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1.  Prognostic Factors Related to Dementia with Lewy Bodies Complicated with Pneumonia: An Autopsy Study 
Internal Medicine  2016;55(19):2771-2776.
Objective In patients demonstrating dementia with Lewy bodies (DLB), pneumonia is a common complication. However, the prognostic factors for the survival time in DLB with pneumonia have not been investigated by autopsy in patients with neuropathologically confirmed DLB.
Methods We conducted a retrospective study of the medical and autopsy reports of 42 patients admitted to a Japanese hospital between 2005 and 2014. The patients were neuropathologically diagnosed as having DLB by post-mortem examinations. We analyzed the effects of various factors on the time from DLB onset to death.
Results Thirty-nine of the 42 patients with DLB (92.9%) developed pneumonia during hospitalization. The median age at DLB onset was 78 years and the median time from DLB onset to death was 8 years. The Cox proportional hazard model demonstrated cerebral infarction [Hazard Ratio (HR), 2.36 (95% CI 1.12-4.96), p=0.023], muscle weakness [HR, 2.04 (0.95-4.39), p=0.067], male sex [HR, 2.84 (1.24-6.50), p=0.014], and age at onset (≥78 years.) [HR, 4.71 (1.82-12.18), p=0.001] to be prognostic factors for a shorter time from DLB onset to death.
Conclusion Careful treatment of cerebral infarction and muscle weakness of the lower extremities is crucial for DLB patients with pneumonia, especially for those over 78 years of age, in order to maximize the patients' life expectancies.
PMCID: PMC5088536  PMID: 27725535
dementia with Lewy bodies; pneumonia; cerebral infarction; muscle weakness of the lower extremities; autonomic dysfunction; DLB
2.  Association between Smoking Status and Obesity in a Nationwide Survey of Japanese Adults 
PLoS ONE  2016;11(3):e0148926.
A positive association between the number of cigarettes smoked per day and obesity has been reported, whereas how other smoking-related indices, such as pack-years and duration of smoking, are related with obesity has been less investigated. We analyzed the age-adjusted cross-sectional association between smoking and obesity in a general Japanese population.
We used data from a nationwide epidemiological study of Japanese adults (N = 23,106). We compared the prevalence of obesity (defined as body mass index ≥ 25kg/m2) among groups classified by smoking behavior, pack-years, number of cigarettes per day, duration of smoking, and duration and time of smoking cessation.
In men, current smokers had a lower odds ratio (OR) for obesity of 0.80 (95% confidence interval (CI): 0.72–0.88) compared to non-smokers, whereas past smokers had a higher OR of 1.23 (95% CI: 1.09–1.37) compared to current smokers. In women, there were no differences in obesity between the three groups classified by smoking behavior. However, in both sexes, the prevalence of obesity tended to increase with pack-years and the number of cigarettes per day, but not with duration of smoking in current and past smokers. Further, in male smokers, the risks for obesity were markedly higher in short-term heavy smokers compared with long-term light smokers, even with the same number of pack-years. Regarding the impact of smoking cessation, female past smokers who quit smoking at an age > 55-years had an elevated OR of 1.60 (95% CI:1.05–2.38) for obesity.
In a general Japanese population, obesity is progressively associated with pack-years and number of cigarettes per day, but not with the duration of smoking. When investigating the association between obesity and cigarette smoking, the daily smoking burden and the duration of smoking require to be independently considered.
PMCID: PMC4805304  PMID: 27007232
3.  S-1-containing chemotherapy for patients with non-small-cell lung cancer: A population-based observational study by the Ibaraki thoracic integrative (POSITIVE) research group 
Molecular and Clinical Oncology  2016;4(6):1025-1030.
To evaluate the efficacy and safety of S-1 monotherapy, S-1-containing combined chemotherapy and S-1 containing chemoradiotherapy for non-small cell lung cancer (NSCLC), a population-based observational study was performed. The efficacy and safety of the chemotherapies were evaluated at 13 institutes in a prefecture of Japan between April 2011 and March 2015. Datasets were obtained from 282 patients with NSCLC. For either wild-type or mutated epidermal growth factor receptor (EGFR), these three therapy groups generated almost identical response results and toxicity profiles as those in previously reported clinical trials, although the present study appeared to have slightly lower survival rates compared with those in the previous clinical trials. This may be due to the inclusion of patients in poor condition, and S-1 therapy being administered in the second, or later, line of therapy. In conclusion, the present study has confirmed that S-1-containing chemotherapy is effective against wild- and mutated-type EGFR NSCLC, and it is also tolerable in clinical practice.
PMCID: PMC4887806  PMID: 27284438
S-1; non-small cell lung cancer; observational study; population-based
4.  Effect of acid suppressants on the efficacy of tyrosine kinase inhibitors in patients with epidermal growth factor receptor-mutated non-small-cell lung cancer 
Molecular and Clinical Oncology  2016;4(5):873-877.
This retrospective study was conducted to evaluate whether oral acid suppressant (AS) therapy is associated with decreased efficacy of gefitinib and erlotinib, particularly in patients with mutated epidermal growth factor receptor (EGFR). A total of 46 consecutive patients with pathologically confirmed non-small-cell lung cancer (NSCLC), who were treated with tyrosine kinase inhibitors (TKIs) in two tertiary hospitals between September, 2005 and May, 2013, were retrospectively analyzed. Of the 46 patients, 11 received AS treatment. As regards age, gender, smoking history, performance status, histology of lung cancer, clinical stage, body surface area (BSA) and type of EGFR mutation, there were no statistically significant differences between patients with and those without AS treatment. There was no statistically significant difference in progression-free survival (PFS) or overall survival (OS) between the two groups of patients (P=0.296 and 0.613, respectively). As regards the relative dose of TKI/BSA and survival in patients with and those without AS treatment, there were no statistically significant differences in PFS and OS between the two groups of patients. Our study indicates that AS treatment may not compromise TKI efficacy (gefitinib or erlotinib) in NSCLC patients with mutated EGFR. Prospective studies and large-scale confirmation studies investigating the effect of AS co-administration with TKIs in patients with mutated EGFR may be meaningful in clinical practice.
PMCID: PMC4840557  PMID: 27123299
acid suppressants; epidermal growth factor receptor tyrosine kinase inhibitors; efficacy; non-small-cell lung cancer
5.  Overexpression of RORγt Enhances Pulmonary Inflammation after Infection with Mycobacterium Avium 
PLoS ONE  2016;11(1):e0147064.
Mycobacterium avium complex (MAC) is the most common cause of nontuberculous mycobacterial disease in humans. The role of Th17 immunity in the pathogenesis of intracellular bacteria, such as MAC, is not currently understood. Transcription factor RAR-related orphan receptor gamma t (RORγt) is known as the master regulator for Th17 cell development. Here, we investigated the role of RORγt in host responses against MAC infection. Wild-type (WT) mice and RORγt-overexpressing mice were infected with MAC via intratracheal inoculation. Systemic MAC growth was not different between WT mice and RORγt-overexpressing mice. However, neutrophilic pulmonary inflammation following MAC infection was enhanced in RORγt-overexpressing mice compared with that in WT mice. The cytokine expression shifted toward a Th17 phenotype in the lungs of RORγt-overexpressing mice following MAC infection; the levels of IL-6 and IL-17 were significantly higher in the lung of these mice than in WT mice. In addition to the increase in IL-17 single-positive T cells, T cells producing both IL-17 and interferon-γ were elevated in the lung of RORγt-overexpressing mice following MAC infection. These findings suggest that RORγt overexpression-mediated Th17 bias contributes to local inflammation rather than systemic responses, by regulating neutrophil recruitment into the sites of infection during MAC infection.
PMCID: PMC4718649  PMID: 26784959
6.  Role of Lung Function Genes in the Development of Asthma 
PLoS ONE  2016;11(1):e0145832.
Although our previous GWAS failed to identify SNPs associated with pulmonary function at the level of genomewide significance, it did show that the heritability for FEV1/FVC was 41.6% in a Japanese population, suggesting that the heritability of pulmonary function traits can be explained by the additive effects of multiple common SNPs. In addition, our previous study indicated that pulmonary function genes identified in previous GWASs in non-Japanese populations accounted for 4.3% to 12.0% of the entire estimated heritability of FEV1/FVC in a Japanese population. Therefore, given that many loci with individual weak effects may contribute to asthma risk, in this study, we created a quantitative score of genetic load based on 16 SNPs implicated in lower lung function in both Japanese and non-Japanese populations. This genetic risk score (GRS) for lower FEV1/FVC was consistently associated with the onset of asthma (P = 9.6 × 10−4) in 2 independent Japanese populations as well as with the onset of COPD (P = 0.042). Clustering of asthma patients based on GRS levels indicated that an increased GRS may be responsible for the development of a particular phenotype of asthma characterized by early onset, atopy, and severer airflow obstruction.
PMCID: PMC4709100  PMID: 26752288
7.  Mediastinal lymph node metastasis of renal cell carcinoma: A case report 
Oncology Letters  2016;11(2):1600-1602.
Renal cell carcinoma (RCC) may metastasize to mediastinal lymph nodes without any abdominal lymph node involvement. The present study describes an autopsy-proven case of RCC presenting with a large mediastinal mass; the case had been previously misdiagnosed as small cell lung carcinoma due to imaging analysis results, an elevated serum level of neuron-specific enolase and the presence of small atypical cells with a high nuclear/cytoplasmic ratio. Despite RCC occurrence being rare, it should be considered in the differential diagnosis, particularly when a mass located in the kidneys presents with metastases to the mediastinal lymph nodes, even if there is no involvement of the abdominal lymph nodes and the primary lesion is of a small size.
PMCID: PMC4734274  PMID: 26893788
mediastinal lymph node metastasis; renal cell carcinoma; clear cell carcinoma
8.  Efficacy of first-line erlotinib in non-small cell lung cancer patients undergoing dose reduction and those with a low body surface area: A population-based observational study by the Ibaraki Thoracic Integrative (POSITIVE) Research Group 
Molecular and Clinical Oncology  2015;4(3):425-428.
The aim of the present study was to evaluate the efficacy of erlotinib, one of the 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, disease control rate, time to treatment failure and overall survival, were evaluated in patients prescribed first-line erlotinib for EGFR mutated non-small cell lung cancer patients between April 2012 and March 2015. A total of 22 patients received first-line erlotinib during the study period. A dose reduction of erlotinib for the reason of low BSA and poor performance status occurred in 14 (63.6%) of the patients: 6 (27.3%) had initial dose reduction, 6 (27.3%) had dose reduction in their clinical courses, and 2 (9.1%) had both. Dose reduction of erlotinib with the initial dose of erlotinib/BSA was >80 mg/m2, and longest-term prescribed dose of erlotinib/BSA was >50 mg/m2, which may have no association with a survival disadvantage. Dose-reduction estimation studies for TKIs may be crucial, particularly for patients with a low BSA. Future prospective studies and confirmation of these results in population-based retrospective ones investigating the incidence of dose reduction in patients with AEs and those with low BSA may be required for the efficient use of erlotinib in common clinical practice.
PMCID: PMC4774513  PMID: 26998297
erlotinib; dose reduction; survival; first-line; retrospective; population-based
9.  Treatment of choroid metastasis from lung adenocarcinoma with bevacizumab-containing chemotherapy: A case report 
The occurrence of ocular metastasis from lung cancer is uncommon. The present study reports the case of a 69-year-old female patient with lung adenocarcinoma who was found to have a metastatic lesion in the left choroid at the time of presentation. As the patient was found to have a mutation in the epidermal growth factor receptor, treatment with gefitinib was administered; however, the response was evaluated as a progressive disease. Thereafter, the patient received chemotherapy with carboplatin, pemetrexed and bevacizumab. Radiological imaging revealed shrinkage of the primary lesion and choroidal metastasis, and the visual power of the left eye was also shown to improve. Therefore, the present case report demonstrated the efficacy and safety of systemic bevacizumab therapy in combination with a platinum doublet for the treatment of choroid metastasis, with morphological and functional improvements observed with regard to the choroidal metastatic tumor.
PMCID: PMC4726839  PMID: 26889247
choroid metastasis; lung cancer; bevacizumab
10.  Dimethylarginine dimethylaminohydrolase 2 promotes tumor angiogenesis in lung adenocarcinoma 
Virchows Archiv  2015;468:179-190.
Although embryonal proteins have been used as tumor marker, most are not useful for detection of early malignancy. In the present study, we developed mouse monoclonal antibodies against fetal lung of miniature swine, and screened them to find an embryonal protein that is produced at the early stage of malignancy, focusing on lung adenocarcinoma. We found an antibody clone that specifically stained stroma of lung adenocarcinoma. LC-MS/MS identified the protein recognized by this clone as dimethylarginine dimethylaminohydrolase 2 (DDAH2), an enzyme known for antiatherosclerotic activity. DDAH2 was found to be expressed in fibroblasts of stroma of malignancies, with higher expression in minimally invasive adenocarcinoma (MIA) and invasive adenocarcinoma than in adenocarcinoma in situ (AIS). Moreover, tumors with high stromal expression of DDAH2 had a poorer prognosis than those without. In vitro analysis showed that DDAH2 increases expression of endothelial nitric oxide synthase (eNOS), inducing proliferation and capillary-like tube formation of vascular endothelial cells. In resected human tissues, eNOS also showed higher expression in invasive adenocarcinoma than in AIS and normal lung, similarly to DDAH2. Our data indicate that expression of DDAH2 is associated with invasiveness of lung adenocarcinoma via tumor angiogenesis. DDAH2 expression might be a prognostic factor in lung adenocarcinoma.
Electronic supplementary material
The online version of this article (doi:10.1007/s00428-015-1863-z) contains supplementary material, which is available to authorized users.
PMCID: PMC4778151  PMID: 26515557
DDAH2; Angiogenesis; Adenocarcinoma; Malignant stroma; Prognosis
12.  Risk Factors for Aspiration Pneumonia in Older Adults 
PLoS ONE  2015;10(10):e0140060.
Aspiration pneumonia is a dominant form of community-acquired and healthcare-associated pneumonia, and a leading cause of death among ageing populations. However, the risk factors for developing aspiration pneumonia in older adults have not been fully evaluated. The purpose of the present study was to determine the risk factors for aspiration pneumonia among the elderly.
Methodology and Principal Findings
We conducted an observational study using data from a nationwide survey of geriatric medical and nursing center in Japan. The study subjects included 9930 patients (median age: 86 years, women: 76%) who were divided into two groups: those who had experienced an episode of aspiration pneumonia in the previous 3 months and those who had not. Data on demographics, clinical status, activities of daily living (ADL), and major illnesses were compared between subjects with and without aspiration pneumonia. Two hundred and fifty-nine subjects (2.6% of the total sample) were in the aspiration pneumonia group. In the univariate analysis, older age was not found to be a risk factor for aspiration pneumonia, but the following were: sputum suctioning (odds ratio [OR] = 17.25, 95% confidence interval [CI]: 13.16–22.62, p < 0.001), daily oxygen therapy (OR = 8.29, 95% CI: 4.39–15.65), feeding support dependency (OR = 8.10, 95% CI: 6.27–10.48, p < 0.001), and urinary catheterization (OR = 4.08, 95% CI: 2.81–5.91, p < 0.001). In the multiple logistic regression analysis, the risk factors associated with aspiration pneumonia after propensity-adjustment (258 subjects each) were sputum suctioning (OR = 3.276, 95% CI: 1.910–5.619), deterioration of swallowing function in the past 3 months (OR = 3.584, 95% CI: 1.948–6.952), dehydration (OR = 8.019, 95% CI: 2.720–23.643), and dementia (OR = 1.618, 95% CI: 1.031–2.539).
The risk factors for aspiration pneumonia were sputum suctioning, deterioration of swallowing function, dehydration, and dementia. These results could help improve clinical management for preventing repetitive aspiration pneumonia.
PMCID: PMC4596873  PMID: 26444916
13.  LAMA/LABA vs ICS/LABA in the treatment of COPD in Japan based on the disease phenotypes 
In the combined use of bronchodilators of different classes, ie, long-acting β2-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs), bronchodilation is obtained both directly, through LABA-mediated stimulation of β2-adrenergic receptors, and indirectly, through LAMA-mediated inhibition of acetylcholine action at muscarinic receptors. The clinical trial data for LABAs/LAMAs in the treatment of chronic obstructive pulmonary disease (COPD) continue to be promising, and these combinations will provide the convenience of delivering the two major bronchodilator classes, recommended as first-line maintenance options in COPD treatment guidelines. COPD is a complex condition that has pulmonary and extrapulmonary manifestations. These clinical manifestations are highly variable, and several are associated with different responses to currently available therapies. The concept of a COPD phenotype is rapidly evolving from one focusing on the clinical characteristics to one linking the underlying biology to the phenotype of the disease. Identification of the peculiarities of the different COPD phenotypes will permit us to implement a more personalized treatment in which the patient’s characteristics, together with his or her genotype, will be key to choosing the best treatment option. At present in Japan, fixed combinations of inhaled corticosteroids (ICSs) and LABAs are frequently prescribed in the earlier stages of COPD. However, ICSs increase the risk of pneumonia. Notably, 10%–30% of patients with COPD with or without a history of asthma have persistent circulating and airway eosinophilia associated with an increased risk of exacerbations and sensitivity to steroids. Thus, sputum or blood eosinophil counts might identify a subpopulation in which ICSs could have potentially deleterious effects as well as a subpopulation that benefits from ICSs. In this review, I propose one plausible approach to position ICSs and LABAs/LAMAs in clinical practice, based on both the extent of airflow obstruction and the presence of an asthma component or airway eosinophilic inflammation. This approach is a tentative move toward personalized treatment for COPD patients, and with progress in knowledge and developments in physiology, lung imaging, medical biology, and genetics, identification of COPD phenotypes that provide prognostic and therapeutic information that can affect clinically meaningful outcomes is an urgent medical need.
PMCID: PMC4468951  PMID: 26089659
COPD phenotype; LAMA/LABA combination; ICS
14.  Similar survival benefits of a good response and stable disease to platinum-based chemotherapy in non-small cell lung cancer 
Oncology Letters  2015;10(2):1135-1140.
The present study aimed to evaluate the similar survival benefits of a good response [complete response or partial response (CR/PR)] and stable disease (SD) to chemotherapy in non-small cell lung cancer (NSCLC) patients in clinical practice. All 322 patients who were treated between 1999 and 2012 with first-line platinum-based chemotherapy were retrospectively analyzed. Tumor responses were classified according to the response evaluation criteria for solid tumors. A total of 67 (20.8%) patients experienced CR/PR and 165 (51.2%) achieved SD. There was no difference in progression-free survival between the patients with CR/PR and those with SD (P=0.347). There was also no difference between the two groups with regard to overall survival time (P=0.878). In multivariate analysis, disease-control (more than SD) was one of the favorable prognostic factors. In clinical practice, a survival benefit would be provided not only for the patients who have good response, but also for those with SD.
PMCID: PMC4509012  PMID: 26622639
non-small cell lung cancer; stable disease; disease control rate; survival
15.  Lung cancer with spontaneous regression of primary and metastatic sites: A case report 
Oncology Letters  2015;10(1):550-552.
Partial or complete spontaneous cancer regression is a rare phenomenon, particularly in patients with lung cancer. This is the case report of a patient with lung cancer who exhibited spontaneous regression of the primary as well as metastatic lesions, without receiving any treatment. Spontaneous regression commenced within a week of obtaining pathological specimens by transbronchial and percutaneous biopsies from the primary lesion and metastatic lymph nodes of the left side of the neck. The reason for this phenomenon is unknown; however, we hypothesized that there may be an immunological association between the stimulus of the biopsies and the spontaneous regression. This patient should be closely followed up to monitor the clinical course of this unusual case.
PMCID: PMC4487128  PMID: 26171067
lung cancer; spontaneous regression; primary tumor; metastasis
16.  Successful treatment of EGFR-mutated non-small cell lung cancer with reduced-dose gefitinib: A case report 
Epidermal growth factor receptor (EGFR) mutation is a favorable prognostic factor of non-small cell lung cancer (NSCLC). In the majority of patients with EGFR mutations, clinical benefits of EGFR-tyrosine kinase inhibitors (TKIs) have been reported. One of the TKIs, gefitinib, appears to be less toxic to the skin than other TKIs. The present study reports a case of NSCLC with EGFR mutation (exon 19 deletion) in which dose-reduced gefitinib was effective against recurrence. Due to development of a grade 3 skin adverse event (AE) after 2 months of daily administration of gefitinib, the frequency of administration of gefitinib was reduced to every other day for 2 weeks. As the AE continued, the frequency of administration was reduced to once every 3 days. The patient has been in remission for 27 months since treatment with 250 mg gefitinib once every 3 days was initiated, which is the lowest dose to be reported in a successfully treated case of NSCLC with EGFR mutation. Dose reduction of gefitinib might be appropriate for patients with severe AEs and should be considered as a treatment option after 1 or 2 months of regular daily dosing of gefitinib if there is no other satisfactory treatment option.
PMCID: PMC4487036  PMID: 26170967
gefitinib; dose reduction; non-small cell lung cancer
17.  Response to alectinib after one year of discontinuation of crizotinib in anaplastic lymphoma kinase-positive non-small-cell lung cancer: A case report 
Molecular and Clinical Oncology  2015;3(4):889-891.
Therapy with crizotinib achieves prolonged progression-free and overall survival in non-small-cell lung cancer (NSCLC) patients with echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK). It was demonstrated that ALK-positive NSCLCs exhibit a high response rate to the ALK inhibitor, crizotinib. However, a proportion of the patients discontinue crizotinib treatment due to adverse events. This is the case report of a NSCLC patient with EML4-ALK rearrangement, who, following crizotinib discontinuation for one year due to adverse events, exhibited a marked response to alectinib. Even if the incidence is not high, clinicians should not overlook the most common crizotinib-related adverse events. Furthermore, certain patients may continue to benefit from alectinib following long-term discontinuation of crizotinib therapy.
PMCID: PMC4487038  PMID: 26171201
anaplastic lymphoma kinase-positive non-small-cell lung cancer; adenocarcinoma; alectinib; crizotinib
18.  Recurrent pulmonary synovial sarcoma effectively treated with amrubicin: A case report 
Pulmonary synovial sarcoma is a rare but aggressive disease. The present study describes the case of a 68-year-old female with pulmonary synovial sarcoma. The patient was mistakenly treated for small cell lung cancer due to false-positive staining for synaptophysin and cluster of differentiation 56. Despite severe myelotoxicity, platinum-containing chemotherapies (cisplatin plus irinotecan and carboplatin plus etoposide) were not effective. As a third-line therapy, the patient received amrubicin (AMR) monotherapy. A partial response was achieved, and the patient was able to undertake ordinary daily life at home for 13 months from the initiation of AMR chemotherapy. Due to the atypical clinical condition and unusual response to chemotherapy in this patient, the pathological examination was repeated. The SS18 split-signal was detected in fluorescence in situ hybridization analysis. From these results, the tumor was diagnosed as a monophasic synovial sarcoma. To the best of our knowledge, this is the first case of a patient with pulmonary synovial sarcoma who underwent successful treatment with AMR. The present case could demonstrate a specific chemosensitivity of such a rare tumor.
PMCID: PMC4471737  PMID: 26136920
pulmonary synovial sarcoma; chemotherapy; amrubicin
20.  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
21.  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
22.  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
23.  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
24.  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
25.  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

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