Association of Circulating Tumor DNA Testing Before Tissue Diagnosis With Time to Treatment Among Patients With Suspected Advanced Lung Cancer: The ACCELERATE Nonrandomized Clinical Trial.

Importance: Liquid biopsy has emerged as a complement to tumor tissue profiling for advanced non-small cell lung cancer (NSCLC). The optimal way to integrate liquid biopsy into the diagnostic algorithm for patients with newly diagnosed advanced NSCLC remains unclear. Objective: To evaluate the use of circulating tumor DNA (ctDNA) genotyping before tissue diagnosis among patients with suspected advanced NSCLC and its association with time to treatment. Design, Setting, and Participants: This single-group nonrandomized clinical trial was conducted among 150 patients at the Princess Margaret Cancer Centre-University Health Network (Toronto, Ontario, Canada) between July 1, 2021, and November 30, 2022. Patients referred for investigation and diagnosis of lung cancer were eligible if they had radiologic evidence of advanced lung cancer prior to a tissue diagnosis. Interventions: Patients underwent plasma ctDNA testing with a next-generation sequencing (NGS) assay before lung cancer diagnosis. Diagnostic biopsy and tissue NGS were performed per standard of care. Main Outcome and Measures: The primary end point was time from referral to treatment initiation among patients with advanced nonsquamous NSCLC using ctDNA testing before diagnosis (ACCELERATE [Accelerating Lung Cancer Diagnosis Through Liquid Biopsy] cohort). This cohort was compared with a reference cohort using standard tissue genotyping after tissue diagnosis. Results: Of the 150 patients (median age at diagnosis, 68 years [range, 33-91 years]; 80 men [53%]) enrolled, 90 (60%) had advanced nonsquamous NSCLC. The median time to treatment was 39 days (IQR, 27-52 days) for the ACCELERATE cohort vs 62 days (IQR, 44-82 days) for the reference cohort (P < .001). Among the ACCELERATE cohort, the median turnaround time from sample collection to genotyping results was 7 days (IQR, 6-9 days) for plasma and 23 days (IQR, 18-28 days) for tissue NGS (P < .001). Of the 90 patients with advanced nonsquamous NSCLC, 21 (23%) started targeted therapy before tissue NGS results were available, and 11 (12%) had actionable alterations identified only through plasma testing. Conclusions and Relevance: This nonrandomized clinical trial found that the use of plasma ctDNA genotyping before tissue diagnosis among patients with suspected advanced NSCLC was associated with accelerated time to treatment compared with a reference cohort undergoing standard tissue testing. Trial Registration: ClinicalTrials.gov Identifier: NCT04863924.

Isolation of tumour-reactive lymphocytes from peripheral blood via microfluidic immunomagnetic cell sorting.

The clinical use of tumour-infiltrating lymphocytes for the treatment of solid tumours is hindered by the need to obtain large and fresh tumour fractions, which is often not feasible in patients with unresectable tumours or recurrent metastases. Here we show that circulating tumour-reactive lymphocytes (cTRLs) can be isolated from peripheral blood at high yield and purity via microfluidic immunomagnetic cell sorting, allowing for comprehensive downstream analyses of these rare cells. We observed that CD103 is strongly expressed by the isolated cTRLs, and that in mice with subcutaneous tumours, tumour-infiltrating lymphocytes isolated from the tumours and rapidly expanded CD8+CD103+ cTRLs isolated from blood are comparably potent and respond similarly to immune checkpoint blockade. We also show that CD8+CD103+ cTRLs isolated from the peripheral blood of patients and co-cultured with tumour cells dissociated from their resected tumours resulted in the enrichment of interferon-γ-secreting cell populations with T-cell-receptor clonotypes substantially overlapping those of the patients' tumour-infiltrating lymphocytes. Therapeutically potent cTRLs isolated from peripheral blood may advance the clinical development of adoptive cell therapies.

The impact of concordance with a lung cancer diagnosis pathway guideline on treatment access in patients with stage IV lung cancer.

BACKGROUND: Timely access to treatment of lung cancer is dependent on efficient and appropriate patient assessment and early referral for diagnostic workup. This study assesses the impact of Cancer Care Ontario (CCO) Lung Cancer Diagnostic Pathway Guideline (LCDPG) concordance on access to treatment of stage IV lung cancer patients referred to the Diagnostic Assessment Program (DAP) at a Canadian tertiary cancer centre. METHODS: This retrospective cohort study includes patients diagnosed with clinical stage IV lung cancer referred to the DAP at a Canadian tertiary cancer centre between November 1, 2015 and May 31, 2017. Referral concordance was determined based on CCO LCDPG. The primary outcome; time to treatment from initial healthcare presentation; was compared between the concordant and discordant referrals. RESULTS: Two hundred patients were referred for clinical stage IV lung cancer during the study period. Of these referrals, 151 (75.5%) were assessed and referred in concordance with LCDPG. Guideline concordant referrals were associated with reduced time to treatment from first healthcare presentation compared with guideline discordant referrals (55.3 vs. 108.8 days, P<0.001). Time to diagnostic procedure (32.2 vs. 86.7 days, P<0.001) and decision to treat (38.5 vs. 93.8 days, P<0.001) were also reduced with guideline concordance. The most common reason for discordant assessment and referral was delayed or inadequate investigation of symptoms in a high risk patient (32.7% of discordant referrals). CONCLUSIONS: Guideline concordant assessment and referral of stage IV lung cancer patients results in reduced time to diagnosis and treatment. Future research and education should focus on improving factors that delay DAP referral.

Endobronchial ultrasound-guided transbronchial needle aspiration mediastinal lymph node staging in malignant pleural mesothelioma.

BACKGROUND: Given poor survival of patients with malignant pleural mesothelioma (MPM) and extrapleural nodal metastasis, pre-operative mediastinal lymph node (LN) staging has been advocated. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) may be a useful pre-operative adjunct in patients with MPM. This study aims to assess performance of EBUS-TBNA for mediastinal LN staging in MPM. METHODS: A retrospective chart review of patients with diagnosis of MPM referred to the mesothelioma program at a tertiary Canadian cancer center between January 1, 2012 and December 31, 2014 who received mediastinal LN staging with EBUS-TBNA. RESULTS: Forty-eight patients were included. Average age was 70 years (range, 48-84 years). Mesothelioma subtypes were as follows: epithelioid 34/48 (70.8%), sarcomatoid 4/48 (8.3%), biphasic 7/48 (14.6%) and other 3/48 (6.3%). Stage distribution was as follows: I 18.8%, II 10.4%, III 47.9%, and IV 22.9%. On average 3.4 LNs were sampled per patient (range, 1-5). The mean short axis of a sampled LN was 6.8±3.8 mm. Rapid on Site Evaluation (ROSE) was available in 75.0% (36/48) of the assessments. Prevalence of N2/N3 disease was 35.4% (17/48). EBUS-TBNA sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and diagnostic accuracy were: 16.7%, 100%, 100%, 68.8%, and 70.6%, respectively. EBUS-TBNA mediastinal LN staging prevented unnecessary surgery in 18.8% (9/48 patients) by detection of N2/N3 disease (8 patients) and metastatic secondary malignancy (1 patient). There were no EBUS-TBNA related complications. CONCLUSIONS: EBUS-TBNA mediastinal LN staging may impact significantly management of patients with MPM by detecting mediastinal metastatic disease, therefore, preventing morbidity and mortality of surgical management.

Efficacy and Cost of Awake Thoracoscopy and Video-Assisted Thoracoscopic Surgery in the Undiagnosed Pleural Effusion.

BACKGROUND: The study aim is to compare the diagnostic yield, safety, and cost of outpatient awake thoracoscopy (AT) with video-assisted thoracoscopic surgery (VATS) pleural biopsy in undiagnosed pleural effusions. METHODS: The diagnostic yield of pleural biopsy performed by AT or VATS in patients with undiagnosed exudative pleural effusions at a tertiary thoracic surgery center in Canada between 2011 and 2015 was retrospectively evaluated. Test sensitivity, specificity, positive predictive value, and negative predictive value were compared. Procedure safety, hospital length of stay, additional pleural-based interventions, and procedure-related costs were compared. RESULTS: Patients underwent either AT (n = 78) or VATS (n = 99) during the study period. Sensitivity, specificity, positive predictive value, and negative predictive value were 85%, 100%, 100%, and 79% for AT and 93%, 94%, 99%, and 76% for VATS, with no significant difference in diagnostic test performance. There was no difference in the rate of major complications (2 AT [2.6%] versus 4 VATS [4.0%], p = 0.696), minor complications (14 AT [17.9%] versus 16 VATS [16.2%], p = 0.841) or need for additional pleural-based procedures (20 AT [25.6%] versus 18 VATS [18.2%], p = 0.270). The VATS was associated with longer median hospital stay (VATS 3 days [interquartile range: 1 to 4] versus AT 0 days [interquartile range: 0 to 1], z = 6.98, p < 0.001) and a higher procedure-related average cost (VATS Canadian dollars $7,962 [95% confidence interval: $7,134 to $8,790] versus AT Canadian dollars $2,815 [95% confidence interval: $2,010 to $3,620], p < 0.001). CONCLUSIONS: Awake thoracoscopy and VATS have similar diagnostic yield and safety profiles in the assessment of undiagnosed pleural effusions; however, AT is associated with shorter length of stay and lower average per-procedure cost. In the appropriate clinical setting, AT may be the diagnostic test of choice.

A Preclinical Evaluation Comparing the Performance of a Novel 19-G Flexible Needle to a Commercially Available 22-G EBUS-TBNA Sampling Needle.

BACKGROUND: Needle samples may not provide sufficient diagnostic material for the assessment of mediastinal lymph nodes. OBJECTIVE: The study compared the specimen size and diagnostic performance of a new 19-G endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) needle to that of a standard 22-G EBUS-TBNA needle in a swine model of granulomatous lymphadenopathy. METHODS: Granulomatous inflammation was induced in mediastinal lymph nodes (LNs) of 10 domestic swine by injection of talc slurry. The affected LNs were sampled with the 19- and 22-G needles. Collected core tissue area and volume were determined using a specialized software and known needle internal diameter. The sample's quality was assessed using the biopsy core morphology grade (BCMG) as well as the biopsy diagnostic correlation grade (BDCG). RESULTS: There was a significant increase in the average LN size from baseline (11.6 ± 3.2 to 15.2 ± 3.8 mm; p < 0.001) after talc injection. A total of 132 paired samples were collected from 38 LNs. The average mass and volume of the 19-G needle sample were larger than those of the 22-G needle sample: 33.78 ± 47.48 vs. 25.18 ± 32.08 mg (p < 0.002) and 11.40 ± 13.91 vs. 6.91 ± 6.42 mm3 (p < 0.0004), respectively. The pooled needle biopsy samples for the 19- and the 22-G needles had similar BCMG (1.38 ± 0.86 vs. 1.43 ± 0.87, p > 0.2) and BDCG (1.54 ± 0.93 vs. 1.57 ± 0.93, p > 0.2). The 19-G needle samples tended towards less blood contamination (p = 0.057), more often granuloma identification (46 vs. 32%, p = 0.2) and had more cartilage contamination (0.49 ± 1.46 vs. 4.81 ± 16.49% p < 0.003). CONCLUSION: In experienced hands, the 19- and the 22-G EBUS-TBNA needles have a similar diagnostic yield in the swine model of granulomatous lymphadenopathy. The samples collected by the 19-G needle are larger and may have less blood contamination.

Molecular alterations in non-small-cell lung cancer: perspective for targeted therapy and specimen management for the bronchoscopist.

Major advances have occurred over the past decade in our understanding of lung cancer pathobiology. Increasing knowledge of molecular aberrations in lung cancer, specifically the discovery of two driver genes in pharmacologically targetable tyrosine kinases involved in growth factor receptor signalling, epidermal growth factor receptor and anaplastic lymphoma kinase, has been of major therapeutic and prognostic importance. This discovery has allowed for new, personalized approach to the management of lung cancer. Recognizing the importance of molecular signatures of lung cancer, the College of American Pathologists, International Association for the Study of Lung Cancer and Association for Molecular Pathology released the first guidelines for molecular testing in lung cancer. The introduction of minimally invasive needle techniques for the evaluation of lung cancer patients, such as endobronchial ultrasound transbronchial needle aspiration and oesophageal ultrasound-fine-needle aspiration, has revolutionized the way lung cancer patients are assessed. Samples obtained using the minimally invasive needle approaches have been shown to be sufficient not only for routine molecular testing but also for multigenic analysis. This allows bronchoscopist to assume an increasingly important role in the diagnostic workup of patients with lung cancer at all stages of the disease and contribute to personalizing the care of lung cancer patients.