Thin film growth of CaAgAs by molecular beam epitaxy.

We have grown thin films of CaAgAs by molecular beam epitaxy, which was theoretically proposed to be a topological insulator. The temperature dependence of resistivity and the carrier concentration at 4 K were similar to the reported results of bulk samples. However, the magnetoresistance exhibited a steep increase at low magnetic fields, a behavior not observed for bulk samples. This steep increase of resistivity is ascribable to the weak antilocalization effect and provides clues to the nature of the topological surface state of CaAgAs.

Efficacy of platinum combination chemotherapy after first-line gefitinib treatment in non-small cell lung cancer patients harboring sensitive EGFR mutations

Purpose. Gefitinib is an effective first-line chemotherapy for advanced non-small cell lung cancer (NSCLC) patients harboring sensitive EGFR mutations. However, whether second-line platinum combination chemotherapy after first-line gefitinib treatment shows similar effects to first-line platinum combination chemotherapy in these patients remains unclear. Therefore, we here aimed to investigate the efficacy of platinum combination chemotherapy after first-line gefitinib treatment in NSCLC patients harboring sensitive EGFR mutations. Methods/patients. We retrospectively evaluated the clinical effects of second-line platinum combination chemotherapy after first-line gefitinib treatment in NSCLC patients harboring sensitive EGFR mutations (exon 19 deletion or exon 21 L858R mutation) at five institutions. All patients were initially treated with gefitinib (250 mg/day) followed by platinum combination chemotherapy as second-line chemotherapy. Results. Between January 2006 and December 2012, 42 patients [8 men, 34 women; median age, 63 years (range 39–75 years)] were enrolled. The overall response rate, disease control rate, and median progression-free survival (PFS) were 26.2, 61.9 %, and 5.1 months, respectively, after the second-line treatment. The corresponding values for first-line gefitinib treatment were 69.0, 95.2 %, and 11.1 months, respectively. Moreover, second-line platinum combination chemotherapy with pemetrexed or bevacizumab-containing regimens was independently associated with improved PFS. Conclusions. Second-line platinum combination chemotherapy after first-line gefitinib treatment in NSCLC patients harboring sensitive EGFR mutations was effective and showed equivalent outcomes to first-line platinum combination chemotherapy. After failure of first-line gefitinib therapy, second-line platinum combination chemotherapy with pemetrexed or bevacizumab might result in improved PFS (AU)

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Efficacy of platinum combination chemotherapy after first-line gefitinib treatment in non-small cell lung cancer patients harboring sensitive EGFR mutations.

PURPOSE: Gefitinib is an effective first-line chemotherapy for advanced non-small cell lung cancer (NSCLC) patients harboring sensitive EGFR mutations. However, whether second-line platinum combination chemotherapy after first-line gefitinib treatment shows similar effects to first-line platinum combination chemotherapy in these patients remains unclear. Therefore, we here aimed to investigate the efficacy of platinum combination chemotherapy after first-line gefitinib treatment in NSCLC patients harboring sensitive EGFR mutations. METHODS/PATIENTS: We retrospectively evaluated the clinical effects of second-line platinum combination chemotherapy after first-line gefitinib treatment in NSCLC patients harboring sensitive EGFR mutations (exon 19 deletion or exon 21 L858R mutation) at five institutions. All patients were initially treated with gefitinib (250 mg/day) followed by platinum combination chemotherapy as second-line chemotherapy. RESULTS: Between January 2006 and December 2012, 42 patients [8 men, 34 women; median age, 63 years (range 39-75 years)] were enrolled. The overall response rate, disease control rate, and median progression-free survival (PFS) were 26.2, 61.9%, and 5.1 months, respectively, after the second-line treatment. The corresponding values for first-line gefitinib treatment were 69.0, 95.2%, and 11.1 months, respectively. Moreover, second-line platinum combination chemotherapy with pemetrexed or bevacizumab-containing regimens was independently associated with improved PFS. CONCLUSIONS: Second-line platinum combination chemotherapy after first-line gefitinib treatment in NSCLC patients harboring sensitive EGFR mutations was effective and showed equivalent outcomes to first-line platinum combination chemotherapy. After failure of first-line gefitinib therapy, second-line platinum combination chemotherapy with pemetrexed or bevacizumab might result in improved PFS.

ASC amino-acid transporter 2 (ASCT2) as a novel prognostic marker in non-small cell lung cancer.

BACKGROUND: ASC amino-acid transporter 2 (ASCT2) is a major glutamine transporter that has an essential role in tumour growth and progression. Although ASCT2 is highly expressed in various cancer cells, the clinicopathological significance of its expression in non-small cell lung cancer (NSCLC) remains unclear. METHODS: One hundred and four patients with surgically resected NSCLC were evaluated as one institutional cohort. Tumour sections were stained by immunohistochemistry (IHC) for ASCT2, Ki-67, phospho-mTOR (mammalian target of rapamycin), and CD34 to assess the microvessel density. Two hundred and four patients with NSCLC were also validated by IHC from an independent cohort. RESULTS: ASC amino-acid transporter 2 was expressed in 66% of patients, and was closely correlated with disease stage, lymphatic permeation, vascular invasion, CD98, cell proliferation, angiogenesis, and mTOR phosphorylation, particularly in patients with adenocarcinoma (AC). Moreover, two independent cohorts confirmed that ASCT2 was an independent marker for poor outcome in AC patients. CONCLUSIONS: ASC amino-acid transporter 2 expression has a crucial role in the metastasis of pulmonary AC, and is a potential molecular marker for predicting poor prognosis after surgery.

Clinicopathological and prognostic significance of interleukin-8 expression and its relationship to KRAS mutation in lung adenocarcinoma.

BACKGROUND: On the basis of our recent findings of oncogenic KRAS-induced interleukin-8 (IL-8) overexpression in non-small cell lung cancer, we assessed the clinicopathological and prognostic significances of IL-8 expression and its relationship to KRAS mutations in lung adenocarcinomas. METHODS: IL-8 expression was examined by quantitative RT-PCR using 136 of surgical specimens from lung adenocarcinoma patients. The association between IL-8 expression, clinicopathological features, KRAS or EGFR mutation status and survival was analysed. RESULTS: IL-8 was highly expressed in tumours from elderly patients or smokers and in tumours with pleural involvement or vascular invasion. In a non-smokers' subgroup, IL-8 level positively correlated with age. IL-8 was highly expressed in tumours with KRAS mutations compared with those with EGFR mutations or wild-type EGFR/KRAS. Lung adenocarcinoma patients with high IL-8 showed significantly shorter disease-free survival (DFS) and overall survival (OS) than those with low IL8. DFS and OS were significantly shorter in the patients with mutant KRAS/high IL-8 than in those with wild-type KRAS/low IL-8. Cox regression analyses demonstrated that elevated IL-8 expression correlated with unfavourable prognosis. CONCLUSIONS: Our findings suggest that IL-8 expression is associated with certain clinicopathological features including age and is a potent prognostic marker in lung adenocarcinoma, especially in oncogenic KRAS-driven adenocarcinoma.

Blood-brain barrier disruption is more severe in neuromyelitis optica than in multiple sclerosis and correlates with clinical disability.

OBJECTIVES: This study evaluated blood-brain barrier (BBB) integrity, using blood and cerebrospinal fluid (CSF) markers, and assessed the practicality of these markers in the differential diagnosis of neuromyelitis optica (NMO) and multiple sclerosis (MS). METHODS: This was a retrospective observational study of consecutive patients presenting with acute phase NMO or MS (first attack or relapse). Haematological tests (including antiaquaporin-4 antibody levels) and CSF parameters (using primary component analyses) were undertaken; the correlation between BBB permeability and disease severity (by Expanded Disability Status Scale [EDSS] score) was examined. RESULTS: Levels of several markers of BBB permeability were higher in patients with NMO (n=21) than in those with MS (n=52). The CSF:serum albumin ratio (AR) was the one of the main differentiators of NMO and MS. Additionally, there was a significant correlation between AR and clinical severity for NMO but not for MS. CONCLUSIONS: Markers of BBB permeability were significantly higher in NMO patients than in MS patients. AR was the best marker for differentiating NMO and MS. Thus, measurement of BBB disruption markers (such as AR) might help to differentiate the diagnosis of NMO and MS in acute clinical settings.

Incident-simulating device with wireless control for extracorporeal circulation crisis management drills.

Incidents during extracorporeal circulation (ECC) may lead to serious consequences, and troubleshooting exercises are becoming more important. We developed an incident-simulation device operated by remote control for ECC crisis management drills, and evaluated its efficacy at a seminar for perfusionists. This compact device consists of a transmitter and a receiving system and is run by dry batteries without a personal computer. A 4-channel radio-control system is used as the transmitter, and four servomotors placed in a box as the receiving system. To simulate occlusion of 3/8" arterial and venous lines, two servomotors with a rod rotate and the rod compresses the tube. The tilt angle of the stick and the servomotor rotation are in proportion, so that the degree of occlusion is controlled. As a result, the tube lumen becomes "stenotic" and then occluded, depending on the rotation. To cut off the power, the other two servomotors, with a relay system, work as a breaker. When the rod of the servomotor rotates, a micro-switch is turned off. The present device is able to increase perfusion pressure quickly and to simulate inadequate venous drainage quietly. At a seminar for perfusionists, an instructor manipulated the transmitter to create incidents and the participants handled the events effectively. In conclusion, incidents created by this device were perceived as similar to real ECC crises and this device may be useful and educationally effective when used in crisis management drills for perfusionists and trainees.

Allelic losses on chromosome 3p are accumulated in relation to morphological changes of lung adenocarcinoma.

We performed allelotyping analysis at nine regions on chromosome 3p using 56 microdissected samples from 23 primary lung adenocarcinomas to examine the process of progression within individual lung adenocarcinoma with various grades of differentiation. Identical allelic patterns among various grades of differentiation were found in eight cases. Accumulation of allelic losses from high to lower differentiated portions was found in seven cases and accumulation of allelic losses from low to higher differentiated portions was found in five cases. Various allelic patterns among various grades of differentiation were found in three cases. These results suggested that allelic losses on 3p play an important role in morphological changes of lung adenocarcinomas. We also investigated the relationship between allelic losses on 3p and histological subtypes of lung adenocarcinoma. The frequencies of allelic losses at 3p14.2 and telomeric region of 3p21.3 were higher in papillary type tumour (nine out of 14, 64% and 11 out of 15, 73%) than in bronchioloalveolar carcinoma-type tumour (one out of 8, 13%; P=0.031 and four out of 12, 33%; P = 0.057). These results indicated that allelic losses at 3p14.2 and telomeric region of 3p21.3 are related to pattern of the proliferation of lung adenocarcinoma.

[Surgical repair of left ventricular aneurysm; long-term results].

OBJECTIVE: The aim of this study was to evaluate the late results of left ventricular (LV) aneurysm repair. METHODS: From July 1968 to 1999, 86 consecutive patients (74 male, 12 female, mean age 56.0 +/- 9.3) underwent LV aneurysm repair at our institute. The surgical methods were as follows; linear repair in 71 patients, endoaneurysmorrhaphy in 5, endoventricular circular plasty in 4, Jatene method in 1 and plication of aneurysm in 5. Thirty-nine patients underwent concomitant myocardial revascularization. Major arrhythmias occurred in 38 patients. The results were retrospectively reviewed and follow-up was achieved in 95.3%. RESULTS: There were 6 operative deaths and 4 hospital deaths. Actuarial survival rate including the 10 deaths was 72.7% at 5 years and 46.3% at 10 years. In patients with coronary artery bypass grafting (CABG), survival rate was 82.2% at 5 years and 56.3% at 10 years, and was significantly higher than that in those without revascularization (p = 0.01). In patients without arrhythmias, survival rate was 79.2% at 5 years and 55.0% at 10 years, and was significantly higher than that in patients with arrhythmias. CONCLUSIONS: The patients were not homologous and the techniques were not the same; however, in spite of these study limitations, patients who underwent revascularization, and were without major arrhythmias preoperatively, had better long-term survival.

An experimental study of self-expanding ureteric metallic stents: macroscopic and microscopic changes in the canine ureter.

OBJECTIVE: To evaluate the efficacy and safety of self-expanding metallic stents after insertion into the canine ureter. MATERIALS AND METHODS: Actively expanding metallic (Nitinol) stents (diameter 8-10 mm, length 4-6 cm) were placed in eight mongrel dogs (18-34 kg). Under general anaesthesia, a midline abdominal incision was made and a stent inserted directly into the ureter through a small incision; each animal was stented on one side. The dogs were assessed after 6 or 19 days or 2, 5 (two), 6 (two) and 7 months. Ureteric specimens were evaluated both macroscopically and microscopically. RESULTS: Macroscopically there was no leakage of urine in any of the animals. On day 6 the inserted stent was patent despite blood clots in the mesh. The lumen was smooth and shiny in three dogs examined at 5, 6 and 7 months. One of the two dogs assessed at both 5 and 6 months had hydronephrosis associated with papillary hyper-epithelialization inside the stent, while the other animals had no dilatation of the renal pelvis. Microscopically there was loss of epithelium and bleeding of the ureteric wall at 6 days. Epithelial regeneration started after 19 days and was complete in the lumen at 2 months, with the stent incorporated into the wall of the ureter. Epithelialization was maintained up to 7 months, after which the problem of urothelial hyperplasia persisted, but an adequate lumen was maintained by epithelial regeneration. This epithelium was smooth and shiny, and composed of thin layers of cells. CONCLUSION: Self-expanding metallic stents may be effective if hyperplastic epithelialization does not occur, as the stent was epithelialized within 2 months and the regenerated epithelium maintained for up to 7 months. Metallic stents may be useful for treating patients with renal failure caused by ureteric stenosis from malignant tumours.

[Early and mid-term results of all arterial graft coronary artery bypass grafting using bilateral internal thoracic and radial arterial conduits].

From March 1996 to May 2000, 41 patients [age 39-78 (mean 63.5 +/- 8.8) years, 90.2% male] underwent all arterial multiple coronary artery bypass grafting (CABG) using bilateral internal thoracic (BiITA) and radial (RA) arterial conduits. The reason for using RA was that the right gastroepiploic artery (RGEA) was small or occluded on preoperative angiography, a history of upper abdominal surgery or disease, or the right coronary arterial lesion was proximal and mild. The BiITA were used as in situ grafts and the proximal anastomosis of RA was to the ascending aorta in all cases. All patients underwent conventional elective CABG with median sternotomy using cardiopulmonary bypass. The mean number of anastomoses was 3.3 +/- 0.5 branches and complete revascularization rate was 80.5%. Postoperative follow-up averaged 20 months and the longest was 50 months. There was no early death, and overall graft patency 2-3 weeks after surgery was 96.2% (LITA 94.0%, RITA 97.6%, RA 97.6%). Four-year actuarial survival rate was 96.4 +/- 3.5% (1 patient: 9 months, no cardiac death), and cardiac event-free rate after surgery was 89.7 +/- 4.9% [4 patients: percutaneous transluminal coronary angioplasty (PTCA)]. However, once patients were discharged from hospital, cardiac event-free rate was 100%. These excellent results suggest that all arterial graft CABG was satisfactory, and RA can be used as a third suitable arterial bypass conduit, if RGEA cannot be used or is unsuitable for use.

[Dissecting aneurysm of ventricular septum following acute inferior myocardial infarction].

Dissecting aneurysm of the ventricular septum as a complication after myocardial infarction (MI) is very rare. The patient was a 70-year-old women who was diagnosed with acute inferior MI. Three months after MI, catheterization showed a left ventricular aneurysm of the inferior wall, and left-to-right ventricular shunt flow was detected in the aneurysm. Echocardiography showed that the inferior left ventricular free wall was aneurysmal and dissected from the septal wall. Nine months after MI, chronic heart failure was uncontrollable by medication. At surgery, a tear (5 mm long) in the dissecting aneurysm of the ventricular septum was found and closed directly using 2 felt patches, and aneurysmectomy was performed using felt strips. The postoperative course was uneventful and she has been free from any complication for over 1 year.

Inhibition of lung cancer cell growth and induction of apoptosis after reexpression of 3p21.3 candidate tumor suppressor gene SEMA3B.

Semaphorins SEMA3B and its homologue SEMA3F are 3p21.3 candidate tumor suppressor genes (TSGs), the expression of which is frequently lost in lung cancers. To test the TSG candidacy of SEMA3B and SEMA3F, we transfected them into lung cancer NCI-H1299 cells, which do not express either gene. Colony formation of H1299 cells was reduced 90% after transfection with wild-type SEMA3B compared with the control vector. By contrast, only 30-40% reduction in colony formation was seen after the transfection of SEMA3F or SEMA3B variants carrying lung cancer-associated single amino acid missense mutations. H1299 cells transfected with wild-type but not mutant SEMA3B underwent apoptosis. We found that lung cancers (n = 34) always express the neuropilin-1 receptor for secreted semaphorins, whereas 82% expressed the neuropilin-2 receptor. Because SEMA3B and SEMA3F are secreted proteins, we tested conditioned medium from COS-7 cells transfected with SEMA3B and SEMA3F and found that medium from wild-type SEMA3B transfectants reduced the growth of several lung cancer lines 30-90%, whereas SEMA3B mutants or SEMA3F had little effect in the same assay. Sequencing of sodium bisulfite-treated DNA showed dense methylation of CpG sites in the SEMA3B 5' region of lung cancers not expressing SEMA3B but no methylation in SEMA3B-expressing tumors. These results are consistent with SEMA3B functioning as a TSG, the expression of which is inactivated frequently in lung cancers by allele loss and promoter region methylation.

Inactivation of human SRBC, located within the 11p15.5-p15.4 tumor suppressor region, in breast and lung cancers.

A cDNA clone encoding human SRBC [serum deprivation response factor (sdr)-related gene product that binds to c-kinase] was isolated in a yeast two-hybrid screening, with amino acids 1-304 of BRCA1 as the probe. The human SRBC gene (hSRBC) was mapped to chromosome region 11p15.5-p15.4, close to marker D11S1323, at which frequent loss of heterozygosity (LOH) has been observed in sporadic breast, lung, ovarian, and other types of adult cancers as well as childhood tumors. hSRBC-coding region mutations including frame shift and truncation mutations were detected in a few ovarian and lung cancer cell lines. More significantly, the expression of hSRBC protein was down-regulated in a large fraction [30 (70%) of 43] of breast, lung, and ovarian cancer cell lines, whereas strong expression of hSRBC protein was detected in normal mammary and lung epithelial cells. The down-regulation of hSRBC expression in cancer cells was associated with hypermethylation of CpG dinucleotides in its promoter region, and 3 (60%) of 5 primary breast tumors and 11 (79%) of 14 primary lung tumors were also found to be hypermethylated. Treatment of breast cancer MCF7 cells with 5'azacytidine and Trichostatin A resulted in expression of hSRBC, confirming DNA methylation as the mode of inactivation. Our results suggest that epigenetic or mutational inactivation of hSRBC may contribute to the pathogenesis of several types of human cancers, marking hSRBC as a candidate tumor suppressor gene.

Benefit of bilateral over single internal mammary artery grafts for multiple coronary artery bypass grafting.

BACKGROUND: The aim of this study was to evaluate the performance of bilateral internal mammary artery (BIMA) grafts in isolated CABG. METHODS AND RESULTS: Beginning in April 1985, elective primary multiple CABG for multivessel disease was performed in 1131 patients. The early and late results of 688 patients who received single internal mammary artery (SIMA) grafts and 443 patients who received BIMA grafts were compared (median follow-up, 6.15 years). Hospital mortality was not significantly different in the SIMA (0.9%) and BIMA (0.9%) groups. Graft patency was 97.3% in the BIMA group and 94.3% in the SIMA group (P<0.0001). The 7-year repeated CABG-free rate was significantly higher in the BIMA group (P=0.026). The 7-year new myocardial infarction-free rate in all patients tended to be higher in the BIMA group (P=0.06). The hazard ratio for all death or repeated CABG in patients with ejection fractions >0.4 and age <71 years was lower in the BIMA group (P=0.0499). CONCLUSIONS: Our data suggest that the use of BIMA grafts in patients with in situ coronary artery anastomoses achieves a significantly higher repeated CABG-free rate in all patients compared with the use of SIMA.

Overexpression of candidate tumor suppressor gene FUS1 isolated from the 3p21.3 homozygous deletion region leads to G1 arrest and growth inhibition of lung cancer cells.

Recently we identified FUS1 as a candidate tumor suppressor gene (TSG) in the 120 kb 3p21.3 critical region contained in nested lung and breast cancer homozygous deletions. Mutation of FUS1 is infrequent in lung cancers which we have confirmed in 40 other primary lung cancers. In addition, we found no evidence for FUS1 promoter region methylation. Because haploinsufficiency or low expression of Fus1 may play a role in lung tumorigenesis, we tested the effect of exogenously induced overexpression of Fus1 protein and found 60-80% inhibition of colony formation for non-small cell lung cancer lines NCI-H1299 (showing allele loss for FUS1) and NCI-H322 (containing only a mutated FUS1 allele) in vitro. By contrast, a similar level of expression of a tumor-acquired mutant form of FUS1 protein did not significantly suppress colony formation. Also, induced expression of Fus1 under the control of an Ecdysone regulated promoter decreased colony formation 75%, increased the doubling time twofold, and arrested H1299 cells in G1. In conclusion, our data are consistent with the hypothesis that FUS1 may function as a 3p21.3 TSG, warranting further studies of its function in the pathogenesis of human cancers.