Purpose: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors have greatly improved survival in EGFR-mutant (EGFRm) non–small cell lung cancer (NSCLC); however, their effects on the tumor microenvironment (TME) are unknown. We assessed the changes induced by neoadjuvant erlotinib therapy (NE) in the TME of operable EGFRm NSCLC. Materials and Methods: This was a single-arm phase II trial for neoadjuvant/adjuvant erlotinib therapy in patients with stage II/IIIA EGFRm NSCLC (EGFR exon 19 deletion or L858R mutations). Patients received up to 2 cycles of NE (150 mg/day) for 4 weeks, followed by surgery and adjuvant erlotinib or vinorelbine plus cisplatin therapy depending on observed NE response. TME changes were assessed based on gene expression analysis and mutation profiling. Results: A total of 26 patients were enrolled; the median age was 61, 69% were female, 88% were stage IIIA, and 62% had L858R mutation. Among 25 patients who received NE, the objective response rate was 72% (95% confidence interval [CI], 52.4 to 85.7). The median disease-free and overall survival (OS) were 17.9 (95% CI, 10.5 to 25.4) and 84.7 months (95% CI, 49.7 to 119.8), respectively. Gene set enrichment analysis in resected tissues revealed upregulation of interleukin, complement, cytokine, transforming growth factor β, and hedgehog pathways. Patients with upregulated pathogen defense, interleukins, and T-cell function pathways at baseline exhibited partial response to NE and longer OS. Patients with upregulated cell cycle pathways at baseline exhibited stable/progressive disease after NE and shorter OS. Conclusion NE modulated the TME in EGFRm NSCLC. Upregulation of immune-related pathways was associated with better outcomes.

Purpose: This study evaluated whether an addition of simvastatin to chemotherapy improves survival in ever-smokers with extensive disease (ED)–small cell lung cancer (SCLC). Materials and Methods: This is an open-label randomized phase II study conducted in National Cancer Center (Goyang, Korea). Chemonaive patients with ED-SCLC, smoking history (≥ 100 cigarettes lifetime), and Eastern Cooperative Oncology Group performance status of ≤ 2 were eligible. Patients were randomized to receive irinotecan plus cisplatin alone or with simvastatin (40 mg once daily orally) for a maximum of six cycles. Primary endpoint was the the 1-year survival rate. Results: Between September 16, 2011, and September 9, 2021, 125 patients were randomly assigned to the simvastatin (n=62) or control (n=63) groups. The median smoking pack year was 40 years. There was no significant difference in the 1-year survival rate between the simvastatin and control groups (53.2% vs. 58.7%, p=0.535). The median progression-free survival and overall survival between the simvastatin arm vs. the control groups were 6.3 months vs. 6.4 months (p=0.686), and 14.4 months vs. 15.2 months, respectively (p=0.749). The incidence of grade 3-4 adverse events was 62.9% in the simvastatin group and 61.9% in the control group. In the exploratory analysis of lipid profiles, patients with hypertriglyceridemia had significantly higher 1-year survival rates than those with normal triglyceride levels (80.0% vs. 52.7%, p=0.046). Conclusion Addition of simvastatin to chemotherapy provided no survival benefit in ever-smokers with ED-SCLC. Hypertriglyceridemia may be associated with better prognosis in these patient population.

Background: Next-generation sequencing (NGS) is an approved test to select patients for BRAF V600E targeted therapy in Korea. However, the high cost, long turnaround times, and the need for sophisticated equipment and skilled personnel limit the use of NGS in daily practice. Immunohistochemistry (IHC) is a rapid and relatively inexpensive assay available in most laboratories. Therefore, in this study, we evaluate the usefulness of BRAF VE1 IHC in terms of predictive value and interobserver agreement in non–small cell lung cancers (NSCLCs). Methods: A total of 30 cases with known BRAF mutation status were selected, including 20 cases of lung adenocarcinomas, six cases of colorectal adenocarcinomas, and four cases of papillary thyroid carcinomas. IHC for BRAF V600E was carried out using the VE1 antibody. Fifteen pathologists independently scored both the staining intensity and the percentage of tumor cell staining on whole slide images. Results: In the lung adenocarcinoma subset, interobserver agreement for the percentage of tumor cell staining and staining intensity was good (percentage of tumor cell staining, intraclass correlation coefficient = 0.869; staining intensity, kappa = 0.849). The interobserver agreement for the interpretation using the cutoff of 40% was almost perfect in the entire study group and the lung adenocarcinoma subset (kappa = 0.815). Sensitivity, specificity, positive predictive value, and negative predictive value of BRAF VE1 IHC were 80.0%, 90.0%, 88.9%, and 81.8%, respectively. Conclusions BRAF VE1 IHC could be a screening test for the detection of BRAF V600E mutation in NSCLC. However, further studies are needed to optimize the protocol and to establish and validate interpretation criteria for BRAF VE1 IHC.

Molecular biomarker testing is the standard of care for non–small cell lung cancer (NSCLC) patients. In 2017, the Korean Cardiopulmonary Pathology Study Group and the Korean Molecular Pathology Study Group co-published a molecular testing guideline which contained almost all known genetic changes that aid in treatment decisions or predict prognosis in patients with NSCLC. Since then there have been significant changes in targeted therapies as well as molecular testing including newly approved targeted drugs and liquid biopsy. In order to reflect these changes, the Korean Cardiopulmonary Pathology Study Group developed a consensus statement on molecular biomarker testing. This consensus statement was crafted to provide guidance on what genes should be tested, as well as methodology, samples, patient selection, reporting and quality control.

Purpose: Squamous cell carcinomas (SqCC) of the lung often express high levels of thymidylate synthase (TS), which is associated with primary resistance to pemetrexed. We explored the efficacy of pemetrexed in a selected population of patients with lung SqCC with low TS expression. Materials and Methods: In this single-arm phase II trial, we enrolled 32 previously-treated patients with advanced lung SqCC exhibiting low immunohistochemical staining for TS (i.e., in 10% or less of tumor cells). The primary endpoint was 12-week progression-free survival (PFS) rate. Results: Of 32 patients, eight patients (25%) had an Eastern Cooperative Oncology Group performance status of 2, and seven patients (22%) had previously received three or more lines of chemotherapy. The disease control rate from pemetrexed treatment was 30%, and no objective response was observed. The 12-week PFS rate was 24.5% (95% confidence interval [CI], 13.0 to 46.1). Median PFS was 1.3 months (95% CI, 1.3 to 2.7), and median overall survival was 11.8 months (95% CI, 8.1 to not applicable). Most of adverse events were grade 1 or 2. Conclusion Pemetrexed demonstrated modest activity as a salvage chemotherapy in patients with advanced lung SqCC with low TS expression, although its toxicity was generally manageable.

Purpose: Capmatinib, an oral MET kinase inhibitor, has demonstrated its efficacy against non–small cell lung cancer (NSCLC) with MET dysregulation. We investigated its clinical impact in advanced NSCLC with MET exon 14 skipping mutation (METex14) or gene amplification. Materials and Methods: Patients who participated in the screening of a phase II study of capmatinib for advanced NSCLC were enrolled in this study. MET gene copy number (GCN), protein expression, and METex14 were analyzed and the patients’ clinical outcome were retrospectively reviewed. Results: A total of 72 patients were included in this analysis (group A: GCN ≥ 10 or METex14, n=14; group B: others, n=58). Among them, 13 patients were treated with capmatinib (group A, n=8; group B, n=5), and the overall response rate was 50% for group A, and 0% for group B. In all patients, the median overall survival (OS) was 20.2 months (95% confidence interval [CI], 6.9 to not applicable [NA]) for group A, and 11.3 months (95% CI, 8.2 to 20.3) for group B (p=0.457). However, within group A, median OS was 21.5 months (95% CI, 20.8 to NA) for capmatinib-treated, and 7.5 months (95% CI, 3.2 to NA) for capmatinib-untreated patients (p=0.025). Among all capmatinib-untreated patients (n=59), group A showed a trend towards worse OS to group B (median OS, 7.5 months vs. 11.3 months; p=0.123). Conclusion Our data suggest that capmatinib is a new compelling treatment for NSCLC with MET GCN ≥ 10 or METex14 based on the improved survival within these patients.

Molecular biomarker testing is the standard of care for non–small cell lung cancer (NSCLC) patients. In 2017, the Korean Cardiopulmonary Pathology Study Group and the Korean Molecular Pathology Study Group co-published a molecular testing guideline which contained almost all known genetic changes that aid in treatment decisions or predict prognosis in patients with NSCLC. Since then there have been significant changes in targeted therapies as well as molecular testing including newly approved targeted drugs and liquid biopsy. In order to reflect these changes, the Korean Cardiopulmonary Pathology Study Group developed a consensus statement on molecular biomarker testing. This consensus statement was crafted to provide guidance on what genes should be tested, as well as methodology, samples, patient selection, reporting and quality control.

BACKGROUND: Acinetobacter baumannii infection is a significant health problem worldwide due to increased drug resistance. The limited antimicrobial alternatives for the treatment of severe infections by multidrug-resistant A. baumannii (MDRAB) make the search for other therapeutic options more urgent. Linalool, the major oil compound in Coriandrum sativum, was recently found to have high antibacterial activity against A. baumannii. The purpose of this study was to investigate the synergistic effect of linalool and colistin combinations against MDRAB and extensively drug-resistant A. baumannii (XDRAB). METHODS: A total of 51 strains of A. baumannii clinical isolates, consisting of 10 MDRAB and 41 XDRAB were tested. We determined the minimum inhibitory concentration (MIC) of linalool for the test strains using the broth microdilution method and searched for interactions using the time-kill assay. RESULTS: The time-kill assay showed that the linalool and colistin combination displayed a high rate of synergy (92.1%) (by synergy criteria 2), low rate of indifference (7.8%), and a high rate of bactericidal activity (74.5%) in the 51 clinical isolates of A. baumannii. The synergy rates for the linalool and colistin combination against MDRAB and XDRAB were 96% and 92.1%, respectively. No antagonism was observed for the linalool and colistin combination. CONCLUSION The combination of linalool and colistin showed a high synergy rate, which may be beneficial for controlling MDRAB infections. Therefore, this combination is a good candidate for in vivo studies to assess its efficacy in the treatment of MDRAB infections.

PURPOSE: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is widely used for the diagnosis and staging of lung cancer. However, evidence of its usefulness for re-biopsy in treated lung cancer, especially according to the previous treatment, is limited. We evaluated the role of EBUS-TBNA for re-biopsy and its diagnostic values in patients with different treatment histories. MATERIALS AND METHODS: We reviewed the medical records of patients who underwent EBUS-TBNA for re-biopsy of suspicious recurrent or progressive lesions between January 2006 and December 2016 at the National Cancer Center in South Korea. Patients were categorized into three groups based on the previous treatment modalities: surgery, radiation, and palliation. RESULTS: Among the 367 patients (surgery, n=192; radiation, n=40; palliation, n=135) who underwent EBUS-TBNA for re-biopsy, the overall sensitivity, negative predictive value (NPV), and diagnostic accuracy of EBUS-TBNA in detecting malignancy were 95.6%, 82.7%, and 96.3%, respectively. The sensitivity was lower in the radiation group (83.3%) when compared with the surgery (95.7%, p=0.042) and palliation (97.7%, p=0.012) groups. The NPV was lower in the palliation group (50.0%) than in the surgery group (88.5%, p=0.042). The sample adequacy of EBUS-TBNA specimens was lower in the radiation group (80.3%) than in the surgery (95.4%, p < 0.001) or palliation (97.8%, p < 0.001) groups. EGFR mutation analysis was feasible in 94.6% of the 92 cases, in which mutation analysis was requested. There were no major complications. Minor complications were reported in 12 patients (3.3%). CONCLUSION: EBUS-TBNA showed high diagnostic values and high suitability for EGFR mutation analysis with regard to re-biopsy in patients with previously treated lung cancer. The sensitivity was lower in the radiation group and NPV was lower in the palliation group. The complication rate was low.
Biopsy ; Diagnosis ; Humans ; Korea ; Lung Neoplasms ; Lung ; Medical Records ; Needles

Liquid biopsy for detection of mutation from circulating tumor DNA is a new technology which is attractive in that it is non-invasive. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) is an effective first line drug for advanced non-small cell lung cancer patients who harbor activating EGFR mutation. During the course of treatment, resistance against TKI arises which can be contributed to EGFR T790M mutation in about 50–60% of patients. Third generation TKI may overcome the resistance. In patients who cannot undergo tissue biopsy due to variable reasons, liquid biopsy is an excellent alternative for the detection of EGFR T790M mutation. However, this relatively novel method requires standardization and vigorous quality insurance. Thus, a standard set of guideline recommendations for liquid biopsy for EGFR mutation testing suitable for the Korean medical community is necessary. In this article, we propose a set of provisional guideline recommendations that was discussed and approved by the Cardiopulmonary Pathology Study Group of the Korean Society of Pathologists.
Biopsy ; Carcinoma, Non-Small-Cell Lung ; DNA ; Genes, erbB-1 ; Humans ; Insurance ; Lung Neoplasms ; Lung ; Methods ; Pathology ; Protein-Tyrosine Kinases ; Receptor, Epidermal Growth Factor