Modern era systemic therapies: Expanding concepts of cure in early and locally advanced non-small cell lung cancer.

Cure of cancer is a sensitive and multidimensional concept that is challenging to define, difficult to assert at the individual patient level, and often surrounded by controversy. The notion of cure in non-small cell lung cancer (NSCLC) has changed and continues to evolve with improvements in diagnosis and treatment. Targeted and immune therapies have recently entered the treatment landscape of stage I-III NSCLC. While some initial pivotal trials of such agents failed to improve survival, recently approved epidermal growth factor receptor (EGFR) inhibitors (in EGFR-mutated NSCLC) and immune checkpoint inhibitors have shown delays in disease recurrence or progression and unprecedented survival gains compared to previous standards of care. Additional data is now emerging supporting the benefit of treatment strategies based on alternation-matched targeting (anaplastic lymphoma kinase [ALK] inhibition in ALK-altered disease) and immune checkpoint inhibition in stage I-III NSCLC. Similar to previous developments in the treatment of early and locally advanced NSCLC, it is expected that statistically significant and clinically meaningful trial-level benefits will translate into real-world benefits, including improvements in cure measures. Parallel advances in molecular testing (e.g., circulating tumor DNA analyses) are also allowing for a deeper and more comprehensive characterization of disease status and treatment response. Given the impact that curative-intent treatments have on survival, it is critical that various stakeholders, including clinicians and patients, are aware of new opportunities to pursue cure in stage I-III NSCLC.

Surgically Resectable Non-Small Cell Lung Cancer: A Contemporary Approach.

New treatment paradigms for resectable non-small cell lung cancer (NSCLC), with an emphasis on personalized care and a multidisciplinary approach, have significantly improved patient outcomes. The incorporation of immune checkpoint inhibitors into neoadjuvant, perioperative and adjuvant treatment algorithms is reshaping the standard of care for resectable NSCLC. Adjuvant targeted therapy trials have also paved the way for a much-needed personalized approach for patients with actionable genomic alterations. Innovative surgical techniques and judicious use of post operative radiotherapy may mitigate the toxicity associated with a multimodality approach. Amidst many new treatment options, questions remain about the best approach to consider for each patient. Measurement of minimal residual disease and achievement of pathologic complete response are emerging biomarkers of interest to help further refine treatment selection. This review summarizes the current management of resectable NSCLC, focusing on ongoing and recent advances in surgical approaches, the role of postoperative radiotherapy, and the rapidly changing field of systemic therapies.

Canadian Consensus Recommendations for the Management of Operable Stage II/III Non-Small-Cell Lung Cancer: Results of a Modified Delphi Process.

The treatment paradigm for patients with stage II/III non-small-cell lung cancer (NSCLC) is rapidly evolving. We performed a modified Delphi process culminating at the Early-stage Lung cancer International eXpert Retreat (ELIXR23) meeting held in Montreal, Canada, in June 2023. Participants included medical and radiation oncologists, thoracic surgeons and pathologists from across Quebec. Statements relating to diagnosis and treatment paradigms in the preoperative, operative and postoperative time periods were generated and modified until all held a high level of consensus. These statements are aimed to help guide clinicians involved in the treatment of patients with stage II/III NSCLC.

Effect of colchicine on perioperative atrial fibrillation and myocardial injury after non-cardiac surgery in patients undergoing major thoracic surgery (COP-AF): an international randomised trial.

BACKGROUND: Higher levels of inflammatory biomarkers are associated with an increased risk of perioperative atrial fibrillation and myocardial injury after non-cardiac surgery (MINS). Colchicine is an anti-inflammatory drug that might reduce the incidence of these complications. METHODS: COP-AF was a randomised trial conducted at 45 sites in 11 countries. Patients aged 55 years or older and undergoing major non-cardiac thoracic surgery were randomly assigned (1:1) to receive oral colchicine 0·5 mg twice daily or matching placebo, starting within 4 h before surgery and continuing for 10 days. Randomisation was done with use of a computerised, web-based system, and was stratified by centre. Health-care providers, patients, data collectors, and adjudicators were masked to treatment assignment. The coprimary outcomes were clinically important perioperative atrial fibrillation and MINS during 14 days of follow-up. The main safety outcomes were a composite of sepsis or infection, and non-infectious diarrhoea. The intention-to-treat principle was used for all analyses. This trial is registered with ClinicalTrials.gov, NCT03310125. FINDINGS: Between Feb 14, 2018, and June 27, 2023, we enrolled 3209 patients (mean age 68 years [SD 7], 1656 [51·6%] male). Clinically important atrial fibrillation occurred in 103 (6·4%) of 1608 patients assigned to colchicine, and 120 (7·5%) of 1601 patients assigned to placebo (hazard ratio [HR] 0·85, 95% CI 0·65 to 1·10; absolute risk reduction [ARR] 1·1%, 95% CI -0·7 to 2·8; p=0·22). MINS occurred in 295 (18·3%) patients assigned to colchicine and 325 (20·3%) patients assigned to placebo (HR 0·89, 0·76 to 1·05; ARR 2·0%, -0·8 to 4·7; p=0·16). The composite outcome of sepsis or infection occurred in 103 (6·4%) patients in the colchicine group and 83 (5·2%) patients in the placebo group (HR 1·24, 0·93-1·66). Non-infectious diarrhoea was more common in the colchicine group (134 [8·3%] events) than the placebo group (38 [2·4%]; HR 3·64, 2·54-5·22). INTERPRETATION: In patients undergoing major non-cardiac thoracic surgery, administration of colchicine did not significantly reduce the incidence of clinically important atrial fibrillation or MINS but increased the risk of mostly benign non-infectious diarrhoea. FUNDING: Canadian Institutes of Health Research, Accelerating Clinical Trials Consortium, Innovation Fund of the Alternative Funding Plan for the Academic Health Sciences Centres of Ontario, Population Health Research Institute, Hamilton Health Sciences, Division of Cardiology at McMaster University, Canada; Hanela Foundation, Switzerland; and General Research Fund, Research Grants Council, Hong Kong.

Benzonatate as a local anesthetic.

INTRODUCTION: Benzonatate is an FDA-approved antitussive agent that resembles tetracaine, procaine, and cocaine in its chemical structure. Based on structural similarities to known local anesthetics and recent findings of benzonatate exerting local anesthetic-like effects on voltage-gated sodium channels in vitro, we hypothesized that benzonatate will act as a local anesthetic to yield peripheral nerve blockade. METHODS: Benzonatate was injected at the sciatic nerve of Sprague-Dawley rats. Sensory and motor blockade were assessed using a modified hot plate test and a weight-bearing test, respectively. Additionally, the effect of co-injection with tetrodotoxin and Tween 80 (a chemical permeation enhancer) was examined. Myotoxicity of benzonatate was assessed in vivo by histological analysis. RESULTS: Benzonatate produced a concentration-dependent sensory and motor nerve blockade with no appreciable systemic effects. Co-injection with tetrodotoxin or Tween 80 produced prolongation of sensory nerve blockade. Histologic assessment showed significant inflammation and myotoxicity from benzonatate injection, even at low concentrations. CONCLUSION: This study demonstrates that benzonatate does act as a local anesthetic at the peripheral nerve, with sensory and motor nerve blockade. Benzonatate interacts with tetrodotoxin and Tween 80 to prolong nerve blockade. However, benzonatate causes significant myotoxicity, even at subtherapeutic concentrations.

Lung Transplantation for COVID-19 Acute Respiratory Distress Syndrome: The British Columbian Experience With New Disease Pathology.

Lung transplantation is a life-saving treatment for patients with end-stage lung disease. COVID-19 has been associated with a severe and rapid decline in pulmonary function, in which case lung transplantation has been described to be effective. We herein describe 9 patients who underwent lung transplantation for COVID-19 acute respiratory distress syndrome, of whom 6 were bridged with extracorporeal membrane oxygenation (ECMO). The median time of pre-operative observation periods was 54 days to ensure no lung function recovery and the time to wean off extracorporeal membrane oxygenation was 3 days. Patients had comparable short-term survival outcomes to non-COVID-19 lung transplant recipients at our institution during the same time period. Lung transplantation for COVID-19-associated lung disease is feasible with comparable short-term outcomes and may liberate patients from extracorporeal supports.

Efficacy of ultrasound-guided single-injection erector spinae plane block for thoracoscopic wedge resection: a prospective randomized control trial.

BACKGROUND: Despite advances in minimally invasive thoracic surgery, patients remain at risk of adverse pulmonary events with suboptimal postoperative analgesia. Novel methods of regional analgesia are warranted. Our objective was to prospectively evaluate the impact of ultrasound-guided single-injection erector spinae plane (ESP) block with ropivacaine compared with placebo control on standard of care postoperative recovery in subjects undergoing video-assisted thoracoscopic surgery (VATS) wedge resection. METHODS: This prospective, randomized, placebo-controlled, double-blinded study was conducted at a tertiary thoracic surgical center. Consecutive subjects undergoing VATS wedge resection were randomized to receive a single-injection ESP block with 0.5% ropivacaine or 0.9% saline placebo, in addition to the current standard of care of multimodal analgesia including patient-controlled analgesia and surgical local anesthetic wound infiltration. The primary outcome was difference in 40-point Quality of Recovery (QoR-40) on day 1 postoperatively. The secondary outcomes included opioid consumption, Visual Analog Pain Scale (VAS) score, time spent in the postanesthesia care unit (PACU), and block-related and postoperative complications. RESULTS: Eighty subjects were enrolled, 40 in each group, with 76 completing follow-up (38 subjects in each group). There was no difference in the median QoR-40 score between groups, 169.5 for the ropivacaine group and 172.5 for the control group (difference 3, p=0.843). No significant differences existed between groups in all secondary outcomes, with the exception of the ropivacaine group having lower VAS pain scores measured at 1 hour postoperatively and a shorter duration of stay in the PACU of 117 min. CONCLUSIONS: Following VATS wedge resection, the addition of an ESP block with ropivacaine to standard multimodal analgesia is unlikely to add meaningful clinical value. TRIAL REGISTRATION NUMBER: NCT03419117.

The Clinically Actionable Molecular Profile of Early versus Late-Stage Non-Small Cell Lung Cancer, an Individual Age and Sex Propensity-Matched Pair Analysis.

Background: Despite meticulous surgery for non-small cell lung cancer (NSCLC), relapse is as high as 70% at 5 years. Many institutions do not conduct reflexive molecular testing on early stage specimens, although targeted gene therapy may extend life by years in the event of recurrence. This ultimately delays definitive treatment with additional biopsy risking suboptimal tissue acquisition and quality for molecular testing. Objective: To compare molecular profiles of genetic alterations in early and late NSCLC to provide evidence that reflexive molecular testing provides clinically valuable information. Methods: A single-center propensity matched retrospective analysis was conducted using prospectively collected data. Adults with early and late-stage NSCLC had tissue subject to targeted panel-based NGS. Frequencies of putative drivers were compared, with 1:3 matching on the propensity score; p < 0.05 deemed statistically significant. Results: In total, 635 NSCLC patients underwent NGS (59 early, 576 late); 276 (43.5%) females; age 70.9 (±10.2) years; never smokers 140 (22.0%); 527 (83.0%) adenocarcinomas. Unadjusted frequencies of EGFR mutations were higher in the early cohort (30% vs. 18%). Following adjustment for sex and smoking status, similar frequencies for both early and late NSCLC were observed for variants in EGFR, KRAS, ALK, MET, and ROS1. Conclusion: The frequency of clinically actionable variants in early and late-stage NSCLC was found to be similar, providing evidence that molecular profiling should be performed on surgical specimens. This pre-determined profile is essential to avoid treatment delay for patients who will derive clinical benefit from targeted systemic therapy, in the high likelihood of subsequent relapse.

Disparate Time-to-Treatment and Varied Incidence of Actionable Non-Small Cell Lung Cancer Molecular Alterations in British Columbia: A Historical Cohort Study.

Background: non-small cell lung cancer (NSCLC) outcomes remain suboptimal for early-stage disease despite emerging advances in systemic therapy for the peri-operative period. Next-generation sequencing (NGS) identifies driver mutations for which targeted therapies have been developed that improve survival. The BC lung cancer screening program, which was initiated in May 2022, is expected to identify people with early and late stages of NSCLC. It is crucial to first understand the molecular epidemiology and patterns of time to initiate treatment across its five health authorities (HA) to optimize the delivery of care for NSCLC in BC. In this way, we may harness the benefits of targeted therapy for more people with NSCLC as novel advances in therapy continue to emerge. Objective: to compare (a) the frequency of actionable NSCLC molecular alterations among HAs and (b) the time to treatment initiation. Methods: a retrospective observational study was conducted with prospectively collected data from the BC CGL Database. Adults with late stage NSCLC who underwent targeted NGS were included for the time period from May 2020 to June 2021. Demographics, actionable molecular alterations, PDL-1 expression, and time to treatment across HAs were examined. Using appropriate statistical tests for comparison among HAs, p>0.05 was deemed significant. Results: 582 patients underwent NGS/IHC and analysis during the study period. The mean age was 71 (10.1), and 326 (56%) patients were female. A significantly higher proportion of all EGFRm+ were identified within Vancouver Coastal Health (VCHA) and Fraser Health Authority (FHA) compared to the other health authorities (p < 0.001). This also holds true for common sensitizing EGFRm+ alone (p < 0.001) and for sensitizing EGFRm+ when adjusted for females and smoker status (OR 0.75; 95% CI 0.62, 0.92; p = 0.005). Patients residing within the Northern, Interior, and Island HAs were less likely to receive treatment at the same rate as those in VCHA and FHA HAs. Conclusion: actionable NSCLC driver mutations are present in all regional HAs, with disparity noted in time to initiate treatment between HAs. This provides evidence for the importance of molecular testing for patients in all BC HAs to guide personalized and timely NSCLC treatment.

High-Ambient Air Pollution Exposure Among Never Smokers Versus Ever Smokers With Lung Cancer.

INTRODUCTION: Air pollution may play an important role in the development of lung cancer in people who have never smoked, especially among East Asian women. The aim of this study was to compare cumulative ambient air pollution exposure between ever and never smokers with lung cancer. METHODS: A consecutive case series of never and ever smokers with newly diagnosed lung cancer were compared regarding their sex, race, and outdoor and household air pollution exposure. Using individual residential history, cumulative exposure to outdoor particulate matter (PM2.5) in a period of 20 years was quantified with a high-spatial resolution global exposure model. RESULTS: Of the 1005 patients with lung cancer, 56% were females and 33% were never smokers. Compared with ever smokers with lung cancer, never smokers with lung cancer were significantly younger, more frequently Asian, less likely to have chronic obstructive pulmonary disease or a family history of lung cancer, and had higher exposure to outdoor PM2.5 but lower exposure to secondhand smoke. Multivariable logistic regression analysis revealed a significant association with never-smoking patients with lung cancer and being female (OR = 4.01, 95% confidence interval [CI]: 2.76-5.82, p < 0.001), being Asian (ORAsian versus non-Asian = 6.48, 95% CI: 4.42-9.50, p < 0.001), and having greater exposure to air pollution (ORln_PM2.5 = 1.79, 95% CI: 1.10-7.2.90, p = 0.019). CONCLUSIONS: Compared with ever-smoking patients with lung cancer, never-smoking patients had strong associations with being female, being Asian, and having air pollution exposures. Our results suggest that incorporation of cumulative exposure to ambient air pollutants be considered when assessing lung cancer risk in combination with traditional risk factors.

Thoracic Surgeon Impressions of the Impact of the COVID-19 Pandemic on Lung Cancer Care-Lessons from the First Wave in Canada.

BACKGROUND: COVID-19 has invariably changed the way lung cancer surgical care is provided in Canada. Despite relevant management guidelines, the way in which cancer care has been affected has yet to be described for thoracic surgical populations. Routine lung cancer physiologic and staging assessments are unique in that they are droplet producing and aerosolizing procedures. Our objective was to quantify the effect of the COVID-19 pandemic on surgical lung cancer care as perceived by practicing thoracic surgeons during the first wave of the pandemic in Canada. METHODS: An electronic survey was distributed to members of the Canadian Association of Thoracic Surgeons. The survey was designed to determine surgeon perception of lung cancer preoperative care during the Canadian pandemic-instilled period of resource reallocation compared to standard care. Planned analyses were exploratory in nature; with count and frequency distributions of responses quantified. RESULTS: Fifty-three thoracic surgeons completed the survey. Responses were collected from all Canadian provinces. Little change in access to preoperative imaging was noted. However, a significant decrease in access to lung function and bronchoscopy testing occurred. Pulmonary surgery was perceived to be lengthier with reduced operating theater availability. Despite decreased OR access, only 40% of surgeons were aware of respective institutional mitigation strategies. SUMMARY: The COVID-19 pandemic has had an impact on standard lung cancer care preoperative workup. Further inquiry using institutional data is warranted to quantify its impact on cancer patient outcomes. Assessing the extent and effects of newly present barriers to standard lung cancer care is essential in forming appropriate mitigation strategies and planning for future pandemic waves.

Emergency department utilization following pediatric gastrostomy tube placement is driven by a small cohort of patients.

PURPOSE: Pediatric gastrostomy tubes (G-tubes) are associated with frequent postoperative problems and consumption of healthcare resources. We hypothesized that a small cohort of patients disproportionately drives healthcare resource utilization after G-tube insertion. This study aimed to characterize this population in order to implement evidence-based pathways to reduce healthcare utilization after G-tube insertion. METHODS: All surgically placed pediatric G-tubes at a quaternary care center between March 2011 and June 2018 were retrospectively reviewed. Healthcare utilization including radiographic studies, emergency department (ED) visits, hospital admissions, procedures, and diagnoses was abstracted. Encounter specific charges based on CPT codes were collected. Statistical analyses were performed with Mann Whitney U, Fisher's Exact Test, and multivariate nominal logistic regression. Institutional review board approval was obtained. RESULTS: During the study period, 189 patients underwent G-tube insertion; 24% of patients presented to the ED two or more times and accounted for 82% of ED visits. This cohort of high ED utilizers was more likely to present with G-tube dislodgement [both within the first three months (early) and after three months (late)], required more radiographic studies, and accrued significantly more charges compared to low ED utilizers. Multivariate analyses demonstrated high ED utilization was significantly associated with non-Caucasian race and the surgeon performing the procedure. CONCLUSIONS: At our institution, a significant proportion of healthcare utilization following G-tube placement is consumed by a relatively small cohort of children. Future efforts will target patients with two or more G-tube related ED visits or an early G-tube dislodgement for additional education and integration with outpatient resources. TYPE OF STUDY: Retrospective study. LEVEL OF EVIDENCE: Level II.

Pediatric hepatic vascular tumors.

Vascular liver tumors in the pediatric population can present a diagnostic dilemma. The most common hepatic vascular tumors are hepatic hemangiomas; however the differential diagnosis can also include other benign lesions and malignant masses. Management is unique to the type and nature of the specific lesion. Thus, correct diagnosis and timely intervention is critical. The work up, diagnosis, and management of the different hepatic lesions are discussed in this paper.

Colorectal Vascular Anomalies.

Vascular anomalies represent a diverse group of tumors and malformations. Those involving the colon and rectum can greatly impact patients' quality of life. Proper workup to ensure the correct diagnosis can vary and may include endoscopic and radiographic studies. These lesions can also be challenging to treat and often require a multidisciplinary approach to ensure the best possible outcome. Treatment can include medical therapy, sclerotherapy, endoscopic, and operative intervention. Many patients will require multimodal therapy. We discuss the workup and management of vascular lesions of the colon and rectum.

Arteriovenous malformation phenotype resembling congenital hemangioma contains KRAS mutations.

Extracranial arteriovenous malformation (AVM) is most commonly caused by a somatic mutation in MAP2K1. We report two patients with vascular anomalies that had an unclear clinical diagnosis most consistent with either an AVM or congenital hemangioma. Lesions were cutaneous, reddish-purple with telangiectasias, present at birth, and had defined borders. Histopathology indicated AVM and both lesions contained somatic KRAS mutations. A rare AVM phenotype exists that shares clinical features with congenital hemangioma.

The Diagnostic Accuracy and Sensitivity for Malignancy of Radial-Endobronchial Ultrasound and Electromagnetic Navigation Bronchoscopy for Sampling of Peripheral Pulmonary Lesions: Systematic Review and Meta-analysis.

BACKGROUND: Lung cancer screening with computed tomography chest is identifying peripheral pulmonary lesions (PPLs) suspicious for early-stage lung cancer at increasing rates. Radial-endobronchial ultrasound (R-EBUS) and electromagnetic navigation bronchoscopy (ENB) are 2 methods to sample PPLs to diagnose and treat early lung cancer. ENB has a higher operating financial cost, however, the rationale for its use is possible higher diagnostic accuracy versus R-EBUS. OBJECTIVE: The objective of this study was to determine the comparative diagnostic accuracy, sensitivity, and negative predictive value for R-EBUS and ENB in sampling PPLs. METHODS: A systematic review and meta-analysis were conducted. The Ovid Medline database was queried for original research reporting a diagnostic yield of R-EBUS or ENB for PPLs identified on computed tomography chest suspicious for malignancy. The I statistic assessed study heterogeneity. Random effects models produced pooled estimates of diagnostic accuracy and sensitivity for malignancy. Reasons for heterogeneity were explored with meta-regression. Publication bias and small study effects were assessed. RESULTS: A total of 41 studies involved 2988 lung nodules (R-EBUS 2102, ENB 886) in 3204 patients (R-EBUS 2097, ENB 1107). Overall sensitivity to detect cancer was 70.7% [95% confidence interval (CI): 67.2-74.0]; R-EBUS 70.5% (95% CI: 66.1-74.8), ENB 70.7% (95% CI: 64.7-76.8). Pooled overall diagnostic accuracy was 74.2% (95% CI: 71.0-77.3); R-EBUS 72.4% (95% CI: 68.7-76.1), ENB 76.4% (95% CI: 70.8-82.0). The localization modalities had comparative safety profiles of <2% complications. CONCLUSION: Both technologies have a high proportion of successful PPL localization with similar sensitivity for malignancy and accuracy. As such, both reasonable options for health care authorities to employ diagnostic algorithms.