Read Count Patterns and Detection of Cancerous Copy Number Alterations in Plasma Cell-Free DNA Whole Exome Sequencing Data for Advanced Non-Small Cell Lung Cancer.

Plasma cell-free DNA (cfDNA) sequencing data have been widely studied for early diagnosis and treatment response or recurrence monitoring of cancers because of the non-invasive benefits. In cancer studies, whole exome sequencing (WES) is mostly used for discovering single nucleotide variants (SNVs), but it also has the potential to detect copy number alterations (CNAs) that are mostly discovered by whole genome sequencing or microarray. In clinical settings where the quantity of the acquired blood from the patients is limited and where various sequencing experiments are not possible, providing various types of mutation information such as CNAs and SNVs using only WES will be helpful in the treatment decision. Here, we questioned whether the plasma cfDNA WES data for patients with advanced non-small cell lung cancer (NSCLC) could be exploited for CNA detection. When the read count (RC) signals of the WES data were investigated, a similar fluctuation pattern was observed among the signals of different samples, and it can be a major challenge hindering CNA detection. When these RC patterns among cfDNA were suppressed by the method we proposed, the cancerous CNAs were more distinguishable in some samples with higher cfDNA quantity. Although the potential to detect CNAs using the plasma cfDNA WES data for NSCLC patients was studied here, further studies with other cancer types, with more samples, and with more sophisticated techniques for bias correction are required to confirm our observation. In conclusion, the detection performance for cancerous CNAs can be improved by controlling RC bias, but it depends on the quantity of cfDNA in plasma.

High resolution metabolomics to discriminate compounds in serum of male lung cancer patients in South Korea.

BACKGROUND: The cancer death rate escalated during 20th century. In South Korea, lung cancer is expected to contribute 12,736 deaths in men, the highest amount among all cancers. Several risk factors may increase the chance to acquiring lung cancer, with mostly related to exogenous compounds found in cigarette smoke and synthetic manufacturing materials. As the mortality rate of lung cancer increases, deeper understanding is necessary to explore risk factors that may lead to this malignancy. In this regard, this study aims to apply high resolution metabolomics (HRM) using LC-MS to detect significant compounds that might contribute in inducing lung cancer and find the correlation of these compounds to the subjects' smoking habit. METHODS: The comparison was made between healthy control and lung cancer groups for metabolic differences. Further analyses to determine if these differences are related to tobacco-induced lung cancer (past-smoker control vs. past-smoker lung cancer patients (LCPs) and non-smoker control vs. current-smoker LCPs) were selected. The univariate analysis was performed, including a false discovery rate (FDR) of q = 0.05, to determine the significant metabolites between the analyses. Hierarchical clustering analysis (HCA) was done to discriminate metabolites between the control and case subjects. Selected compounds based on significant m/z features of human serum then experienced MS/MS examination, showing that for many m/z, the patterns of ion dissociation matched with standards. Then, the significant metabolites were identified using Metlin database and features were mapped on the human metabolic pathway mapping tool of the Kyoto Encyclopedia of Genes and Genomes (KEGG). RESULTS: Using metabolomics-wide association studies, metabolic changes were observed among control group and lung cancer patients. Bisphenol A (211.11, [M + H-H2O](+)), retinol (287.23, [M + H](+)) and L-proline (116.07, [M + H](+)) were among the significant compounds found to have contributed in the discrimination between these groups, suggesting that these compounds might be related in the development of lung cancer. Retinol has been seen to have a correlation with smoking while both bisphenol A and L-proline were found to be unrelated. CONCLUSIONS: Two potential biomarkers, retinol and L-proline, were identified and these findings may create opportunities for the development of new lung cancer diagnostic tools.

Belotecan/cisplatin versus etoposide/cisplatin in previously untreated patients with extensive-stage small cell lung carcinoma: a multi-center randomized phase III trial.

BACKGROUND: No novel chemotherapeutic combinations have demonstrated superior efficacy to etoposide/cisplatin (EP), a standard treatment regimen for extensive-stage small cell lung carcinoma (ES-SCLC) over the past decade. We aimed to compare the efficacy and safety of belotecan/cisplatin (BP) and EP regimens in chemotherapy- and radiotherapy-naïve patients with previously untreated ES-SCLC. METHODS: We conducted a multi-center, randomized, open-label, parallel-group, phase III clinical study. A total of 157 patients were recruited at 14 centers with 147 patients meeting the inclusion/exclusion criteria and randomized to either BP (n = 71) or EP (n = 76) treatment arms. A non-inferior response rate (RR) in the BP arm, analyzed by intent-to-treat analysis according to Response Evaluation Criteria in Solid Tumors version 1.0 criteria, was used as the primary endpoint. The secondary endpoints were progression-free survival (PFS) and overall survival (OS). RESULTS: In the BP arm, one patient had a complete response, 41 had a partial response (PR), and 17 had stable disease (SD). In the EP arm, 35 patients had PR and 28 had SD. The RR in the BP arm was non-inferior to the EP regimen in patients with ES-SCLC (BP: 59.2 %, EP: 46.1 %, difference: 13.1 %, 90 % two-sided confidence interval: -0.3-26.5, meeting the predefined non-inferiority criterion of -15.0 %). No significant differences in OS or PFS were observed between the treatment arms. Hematologic toxicities, including grade 3/4 anemia and thrombocytopenia, were significantly more prevalent in the BP arm than the EP arm. CONCLUSIONS: The RR to the BP regimen was non-inferior to the EP regimen in chemotherapy- and radiotherapy-naïve patients with previously untreated ES-SCLC. Hematologic toxicities were significantly more prevalent in the BP group, indicating that BP should be used with care, particularly in patients with a poor performance status. Further studies assessing PFS and OS are required to validate the superiority of the BP regimen. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT00826644 . Date of Registration: January 21, 2009.

The Mining Minds digital health and wellness framework.

BACKGROUND: The provision of health and wellness care is undergoing an enormous transformation. A key element of this revolution consists in prioritizing prevention and proactivity based on the analysis of people's conducts and the empowerment of individuals in their self-management. Digital technologies are unquestionably destined to be the main engine of this change, with an increasing number of domain-specific applications and devices commercialized every year; however, there is an apparent lack of frameworks capable of orchestrating and intelligently leveraging, all the data, information and knowledge generated through these systems. METHODS: This work presents Mining Minds, a novel framework that builds on the core ideas of the digital health and wellness paradigms to enable the provision of personalized support. Mining Minds embraces some of the most prominent digital technologies, ranging from Big Data and Cloud Computing to Wearables and Internet of Things, as well as modern concepts and methods, such as context-awareness, knowledge bases or analytics, to holistically and continuously investigate on people's lifestyles and provide a variety of smart coaching and support services. RESULTS: This paper comprehensively describes the efficient and rational combination and interoperation of these technologies and methods through Mining Minds, while meeting the essential requirements posed by a framework for personalized health and wellness support. Moreover, this work presents a realization of the key architectural components of Mining Minds, as well as various exemplary user applications and expert tools to illustrate some of the potential services supported by the proposed framework. CONCLUSIONS: Mining Minds constitutes an innovative holistic means to inspect human behavior and provide personalized health and wellness support. The principles behind this framework uncover new research ideas and may serve as a reference for similar initiatives.

Design, implementation and validation of a novel open framework for agile development of mobile health applications.

The delivery of healthcare services has experienced tremendous changes during the last years. Mobile health or mHealth is a key engine of advance in the forefront of this revolution. Although there exists a growing development of mobile health applications, there is a lack of tools specifically devised for their implementation. This work presents mHealthDroid, an open source Android implementation of a mHealth Framework designed to facilitate the rapid and easy development of mHealth and biomedical apps. The framework is particularly planned to leverage the potential of mobile devices such as smartphones or tablets, wearable sensors and portable biomedical systems. These devices are increasingly used for the monitoring and delivery of personal health care and wellbeing. The framework implements several functionalities to support resource and communication abstraction, biomedical data acquisition, health knowledge extraction, persistent data storage, adaptive visualization, system management and value-added services such as intelligent alerts, recommendations and guidelines. An exemplary application is also presented along this work to demonstrate the potential of mHealthDroid. This app is used to investigate on the analysis of human behavior, which is considered to be one of the most prominent areas in mHealth. An accurate activity recognition model is developed and successfully validated in both offline and online conditions.

mDurance: A Novel Mobile Health System to Support Trunk Endurance Assessment.

Low back pain is the most prevalent musculoskeletal condition. This disorder constitutes one of the most common causes of disability worldwide, and as a result, it has a severe socioeconomic impact. Endurance tests are normally considered in low back pain rehabilitation practice to assess the muscle status. However, traditional procedures to evaluate these tests suffer from practical limitations, which potentially lead to inaccurate diagnoses. The use of digital technologies is considered here to facilitate the task of the expert and to increase the reliability and interpretability of the endurance tests. This work presents mDurance, a novel mobile health system aimed at supporting specialists in the functional assessment of trunk endurance by using wearable and mobile devices. The system employs a wearable inertial sensor to track the patient trunk posture, while portable electromyography sensors are used to seamlessly measure the electrical activity produced by the trunk muscles. The information registered by the sensors is processed and managed by a mobile application that facilitates the expert's normal routine, while reducing the impact of human errors and expediting the analysis of the test results. In order to show the potential of the mDurance system, a case study has been conducted. The results of this study prove the reliability of mDurance and further demonstrate that practitioners are certainly interested in the regular use of a system of this nature.

Phase II open-label multicenter study to assess the antitumor activity of afatinib in lung cancer patients with activating epidermal growth factor receptor mutation from circulating tumor DNA: Liquid-Lung-A.

BACKGROUND: Mutation analysis of circulating tumor DNA (ctDNA) is used for diagnosing lung cancer. This trial aimed to assess the efficacy of afatinib in treatment-naïve patients with lung cancer harboring epidermal growth factor receptor mutations (EGFRm, exon 19 deletions or exon 21 point mutations) detected based on ctDNA. METHODS: The primary objective was the objective response rate (ORR) in the response evaluable (RE) population. EGFRm analysis of ctDNA was performed using PANA Mutype. Of the 331 patients screened, ctDNA was positive in 21% (68/331) in the detection of activating EGFRm. Among 81 subjects with tumor EGFRm, 48 showed matched EGFRm in their ctDNA (59% sensitivity). RESULTS: Therapy with afatinib 40 mg was initiated in 21 (female, 17; adenocarcinoma, 20) patients (intention-to-treat, ITT); dose modifications were made in 15 (71%). The ORR was 74% in the RE population (14/19); 11 patients showed EGFRm only in ctDNA (Group A), whereas 10 exhibited the same EGFRm in their ctDNA and tumor DNA (Group B). There was no significant difference in ORR between Groups A and B (80% and 67% RE, respectively). Median progression-free survival (PFS) was 12.0 months, and no significant difference was observed according to the final afatinib dose, type of EGFRm, and Group A versus B. After progression, T790M mutation was found in 40% (6/15) of patients, and osimertinib was used as a second-line treatment. CONCLUSIONS: Afatinib showed similar ORR and PFS in patients with lung cancer harboring EGFRm in their ctDNA regardless of tumor EGFRm results. KEY POINTS: SIGNIFICANT FINDINGS OF THE STUDY: Afatinib showed favorable ORR and PFS regardless of the tumor EGFR mutation status results, similar to the findings of previous trials assessing afatinib as first-line treatment of EGFR-mutated non-small cell lung cancer based on tumor genotyping. WHAT THIS STUDY ADDS: Our findings emphasize that the survival benefit of afatinib treatment can be achieved not only by appropriate dose reduction with frequent and detailed monitoring of toxicities, but also by using noninvasive (ctDNA) assays in a real-world setting.

Association of snoring with chronic bronchitis.

BACKGROUND: Snoring is more prevalent in patients with chronic bronchitis than in persons without it. Few studies have examined the effect of snoring on chronic bronchitis. We prospectively investigated the association between snoring and the incidence of chronic bronchitis. METHODS: The baseline study was conducted from June 25, 2001, to January 29, 2003. Members of the study cohort consisted of 5015 male and female Korean citizens aged 40 to 69 years at baseline who participated in a comprehensive health examination and on-site interviews at Korea University Ansan Hospital. Of these, 4270 participants (52% men and 48% women) entered the analysis for the first 2-year follow-up from April 17, 2003, to February 20, 2005, and those who met the same inclusion criteria remained in the analysis for a second 2-year follow-up period from February 21, 2005, to November 17, 2006. We collected information on snoring at baseline and identified incident cases of chronic bronchitis during a 4-year follow-up period. On the baseline questionnaire, we excluded participants who reported the presence of cough and sputum production on most days for at least 3 months a year. RESULTS: During 4 years of follow-up, we documented 314 cases of new-onset chronic bronchitis (27.1 cases per 1000 person-years). After taking into account age, smoking, and other risk factors for chronic bronchitis, the multivariate relative risks of chronic bronchitis were 1.25 (95% confidence interval [CI], 0.95-1.64) for persons snoring 5 times per week or less and 1.68 (95% CI, 1.17-2.42) for those snoring 6 to 7 times per week compared with never snorers (P for trend = .049). The analyses stratified by risk factors, including smoking, occupation, and body mass index, showed a stronger association among never smokers, house workers, and overweight persons. In analysis for the joint effect of smoking and snoring, the relative risks of chronic bronchitis were 1.39 (95% CI, 1.01-1.90) for nonsmoking and snoring, 2.31 (95% CI, 1.38-3.87) for smoking and never snoring, and 2.86 (95% CI, 1.91-4.27) for smoking and snoring compared with nonsmoking and never snoring. CONCLUSIONS: This prospective study observed that snoring is associated with chronic bronchitis. Our findings provide support for the hypothesis that snoring influences the development of chronic bronchitis.

Aspiration pneumonia due to polyethylene glycol-electrolyte solution (Golytely) treated by bronchoalveolar lavage.

Polyethylene glycol (PEG)-electrolyte solution (Golytely), is most commonly used for bowel preparation before colonoscopy, as well as for barium enema and colon surgery. In this case, a 70-year-old man developed ARDS following the administration of Golytely by mouth before a scheduled colonoscopy. Aspiration of PEG-electrolyte solution was suspected, and the patient was successfully treated by BAL. Therefore, early bronchoscopy and BAL should be considered as initial treatment for PEG aspiration, because removal of PEG is most important for managing the disease.

Comparisons of ergonomic evaluation tools (ALLA, RULA, REBA and OWAS) for farm work.

INTRODUCTION: The purpose of this study was to validate the agricultural lower limb assessment (ALLA) ergonomic checklist, which was developed for various agricultural tasks in Korea. METHODS: One hundred and ninety-six working postures were selected from the real agricultural tasks to verify ALLA, a lower limb body posture assessment tool, and then evaluated by 16 ergonomic experts. Hit rate, quadratic weighted κ, one-way analysis of variance and t-test analyses were applied to compare ALLA with other assessment tools. RESULTS: ALLA analysis had a superior hit rate with ergonomic expert assessment compared with other assessment tools. Quadratic weighted κ analysis also showed that ALLA provided superior estimates of risk levels for farm working postures. DISCUSSION: ALLA would be an appropriate assessment tool to estimate risk factors for various lower limb body postures which frequently occur in agricultural tasks in Korea. ALLA is a simple and accurate risk assessment tool that could be usefully applied to identify and mitigate risk factors and work-related musculoskeletal disorders in agricultural tasks, and also to evaluate the effects of control and intervention for working conditions.

Evaluation of the controlled grip force exertion tasks associated with age, gender, handedness and target force level.

INTRODUCTION: Force control of the hand is an essential factor for operating tools and moving objects. Therefore, a method for quantifying hand functionality more accurately and objectively is very important. METHODS: The present study included 60 healthy participants (30 elderly and 30 young adults) to evaluate the effects of age, gender and target force levels on tracking performance. Tracking performance was quantified by measuring the difference between target force levels and exerted force. RESULTS: Females exerted 59.6% of the maximum grip strength of males and the elderly group exerted 70.5% of maximum grip strength compared with the young group. The elderly group showed 3.1 times larger tracking error than the young group. There was a significant difference in females between the young and elderly groups, indicating age-related decline in hand function is more pronounced in females. The difference in grip force control ability between the elderly and young groups was significant at the low target force level (5% maximum voluntary contraction). CONCLUSIONS: The results of this study could be used for hand function evaluation guidelines. In addition, this study could be used as a tool for physiotherapy to improve hand function and prevent its decline in elderly people.

A pilot study identifying a potential plasma biomarker for determining EGFR mutations in exons 19 or 21 in lung cancer patients.

The most common type of lung cancer is non­small cell lung cancer (NSCLC), which is frequently characterized by a mutation in the epidermal growth factor receptor (EGFR). Determining the presence of an EGFR mutation in lung cancer is important, as it determines the type of treatment that a patients will receive. Therefore, the aim of the present study was to apply high­resolution metabolomics (HRM) using liquid chromatography­mass spectrometry to identify significant compounds in human plasma samples obtained from South Korean NSCLC patients, as potential biomarkers for providing early detection and diagnosis of minimally­invasive NSCLC. The metabolic differences between lung cancer patients without EGFR mutations were compared with patients harboring EGFR mutations. Univariate analysis was performed, with a false discovery rate of q=0.05, in order to identify significant metabolites between the two groups. In addition, hierarchical clustering analysis was performed to discriminate between the metabolic profiles of the two groups. Furthermore, the significant metabolites were identified and mapped using Mummichog software, in order to generate a potential metabolic network model. Using metabolome­wide association studies, metabolic alterations were identified. Linoleic acid [303.23 m/z, (M+Na)+], 5­methyl tetrahydrofolate [231.10 m/z, (M+2H)+] and N­succinyl­L­glutamate­5 semialdehyde [254.06 m/z, (M+Na)+], were observed to be elevated in patients harboring EGFR mutations, whereas tetradecanoyl carnitine [394.29 m/z, (M+Na)+] was observed to be reduced. This suggests that these compounds may be affected by the EGFR mutation. In conclusion, the present study identified four potential biomarkers in patients with EGFR mutations, using HRM combined with pathway analysis. These results may facilitate the development of novel diagnostic tools for EGFR mutation detection in patients with lung cancer.

Long-term clinical outcomes of the single-incision technique for implantation of implantable venous access ports via the axillary vein.

PURPOSE: To evaluate long-term clinical outcomes and complications of the single-incision technique for implantation of totally implantable venous access ports (TIVAPs) via the axillary vein. MATERIALS AND METHODS: A total of 932 TIVAPs were placed in 927 patients between May 2012 and October 2014 using a single-incision technique. Patients included 620 men and 307 women with a mean age of 60.0 years. TIVAPs were placed via the left (n = 475) and right (n = 457) axillary veins after making a single oblique vertical incision and medial side pocket without subcutaneous tunneling. We retrospectively reviewed medical records to evaluate status of the patients and TIVAPs, complications, and reasons for explantation. In patients who still had a TIVAP in place, we calculated the duration of TIVAP use from the cut-off day of November 1, 2015. RESULTS: Clinical follow-up was obtained for a total device service period of 311,069 days with a median indwelling time of 467 days (range: 3-1097 days). A total of 37 (4.0%) complications developed. Early complications (n = 4) were one case each of stenosis of the brachiocephalic vein by tumor growth, thrombosis of axillary vein, intravascular migration, and malfunction depending on patient's position. Late complications (n = 33) were suspected catheter-related blood stream infection (n = 23), local infection of the pocket (n = 4), symptomatic stenosis and thrombosis of central vein (n = 4), malfunction by fibrin sleeve (n = 1), and intravascular migration (n = 1). CONCLUSIONS: A single-incision technique for TIVAP implantation via the axillary vein seems to be safe with a low risk of complication.

Effect of platelet-rich plasma and platelet-rich fibrin on peri-implant bone defects in dogs.

The purpose of this study was to evaluate the effect of tooth ash and platelet-rich plasma (PRP), and platelet-rich fibrin (PRF) grafts into bone defects around implants on bone formation. Six adult dogs were used as experimental subjects. Graft materials were used to create a particulate material. Forty-eight tapered-type implants, 3.7 mm in diameter, 10 mm in length, and with surface treated with hydroxyapatite (HA) coating, were used as implant fixtures. Using a trephine bur, four bone defects were formed and implants were placed in the femurs of the adult dogs. Bone grafts were not performed in the control group. Tooth ash was grafted into the defects in group 1. In group 2, a mixture of tooth ash and PRP (1:1 ratio by volume) was grafted into the defects. In group 3, a mixture of tooth ash and PRF (ratio of 1:1) was grafted in the defect area. Animals were sacrificed after 4 or 8 weeks. Based on histopathological examination, the amount and rate of new bone formation were evaluated. Histomorphometric examination revealed that the rate of new bone formation in group 3 of the 4-week group was significantly higher than that in the control group. In addition, in the 8-week group, a significant increase in new bone formation was confirmed in group 3. In this study, a bone graft method using a mixture of tooth ash and PRF was found to increase new bone formation compared to the method using PRP. In addition, it was confirmed that this effect was more prominent in the initial stage of the bone graft.

Lung cancer patients who are asymptomatic at diagnosis show favorable prognosis: a korean Lung Cancer Registry Study.

PURPOSE AND METHODS: The outcomes of lung cancer patients who were asymptomatic at diagnosis have never been reported as part of a large-scale study. A national survey of lung cancer in South Korea registered a total of 8788 patients diagnosed in 2005. We report the results herein, with an emphasis on the prognosis of the asymptomatic lung cancer patients. RESULTS: Adenocarcinoma was the most frequent (36.1%) histopathologic type, followed by squamous cell carcinoma (32.1%), large cell carcinoma (1.5%), and small cell carcinoma (13.5%). In most cases, lung cancer was detected with subjective symptoms, but 6.5% of cases had no symptoms indicative of lung cancer at the time of diagnosis. Compared to symptomatic patients, asymptomatic patients were younger, more often female, non-smokers, and more frequently presented with adenocarcinoma. Initial treatments were surgery (22.1%), radiation therapy (7.8%), chemo-radiation therapy (5.4%), and chemotherapy (38%), while 26.6% of patients were recorded to have supportive care only. Asymptomatic patients received surgery in 60.0% of cases, and they showed significantly longer survival times than symptomatic patients. Absence of symptoms at diagnosis significantly reduced the risk of death from non-small cell lung cancer, regardless of patient age, patient gender, stage at diagnosis, smoking history, or whether treatment was performed, but did not reduce the risk of death from small cell lung cancer. CONCLUSIONS: Adenocarcinoma has grown to be the leading histopathologic type of lung cancer in South Korea. Absence of symptom at diagnosis is a favorable prognostic factor for patients with non-small cell lung cancer.

Renal excretion of ingested gastrografin: clinical relevance in early postoperative treatment of patients who have undergone gastric surgery.

OBJECTIVE: We performed this study to evaluate the clinical relevance of renal excretion of ingested Gastrografin (methylglucamine diatrizoate) revealed on CT in the early treatment of patients who have undergone gastric surgery. SUBJECTS AND METHODS: Unenhanced abdominal CT was performed before and then 1 hr to 1 hr 30 min after Gastrografin ingestion in 30 patients 7 days after gastric surgery and in 19 healthy adults who served as the control group. CT scans were reviewed for the opacification of the renal collecting system or urinary bladder after Gastrografin ingestion, a finding that represents renal excretion of the ingested contrast medium. RESULTS: In the control group, four (21 %) of the 19 healthy adults showed renal excretion of ingested Gastrografin visualized as opacification of the urinary tract on CT scans obtained 1 hr to 1 hr 30 min after ingestion of the substance. Renal excretion of the ingested Gastrografin was seen in 19 (63%) of the 30 patients, a significantly larger percentage than in the control group (z score, p < 0.01). No patient showed either radiologic or clinical evidence of leakage from the anastomotic site. CONCLUSION: Renal excretion of ingested Gastrografin is frequently visualized on CT in patients without anastomotic leakage during the early postoperative period after gastric surgery, and this phenomenon is not rare, even in healthy adults. Therefore, renal excretion seen on CT should not be regarded as a sign of anastomotic leakage in early postoperative patients.