Sterile Neutrino Search at the NEOS Experiment.

An experiment to search for light sterile neutrinos is conducted at a reactor with a thermal power of 2.8 GW located at the Hanbit nuclear power complex. The search is done with a detector consisting of a ton of Gd-loaded liquid scintillator in a tendon gallery approximately 24 m from the reactor core. The measured antineutrino event rate is 1976 per day with a signal to background ratio of about 22. The shape of the antineutrino energy spectrum obtained from the eight-month data-taking period is compared with a hypothesis of oscillations due to active-sterile antineutrino mixing. No strong evidence of 3+1 neutrino oscillation is found. An excess around the 5 MeV prompt energy range is observed as seen in existing longer-baseline experiments. The mixing parameter sin^{2}2θ_{14} is limited up to less than 0.1 for Δm_{41}^{2} ranging from 0.2 to 2.3 eV^{2} with a 90% confidence level.

Distinctive patterns of pulmonary function change according to baseline lung volume and diffusing capacity.

SETTING: Multicentre retrospective study in South Korea.OBJECTIVE: To longitudinally evaluate changes in lung volume and diffusing capacity for carbon monoxide (DLCO) with forced expiratory volume in 1 sec (FEV1).DESIGN: A total of 155 patients with chronic obstructive pulmonary disease (COPD), whose pulmonary function parameters were measured annually for 5 years, were selected from a prospective cohort in South Korea. A random coefficients model was used to estimate mean annual FEV1, lung volume parameter and DLCO change rates.RESULTS: Patients were classified into four groups based on baseline DLCO and residual volume/total lung capacity (RV/TLC) measurements. The annual FEV1 decline rate was greater in patients with low DLCO than in those with normal DLCO, with the greatest decline occurring in patients with low DLCO and normal RV/TLC. RV and RV/TLC declined in patients with high RV/TLC, whereas these increased in patients with normal RV/TLC. DLCO decreased longitudinally in all four groups, with the greatest decline occurring in patients with normal DLCO and normal RV/TLC.CONCLUSIONS: Different subgroups of patients with COPD exhibited distinctive pulmonary function change patterns. Baseline DLCO and RV/TLC may be used as physiological markers to predict long-term changes in pulmonary function.

Clinical and radiological comparison of unipedicular versus bipedicular balloon kyphoplasty for the treatment of vertebral compression fractures.

SUMMARY: To evaluate the efficacy of unipedicular kyphoplasty in the treatment of patients with osteoporotic vertebral compression fractures, we compared the pre- and postoperative clinical and radiological results in the unipedicular and bipedicular kyphoplasty groups. The clinical and radiological results of unipedicular kyphoplasty were as good as those of bipedicular kyphoplasty. INTRODUCTION: The purpose of this study was to evaluate the efficacy of unipedicular kyphoplasty in the treatment of patients with osteoporotic vertebral compression fractures. We compared the pre- and postoperative compression ratios (CRs), kyphotic angles (KAs), and visual analogue scale (VAS) scores of the patients in the unipedicular and bipedicular kyphoplasty groups. The results showed that the clinical and radiological results of unipedicular kyphoplasty were as good as those of bipedicular kyphoplasty. Percutaneous balloon kyphoplasty is a therapeutic option for patients with painful osteoporotic vertebral compression fractures (VCFs). Due to the relatively high-risk nature of the patient population, complications such as myocardial events, seizures, agitation, or dyspnea may occur and render completion of the procedure imprudent. We analyzed the clinical and radiological results of unipedicular and bipedicular balloon kyphoplasty for the treatment of vertebral compression fractures. METHODS: We retrospectively reviewed the records of 45 patients who underwent balloon kyphoplasty for the treatment of VCFs between January 2005 and April 2008. A unipedicular approach was used in 15 patients and a bipedicular approach was used in 30 patients. The CR, KA, and 100-point VAS score for pain were measured pre- and postoperatively in each patient. RESULTS: There was no significant difference in restoration of the CR (p = 0.376) and KA (p = 0.888) between the unipedicular and bipedicular kyphoplasty groups. The patients in the unipedicular group showed greater improvement in VAS score than those in the bipedicular group (p < 0.001). There were no postoperative complications, such as nerve injury or pedicle fracture, in either of the two groups. CONCLUSION: The clinical and radiological results of unipedicular balloon kyphoplasty for the treatment of VCFs were as good as those of bipedicular balloon kyphoplasty. Thus, unipedicular balloon kyphoplasty can be used as an alternative treatment for patients with VCFs.

Combined use of QuantiFERON-TB Gold assay and chest computed tomography in a tuberculosis outbreak.

OBJECTIVE: To evaluate the value of the QuantiFERON-TB Gold (QFT-G) assay and chest computed tomography (CT), in addition to the conventional use of the tuberculin skin test (TST) and chest radiography (CXR), in a contact investigation of a tuberculosis (TB) outbreak. DESIGN: In a contact investigation of a TB outbreak in a high school, TST and CXR were performed on all 1044 employees and students. QFT-G was performed on TST-positive subjects, and CT on QFT-G-positive subjects and students with TST > or =20 mm. RESULTS: TST was positive in 388 subjects (37.2%), while QFT-G was positive in 7.6% (30/394). CXR showed abnormal findings suggestive of TB in 10 (1.0%) subjects, all of whom were TST-positive and six of whom were QFT-G-positive. Findings suggestive of active TB were noted in 17 (32.7%) of 52 subjects by CT. Collectively, among 21 (1.1%) TB patients, all were TST-positive, 12 (57.1%) were QFT-G-positive and active TB was diagnosed by CT, and not by CXR, in 11 subjects. CONCLUSION: Compared to the conventional approach, the additional use of QFT-G in TST-positive subjects and chest CT in subgroups with a high probability of infection was found to be more effective in the differentiation between active TB, latent TB and non-infected subjects in a contact investigation.

Association of plasma fibrinogen concentrations and blood eosinophil counts with clinical phenotypes of COPD.

BACKGROUND: In patients with chronic obstructive pulmonary disease (COPD), the plasma fibrinogen level is associated with a decline in lung function and exacerbation of COPD. High blood eosinophil count is also associated with exacerbation of COPD in some studies but not others.OBJECTIVE: To investigate the associations between clinical phenotypes and plasma fibrinogen levels and blood eosinophil counts in patients with COPD.METHODS: Outpatients with COPD, in whom plasma fibrinogen level and blood eosinophil count were measured at least once simultaneously, were analysed retrospectively. Patients were classified into four groups, based on plasma fibrinogen level (threshold, 350 mg/dl) and blood eosinophil percentage (threshold, 2%). Clinical characteristics, comorbidities, laboratory data, COPD severity and exacerbations were compared in the four groups.RESULTS: Of 370 patients with COPD, the group with both high fibrinogen levels and eosinophil counts had more severe airflow limitation, more comorbidities and higher COPD severity indexes than the groups with low plasma fibrinogen. The annual rates of severe (0.29/year) and total (0.42/year) exacerbations were significantly higher in patients with both high fibrinogen and eosinophils than in the other three groups.CONCLUSION: Plasma fibrinogen levels and blood eosinophil counts may predict the clinical phenotype and frequency of exacerbations of COPD.

Pulmonary tuberculosis with acute respiratory failure.

The aim of the present study was to evaluate the clinical characteristics, prognoses and predictors of mortality of patients with pulmonary tuberculosis (TB) with acute respiratory failure (ARF), and to investigate the adjunctive use of corticosteroids in such cases. TB patients with ARF requiring mechanical ventilation (n = 90) were enrolled retrospectively during 1989-2006. The patients were divided into two groups: tuberculous pneumonia (TBP; n = 66), and miliary TB (MTB; n = 24). The TBP patients were older than the MTB patients (mean age 68.0 versus 54.5 yrs), and the mean+/-SD interval from hospital admission to start of anti-TB treatment was longer for the TBP than for the MTB group (5.0+/-7.0 versus 2.8+/-2.5 days). However, there was no difference in in-hospital mortality rate between the two groups (68.2 versus 58.3%). In the TBP patients, multivariate analysis showed that advanced age and shock unrelated to sepsis were associated with poor outcomes. Even though corticosteroid use was a predictor of survival in TBP patients, it was difficult to conclusively determine the efficacy of corticosteroids in TBP with ARF because of the retrospective study design. The present study reveals the need for randomised controlled trials to clarify the role of corticosteroids as adjunctive therapy in the management of tuberculous pneumonia with acute respiratory failure.

Incidence of tuberculosis among health care workers at a private university hospital in South Korea.

SETTING: A private university hospital in South Korea. OBJECTIVE: To investigate the incidence of tuberculosis (TB) among health care workers (HCWs) employed at a university hospital in South Korea. DESIGN: The occurrence of TB cases among HCWs over a 6-year period (2001-2006) was reviewed. The prevalence of TB was compared with that of the general population using a prevalence ratio (PR) adjusted by age and sex. RESULTS: The study involved 8433 people. TB developed in 61 HCWs (0.72%). The prevalence ratio among all HCWs was 1.05 (95%CI 0.80-1.35). In occupational subgroups, the PRs for doctors, nurses and employees in other departments were respectively 0.58 (95%CI 0.30-1.01), 1.81 (95%CI 1.21-2.59) and 0.95 (95% CI 0.58-1.46). For nurses working in TB-related departments, the relative risk of developing TB was 3.4 times higher (95%CI 1.52-8.25) than for employees in other departments (P=0.005). The PR for nurses working in TB-related department was 5.1 (95%CI 3.23-8.42). CONCLUSION: Among HCWs, nurses working in TB-related departments were at increased risk of developing TB. This suggests that some TB develops via in-hospital infection.

Comparison of manikin versus porcine models in cricothyrotomy procedure training.

OBJECTIVE: To compare the usefulness for training of a porcine model (larynx, trachea, and pig skin) and a manikin model using a Portex cricothyrotomy kit (PCK). METHODS: In a prospective randomised crossover trial, participants in the airway workshop performed crico-thyrotomy using a PCK on the porcine and manikin models (Tracheostomy Trainer and Case). The porcine model was made with larynxes and trachea from freshly slaughtered pigs and covered with a piece of thinned pigskin stapled to a wooden board. Participants were asked to assess the following: reality of skin turgor; difficulty with skin penetration, landmark recognition and procedure; reality of the model; and preference for each model using a visual analogue scale (VAS) of 0-10 cm. The VAS scores for each model were compared. RESULTS: 49 participants were included in the study. Mean (SD) VAS scores for the reality of skin turgor, degree of difficulty with skin penetration and landmark recognition were higher with the porcine model than with the manikin model (7.0 (2.1) vs 4.7 (2.0), 6.4 (2.4) vs 3.6 (2.2), 5.1 (2.2) vs 4.2 (2.5), respectively). There was no difference between the models in the difficulty of the procedure (5.0 (2.4) vs 4.7 (3.2)). The porcine model had a higher VAS score for overall reality and preference of the model (7.1 (2.0) vs 4.8 (2.3) and 7.1 (2.0) vs 4.8 (2.2), respectively). CONCLUSION: The porcine model is a more useful training tool than the manikin model for cricothyrotomy with PCK because of its reality and similarity to human anatomy.

Identification of chronic obstructive pulmonary disease subgroups in 13 Asian cities.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a heterogeneous condition that can differ in its clinical manifestation, structural changes and response to treatment. OBJECTIVE: To identify subgroups of COPD with distinct phenotypes, evaluate the distribution of phenotypes in four related regions and calculate the 1-year change in lung function and quality of life according to subgroup. METHODS: Using clinical characteristics, we performed factor analysis and hierarchical cluster analysis in a cohort of 1676 COPD patients from 13 Asian cities. We compared the 1-year change in forced expiratory volume in one second (FEV1), modified Medical Research Council dyspnoea scale score, St George's Respiratory Questionnaire (SGRQ) score and exacerbations according to subgroup derived from cluster analysis. RESULTS: Factor analysis revealed that body mass index, Charlson comorbidity index, SGRQ total score and FEV1 were principal factors. Using these four factors, cluster analysis identified three distinct subgroups with differing disease severity and symptoms. Among the three subgroups, patients in subgroup 2 (severe disease and more symptoms) had the most frequent exacerbations, most rapid FEV1 decline and greatest decline in SGRQ total score. CONCLUSION: Three subgroups with differing severities and symptoms were identified in Asian COPD subjects.

Impact of short-term exposure to fluoroquinolones on ofloxacin resistance in HIV-negative patients with tuberculosis.

SETTING: Seoul, Korea, a country with an intermediate tuberculosis (TB) burden and low prevalence of human immunodeficiency virus (HIV) infection. OBJECTIVES: To determine the frequency of ofloxacin (OFX) resistance in Mycobacterium tuberculosis, and to assess whether short-term use of fluoroquinolones (FQNs) induces ofloxacin-resistant M. tuberculosis. DESIGN: The subject cohort consisted of 2788 patients with culture-confirmed TB with drug susceptibility testing data; only four were HIV-positive. The patients were divided into two groups: those who were or were not recently exposed to FQNs. RESULTS: Of the 2788 isolates, the rates of OFX resistance were 1.1% and 8.5% in initially treated and retreated patients, respectively (P < 0.05). Of the 94 OFX-resistant isolates, 83 (88.3%) were multidrug-resistant (MDR). There was no difference in rates of OFX resistance throughout the study period, or between the FQN-exposed (1/39, 2.6%) and control groups (93/2749, 3.4%). The median duration of FQN treatment was 7 days (range 1-47 days). One OFX-resistant isolate in the FQN-exposed group was MDR. CONCLUSION: The rate of OFX-resistant M. tuberculosis was low and stationary throughout the study period in Korea. Most OFX resistance was accompanied by MDR, and the frequency of OFX-resistant M. tuberculosis was low in subjects taking short-term FQNs.

Deep tracheal laceration after balloon dilation for benign tracheobronchial stenosis: case reports of two patients.

We report two cases of deep tracheal laceration in female patients after balloon dilation for benign tracheobronchial stenosis. Immediate post-procedure bronchoscopy and CT including 3D reconstructions showed deep lacerations in the posterior tracheal wall. Clinically, the patients' dyspnoea subsided and there has been no recurrence during follow-up after balloon dilation. On the follow-up 3D-reconstructed CT scans obtained 2 months and 8 months following balloon dilation, respectively, the lacerations had healed completely and there was considerable improvement in lumen size.

Factors affecting the trajectory of health-related quality of life in COPD patients.

BACKGROUND: Health-related quality of life (HR-QoL) is an important issue in patients with chronic obstructive pulmonary disease (COPD), as in other chronic illness groups. However, there is limited information on longitudinal changes in HR-QoL over time with the illness trajectory model. OBJECTIVE: To identify different patterns of HR-QoL changes in longitudinal data, and reveal potential predictors affecting these trajectories. METHODS: Subjects with COPD (n = 249) were drawn from the Korean Obstructive Lung Disease cohort, which was conducted from 2005 to 2012. Longitudinal data were drawn from the St George's Respiratory Questionnaire and clinical measures. Growth mixture modelling was used to estimate distinct patterns, and binary and ordinal logistic regression were used to determine factors affecting different trajectory HR-QoL patterns using STATA 12.0. RESULTS: Five distinct HR-QoL patterns were identified. Results show that the level of baseline HR-QoL was significantly associated with age, the BODE (Body mass index, airflow Obstruction, Dyspnea, and Exercise capacity) index at baseline, sleep disturbance, experience of exacerbation in previous year and level of depression. Distinct patterns in HR-QoL that improved vs. worsened were significantly associated with BODE index, number of respiratory symptoms and depression level. CONCLUSIONS: These findings suggest that comprehensive assessment and individualised management programmes are needed to improve HR-QoL in COPD patients.

Vertebral compression fractures may increase mortality in male patients with chronic obstructive pulmonary disease.

BACKGROUND: Vertebral compression fracture (VCF) is frequent in chronic obstructive pulmonary disease (COPD) patients. However, little is known about whether VCF affects mortality in COPD patients. OBJECTIVE: To investigate whether VCFs might increase death in COPD patients. METHODS: In this retrospective cohort study, we enrolled 254 COPD patients with a recent history of hospitalisation due to respiratory problems. Patients were assessed for VCF using quantitative morphometric analyses of lateral chest radiographs; 211 patients received follow-up examinations for 2 years. RESULTS: Of the 211 COPD patients analysed, 60 (28.4%) had VCF at enrolment. During the follow-up period, 33/60 (55.0%) patients with and 46/151 patients (30.5%) without VCF died (P = 0.003, log-rank test). Cox proportional hazard analysis revealed that VCF is an independent risk factor for death after adjusting for age, sex, body mass index, smoking, dyspnoea scale, forced expiratory volume in 1 sec (FEV1) and comorbidities (hazard ratio for VCF = 1.79, 95%CI 1.11-2.89, P = 0.02). CONCLUSION: VCF might be an independent risk factor for death in male COPD patients.

Asthma and COPD overlap syndrome is associated with increased risk of hospitalisation.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is associated with poor prognosis and a high health care burden. The incidence of asthma and COPD overlap syndrome is increasing, and contributes to a high financial burden and poor prognosis. OBJECTIVE: To investigate clinical features of the overlap syndrome among Asian patients and to analyse its impact on hospitalisation due to respiratory problems or death compared to COPD alone. DESIGN: We performed a retrospective cohort analysis of 2933 COPD patients presenting at the Asan Medical Center from 1 January 2000 to 31 December 2009. Kaplan-Meier and Cox proportional hazard models were used to analyse the significance of clinical parameters, including age, sex, smoking history, body mass index (BMI), severity of airflow limitation, airway obstruction reversibility and overlap syndrome with hospitalisation due to respiratory problems or death. RESULTS: Overlap syndrome patients were older, included smaller proportions of males and of smokers and had lower forced expiratory volume in 1 s (FEV1) (% predicted). Shorter hospitalisation-free and survival periods were noted among overlap syndrome patients. Overlap syndrome was significantly associated with risk of hospitalisation due to respiratory problems after adjusting for age, smoking history, BMI, FEV1 (% predicted) and changes in FEV1 (P < 0.001). CONCLUSION: Asthma and COPD overlap syndrome is associated with a higher risk of hospitalisation due to respiratory problems than COPD alone.

Synthetic lethal screening reveals FGFR as one of the combinatorial targets to overcome resistance to Met-targeted therapy.

Met is a receptor tyrosine kinase that promotes cancer progression. In addition, Met has been implicated in resistance of tumors to various targeted therapies such as epidermal growth factor receptor inhibitors in lung cancers, and has been prioritized as a key molecular target for cancer therapy. However, the underlying mechanism of resistance to Met-targeting drugs is poorly understood. Here, we describe screening of 1310 genes to search for key regulators related to drug resistance to an anti-Met therapeutic antibody (SAIT301) by using a small interfering RNA-based synthetic lethal screening method. We found that knockdown of 69 genes in Met-amplified MKN45 cells sensitized the antitumor activity of SAIT301. Pathway analysis of these 69 genes implicated fibroblast growth factor receptor (FGFR) as a key regulator for antiproliferative effects of Met-targeting drugs. Inhibition of FGFR3 increased target cell apoptosis through the suppression of Bcl-xL expression, followed by reduced cancer cell growth in the presence of Met-targeting drugs. Treatment of cells with the FGFR inhibitors substantially restored the efficacy of SAIT301 in SAIT301-resistant cells and enhanced the efficacy in SAIT301-sensitive cells. In addition to FGFR3, integrin ß3 is another potential target for combination treatment with SAIT301. Suppression of integrin ß3 decreased AKT phosphorylation in SAIT301-resistant cells and restored SAIT301 responsiveness in HCC1954 cells, which are resistant to SAIT301. Gene expression analysis using CCLE database shows that cancer cells with high levels of FGFR and integrin ß3 are resistant to crizotinib treatment, suggesting that FGFR and integrin ß3 could be used as predictive markers for Met-targeted therapy and provide a potential therapeutic option to overcome acquired and innate resistance for the Met-targeting drugs.

A case of parenchymal pulmonary endometriosis.

Pulmonary Endometriosis is a rare disease entity and we report a 23-year-old single woman with a history of hemoptysis in association with menstruation. She was previously treated effectively with hormone therapy for 3 months, but decided to undergo surgical resection because of the high cost of hormone therapy. Radiographic finding of the chest showed haziness in the right lower lung field, and chest CT showed a ground-glass appearance in the posterobasal and laterobasal segment. The patient underwent basal segmentectomy of the right lower lobe. There was no incidence of hemoptysis during her menstruation following the operation.

Unique features of non-obstructive emphysema and pure airway obstruction.

SETTING: Emphysema without airway obstruction or airway obstruction without emphysema are often detected clinically, although they are commonly co-existent. We therefore tested the hypothesis that non-obstructive emphysema and pure airway obstruction have unique features. METHODS: A case-control observation study was undertaken retrospectively in a patient cohort at a single centre. Among 2662 subjects who underwent chest computed tomography and pulmonary function tests, we enrolled 90 patients with non-obstructive emphysema, 119 with pure airway obstruction, 81 with obstructive emphysema and 2031 subjects as normal controls. The features of the four groups were analysed and compared. RESULTS: Higher serum homocysteine (13.4 ± 7.4 vs. 11.6 ± 4.6 mol/l), higher rate of osteoporosis (15.8% vs. 4.5%), higher leukocyte count, higher male ratio, lower serum albumin and lower body mass index were observed in subjects with non-obstructive emphysema than in controls (P < 0.05). In multiple logistic regression analysis of groups without airway obstruction, osteoporosis, hyperhomocysteinaemia, hypoalbuminaemia and higher leukocyte count were independent factors associated with non-obstructive emphysema (P < 0.05). CONCLUSION: Hyperhomocysteinaemia, hypoalbuminaemia, osteoporosis and higher leukocyte count were independent predictors of non-obstructive emphysema.

Emphysematous phenotype is an independent predictor for frequent exacerbation of COPD.

SETTING: Frequent exacerbation is an important phenotype in chronic obstructive pulmonary disease (COPD), while emphysema is associated with many comorbidities and lung function decline. OBJECTIVE: To investigate unique features of frequent exacerbators and test the hypothesis that emphysematous phenotype is associated with frequent exacerbations of COPD. METHODS: A total of 380 COPD patients were recruited from 16 hospitals in Korea from June 2005 to April 2012 for analysis. We searched for independent predictors of frequent exacerbators in comparison with non-exacerbators. RESULTS: As the severity of emphysema increased, forced expiratory volume in 1 s (FEV1), and FEV1/FVC (forced volume capacity) worsened; hyperinflationary features characterised by higher total lung capacity (TLC) were observed (P < 0.05). Frequent exacerbators had lower body mass index (BMI), higher St George's Respiratory Questionnaire (SGRQ) scores, higher residual volume (RV)/TLC, more severe airflow limitation (lower FEV1 and FEV1/FVC), lower carbon monoxide diffusion capacity, lower serum protein levels and a higher emphysema index than non-exacerbators (P < 0.05). In multivariate analysis, frequent exacerbators were independently associated with a higher emphysema index, lower serum protein levels and higher RV/TLC (P < 0.05). CONCLUSION: Our data show that the severity of emphysema, severe static hyperinflation and serum lower protein levels are independent predictors of frequent exacerbations in COPD patients.

Health care use and economic burden of patients with diagnosed chronic obstructive pulmonary disease in Korea.

BACKGROUND: The prevalence and economic burden of chronic obstructive pulmonary disease (COPD) are increasing worldwide. However, little information is available concerning COPD-associated health care use and costs in Korea. OBJECTIVE: To analyse 1) health care use, medical costs and medication use in 2009, and 2) changes in costs and medication use over 5 years (2006-2010). DESIGN: Using the database of the Korean Health Insurance Review and Assessment Service, COPD patients were identified by searching on both ICD-10 codes and COPD medication. RESULTS A total of 192,496 COPD patients were identified in 2009. Total medical costs per person were US$2803 ± 3865; the average annual number of days of out-patient care and days of hospitalisation were respectively 40 ± 36 and 11 ± 33. Methylxanthine and systemic beta-agonists were the most frequently used drugs. However, the number of prescriptions for long-acting muscarinic antagonist increased rapidly. The total cost of COPD-related medications increased by 33.1% over 5 years. CONCLUSION: The present study provides new insight into health care use and the economic burden of COPD in Korea. Changing patterns of COPD-related medication use could help inform COPD management policies.

Cbl-independent degradation of Met: ways to avoid agonism of bivalent Met-targeting antibody.

The Met receptor tyrosine kinase, found to be constitutively activated in many tumors, has become a leading target for cancer therapy. Disruptions in Met downregulation have been associated with aggressive tumor progression with several therapeutic strategies addressing this aspect of Met biology. Castias B-lineage lymphoma (Cbl) E3 ligase-mediated degradation, which attenuates Met signaling via ligand-dependent Met internalization, is a major negative regulator of Met expression. It is believed that one of the mechanisms by which the therapeutic anti-Met antibodies induce cancer cell death in Met overexpressing tumors is via internalization and subsequent degradation of Met from the cell surface. However, a previously reported Met-targeting antibody demonstrated intrinsic agonistic activity while being capable of inducing Cbl-mediated degradation of Met, suggesting that Cbl-mediated degradation requires receptor activation and impedes therapeutic application. We have developed a potent and selective bivalent Met-targeting antibody (SAIT301) that invokes Met degradation using an alternative regulator LRIG1. In this report, we demonstrate that LRIG1 mediates degradation of Met by SAIT301 and this degradation does not require Met activation. Furthermore, SAIT301 was able to downregulate Met and dramatically inhibit growth of tumors with low or no Cbl expression, as well as tumors with Met exon 14 deletion that prevents Met binding to Cbl. In summary, we demonstrate the enhanced therapeutic potential of a novel tumor-inhibiting anti-Met antibody, SAIT301, which utilizes a Cbl-independent, LRIG1-mediated Met degradation pathway and thereby avoids the agonism that limits the effectiveness of previously reported anti-Met antibodies.