An ultrasensitive method for detection of cell-free RNA.

Sensitive methods for detection of cell-free RNA (cfRNA) could facilitate non-invasive gene expression profiling and monitoring of diseases. Here we describe RARE-seq (random priming and affinity capture of cfRNA fragments for enrichment analysis by sequencing), a method optimized for cfRNA analysis. We demonstrate that platelet contamination can substantially confound cfRNA analyses and develop an approach to overcome it.

Lung Carcinoid Tumors With Potentially Actionable Genomic Alterations and Responses to Targeted Therapies.

Background: Effective treatments for patients with advanced lung carcinoids remain limited. The prevalence of potentially actionable genomic alterations (AGAs) among lung carcinoids is not well-understood.

Materials And Methods: Lung carcinoids submitted for next-generation sequencing (NGS) at a Clinical Laboratory Improvement Amendments (CLIA)-certified genomics laboratory from September 2013 to March 2024 were retrospectively investigated to determine prevalence of AGAs.

Phase I/II Investigator-Initiated Study of Olaparib and Temozolomide in SCLC: Final Analysis and CNS Outcomes.

Purpose: Temozolomide plus PARP inhibition has shown promise in small cell lung cancer (SCLC). We previously reported outcomes from the first 50 patients (cohort 1) of a phase I/II trial of olaparib/temozolomide in recurrent SCLC. In this study, we report a final analysis of this trial, including a second cohort with an alternate dosing strategy and an exploratory analysis of central nervous system (CNS)-specific outcomes.

Detecting Small Cell Transformation in Patients with Advanced EGFR Mutant Lung Adenocarcinoma through Epigenomic cfDNA Profiling.

Purpose: Histologic transformation to small cell lung cancer (SCLC) is a mechanism of treatment resistance in patients with advanced oncogene-driven lung adenocarcinoma (LUAD) that currently requires histologic review for diagnosis. Herein, we sought to develop an epigenomic cell-free DNA (cfDNA)-based approach to noninvasively detect small cell transformation in patients with EGFR mutant (EGFRm) LUAD.

Experimental Design: To characterize the epigenomic landscape of transformed (t)SCLC relative to LUAD and de novo SCLC, we performed chromatin immunoprecipitation sequencing (ChIP-seq) to profile the histone modifications H3K27ac, H3K4me3, and H3K27me3; methylated DNA immunoprecipitation sequencing (MeDIP-seq); assay for transposase-accessible chromatin sequencing; and RNA sequencing on 26 lung cancer patient-derived xenograft (PDX) tumors.

Acquired Cross-Resistance in Small Cell Lung Cancer due to Extrachromosomal DNA Amplification of MYC Paralogs.

Unlabelled: Small cell lung cancer (SCLC) presents as a highly chemosensitive malignancy but acquires cross-resistance after relapse. This transformation is nearly inevitable in patients but has been difficult to capture in laboratory models. Here, we present a preclinical system that recapitulates acquired cross-resistance, developed from 51 patient-derived xenograft (PDX) models.

Concordance of ASCL1, NEUROD1 and POU2F3 transcription factor-based subtype assignment in paired tumour samples from small cell lung carcinoma.

Aims: Small cell lung carcinoma (SCLC) can be classified into transcription factor-based subtypes (ASCL1, NeuroD1, POU2F3). While in-vitro studies suggest intratumoral heterogeneity in the expression of these markers, how SCLC subtypes vary over time and among locations in patients remains unclear.

Methods And Results: We searched a consecutive series of patients at our institution in 2006-22 for those with greater than one available formalin-fixed paraffin-embedded SCLC sample in multiple sites and/or time-points.

Acquired Cross-resistance in Small Cell Lung Cancer due to Extrachromosomal DNA Amplification of paralogs.

Unlabelled: Small cell lung cancer (SCLC) presents as a highly chemosensitive malignancy but acquires cross-resistance after relapse. This transformation is nearly inevitable in patients but has been difficult to capture in laboratory models. Here we present a pre-clinical system that recapitulates acquired cross-resistance in SCLC, developed from 51 patient-derived xenografts (PDXs).

MCT4-dependent lactate secretion suppresses antitumor immunity in LKB1-deficient lung adenocarcinoma.

Inactivating STK11/LKB1 mutations are genomic drivers of primary resistance to immunotherapy in KRAS-mutated lung adenocarcinoma (LUAD), although the underlying mechanisms remain unelucidated. We find that LKB1 loss results in enhanced lactate production and secretion via the MCT4 transporter. Single-cell RNA profiling of murine models indicates that LKB1-deficient tumors have increased M2 macrophage polarization and hypofunctional T cells, effects that could be recapitulated by the addition of exogenous lactate and abrogated by MCT4 knockdown or therapeutic blockade of the lactate receptor GPR81 expressed on immune cells.

Role of Adjuvant Chemotherapy in Early-Stage Combined Small Cell Lung Cancer.

Background: The role of adjuvant therapy in completely resected primary tumors that have components of both non-small cell lung cancer and small cell lung cancer (combined SCLC) is poorly understood. We sought to determine the potential benefits of adjuvant chemotherapy in patients who undergo complete resection for early-stage combined SCLC.

Methods: Overall survival of patients with pathologic T1-2 N0 M0 combined SCLC who underwent complete resection in the National Cancer Database from 2004 to 2017, stratified by adjuvant chemotherapy vs surgery alone, was evaluated by multivariable Cox proportional hazards modeling and propensity score-matched analysis.

Biology and impact of lineage plasticity in ALK-positive NSCLC: a narrative review.

Background And Objective: Lineage transformation is a known mechanism of acquired resistance to targeted therapies in non-small cell lung cancer (NSCLC). Transformation to small cell and squamous carcinoma and epithelial-to-mesenchymal transition (EMT) have all been identified as recurrent but rare events in ALK-positive NSCLC. However, centralized data informing our understanding of the biology and clinical implications of lineage transformation in ALK-positive NSCLC are lacking.

Spatial analysis of human lung cancer reveals organized immune hubs enriched for stem-like CD8 T cells and associated with immunotherapy response.

The organization of immune cells in human tumors is not well understood. Immunogenic tumors harbor spatially-localized multicellular 'immunity hubs' defined by expression of the T cell-attracting chemokines and abundant T cells. Here, we examined immunity hubs in human pre-immunotherapy lung cancer specimens, and found that they were associated with beneficial responses to PD-1-blockade.

Brief Report: Declining Rates of SARS-CoV-2 Vaccine Uptake Among Patients With Thoracic Malignancies.

• Patients with primary thoracic malignancies are at increased risk of complications and death from COVID-19. Multiple studies have demonstrated humoral immune responses to SARS-CoV-2 vaccinations in patients with cancer, though the degree of immunogenicity varies. Over the last year the United States CDC has issued recommendations for multiple additional ‘booster’ vaccine doses for patients with cancer for protection against severe disease.

A Tale of Two Histologies: Dissecting the Biology of Lineage Transformation in Lung Cancer.

Lineage plasticity is an important, and likely underappreciated, mechanism of treatment resistance in lung cancer. Here, Quintanal-Villalonga and colleagues integrate results from multiomic analyses to provide key new insights into the biology of lineage plasticity. See related article by Quintanal-Villalonga et al.

Targeting Exon 20 Insertions in Non-Small Cell Lung Cancer: Recent Advances and Clinical Updates.

Approximately 10% of -activating mutations occur as in-frame insertion mutations in exon 20 of the kinase domain ( ins20). ins20 mutations have not demonstrated the same sensitivity to early generations of EGFR tyrosine kinase inhibitors (TKI) as canonical activating mutations such as del19 and L858R. Development of effective therapies for this subset of patients has been challenging, but recent years have seen more rapid progress in these efforts.

High Sensitivity of Plasma Cell-Free DNA Genotyping in Cases With Evidence of Adequate Tumor Content.

Unlabelled: Plasma cell-free DNA (cfDNA) sequencing is a compelling diagnostic tool in solid tumors and has been shown to have high positive predictive value. However, limited assay sensitivity means that negative plasma genotyping, or the absence of detection of mutation of interest, still requires reflex tumor biopsy.

Methods: We analyzed two independent cohorts of patients with advanced non-small-cell lung cancer (NSCLC) with known canonical driver and resistance mutations who underwent plasma cfDNA genotyping.

Coronavirus Disease 2019 Infection in a Patient Population with Lung Cancer: Incidence, Presentation, and Alternative Diagnostic Considerations.

Introduction: Lung cancer is associated with severe coronavirus disease 2019 (COVID-19) infections. Symptom overlap between COVID-19 and lung cancer may complicate diagnostic evaluation. We aimed to investigate the incidence, symptoms, differential diagnosis, and outcomes of COVID-19 in patients with lung cancer.

Acquired resistance to targeted therapies in NSCLC: Updates and evolving insights.

While significant advancements have been made in the available therapies for metastatic non-small cell lung cancer (NSCLC), acquired resistance remains a major barrier to treatment. We have not yet achieved the ability to cure advanced NSCLC with systemic therapy, despite our growing understanding of many of the oncogenic drivers of this disease. Rather, the emergence of drug-tolerant and drug-resistant cells remains the rule, even in the face of increasingly potent targeted therapies.

Improved Prognosis and Increased Tumor-Infiltrating Lymphocytes in Patients Who Have SCLC With Neurologic Paraneoplastic Syndromes.

Background: Approximately 10% of patients with SCLC develop a paraneoplastic syndrome (PNS). Neurologic PNS are thought to improve prognosis, which we hypothesized is related to increased tumor-infiltrating lymphocytes and immune recognition.

Methods: We queried 2,512,042 medical records from a single institution to identify patients who have SCLC with and without PNS and performed manual, retrospective chart review.

Effective Cancer Genotyping-Many Means to One End.

Precision cancer medicine requires effective genotyping of every patient's tumor to optimally design treatment plans. Despite its imperfect sensitivity, the rapidity and convenience of cell-free DNA sequencing makes it an essential complement to tumor genotyping, which, when used appropriately, can aid the pursuit of effective genotyping for all patients..

Longitudinal Cell-Free DNA Analysis in Patients with Small Cell Lung Cancer Reveals Dynamic Insights into Treatment Efficacy and Disease Relapse.

Introduction: Patients with SCLC have a poor prognosis and limited treatment options. Because access to longitudinal tumor samples is very limited in patients with this disease, we chose to focus our studies on the characterization of plasma cell-free DNA (cfDNA) for rapid, noninvasive monitoring of disease burden.

Methods: We developed a liquid biopsy assay that quantifies somatic variants in cfDNA.