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It is not uncommon for patients with lung cancer to receive supportive care alone. However, the clinical characteristics of these patients have not been fully studied. We conducted a retrospective study to identify the clinical characteristics of definitive lung cancer patients treated with supportive care alone. We retrospectively analyzed the percentage of and reasons for definitive lung cancer patients treated with supportive care alone at a regional cancer center. We also investigated the histological diagnostic approaches, palliative therapy types, primary treatment locations after hospital consultation, and places of death. A total of 1,223 patients were histologically diagnosed as having lung cancer between 2011 and 2014. Of these, 160 (13%) patients were treated with supportive care alone. The primary reason for treatment with supportive care alone was a poor performance status (PS) in almost half of the patients. Overall, 40% of the patients received supportive care at home, and 17% were admitted to a palliative care unit (PCU). Death occurred at home for 17% of the patients and in the PCU for 42% of the patients. This study revealed that 13% of histologically proven lung cancer patients were treated with supportive care alone, mostly because of a poor PS. Only 40% of these patients received home care, suggesting the need for a more accessible home care system for patients and their families.

Tumor-associated macrophages influence tumor progression and resistance to immune checkpoint therapy. Chemokine signaling is a key regulator of macrophage accumulation and activity. Here, we report that the chemokine receptor-binding protein FROUNT modulates tumor-associated macrophage responses and is an important regulator of tumor progression. By screening 131,200 compounds, we identified the anti-alcoholism drug disulfiram (DSF) as a potent inhibitor of FROUNT that interferes with FROUNT-chemokine receptor interaction by directly binding to FROUNT. Both DSF-treatment and FROUNT-deficiency markedly reduced tumor progression and decreased the tumor-promoting activity of macrophages. Studies using clinical specimens and FROUNT-GFP reporter mice showed that FROUNT was highly expressed in macrophages, and myeloid-specific deletion of FROUNT impaired tumor growth. Low FROUNT expression in patients with lung adenocarcinoma was correlated with better clinical outcomes. Moreover, co-treatment of DSF with an immune checkpoint antibody synergistically inhibited tumor growth. Together, inhibition of FROUNT by DSF presents a strategy for macrophage-targeted cancer therapy.

Background Integrated positron emission tomography (PET) with computed tomography (CT) is a useful modality to investigate lymph node metastases for non-small cell lung cancer, but is less sensitive for normal-sized lymph nodes. We sometimes encounter cases with radiologically normal lymph nodes and unsuspected mediastinal metastases detected by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA). However, few studies have investigated staging in patients with radiologically normal mediastina, and the accuracy of EBUS-TBNA staging for radiologically normal mediastina and hila is unclear. Methods This study was a retrospective, single-institution review of a prospectively maintained database at Chiba Cancer Center between May 1, 2008, and September 1, 2013. We analyzed 113 non-small cell lung cancer patients with both CT-negative and PET/CT-negative lymph nodes (N0) in preoperative nodal staging performed by EBUS-TBNA. After preoperative staging was performed, patients with either N0 or N1 clinical staging underwent surgery. Final N factors were determined by mediastinal lymphadenectomy. Results In our study, the overall rate of N2 disease was 17.6% (20 of 113). For nodal staging by EBUS-TBNA, the sensitivity, specificity, negative predictive value, and diagnostic accuracy were 35.0% (7 of 20), 100% (93 of 93), 87.7% (93 of 106), and 88.4% (100 of 113), respectively. There were no severe complications from EBUS-TBNA staging. Conclusions The overall rate of unsuspected N2 was not low. EBUS-TBNA was accurate and feasible for preoperative mediastinal nodal staging of non-small cell lung cancer with both CT-negative and PET/CT-negative lymph nodes. The sensitivity of EBUS-TBNA for radiologically normal mediastina and hila was low. Further investigations are required.

The brain is a frequent site of metastases from non-small-cell lung cancer (NSCLC). We analyzed the frequency of brain metastases (BMs) from NSCLC in the era of magnetic resonance images, and evaluated the correlation between epidermal growth factor receptor (EGFR) mutations and BMs among East Asian patients. Frequency, number, and size of BMs, and survival of 1,127 NSCLC patients were retrospectively reviewed. Mutation status of EGFR was evaluated in all cases, and its association with BMs was statistically evaluated. EGFR mutations were found for 331 cases (29.4 %). BM was the cause of primary symptoms for 52 patients (4.6 %), and found before initiation of treatment for 102 other patients (9.1 %); In addition to these 154 patients, 107 patients (9.5 %) developed BMs, giving a total of 261 patients (23.2 %) who developed BMs from 1,127 with NSCLC. BM frequency was higher among EGFR-mutated cases (31.4 %) than EGFR-wild cases (19.7 %; odds ratio: 1.86; 95 % confidence interval (CI) 1.39–2.49; P

Background Brain metastases (BM) are a common in patients with lung cancer. Although whole-brain radiation therapy (WBRT) is the standard therapy, it may have a risk of decline in cognitive function of patients. In this study, we evaluated the efficacy of gefitinib alone without radiation therapy for the treatment of patients with BM from lung adenocarcinoma. Materials and methods Eligible patients had BM from lung adenocarcinoma with epidermal growth factor receptor (EGFR) mutations. Gefitinib was given at 250mg orally once a day until tumor progression or unacceptable toxicity. Results Forty-one patients were enrolled. The response rate was 87.8%. No patient experienced grade ≥4 toxicity. The median progression-free survival time was 14.5 months (95% CI, 10.2–18.3 months), and the median overall survival time was 21.9 months (95% CI, 18.5–30.3 months). In compared with L858R, exon 19 deletion was associated with better outcome of patients after treatment with gefitinib in both progression-free ( p =0.003) and overall survival ( p =0.025). Conclusion Favorable response of BM to gefitinib even without irradiation was demonstrated. Exon 19 deletion was both a predictive and prognostic marker of patients with BM treated by gefitinib.

Background Anaplastic lymphoma kinase (ALK) fusion gene-positive lung cancer accounts for 4–5% of non-small cell lung carcinoma. A clinical trial of the specific inhibitor of ALK fusion-type tyrosine kinase is currently under way. Methods ALK fusion gene products were analyzed immunohistochemically with the materials obtained by surgery or by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA). The echinoderm microtubule-associated protein-like 4(EML4)-ALK or kinesin family member 5B (KIF5B)-ALK translocation was confirmed by the reverse transcription polymerase chain reaction (RT-PCR) and fluorescence in situ hybridization (FISH). After eligibility criteria were met and informed consent was obtained, 3 patients were enrolled for the Pfizer Study of Crizotinib (PF02341066), Clinical Trial A8081001, conducted at Seoul National University. Results Out of 404 cases, there were 14 of EML4-ALK non-small cell carcinoma (NSCLC) and one KIF5B-ALK NSCLC case (8 men, 7 women; mean age, 61.9 years, range 48–82). Except for 2 light smokers, all patients were non-smokers. All cases were of adenocarcinoma with papillary or acinar subtypes. Three were of stage IA, 5 of stage IIIA, 1 of stage IIIB and 6 of stage IV. Ten patients underwent thoracotomy, 3 received chemotherapy and 2 only best supportive care (BSC). One BSC and 2 chemotherapy cases were enrolled for the clinical trial. Patients with advanced stages who received chemotherapy or best supportive care were younger (54.0 ± 6.3) than those who were surgically treated (65.8 ± 10.1) (p The powerful effect of ALK inhibitor on EML4-ALK NSCLC was observed. Soon after its administration, almost all the multiple bone and lymph node metastases quickly disappeared. Nausea, diarrhea and the persistence of a light image were the main side effects, but they diminished within a few months. Conclusion ALK-fusion gene was found in 3.7% (15/404) NSCLC cases and advanced disease with this fusion gene was correlated with younger generation. The ALK inhibitor presented in this study is effective in EML4-ALK NSCLC cases. A further study will be necessary to evaluate the clinical effectiveness of this drug.

Background and objective: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has typically been performed using the 22gauge (G) dedicated TBNA needle. Recently a new 21G TBNA needle has been introduced. The efficacy of using a larger gauge biopsy needle during EBUS-TBNA has not been reported. The purpose of this study was to compare the diagnostic yield and utility of 21G and 22G needles during EBUS-TBNA. Methods: EBUS-TBNA was performed using both 21G and 22G needles. Cytological and histological findings were recorded for each samples obtained by an independent cytologist and pathologist. The cellularity and blood contamination were evaluated in the cytological samples. The quality of the histological core was evaluated by the amount of blood clots versus the actual tissue. Each factor was compared within two slides from the two different size needles. The diagnostic yield and the differences of the cytology and histology were analysed. Results: The evaluation of 45 lesions by EBUS-TBNA revealed that tumour cells were equally detected by both 21G and 22G needles. Two patients of adenocarcinoma were histologically diagnosed only by the 21G needle. Although histological structure was better preserved in five lesions collected by the 21G needle, there was more blood contamination with the 21G needle (P

We herein report two cases of thymomas diagnosed by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA). In both cases, the tumor was adjacent to the central airway. Therefore, we attempted to perform EBUS-TBNA in order to obtain specimens for a histopathological examination, which resulted in a diagnosis of thymoma. In one case, surgical resection was conducted and the histological evaluation of the resected specimen confirmed thymoma type AB, consistent with the histology from the EBUS-TBNA specimen. As a safe and minimally invasive procedure, EBUS-TBNA may be considered for the diagnosis of mediastinal tumors, including thymoma.

Pulmonary artery sarcoma (PAS) is a rare tumor that is often detected at an advanced stage, when disease is so widespread that a radical surgical procedure is no longer indicated. Therefore, less invasive biopsy techniques are required to establish a definitive preoperative diagnosis. Endobronchial ultrasound (EBUS) is useful for producing real-time images of both lymph nodes and the interior of pulmonary arteries adjacent to the bronchi. We report a case with masslike lesions in the pulmonary artery that were observed by EBUS and from which tissue was obtained by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) to establish a diagnosis of PAS.

A 33 year-old man was referred to our center with swelling of the left scrotum. He underwent resection of the left testis,and pathological diagnosis indicated a germ cell tumor of that testis. His past history included lung cancer resection 5 yearsbefore the testicular surgery. Precise pathological reevaluation of the lung cancer using immunohistochemical methodsindicated that the tumor originally diagnosed as lung cancer was a metastasis of the germ cell tumor of the left testis.

Chemokine-chemokine receptor interaction plays an essential role in leukocyte/dendritic cell (DC) trafficking in inflammation and immune responses. We investigated the pathophysiological roles of secondary lymphoid tissue chemokine (SLC; CCL21) and macrophage inflammatory protein-2 (MIP-2) in the development of acute pulmonary inflammation induced by an intratracheal injection of Propionibacterium acnes in mice. Immunohistochemical studies revealed that SLC was constitutively expressed in the peribronchial areas and perivascular lymphatics in normal mice. MIP-2-positive cells were observed in alveolar spaces in mice challenged with P. acnes. Both neutralization Abs against MIP-2 and CXC chemokine receptor 2 alleviated the P. acnes-induced pulmonary inflammation when injected before P. acnes Ag challenge. On the other hand, polyclonal anti-SLC Abs (pAbs) exacerbated the pulmonary inflammation. The numbers of mature DCs (MHC class II +, CD11c+, and CD86+) as well as macrophages and neutrophils in the P. acnes Ag-challenged lungs were increased, whereas the number of CD4+ T cells, including memory T cells, was decreased. The numbers of mature and proliferating CD4+ T cells (bromodeoxyuridine+CD4+) in regional lymph nodes were decreased in mice injected with anti-SLC pAbs compared with those in mice treated with control Abs. An in vitro proliferation assay confirmed the impairment of the Ag-specific T cell response in regional lymph nodes of mice treated with anti-SLC pAbs. These results indicate for the first time a regulatory role for SLC-recruited mature DCs in bridging an acute inflammatory response (innate immunity) and acquired immunity in the lung.

Dendritic cells (DCs) are highly specialized antigen-presenting cells that distribute widely in all organs. DCs initiate the primary immune response and activate naive T cells and B cells responsible for the acquired immunity. In this study, CCR7 mRNA was proved to be expressed in DCs and their precursors derived from murine bone marrow-derived hematopoietic progenitor cells (HPCs), whereas CCR1 mRNA was expressed in both CD11b−/dullCD11c+ and CD11b+hiCD11c+ DC precursors. CCR6 mRNA was not detected in any murine DC populations. In agreement with the chemokine receptor mRNA expression by each population in the DC differentiation pathway, SLC (also termed as MIP-3β), one of the ligands for CCR7, strongly and selectively chemoattracted both CD11b−/dullCD11c+ and CD11b+hiCD11c+ DC precursors (days 6 to 7) and more mature DCs (days 13 to 14). We have recently found that transforming growth factor-β1 (TGF-β1), a cytokine that is essential for the appearance of Langerhans cells in the skin, polarizes murine HPCs to generate Langerhans-like cells through monocyte/macrophage differentiation pathway. We observed here that TGF-β1 not only inhibited the expression of CCR7 in DCs and DC precursors derived from HPCs, but also inhibited the migration of these cells in response to SLC. This is the first report describing the chemokine and chemokine receptors responsible for murine DC migration and downregulation of DC migration by TGF-β1.

Background: Chemokines and chemokine receptors not only have significant roles in cancer metastasis and tumorigenesis but also act as antitumour agents. The interaction between the Crk-like adaptor protein (CrkL), which is encoded by the CRKL gene, and non-receptor tyrosine kinase c-ABL is reported to transform many cells into malignant cells. We examined the effects of CC chemokine receptor 7 (CCR7), CCR7 ligands and CrkL and c-ABL in lung adenocarcinoma. Methods: One hundred and twenty patients with lung adenocarcinoma were included in this historical cohort analysis. We examined CCR7 and CCR7 ligands and CrkL and c-ABL mRNA expressions in surgically resected lung adenocarcinoma specimens and evaluated their contribution to prognosis, and the relationship with epidermal growth factor receptor (EGFR) and TP53 mutations. Results: High CCR7 mRNA expressions indicated better prognoses than those of the groups with low CCR7 mRNA expressions (P=0.007, HR=2.00, 95% CI of ratio: 1.22 –3.31). In lung adenocarcinoma, CrkL and c-ABL mRNAs were related to CCR7 mRNA expression (P

Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has typically been performed using the 22 gauge (G) dedicated TBNA needle. Recently a new 21G TBNA needle has been introduced. The efficacy of using a larger gauge biopsy needle during EBUS-TBNA has not been reported. The purpose of this study was to compare the diagnostic yield and utility of 21G and 22G needles during EBUS-TBNA.EBUS-TBNA was performed using both 21G and 22G needles. Cytological and histological findings were recorded for each samples obtained by an independent cytologist and pathologist. The cellularity and blood contamination were evaluated in the cytological samples. The quality of the histological core was evaluated by the amount of blood clots versus the actual tissue. Each factor was compared within two slides from the two different size needles. The diagnostic yield and the differences of the cytology and histology were analysed.The evaluation of 45 lesions by EBUS-TBNA revealed that tumour cells were equally detected by both 21G and 22G needles. Two patients of adenocarcinoma were histologically diagnosed only by the 21G needle. Although histological structure was better preserved in five lesions collected by the 21G needle, there was more blood contamination with the 21G needle (P 0.0001).There were no differences in the diagnostic yield between the 21G and 22G needles during EBUS-TBNA. The preserved histological structure of the samples obtained by the 21G needle may be useful for the diagnosis of mediastinal and hilar adenopathy of unknown aetiology which may be a challenge with the 22G needle.

We present two cases of inoperable advanced lung cancer in which the main lesions were mediastinal lymph nodes detected with positive positron emission tomography (PET). Drug therapy was very effective, and post-treatment PET results were negative. Restaging by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) was performed on the mediastinal lymph nodes with a short axisor = 10 mm measured by computed tomography (CT). Cancer cells were detected, which helped determine the therapeutic strategy. Re-evaluation of mediastinal lymph nodes using EBUS-TBNA appears to be useful, even among patients with inoperable advanced lung cancer.

We report a 90-year-old woman who had complained of bloody sputum and for whom a chest CT showed a nodular lesion on the right lower lobe. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) was performed and adenocarcinoma was revealed in both a subcarinal lymph node (#7) and in the primary lung tumor. Epidermal growth factor receptor (EGFR) gene mutation status was evaluated, and an exon 21 point mutation (L858R) was identified by direct sequencing. Two weeks after administration of gefitinib, the tumor size decreased and bloody sputum disappeared. The patient has remained in good condition for 6 months.

We report a case of schwannoma arising from the 9th intercostal nerve, which caused a bloodstained pleural effusion. The patient, a 37-year-old woman, presented with left-sided back pain. A chest X-ray showed left pleural effusion, which was subsequently found to be bloodstained but without malignant cells. Chest magnetic resonance imaging showed a 76-mm tumor arising from the 9th intercostal nerve. The tumor and intercostal nerve were successfully resected. Histological examination revealed that the tumor comprised spindle cells with both Antoni types A and B patterns. There were necrotic changes and cystic degeneration, but no atypical or mitotic cells. Based on these findings, benign schwannoma was diagnosed. Schwannoma is rarely accompanied by bloody pleural effusion, which we assume was caused by partial tumor rupture. Magnetic resonance imaging proved very useful in localizing and characterizing the tumor in this case.

Vascular endothelial growth factor (VEGF) is a potent angiogenic factor related to tumor growth and metastasis. However, little is known about the clinical significance of circulating VEGF in cancer patients.Eighteen patients with non-small cell lung cancer received chemotherapy using carboplatin and paclitaxel. Plasma levels of VEGF were analyzed at baseline and after 2 cycles of chemotherapy.Partial remission was observed in 3 patients (16.7%), stable disease in 10 patients (55.6%) and progressive disease in 5 patients (27.8%). Patients with partial remission or stable disease had significantly lower levels of plasma VEGF than did patients with progressive disease, both at baseline (p=0.0341) and after 2 cycles of chemotherapy (p=0.0265). There were no significant changes of plasma VEGF during chemotherapy.Pretreatment plasma levels of VEGF are a useful marker for predicting disease control by chemotherapy.

Patients who had undergone gastric resection are considered to be high risk of developing tuberculosis. We investigated the factors leading to pulmonary tuberculosis after gastrectomy.We retrospectively examined 654 pulmonary tuberculosis patients discharged from Chiba-East National Hospital from January 1999 to December 2001.Fifty-five patients (31-84 years old, mean 63.5 +/- 12.5 years, 48 males and 7 females) had the history of gastric resection. The proportion of patients receiving gastrectomy among patients with pulmonary tuberculosis was 8.4 percent. The mean age of patients received gastric resection was 50.2 +/- 16.6 years, and the mean interval from gastrectomy to the development of pulmonary tuberculosis was 13.6 +/- 11.0 years. On admission to our hospital, 34 out of 55 cases were smear positive by sputum examination for acid-fast bacilli and 39 cases had cavitary lesions on chest X-ray. Gastrectomy was done due to carcinoma of the stomach in 31 cases, peptic ulcer in 21 cases, adenomatous polyp in two cases, and accidental injury in one case. Out of total 55 cases, 52 patients improved, but three cases died of pulmonary tuberculosis. None had the recurrence of carcinoma of the stomach. Body weight, Body mass index, Prognostic nutritional index (PNI; 10 x serum albumin concentration + 0.005 x peripheral lymphocyte count) which was proposed by Onodera, serum albumin level and serum total cholesterol level were lower in the gastrectomy group than in the non-gastrectomy group. The odds ratio of developing tuberculosis among gastrectomy patients compared with the appropriate controls in 30 to 59 year-old-men was 3.8.This study confirms that gastrectomy is one of the risk factors of developing tuberculosis in 30 to 59 year-old-men. However, whether gastrectomy in itself is a risk factor or whether it is secondarily associated with another risk factor such as underweight status and/or inadequate nutrition following surgery remains unclear.

To investigate the factors leading to the retreatment for tuberculosis.Forty-seven retreatment cases with pulmonary tuberculosis, who were discharged from the National Chiba Higashi Hospital from 2000 to 2002.Data on all retreatment cases were studied as to the condition of the original treatment and factors leading to the retreatment.Of the 47 cases, 33 cases received the original treatment in our hospital. Of the 33 cases, 24 cases were relapsed cases and 9 cases were defaulters. Most relapsed cases were male aged 50s and 12 cases (50%) were jobless. As the factors leading to retreatment, the delay in the negative conversion of sputum culture accounted for 11 cases (45.8%) out of 24 cases. No specific factors were found in three cases (12.5%). Among the defaulters, no bias was seen as to age and occupation of cases, but all the cases were male, and they defaulted during the maintenance phase of treatment at the out-patient department. CONSIDERATION: The delay in the negative conversion of sputum culture was the main factor relating to the relapse. Diabetes mellitus (DM) is one of the factors leading to the relapse, but many factors were observed in DM patients. Male cases aged 50s had many factors leading to the relapse. An intensive management for out-patients and involvement of welfare department aiming at the completion of treatment for the socially vulnerable groups might be necessary as the measure to prevent defaulting.The delay in the negative conversion of sputum culture was the main factor leading to relapse, and intensive management for out-patients aiming at the completion of treatment is necessary to prevent the defaulting.

Backgrounds Whole-brain radiation therapy (WBRT) and/or stereotactic radiosurgery (SRS) are standard treatments for brain metastases (BMs). However, patients (pts) treated by radiation therapy (RT) have a risk of decline in learning and memory functions. The aim of this study is to clarify the efficacy and safety of chemotherapy without RT for BMs. Materials and methods BMs from lung adenocarcinomas (Ads) with EGFR-mutation were enrolled. As tyrosine kinase inhibitors (TKIs), gefitinib was used at first, and erlotinib was administrated at tumor progression. Erlotinib was also selected for pts in whom intracranial lesions appeared after gefitinib. The response to TKIs was evaluated on MRI. WBRT or SRS was performed only at tumor progression after TKIs. The primary endpoint was overall survival, and the secondary endpoints were maximum response to TKIs, progression-free survival and time to RT after diagnosis of BMs. Results In this study, 37 pts were enrolled. The types of EGFR-mutations were as follows: Ex19 deletion (Ex19del) in 20, Ex21L858R in 14, and other types of mutations in 3 cases. The maximum response was PD in one, SD in 3, PR in 22 and CR in 9 pts (response rate: 83.8%). The progression-free and overall survival times were 8.9 and 28.3 months. The median time to RT (WBRT in 14 and SRS in 3 cases) from diagnosis of BMs was 14.3 months. During the follow-up period, 9 deaths were observed but none of them were owing to the intracranial lesions. Among these 9 pts, no RT was required in 2. Pneumonitis was observed in one case after gefitinib, but no other severe adverse event was observed. When we divided the pts owing to the types of mutations (Ex19del vs. others), response to TKI was superior in Ex19 deleted cases (p = 0.031), and the progression-free survival time was significantly longer in cases with Ex19del (14.5 months) in compared with those with other types of mutations (8.0 months, p = 0.002). In Ex19 deleted cases, TKIs could delay RT for 18.3 months. Conclusions TKIs showed favorable effect on control of EGFR-mutant BMs, and it delayed RT for more than one year. Ex19del was the significant predictor of response to TKIs in BMs. TKIs without RT was safe and acceptable treatment for BMs from EGFR-mutant lung Ads. Disclosure All authors have declared no conflicts of interest.

Background: Prior to 2012, bevacizumab was contraindicated for patients with brain metastases in Japan due to concerns about cerebral hemorrhage. The package insert changed in 2012 to allow careful administration of bevacizumab; however, we still have insufficient data describing the safety and efficacy of bevacizumab-containing chemotherapy. Because bevacizumab may be effective in the treatment of edema associated with brain metastases and radiation necrosis, it may have additional clinical uses. Methods: We retrospectively evaluated non-small cell lung cancer (NSCLC) patients with brain metastases who had received chemotherapy containing bevacizumab at Chiba Cancer Center between April 2012 and December 2013. Results: Thirty patients were eligible for participation in this study. Of the patients in this study, 15 were men, and 15 were women; patients had a median age of 62.5 years, and all except one had histological adenocarcinoma. Surgery, stereotactic radiosurgery, whole brain radiation, and other therapies were performed in 9, 13, 2, and 1 patients, respectively; 5 patients were not treated. Additionally, 26, 1, 2, and 1 patients received the following chemotherapies: CBDCA + PTX + BEV, CDDP + PEM + BEV, PEM + BEV, or BEV monotherapy, respectively. RECIST classifications of brain metastases were complete response in 2 patients, partial response in 7 patients, stable disease in 11 patients, progressive disease in 1 patients, and NE in 9 patients. Grade 3 adverse events included sensory neuropathy in 1 patient, epileptic seizure in 1 patient, dysbasia in 1 patient, viral encephalitis in 1 patient, febril neutropenia in 1 patient, and subcutaneous abscess of the buttocks in 1 patient. Grade 4 epileptic seizure was occurred in 1 patient. There were no cerebral hemorrhage. Conclusion: Bevacizumab did not increase toxicities in patients with brain metastases and appeared to be effective in the treatment of NSCLC patients with brain metastases.

We have studied the recruitment and roles of distinct dendritic cell (DC) precursors from the circulation into Propionibacterium acnes–induced granulomas in mouse liver. During infection, F4/80−B220−CD11c+ DC precursors appeared in the circulation, migrated into the perisinusoidal space, and matured within newly formed granulomas. Recruited DCs later migrated to the portal area to interact with T cells in what we term “portal tract–associated lymphoid tissue” (PALT). Macrophage inflammatory protein 1α attracted blood DC precursors to the sinusoidal granuloma, whereas secondary lymphoid organ chemokine (SLC) attracted mature DCs to the newly identified PALT. Anti-SLC antibody diminished PALT expansion while exacerbating granuloma formation. Therefore, circulating DC precursors can migrate into a solid organ like liver, and participate in the granulomatous reaction in response to specific chemokines.

We have investigated the involvement of chemokine receptor CCR1-positive cells in bleomycin-induced lung injury, a model of pulmonary fibrosis. After bleomycin challenge in C57BL/6J mice, the expression of CCR1 mRNA increased and peaked at day 7, which paralleled to the expression of its ligands, macrophage-inflammatory protein-1α and RANTES. Immunohistochemical study showed that CCR1-positive cells accumulated in the interstitial inflammatory site. Furthermore, the treatment of anti-CCR1 Ab significantly reduced the accumulation of inflammatory cells and collagen deposition, resulting in dramatic improvement of survival. These results suggest that CCR1-positive cells play significant roles in the pathogenesis of pulmonary fibrosis subsequent to bleomycin-induced lung injury, and that CCR1 could be a novel molecular target for intervention therapy against pulmonary fibrosis.

e21054 Background: Chemokines and chemokine receptors not only have the powerful ability in cancer metastasis and tumorigenesis, but also act as anti-tumorgenic ability. Lung Krueppel-like factor (LKLF, KLF2) is a member of the family of the Krueppel-like factors (KLFs). KLF2 was initially described as a lung-specific transcription factor. KLF2 is reported to regulate some malignant cells. We examined and evaluated the effect of KLF2 on pulmonary adenocarcinoma and the relationship of their mRNA expression with CCR7, EGFR and p53 genetical mutations in pulmonary adenocarcinoma. Methods: 120 patients of stage I to IV with pulmonary adenocarcinoma were included in this retrospective analysis. The expression of CCR7 and KLF2 mRNA expression in surgically resected pulmonary adenocarcinoma specimens were examined and evaluated the relation to prognosis, the effect of EGFR and p53 genetical mutations. Results: High mRNA expression of KLF2 in lung cancer patients indicated significantly good prognosis than the groups of low expressions (p= 0.0066, HR= 2.008, 95% CI of ratio 1.215 to 3.319). The expression of KLF2 mRNA had relationships with CCR7 mRNA expression in pulmonary adenocarcinoma. Moreover the mRNA expression of KLF2 in pulmonary adenocarcinoma specimens was influenced by the mutation of p53 mutation in lung cancer specimens. There was no significant difference within KLF2 mRNA expression quantities of EGFR mutation positive and negative group. Conclusions: We propose KLF2 as clinical good prognostic factors and that KLF2 has strong relation with CCR7 and p53 genetical mutation mRNA expression in pulmonary adenocarcinoma.