Clinical Validation of the Canada Lymph Node Score for Endobronchial Ultrasound.

BACKGROUND: The Canada Lymph Node Score (CLNS) uses 4 sonographic criteria to predict the risk of malignancy in lymph nodes during endobronchial ultrasound. The CLNS may play a role in identifying targets for biopsy or rebiopsy during invasive mediastinal staging for lung cancer. However the CLNS has not yet been prospectively validated in routine clinical practice. METHODS: CLNSs for each lymph node biopsied during endobronchial ultrasound were prospectively captured for 1 year (2019). The CLNS and the presence of malignancy in each node were compared. Univariate binary logistic regression was completed for each ultrasonographic feature and multivariate logistic regression model. RESULTS: CLNSs and diagnostic pathology results were available for 367 lymph nodes. Incidence of malignancy increased with higher scores. Scores ≥ 3 were significantly associated with malignancy (specificity, 84.4%; positive likelihood ratio, 4.0). Area under the curve was 0.76, indicating a good ability of the model to predict presence or absence of malignancy. Nodes scoring < 2 and negative on computed tomography and positron emission tomography were malignant in 10.1%. CONCLUSIONS: The CLNS correlates with the presence or absence of malignancy in thoracic lymph nodes and may serve as an adjunct to currently available methods of invasive and noninvasive mediastinal staging. The CLNS may be most helpful in selecting which nondiagnostic lymph nodes require rebiopsy. There is a significant risk of a false-negative result even with a score of 0, and using a combination of low CLNSs and negative conventional radiology to obviate the need for any initial biopsy remains to be studied in prospective trials.

Routine systematic sampling versus targeted sampling during endobronchial ultrasound: A randomized feasibility trial.

OBJECTIVE: Triple normal lymph nodes, appearing benign on computed tomography, positron emission tomography, and endobronchial ultrasound, have less than a 6% probability of malignancy. We hypothesized that targeted sampling (TS), which omits biopsy of triple normal lymph nodes during endobronchial ultrasound, is not an inferior staging strategy to systematic sampling (SS) of all lymph nodes. METHODS: A prospective randomized feasibility trial was conducted to decide on the progression to a pan-Canadian trial comparing TS with SS. Patients with cN0-N1 non-small cell lung cancer undergoing endobronchial ultrasound were randomized to TS or SS. Lymph nodes in the TS arm crossed over to receive SS. Progression criteria included recruitment rate (70% minimum), procedure length (no significant increase for TS), and incidence of missed nodal metastasis (<6%). Mann-Whitney U test and McNemar's test on paired proportions were used for statistical comparisons. RESULTS: The progression criterion of 70% recruitment rate was achieved early, triggering a planned early stoppage of the trial. Nineteen patients were allocated to each arm. The median procedure length for TS was significantly shorter than SS (3.07 vs 19.07 minutes; P < .001). After crossover analysis, 5.45% (95% confidence interval, 1.87-14.85) of lymph nodes in the TS arm were upstaged from N0 to N2, but this incidence of missed nodal metastasis was below the 6% threshold. During surgical resection, the nodal upstaging incidence from N0 to N2 was 0% for 15 lymph nodes in each arm. CONCLUSIONS: Progression criteria to a pan-Canadian, noninferiority crossover trial comparing TS with SS have been met, and such a trial is warranted.

An Artificial Intelligence Algorithm to Predict Nodal Metastasis in Lung Cancer.

BACKGROUND: Endobronchial ultrasound (EBUS) has features that allow a high accuracy for predicting lymph node (LN) malignancy. However their clinical application remains limited because of high operator dependency. We hypothesized that an artificial intelligence algorithm (NeuralSeg; NeuralSeg Ltd, Hamilton, Ontario, Canada) is capable of accurately identifying and predicting LN malignancy based on EBUS images. METHODS: In the derivation phase EBUS images were segmented twice by an endosonographer and used as controls in 5-fold cross-validation training of NeuralSeg. In the validation phase the algorithm was tested on new images it had not seen before. Logistic regression and receiver operator characteristic curves were used to determine NeuralSeg's capability of discrimination between benign and malignant LNs, using pathologic specimens as the gold standard. RESULTS: Two hundred ninety-eight LNs from 140 patients were used for derivation and 108 LNs from 47 patients for validation. In the derivation cohort NeuralSeg was able to predict malignant LNs with an accuracy of 73.8% (95% confidence interval [CI], 68.4%-78.7%). In the validation cohort NeuralSeg had an accuracy of 72.9% (95% CI, 63.5%-81.0%), specificity of 90.8% (95% CI, 81.9%-96.2%), and negative predictive value of 75.9% (95% CI, 71.5%-79.9%). NeuralSeg showed higher diagnostic discrimination during validation compared with derivation (c-statistic = 0.75 [95% CI, 0.65-0.85] vs 0.63 [95% CI, 0.54-0.72], respectively). CONCLUSIONS: NeuralSeg is able to accurately rule out nodal metastasis and can possibly be used as an adjunct to EBUS when nodal biopsy is not possible or inconclusive. Future work to evaluate the algorithm in a clinical trial is required.

Use of Incentive Spirometry in Adults following Cardiac, Thoracic, and Upper Abdominal Surgery to Prevent Post-Operative Pulmonary Complications: A Systematic Review and Meta-Analysis.

BACKGROUND: Currently, consensus on the effectiveness of incentive spirometry (IS) following cardiac, thoracic, and upper abdominal surgery has been based on randomized controlled trials (RCTs) and systematic reviews of lower methodological quality. To improve the quality of the research and to account for the effects of IS following thoracic surgery, in addition to cardiac and upper abdominal surgery, we performed a meta-analysis with thorough application of the Grading of Recommendations Assessment, Development and Evaluation scoring system and extensive reference to the Cochrane Handbook for Systematic Reviews of Interventions. OBJECTIVE: The objective of this study was to determine, with rigorous methodology, whether IS for adult patients (18 years of age or older) undergoing cardiac, thoracic, or upper abdominal surgery significantly reduces30-day post-operative pulmonary complications (PPCs), 30-day mortality, and length of hospital stay (LHS) when compared to other rehabilitation strategies. METHODS: The literature was searched using Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, CINAHL, and Web of Science for RCTs between the databases' inception and March 2019. A random-effect model was selected to calculate risk ratios (RRs) with 95% confidence intervals (CIs). RESULTS: Thirty-one RCTs involving 3,776 adults undergoing cardiac, thoracic, or upper abdominal surgery were included. By comparing the use of IS to other chest rehabilitation strategies, we found that IS alone did not significantly reduce 30-day PPCs (RR = 1.00, 95% CI: 0.88-1.13) or 30-day mortality (RR = 0.73, 95% CI: 0.42-1.25). Likewise, there was no difference in LHS (mean difference = -0.17,95% CI: -0.65 to 0.30) between IS and the other rehabilitation strategies. None of the included trials significantly impacted the sensitivity analysis and publication bias was not detected. CONCLUSIONS: This meta-analysis showed that IS alone likely results in little to no reduction in the number of adult patients with PPCs, in mortality, or in the LHS, following cardiac, thoracic, and upper abdominal surgery.

Endobronchial Ultrasound Staging of Operable Non-small Cell Lung Cancer: Do Triple-Normal Lymph Nodes Require Routine Biopsy?

BACKGROUND: Staging guidelines for lung cancer recommend endobronchial ultrasound (EBUS) and systematic biopsy of at least three mediastinal lymph node (LN) stations for accurate staging. A four-point ultrasonographic score (Canada Lymph Node Score [CLNS]) was developed to determine the probability of malignancy in each LN. A LN with a CLNS of < 2 is considered low probability for malignancy. We hypothesized that, in patients with cN0 non-small cell lung cancer, LNs with CLNS of < 2 may not require routine biopsy because they represent true node-negative disease. RESEARCH QUESTION: Do LNs considered triple normal on CT scanning, PET scanning, and CLNS evaluation require routine biopsy? STUDY DESIGN AND METHODS: LNs were evaluated for ultrasonographic features at the time of EBUS and the CLNS was applied. Triple-normal LNs were defined as cN0 on CT scanning (short axis, < 1 cm), PET scanning (no hypermetabolic activity), and EBUS (CLNS, < 2). Specificity and negative predictive value (NPV) were calculated against the gold standard pathologic diagnosis from surgically excised specimens. RESULTS: In total, 143 LNs from 57 cN0 patients were assessed. Triple-normal LNs showed a specificity and NPV of 60% (95% CI, 51.2%-68.3%) and 93.1% (95% CI, 85.6%-97.4%), respectively. After pathologic assessment, only 5.6% (n = 8/143) of triple-normal nodes were proven to be malignant. INTERPRETATION: At the time of staging for lung cancer, combining CT scanning, PET scanning, and CLNS criteria can identify triple-normal LNs that have a high NPV for malignancy. This raises the question of whether triple-normal LNs require routine sampling during EBUS and transbronchial needle aspiration. A prospective trial is required to confirm these findings.

Economic evaluation of robot-assisted radical prostatectomy compared to open radical prostatectomy for prostate cancer treatment in Ontario, Canada.

INTRODUCTION: Recent health technology assessments (HTAs) of robot-assisted radical prostatectomy (RARP) in Ontario and Alberta, Canada, resulted in opposite recommendations, calling into question whether benefits of RARP offset the upfront investment. Therefore, the study objectives were to conduct a cost-utility analysis from a Canadian public payer perspective to determine the cost-effectiveness of RARP. METHODS: Using a 10-year time horizon, a five-state Markov model was developed to compare RARP to open radical prostatectomy (ORP). Clinical parameters were derived from Canadian observational studies and a recently published systematic review. Costs, resource utilization, and utility values from recent Canadian sources were used to populate the model. Results were presented in terms of increment costs per quality-adjusted life years (QALYs) gained. A probabilistic analysis was conducted, and uncertainty was represented using cost-effectiveness acceptability curves (CEACs). One-way sensitivity analyses were also conducted. Future costs and QALYs were discounted at 1.5%. RESULTS: Total cost of RARP and ORP were $47 033 and $45 332, respectively. Total estimated QALYs were 7.2047 and 7.1385 for RARP and ORP, respectively. The estimated incremental cost-utility ratio (ICUR) was $25 704 in the base-case analysis. At a willingness-to-pay threshold of $50 000 and $100 000 per QALY gained, the probability of RARP being cost-effective was 0.65 and 0.85, respectively. The model was most sensitive to the time horizon. CONCLUSIONS: The results of this analysis suggest that RARP is likely to be cost-effective in this Canadian patient population. The results are consistent with Alberta's HTA recommendation and other economic evaluations, but challenges Ontario's reimbursement decision.

A novel online education module to teach clinicians how to correctly identify ultrasonographic features of mediastinal lymph nodes during endobronchial ultrasound

Background: Ultrasonographic features can be used to predict mediastinal lymph node malignancy during endobronchial ultrasonography. Despite the validity of using these features for this purpose, the features are not being widely used in clinical practice. This may be attributable to the absence of educational programs that teach clinicians how to identify the features. To address this knowledge gap, we developed an online educational module to teach clinicians how to correctly interpret ultrasonographic features. Methods: The module was designed using corrective feedback and test-enhanced learning theories and distributed to clinicians in relevant specialties. The efficacy of the program was determined by comparing the percentages of correctly identified ultrasonographic features as each clinician progressed through the module. Participants were also asked to self-rate their confidence during the module. Analysis of variance was conducted, and a learning curve and descriptive statistics were generated. Results: Twenty-two of the 29 participants (76%) completed the module. Analysis of variance indicated that the percentage of correctly identified features increased significantly as clinicians completed the module (p = 0.004); this finding is supported by the positive slope of the learning curve. Even though they initially reported some difficulty with identifying certain features, their confidence increased as they progressed through the module. When asked, 86% of participants reported that they found the educational module helpful and 90% reported that they would recommend it to others. Conclusion: Participating clinicians were receptive to the interactive educational module. It enhances clinician skill and confidence in interpreting ultrasonographic features. The results of this study provide the foundation needed to test the validity of the educational module in clinical settings and to further explore clinician preferences for educational programs.

Contexte: Les caractéristiques échographiques permettent de prédire la malignité des ganglions lymphatiques médiastinaux durant l'échographie endobronchique. Malgré leur validité à cette fin, ces caractéristiques ne sont pas très utilisées dans la pratique clinique. Cela pourrait être attribuable à l'absence de programmes de formation pour enseigner aux médecins comment repérer ces caractéristiques. Pour répondre à cette lacune au plan des connaissances, nous avons conçu un module de formation en ligne pour enseigner aux médecins comment interpréter correctement les caractéristiques échographiques. Méthodes: Le module a été conçu selon les théories de rétroaction corrective et d'apprentissage par test et a été distribué aux médecins des spécialités concernées. L'efficacité du programme a été déterminée en comparant les pourcentages de caractéristiques échographiques correctement identifiées à mesure que chaque médecin progressait d'une étape à l'autre du module. Les participants ont aussi été invités à autoévaluer leur degré de confiance pendant la réalisation du module. On a ensuite procédé à une analyse de la variance et on a généré une courbe d'apprentissage et des statistiques descriptives. Résultats: Vingt-deux participants sur 29 (76 %) ont mené le module à terme. L'analyse de la variance a indiqué que le pourcentage de caractéristiques correctement identifiées augmentait significativement à mesure que les médecins finalisaient leur module (p = 0,004); cette observation est confirmée par la courbe d'apprentissage positive. Même s'ils avaient initialement fait état de certaines difficultés à identifier des caractéristiques, leur degré de confiance a augmenté au fur et à mesure qu'ils avançaient. Quatre-vingt-six pour cent des participants ont indiqué avoir trouvé le module utile et 90 % ont dit qu'ils le recommanderaient. Conclusion: Les médecins participants ont bien accueilli ce module éducatif interactif : il améliore les habiletés et le degré de confiance des médecins en leur capacité d'interpréter les caractéristiques échographiques. Les résultats de cette étude servent de point de départ pour tester la validité du module en milieu clinique et pour continuer d'explorer les préférences des médecins en ce qui concerne les programmes de formation.

The Canada Lymph Node Score for prediction of malignancy in mediastinal lymph nodes during endobronchial ultrasound.

OBJECTIVE(S): During endobronchial ultrasound (EBUS) staging, ultrasonographic features can be used to predict mediastinal lymph node (LN) malignancy. We sought to develop the Canada Lymph Node Score a tool capable of predicting LN metastasis at the time of EBUS. METHODS: Patients undergoing EBUS staging for lung and esophageal cancer were prospectively enrolled. Features were identified in real time by an endoscopist and video-recorded. Videos were sent to raters. Pathologic specimens from biopsies/surgical resections were used as the gold-standard reference test. Logistic regression, receiver operator characteristic curve, and Gwet's AC1 analyses were used to test the performance, discrimination, and inter-rater reliability, respectively. RESULTS: In total, 300 LNs from 140 patients were analyzed by 12 endoscopists (raters) across 7 Canadian centers. Beta-coefficients from a multivariate regression model were used to create a 4-point score: short-axis diameter, margins, central hilar structure, and necrosis. The model showed good discriminatory power (c-statistic = 0.72 ± 0.04, 95% confidence interval [CI], 0.64-0.80; bias-corrected c-statistic: 0.66, 95% CI, 0.55-0.76). LNs scoring 3/4 or 4/4 had odds ratios of 15.17 (P < .0001) and 50.56 (P = .001) for predicting malignancy, respectively. Inter-rater reliability for a score ≥3 was 0.81 ± 0.02 (95% CI, 0.77-0.85). CONCLUSIONS: The Canada Lymph Node Score is a 4-point score demonstrating excellent performance in identifying malignant LNs during EBUS. A cut-off of ≥3 may inform decision-making regarding biopsy, repeat biopsy, or mediastinoscopy if the initial results are inconclusive.

Development of the IRIS-AR strategy: an intervention to improve rates of accrual and retention for the VTE-PRO randomized controlled trial.

BACKGROUND: The Venous Thromboembolism Prophylaxis (VTE-PRO) randomized trial is a pilot study evaluating the impact of extended-duration prophylaxis on venous thromboembolic events in patients undergoing lung cancer resection. Enrolled VTE-PRO participants self-inject either low-molecular weight heparin or a saline placebo for 30 days postoperatively. Study outcomes include feasibility, incidence of venous thromboembolism, and venous thromboembolism-related morbidity and mortality. Initial analyses demonstrated low rates of accrual and retention for the VTE-PRO pilot. Therefore, the purpose of the current study was to develop a knowledge translation intervention to improve VTE-PRO pilot trial accrual and retention. METHODS: Eligible participants were surveyed to identify the barriers to VTE-PRO participation. The Theoretical Domains Framework was used to categorize these barriers. Barriers were mapped to the capabilities, opportunities, and behavior (COM-B) behavioral change wheel to identify potential interventions to support trial accrual and retention. The resulting knowledge translation intervention was titled Inform, Remind, Involve and Support to improve Accrual and Retention (IRIS-AR). Key informant interviews with patients were held to refine and confirm the validity of identified barriers and perceived acceptability of the proposed IRIS-AR intervention. Institutional Review Board approval was granted for this study. RESULTS: The resulting intervention included: information booklets and counseling sessions to identify unique participant challenges to trial participation (Inform); daily reminders to administer injections (Remind); involvement of family/caregivers in study processes (Involve); and leverage of an existing home-care nursing program to provide injection support when needed (Support). Twenty-six key informant participants were interviewed. The most common barriers to trial participation included lack of social support and fear of needle injection. Participants generally supported use of information booklets, involvement of family/caregivers, and support by a home-care nursing program; however, not all supported the use of daily reminders. CONCLUSION: Developed using theory and integrated knowledge translation, the IRIS-AR presents a patient-centered intervention that leverages existing programs to promote trial engagement. The proposed strategy can likely be adapted to improve compliance with other patient-directed interventions. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02334007 . Registered on 8 January 2015.

Ultrasonographic characteristics of lymph nodes as predictors of malignancy during endobronchial ultrasound (EBUS): A systematic review.

OBJECTIVES: The primary objective of this study is to systematically review all pertinent literature related to the use of ultrasonographic features to predict malignancy in mediastinal lymph nodes seen during endobronchial ultrasound (EBUS) procedures. MATERIALS AND METHODS: Two independent reviewers completed the search and review (PubMed, EMBASE, Medline, and Cochrane databases) of the resulting titles and abstracts. Following full-text screening, thirteen articles met the inclusion criteria. Heterogeneity prevented any meta-analysis, instead a narrative review was completed. Results from each included article are categorized by the following ultrasonographic features: shape, echogenicity, margin status, central necrosis, short axis length, and central hilar structure. Diagnostic tools are also described in detail. RESULTS: Absence of a central hilar structure and heterogeneous echogenicity were often associated with malignancy; however, consensus was not achieved amongst the included articles. The remaining ultrasonographic features were not consistently associated with malignancy or benign disease status, suggesting a need for prospective analysis. Four diagnostic tools were also assessed. These tools demonstrate that a combination of ultrasonographic features may accurately predict lymph node malignancy rather than a single feature. CONCLUSION: Analysis of ultrasonographic features may prevent the need for repeat EBUS procedures when initial biopsy results are inconclusive. However, prospective external validation of these features is required to determine their true predictive capability. PROSPERO registration number: CRD42017068468.

Does consecutive influenza vaccination reduce protection against influenza: A systematic review and meta-analysis.

INTRODUCTION: Vaccination against influenza on an annual basis is widely recommended, yet recent studies suggest consecutive vaccination may reduce vaccine effectiveness (VE). PURPOSE: To assess whether when examining the entirety of existing data consecutive influenza vaccination reduces VE compared to current season influenza vaccination. DATA SOURCES: MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials (CENTRAL) from inception to April 26, 2017; citations of included studies. STUDY SELECTION: Randomized, controlled trials (RCTs) and observational studies of children, adults and/or the elderly that reported laboratory-confirmed influenza infection over 2 or more consecutive influenza seasons were eligible. DATA EXTRACTION: Data related to study characteristics, participant demographics, cases of influenza infection by vaccination group and risk of bias assessment was extracted in duplicate. DATA SYNTHESIS: Five RCTs involving 11,987 participants did not show a significant reduction in VE when participants vaccinated in two consecutive seasons (VE 71%, 95% CI 62-78%) were compared to those vaccinated in the current season (VE 58%, 95% CI 48-66%) (odds ratio [OR] 0.88, 95% CI 0.62-1.26, p = 0.49, I2 = 39%). Twenty-eight observational studies involving 28,627 participants also did not show a reduction (VE for two consecutive seasons 41%, 95% CI 30-51% compared to VE for current season 47%, 95% CI 39-54%; OR 1.14, 95% CI 0.98-1.32, p = 0.09, I2 = 63%). Results from subgroup analyses by influenza type/subtype, vaccine type, age, vaccine match and co-morbidity support these findings; however, dose-response results were inconsistent. Certainty in the evidence was assessed to be very low due to unexplained heterogeneity and imprecision. LIMITATIONS: The inclusion of studies with relatively small sample sizes and low event rates contributed to the imprecision of summary VE and OR estimates, which were based on unadjusted data. CONCLUSION: Available evidence does not support a reduction in VE with consecutive influenza vaccination, but the possibility of reduced effectiveness cannot be ruled out due to very low certainty in this evidence. FUNDING SOURCE: CIHR Foundation Grant (PROSPERO: CRD42017059893).