Radiation Impacts Early Atherosclerosis by Suppressing Intimal LDL Accumulation.

RATIONALE: Bone marrow transplantation (BMT) is used frequently to study the role of hematopoietic cells in atherosclerosis, but aortic arch lesions are smaller in mice after BMT. OBJECTIVE: To identify the earliest stage of atherosclerosis inhibited by BMT and elucidate potential mechanisms. METHODS AND RESULTS: Ldlr-/- mice underwent total body γ-irradiation, bone marrow reconstitution, and 6-week recovery. Atherosclerosis was studied in the ascending aortic arch and compared with mice without BMT. In BMT mice, neutral lipid and myeloid cell topography were lower in lesions after feeding a cholesterol-rich diet for 3, 6, and 12 weeks. Lesion coalescence and height were suppressed dramatically in mice post-BMT, whereas lateral growth was inhibited minimally. Targeted radiation to the upper thorax alone reproduced the BMT phenotype. Classical monocyte recruitment, intimal myeloid cell proliferation, and apoptosis did not account for the post-BMT phenotype. Neutral lipid accumulation was reduced in 5-day lesions, thus we developed quantitative assays for LDL (low-density lipoprotein) accumulation and paracellular leakage using DiI-labeled human LDL and rhodamine B-labeled 70 kD dextran. LDL accumulation was dramatically higher in the intima of Ldlr-/- relative to Ldlr+/+ mice, and was inhibited by injection of HDL mimics, suggesting a regulated process. LDL, but not dextran, accumulation was lower in mice post-BMT both at baseline and in 5-day lesions. Since the transcript abundance of molecules implicated in LDL transcytosis was not significantly different in the post-BMT intima, transcriptomics from whole aortic arch intima, and at single-cell resolution, was performed to give insights into pathways modulated by BMT. CONCLUSIONS: Radiation exposure inhibits LDL entry into the aortic intima at baseline and the earliest stages of atherosclerosis. Single-cell transcriptomic analysis suggests that LDL uptake by endothelial cells is diverted to lysosomal degradation and reverse cholesterol transport pathways. This reduces intimal accumulation of lipid and impacts lesion initiation and growth.

Endothelial HMGB1 Is a Critical Regulator of LDL Transcytosis via an SREBP2-SR-BI Axis.

OBJECTIVE: LDL (low-density lipoprotein) transcytosis across the endothelium is performed by the SR-BI (scavenger receptor class B type 1) receptor and contributes to atherosclerosis. HMGB1 (high mobility group box 1) is a structural protein in the nucleus that is released by cells during inflammation; extracellular HMGB1 has been implicated in advanced disease. Whether intracellular HMGB1 regulates LDL transcytosis through its nuclear functions is unknown. Approach and Results: HMGB1 was depleted by siRNA in human coronary artery endothelial cells, and transcytosis of LDL was measured by total internal reflection fluorescence microscopy. Knockdown of HMGB1 attenuated LDL transcytosis without affecting albumin transcytosis. Loss of HMGB1 resulted in reduction in SR-BI levels and depletion of SREBP2 (sterol regulatory element-binding protein 2)-a transcription factor upstream of SR-BI. The effect of HMGB1 depletion on LDL transcytosis required SR-BI and SREBP2. Overexpression of HMGB1 caused an increase in LDL transcytosis that was unaffected by inhibition of extracellular HMGB1 or depletion of RAGE (receptor for advanced glycation endproducts)-a cell surface receptor for HMGB1. The effect of HMGB1 overexpression on LDL transcytosis was prevented by knockdown of SREBP2. Loss of HMGB1 caused a reduction in the half-life of SREBP2; incubation with LDL caused a significant increase in nuclear localization of HMGB1 that was dependent on SR-BI. Animals lacking endothelial HMGB1 exhibited less acute accumulation of LDL in the aorta 30 minutes after injection and when fed a high-fat diet developed fewer fatty streaks and less atherosclerosis. CONCLUSIONS: Endothelial HMGB1 regulates LDL transcytosis by prolonging the half-life of SREBP2, enhancing SR-BI expression. Translocation of HMGB1 to the nucleus in response to LDL requires SR-BI.

Role of myeloid-derived chemokine CCL5/RANTES at an early stage of atherosclerosis.

One of the hallmarks of atherosclerosis is ongoing accumulation of macrophages in the artery intima beginning at disease onset. Monocyte recruitment contributes to increasing macrophage abundance at early stages of atherosclerosis. Although the chemokine CCL5 (RANTES) has been studied in atherosclerosis, its role in the recruitment of monocytes to early lesions has not been elucidated. We show that expression of Ccl5 mRNA, as well as other ligands of the CCR5 receptor (Ccl3 and Ccl4), is induced in the aortic intima of Ldlr-/- mice 3 weeks after the initiation of cholesterol-rich diet (CRD)-induced hypercholesterolemia. En face immunostaining revealed that CCL5 protein expression is also upregulated at 3 weeks of CRD. Blockade of CCR5 significantly reduced monocyte recruitment to 3-week lesions, suggesting that chemokine signaling through CCR5 is critical. However, we observed that Ccl5-deficiency had no effect on early lesion formation and CCL5-blockade did not affect monocyte recruitment in Ldlr-/- mice. Immunostaining of the lesions in Ldlr-/- mice and reciprocal bone marrow transplantation (BMT) of Ccl5+/+ and Ccl5-/- mice revealed that CCL5 is expressed by both myeloid and endothelial cells. BMT experiments were carried out to determine if CCL5 produced by distinct cells has functions that may be concealed in Ccl5-/-Ldlr-/- mice. We found that hematopoietic cell-derived CCL5 regulates monocyte recruitment and the abundance of intimal macrophages in 3-week lesions of Ldlr-/- mice but plays a minor role in 6-week lesions. Our findings suggest that there is a short window in early lesion formation during which myeloid cell-derived CCL5 has a critical role in monocyte recruitment and macrophage abundance.

Prolyl hydroxylase domain protein 2 plays a critical role in diet-induced obesity and glucose intolerance.

BACKGROUND: Recent studies suggest that the oxygen-sensing pathway consisting of transcription factor hypoxia-inducible factor and prolyl hydroxylase domain proteins (PHDs) plays a critical role in glucose metabolism. However, the role of adipocyte PHD in the development of obesity has not been clarified. We examined whether deletion of PHD2, the main oxygen sensor, in adipocytes affects diet-induced obesity and associated metabolic abnormalities. METHODS AND RESULTS: To delete PHD2 in adipocyte, PHD2-floxed mice were crossed with aP2-Cre transgenic mice (Phd2(f/f)/aP2-Cre). Phd2(f/f)/aP2-Cre mice were resistant to high-fat diet-induced obesity (36.7±1.7 versus 44.3±2.0 g in control; P<0.01) and showed better glucose tolerance and homeostasis model assessment-insulin resistance index than control mice (3.6±1.0 versus 11.1±2.1; P<0.01). The weight of white adipose tissue was lighter (epididymal fat, 758±35 versus 1208±507 mg in control; P<0.01) with a reduction in adipocyte size. Macrophage infiltration into white adipose tissue was also alleviated in Phd2(f/f)/aP2-Cre mice. Target genes of hypoxia-inducible factor, including glycolytic enzymes and adiponectin, were upregulated in adipocytes of Phd2(f/f)/aP2-Cre mice. Lipid content was decreased and uncoupling protein-1 expression was increased in brown adipose tissue of Phd2(f/f)/aP2-Cre mice. Knockdown of PHD2 in 3T3L1 adipocytes induced a decrease in the glucose level and an increase in the lactate level in the supernatant with upregulation of glycolytic enzymes and reduced lipid accumulation. CONCLUSIONS: PHD2 in adipose tissue plays a critical role in the development of diet-induced obesity and glucose intolerance. PHD2 might be a novel target molecule for the treatment of obesity and associated metabolic abnormalities.

Suppression of abdominal aortic aneurysm formation by inhibition of prolyl hydroxylase domain protein through attenuation of inflammation and extracellular matrix disruption.

In the present study we sought to determine the effect of CoCl2, an inhibitor of PHD (prolyl hydroxylase domain protein), on the development of AAA (abdominal aortic aneurysm). AAA was induced in C57BL/6 mice by periaortic application of CaCl2 (AAA group). NaCl (0.9%)-treated mice were used as a sham control (SHAM group). Mice were treated with 0.05% CoCl2 in the drinking water (AAA/CoCl2 group). At 1 and 6 weeks after the operation, aortic tissue was excised for further examination. After 6 weeks of CaCl2 treatment, aortic diameter and macrophage infiltration into the aortic adventitia were increased in the AAA group compared with the SHAM group. Treatment with CoCl2 reduced the aneurysmal size and macrophage infiltration compared with the AAA group. Aortic expression of inflammatory cytokines and MCP-1 (monocyte chemoattractant protein-1) and the activities of MMP-9 (matrix metalloproteinase-9) and MMP-2 were enhanced in the AAA group and attenuated in the AAA/CoCl2 group. Expression of cytokines and the activities of MMPs were already increased after 1 week of CaCl2 treatment, but were suppressed by CoCl2 treatment in association with reduced NF-κB (nuclear factor κB) phosphorylation. Treatment with CoCl2 in mice prevented the development of CaCl2-induced AAA in association with reduced inflammation and ECM (extracellular matrix) disruption. The results of the present study suggest that PHD plays a critical role in the development of AAA and that there is a therapeutic potential for PHD inhibitors in the prevention of AAA development.

Right Coronary Artery with an Intramural and Interarterial Course as a Unique Cause of Myocardial Ischemia: The Unroofing Method Might Still Be the Best Solution.

A 39-year-old man was admitted because of cardiac arrest. Emergent coronary angiography revealed a preserved coronary blood flow; however, multiple-row detector computed tomography (MDCT) revealed that the proximal right coronary artery (RCA) was running inside the aortic wall, creating proximal stenosis without atherosclerotic changes. Surgical intervention with unroofing was performed; however, postoperative stenosis of the proximal RCA required additional coronary artery bypass grafting (CABG). Intraoperative findings during CABG did not reveal hematoma or coronary dissection. However, MDCT one year after CABG depicted improvement of the RCA and graft stenoses, suggesting that the post-unroof stenosis may have been caused by an inflammatory reaction after surgical intervention.

Acetylcholinesterase inhibitors attenuate angiogenesis.

Donepezil {(RS)-2-[(1-benzyl-4-piperidyl)methyl]-5,6-dimethoxy-2,3-dihydroinden-1-one} is a reversible acetylcholinesterase inhibitor and used for treatment of patients with AD (Alzheimer's disease). Recent studies showed that treatment with donepezil reduced production of inflammatory cytokines in PBMCs (peripheral blood mononuclear cells). It was also reported that muscle-derived inflammatory cytokines play a critical role in neovascularization in a hindlimb ischaemia model. We sought to determine whether donepezil affects angiogenesis. A hindlimb ischaemia model was created by unilateral femoral artery ligation. Blood flow recovery examined by laser Doppler perfusion imaging and capillary density by immunohistochemical staining of CD31-positive cells in the ischaemic hindlimb were significantly decreased in donepezil- and physostigmine-treated mice compared with control mice after 2 weeks. Donepezil reduced expression of IL (interleukin)-1ß and VEGF (vascular endothelial growth factor) in the ischaemic hindlimb. Intramuscular injections of IL-1ß to the ischaemic hindlimb reversed the donepezil-induced VEGF down-regulation and the anti-angiogenic effect. Hypoxia induced IL-1ß expression in C2C12 myoblast cells, which was inhibited by pre-incubation with ACh (acetylcholine) or LY294002, a PI3K (phosphoinositide 3-kinase) inhibitor. Donepezil inhibited phosphorylation of Akt [also known as PKB (protein kinase B)], a downstream kinase of PI3K, in the ischaemic hindlimb. These findings suggest that cholinergic stimulation by acetylcholinesterase inhibitors suppresses angiogenesis through inhibition of PI3K-mediated IL-1ß induction, which is followed by reduction of VEGF expression. Acetylcholinesterase inhibitor may be a novel anti-angiogenic therapy.

Macrophage Jak2 deficiency accelerates atherosclerosis through defects in cholesterol efflux.

Atherosclerosis is a chronic inflammatory condition in which macrophages play a major role. Janus kinase 2 (JAK2) is a pivotal molecule in inflammatory and metabolic signaling, and Jak2V617F activating mutation has recently been implicated with enhancing clonal hematopoiesis and atherosclerosis. To determine the essential in vivo role of macrophage (M)-Jak2 in atherosclerosis, we generate atherosclerosis-prone ApoE-null mice deficient in M-Jak2. Contrary to our expectation, these mice exhibit increased plaque burden with no differences in macrophage proliferation, recruitment or bone marrow clonal expansion. Notably, M-Jak2-deficient bone marrow derived macrophages show a significant defect in cholesterol efflux. Pharmacologic JAK2 inhibition with ruxolitinib also leads to defects in cholesterol efflux and accelerates atherosclerosis. Liver X receptor agonist abolishes the efflux defect and attenuates the accelerated atherosclerosis that occurs with M-Jak2 deficiency. Macrophages of individuals with the Jak2V617F mutation show increased efflux which is normalized when treated with a JAK2 inhibitor. Together, M-Jak2-deficiency leads to accelerated atherosclerosis primarily through defects in cholesterol efflux from macrophages.

Inhibition of prolyl hydroxylase domain-containing protein suppressed lipopolysaccharide-induced TNF-alpha expression.

OBJECTIVE: Prolyl hydroxylase domain-containing proteins (PHDs) play pivotal roles in oxygen-sensing system through the regulation of alpha-subunit of hypoxia-inducible factor (HIF), a key transcription factor governing a large set of gene expression to adapt hypoxia. Although tissue hypoxia plays an essential role in maintaining inflammation, the role of PHDs in the inflammatory responses has not been clearly determined. Here, we investigated the role of PHDs in lipopolysaccharide (LPS)-induced tumor necrosis factor alpha (TNF-alpha) induction in macrophages. METHODS AND RESULTS: Northern blot analysis and ELISA revealed that LPS-induced TNF-alpha upregulation was strongly suppressed by PHD inhibitors, dimethyloxallyl glycine (DMOG), and TM6008 in RAW264.7 macrophages. DMOG suppressed LPS-induced TNF-alpha upregulation in HIF-1alpha-depleted cells and HIF-1alpha overexpression failed to suppress the induction of TNF-alpha. DMOG rather suppressed LPS-induced NF-kappaB transcriptional activity. Downregulation of Phd1 or Phd2 mRNA by RNA interference partially attenuated LPS-induced TNF-alpha induction. DMOG also inhibited LPS-induced TNF-alpha production in peritoneal macrophages as well as human macrophages. CONCLUSIONS: PHD inhibition by DMOG or RNA interference inhibited LPS-induced TNF-alpha upregulation in macrophages possibly through NF-kappaB inhibition, which is independent of HIF-1alpha accumulation. This study suggests that PHDs are positive regulators of LPS-induced inflammatory process, and therefore inhibition of PHD may be a novel strategy for the treatment of inflammatory diseases.

Suppression of abdominal aortic aneurysm formation by AR-R17779, an agonist for the α7 nicotinic acetylcholine receptor.

OBJECTIVE: Activation of vagal nerve suppresses inflammatory responses through activation of α7 nicotinic acetylcholine receptor (nAchR). We sought to determine whether AR-R17779, a selective agonist of α7nAchR, affects the development of abdominal aortic aneurysm (AAA). METHODS AND RESULTS: AAA was induced by topical application of calcium chloride (CaCl2) to abdominal aorta (AAA group). NaCl (0.9%) was substituted for CaCl2 as a sham operation (SHAM group). AR-R17779 was administered in drinking water (AAA/AR-R group). One and 6 weeks after the operation, aortic tissue was excised for histological and molecular analyses. Aortic diameter and macrophage infiltration into the aortic adventitia were increased in AAA group compared with SHAM group at 6 weeks. Treatment with AR-R17779 reduced the diameter of the aorta and macrophage infiltration compared with AAA group. Wavy morphology of the elastic lamellae was lost in AAA group while it was preserved in AAA/AR-R group. Expression of inflammatory cytokines and matrix metalloproteinase (MMP) activities were enhanced in AAA group, which was suppressed in AAA/AR-R group. AR-R17779 treatment suppressed CaCl2-induced expression of cytokines, activities of MMPs and NF-κB activation at 1 week when aortic dilatation had not developed. CONCLUSION: Treatment with AR-R17779 prevented the enlargement of abdominal aorta induced by CaCl2 in association with reduced inflammation and extracellular matrix disruption. These findings suggest therapeutic potential of α7nAchR activation for prevention of AAA development.

Serum carcinoembryonic antigen as a predictive marker for sensitivity to gefitinib in advanced non-small cell lung cancer.

Gefitinib is an inhibitor of epidermal growth factor receptor tyrosine kinase, which has a tumour reducing effect in non-small cell lung cancer (NSCLC). In this study, we retrospectively reviewed the clinical data from 105 patients with advanced NSCLC treated with gefitinib at our department between May 2002 and April 2004. The overall response rate was 27.8% and the median survival time was 9.3 months. Pretreatment characteristics suggested that those with no history of smoking or an elevated serum carcinoembryonic antigen (CEA) level were more likely to be sensitive to gefitinib (P = 0.009). A multivariate analysis indicated good PS (P < 0.0001) and elevated serum CEA level (P = 0.0027) to be independent prognostic factors. These data show that the serum CEA level can be a predictive factor for the efficacy of gefitinib treatment while it is also a prognostic factor for advanced NSCLC patients undergoing this treatment.

Long-term survivors in stage IV non-small cell lung cancer.

BACKGROUND AND OBJECTIVES: To determine the prognostic factors for long-term survivors (LTS) with stage IV non-small cell lung cancer (NSCLC) who had undergone various treatments. PATIENTS AND METHODS: From 1990 to 1999, 222 NSCLC patients with stage IV disease, who had been treated in our department, were reviewed. As the initial treatment, 135 patients (48%) were treated with chemotherapy alone, 52 patients with a combination of chemotherapy and radiotherapy, 19 patients underwent an operation with or without any other therapeutic modalities and 16 were received radiotherapy alone. RESULTS: Seventeen (7.7%) patients survived for more than 2 years, and all but one had adenocarcinoma. Among these LTS, eight patients received surgery as the initial therapy, and 16 (94.1%) received some type of local-control therapy, including surgery or radiotherapy, during the course of their disease. Regarding the clinical characteristics between LTS and others (non-LTS), an early N status, a single metastatic site, a good performance status, and surgery for initial therapy were all found to be significantly important factors for LTS. A multivariate analysis using a logistic regression model also showed an early N status and surgical treatment to be significantly associated with LTS. CONCLUSIONS: Selected patients with an early N status may be appropriate candidates for aggressive multimodality treatment including surgery, in order to provide a long-term survival for stage IV NSCLC.

Long-term survival after an aggressive surgical resection and chemotherapy for stage IV pulmonary giant cell carcinoma.

BACKGROUND: Pulmonary giant cell carcinoma is one of the rare histological subtypes with pleomorphic, sarcomatoid or sarcomatous elements. The prognosis of patients with this tumor tends to be poor, because surgery, irradiation and chemotherapy are not usually effective. CASE PRESENTATION: We herein report a patient with pulmonary giant cell carcinoma with stage IV disease in whom aggressive multi-modality therapy resulted in a long-term survival. A 51-year-old male underwent an emergent operation with a partial resection of small intestinal metastases due to bleeding from the tumor. The patient also underwent a left pneumonectomy due to hemothorax as a result of the rapid growth of the primary tumor. Thereafter, two different regimens of chemotherapy and a partial resection for other site of small intestinal metastases and a splenectomy for splenic metastases were performed. The patient is presently doing well without any evidence of recurrence for 3 years after the initial operation. CONCLUSION: This is a first report of a rare case with stage IV pulmonary giant cell carcinoma who has survived long-term after undergoing aggressive surgical treatment and chemotherapy.

PPARγ Agonists Attenuate Palmitate-Induced ER Stress through Up-Regulation of SCD-1 in Macrophages.

BACKGROUND: Clinical trials have shown that treatment of patients with type 2 diabetes with pioglitazone, a peroxisome proliferator-activated receptor (PPAR)γ agonist, reduces cardiovascular events. However, the effect of PPARγ agonists on endoplasmic reticulum (ER) stress that plays an important role in the progression of atherosclerosis has not been determined. We sought to determine the effect of PPARγ agonists on ER stress induced by palmitate, the most abundant saturated fatty acid in the serum. METHODS AND RESULTS: Protein expression of ER stress marker was evaluated by Western blot analysis and stearoyl-CoA desaturase1 (SCD-1) mRNA expression was evaluated by qRT-PCR. Macrophage apoptosis was detected by flowcytometry. Pioglitazone and rosiglitazone reduced palmitate-induced phosphorylation of PERK, a marker of ER stress, in RAW264.7, a murine macrophage cell line. Pioglitazone also suppressed palmitate-induced apoptosis in association with inhibition of CHOP expression, JNK phosphorylation and cleavage of caspase-3. These effects of pioglitazone were reversed by GW9662, a PPARγ antagonist, indicating that PPARγ is involved in this process. PPARγ agonists increased expression of SCD-1 that introduces a double bond on the acyl chain of long-chain fatty acid. 4-(2-Chlorophenoxy)-N-(3-(3-methylcarbamoyl)phenyl)piperidine-1-carboxamide, an inhibitor of SCD-1, abolished the anti-ER stress and anti-apoptotic effects of pioglitazone. These results suggest that PPARγ agonists attenuate palmitate-induced ER stress and apoptosis through SCD-1 induction. Up-regulation of SCD-1 may contribute to the reduction of cardiovascular events by treatment with PPARγ agonists.

Prognostic value of visceral pleural invasion in resected non-small cell lung cancer diagnosed by using a jet stream of saline solution.

OBJECTIVE: Visceral pleural invasion caused by non-small cell lung cancer is a factor in the poor prognosis of patients with that disease. We investigated the relationship between the diagnosis of visceral pleural invasion by using a jet stream of saline solution, which was previously reported as a new cytologic method to more accurately detect the presence of visceral pleural invasion, and prognosis. METHODS: From January 1992 through December 1998, 143 consecutive patients with peripheral non-small cell lung cancer that appeared to reach the visceral pleura underwent a surgical resection at the Department of Thoracic Oncology, National Kyushu Cancer Center. The surface of the visceral pleura in patients undergoing lung cancer resection was irrigated with a jet stream of saline solution. The diagnosis of visceral pleural invasion was determined by means of either a pathologic examination or by means of a jet stream of saline solution. In addition, a cytologic examination of the pleural lavage fluid obtained immediately after a thoracotomy was evaluated. RESULTS: Forty-nine (34%) resected tumors were identified as having visceral pleural invasion. The diagnosis of visceral pleural invasion in 31, 6, and 12 patients was determined by using a jet stream of saline solution alone, pathologic examination alone, or both, respectively. The visceral pleural invasion and positive findings of intrapleural lavage cytology were linked. Although there was no significant difference between the incidence of distant metastases in the patients with visceral pleural invasion and those without visceral pleural invasion, the incidence of local recurrence, especially regarding carcinomatous pleuritis (malignant pleural effusion, pleural dissemination, or both), in the patients with visceral pleural invasion was significantly higher than in those without visceral pleural invasion. The recurrence-free survival of patients with visceral pleural invasion was significantly shorter than that of patients without visceral pleural invasion (P =.004), even patients with stage I disease (P =.02). There was also a significant difference between the patients with or without visceral pleural invasion in the overall survival (P =.02). Visceral pleural invasion was independently associated with a poor recurrence-free survival on the basis of multivariate analyses (P =.03), as were sex (P =.03), age (P = 002), and the stage of the disease (P <.0001). CONCLUSIONS: This study confirmed that the jet stream of saline solution method in addition to ordinary pathologic examination was useful for detecting visceral pleural invasion, which is considered to be one of the causes of local recurrence, especially in carcinomatous pleuritis.

Induction chemoradiotherapy and surgical resection for selected stage IIIB non-small-cell lung cancer.

BACKGROUND: Combination chemotherapy using an oral combination of uracil and tegafur (UFT) plus cisplatin and concurrent thoracic radiotherapy is reported to have a high response rate and less toxicity for locally advanced non-small-cell lung cancer (NSCLC) patients. We performed a phase II trial using this chemoradiotherapy as an induction treatment. METHODS: Patients with marginally resectable stage IIIB NSCLC, an age younger than 70 years, a performance status of 0 or 1, and good organ function were eligible. The UFT (400 mg/m(2)) was administered orally on days 1 through 14 and 22 through 35 and cisplatin (80 mg/m(2)) was injected intravenously on days 8 and 29. Radiotherapy with a total dose of 40 Gy was delivered in 20 fractions from day 1. A surgical resection was performed from 3 to 6 weeks after completing the induction treatment. RESULTS: Twenty-seven patients, 18 male and 9 female with a median age of 56 years and ranging from 36 to 69 years, were entered into the phase II trial. Clinical T4 and N3 cancers were observed in 22 and 7 patients, respectively. Twenty-five (93%) achieved a partial response. The most frequently observed adverse event was grade 3 leukopenia in 26%. Of 25 patients who underwent a thoracotomy, 22 had a tumor resection. In all 22 patients a complex resection including a resection of the superior vena cava, carina, and vertebrae was required. Operative morbidity and mortality rates were 36% and 4% respectively. The calculated 1-year and 3-year survival rates of all 27 patients were 73% and 56% respectively. CONCLUSIONS: Chemotherapy using UFT plus cisplatin and concurrent radiotherapy as induction treatment and a surgical resection for patients with marginally resectable stage IIIB NSCLC is feasible and promising. However it is difficult to conduct multi-institutional trials even for selected stage IIIB disease as a complex resection in almost all patients is necessary.

Necessity of preoperative screening for brain metastasis in non-small cell lung cancer patients without lymph node metastasis.

BACKGROUND: The exclusion of brain metastasis is important to determine the optimal treatment plan in patients with non-small cell lung cancer (NSCLC). However, a routine examination using magnetic resonance imaging (MRI) for the brain remains controversial in preoperative patients with resectable disease. METHODS: To assess the necessity of routine brain MRI for preoperative patients, a retrospective analysis for a consecutive series of 338 patients with NSCLC was performed. Among the 338 patients, 141 patients who were considered to have potentially resectable diseases through an examination of the chest plus an upper abdominal computed tomography scan and bone radioisotope scan with no neurological symptoms received MRI for examination of brain metastasis. RESULTS: The incidence of brain metastasis detected by MRI was 2.1% (three of 141) in all patients, 0% (zero of 80) in patients with N0 disease, 5.2% (one of 19) in N1, and 4.7% (two of 42) in N2 cases. CONCLUSION: In patients with resectable NSCLC, a brain MRI is not considered to be useful due to the low incidence of asymptomatic brain metastasis.

[A case of preoperative concurrent chemoradiotherapy and curative resection for locally advanced non-small-cell lung cancer].

We report the case of a 58-year-old man who underwent complete resection for locally advanced non-small-cell lung cancer (cT4N2M0). The patient received UFT (400 mg/m2 orally on days 1-14 and 22-35) and cisplatin (80 mg/m2 intravenously on days 8, 29) with a total 40 Gy, delivered in 20 fractions on days 1-26. The tumor reduction rate was 76%, and no remarkable toxicities were observed. The patient underwent complete resection and a pathologic complete response was observed. This induction concurrent chemoradiotherapy (followed by surgery) is considered to be effective and safe.

Stimulation of α7 nicotinic acetylcholine receptor by AR-R17779 suppresses atherosclerosis and aortic aneurysm formation in apolipoprotein E-deficient mice.

Atherosclerosis is a chronic inflammatory disease. It has been appreciated that vagus nerve inhibits macrophage activation via α7 nicotinic acetylcholine receptor (nAChR), termed the cholinergic anti-inflammatory pathway. We explored the effects of AR-R17779, a selective α7nAChR agonist, on atherosclerosis and aneurysm formation in apolipoprotein E (ApoE)-deficient mice. ApoE-deficient mice were fed a high-fat diet (HFD) and angiotensin II (Ang II) was infused by osmotic minipumps from 10-week-old for 4weeks. AR-R17779 was given in drinking water ad libitum. Oil red O staining of the aorta showed that combined loading of HFD and Ang II induced marked atherosclerosis compared with control mice fed a normal chow. Treatment with AR-R17779 significantly reduced atherosclerotic plaque area and improved survival of mice. Treatment with AR-R17779 also suppressed abdominal aortic aneurysm formation. Quantitative RT-PCR of the aorta revealed that mRNA expression levels of interleukin-1ß, interleukin-6 and NOX2 were significantly decreased in AR-R17779-treated mice compared with Ang II+HFD mice. AR-R17779 treatment also reduced blood pressure and serum lipid levels. In conclusion, α7nAChR activation attenuates atherogenesis and aortic abdominal aneurysm formation in ApoE-deficient mice possibly through an anti-inflammatory effect and reduction of blood pressure and lipid levels. Pharmacological activation of α7nAChR may have a therapeutic potential against atherosclerotic vascular diseases through multiple mechanisms.