Detection and characterization of lung cancer using cell-free DNA fragmentomes.

Non-invasive approaches for cell-free DNA (cfDNA) assessment provide an opportunity for cancer detection and intervention. Here, we use a machine learning model for detecting tumor-derived cfDNA through genome-wide analyses of cfDNA fragmentation in a prospective study of 365 individuals at risk for lung cancer. We validate the cancer detection model using an independent cohort of 385 non-cancer individuals and 46 lung cancer patients. Combining fragmentation features, clinical risk factors, and CEA levels, followed by CT imaging, detected 94% of patients with cancer across stages and subtypes, including 91% of stage I/II and 96% of stage III/IV, at 80% specificity. Genome-wide fragmentation profiles across ~13,000 ASCL1 transcription factor binding sites distinguished individuals with small cell lung cancer from those with non-small cell lung cancer with high accuracy (AUC = 0.98). A higher fragmentation score represented an independent prognostic indicator of survival. This approach provides a facile avenue for non-invasive detection of lung cancer.

Multimodal soft tissue markers for bridging high-resolution diagnostic imaging with therapeutic intervention.

Diagnostic imaging often outperforms the surgeon's ability to identify small structures during therapeutic procedures. Smart soft tissue markers that translate the sensitivity of diagnostic imaging into optimal therapeutic intervention are therefore highly warranted. This paper presents a unique adaptable liquid soft tissue marker system based on functionalized carbohydrates (Carbo-gel). The liquid state of these markers allows for high-precision placement under image guidance using thin needles. Based on step-by-step modifications, the image features and mechanical properties of markers can be optimized to bridge diagnostic imaging and specific therapeutic interventions. The performance of Carbo-gel is demonstrated for markers that (i) have radiographic, magnetic resonance, and ultrasound visibility; (ii) are palpable and visible; and (iii) are localizable by near-infrared fluorescence and radio guidance. The study demonstrates encouraging proof of concept for the liquid marker system as a well-tolerated multimodal imaging marker that can improve image-guided radiotherapy and surgical interventions, including robotic surgery.

Listening to music prior to bronchoscopy reduces anxiety - a randomised controlled trial.

Background: Listening to music as a means of relieving anxiety before and during endoscopy has been examined in several studies but results so far are contradictory and inconclusive. Aims: We aimed to determine whether listening to music could reduce anxiety prior to and during bronchoscopy, and whether it is influenced by the patient's preference in music. Methods: 300 patients undergoing bronchoscopy for suspected lung cancer were randomly assigned to: self-selected music, specially-designed music (MusiCureTM), or control (no sound). Spielberger's State-Trait Anxiety Inventory (STAI) was administered three times: at admission, after 20 min with or without music (preceding bronchoscopy), and shortly before discharge. The primary outcome was STAI state score after 20 min, with or without exposure to music prior to bronchoscopy. Results: On average, music reduced the STAI score by 2.5 points (95% CI, 1.1 to 4.0; p < 0.001) compared with the control group. This reduction was largest in the self-selected music group (3.4; 95% CI, 1.5 to 5.3; p < 0.001). In contrast, specially designed music did not significantly reduce STAI score (1.7; 95% CI, -0.3 to 3.6; p = 0.1). Conclusion: Listening to music reduces anxiety in patients undergoing bronchoscopy, provided that the music complies with the patient's preferences.

Bronchoscopic mucosal cryobiopsies as a method for studying airway disease.

BACKGROUND: Investigating disease mechanisms and treatment responses in obstructive airway diseases with invasive sampling are hampered by the small size and mechanical artefacts that conventional forceps biopsies suffer from. Endoscopic cryobiopsies are larger and more intact and are being increasingly used. However, the technique has not yet been explored for obtaining mucosa biopsies. OBJECTIVE: To investigate differences in size and quality of endobronchial mucosal biopsies obtained with cryotechnique and forceps. Further, to check for eligibility of cryobiopsies to be evaluated with immunohistochemistry and in situ hybridization and to investigate tolerability and safety of the technique. METHODS: Endobronchial mucosal biopsies were obtained with cryotechnique and forceps from patients with haemoptysis undergoing bronchoscopy and evaluated by quantitative morphometry, automated immunohistochemistry and in situ hybridization. RESULTS: A total of 40 biopsies were obtained from 10 patients. Cross-sectional areas were threefold larger in cryobiopsies (median: 3.08 mm2 (IQR: 1.79) vs 1.03 mm2 (IQR: 1.10), P < 0.001). Stretches of intact epithelium were 8-fold longer (median: 4.61 mm (IQR: 4.50) vs 0.55 mm (IQR: 1.23), P = 0.001). Content of glands (median: 0.095 mm2 (IQR: 0.30) vs 0.00 mm2 (IQR: 0.01), P = 0.002) and airway smooth muscle (median: 0.25 mm2 (IQR: 0.30) vs 0.060 mm2 (IQR: 0.11), P = 0.02) was higher in the cryobiopsies compared with forceps biopsies. Further, the cryobiopsies had well-preserved protein antigens and mRNA. Mild to moderate bleeding was the only complication observed. CONCLUSION AND CLINICAL RELEVANCE: By yielding significantly larger and more intact biopsies, the cryotechnique represents a valuable new research tool to explore the bronchi in airway disease. Ultimately with the potential to create better understanding of underlying disease mechanisms and improvement of treatments.

Effect of postsurgical rehabilitation programmes in patients operated for lung cancer: A systematic review and meta-analysis.

OBJECTIVE: To review the evidence concerning the effects of postoperative exercise interventions on exercise capacity and health-related quality of life following resection for non-small cell lung cancer, and to review whether different initiation times of exercise produce different effects on exercise capacity. DATA SOURCES: Comprehensive literature search of MEDLINE, Embase, CENTRAL, CINAHL and PEDro. STUDY SELECTION: Randomized controlled trials examining the effects of exercise interventions were eligible for inclusion. DATA EXTRACTION: Postoperative outcome measurements were extracted and the quality of evidence was graded using Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group. DATA SYNTHESIS: Four randomized controlled trials were identified involving 262 participants. Short-term follow-up (12-20 weeks) showed significantly higher exercise capacity and physical component of health-related quality of life in the intervention group (standardized mean difference (SMD) 0.48; 95% confidence interval (CI) 0.04-0.93) compared with the control group (SMD 0.50; 95% CI 0.19-0.82). There was no difference between the effect of late- and early-initiated exercise intervention. CONCLUSION: Exercise has a small-to-moderate effect at short-term follow-up on exercise capacity and the physical component of health-related quality of life in patients operated for lung cancer. The long-term effects of exercise capacity are unknown. Early-initiated exercise programmes (2 weeks post-operation) did not show an effect on exercise capacity. These findings should be interpreted with caution.

Changes in Health-Related Quality of Life During Rehabilitation in Patients With Operable Lung Cancer: A Feasibility Study (PROLUCA).

INTRODUCTION: Surgical resection in patients with non-small cell lung cancer (NSCLC) may be associated with significant morbidity, functional limitations, and decreased quality of life. OBJECTIVES: The objective is to present health-related quality of life (HRQoL) changes over time before and 1 year after surgery in patients with NSCLC participating in a rehabilitation program. METHODS: Forty patients with NSCLC in disease stage I to IIIa, referred for surgical resection at the Department of Cardiothoracic Surgery RT, Rigshospitalet, were included in the study. The rehabilitation program comprised supervised group exercise program, 2 hours weekly for 12 weeks, combined with individual counseling. The study endpoints were self-reported HRQoL (Functional Assessment of Cancer Therapy-Lung, European Organization for Research and Treatment in Cancer-Quality of Life Questionnaire-QLQ-C30, Short-Form-36) and self-reported distress, anxiety, depression, and social support (National Comprehensive Cancer Network Distress Thermometer, Hospital Anxiety and Depression Scale, Multidimensional Scale of Perceived Social Support), measured presurgery, postintervention, 6 months, and 1 year after surgery. RESULTS: Forty patients were included, 73% of whom completed rehabilitation. Results on emotional well-being ( P < .0001), global quality of life ( P = .0032), and mental health component score ( P = .0004) showed an overall statistically significant improvement during the study. CONCLUSION: This feasibility study demonstrated that global quality of life, mental health, and emotional well-being improved significantly during the study, from time of diagnosis until 1 year after resection, in patients with NSCLC participating in rehabilitation.

The prevalence of ALK rearrangement in pulmonary adenocarcinomas in an unselected Caucasian population from a defined catchment area: impact of smoking.

AIMS: To assess the prevalence of EML4-ALK rearrangement gene measured by immunohistochemistry in an unselected population-based consecutive cohort of patients with adenocarcinoma of the lung (ACL), and the correlation with smoking history, thyroid transcription factor 1 (TTF1), gender and age. METHODS AND RESULTS: All patients diagnosed in the population of the greater Copenhagen area were included, irrespective of gender, age, smoking habits, stage or type of available diagnostic material. Tumours were stained with immunohistochemistry (clone 5A4). Immunohistochemistry-positive tumours were tested by fluorescence in-situ hybridization (FISH). During a 16-month period, 760 patients in the population were diagnosed with ACL. In 2.6% there was insufficient material for ALK testing (20 of 760). Eleven per cent of the remaining 740 ACL patients were never smokers, 43% were ex-smokers smokers and 46% were current smokers. Fourteen patients [1.9%, 95% confidence interval (CI) = 1.1-3.2] were ALK-positive by immunohistochemistry. Nine of 82 never-smokers (11%, 95% CI = 5.9-19.6) and five of 652 ex- or current smokers (0.8%, 95% CI = 0.4-2.1) were ALK-positive. Only two ALK-positive patients were found among 586 heavy smokers (> 15 pack-years) (0.3%, 95% CI = 0.09-1.2). Thirteen of the 14 immunohistochemistry-positive patients were FISH-positive. All ALK-positive tumours were TTF1-positive. The number needed to test (NNT) to identify one ALK positive patient was 9, 22 and 293 among never smokers, light and heavy smokers, respectively. CONCLUSIONS: Immunohistochemical analysis of ALK rearrangement was possible in 97.4% of patients. ALK rearrangement was found primarily in never smokers. NNT to identify one ALK-positive patient was 9, 22 and 293 among never smokers, light and heavy smokers, respectively.

Music does not alter anxiety in patients with suspected lung cancer undergoing bronchoscopy: a randomised controlled trial.

BACKGROUND: The use of music to relieve anxiety has been examined in various studies, but the results are inconclusive. METHODS: From April to October 2015, 160 patients undergoing examination of pulmonary nodules were randomly assigned to MusiCure or no music. MusiCure was administered through earplugs to ensure blinding of the staff and was played from admission to the operating theatre to the end of the bronchoscopy. Spielberger's State-Trait Anxiety Inventory (STAI) was administered on admission, immediately before bronchoscopy, and on discharge. Secondary outcomes were p-cortisol, physiological variables, dosage of sedatives, movements measured by Actigraph, bronchoscopy duration, number of re-examinations, and overall perception of the sounds in the operating theatre measured by Visual analogue scale. RESULTS: The STAI scores were similar on admission, but after a 10-min wait in the operating theatre, scores varied significantly between patients with and without music, with lower scores in the music group [median (interquartile range, IQR) 35 (18) vs. 43 (25); p=0.03]. Post hoc multiple regression revealed treatment group as insignificant when adjusting for sex and baseline anxiety. However, there was a significantly more positive perception of the sounds in the operating theatre in the music group (median (IQR) 8.2 (1.8) vs. 5.4 (6.8); p<0.0001) and fewer re-examinations in the music group (19.2% vs. 7.7%, p<0.032). CONCLUSIONS: Ten minutes with MusiCure does not alter anxiety when adjusting for baseline anxiety and sex. The current study indicates that this field of research has many confounders.

Bronchoscopy as a supplement to computed tomography in patients with haemoptysis may be unnecessary.

BACKGROUND: Haemoptysis is a common symptom and can be an early sign of lung cancer. Careful investigation of patients with haemoptysis may lead to early diagnosis. The strategy for investigation of these patients, however, is still being debated. OBJECTIVES: We studied whether the combination of computed tomography (CT) and bronchoscopy had a higher sensitivity for malignant and non-malignant causes of haemoptysis than CT alone. METHODS: The study was a retrospective, non-randomised, two-centre study and included patients who were referred from primary care for the investigation of haemoptysis. RESULTS: A total of 326 patients were included in the study (mean age 60.5 [SD 15.3] years, 63.3% male). The most common aetiologies of haemoptysis were cryptogenic (52.5%), pneumonia (16.3%), emphysema (8.0%), bronchiectasis (5.8%) and lung cancer (4.0%). In patients diagnosed with lung cancer, bronchoscopy, CT and the combination of bronchoscopy and CT had a sensitivity of 0.61, 0.92 (p<0.05) and 0.97 (p=0.58), respectively. In patients with non-malignant causes of haemoptysis, most aetiologies were diagnosed by CT and comprised mainly pneumonia, emphysema and bronchiectasis. Bronchoscopy did not reveal these conditions and the sensitivity to these conditions was not increased by combining CT and bronchoscopy. CONCLUSIONS: CT can stand alone as a diagnostic workup for patients with haemoptysis referred to an outpatient clinic. Bronchoscopy does not identify any malignant aetiologies not already diagnosed by CT. Combining the two test modalities does not result in a significant increase in sensitivity for malignant or non-malignant causes of haemoptysis.

Perioperative Rehabilitation in Operable Lung Cancer Patients (PROLUCA): A Feasibility Study.

Introduction Surgical resection in patients with non-small cell lung cancer (NSCLC) may be associated with significant morbidity, functional limitations, and decreased quality of life. Objectives The safety and feasibility of a preoperative and early postoperative rehabilitation program in patients operated for NSCLC was determined in a nonhospital setting, with focus on high-intensity interval exercise. Methods Forty patients with biopsy-proven NSCLC stages I to IIIa referred for surgical resection at the Department of Cardiothoracic Surgery RT, Rigshospitalet, University of Copenhagen, were randomly assigned to 1 of 4 groups (3 intervention groups and 1 control group). The preoperative intervention consisted of a home-based exercise program, while the postoperative exercise program comprised a supervised group exercise program involving resistance and high-intensity interval cardiorespiratory exercise 2 hours weekly for 12 weeks combined with individual counseling. The study endpoints were inclusion rate, adherence, and number of adverse events. Results Forty patients (of 124 screened; 32%) were included and randomized into the 4 groups. The postoperative exercise was completed by 73% of the patients randomized to this intervention. No adverse events were observed, indicating that the early postoperative exercise program is safe. The preoperative home-based exercise program was not feasible due to interfering diagnostic procedures and fast-track surgery that left only 1 to 2 weeks between diagnosis and surgery. Conclusion The early postoperative exercise program for patients with NSCLC was safe and feasible, but in a fast-track set up, a preoperative home-based exercise program was not feasible for this population.

Results of the Randomized Danish Lung Cancer Screening Trial with Focus on High-Risk Profiling.

RATIONALE: As of April 2015, participants in the Danish Lung Cancer Screening Trial had been followed for at least 5 years since their last screening. OBJECTIVES: Mortality, causes of death, and lung cancer findings are reported to explore the effect of computed tomography (CT) screening. METHODS: A total of 4,104 participants aged 50-70 years at the time of inclusion and with a minimum 20 pack-years of smoking were randomized to have five annual low-dose CT scans (study group) or no screening (control group). MEASUREMENTS AND MAIN RESULTS: Follow-up information regarding date and cause of death, lung cancer diagnosis, cancer stage, and histology was obtained from national registries. No differences between the two groups in lung cancer mortality (hazard ratio, 1.03; 95% confidence interval, 0.66-1.6; P = 0.888) or all-cause mortality (hazard ratio, 1.02; 95% confidence interval, 0.82-1.27; P = 0.867) were observed. More cancers were found in the screening group than in the no-screening group (100 vs. 53, respectively; P < 0.001), particularly adenocarcinomas (58 vs. 18, respectively; P < 0.001). More early-stage cancers (stages I and II, 54 vs. 10, respectively; P < 0.001) and stage IIIa cancers (15 vs. 3, respectively; P = 0.009) were found in the screening group than in the control group. Stage IV cancers were nonsignificantly more frequent in the control group than in the screening group (32 vs. 23, respectively; P = 0.278). For the highest-stage cancers (T4N3M1, 21 vs. 8, respectively; P = 0.025), this difference was statistically significant, indicating an absolute stage shift. Older participants, those with chronic obstructive pulmonary disease, and those with more than 35 pack-years of smoking had a significantly increased risk of death due to lung cancer, with nonsignificantly fewer deaths in the screening group. CONCLUSIONS: No statistically significant effects of CT screening on lung cancer mortality were found, but the results of post hoc high-risk subgroup analyses showed nonsignificant trends that seem to be in good agreement with the results of the National Lung Screening Trial. Clinical trial registered with www.clinicaltrials.gov (NCT00496977).

Perioperative rehabilitation in operation for lung cancer (PROLUCA) - rationale and design.

BACKGROUND: The purpose of the PROLUCA study is to investigate the efficacy of preoperative and early postoperative rehabilitation in a non-hospital setting in patients with operable lung cancer with special focus on exercise. METHODS: Using a 2 x 2 factorial design with continuous effect endpoint (Maximal Oxygen Uptake (VO2peak)), 380 patients with non-small cell lung cancer (NSCLC) stage I-IIIa referred for surgical resection will be randomly assigned to one of four groups: (1) preoperative and early postoperative rehabilitation (starting two weeks after surgery); (2) preoperative and late postoperative rehabilitation (starting six weeks after surgery); (3) early postoperative rehabilitation alone; (4) today's standard care which is postoperative rehabilitation initiated six weeks after surgery. The preoperative rehabilitation program consists of an individually designed, 30-minute home-based exercise program performed daily. The postoperative rehabilitation program consists of a supervised group exercise program comprising cardiovascular and resistance training two-hour weekly for 12 weeks combined with individual counseling. The primary study endpoint is VO2peak and secondary endpoints include: Six-minute walk distance (6MWD), one-repetition-maximum (1RM), pulmonary function, patient-reported outcomes (PROs) on health-related quality of life (HRQoL), symptoms and side effects of the cancer disease and the treatment of the disease, anxiety, depression, wellbeing, lifestyle, hospitalization time, sick leave, work status, postoperative complications (up to 30 days after surgery) and survival. Endpoints will be assessed at baseline, the day before surgery, pre-intervention, post-intervention, six months after surgery and one year after surgery. DISCUSSION: The results of the PROLUCA study may potentially contribute to the identification of the optimal perioperative rehabilitation for operable lung cancer patients focusing on exercise initiated immediately after diagnosis and rehabilitation shortly after surgery. TRIAL REGISTRATION: NCT01893580.

Development and validation of a theoretical test in endosonography for pulmonary diseases.

BACKGROUND: Theoretical testing provides the necessary foundation to perform technical skills. Additionally, testing improves the retention of knowledge. OBJECTIVES: The aims of this study were to develop a multiple-choice test in endosonography for pulmonary diseases and to gather validity evidence for this test. METHODS: Initially, 78 questions were constructed after informal conversational interviews with 4 international experts in endosonography. The clarity and content validity of the questions were tested using a Delphi-like approach. Construct validity was explored by administering the test to 3 groups with different levels of endosonography experience: 27 medical students, 18 respiratory physicians with limited endosonography experience, and 14 experts in endosonography. RESULTS: Two Delphi iterations reduced the test to 52 questions. After item analysis, the final test consisted of 46 questions with a mean item discrimination of 0.47 and a mean item difficulty of 0.63. The internal consistency reliability was calculated at 0.91. The 3 groups performed significantly differently (ANOVA: p < 0.001), and post hoc tests were significant. The experts performed significantly more consistently than the novices (p = 0.037) and the intermediates (p < 0.001). CONCLUSIONS: This study provides a theoretical test in endosonography consisting of multiple-choice questions. Validity evidence was gathered, and the test demonstrated content and construct validity.

Multimodality approach to mediastinal staging in non-small cell lung cancer. Faults and benefits of PET-CT: a randomised trial.

BACKGROUND: Correct mediastinal staging is a cornerstone in the treatment of patients with non-small cell lung cancer. A large range of methods is available for this purpose, making the process of adequate staging complex. The objective of this study was to describe faults and benefits of positron emission tomography (PET)-CT in multimodality mediastinal staging. METHODS: A randomised clinical trial was conducted including patients with a verified diagnosis of non-small cell lung cancer, who were considered operable. Patients were assigned to staging with PET-CT (PET-CT group) followed by invasive staging (mediastinoscopy and/or endoscopic ultrasound with fine needle aspiration (EUS-FNA)) or invasive staging without prior PET-CT (conventional work up (CWU) group). Mediastinal involvement (dichotomising N stage into N0-1 versus N2-3) was described according to CT, PET-CT, mediastinoscopy, EUS-FNA and consensus (based on all available information), and compared with the final N stage as verified by thoracotomy or a conclusive invasive diagnostic procedure. RESULTS: A total of 189 patients were recruited, 98 in the PET-CT group and 91 in the CWU group. In an intention-to-treat analysis the overall accuracy of the consensus N stage was not significantly higher in the PET-CT group than in the CWU group (90% (95% confidence interval 82% to 95%) vs 85% (95% CI 77% to 91%)). Excluding the patients in whom PET-CT was not performed (n=14) the difference was significant (95% (95% CI 88% to 98%) vs 85% (95% CI 77% to 91%), p=0.034). This was mainly based on a higher sensitivity of the staging approach including PET-CT. CONCLUSION: An approach to lung cancer staging with PET-CT improves discrimination between N0-1 and N2-3. In those without enlarged lymph nodes and a PET-negative mediastinum the patient may proceed directly to surgery. However, enlarged lymph nodes on CT needs confirmation independent of PET findings and a positive finding on PET-CT needs confirmation before a decision on surgery is made. CLINICAL TRIAL NUMBER: NCT00867412.

Airway responses to eucapnic hyperpnea, exercise, and methacholine in elite swimmers.

PURPOSE: The International Olympic Committee Medical Commission (IOC-MC) requires athletes to provide the result of an objective test to support a diagnosis of asthma or exercise-induced bronchoconstriction (EIB) if they want to inhale a beta-2-agonist. The purpose of the study was to evaluate the airway response to a methacholine challenge and to hyperpnea induced by exercise in the field and in the laboratory or that induced voluntarily by eucapnic hyperpnea in a group of female elite swimmers. METHODS: Sixteen female nonasthmatic elite swimmers performed a eucapnic voluntary hyperpnea (EVH) test, a field-based exercise test (FBT), a laboratory-based exercise test (LBT), and a methacholine challenge. The criteria suggested by the IOC-MC were used to define a positive response to the challenges (EVH, field test, and laboratory test: minimum 10% decrease in FEV1; methacholine: PD20 < or = 2 micromol). RESULTS: Eight swimmers (50%) had at least one positive test to hyperpnea. Five were identified with the EVH test, four with FBT, and four with LBT. None were identified using methacholine. Three swimmers with airway hyperresponsiveness to exercise would have been identified using a higher cutoff for methacholine (PD20 < or = 8 micromol). CONCLUSIONS: The EVH test is the test that diagnoses most swimmers with an abnormal response to hyperpnea, but not all cases of EIB are identified with the EVH test. Performing a methacholine test using IOC-MC's cutoff value does not improve the chances of diagnosing EIB. We recommend performing the EVH test when diagnosing and evaluating EIB in elite swimmers and if EVH test negative then proceeding to a strenuous LBT.