Anti-Inflammatory Effects of Japanese Herbal Medicine Hochuekkito in a Mouse Model of Acute Exacerbation of Chronic Obstructive Pulmonary Disease.

INTRODUCTION: The traditional Japanese herbal medicine hochuekkito (TJ-41) has been reported to ameliorate systemic inflammation and malnutrition in patients with chronic obstructive pulmonary disease (COPD). TJ-41 has also been known to have preventive effects against influenza virus infection. However, its role in the acute exacerbation of COPD (AECOPD) remains to be elucidated. Our previous study established a murine model of viral infection-associated AECOPD that was induced by intratracheal administration of porcine pancreatic elastase (PPE) and polyinosinic-polycytidylic acid [poly(I:C)]. Here, we used this model and investigated the effects of TJ-41 in AECOPD. METHODS: Specific pathogen-free C57BL/6J mice were used. A COPD model was induced by treating mice intratracheally with PPE on day 0. To generate the murine model of AECOPD, poly(I:C) was administered intratracheally following PPE treatment on days 22-24. Mice were sacrificed and analyzed on day 25. Mice were fed a diet containing 2% TJ-41 or a control diet. RESULTS: Daily oral intake of TJ-41 significantly decreased the numbers of neutrophils and lymphocytes in the bronchoalveolar lavage fluid (BALF), which was accompanied by decreased transcripts of CXC chemokines involved in neutrophil migration, viz., Cxcl1 and Cxcl2, in whole lung homogenates and reduced Cxcl2 concentration in BALF. CONCLUSION: This study demonstrates the anti-inflammatory effects of TJ-41 in a mouse model of AECOPD, suggesting the effectiveness of TJ-41 for the management of COPD. Clinical investigations evaluating the therapeutic efficacy of TJ-41 in AECOPD would be meaningful.

Naftopidil reduced the proliferation of lung fibroblasts and bleomycin-induced lung fibrosis in mice.

Naftopidil, an α-1 adrenoceptor antagonist with few adverse effects, is prescribed for prostate hyperplasia. Naftopidil inhibits prostate fibroblast proliferation; however, its effects on lung fibroblasts and fibrosis remain largely unknown. Two normal and one idiopathic pulmonary fibrosis human lung fibroblast lines were cultured with various naftopidil concentrations with or without phenoxybenzamine, an irreversible α-1 adrenoceptor inhibitor. We examined the incorporation of 5-bromo-2'-deoxyuridine into DNA and lactic acid dehydrogenase release by enzyme-linked immunosorbent assay, cell cycle analysis by flow cytometry, scratch wound-healing assay, and mRNA expressions of type IV collagen and α-smooth muscle actin by polymerase chain reaction. Effects of naftopidil on bleomycin-induced lung fibrosis in mice were evaluated using histology, micro-computed tomography, and surfactant protein-D levels in serum. Naftopidil, dose-dependently but independently of phenoxybenzamine, inhibited 5-bromo-2'-deoxyuridine incorporation in lung fibroblasts. Naftopidil induced G1 cell cycle arrest, but lactic acid dehydrogenase release and migration ability of lung fibroblasts were unaffected. Naftopidil decreased mRNA expressions of type IV collagen and α-smooth muscle actin in one normal lung fibroblast line. Histological and micro-computed tomography examination revealed that naftopidil attenuated lung fibrosis and decreased serum surfactant protein-D levels in bleomycin-induced lung fibrosis in mice. In conclusion, naftopidil may have therapeutic effects on lung fibrosis.

Small lung tumor biopsy samples are feasible for high quality targeted next generation sequencing.

Next-generation sequencing (NGS) has been implemented in clinical oncology to analyze multiple genes and to guide therapy. In patients with advanced lung cancer, small biopsies such as computed tomography-guided needle biopsy (CTNB), endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and transbronchial biopsy (TBB) are less invasive and are preferable to resection to make a pathological diagnosis. However, the quality of DNA/RNA and NGS from small lung tumor biopsy samples is unknown. Between April 2017 and March 2018, 107 consecutive samples were obtained from thoracic tumors or metastatic sites for targeted NGS analysis. Fifteen samples were obtained through CTNB, 11 through EBUS-TBNA, 11 through TBB and 70 through surgical resection. All samples were formalin-fixed and paraffin-embedded. DNA and RNA quality was measured using the ddCq method and the percentage of RNA fragments above 200 nucleotides (DV200), respectively. Our custommade probes were designed to capture exon sequences of 464 cancer-related genes and transcripts of 463 genes. DNA and RNA yield from the 3 biopsy methods were similar, and less than the yield obtained from resected samples. The quality of DNA and RNA was similar across all methods. Overall, 12 of 15 CTNB samples (80%), all 11 EBUS-TBNA samples, and 9 of 11 TBB samples (82%) underwent successful NGS assays from DNA. NGS analysis from RNA was successful in all 12 CTNB samples, 9 of 11 EBUS-TBNA samples (82%), and 8 of 11 TBB samples (73%). CTNB, EBUS-TBNA and TBB mostly resulted in adequate DNA and RNA quality and enabled high-quality targeted NGS analysis.

Hospital Volume and Mortality following Diagnostic Bronchoscopy in Lung Cancer Patients: Data from a National Inpatient Database in Japan.

BACKGROUND: Recent advances in bronchoscopy utilizing endobronchial ultrasound (EBUS) as well as lung cancer therapy may have driven physicians to perform diagnostic bronchoscopy (DB) for high-risk patients. OBJECTIVES: The aim of this study was to clarify the relationship between hospital volume (HV) and outcomes of DB. METHODS: We collected data on inpatients with lung cancer who underwent DB from July 2010 to March 31, 2014. The annual HV of DB was classified as "very low" (≤50 cases/year), "low" (51-100 cases/year), "high" (101-300 cases/year), or "very high" (> 300 cases/year). The primary outcome was all-cause 7-day mortality after DB. Multivariable logistic regression fitted with a generalized estimation equation was performed to evaluate the association between HV and all-cause 7-day mortality after DB, adjusted for patient background factors. RESULTS: We identified a total of 77,755 eligible patients in 954 hospitals. All-cause 7-day mortality was 0.5%. Compared with the low-volume group, 7-day mortality was significantly lower in the high-volume group (odds ratio [OR] = 0.69, 95% confidence interval [CI]: 0.52-0.92, p = 0.010), and a similar trend was shown in the very-high-volume group (OR = 0.67; 95% CI: 0.43-1.05, p = 0.080). Radial EBUS with the guide sheath method and EBUS-guided transbronchial needle aspiration showed a significantly lower 7-day mortality. CONCLUSIONS: All-cause 7-day mortality was inversely associated with HV. The risk of DB in patients with lung cancer should be recognized, and the exploitation of EBUS may help reduce mortality after DB.

CISH is a negative regulator of IL-13-induced CCL26 production in lung fibroblasts.

BACKGROUND: Bronchial asthma is a chronic airway disease characterized by eosinophilic airway inflammation. Lung fibroblasts activated by IL-13 serve as important sources of chemokines, such as eotaxins, contributing to persistent eosinophilic inflammation. Src-homology 2-containing protein (CISH), belonging to the suppressor of cytokine signaling (SOCS) family, acts as a negative regulator of cytokine induction. The aim of this study was to elucidate the role of CISH in the production of eosinophil chemotactic chemokines in human lung fibroblasts. METHODS: Normal human lung fibroblasts were stimulated by IL-13, and global gene expression profile was assessed by cDNA microarray. Expression changes and downstream of IL-13 signaling were evaluated by quantitative RT-PCR, ELISA or western blotting. Loss- and gain-of-function analyses of CISH were performed by small interfering RNA and vector overexpression, respectively. RESULTS: Ingenuity pathway analysis revealed that IL-13 induced chemokine signaling, including the eotaxin family, while significantly suppressing IFN-α/ß signaling. Among eight SOCS family members, CISH was most strongly induced by IL-13 via phosphorylation of signal transducer and activator of transcription 6 (STAT6). Loss- and gain-of-function studies demonstrated that CISH negatively regulated the expression of CCL26. CONCLUSIONS: These findings suggest that CISH plays a key role in the eosinophilic inflammation associated with bronchial asthma by regulating IL-13-induced CCL26 production. Augmentation of CISH function could be a novel approach for treating eosinophilic inflammation in severe asthma.

Adjuvant chemotherapy versus chemoradiotherapy for small cell lung cancer with lymph node metastasis: a retrospective observational study with use of a national database in Japan.

BACKGROUND: The optimal postoperative treatment strategy for small cell lung cancer (SCLC) remains unclear, especially in patients with lymph node metastasis. We aimed to compare the outcomes of patients with SCLC and lymph node metastasis treated with postoperative adjuvant chemotherapy or chemoradiotherapy. METHODS: We retrospectively collected data on patients with postoperative SCLC diagnosed with N1 and N2 lymph node metastasis from the Diagnosis Procedure Combination database in Japan, between July 2010 and March 2015. We extracted data on patient age, sex, comorbidities, and TNM classification at lung surgery; operative procedures, chemotherapy drugs, and radiotherapy during hospitalization; and discharge status. Recurrence-free survival was compared between the chemotherapy and chemoradiotherapy groups using multivariable Cox regression analysis. RESULTS: Median recurrence-free survival was 1146 days (95% confidence interval [CI], 885-1407) in the chemotherapy group (n = 489) and 873 days (95% CI, 464-1282) in the chemoradiotherapy group (n = 75). There was no significant difference between these after adjusting for patient backgrounds (hazard ratio, 1.29; 95% CI, 0.91-1.84). CONCLUSIONS: There was no significant difference in recurrence-free survival between patients with SCLC and N1-2 lymph node metastasis treated with postoperative adjuvant chemotherapy and chemoradiotherapy. Further randomized clinical trials are needed to address this issue.

Bronchoscopic Re-biopsy for Mutational Analysis of Non-small Cell Lung Cancer.

OBJECTIVES: Currently, several acquired resistance mechanisms and rare driver oncogenes are identified in non-small cell lung cancer (NSCLC) relapses. Re-biopsy increases valuable information to guide treatment strategies, but the utility and feasibility of bronchoscopic re-biopsy has not been investigated. METHODS: We studied 70 patients who underwent bronchoscopic for re-biopsy of NSCLC that was resistant to at least one regimen of chemotherapy or molecular-targeted therapy between January 2013 and December 2014. We assessed clinical data, technical success rate, and mutational analysis. RESULTS: Procedures performed were transbronchial biopsy (n = 52) and endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) (n = 18). Overall detection rate of re-biopsy for malignant cells was 87 % (83 % for TBB and 100 % for EBUS-TBNA). Mutational analysis was possible in almost all technically successful cases; likewise, acquired-resistant mutations (55 % of EGFR mutants) and small cell lung cancer transformation were identified from the bronchoscopy specimens. Other driver mutations were seen in four cases, including ALK fusion gene (n = 2) and ROS1 fusion gene (n = 2). There were no associated severe complications. CONCLUSION: This study shows that bronchoscopic re-biopsy for NSCLC is feasible and provides adequate samples that enable identification of resistance mutations and rare driver oncogenes.

TIM-3 is not essential for development of airway inflammation induced by house dust mite antigens.

BACKGROUND: T cell immunoglobulin domain and mucin domain-containing molecule 3 (TIM-3), which is preferentially expressed on Th1 cells rather than Th2 cells, is considered to be a negative regulator of Th1 cell function. This suggests that TIM-3 indirectly enhances Th2-type immune responses by suppressing Th1 cell function. METHODS: To investigate TIM-3's possible involvement in Th2-type acute and chronic airway inflammation, wild-type and TIM-3-deficient (TIM-3-/-) mice were sensitized and challenged with a house dust mite (HDM) extract. Airway inflammation and the number of inflammatory cells in bronchoalveolar lavage fluids (BALFs) in the mice were determined by histological analysis and with a hemocytometer, respectively. Expression of mRNA in the lungs was determined by quantitative PCR, while the levels of cytokines in the BALFs and IgE in sera were determined by ELISA. RESULTS: Despite constitutive expression of TIM-3 mRNA in the lungs, the number of eosinophils in bronchoalveolar lavage fluids (BALFs) and the score of pulmonary inflammation were comparable between wild-type and TIM-3-/- mice during both acute and chronic HDM-induced airway inflammation. On the other hand, the number of lymphocytes in the BALFs of TIM-3-/- mice was significantly increased compared with wild-type mice during HDM-induced chronic, but not acute, airway inflammation, while the levels of Th2 cytokines in the BALFs and HDM-specific IgG1 and IgG2a and total IgE in the sera were comparable in both groups. CONCLUSIONS: Our findings indicate that, in mice, TIM-3 is not essential for development of HDM-induced acute or chronic allergic airway inflammation, although it appears to be involved in reduced lymphocyte recruitment during HDM-induced chronic allergic airway inflammation.

Diagnostic yield of flexible bronchoscopy for immunocompromised patients with lung infiltrates: A single-center, retrospective study.

BACKGROUND: Pulmonary complications are associated with mortality in immunocompromised patients. The usefulness of bronchoscopy has been reported. However, clinical factors and procedures that influence diagnostic yield are still not established. MATERIALS AND METHODS: We retrospectively analyzed 115 bronchoscopies performed on 108 immunocompromised patients, defined as those who take corticosteroids and/or immunosuppressants. We evaluated clinical factors, sampling procedures, final diagnosis, and severe complications of bronchoscopy. RESULTS: The clinical diagnosis was obtained in 51 patients (44%). Of those, 33 cases were diagnosed as infectious diseases and 18 as non-infectious diseases. Nine out of 115 cases (7.8%) initiated new immunosuppressive treatment for an underlying disorder based on the negative microbiological results obtained with bronchoscopy. Collagen vascular disease was the most common underlying disorders (62 patients, 54%). Bronchoscopy was useful regardless of whether the patient was immunosuppressed to treat collagen vascular disease (P = 0.47). Performing transbronchial biopsy correlated with better diagnostic yield of bronchoscopy (54.7% vs 35.5%, P = 0.049). Other clinical factors, such as radiological findings, respiratory failure or antibiotic use at the time of bronchoscopy did not significantly influence diagnostic yield. Respiratory failure requiring intubation after bronchoscopy occurred only in one case (0.9%). CONCLUSIONS: Our study implied the transbronchial biopsy may be a useful procedure for reaching a diagnosis in immunocompromised patients with pulmonary infiltrates. In addition, our data suggest the usefulness of bronchoscopy for immunocompromised patients due to the treatment of collagen vascular disease as well as other underlying disorders.

A Japanese herbal medicine (kampo), hochuekkito (TJ-41), has anti-inflammatory effects on the chronic obstructive pulmonary disease mouse model.

Chronic obstructive pulmonary disease (COPD) is a progressive disease that is characterized by chronic airway inflammation. A Japanese herbal medicine, hochuekkito (TJ-41), is prominently used for chronic inflammatory diseases in Japan. This study aimed to analyze the anti-inflammatory effect of TJ-41 in vivo and its underlying mechanisms. We created a COPD mouse model using intratracheal administration of porcine pancreatic elastase and lipopolysaccharide (LPS) and analyzed them with and without TJ-41 administration. A TJ-41-containing diet reduced inflammatory cell infiltration of the lungs in the acute and chronic phases and body weight loss in the acute phase. In vitro experiments revealed that TJ-41 treatment suppressed the LPS-induced inflammatory cytokines in BEAS-2B cells. Furthermore, TJ-41 administration activated the AMP-activated protein kinase (AMPK) pathway and inhibited the mechanistic target of the rapamycin (mTOR) pathway, both in cellular and mouse experiments. We concluded that TJ-41 administration reduced airway inflammation in the COPD mouse model, which might be regulated by the activated AMPK pathway, and inhibited the mTOR pathway.

Endoscopic reflux esophagitis and decline in pulmonary function in nonsmokers: A retrospective cohort study.

BACKGROUND: The association between reflux esophagitis and pulmonary function remains controversial. Thus, evaluating the relationship between endoscopic reflux esophagitis and changes in pulmonary function over time in a nonsmoking population is an important clinical issue. METHODS: In this single-center retrospective cohort study, a medical examination database at Kameda Medical Center Makuhari was employed to identify nonsmokers who underwent upper gastrointestinal endoscopy and spirometry in 2010 and were followed up in 2015. Gastroenterologists carefully double-checked the diagnosis of reflux esophagitis. Multiple linear regression analyses were performed to compare the decline in the percentage of predicted vital capacity (%VC), forced vital capacity (%FVC), and forced expiratory volume in 1 s (%FEV1) between participants with reflux esophagitis and those without. Furthermore, using multivariable logistic regression analyses, we evaluated the factors associated with rapid decline in %VC, %FVC, and %FEV1, which is defined as a decrease of >10% in each parameter over the 5-year observation period. RESULTS: We identified 3098 eligible subjects, including 72 and 44 participants who had a Los Angeles classification grade A and B-C (severe) reflux esophagitis in 2010, respectively. The decline in %VC was significantly larger in the participants with severe reflux esophagitis than in the control subjects (standardized coefficient, -0.037; 95% confidence interval, -0.071 to -0.004). Moreover, reflux esophagitis was significantly associated with a rapid decline in %VC and %FVC but not in %FEV1 (P for trend: 0.009, 0.009, and 0.276, respectively). CONCLUSIONS: Severe reflux esophagitis among nonsmokers had clinical disadvantages in terms of a decline in %VC.

Clinical and pathological predictors of engraftment for patient-derived xenografts in lung adenocarcinoma.

Patient-derived xenografts (PDXs) are increasingly utilized in preclinical drug efficacy studies due to their ability to retain the molecular, histological, and drug response characteristics of patient tumors. This study aimed to investigate the factors influencing the successful engraftment of PDXs. Lung adenocarcinoma PDXs were established using freshly resected tumor tissues obtained through surgery. Radiological data of pulmonary nodules from this PDX cohort were analyzed, categorizing them into solid tumors and tumors with ground-glass opacity (GGO) based on preoperative CT images. Gene mutation status was obtained from next generation sequencing data and MassARRAY panel. A total of 254 resected primary lung adenocarcinomas were utilized for PDX establishment, with successful initial engraftment in 58 cases (22.8 %); stable engraftment defined as at least three serial passages was observed in 43 cases (16.9 %). The stable engraftment rates of PDXs from solid tumors and tumors with GGO were 22.1 % (42 of 190 cases) and 1.6 % (1 of 64 cases), respectively (P < 0.001). Adenocarcinomas with advanced stage, poor differentiation, solid histologic subtype, and KRAS or TP53 gene mutations were associated with stable PDX engraftment. Avoiding tumors with GGO features could enhance the cost-effectiveness of establishing PDX models from early-stage resected lung adenocarcinomas.

Transbronchial real-time lung tumor localization with folate receptor-targeted near-infrared molecular imaging: A proof of concept study in animal models.

OBJECTIVE: The diagnostic yield of bronchoscopy is not satisfactory, even with recent navigation technologies, especially for tumors located outside of the bronchial lumen. Our objective was to perform a preclinical assessment of folate receptor-targeted near-infrared imaging-guided bronchoscopy to detect peribronchial tumors. METHODS: Pafolacianine, a folate receptor-targeted molecular imaging agent, was used as a near-infrared fluorescent imaging agent. An ultra-thin composite optical fiberscope was used for laser irradiation and fluorescence imaging. Subcutaneous xenografts of KB cells in mice were used as folate receptor-positive tumors. Tumor-to-background ratio was calculated by the fluorescence intensity value of muscle tissues acquired by the ultra-thin composite optical fiberscope system and validated using a separate spectral imaging system. Ex vivo swine lungs into which pafolacianine-laden KB tumors were transplanted at various sites were used as a peribronchial tumor model. RESULTS: With the in vivo murine model, tumor-to-background ratio observed by ultra-thin composite optical fiberscope peaked at 24 hours after pafolacianine injection (tumor-to-background ratio: 2.56 at 0.05 mg/kg, 2.03 at 0.025 mg/kg). The fluorescence intensity ratios between KB tumors and normal mouse lung parenchyma postmortem were 6.09 at 0.05 mg/kg and 5.08 at 0.025 mg/kg. In the peribronchial tumor model, the ultra-thin composite optical fiberscope system could successfully detect fluorescence from pafolacianine-laden folate receptor-positive tumors with 0.05 mg/kg at the carina and those with 0.025 mg/kg and 0.05 mg/kg in the peripheral airway. CONCLUSIONS: Transbronchial detection of pafolacianine-laden folate receptor-positive tumors by near-infrared imaging was feasible in ex vivo swine lungs. Further in vivo preclinical assessment is needed to confirm the feasibility of this technology.

Preclinical feasibility of bronchoscopic fluorescence-guided lung sentinel lymph node mapping.

OBJECTIVE: Lung sentinel lymph node mapping, where peritumorally injected material is tracked through the lymphatics, aims to find the first potential sites of nodal metastasis. We sought to evaluate the preclinical feasibility of bronchoscopic fluorescence-guided sentinel lymph node mapping. METHODS: Healthy Yorkshire pigs were used; sentinel lymph node mapping was performed with indocyanine green. The primary fluorescence imaging method was an ultrathin composite fiberscope placed in the bronchoscope working channel. Secondary methods used a fluorescence thoracoscope placed in the trachea (rigid bronchoscopy) and pretracheal fascial plane (mediastinoscopy) to validate ultrathin composite fiberscope settings for sentinel lymph node detection. A tracheostomy was created, and the pig was placed in a lateral decubitus position. Transbronchial intraparenchymal indocyanine green injection was performed primarily in the right lower lobe. Ultrathin composite fiberscope and rigid bronchoscopy were performed with (n = 6) or without (n = 2) mediastinoscopy, with the former group guiding dose and ultrathin composite fiberscope optimization. Fluorescent targets were interrogated by endobronchial ultrasound before ultrathin composite fiberscope-guided transbronchial needle aspiration. Specimen fluorescence was documented before creating cytological smears. Pigs were killed postprocedure for nodal dissection. RESULTS: A total of 100 µL of 10 mg/mL indocyanine green generated strong transbronchial fluorescence with low risk of indocyanine green contamination. Fluorescence was detectable by 10 minutes postinjection. There was concordance among ultrathin composite fiberscope, rigid bronchoscopy, and mediastinoscopy. Except for 1 pig with airway contamination, ultrathin composite fiberscope-guided endobronchial ultrasound transbronchial needle aspiration obtained fluorescent material in all pigs. Specimen fluorescence was associated with specimen adequacy. CONCLUSIONS: Bronchoscopic fluorescence-guided sentinel lymph node mapping was feasible, with specimen fluorescence providing real-time feedback on sentinel lymph node biopsy success. If translated to clinical practice, attention must be paid to minimizing indocyanine green leakage.

Repeated photodynamic therapy mediates the abscopal effect through multiple innate and adaptive immune responses with and without immune checkpoint therapy.

In combination with immune checkpoint inhibitors, photodynamic therapy can induce robust immune responses capable of preventing local tumor recurrence and delaying the growth of distant, untreated disease (ie. the abscopal effect). Previously, we found that repeated photodynamic therapy (R-PDT) using porphyrin lipoprotein (PLP) as a photosensitizer, without the addition of an immune checkpoint inhibitor, can induce the abscopal effect. To understand why PLP mediated R-PDT alone can induce the abscopal effect, and how the addition of an immune checkpoint inhibitor can further strengthen the abscopal effect, we investigated the broader immune mechanisms facilitated by R-PDT and combination R-PDT + anti-PD-1 monoclonal antibody (αPD-1) in a highly aggressive, subcutaneous AE17-OVA mesothelioma dual tumor-bearing C57BL/6 mice. We found a 46.64-fold and 61.33-fold increase in interleukin-6 (IL-6) after R-PDT and combination R-PDT + αPD-1 relative to PBS respectively, suggesting broad innate immune activation. There was a greater propensity for antigen presentation in the spleen and distal, non-irradiated tumor draining lymph nodes, as dendritic cells and macrophages had increased expression of MHC class II, CD80, and CD86, after R-PDT and combination R-PDT + αPD-1. Concurrently, there was a shift in the proportions of CD4+ T cell subsets in the spleen, and an increase in the frequency of CD8+ T cells in the distal, non-irradiated tumor draining lymph nodes. While R-PDT had an acceptable safety profile, combination R-PDT + αPD-1 induced 1.26-fold higher serum potassium and 1.33-fold phosphorus, suggestive of mild laboratory tumor lysis syndrome. Histology revealed an absence of gross inflammation in critical organs after R-PDT and combination R-PDT + αPD-1 relative to PBS-treated mice. Taken together, our findings shed light on how the abscopal effect can be induced by PDT and strengthened by combination R-PDT + αPD-1, and suggests minimal toxicities after R-PDT.

Assessment of effectiveness and safety of thrombolytic therapy to pulmonary emboli by endobronchial ultrasound-guided transbronchial needle injection.

Objective: Endobronchial ultrasound-guided transbronchial needle injection (EBUS-TBNI) may effectively treat acute pulmonary embolisms (PEs). Here, we assessed the effectiveness of clot dissolution and safety of tissue plasminogen activator (t-PA) injection using EBUS-TBNI in a 1-week survival study of a porcine PE model. Methods: Six pigs with bilateral PEs were used: 3 for t-PA injection using EBUS-TBNI (TBNI group) and 3 for systemic administration of t-PA (systemic group). Once bilateral PEs were created, each 25 mg of t-PA injection using EBUS-TBNI for bilateral PEs (a total of 50 mg t-PA) and 100 mg of t-PA systemic administration was performed on day 1. Hemodynamic parameters, blood tests, and contrast-enhanced computed tomography scans were carried out at several time points. On day 7, pigs were humanely killed to evaluate the residual clot volume in the pulmonary arteries. Results: The average of percent change of residual clot volumes was significantly lower in the TBNI group than in the systemic group (%: systemic group 36.6 ± 22.6 vs TBNI group 9.6 ± 6.1, P < .01) on day 3. Considering the elapsed time, the average decrease of clot volume per hour at pre-t-PA to post t-PA was significantly greater in the TBNI group than in the systemic group (mm3/hour: systemic 68.1 ± 68.1 vs TBNI 256.8 ± 148.1, P < .05). No hemorrhage was observed intracranially, intrathoracically, or intraperitoneally on any contrast-enhanced computed tomography images. Conclusions: This study revealed that t-PA injection using EBUS-TBNI is an effective and safe way to dissolve clots.

[A case of an asthma patient receiving omalizumab during pregnancy].

We describe the first report in Japan of a woman who received omalizumab during pregnancy and delivery. Her asthma was so severe that she had been taking systemic corticosteroids since 22 years old, but asthma was poorly controlled. She had been pregnant seven times before, but almost every time asthma control had worsened and spontaneous abortion resulted, so she had only one child. She confirmed that she was not intending to become pregnant, and initiated use of omalizumab in August 2009. However, pregnancy was identified after she had taken the drug 3 times. We explained the risks in detail, but the patient wanted to keep taking omalizumab, as her asthma control was improved and she thought she could continue the pregnancy. We therefore decided to continue with omalizumab therapy. In October, she caught a cold and experienced asthma exacerbation. Despite the risk, she decided to suspend omalizumab therapy after taking the drug 7 times, as she was not feeling any benefit from therapy. Threat of abortion was identified in February 2010, so a 544-g female baby was delivered at 26 weeks gestation by Cesarean section. The baby had to be hospitalized in the neonatal intensive care unit because of low birth weight, but she has been developing and growing without handicap. We report this case as the first known case of pregnancy and delivery for a woman receiving omalizumab in Japan. Omalizumab may be safe to use in pregnant women with difficult-to-control asthma.

[Efficacy of combination therapy with EGFR-TKI and cytotoxic drug in lung adenocarcinoma already treated with EGFR-TKI].

UNLABELLED: OBJECITVE: To assess the efficacy of combination therapy with EGFR-TKI and a cytotoxic drug in lung adenocarcinoma already being treated with EGFR-TKI. METHODS: Eight patients with adenocarcinoma who were treated with combination therapy of EGFR-TKI and a cytotoxic drug between April 2008 and December 2010 were retrospectively evaluated for response rate, disease-control rate, progression-free survival(PFS), time-to-treatment-failure(TTF)and overall survival(OS). RESULTS: Among the 7 patients with tumor samples available, EGFR-mutations were detected in six.The median number of prior therapy regimens received by the patients was 5.All the patients had been treated before with both gefitinib and erlotinib.Among 8 patients, six showed stable disease, including three patients intolerant because of severe hematological toxicities, and 2 with progressive disease.The disease-control rate was 75%, and median TTF, PFS, and OS were 42 days, 84 days, and 495 days, respectively. CONCLUSION: Combination therapy with EGFR-TKI and a cytotoxic drug after the failure of EGFR-TKI may be a useful therapeutic option for selected patients.

Multiple cerebral infarctions in ROS1-rearranged lung adenocarcinoma.

Rearrangements of specific tyrosine kinases are associated with an elevated risk of venous thrombosis in lung adenocarcinoma, although their effects on arterial thrombosis have not been fully elucidated. Here, we report two cases of ROS proto-oncogene 1 (ROS1)-rearranged lung adenocarcinoma with cerebral infarction during the peri-diagnostic period. Two cases took contrasting clinical courses: one patient could not receive targeted therapy because of a significant decline in performance status, whereas in the other patient, the performance status was maintained and targeted therapy drastically reduced the tumour size. Our cases suggest close monitoring could be considered in the selected cohort.