Search

Inhalation therapy can effectively treat chronic obstructive pulmonary disease (COPD), but the physical factors determining the appropriate aerosol delivery into the targeted airways remain unclear. The problem is nontrivial because pulmonary structures differ among individual patients with COPD and depend on the severity of the disease. In an in silico evaluation, the present study investigates the differences in particle transport and deposition in the airways of three patients with different degrees of COPD. Specific pulmonary airway models were reconstructed based on the computed tomography data of three patients with a different degree of COPD severity. The transport and deposition of inhaled particles in the airways were evaluated in a computational fluid dynamics simulation and a Lagrangian multiphase model. The sizes of the inhaled particles (1.0, 2.5, 5.5, 8.5, and 10.0 μm) were representative of drug particles delivered from inhalation devices, including dry powder inhalers (DPIs). The deposition behaviors of the inhaled particles strongly depended on the individual geometrical structure of the airways. The largest inhaled particles (10.0 μm) were most strongly affected by inertia and were deposited mostly in the oropharynx; consequently, they were rare in the bronchi. In contrast, the smallest inhaled particles (1.0 μm) were effectively delivered distally with the airflow. The spatial distributions and amounts of deposited particles in the airways obviously differed among the three COPD patients. Small particles are preferred as they can penetrate the inner lung regions. The results can assist the design and development of powder formulations and DPIs for patients with various severities of COPD.

PDF file - 130K, EGFR is expressed in SBC-3/ETP cells but not in SBC-3/SN-38 cells. Immunoblotting analysis revealed that expression of EGFR, another target molecule of lapatinib, is upregulated in SBC-3/ETP cells but not in SBC-3/SN-38 cells.

PDF file - 62K, Reversal effect of lapatinib on multidrug resistance. Cells (5�103 cells/well) were plated onto 96-well tissue culture-treated plates and treated with serially diluted cytotoxic drugs with or without lapatinib in serum containing medium for 72 h. The relative number of viable cells was quantified using CCK-8. IC50 concentration for each drug was calculated and presented as the mean � SD. Each experiment was done in triplicate and repeated at least thrice.

PDF file - 54K

PDF file - 66K, HER2 is successfully knocked down using siRNA technique. Successful knock down of HER2 using siRNA technique in SBC-3/ETP cells and SBC-3/SN-38 cells was confirmed by FACS and immunoblotting. HER2-targeting siRNA markedly suppressed HER2 expression without affecting ABCB1 and ABCG2 expression.

PDF file - 73K

Purpose: Positron emission tomography (PET) with [18F]fluorodeoxyglucose (FDG) is increasingly used in early assessment of tumor response after chemotherapy. We investigated whether a change in [18F]FDG uptake at 2 days of gefitinib treatment predicts outcome in patients with lung adenocarcinoma.Experimental Design: Twenty patients were enrolled. [18F]FDG-PET/computed tomographic (CT) scan was carried out before and 2 days after gefitinib treatment. Maximum standardized uptake values (SUV) were measured, and post-gefitinib percentage changes in SUV were calculated. Early metabolic response (SUV decline < −25%) was compared with morphologic response evaluated by CT scan and with progression-free survival (PFS).Results: At 2 days of gefitinib treatment, 10 patients (50%) showed metabolic response, 8 had metabolic stable disease, and 2 had progressive metabolic disease. Percentage changes of SUV at 2 days were correlated with those of tumor size in CT at 1 month (R2 = 0.496; P = 0.0008). EGFR gene was assessable in 15 patients, and of 12 patients with EGFR mutations, 8 showed metabolic response at 2 days and 6 showed morphologic response at 1 month. None of 3 patients with wild-type EGFR showed metabolic or morphologic response. Metabolic response at 2 days was not statistically associated with PFS (P = 0.095), but when a cutoff value of −20% in SUV decline was used, metabolic responders had longer PFS (P < 0.0001).Conclusion: Early assessment of [18F]FDG tumor uptake with PET at 2 days of gefitinib treatment could be useful to predict clinical outcome earlier than conventional CT evaluation in patients with lung adenocarcinoma. Clin Cancer Res; 18(1); 220–8. ©2011 AACR.

PDF file - 64K

PDF file - 117K, Genes up-regulated (>2.0) in Stat3delta/delta compared with Stat3flox/flox

PDF file - 63K, Up-regulated PPI network

PDF file - 126K, Genes down-regulated (

PDF file - 76K, Enriched KEGG pathway association (p

PDF file - 72K, The expression and activation of Stat3 was intact in both myeloid and lymphocyte lineages in Stat3delta/delta mice

PDF file - 81K

PDF file - 41K, Stat3delta/delta did not acquire large tumors compared to Stat3flox/flox mice

A 50-year-old woman who had previously undergone right hemicolectomy and chemotherapy for colorectal cancer was hospitalized with respiratory failure. Chest computed tomography showed reticulonodular opacities and enlarged lymph nodes. A transbronchial biopsy revealed adenocarcinoma with epidermal growth factor receptor (EGFR) mutations T790M and L861Q. Treatment with the EGFR-tyrosine kinase inhibitor (TKI) osimertinib was started, and she achieved a partial response. We diagnosed her with metastatic lung tumors from colorectal cancer based on additional immunohistochemical staining and the EGFR mutation status (L861Q) of the specimens. Although cases with EGFR mutations have been rarely reported, an EGFR-TKI can be an effective treatment option for colorectal cancer.

The patient in this report was a 57‐year‐old man with metastatic non‐small cell lung cancer (NSCLC). After no response to two lines of systemic chemotherapy, he was treated with nivolumab as third‐line therapy, which resulted in a partial response. After 17 months of nivolumab treatment, he developed bone metastasis in his left femur which was treated with radiation therapy. Nivolumab was restarted after radiation therapy. Four months after radiation therapy, he developed another metastatic lesion in the small intestine which was surgically resected. Because there were no recurrent NSCLC lesions after surgical resection, nivolumab was restarted again. At 18 months after surgery, there were no recurrent NSCLC lesions. Immunohistochemical analysis of peritumoral T lymphocytes showed higher expression of T cell immunoglobulin and mucin domain‐containing protein 3 (TIM‐3) and lymphocyte activation gene 3 (LAG‐3) in recurrent lesions of bone and small intestine than in primary lesions. Upregulation of TIM‐3 and LAG‐3 could be associated with mechanisms of adaptive resistance to nivolumab in this case. Here, we report a successful case of continued nivolumab therapy with remission after local treatments consisting of radiation therapy and surgical resection for oligometastases. Continuation of immune checkpoint inhibitor (ICI) treatment may be worth considering if oligometastases can be controlled. Key points Significant findings of the study We report a successful case of continued nivolumab treatment with remission after local treatment (radiation therapy and surgical resection) for oligometastases. What this study adds Upregulation of T cell immunoglobulin and mucin domain‐containing protein 3 and lymphocyte‐activation gene 3 could be associated with mechanisms of adaptive resistance to nivolumab., We report the first successful case of continued nivolumab treatment with remission after local treatment (radiation therapy and surgical resection) for oligometastases. The upregulation of T‐cell immunoglobulin and mucin domain‐containing protein 3 (TIM‐3) and lymphocyte‐activation gene 3 (LAG‐3) could be associated with mechanisms of adaptive resistance to nivolumab in this case.

The patient was a 73-year-old woman with lung adenocarcinoma and systemic lupus erythematosus (SLE) who was treated with pembrolizumab. After six cycles of pembrolizumab, she developed symptoms suggestive of neuropsychiatric SLE, such as resting tremor, confusional state, depression, mood disorder, and anxiety disorder. In addition, her cerebrospinal fluid level of interleukin-6 was elevated. Her symptoms resolved one month after the discontinuation of pembrolizumab. This is the first report of neuropsychiatric symptoms in a patient with lung cancer and SLE on immune checkpoint blockade therapy.

Compared with oral and parenteral formulations, inhaled formulations are attractive because of their great benefit and potential to enhance therapeutic effects of medications. Among the available inhaled formulations, powders used with dry-powder inhalers (DPIs) have become a preferred option because of their many advantages over other inhaled formulations. Additionally, a powder technological approach is required and available for sophisticated design of DPI formulations. To provide appropriate treatment using a DPI formulation, inhaled particles containing drugs should be delivered to the appropriate sites in the lungs of individual patients. It is indispensable that the design of DPI formulations specify particle properties suitable for a specific disease and the appropriate positions in the lungs to which the inhaled particles must be delivered. This article focuses on the current particle technological approach toward designing DPI formulations and numerical simulation analysis of behavior and deposition of inhaled particles in the lungs. As a future perspective from the viewpoint of pharmaceutical particle technology, a combination of experimental and simulation approaches is expected to improve the ability to obtain maximum lung delivery as well as target the site of deposition in the lungs of individual patients.

A 57-year-old man with lung adenocarcinoma was treated with chemotherapy and immune checkpoint blockade. After two cycles of carboplatin, pemetrexed, and pembrolizumab, he developed a persistent fever. Chest computed tomography (CT) suggested inflammation of the aortic wall. We treated the patient with corticosteroids. After four cycles of carboplatin, pemetrexed, and pembrolizumab, chest CT showed an aneurysm in the ascending aorta. We diagnosed him with inflammatory thoracic aortic aneurysm induced by pembrolizumab and performed surgical replacement of the ascending aorta. Although this might be a very rare case, we should be aware of aortitis as a potential adverse effect of pembrolizumab.

Eosinophilia in asthma or rhinitis is usually considered to be reactive to the allergic diseases. We report a 33-year-old man with asthma and rhinitis, and progressive hypereosinophilia. Fluorescence in situ hybridization analysis detected interstitial chromosomal deletion at 4q12 in cells of the bone marrow. The patient was diagnosed as myeloproliferative neoplasm with a FIP1L1-PDGFRA fusion gene, and successfully treated with the tyrosine kinase inhibitor, imatinib. Clonal expansion of eosinophils due to the FIP1L1-PDGFRA fusion gene could underlie refractory mechanisms in patients with bronchial asthma or allergic rhinitis.

Chronic obstructive pulmonary disease (COPD) is an intractable pulmonary disease that causes widespread and irreversible alveolar collapse. Although COPD occurs worldwide, only symptomatic therapy is currently available. Our objective is the development of therapeutic agents to eradicate COPD. Therefore, we focused on 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) carbamoyl] benzoic acid (Am80), which is a derivative of all-trans retinoic acid. We evaluated the effects of Am80 on alveolar repair in a novel COPD model of adiponectin-deficient mice. This mouse model has more symptoms similar to human COPD than the classic elastase-induced emphysema mouse model. Lung volume, computed tomography (CT) values, low-attenuation area ratios, and bone and fat mass were measured by CT. However, the administration of Am80 did not affect these results. To examine the degree of destruction in the alveoli, the mean linear intercept of the alveolar walls was calculated, and assessment of this value confirmed that there was a significant difference between the control (46.3 ± 2.3 μm) and 0.5 mg/kg Am80-treated group (34.4 ± 1.7 µm). All mice survived the treatment, which lasted for more than 6 months, and we did not observe any abnormalities in autopsies performed at 80 weeks of age. These results suggested that Am80 was effective as a novel therapeutic compound for the treatment of COPD.

SummaryRegulatory B cells (Breg) have immune suppressive functions in various autoimmune/inflammation models and diseases and are found to be enriched in diverse B cell subsets. The lack of a unique marker or set of markers efficiently identifying Breg cells impedes detailed investigation into their origin, development, and immunological roles. Here, we perform transcriptome analysis of IL-10-expressing B cells to identify key regulators for Breg biogenesis and function and identify CD9, a tetraspanin-family transmembrane protein, as a key surface marker for most mouse IL-10+ B cells and their progenitors. CD9 plays a role in the suppressive function of IL-10+ B cells in ex vivo T cell proliferation assays through a mechanism that is dependent upon B/T cell interactions. CD9+ B cells also demonstrate inhibition of Th1-mediated contact hypersensitivity in an in vivo model system. Taken together, our findings implicate CD9 in the immunosuppressive activity of regulatory B cells.

SummaryBackground and objectives Assessment of the effects of long-term management on patient quality of life (QOL) would be extremely useful for determining asthma treatment strategies. However, no studies have evaluated QOL over an extended period of time. This study evaluated the changes in QOL, drug management and disease severity in the same asthma patients at an interval of approximately 9 years. Methods We re-surveyed asthma patients enrolled in a survey conducted in 2004 to evaluate the effects of approximately a decade of treatment on disease severity and QOL assessed by the Japanese Asthma Health Questionnaire (AHQ-JAPAN). Results A total of 2179 patients were enrolled in the study from 93 centres, and 1332 patients were included in the per-protocol analysis. Usage rates of inhaled corticosteroids (ICS) for treatment of stable asthma were over 90% at both time points. The AHQ-JAPAN total score improved significantly from 22.2±19.7 in 2004 to 19.7±19.9 in 2013 (P