Spine Metastasis Is Associated with the Development of Brain Metastasis in Non-Small-Cell Lung Cancer Patients.

Background and Objectives: The mechanisms involved in the development of brain metastasis (BM) remain elusive. Here, we investigated whether BM is associated with spine involvement in patients with non-small-cell lung cancer (NSCLC). Materials and Methods: A consecutive 902 patients with metastatic NSCLC were included from the Inha Lung Cancer Cohort. Patients with BM at diagnosis or subsequent BM development were evaluated for both spine involvement in NSCLC and anatomic proximity of BM to the cerebrospinal fluid (CSF) space. Results: At diagnosis, BM was found in 238 patients (26.4%) and bone metastasis was found in 393 patients (43.6%). In patients with bone metastasis, spine involvement was present in 280 patients. BM subsequently developed in 82 (28.9%) of 284 patients without BM at diagnosis. The presence of spine metastasis was associated with BM at diagnosis and subsequent BM development (adjusted odd ratios and 95% confidence intervals = 2.42 and 1.74-3.37, p < 0.001; 1.94 and 1.19-3.18, p = 0.008, respectively). Most patients with spine metastasis, either with BM at diagnosis or subsequent BM, showed BM lesions located adjacent (within 5mm) to the CSF space (93.8% of BM at the diagnosis, 100% of subsequent BM). Conclusions: These findings suggest that the presence of spine involvement is a risk factor for BM development in NSCLC patients with bone metastasis.

Monitoring Circulating Tumor DNA in Untreated Non-Small-Cell Lung Cancer Patients.

Circulating tumor DNA (ctDNA) has been utilized to monitor the clinical course of patients of non-small-cell lung cancer (NSCLC) who receive therapies targeting druggable mutations. However, despite providing valuable information on how NSCLC would naturally progress, the clinical utility of ctDNA for clinical-course monitoring and prediction of treatment-naïve NSCLC patients without druggable mutations remain unknown. We longitudinally followed a total of 12 treatment-naïve NSCLC patients, who did not harbor EGFR and ALK mutations, by collecting clinical information, radiological data, and plasma samples. Changes in ctDNA levels and tumor burden (TB) were compared with each other. New metastasis development, volume doubling time (VDT), and overall survival (OS) were analyzed regarding ctDNA detection at diagnosis. ctDNA was detected in the plasma of seven (58.3%) patients. Changes in ctDNA levels correlated with those in TB in a substantial fraction (57.1%) of patients and was also associated with brain metastasis, tumor necrosis, or pneumonia in other patients. All patients with ctDNA detection developed new metastasis during follow-ups in the organs that had been devoid of metastasis at diagnosis. The patients without ctDNA detection did not develop new metastasis (median duration of follow-ups: 9.8 months). In addition, patients with ctDNA detection had shorter VDT (p = 0.039) and worse OS (p = 0.019) than those without ctDNA detection. The natural course of NSCLC progression can be monitored by measuring ctDNA levels. Detection of ctDNA at diagnosis can predict development of new metastasis, rapid tumor growth and poor survival of NSCLC patients.

Comparison of epidermal growth factor receptor tyrosine kinase inhibitors for patients with lung adenocarcinoma harboring different epidermal growth factor receptor mutation types.

BACKGROUND: Epidermal growth factor receptor (EGFR) mutations in non-small-cell lung cancer predict sensitivity to EGFR tyrosine kinase inhibitors (TKIs). EGFR mutation types are associated with efficacy of EGFR TKIs. We investigated the clinical outcomes of afatinib, erlotinib, and gefitinib according to EGFR mutation type in patients with lung adenocarcinoma. METHODS: Between May 2010 and December 2018, we investigated 363 patients with advanced lung adenocarcinoma harboring EGFR mutations who received EGFR TKIs. Efficacies of EGFR TKIs such as response rate, progression-free survival (PFS), and overall survival (OS) were retrospectively evaluated according to exon 19 deletion (E19del), L858R point mutation (L858R) and uncommon mutations. RESULTS: The frequency of E19del was 48.2%, that of L858R was 42.4%, and that of uncommon mutations was 9.4%. E19del and L858R were associated with superior PFS and OS compared with uncommon mutations. Erlotinib showed significantly inferior OS than other TKIs (30.8 ± 3.3 in erlotinib vs. 39.1 ± 4.3 in afatinib vs. 48.4 ± 6.3 in gefitinib; p = 0.031) in patients with L858R. Gefitinib showed significantly inferior PFS (4.6 ± 1.1 in gefitinib vs. 11.6 ± 2.7 in afatinib vs. 10.6 ± 2.7 in erlotinib; p = 0.049) in patients with uncommon mutations. CONCLUSION: Afatinib was significantly associated with a longer PFS, presenting constant effectiveness in all EGFR mutation types. Caution may be needed on the use of erlotinib for L858R and the use of gefitinib for uncommon EGFR mutations.

Adverse Events in Healthcare Workers after the First Dose of ChAdOx1 nCoV-19 or BNT162b2 mRNA COVID-19 Vaccination: a Single Center Experience.

Coronavirus disease 2019 vaccinations for healthcare workers (HCWs) have begun in South Korea. To investigate adverse events (AEs) of the first dose of each vaccine, any symptom was collected daily for seven days after vaccination in a tertiary hospital. We found that 1,301 of 1,403 ChAdOx1 nCoV-19 recipients and 38 of 80 BNT162b2 recipients reported AEs respectively (90.9% vs. 52.5%): injection-site pain (77.7% vs. 51.2%), myalgia (60.5% vs. 11.2%), fatigue (50.7% vs. 7.5%), headache (47.4% vs. 7.5%), and fever (36.1% vs. 5%; P < 0.001 for all). Young HCWs reported more AEs with ChAdOx1 nCoV-19 than with BNT162b2. No incidences of anaphylaxis were observed. Only one serious AE required hospitalization for serious vomiting, and completely recovered. In conclusion, reported AEs were more common in recipients with ChAdOx1 nCoV-19 than in those with BNT162b2. However, most of the reported AEs were mild to moderate in severity. Sufficient explanation and preparation for expected AEs required to promote widespread vaccination.

Feasibility of Bronchial Washing Fluid-Based Approach to Early-Stage Lung Cancer Diagnosis.

A blood-based approach such as circulating tumor DNA remains challenging in diagnosis for early-stage disease. Bronchial washing (BW) is a minimally invasive procedure that yields fluids that may contain tumor DNA. Therefore, we prospectively enrolled 12 patients with early-stage non-small cell lung cancer without endoscopically visible tumors. Somatic mutations were analyzed using ultra-deep next-generation sequencing in 48 paired specimens (primary tumor tissue, normal tissue, BW supernatant, and BW precipitate). In primary tumors, 130 missense mutations/indels (5-16 per patient) and 20 driver mutations (0-3 per patient) were found. Concordance of driver mutations between BW fluids and primary tumors was 95.0%. The allele frequencies for missense mutations/indels in BW supernatants significantly correlated with those in primary tumors and were higher than those in BW precipitates. These findings suggest that BW supernatants are reflective of tumor-associated mutations and could be used for early-stage lung cancer diagnosis.

A Prospective Observational Study Evaluating the Correlation of c-MET Expression and EGFR Gene Mutation with Response to Erlotinib as Second-Line Treatment for Patients with Advanced/Metastatic Non-Small-Cell Lung Cancer.

OBJECTIVES: We aimed to evaluate the prevalence and predictive role of c-MET expression and EGFR mutation in the efficacy of erlotinib in non-small-cell lung cancer (NSCLC). METHODS: We prospectively recruited 196 patients with stage IV or recurrent NSCLC treated with erlotinib after failure of first-line chemotherapy. Immunohistochemistry was used to evaluate c-MET overexpression, silver in situ hybridization (SISH) to assess gene copy number, and real-time polymerase chain reaction to detect EGFR mutations, respectively, in tumor tissue. RESULTS: The major histologic type was adenocarcinoma (66.8%). c-MET was overexpressed in 55.8% (87/156) and dominant in females as well as non-squamous histology. Although c-MET gene amplification and high polysomy were observed in 2.0% (3/152) and 11.2% (17/152), they did not correlate with any characteristics. EGFR mutation was detected in 13.1% (20/153). The objective response rate of erlotinib was higher (61.1 vs. 3.7%, p < 0.001) and the median progression-free survival (PFS) was longer (10.2 vs. 1.9 months, p < 0.001) in EGFR-sensitizing mutations. However, c-MET positivity did not show a significant correlation with response to erlotinib or PFS. CONCLUSION: We reconfirmed EGFR mutation as a strong predictive marker of NSCLC. However, c-MET positivity was not associated with response or PFS, although c-MET overexpression correlated with some clinical characteristics.

Prognostic impact of a new score using neutrophil-to-lymphocyte ratios in the serum and malignant pleural effusion in lung cancer patients.

BACKGROUNDS: Various studies have reported that the neutrophil-to-lymphocyte ratio in the serum (sNLR) may serve as a cost-effective and useful prognostic factor in patients with various cancer types. However, no study has reported the prognostic impact of the NLR in malignant pleural effusion (MPE). To address this gap, we investigated the clinical impact of NLR as a prognostic factor in MPE (mNLR) and a new scoring system that use NLRs in the serum and MPE (smNLR score) in lung cancer patients. METHODS: We retrospectively reviewed all of the patients who were diagnosed with lung cancer and who presented with pleural effusion. To maintain the quality of the study, only patients with malignant cells in the pleural fluid or tissue were included. The patients were classified into three smNLR score groups, and clinical variables were investigated for their correlation with survival. RESULTS: In all, 158 patients were classified into three smNLR score groups as follows: 84 (53.2%) had a score of 0, 58 (36.7%) had a score of 1, and 16 (10.1%) had a score of 2. In a univariate analysis, high sNLR, mNLR, and increments of the smNLR score were associated with shorter overall survival (p < 0.001, p = 0.004, and p < 0.001, respectively); moreover, age, Eastern Cooperative Oncology Group performance status (ECOG PS), histology, M stage, hemoglobin level, albumin level, and calcium level were significant prognostic factors. A multivariable analysis confirmed that ECOG PS (p < 0.001), histology (p = 0.001), and smNLR score (p < 0.012) were independent predictors of overall survival. CONCLUSIONS: The new smNLR score is a useful and cost-effective prognostic factor in lung cancer patients with MPE. Although further studies are required to generalize our results, this information will benefit clinicians and patients in determining the most appropriate therapy for patients with MPE.

Veliparib in combination with whole-brain radiation therapy for patients with brain metastases from non-small cell lung cancer: results of a randomized, global, placebo-controlled study.

Veliparib is a potent, orally bioavailable, poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitor that crosses the blood-brain barrier and has been shown to potentiate the effects of radiation in preclinical and early clinical studies. This phase 2, randomized, global study evaluated the efficacy and safety of veliparib in combination with whole-brain radiation therapy (WBRT) in patients with brain metastases from non-small cell lung cancer (NSCLC). Three-hundred and seven patients with brain metastases from NSCLC were randomized 1:1:1 to WBRT (30 Gy in 10 fractions) plus 50 mg veliparib twice daily (BID; n = 103), 200 mg veliparib BID (n = 102), or placebo BID (n = 102). Treatment began within 28 days of diagnosis. Tumor response and safety were assessed; the primary endpoint was overall survival (OS). Patients who received ≥1 dose of treatment were included in the safety analysis. All randomized patients were included in the efficacy endpoint analyses. Patient characteristics were well balanced between treatment arms. Median OS was 185 days for patients treated with WBRT plus placebo and 209 days for WBRT plus veliparib (50 or 200 mg). No statistically significant differences in OS, intracranial response rate, and time to clinical or radiographic progression between any of the treatment arms were noted. No differences were observed in adverse events (all grades) across treatment arms; nausea, fatigue, alopecia, and headache were the most commonly reported. No new safety signals were identified for veliparib. A significant unmet need for therapies that improve the outcomes of patients with brain metastases from NSCLC remains.

Minimal Pleural Effusion in Small Cell Lung Cancer: Proportion, Mechanisms, and Prognostic Effect.

PURPOSE: To determine the frequency and investigate possible mechanisms and prognostic relevance of minimal (<10-mm thickness) pleural effusion in patients with small cell lung cancer (SCLC). MATERIALS AND METHODS: The single-center retrospective study was approved by the institutional review board of the hospital, and informed consent was waived by the patients. A cohort of 360 consecutive patients diagnosed with SCLC by using histologic analysis was enrolled in this study. Based on the status of pleural effusion on chest computed tomographic (CT) scans at diagnosis, patients were classified into three groups: no pleural effusion, minimal pleural effusion, and malignant pleural effusion. Eighteen variables related to patient, environment, stage, and treatment were included in the final model as potential confounders. RESULTS: Minimal pleural effusion was present in 74 patients (20.6%) and malignant pleural effusion in 83 patients (23.0%). Median survival was significantly different in patients with no, minimal, or malignant pleural effusion (median survival, 11.2, 5.93, and 4.83 months, respectively; P < .001, log-rank test). In the fully adjusted final model, patients with minimal pleural effusion had a significantly increased risk of death compared with those with no pleural effusion (adjusted hazard ratio, 1.454 [95% confidence interval: 1.012, 2.090]; P = .001). The prognostic effect was significant in patients with stage I-III disease (adjusted hazard ratio, 2.751 [95% confidence interval: 1.586, 4.773]; P < .001), but it disappeared in stage IV disease. An indirect mechanism representing mediastinal lymphadenopathy was responsible for the accumulation in all but one patient with minimal pleural effusion. CONCLUSIONS: Minimal pleural effusion is a common clinical finding in staging SCLC. Its presence is associated with worse survival in patients and should be considered when CT scans are interpreted.

A prospective, open-label, multicenter study of the clinical efficacy of extended-release hydromorphone in treating cancer pain inadequately controlled by other analgesics.

PURPOSE: The objective of this study was to evaluate whether extended-release hydromorphone (osmotic-controlled release oral delivery system [OROS] hydromorphone) treatment provided pain relief in cancer patients whose pain was inadequately controlled by other analgesics. METHODS: In this prospective, open-label, multicenter trial, patients who have sustained cancer pain with other analgesics were enrolled. After the baseline evaluation (visit 1), OROS hydromorphone was administered. Two evaluations (visits 2 and 3) were made: 29 ± 7 and 57 ± 7 days later, respectively. The primary end point was the pain intensity difference (PID) at visit 3 relative to visit 1 (expressed as percent PID). RESULTS: In total, 879 patients were screened and 432 completed all three visits. Of the 874 full analysis set patients, 343 (39.2 %) improved by more than 30 % PID. Of the 432 per-protocol patients, 282 (65.3 %) improved by more than 30 % PID. At visits 2 and 3, the degree of sleep disturbance, the number of awakenings, and the degree of sleep satisfaction were significantly better than at visit 1 (all P < 0.0001 for both visit 1-visit 2 and visit 1-visit 3). However, this pain relief was not associated with improved quality of life (P = 0.326 and P = 0.055 for visit 1-visit 2 and visit 1-visit 3, respectively). CONCLUSIONS: This study suggested that active pain management using the strong opioid OROS hydromorphone was beneficial in the management of cancer pain that was not controlled by other analgesics.

Bronchial washing fluid sequencing is useful in the diagnosis of lung cancer with necrotic tumor.

BACKGROUND: Early-stage lung cancers detected by low-dose computed tomography (CT) often require confirmation through invasive procedures due to the absence of endobronchial lesions. This study assesses the diagnostic utility of bronchial washing fluid (BW) sequencing, a less invasive alternative, aiming to identify patient characteristics most suited for this approach. METHODS: From June 2017 to March 2018, we conducted a prospective cohort study by enrolling patients with incidental lung lesions suspected of early-stage lung cancer at two independent hospitals, and 114 were diagnosed with lung cancer while 50 were diagnosed with benign lesions. BW sequencing was performed using a targeted gene panel, and the clinical characteristics of patients detected with cancer through sequencing were identified. RESULTS: Malignant cells were detected in 33 patients (28.9 %) through BW cytology. By applying specificity-focused mutation criteria, BW sequencing classified 42 patients (36.8 %) as having cancer. Among the cancer patients who were BW sequencing positive and BW cytology negative, 15 patients (75.0 %) showed necrosis on CT. The sensitivity of BW sequencing was particularly enhanced in patients with necrotic tumors, reaching 75 %. CONCLUSIONS: BW sequencing presents a viable, non-invasive diagnostic option for early-stage lung cancer, especially valuable in patients with necrotic lesions. By potentially reducing the reliance on more invasive diagnostic procedures, this method could streamline clinical workflows, decrease patient burden, and improve overall diagnostic efficiency.

Real-world outcome of crizotinib for anaplastic lymphoma kinase-positive lung cancer: Multicenter retrospective analysis in South Korea.

BACKGROUND: About 3%-5% of non-small cell lung cancer (NSCLC) presents positive anaplastic lymphoma kinase (ALK). Recently, several target agents have been approved as a treatment for ALK-positive NSCLC. This study aimed to analyze the real-world efficacy and outcome when administered crizotinib, the first approved target agent for ALK-positive NSCLC, according to first- or late-line treatment. METHODS: A total of 290 patients with ALK-positive advanced NSCLC who were treated with crizotinib in 15 institutions in South Korea from January 2009 to December 2018 were enrolled. RESULTS: The median age of patients was 57.0 years, and 50.3% were male. The median follow-up duration was 29.3 months. Among them, 113 patients received crizotinib as first-line therapy. The objective response rate (ORR) was 60.1% (57.0% for first-line recipients, 61.8% for second-/later-line). Median (95% CI) progression-free survival (PFS) was 13.7 (11.6-17.0) months. For first-line recipients, overall survival (OS) was 26.3 (17.6-35.0) months. No significant difference in ORR, PFS and OS, according to the setting of crizotinib initiation, was observed. In a multivariate Cox regression analysis, old age, male gender, initially metastatic, and number of metastatic organs were associated with poor PFS and OS. The most common adverse events were nausea and vomiting, and severe adverse event leading to dose adjustment was hepatotoxicity. CONCLUSIONS: ORR, PFS, OS, and adverse event profiles were comparable to previous clinical trials. Our findings could aid in the efficient management of ALK-positive lung cancer patients.

Effect of whole-brain radiotherapy with platinum-based chemotherapy in non-small cell lung cancer patients with multiple metastases including brain metastases.

Current guidelines recommend that cytotoxic chemotherapy be considered first in non-small cell lung cancer (NSCLC) patients with multiple metastases, and whole-brain radiotherapy (WBRT) is not initially recommended even if brain metastases are present. However, cytotoxic chemotherapeutic agents are less effective in brain metastases due to poor blood-brain barrier permeability. We investigated the effect of WBRT in combination with cytotoxic chemotherapy on survival in NSCLC patients who were EGFR, ALK, and PD-L1 negative, had an ECOG PS of 2, and had multiple metastases including brain metastases. From January 2005 to December 2018, histologically confirmed NSCLC patients who were EGFR, ALK, and PD-L1 negative, had an ECOG PS of 2, and had multiple metastases including brain metastases were included in this study. Patients were classified into two groups based on receiving WBRT prior to or concurrently with administration of first-line chemotherapeutic agents or receiving chemotherapy only. We compared intracranial progression-free survival (iPFS) and overall survival (OS). Of the 240 NSCLC patients with brain metastases at diagnosis and an ECOG PS of 2, 67 patients were EGFR, ALK, and PD-L1 negative with multiple metastases including brain metastases. Among those patients, 43 (64.2%) received WBRT prior to or concurrently with platinum-based chemotherapy. Patients who received WBRT prior to or concurrently with chemotherapy had better iPFS (7.7 months [4.8-10.6] vs. 3.5 months [2.1-4.9], p = 0.009) and OS (10.8 months [5.9-15.7] vs. 6.1 months [1.9-10.3], p = 0.038) than those who did not receive WBRT. In multivariate analyses, WBRT was significantly associated with iPFS (HR: 1.94 and 95% CI 1.11-3.40, p = 0.020) and OS (HR: 1.92 and 95% CI 1.08-3.42, p = 0.027). In NSCLC patients who are EGFR, ALK, and PD-L1 negative, have an ECOG PS of 2, and have multiple metastases including brain metastases, WBRT prior to or concurrently with chemotherapy could improve iPFS and OS. Therefore, the combination of WBRT with cytotoxic chemotherapy should be considered in these patients.

Real-world first-line afatinib for advanced EGFR mutation-positive non-small cell lung cancer in Korea: updated survival data.

Background: Data from clinical trials and real-world studies show that afatinib is effective in treating non-small cell lung cancer (NSCLC) harboring activating mutations in the epidermal growth factor receptor (EGFR) gene. A previous analysis of patients enrolled in the Korean Academy of Tuberculosis and Respiratory Disease (KATRD) EGFR cohort showed that first-line afatinib was well tolerated and effectiveness results were encouraging. At the time of the previous analysis, survival data were not mature. Here we briefly present updated survival data from the cohort. Methods: The study was a retrospective, multicenter (15 sites) review of electronic records of Korean adult patients (aged >20 years) with advanced EGFR mutation-positive NSCLC who initiated first-line afatinib (N=421). Progression-free survival (PFS) and overall survival (OS) were evaluated using Kaplan-Meier survival curves. Results: Overall, median PFS was 20.2 months and median OS was 48.6 months. OS rates at 36 and 60 months were 60.1% and 42.3%, respectively. Presence vs. absence of baseline brain metastases was associated with significantly reduced median PFS (14.9 vs. 28.0 months; P<0.001) and median OS (32.2 vs. 65.6 months; P<0.001). The presence of common baseline EGFR mutations (Del19, L858R) was associated with significantly prolonged median OS (49.6 vs. 30.1 months; P=0.017). In patients stratified by the presence/absence of T790M EGFR mutation, the T790M mutation was associated with significantly reduced median PFS (P=0.0005) but there was no significant difference between groups in survival (P=0.263). There were no significant differences in PFS or OS for patients stratified by afatinib dose reduction or by age group (<70 vs. ≥70 years). Conclusions: Afatinib was effective in Korean patients with EGFR mutation-positive NSCLC with median OS over 4 years. The presence of baseline brain metastases and/or uncommon EGFR mutations were associated with reduced survival. In the absence of baseline brain metastases, median OS was more than 5 years.

Real-world analysis of first-line afatinib in patients with EGFR-mutant non-small cell lung cancer and brain metastasis: survival and prognostic factors.

Background: Overall survival (OS) in patients with non-small cell lung cancer (NSCLC) and brain metastases (BMs) is poor. We aimed to identify prognostic factors and ascertain treatment outcomes of first-line afatinib for patients with epidermal growth factor receptor (EGFR)-mutant NSCLC with BM in a real-world setting. Methods: This retrospective observational study reviewed electronic records of patients with EGFR-mutant NSCLC who received first-line afatinib treatment between October 2014 and October 2019 in 16 hospitals across South Korea. The Kaplan-Meier method estimated time on treatment (TOT) and OS; multivariate analyses were performed using Cox proportional hazards (PH) models. Results: Among 703 patients who received first-line afatinib, 262 (37.3%) had baseline BM. Of 441 patients without baseline BM, 92 (20.9%) developed central nervous system (CNS) failure. Compared with patients without CNS failure, those with CNS failure during afatinib treatment were younger (P=0.012), had a higher Eastern Cooperative Oncology Group (ECOG) performance status (PS) (P<0.001), increased metastatic site involvement (P<0.001), advanced stage disease (P<0.001), with liver metastasis (P=0.008) and/or bone metastasis (P<0.001) at baseline. Cumulative incidence of CNS failure in years 1, 2 and 3 was 10.1%, 21.5% and 30.0%, respectively. In multivariate analysis, cumulative incidence was significantly higher in patients with ECOG PS ≥2 (P<0.001), uncommon EGFR mutations (P=0.001), and no baseline pleural metastasis (P=0.017). Median TOT was 16.0 months (95% CI: 14.8-17.2) and, in patients with CNS failure, without CNS failure, and with baseline BM was 12.2, 18.9, and 14.1 months, respectively (P<0.001). Median OS was 52.9 months (95% CI: 45.4-60.3) and, in patients with CNS failure, without CNS failure, and with baseline BM was 29.1, 67.3 and 48.5 months, respectively (P<0.001). Conclusions: First-line afatinib in the real-world setting showed clinically meaningful effectiveness in patients with EGFR-mutant NSCLC and BM. CNS failure was a poor prognostic factor for TOT and OS correlating with younger age, poor ECOG PS, higher metastatic number, advanced disease stage, uncommon EGFR mutations, and baseline liver and/or bone metastases.

Final Report on Real-World Effectiveness of Sequential Afatinib and Osimertinib in EGFR-Positive Advanced Non-Small Cell Lung Cancer: Updated Analysis of the RESET Study.

PURPOSE: This study aimed to report the final analysis of time-on-treatment (TOT) and overall survival (OS) in patients with advanced-stage epidermal growth factor receptor (EGFR)+ non-small cell lung cancer (NSCLC) who received sequential afatinib and osimertinib and to compare the outcomes with other second-line regimens (comparator group). MATERIALS AND METHODS: In this updated report, the existing medical records were reviewed and rechecked. TOT and OS were updated and analyzed according to clinical features using the Kaplan-Meier method and log-rank test. TOT and OS were compared with those of the comparator group, in which most patients received pemetrexed-based treatments. A multivariable Cox proportional hazard model was used to evaluate features that could affect survival outcomes. RESULTS: The median observation time was 31.0 months. The follow-up period was extended to 20 months. A total of 401 patients who received first-line afatinib were analyzed (166 with T790M+ and second-line osimertinib, and 235 with unproven T790M and other second-line agents). Median TOTs on afatinib and osimertinib were 15.0 months (95% confidence interval [CI], 14.0 to 16.1) and 11.9 months (95% CI, 8.9 to 14.6), respectively. The median OS in the osimertinib group was 54.3 months (95% CI, 46.7 to 61.9), much longer than that in the comparator group. In patients who received osimertinib, the OS was longest with Del19+ (median, 59.1; 95% CI, 48.7 to 69.5). CONCLUSION: This is one of the largest real-world studies reporting the encouraging activity of sequential afatinib and osimertinib in Asian patients with EGFR+ NSCLC who acquired the T790M mutation, particularly Del19+.

Lack of association of genetic variations of deoxycytidine kinase with toxicity or survival of non-small-cell lung cancer patients treated with gemcitabine plus cisplatin.

The aim of this study was to determine whether tagging polymorphisms (tSNPs) of deoxycytidine kinase (DCK) have an effect on toxicity or prognosis in patients with non-small-cell lung cancer (NSCLC) treated with gemcitabine plus cisplatin. Three tSNPs (-201 C>T, rs2306744; IVS2+9846 G>A, rs12648166; IVS6+1392 T>C, rs4694362) were chosen using the international HapMap Project and Japanese Single-Nucleotide Polymorphisms. We evaluated the associations of the tSNPs with hematologic toxicity or overall survival of 139 NSCLC patients at stages IIIA/IIIB (59) and IV (80). Hematologic toxicity such as neutropenia, thrombocytopenia, and anemia were not different by the three tSNPs or haplotypes (CGT, CAT, and CAC) of DCK. The genetic variations did not affect survival of the patients (log-rank p: 0.248 for -201 C>T, 0.571 for IVS2+9846 G>A, 0.686 for IVS6+1392 T>C, 0.556 for CGT, 0.453 for CAT, and 0.845 for CAC). In a Cox model, these tSNPs and haplotypes did not reveal prognostic relevance (aHR and 95% CI: 0.954 and 0.611 to 1.489 for -201 C>T; 1.193 and 0.719 to 1.979 for IVS2+9846 G>A; 1.072 and 0.674 to 1.706 for IVS6+1392 T>C, 0,668 and 0.205 to 2.175 for CGT, 1.043 and 0.713 to 1.525 for CAT, and 1.043 and 0.701 to 1.550 for CAC). This is the first study to focus on the association of tSNPs and their haplotypes of DCK with toxicity and survival in NSCLC patients. This suggests that genetic variations of DCK have no effect on the outcomes in the patients treated with gemcitabine-based chemotherapy.

Mediastinal lymphangioma treated using endobronchial ultrasound-guided transbronchial needle aspiration.

Lymphangiomas are localized malformations of the lymphatic system that most commonly occur in the head and neck. However, less than 1% of all lymphangiomas are confined to the mediastinum. The standard treatment has been surgical excision, but the involvement of vital structures in the area local to the lymphangioma makes total excision virtually impossible in most cases. To our knowledge, there has been no report of mediastinal lymphangioma treated with endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA). We report here the first case of safe, effective treatment of a very large mediastinal lymphangioma using EBUS-TBNA in a 29-year-old man.

Clinicopathologic and molecular characteristics of lung adenocarcinoma arising in young patients.

Lung cancer rarely occurs in young patients. Recent studies have demonstrated that epidemiologic data are closely correlated to some molecular characteristics. We investigated the clinicopathologic characteristics of lung adenocarcinoma in young patients and evaluated immunohistochemically detected epidermal growth factor receptor (EGFR) mutation status and anaplastic lymphoma kinase (ALK) positivity. Among lung adenocarcinoma patients, 31 cases were of the ≤ 40 yr-old group and 261 cases of > 50 yr-old group. Young patients were more likely to be females (67.7% vs 40.2%), and nonsmokers (58.1% vs 45.2%) and more often had high TNM stage (stage IV was 80.6% vs 52.1%) and had a high rate of distant metastasis (51.6% vs 28.0%) compared with older patients. The signet ring cell feature was more common (25.8% vs 11.5%) and lepidic growth pattern was rarely present (3.2% vs 16.5%) in the adenocarcinoma of young patients. There was no significant survival difference between the two age groups. The rate of EGFR mutation status and ALK positivity did not show a statistical difference between two groups. In conclusion, lung adenocarcinoma of young patients demonstrates distinct pathologic features with frequent presence of a signet ring cell feature and rare occurrence of lepidic growth pattern. Further investigation for other genetic abnormalities would be needed.

First-line Afatinib in Patients With Non-small-cell Lung Cancer With Uncommon EGFR Mutations in South Korea.

BACKGROUND/AIM: Non-small cell lung cancers (NSCLCs) harboring uncommon epidermal growth factor receptor (EGFR) mutations are heterogeneous and show variable prevalence and clinical responses to EGFR tyrosine kinase inhibitors. We investigated the characteristics of uncommon EGFR mutations and the clinical efficacy of afatinib in patients with NSCLC harboring uncommon EGFR mutations. PATIENTS AND METHODS: In this multicenter, retrospective study, we analyzed patients with NSCLC with uncommon EGFR mutations in 16 South Korean institutes. Mutations were categorized according to their incidence: 1) major uncommon mutations (G719X and L861Q), 2) compound mutations, and 3) minor uncommon mutations (exon 20 insertion, S768I, and de novo T790M). RESULTS: Of 703 patients with EGFR-mutant NSCLC, 64 (9.1%) had uncommon EGFR mutations. Afatinib demonstrated activity against tumors harboring major uncommon mutations [median time of treatment (TOT): 20.3 months, 95% confidence interval (CI)=15.1-25.5; overall survival (OS): 30.6 months, 95% CI=26.3-34.8] and compound mutations (median TOT: 12.3 months, 95% CI=7.7-17.0; OS: 29.1 months, 95% CI=20.4-37.7) but not against tumors harboring minor uncommon mutations (median TOT: 3.8 months, 95% CI=1.7-6.0; OS: 8.5 months, 95% CI=5.2-11.7). The S768I mutation was present in 14 patients (1.99%). The median TOT and OS were not significantly different between S768I mutations and resistant exon 20 mutations. CONCLUSION: Afatinib is effective in patients with NSCLC harboring major uncommon and compound EGFR mutations.