-8 was significantly lower in the RHEBR group than in the RH group (14.0 % in the RH; 7.9 % in the RHEBR group, p < 0.001). Especially type of surgery (RHEBR) was the only independent risk factor for an impaired liver regeneration rate by univariate and multivariate analyses. Furthermore, estimated hepatic regeneration rate by stepwise linear regression analysis in the RHEBR group was 7.1 % lower (95 % confidence interval 1.8-12.3, p = 0.011) than in the RH group. CONCLUSION: These results suggest that the procedure of extrahepatic bile duct resection has a possibility of adverse impact on the postoperative outcome after major hepatectomy.

Thrombomodulin modulates dendritic cells via both antagonism of high mobility group protein B1 and an independent mechanism.

BACKGROUND: Thrombomodulin treatment modulates the properties of dendritic cells (DCs) converting them from immunogenic to tolerogenic and inducing its own expression on DCs. Thrombomodulin binds to the inflammatory mediator, high mobility group protein B1 (HMGB1), antagonizing signalling through its receptor, receptor for advanced glycation end products (RAGE). METHODS: To test if soluble thrombomodulin could antagonize HMGB1 signaling via RAGE on DCs. DCs were prepared from mouse bone marrow cells or human monocytes. In some experiments dendritic cells were sorted into thrombomodulin+ and thrombomodulin- populations. Expression of surface maturation markers was determined by flow cytometry following treatment with thrombomodulin in the presence or absence of HMGB1. RESULTS: Thrombomodulin+ dendritic cells secrete less HMGB1 into the medium. HMGB1 reduces the effects of thrombomodulin on expression of DC maturation markers. Treatment with thrombomodulin reduces the expression of maturation markers such as CD80 and CD86 and increases the expression of thrombomodulin on the DC surface. Treatment of DCs with neutralizing anti-HMGB1 antibody acted synergistically with thrombomodulin in increasing thrombomodulin expression on DCs. Treatment with thrombomodulin can still reduce the expression of surface markers on DCs derived from mice that are deficient in RAGE showing that thrombomodulin can affect DCs by an alternative mechanism. CONCLUSIONS: The results of this study show that thrombomodulin modulates DCs both by antagonizing the interaction of HMGB1 with RAGE and by an independent mechanism.

Thrombin-activatable fibrinolysis inhibitor protects against acute lung injury by inhibiting the complement system.

Acute lung injury (ALI) is a devastating disease with an overall mortality rate of 30 to 40%. The coagulation/fibrinolysis system is implicated in the pathogenesis of ALI. Thrombin-activatable fibronolysis inhibitor (TAFI) is an important component of the fibrinolysis system. Recent studies have shown that the active form of TAFI can also regulate inflammatory responses by its ability to inhibit complement C3a, C5a, and osteopontin. We hypothesized that TAFI might have a protective role in ALI. To demonstrate this hypothesis, the development of ALI was compared between wild-type (WT) and TAFI-deficient mice. ALI was induced by intratracheal instillation of LPS. Control mice were treated with saline. Animals were killed 24 hours after LPS. The number of inflammatory cells and the concentration of total protein and inflammatory cytokines were significantly increased in bronchoalveolar lavage fluid from LPS-treated, TAFI-deficient mice compared with their WT counterparts. Significantly higher concentrations of C5a were found in bronchoalveolar lavage fluid and plasma in LPS-treated TAFI knockout mice compared with WT mice. Pretreatment with inhaled C5a receptor antagonist blocked the detrimental effects of TAFI deficiency to levels found in WT mice. Our results show that TAFI protects against ALI, at least in part, by inhibiting the complement system.

Surgical Management of Breast Cancer Developing Along the Pathway of a Ventriculoperitoneal Shunt: A Case Report.

BACKGROUND Ventriculoperitoneal shunts are commonly used in neurosurgery for the treatment of hydrocephalus. This case report details an unusual instance where breast cancer developed along the pathway of an existing ventriculoperitoneal shunt. CASE REPORT An 86-year-old woman, who previously underwent ventriculoperitoneal shunt placement for normal-pressure hydrocephalus, visited our hospital upon detecting a mass in her left breast. The physical examination discovered an irregular mass located at the 9 o'clock position of the left breast. Subsequent breast ultrasonography identified a 36 mm mass with indistinct borders, rough margins, and signs of skin infiltration. Invasive ductal carcinoma of a triple-negative subtype was diagnosed through a core-needle biopsy. Contrast-enhanced computed tomography indicated the ventriculoperitoneal shunt's pathway, running from the left ventricle, passing through the center of the breast mass, and leading into the abdominal cavity. Fears of shunt occlusion and potential infection due to the untreated breast cancer prompted surgical intervention after consultation with the neurosurgeon. The surgery involved rerouting the ventriculoperitoneal shunt from the left thoracoabdomen to the right, performing a left mastectomy, and removing the fistula in the abdominal wall to minimize the risk of cancer recurrence along the shunt pathway. Postoperative histopathological examination confirmed the initial diagnosis of invasive ductal carcinoma of a triple-negative subtype, with no malignancy detected in the removed abdominal wall fistula. CONCLUSIONS Taking into account prior cases of cancer metastasizing distantly due to ventriculoperitoneal shunts, our case emphasizes the necessity to consider additional preventative measures against cancer seeding. This approach is particularly significant when treating breast cancer that arises along the pathway of a ventriculoperitoneal shunt, apart from performing conventional breast cancer surgery.

Development and preclinical efficacy of novel transforming growth factor-ß1 short interfering RNAs for pulmonary fibrosis.

Idiopathic pulmonary fibrosis is a chronic devastating disease of unknown etiology. No therapy is currently available. A growing body of evidence supports the role of transforming growth factor (TGF)-ß1 as the major player in the pathogenesis of the disease. However, attempts to control its expression and to improve the outcome of pulmonary fibrosis have been disappointing. We tested the hypothesis that TGF-ß1 is the dominant factor in the acute and chronic phases of pulmonary fibrosis and developed short interfering (si)RNAs directed toward molecules implicated in the disease. This study developed novel sequences of siRNAs targeting the TGF-ß1 gene and evaluated their therapeutic efficacy in two models of pulmonary fibrosis: a model induced by bleomycin and a novel model of the disease developed spontaneously in mice overexpressing the full length of human TGF-ß1 in the lungs. Intrapulmonary delivery of aerosolized siRNAs of TGF-ß1 with sequences common to humans and rodents significantly inhibited bleomycin-induced pulmonary fibrosis in the acute and chronic phases of the disease and in a dose-dependent manner. Aerosolized human-specific siRNA also efficiently inhibited pulmonary fibrosis, improved lung function, and prolonged survival in human TGF-ß1 transgenic mice. Mice showed no off-target effects after intratracheal administration of siRNA. These results suggest the applicability of these novel siRNAs as tools for treating pulmonary fibrosis in humans.

Correlation between circulating fibrocytes, and activity and progression of interstitial lung diseases.

BACKGROUND AND OBJECTIVE: Interstitial lung diseases (ILD) are characterized by progressive interstitial pulmonary fibrosis and a decline in lung function. Fibrocytes are bone marrow-derived mesenchymal progenitor cells that may play a role in the pathogenesis of pulmonary fibrosis. Circulating fibrocyte numbers have been correlated with the prognosis of patients with idiopathic pulmonary fibrosis. The aim of the present study was to evaluate the relationship between circulating fibrocytes, and parameters of disease activity and progression in several groups of patients with ILD. METHODS: The study population comprised 41 patients with ILD and seven healthy control subjects. Circulating CD45(+) collagen-I(+) fibrocytes were evaluated by flow cytometry. RESULTS: The number of circulating fibrocytes was significantly increased in all patients with ILD and particularly in patients with idiopathic interstitial pneumonitis and interstitial pneumonitis associated with collagen vascular disease as compared with healthy control subjects. The numbers of circulating fibrocytes were significantly correlated with pulmonary function test parameters and with serum levels of sialylated carbohydrate antigen, a marker of disease activity. Temporal changes in circulating fibrocyte numbers were evaluated in two patients, and the results suggested that these changes correlated with the activity of ILD. CONCLUSIONS: The results from this study provide further evidence for the role of circulating fibrocytes in fibrotic lung diseases.

Role of thrombin-activatable fibrinolysis inhibitor in allergic bronchial asthma.

BACKGROUND: Bronchial asthma is an inflammatory disease of the airways. Thrombin-activatable fibrinolysis inhibitor (TAFI) is a carboxypeptidase that besides inhibiting fibrinolysis, also regulates inflammatory processes. The only validated substrate known for TAFI is fibrin. In the present study we evaluated the role of TAFI in bronchial asthma by comparing the development of allergic bronchial asthma between wild-type (WT) and TAFI-deficient mice (KO). METHODS: Asthmatic inflammation was induced by sensitization and challenge with ovalbumin in WT (WT/OVA) and TAFI KO (KO/OVA) mice. WT mice (WT/SAL) and TAFI KO (KO/SAL) were used as controls. Cytokines, markers of inflammation, and coagulation were measured in bronchoalveolar lavage fluid (BALF). RESULTS: Airway hyperresponsiveness was worse in KO/OVA mice than in WT/OVA mice or control mice. Markers of lung injury were significantly increased in BALF from KO/OVA mice compared to WT/OVA mice. Airway hyperresponsiveness and the BALF concentrations of IL-5 and osteopontin were significantly increased in KO/OVA mice compared to WT/OVA mice. Treatment of WT/OVA and KO/OVA mice with a C5a receptor antagonist significantly decreased hyperresponsiveness along with the BALF concentrations of total protein and C5a compared to untreated asthmatic mice. CONCLUSION: The results of this study suggest that TAFI plays a protective role in the pathogenesis of allergic inflammation probably by inhibiting the complement system.

Inhibition of allergic bronchial asthma by thrombomodulin is mediated by dendritic cells.

RATIONALE: bronchial asthma is caused by inappropriate acquired immune responses to environmental allergens. It is a major health problem, with a prevalence that is rapidly increasing. Curative therapy is not currently available. OBJECTIVES: to test the hypothesis that thrombomodulin (TM) inhibits allergic bronchial asthma by inducing tolerogenic dendritic cells (DCs). METHODS: the protective effect of TM was evaluated using a murine asthma model. Asthma was induced in mice by exposure to chicken egg ovalbumin, and the effects of inhaled TM or TM-treated DCs were assessed by administering before ovalbumin exposure. MEASUREMENTS AND MAIN RESULTS: treatment with TM protects against bronchial asthma measured as improved lung function and reduced IgE and cells in alveolar lavage fluid by inducing tolerogenic dendritic dells. These are characterized by high expression of surface TM (CD141/TM(+)) and low expression of maturation markers and possess reduced T-cell costimulatory activity. The CD141/TM(+) DCs migrate less toward chemokines, and after TM treatment there are fewer DCs in the draining lymph node and more in the lungs. The TM effect is independent of its role in coagulation. Rather, it is mediated via the TM lectin domain directly interacting with the DCs. CONCLUSIONS: the results of this study show that TM is a modulator of DC immunostimulatory properties and a novel candidate drug for the prevention of bronchial asthma in atopic patients.

Advanced esophagogastric junction cancer with brain, bone and gastric intramural metastases responding to combined modality therapy.

A 63-year-old man was admitted to our hospital in March 2017 with dysphagia and right homonymous hemianopsia. We diagnosed him with esophagogastric junction cancer (adenocarcinoma) with metastases to the cerebral occipital lobe, bone, and lymph nodes. After one cycle of 5FU + cisplatin (FP), the brain metastasis was resected because of the hemiplegic symptoms he developed. Histology of the resected tissue showed no viable tumor cells. After three cycles of FP, the primary lesion and metastases were resolved. Upper gastrointestinal endoscopy revealed a scar at the primary site. This was considered a complete response (CR). In April 2018, CT revealed a mass at the cardia, which was considered as lymph node metastases with gastric wall invasion. Although two additional cycles of FP were administered for recurrent tumors, the efficacy was progressive. In August 2018, proximal gastrectomy and D1 + lymph node dissection were performed. The pathological diagnosis was gastric intramural metastases and lymph node metastases (ypN1 [2/22]). Weekly paclitaxel therapy was administered for three months after surgery. Two years have passed since the last surgery without recurrence. We report a rare case of esophagogastric junction cancer with brain, bone, and gastric intramural metastases that responded to combined modality therapy.

Oral Limonite Supplement Ameliorates Glucose Intolerance in Diabetic and Obese Mice.

INTRODUCTION: Diabetes mellitus is a serious threat to public health worldwide. It causes a substantial economic burden, mental and physical disabilities, poor quality of life, and high mortality. Limonite is formed when iron-rich materials from the underground emerge and oxidized on the ground surface. It is currently used to purify contaminated water, absorption of irritant gases, and improve livestock breeding. Limonite can change the composition of environmental microbial communities. In the present study, we evaluated whether limonite can ameliorate glucose metabolism abnormalities by remodeling the gut microbiome. METHODS: The investigation was performed using mouse models of streptozotocin-induced diabetes mellitus and high-calorie diet-induced metabolic syndrome. RESULTS: Oral limonite supplement was associated with significant body weight recovery, reduced glycemia with improved insulin secretion, increased number of regulatory T cells, and abundant beneficial gut microbial populations in mice with diabetes mellitus compared to control. Similarly, mice with obesity fed with limonite supplements had significantly reduced body weight, insulin resistance, steatohepatitis, and systemic inflammatory response with significant gut microbiome remodeling. CONCLUSION: This study demonstrates that limonite supplement ameliorates abnormal glucose metabolism in diabetes mellitus and obesity. Gut microbiome remodeling, inhibition of inflammatory cytokines, and the host immune response regulation may explain the limonite's beneficial activity under pathological conditions in vivo.

The coagulation and protein C pathways in patients with sleep apnea.

Patients with obstructive sleep apnea (OSA) have a high frequency of cardiovascular diseases and hypercoagulability is believed to be involved in the mechanism of those vascular events. We evaluated whether there is a dysfunction in the protein C anticoagulant pathway in patients with obstructive sleep apnea. Two hundred ninety-three patients were enrolled. To confirm the diagnosis of OSA, all-night polysomnography, including determination of SpO(2), was carried out. The apnea-hypopnea index (AHI) was used for judging the presence of sleep-breathing disorder. The plasma levels of the thrombin-antithrombin complex were higher in patients with AHI > 5 than in those without OSA, defined as AHI < 5. However, there was no statistically significant difference in the plasma level of either activated protein C/alpha-antitrypsin complex or soluble thrombomodulin between patients with AHI > 5 and those with AHI < 5. The results of this study showed for the first time that markers of the protein C anticoagulant pathway are not affected in patients with OSA and that the protein C pathway is probably not involved in the mechanism of hypercoagulability in subjects with sleep-disordered breathing.

Role of the coagulation system in allergic inflammation in the upper airways.

Thrombin has been detected and demonstrated to play a role in the airways of patients with bronchial asthma, but its role in the upper airways including during allergic rhinitis is unknown. This study was conducted to explore whether thrombin is presence in the upper airways and, if so, whether it affects mucin secretion. Fifteen patients with allergic rhinitis were enrolled in the clinical study; primary nasal septum epithelial cells and normal bronchial epithelial cells were used for in vitro evaluation, and rats as animal models. Significant concentrations of thrombin were found in nasal secretion after allergic provocation in allergic patients, and thrombin and its agonistic receptor peptide induced significant secretion of mucin in primary nasal cells and normal bronchial epithelial cells as compared to non-stimulated cells. Increased mucosubstance secretion in septum epithelial cells was also induced after nasal instillation of thrombin in rats. Further, the anticoagulant, activated protein C, significantly inhibited thrombin-induced mucin secretion from septum epithelial cells in rats. The results of this study suggest that activation of the coagulation system occurs during the allergic response and that thrombin plays a crucial role in the regulation of mucin production in the upper airways.

Role of thrombin in interleukin-5 expression from basophils.

Interleukin-5 (IL-5) plays a key role in the pathogenesis of bronchial asthma. Thrombin is a procoagulant factor that has been also reported to participate in the inflammatory response by stimulating the secretion of cytokines. Interaction of inflammatory cells with airway epithelial cells may also promote the secretion of cytokines. However, the role of thrombin and cell-to-cell interaction in pathogenesis of allergic inflammation is unclear. In this study, we evaluated the role of thrombin and cell-to-cell interaction in the secretion of IL-5 from basophils. The human basophil cell line KU-812 was used in the assays. Thrombin and co-culture with alveolar epithelial cells significantly stimulated the secretion of IL-5 from KU-812 cells as compared to controls. Secretion of IL-5 was synergistically stimulated when KU-812 cells were incubated in the presence of both thrombin and alveolar epithelial cells. Co-culture of KU-812 cells with epithelial cells significantly increased the expression of tissue factor, an activator of coagulation activation, in a cell dose-dependent manner. Secretion of IL-5 from KU-812 basophils co-cultured with epithelial cells was significantly inhibited by LY294002, an inhibitor of phosphatidylinositol 3-kinase. These results suggest that thrombin and cell interaction with lung epithelial cells may augment the inflammatory response in allergic diseases by stimulating the secretion of IL-5 from basophils.

Inhibition of nuclear factor-kappaB in T cells suppresses lung fibrosis.

RATIONALE: Cytokines secreted by T cells play a pivotal role in the pathogenesis of lung injury and fibrosis, and the transcription factors nuclear factor (NF)-kappaB and activator protein (AP)-1 are involved in the expression of cytokines from T cells during lung injury. OBJECTIVES: We assessed the potential therapeutic effect of SP100030, a specific inhibitor of T-cell NF-kappaB and AP-1 in lung fibrosis. METHODS: The effect of SP100030 was evaluated using a mouse model of chronic lung fibrosis. MEASUREMENTS AND MAIN RESULTS: Mice treated with SP100030, as compared with untreated mice, had significantly less cachexia and less lung injury and had decreased levels of inflammatory cytokines and growth factors, decreased activation of coagulation activation, and decreased collagen deposition in the lung. The inhibitory activity of SP100030 was dose dependent and was effective in acute and chronic phases of lung fibrosis. SP100030 inhibited the activation of the protein kinase C-isoform in T-cell lines and suppressed NF-kappaB-driven cytokine expression in CD4(+) and CD8(+) T cells. CONCLUSIONS: These results suggest that the specific inhibition of NF-kappaB could be useful for the treatment of lung fibrosis.

Vimentin Regulates Invasiveness and Is a Poor Prognostic Marker in Non-small Cell Lung Cancer.

BACKGROUND: Lung cancer cells often express vimentin. However, the function of vimentin in lung cancer cells has not been fully evaluated. MATERIALS AND METHODS: We evaluated the association between vimentin expression in resected non-small cell lung cancer (NSCLC) specimens and prognosis. Short-interfering RNA targeting vimentin and establishment of an invasive cell line by repeated selection of invasive cells using a Matrigel membrane invasion chamber system (MICS) were performed. MICS was used to reveal the relationship between invasiveness and vimentin. RESULTS: Vimentin positivity was significantly associated with a poor prognosis and was significantly lower in squamous cell carcinoma than in adenocarcinoma. In in vitro experiments, silencing of vimentin reduced invasiveness. Highly invasive cell lines exhibited higher expression of vimentin than did parental cells, and invasive ability was reduced by knockdown of vimentin. CONCLUSION: Vimentin expression is associated with prognosis via alteration of the invasive ability of NSCLC cells.

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.

[Combination therapy of micafungin and itraconazole for a case of pulmonary aspergillosis].

The patient was a 73-year-old female who visited a physician with a chief complaint of fever, and was diagnosed with pneumonia. Ampicillin/sulbactam was administered, but ineffective, and the patient was referred to our hospital. In addition to severe inflammatory findings, cavity lesions were observed in the right upper lobe on plain chest X-ray and thoracic CT. Since Aspergillus fumigatus was cultured in bronchoalveolar lavage, a definite diagnosis of pulmonary aspergillosis was made. Intravenous administration of micafungin was initiated, but severe inflammatory findings persisted, and infiltrative shadows rapidly expanded. Oral itraconazole was concomitantly administered, and clinical symptoms and findings slowly improved. The plasma trough levels of micafungin, itraconazole, and hydroxyitraconazole were higher than the minimal inhibitory concentrations for the etiologic fungus, A. fumigatus, throughout the treatment period. No adverse events of the concomitant treatment were observed. Combination of the two antifungal agents may be effective for intractable pulmonary aspergillosis.