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2.  Blood-patch pleurodesis for pneumothorax in lung fibrosis due to progressive systemic sclerosis: A case report 
Pneumothorax in patients with progressive systemic sclerosis (PSS) often presents as a difficult-to-treat disease. Autologous blood-patch pleurodesis has previously been used for the treatment of pneumothorax. Blood outside its own environment is an irritant; therefore, chest physicians must watch closely for an allergic reaction. The injection is simple, painless, causes no side effects, is an inexpensive treatment for pneumothorax and is available not only in patients with persistent air leak but also in those with residual air space. A case is reported here of blood-patch pleurodesis for pneumothorax in lung fibrosis due to PSS. As an alternative therapy for difficult-to-treat pneumothorax in patients with PSS with persistent air leak and residual air space, autologous blood-patch pleurodesis would be one of the treatment options.
PMCID: PMC4218704  PMID: 25371756
blood-patch pleurodesis; pneumothorax; lung fibrosis; progressive systemic sclerosis
3.  Specific organ metastases and survival in metastatic non-small-cell lung cancer 
Molecular and Clinical Oncology  2014;3(1):217-221.
The present retrospective study was performed to evaluate the clinicopathological characteristics associated with distant metastasis from non-small-cell lung cancer (NSCLC). The records of NSCLC patients with metastasis at the time of diagnosis between 1999 and 2012 were reviewed. Of the consecutive 1,542 NSCLC patients diagnosed during the study period, 729 (47.3%) patients presented with distant metastasis. Among those 729 metastatic NSCLC patients, 250 (34.3%), 234 (32.1%), 207 (28.4%), 122 (16.7%), 98 (13.4%) and 69 (9.5%) had bone, lung, brain, adrenal gland, liver and extrathoracic lymph node metastasis, respectively. In a multivariate analysis using the Cox proportional hazards model, liver and adrenal gland metastases were unfavorable prognostic factors. However, brain and bone metastases were not statistically significant prognostic factors. Using a logistic regression analysis, metastasis to the adrenal glands and the presence of pleural and/or pericardial fluid effusion were correlated with a poor performance status. Therefore, when planning the treatment of NSCLC patients, particularly those with liver and adrenal gland metastases, we should take into consideration information regarding these unfavorable organ metastases.
PMCID: PMC4251107  PMID: 25469298
non-small-cell lung cancer; metastasis; survival
4.  Superficial-type endobronchial metastases from colon cancer: A case report 
Oncology Letters  2014;8(5):2310-2312.
Certain internal malignancies, including colon cancer, can develop endobronchial metastasis. The present study reports a case of colon cancer with superficial-type endobronchial metastases in a 76-year-old male. Chest computed tomography revealed small masses and infiltrates in each lung, with bilateral hilar lymph node swelling. Superficial endobronchial tumors in each of the bronchi were unexpectedly found by bronchoscopic examination. A biopsy specimen obtained from the endobronchial tumor was diagnosed as colon cancer. Superficial-type endobronchial metastasis from colon cancer is extremely rare, however, such metastasis should be considered for patients who have a history of colon cancer. There should be no hesitation in performing a bronchoscopic biopsy as an additional examination.
PMCID: PMC4186526  PMID: 25289110
colon cancer; pulmonary metastasis; endobronchial metastasis
5.  Ossification and increased bone mineral density with zoledronic acid in a patient with lung adenocarcinoma: A case report 
Cases of ossification and increased bone mineral density (BMD) at sites of bone metastasis following zoledronic acid (ZA) treatment have not been reported. The current study presents the case of a 65-year-old patient with lung adenocarcinoma and bone metastases in the lumbar vertebrae and femurs. Ossification and an increase in BMD at the metastatic sites was achieved following treatment with ZA and irradiation of the bone metastatic sites. The patient was able to maintain a normal lifestyle for over two years, despite the bone metastases. Therefore, as treatment with ZA was demonstrated to improve patient quality of life, physicians should consider this treatment strategy, particularly for the treatment of metastasis in weight-bearing bones.
PMCID: PMC4151632  PMID: 25187837
bone metastasis; zoledronic acid; lung cancer; bone mineral density; ossification
6.  High-dose concurrent chemo–proton therapy for Stage III NSCLC: preliminary results of a Phase II study 
Journal of Radiation Research  2014;55(5):959-965.
The aim of this report is to present the preliminary results of a Phase II study of high-dose (74 Gy RBE) proton beam therapy (PBT) with concurrent chemotherapy for unresectable locally advanced non-small-cell lung cancer (NSCLC). Patients were treated with PBT and chemotherapy with monthly cisplatin (on Day 1) and vinorelbine (on Days 1 and 8). The treatment doses were 74 Gy RBE for the primary site and 66 Gy RBE for the lymph nodes without elective lymph nodes. Adapted planning was made during the treatment. A total of 15 patients with Stage III NSCLC (IIIA: 4, IIIB: 11) were evaluated in this study. The median follow-up period was 21.7 months. None of the patients experienced Grade 4 or 5 non-hematologic toxicities. Acute pneumonitis was observed in three patients (Grade 1 in one, and Grade 3 in two), but Grade 3 pneumonitis was considered to be non-proton-related. Grade 3 acute esophagitis and dermatitis were observed in one and two patients, respectively. Severe ( ≥ Grade 3) leukocytopenia, neutropenia and thrombocytopenia were observed in 10 patients, seven patients and one patient, respectively. Late radiation Grades 2 and 3 pneumonitis was observed in one patient each. Six patients (40%) experienced local recurrence at the primary site and were treated with 74 Gy RBE. Disease progression was observed in 11 patients. The mean survival time was 26.7 months. We concluded that high-dose PBT with concurrent chemotherapy is safe to use in the treatment of unresectable Stage III NSCLC.
PMCID: PMC4202292  PMID: 24864278
proton therapy; radiotherapy; lung cancer; Phase II study; chemo–proton therapy
7.  Efficacy of tyrosine kinase inhibitors in non-small-cell lung cancer patients undergoing dose reduction and those with a low body surface area 
Molecular and Clinical Oncology  2014;2(4):604-608.
The objective of this study was to evaluate the efficacy of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) in patients undergoing dose reduction and in those with a low body surface area (BSA). The association between dose reduction, low BSA and efficacy, including response rate (RR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS), were evaluated in patients prescribed TKIs between September, 2002 and May, 2013. A total of 282 patients received EGFR-TKIs during the study period, 53 (18.8%) of whom underwent a dose reduction (21.4 and 31.6% of the patients with a BSA of <1.5 and <1.25 m2, respectively). Eleven (20.8%) of these 53 patients had a dose reduction due to adverse events (AEs) >grade 3. In either gefitinib or erlotinib treatment, the RR, DCR, PFS and OS in EGFR-mutated patients with a BSA of <1.5 m2 were not different from those in patients with a BSA of >1.5 m2. In addition, there were no differences in these parameters between patients with and those without a dose reduction of TKIs. The dose of TKIs in patients with AEs and in those with low BSA should be determined with caution. To confirm the equal efficacy of TKIs in patients undergoing a dose reduction, prospective observational studies with less patient heterogeneity are required.
PMCID: PMC4051560  PMID: 24940504
body surface area; dose reduction; epidermal growth factor receptor-tyrosine kinase inhibitor; gefitinib; erlotinib; non-small-cell lung cancer
8.  Potential Involvement of IL-17F in Asthma 
Journal of Immunology Research  2014;2014:602846.
The expression of IL-17F is seen in the airway of asthmatics and its level is correlated with disease severity. Several studies have demonstrated that IL-17F plays a pivotal role in allergic airway inflammation and induces several asthma-related molecules such as CCL20. IL-17F-induced CCL20 may attract Th17 cells into the airway resulting in the recruitment of additional Th17 cells to enhance allergic airway inflammation. We have recently identified, for the first time, that bronchial epithelial cells are its novel cell source in response to IL-33 via ST2-ERK1/2-MSK1 signaling pathway. The receptor for IL-17F is the heterodimeric complex of IL-17RA and IL-17RC, and IL-17F activates many signaling pathways. In a case-control study of 867 unrelated Japanese subjects, a His161 to Arg161 (H161R) substitution in the third exon of the IL-17F gene was associated with asthma. In atopic patients with asthma, prebronchodilator baseline FEV1/FVC values showed a significant association with the H161R variant. Moreover, this variant is a natural antagonist for the wild-type IL-17F. Moreover, IL-17F is involved in airway remodeling and steroid resistance. Hence, IL-17F may play an orchestrating role in the pathogenesis of asthma and may provide a valuable therapeutic target for development of novel strategies.
PMCID: PMC4009148  PMID: 24829928
9.  Long-term safety of budesonide/formoterol for the treatment of elderly patients with bronchial asthma 
The long-term safety of budesonide/formoterol (BUD/FM) inhalation has not been fully evaluated, particularly in elderly patients with bronchial asthma. To evaluate the 12-month safety of BUD/FM inhalation for elderly asthmatic patients, the changes in serum potassium levels and pulse rate were examined. A retrospective chart review was conducted of consecutive patients who were treated with BUD/FM inhalation (two inhalations of 160/4.5 mg, twice daily; Symbicort Turbuhaler, AstraZeneca) at a hospital between February 2010 and January 2012. A total of 350 patients were treated with BUD/FM inhalation during the study period and were followed up over 12 months. The mean age of the patients was 60 years, and 19.4% and 21.4% of the patients were aged 65–74 years and ≥75 years, respectively. One hundred and fourteen (32.6%) of the 350 patients continued the inhalation therapy for >12 months. Compared with the pretreatment data, reductions in serum potassium levels at 1, 6 and 12 months were not observed, even in the patients aged 65–74 and ≥75 years. There was also no increase in the pulse rate at 1, 6 and 12 months, even in the patients aged 65–74 and ≥75 years. The usual dosage of BUD/FM showed no adverse effects on the serum potassium levels and pulse rate in the adults, including the elderly with persistent asthma.
PMCID: PMC3965132  PMID: 24669267
bronchial asthma; budesonide/formoterol; inhalation; elderly; pulse rate; serum potassium
10.  Brain metastasis as an isolated late recurrence in small-cell lung cancer 
Molecular and Clinical Oncology  2013;2(2):305-307.
The brain is one of the most common sites of metastasis of small-cell lung cancer (SCLC). In this study, we reported 6 cases with isolated brain relapse of SCLC ≥1 year after the completion of the initial treatment for SCLC. Of the 6 patients, 2 had a solitary brain metastasis and 4 had ≥2 brain metastatic sites. The metastases were identified during a regular check-up computed tomography (CT) scan and were successfully treated. The median interval from the initial diagnosis to the development of brain metastasis was 16 months (range, 13–30 months). All patients received whole-brain irradiation and achieved a complete response. Only one patient developed disturbances of the higher cerebral function. The median interval from whole-brain irradiation to death or last follow-up was 33 months (range, 8–90 months). To the best of our knowledge, these are the first reported cases with isolated brain relapse of SCLC. Although a rare finding, clinicians should be alert on the possibility of such recurrence, particularly in patients who refused prophylactic cranial irradiation.
PMCID: PMC3919122  PMID: 24649352
isolated brain metastasis; relapse; small-cell lung cancer
11.  Th17-Associated Cytokines as a Therapeutic Target for Steroid-Insensitive Asthma 
Steroid-insensitive asthma is an infrequent but problematic airway disease that presents with persistent symptoms, airflow limitation, or recurrent exacerbations even when treated with steroid-based therapies. Because of unsatisfactory results obtained from currently available therapies for steroid-insensitive asthma, a better understanding of its pathogenesis and the development of new targeted molecular therapies are warranted. Recent studies indicated that levels of interleukin (IL)-17 are increased and both eosinophils and neutrophils infiltrate the airways of severe asthmatics. IL-17 is a proinflammatory cytokine mainly secreted from helper T (Th) 17 cells and is important for the induction of neutrophil recruitment and migration at sites of inflammation. This review focuses on the pathogenetic role of Th17 cells and their associated cytokines in steroid-insensitive asthma and discusses the prospects of novel therapeutic options targeting the Th17 signaling pathway.
PMCID: PMC3886588  PMID: 24454477
12.  Retroperitoneal abscess shortly after chemotherapy for lung cancer: A case report 
Molecular and Clinical Oncology  2013;2(2):302-304.
To the best of our knowledge, the formation of a retroperitoneal abscess due to acute appendicitis shortly after administration of chemotherapy for lung cancer has not been previously reported. This is the case report of a 59-year-old male who was admitted to the Mito Medical Center (Mito, Japan) and diagnosed with lung adenocarcinoma with pleuritis carcinomatosis. Although no distant metastasis was identified, combination chemotherapy with cisplatin and pemetrexed was administered. Nine days after initiating chemotherapy, the patient developed right lower quadrant abdominal pain and high fever. Computed tomography (CT) of the abdomen and pelvis revealed the collection of gas and fluid in the retroperitoneum adjacent to the cecum. The abscess was locally drained; however, the infection continued to spread, with subsequent development of a scrotal abscess. Consequently, appendectomy was performed. The patient recovered well and the lung adenocarcinoma was treated with additional courses of chemotherapy following the remission of the local inflammation. Retroperitoneal abscess due to acute appendicitis is an unusual finding; however, this rare complication should be considered during or shortly after chemotherapy in patients with lung cancer.
PMCID: PMC3917762  PMID: 24649351
retroperitoneal abscess; chemotherapy; lung cancer
13.  Genome-Wide Association Study for Levels of Total Serum IgE Identifies HLA-C in a Japanese Population 
PLoS ONE  2013;8(12):e80941.
Most of the previously reported loci for total immunoglobulin E (IgE) levels are related to Th2 cell-dependent pathways. We undertook a genome-wide association study (GWAS) to identify genetic loci responsible for IgE regulation. A total of 479,940 single nucleotide polymorphisms (SNPs) were tested for association with total serum IgE levels in 1180 Japanese adults. Fine-mapping with SNP imputation demonstrated 6 candidate regions: the PYHIN1/IFI16, MHC classes I and II, LEMD2, GRAMD1B, and chr13∶60576338 regions. Replication of these candidate loci in each region was assessed in 2 independent Japanese cohorts (n = 1110 and 1364, respectively). SNP rs3130941 in the HLA-C region was consistently associated with total IgE levels in 3 independent populations, and the meta-analysis yielded genome-wide significance (P = 1.07×10−10). Using our GWAS results, we also assessed the reproducibility of previously reported gene associations with total IgE levels. Nine of 32 candidate genes identified by a literature search were associated with total IgE levels after correction for multiple testing. Our findings demonstrate that SNPs in the HLA-C region are strongly associated with total serum IgE levels in the Japanese population and that some of the previously reported genetic associations are replicated across ethnic groups.
PMCID: PMC3851760  PMID: 24324648
14.  Expression and Function of Allergin-1 on Human Primary Mast Cells 
PLoS ONE  2013;8(10):e76160.
Mast cells (MC) play an important role in allergic and non-allergic immune responses. Activation of human MC is modulated by several cell surface inhibitory receptors, including recently identified Allergin-1 expressed on both human and mouse MC. Although Allergin-1 suppresses IgE-mediated, mast cell–dependent anaphylaxis in mice, the expression profile and function of Allergin-1 on human primary MC remains undetermined. Here, we established a seven-color flow cytometry method for assessing expression and function of a very small number of human primary MC. We show that Allergin-1S1, a splicing isoform of Allergin-1, is predominantly expressed on human primary MC in both bronchoalveolar lavage (BAL) fluid and nasal scratching specimens. Moreover, Allergin-1S1 inhibits IgE-mediated activation from human primary MC in BAL fluid. These results indicate that Allergin-1 on human primary MC exhibits similar characteristics as mouse Allergin-1 in the expression profile and function.
PMCID: PMC3792105  PMID: 24116093
15.  Volume doubling time of lung cancers detected in a chest radiograph mass screening program: Comparison with CT screening 
Oncology Letters  2012;4(3):513-516.
The aim of this study was to evaluate the volume doubling time (VDT) of lung cancer detected in our annual chest radiograph screening program and to compare it with those previously reported for computed tomography (CT) screening. In total, 209 patients who had a measurable tumor shadow and a history of participating in our chest radiograph mass screening program between 2006 and 2009 were included in this study. Indirect roentgenograms for patients with lung cancer were converted into digital images, and the section showing the tumor was enlarged on the monitor to a size of 0.01 mm. The mean VDT for all the patients was 158 days. Only 3.8% of the patients had a VDT of more than 400 days. In 140 patients with adenocarcinoma, the mean VDT was 177 days, and 5.0% of these patients had a VDT of more than 400 days. In the 44 patients with squamous cell carcinoma, the mean VDT was 133 days, and only 2.3% of these patients had a VDT of more than 400 days. These results were different from those previously reported for CT screening. In several reports on CT screening, more than 20% of the lung cancers had VDTs of more than 400 days. Since it is common knowledge that there are ‘indolent’ lung cancers with a VDT of more than 400 days, screening by annual chest radiography with rare overdiagnosis may need to be reconsidered.
PMCID: PMC3439160  PMID: 22970048
volume doubling time; lung cancer; chest radiograph; mass screening program
16.  Isolated solitary brain metastasis as a relapse of small cell lung cancer 
Oncology Letters  2013;6(4):1108-1110.
The brain is one of the most common sites for the metastasis of small cell lung cancer (SCLC). The present study describes two cases of an isolated solitary brain metastasis as a relapse of SCLC, which occurred more than one year after the completion of the initial successful treatment for SCLC. The tumors were identified during a regular check-up computed tomography (CT) scan and were successfully treated. To the best of our knowledge, this is the first study to report the cases of two patients with an isolated solitary brain metastasis as a relapse of SCLC. Although extremely rare, the possibility of such recurrences should be considered, particularly in patients who have refused prophylactic cranial irradiation.
PMCID: PMC3796411  PMID: 24137472
isolated solitary brain metastasis; relapse; small cell lung cancer
17.  Erlotinib for elderly patients with non-small-cell lung cancer: Subset analysis from a population-based observational study by the Ibaraki Thoracic Integrative (POSITIVE) Research Group 
Molecular and Clinical Oncology  2013;1(5):828-832.
The incidence and mortality of lung cancer have increased worldwide over the last decades, with an observed increased incidence particularly among elderly populations. It has not yet been determined whether erlotinib therapy exhibits the same efficacy and safety in elderly and younger patients with non-small-cell lung cancer (NSCLC). The aim of this retrospective subgroup analysis of data from a population-based observational study was to assess the efficacy and safety of erlotinib in an elderly (≥75 years, n=74) and a younger group of patients (<75 years, n=233) who received treatment for NSCLC. The time to treatment failure was similar in the elderly [median, 62 days; 95% confidence interval (95% CI): 44–80 days] compared with the younger group (median, 46 days; 95% CI: 35–53 days) (P=0.2475). The overall survival did not differ between the elderly and younger groups (median, 170 days; 95% CI: 142–239 days vs. median, 146 days; 95% CI: 114–185 days, respectively) (P=0.7642). The adverse events did not differ in incidence between the groups and were manageable, regardless of age. Among the NSCLC patients receiving erlotinib treatment, the outcomes of the elderly (≥75 years) and younger (<75 years) groups of patients were similar in our population-based observational study.
PMCID: PMC3915644  PMID: 24649255
erlotinib; elderly; non-small-cell lung cancer; observational study; population-based
18.  The search for common pathways underlying asthma and COPD 
Recently, several genes and genetic loci associated with both asthma and chronic obstructive pulmonary disease (COPD) have been described as common susceptibility factors for the two diseases. In complex diseases such as asthma and COPD, a large number of molecular and cellular components may interact through complex networks involving gene–gene and gene–environment interactions. We sought to understand the functional and regulatory pathways that play central roles in the pathobiology of asthma and COPD and to understand the overlap between these pathways. We searched the PubMed database up to September 2012 to identify genes found to be associated with asthma, COPD, tuberculosis, or essential hypertension in at least two independent reports of candidate-gene associations or in genome-wide studies. To learn how the identified genes interact with each other and other cellular proteins, we conducted pathway-based analysis using Ingenuity Pathway Analysis software. We identified 108 genes and 58 genes that were significantly associated with asthma and COPD in at least two independent studies, respectively. These susceptibility genes were grouped into networks based on functional annotation: 12 (for asthma) and eleven (for COPD) networks were identified. Analysis of the networks for overlap between the two diseases revealed that the networks form a single complex network with 229 overlapping molecules. These overlapping molecules are significantly involved in canonical pathways including the “aryl hydrocarbon receptor signaling,” “role of cytokines in mediating communication between immune cells,” “glucocorticoid receptor signaling,” and “IL-12 signaling and production in macrophages” pathways. The Jaccard similarity index for the comparison between asthma and COPD was 0.81 for the network-level comparison, and the odds ratio was 3.62 (P < 0.0001) for the asthma/COPD pair in comparison with the tuberculosis/ essential hypertension pair. In conclusion, although the identification of asthma and COPD networks is still far from complete, these networks may be used as frameworks for integrating other genome-scale information including expression profiling and phenotypic analysis. Network overlap between asthma and COPD may indicate significant overlap between the pathobiology of these two diseases, which are thought to be genetically related.
PMCID: PMC3558318  PMID: 23378757
COPD; asthma; network; common pathways; aryl hydrocarbon receptor signaling
19.  Use of tiotropium in patients with COPD aged 80 years and older 
The purpose of this study was to examine clinical features and treatment modality approaches in patients with chronic obstructive pulmonary disease (COPD), particularly in those aged 80 years and older. Using databases available at Mito Kyodo General Hospital (Japan), the medical records of COPD patients between April 2009 and December 2011 were retrospectively reviewed. The patient population was divided into three age groups; less than 70 years (the <70 age group), between 70–79 years (the 70–79 age group) and 80 years or older (the ≥80 age group). Demographic data, as well as the efficacy and safety of tiotropium, were compared between the three groups. Patients in the ≥80 age group comprised 35.6% of the study population with COPD (n=174). The ≥80 and 70–79 age groups demonstrated a higher proportion of comorbid disease compared with the <70 age group. A subjective improvement of dyspnea on effort as well as no additional adverse effects were observed in the ≥80 age group, similar to the other two age groups. However, higher incidence of acute exacerbation of COPD in patients aged ≥80 years old was found, particularly in those with comorbid disease. The efficacy and safety of tiotropium in COPD patients in the ≥80 age group were almost identical to patients <80 years old, however, physicians must be cautious with acute exacerbation of COPD in the extremely elderly population with comorbid disease.
PMCID: PMC3627447  PMID: 23596463
chronic obstructive pulmonary disease; tiotropium; elderly; octogenarian; comorbid disease
20.  Observational study on the efficacy and safety of erlotinib in patients with non-small cell lung cancer 
Oncology Letters  2012;5(2):435-439.
To evaluate the efficacy and safety of erlotinib for non-small cell lung cancer (NSCLC), we performed a population-based observational study. The study involved 307 patients treated with erlotinib at 14 sites (17 departments) in Ibaraki (Japan) between December 2007 and December 2010. The tumor response and disease control rates were 11.1 and 46.3% in all patients, respectively. The median time to treatment failure and survival time were 1.6 months (95% confidence interval, 41–57 days) and 5.3 months (134–181 days) in all patients, respectively. Survival was significantly prolonged in EGFR mutation-positive patients compared with negative patients. EGFR mutation-negative patients who presented with a skin rash had significantly prolonged survival compared with those without a skin rash. The most common adverse event was skin disorder, followed by diarrhea. Although 45.6% of the patients in this study received erlotinib as a fourth-line or subsequent treatment, the results from this study were similar to those of clinical studies. We deduce that erlotinib is effective against NSCLC and is tolerated in clinical practice.
PMCID: PMC3572994  PMID: 23420613
erlotinib; non-small cell lung cancer; observational study; population-based
21.  Specific organ metastases and survival in small cell lung cancer 
Oncology Letters  2012;4(4):617-620.
The aim of our retrospective study was to evaluate the clinicopathological features associated with distant metastasis from small cell lung cancer (SCLC). We reviewed patients diagnosed with SCLC metastasis at the time of presentation between 1999 and 2010. Among the consecutive 251 SCLC patients diagnosed, 152 (60.6%) patients had distant metastasis, of which 20.3, 18.3, 15.5, 10.0 and 6.0% of patients had liver, bone, brain, lung and adrenal gland metastasis, respectively. In a multivariate analysis using Cox’s proportional hazards model, we identified that liver, bone and brain metastasis as well as the presence of pleural and/or pericardial fluids were unfavorable prognostic factors. However, lung, adrenal gland and extrathoracic lymph node metastasis were not statistically significant prognostic factors. With regard to the treatment of SCLC patients, particularly those with liver, bone and brain metastasis or pleural and/or pericardial fluids, we should take the metastasizing organs into consideration.
PMCID: PMC3506697  PMID: 23205072
small cell lung cancer; metastasis; survival
22.  Thymic Stromal Lymphopoietin Gene Promoter Polymorphisms Are Associated with Susceptibility to Bronchial Asthma 
Thymic stromal lymphopoietin (TSLP) triggers dendritic cell–mediated T helper (Th) 2 inflammatory responses. A single-nucleotide polymorphism (SNP), rs3806933, in the promoter region of the TSLP gene creates a binding site for the transcription factor activating protein (AP)–1. The variant enhances AP-1 binding to the regulatory element, and increases the promoter–reporter activity of TSLP in response to polyinosinic-polycytidylic acid (poly[I:C]) stimulation in normal human bronchial epithelium (NHBE). We investigated whether polymorphisms including the SNP rs3806933 could affect the susceptibility to and clinical phenotypes of bronchial asthma. We selected three representative (i.e., Tag) SNPs and conducted association studies of the TSLP gene, using two independent populations (639 patients with childhood atopic asthma and 838 control subjects, and 641 patients with adult asthma and 376 control subjects, respectively). We further examined the effects of corticosteroids and a long-acting β2-agonist (salmeterol) on the expression levels of the TSLP gene in response to poly(I:C) in NHBE. We found that the promoter polymorphisms rs3806933 and rs2289276 were significantly associated with disease susceptibility in both childhood atopic and adult asthma. The functional SNP rs3806933 was associated with asthma (meta-analysis, P = 0.000056; odds ratio, 1.29; 95% confidence interval, 1.14–1.47). A genotype of rs2289278 was correlated with pulmonary function. Moreover, the induction of TSLP mRNA and protein expression induced by poly(I:C) in NHBE was synergistically impaired by a corticosteroid and salmeterol. TSLP variants are significantly associated with bronchial asthma and pulmonary function. Thus, TSLP may serve as a therapeutic target molecule for combination therapy.
PMCID: PMC3159073  PMID: 20656951
asthma; TSLP; bronchial epithelial cells; combination therapy; genetic polymorphisms
23.  Age-dependent decline in renal function in patients with lung cancer 
Oncology Letters  2012;4(1):38-42.
The aim of this study was to clarify the effect of aging on renal function. Serum creatinine (SCr), blood urea nitrogen (BUN) and 24-h creatinine clearance (measured-CrCl) were examined in lung cancer patients and the measured-CrCl were compared with CrCl estimates by employing two commonly used equations. In total, 787 lung cancer patients who were diagnosed between 2001 and 2010 were retrospectively analyzed. SCr and urine creatinine, BUN and measured-CrCl were evaluated prior to treatment. The Cockcroft-Gault (CG) and modification of diet in renal disease (MDRD) formulae were also used to estimate CrCl. SCr, BUN and measured-CrCl showed a significant decline in the elderly. In the 787 lung cancer patients, a significant correlation coefficient was found between measured-CrCl and age. However, in patients aged 80 years or older, no significant correlation coefficient was found between measured-CrCl and age. In the comparison between the measured CrCl and the CrCls estimated by the two formulae, the CG-CrCl levels were lower than those of the measured-CrCl, whereas the MDRD-CrCl levels were higher. Age is a crucial factor influencing renal function in patients with lung cancer. Particularly in the elderly, a decline in CrCl and greater individual variability in CrCl, as well as discrepancies in measured-CrCl and estimated CrCls are significant factors.
PMCID: PMC3398364  PMID: 22807956
renal function; creatinine clearance; lung cancer; elderly
24.  Serum levels of cystatin C in elderly lung cancer patients 
Oncology Letters  2011;3(2):303-306.
The purpose of this study was to confirm the correlation between serum levels of cystatin C (Cys-C) and those of creatinine (Cre), the most widely used index of renal function in clinical practice, and to evaluate serum levels of Cys-C, with a particular focus on the effects of aging, body mass index (BMI), C-reactive protein (CRP) and disease extent in patients with lung cancer. Serum Cys-C levels in a total of 39 patients (median 72 years), who were diagnosed as having lung cancer were analyzed retrospectively. The serum Cys-C was determined using colloidal gold particles coated with anti-Cys C antibodies. A significant correlation coefficient was found between serum levels of Cys-C and those of Cre (P=0.001), but only moderate agreement. Serum Cys-C levels increased in an age-dependent manner with significant differences among 3 age groups: patients younger than 65 years, those aged 65 to 74 years and those aged 75 years or older (P=0.001). However, no correlation was observed between Cys-C and BMI, Cys-C and CRP, or Cys-C and disease extent of lung cancer. Estimation of renal function is important since renal insufficiency is directly correlated to increased chemotherapeutic complications in oncological practice. Thus, estimation of serum Cys-C levels may be important, but adjustment of Cys-C for age should be taken into consideration.
PMCID: PMC3362379  PMID: 22740900
cystatin C; elderly; lung cancer
25.  Variants of C-C Motif Chemokine 22 (CCL22) Are Associated with Susceptibility to Atopic Dermatitis: Case-Control Studies 
PLoS ONE  2011;6(11):e26987.
Atopic dermatitis (AD) is a common inflammatory skin disease caused by multiple genetic and environmental factors. AD is characterized by the local infiltration of T helper type 2 (Th2) cells. Recent clinical studies have shown important roles of the Th2 chemokines, CCL22 and CCL17 in the pathogenesis of AD. To investigate whether polymorphisms of the CCL22 gene affect the susceptibility to AD, we conducted association studies and functional studies of the related variants. We first resequenced the CCL22 gene and found a total of 39 SNPs. We selected seven tag SNPs in the CCL22 gene, and conducted association studies using two independent Japanese populations (1st population, 916 cases and 1,032 controls; 2nd population 1,034 cases and 1,004 controls). After the association results were combined by inverse variance method, we observed a significant association at rs4359426 (meta-analysis, combined P = 9.6×10−6; OR, 0.74; 95% CI, 0.65–0.85). Functional analysis revealed that the risk allele of rs4359426 contributed to higher expression levels of CCL22 mRNA. We further examined the allelic differences in the binding of nuclear proteins by electrophoretic mobility shift assay. The signal intensity of the DNA-protein complex derived from the G allele of rs223821, which was in absolute LD with rs4359426, was higher than that from the A allele. Although further functional analyses are needed, it is likely that related variants play a role in susceptibility to AD in a gain-of-function manner. Our findings provide a new insight into the etiology and pathogenesis of AD.
PMCID: PMC3219642  PMID: 22125604

Results 1-25 (38)