Different treatment efficacies and T790M acquisition of EGFR-TKIs on NSCLC patients with variable Del-19 subtypes of EGFR.

EGFR exon 19 deletion (Del-19) comprises multiple advanced NSCLC subtypes. EGFR-tyrosine kinase inhibitor (TKI) efficacy and T790M acquisition in various Del-19 subtypes is unknown. We prospectively collected tissue samples from patients harboring NSCLC with Del-19 between 2006 and 2020. We evaluated EGFR-TKI treatment effectiveness among the different Del-19 subtypes. We collected 1391 NSCLC samples from 892 patients with Del-19, and the most common subtype was del E746-A750 (67.5%). 741 patients had taken first- or second-generation EGFR-TKIs. There were no significant differences in response rates between patients with different Del-19 subtypes (P = .630). Patients with indel E746 had the longest median PFS (14.6 months), but those with non-LRE deletions had the shortest PFS (8.9 months; P = .002). For OS analysis, patients with indel E746 also had the longest OS (34.1 months), but those with non-LRE deletions had the shortest OS (21.1 months; P = .046). Patients with different Del-19 subtypes showed no significant differences in the T790M acquisition rates (P = .443). Among the 151 patients with acquired T790M who received third-generation EGFR-TKIs, the Del-19 subtype was not associated with different RR and PFS. In vitro cellular viability and activation of the EGFR pathway analysis were consistent with the clinical findings. In conclusion, compared with del E746-A750, indel E746 was associated with longer PFS and OS, but the non-LRE subtype was correlated with shorter survival prognosis. There were no significant differences in the acquired T790M rate and treatment effectiveness of subsequent third-generation EGFR-TKIs between various Del-19 subgroups.

The incidence and interpretation of large differences in EIT-based measures for PEEP titration in ARDS patients.

Positive end-expiratory pressure (PEEP) can be titrated by electrical impedance tomography (EIT). The aim of the present study was to examine the performance of different EIT measures during PEEP trials with the aim of identifying "optimum" PEEP and to provide possible interpretations of largely diverging results. After recruitment (maximum plateau pressure 35 cmH2O), decremental PEEP trial with steps of 2 cmH2O and duration of 2 min per step was performed. Ventilation gain and loss, the global inhomogeneity (GI) index, trend of end-expiratory lung impedance (EELI) and regional compliance (Creg) for estimation of overdistension and collapse were calculated. Largely diverging results of PEEP selection among the measures were defined as differences ≥ 4 PEEP steps (i.e. ≥ 8 cmH2O). In 30 ARDS patients we examined so far, 3 patients showed significant differences in PEEP selections. Overdistension and collapse estimation based on Creg tended to select lower PEEP while the GI index and EELI trend suggested higher PEEP settings. Regional inspiration times were heterogeneous indicating that the assumption of a uniform driving pressure in the calculation of Creg may not be valid. Judging by the predominant ventilation distribution in the most dependent regions, these patients were non-recruitable with the applied recruitment method or pressure levels. The existence of differences in the recommended PEEP among the analyzed EIT measures might be an indicator of non-recruitable lungs and heterogeneous airway resistances. In these extreme cases, the largely diverging results may prompt the attending clinician to develop individual ventilation strategies.Clinical Trial Registration Registration number NCT03112512, https://clinicaltrials.gov/ Registered 13 April 2017.

Acquired resistance to EGFR tyrosine kinase inhibitors is mediated by the reactivation of STC2/JUN/AXL signaling in lung cancer.

Constitutive activation of the epidermal growth factor receptor (EGFR) signaling pathway is implicated in the initiation and progression of lung cancer. EGFR tyrosine kinase inhibitor (TKI)-targeted therapy has become the standard treatment for nonsmall cell lung cancer (NSCLC) patients. However, acquired resistance to these agents remains a major obstacle for managing NSCLC. Here, we investigated a novel strategy to overcome EGFR TKI resistance by targeting the stanniocalcin 2 (STC2)-JUN-AXL pathway. We revealed that STC2 was expressed at significantly higher levels in EGFR TKI-resistant cells. Further, clinical analysis showed that STC2 expression was increased after the development of EGFR TKI resistance and that higher levels were correlated with shorter progression-free survival in EGFR TKI-treated lung cancer patients. Moreover, STC2 overexpression in EGFR TKI-sensitive cells resulted in EGFR TKI resistance. Conversely, genetic silencing of STC2 rendered EGFR TKI-resistant cells more sensitive to EGFR TKIs. Mechanically, STC2 enhanced AXL promoter activity by increasing the phosphorylation of c-Jun, which is an indispensable transcription factor that transactivates AXL. STC2 promoted activation of the JUN-AXL-extracellular signal-regulated kinase (ERK) signaling axis in lung cancer cells. Pharmacological or genetic inhibition of AXL-ERK activity inhibited STC2-mediated EGFR TKI resistance. We also demonstrated that PE2988 cells, a C797S-independent osimertinib-resistant primary cancer cell line from a lung cancer patient, responded to combined AXL inhibitor and osimertinib treatment. In conclusion, our research indicates that STC2 overexpression is important for acquired resistance to EGFR TKIs and that STC2-JUN-AXL-ERK signaling might be a potential therapeutic target to overcome resistance to EGFR TKIs.

Comparable clinical outcomes in patients with HER2-mutant and EGFR-mutant lung adenocarcinomas.

HER2 is a major proliferative driver in lung cancer. HER2 gene aberrations impact the prognosis of lung adenocarcinoma (ADC). A one-step reverse transcription-polymerase chain reaction was performed using RNA samples from 888 Asian lung cancer patients to detect HER2, EGFR, KRAS, ALK, and ROS1 mutations. The demographic data and treatment outcomes of HER2 mutation-positive lung ADC patients were analyzed and compared to those with HER2 mutation-negative tumors. HER2 mutation was identified in 40 (4.5%) lung ADC patients. HER2 mutations tended to occur in male patients with advanced-stage disease and never-smokers. A775_G776insYVMA (n = 22, 55%) was the most prevalent HER2 mutation, followed by P780_Y781insGSP (n = 4, 10%). For patients diagnosed with stage-IIIB/IV disease, HER2-mutant patients showed clinical outcomes comparable to EGFR-mutant patients (P = 0.721, log-rank test) and a better overall survival (OS) compared to patients lacking driver mutations in the investigated genes (P = 0.033, Breslow test). Specifically, lung ADC patients with stage-IV HER2-mutant tumors treated with chemotherapy or targeted agents, even without afatinib or anti-HER2 targeted therapy, showed similar clinical outcomes to lung ADC patients harboring EGFR exon 19 deletion or L858R mutations (P = 0.870). In addition, multivariate analysis indicated that HER2 mutation status was not a major risk factor for diminished OS in stage-IV lung cancer. In conclusion, lung ADC harboring HER2 mutations showed distinct characteristics from other driver mutations, including increased chemosensitivity with in advanced stage disease.

The optimal corepressor function of nuclear receptor corepressor (NCoR) for peroxisome proliferator-activated receptor γ requires G protein pathway suppressor 2.

Repression of peroxisome proliferator-activated receptor γ (PPARγ)-dependent transcription by the nuclear receptor corepressor (NCoR) is important for homeostatic expression of PPARγ target genes in vivo. The current model states that NCoR-mediated repression requires its direct interaction with PPARγ in the repressive conformation. Previous studies, however, have shown that DNA-bound PPARγ is incompatible with a direct, high-affinity association with NCoR because of the inherent ability of PPARγ to adopt the active conformation. Here we show that NCoR acquires the ability to repress active PPARγ-mediated transcription via G protein pathway suppressor 2 (GPS2), a component of the NCoR corepressor complex. Unlike NCoR, GPS2 can recognize and bind the active state of PPARγ. In GPS2-deficient mouse embryonic fibroblast cells, loss of GPS2 markedly reduces the corepressor function of NCoR for PPARγ, leading to constitutive activation of PPARγ target genes and spontaneous adipogenesis of the cells. GPS2, however, is dispensable for repression mediated by unliganded thyroid hormone receptor α or a PPARγ mutant unable to adopt the active conformation. This study shows that GPS2, although dispensable for the intrinsic repression function of NCoR, can mediate a novel corepressor repression pathway that allows NCoR to directly repress active PPARγ-mediated transcription, which is important for the optimal corepressor function of NCoR for PPARγ. Interestingly, GPS2-dependent repression specifically targets PPARγ but not PPARα or PPARδ. Therefore, GPS2 may serve as a unique target to manipulate PPARγ signaling in diseases.

Differential involvement of E2A-corepressor interactions in distinct leukemogenic pathways.

E2A is a member of the E-protein family of transcription factors. Previous studies have reported context-dependent regulation of E2A-dependent transcription. For example, whereas the E2A portion of the E2A-Pbx1 leukemia fusion protein mediates robust transcriptional activation in t(1;19) acute lymphoblastic leukemia, the transcriptional activity of wild-type E2A is silenced by high levels of corepressors, such as the AML1-ETO fusion protein in t(8;21) acute myeloid leukemia and ETO-2 in hematopoietic cells. Here, we show that, unlike the HEB E-protein, the activation domain 1 (AD1) of E2A has specifically reduced corepressor interaction due to E2A-specific amino acid changes in the p300/CBP and ETO target motif. Replacing E2A-AD1 with HEB-AD1 abolished the ability of E2A-Pbx1 to activate target genes and to induce cell transformation. On the other hand, the weak E2A-AD1-corepressor interaction imposes a critical importance on another ETO-interacting domain, downstream ETO-interacting sequence (DES), for corepressor-mediated repression. Deletion of DES abrogates silencing of E2A activity by AML1-ETO in t(8;21) leukemia cells or by ETO-2 in normal hematopoietic cells. Our results reveal an E2A-specific mechanism important for its context-dependent activation and repression function, and provide the first evidence for the differential involvement of E2A-corepressor interactions in distinct leukemogenic pathways.

Regulated clearance of histone deacetylase 3 protects independent formation of nuclear receptor corepressor complexes.

An important step in transcriptional regulation by corepressors N-CoR and SMRT is the formation of a stable and active histone deacetylase 3 (HDAC3)-containing complex. Although N-CoR and SMRT are thought to bind HDAC3 competitively, multiple studies have shown that they do not interfere with the function of each other. How this functional independence is sustained under the competitive interaction is unclear. Here, we show that the coupling of corepressor expression with HDAC3 degradation allows cells to maintain a stable level of uncomplexed HDAC3, thereby preventing mutual interference in the assembly of N-CoR and SMRT complexes. The free uncomplexed HDAC3 is highly unstable. Unexpectedly, the rate of HDAC3 degradation is inversely correlated with the expression level of corepressors. Our results indicate that reducing one corepressor accelerates HDAC3 clearance, thus preventing an increase in complex formation between HDAC3 and the other corepressor. In addition, this study also indicates that the formation of a stable and active HDAC3-corepressor complex is a stepwise process in which the C terminus of HDAC3 plays a critical role at late steps of the assembly process.

Monitoring the Efficacy of High-Flow Nasal Cannula Oxygen Therapy in Patients with Acute Hypoxemic Respiratory Failure in the General Respiratory Ward: A Prospective Observational Study.

High-flow nasal cannula (HFNC) is widely used to treat hypoxemic respiratory failure. The effectiveness of HFNC treatment and the methods for monitoring its efficacy in the general ward remain unclear. This prospective observational study enrolled 42 patients who had acute hypoxemic respiratory failure requiring HFNC oxygen therapy in the general adult respiratory ward. The primary outcome was the all-cause in-hospital mortality. Secondary outcomes included the association between initial blood test results and HFNC outcomes. Regional ventilation distributions were monitored in 24 patients using electrical impedance tomography (EIT) after HFNC initiation. Patients with successful HFNC treatment had better in-hospital survival (94%) compared to those with failed HFNC treatment (0%, p < 0.001). Neutrophil-to-lymphocyte ratios of ≥9 were more common in patients with failed HFNC (70%) compared to those with successful HFNC (52%, p = 0.070), and these patients had shorter hospital survival rates after HFNC treatment (p = 0.046, Tarone-Ware test). Patients with successful HFNC treatment had a more central ventilation distribution compared to those with failed HFNC treatment (p < 0.05). Similarly, patients who survived HFNC treatment had a more central distribution compared to those who did not survive (p < 0.001). We concluded that HFNC in the general respiratory ward may be a potential rescue therapy for patients with respiratory failure. EIT can potentially monitor patients receiving HFNC therapy.

Non-ST-segment elevation myocardial infarction with non-obstructive coronary arteries due to a type-A thymoma: A case report.

Introduction: Myocardial infarction with non-obstructive coronary arteries (MINOCA) has become an increasingly recognized subgroup in patients with acute myocardial infarction, with a recent cohort study reporting a prevalence of 8.8%. This report describes a patient who presented with non-ST-segment elevation myocardial infarction (NSTEMI) due to an incidental anterior mediastinal mass. Case presentation: An 80-year-old woman presented to our emergency department with a chief complaint of progressive shortness of breath associated with retrosternal chest pain for one day duration. Computed tomography (CT) angiogram of the chest was conducted, which revealed an anterior mediastinal mass. Upon admission, the patient developed an acute episode of recurrent severe chest pain, which was diagnosed as an NSTEMI. Emergent cardiac catheterization was performed because of unstable vital signs; however, the results showed no evidence of atherosclerotic changes in the major coronary arteries, compatible with the diagnosis of MINOCA. The mediastinal mass was later confirmed to be a type A thymoma on CT-guided biopsy. Conclusion: Myocardial infarction in patent coronary arteries due to an anterior mediastinal mass is rare. Further studies are needed to standardize the diagnosis and management protocols for the potential etiologies of MINOCA.

Survival outcomes and prognostic factors of lung cancer patients with the MET exon 14 skipping mutation: A single-center real-world study.

Introduction: The MET exon 14 skipping (METex14) mutation is an important oncogenic driver in lung cancer. We performed a retrospective analysis of clinical data from lung cancer patients with the METex14 mutation to analyze their survival outcomes and associated prognostic factors. Methods: A one-step reverse transcription-polymerase chain reaction to examine the presence of the METex14 mutation was performed using RNA samples from 1374 lung cancer patients with no detected EGFR and ALK mutations. Pathological features and immunohistochemistry (IHC) results for c-MET were analyzed in patients with METex14-positive tumors. Results: METex14 was identified in 69 patients with lung cancer, including 53 adenocarcinoma (ADC) and 16 non-ADC patients. In comparison with patients without the METex14 mutation, lung cancer patients harboring the METex14 mutation were generally elderly individuals, never-smokers, and had poor performance scores. A higher frequency of METex14 mutations was detected in pulmonary sarcomatoid carcinoma (PSC) patients (24.3%, n = 9/37). However, stage IV PSC patients with or without the METex14 mutations showed similarly poor overall survival (OS) (p = 0.429). For all 36 METex14-positive lung ADCs, multivariate analysis showed several poor prognostic factors, including strong c-MET IHC staining (p = 0.006), initial brain metastasis (p = 0.005), and administration of only supportive care (p < 0.001). After excluding seven patients who received only supportive care, we further analyzed 29 stage IV lung ADC patients with METex14 mutations who received anti-cancer treatment. Multivariate analysis showed that pemetrexed treatment (p = 0.003), lung radiotherapy (p = 0.020), initial brain metastasis (p = 0.005), and strong c-MET IHC staining (p = 0.012) were independent prognostic factors for OS in these patients. Conclusions: A higher frequency of METex14 mutations was detected in PSC patients. Stage IV PSC patients with or without the METex14 mutations had similarly poor overall survival. Pemetrexed-based chemotherapy, strong c-MET ICH staining, initial brain metastasis, and lung radiotherapy, may help predict survival outcomes in patients with advanced lung ADCs harboring the METex14 mutation.

MiR-503 pleiotropically regulates epithelial-mesenchymal transition and targets PTK7 to control lung cancer metastasis.

OBJECTIVE: In lung cancer patients, most deaths are caused by the distant dissemination of cancer cells. Epithelial-mesenchymal transition (EMT) and collective cell migration are distinct and important mechanisms involved in cancer invasion and metastasis. Additionally, microRNA dysregulation contributes significantly to cancer progression. In this study, we aimed to explore the function of miR-503 in cancer metastasis. METHODS: Molecular manipulations (silencing or overexpression) were performed to investigate the biological functions of miR-503 including migration and invasion. Reorganization of cytoskeleton was assessed using immunofluorescence and the relationship between miR-503 and downstream protein tyrosine kinase 7 (PTK7) was assessed using quantitative real-time PCR, immunoblotting, and reporter assays. The tail vein metastatic animal experiments were performed. RESULTS: Herein, we demonstrated that the downregulation of miR-503 confers an invasive phenotype in lung cancer cells and provided in vivo evidence that miR-503 significantly inhibits metastasis. We found that miR-503 inversely regulates EMT, identified PTK7 as a novel miR-503 target, and showed the functional effects of miR-503 on cell migration and invasion were restored upon reconstitution of PTK7 expression. As PTK7 is a Wnt/planar cell polarity protein crucial for collective cell movement, these results implicated miR-503 in both EMT and collective migration. However, the expression of PTK7 did not influence EMT induction, suggesting that miR-503 regulates EMT through mechanisms other than PTK7 inhibition. Furthermore, we discovered that PTK7 mechanistically activates focal adhesion kinase (FAK) and paxillin, thereby controlling the reorganization of the cortical actin cytoskeleton. CONCLUSION: Collectively, miR-503 is capable of governing EMT and PTK7/FAK signaling independently to control the invasion and dissemination of lung cancer cells, indicating that miR-503 represents a pleiotropic regulator of cancer metastasis and hence a potential therapeutic target for lung cancer.

Determination of Low Muscle Mass by Muscle Surface Index of the First Lumbar Vertebra Using Low-Dose Computed Tomography.

The muscle index of the first vertebra (L1MI) derived from computed tomography (CT) is an indicator of total skeletal muscle mass. Nevertheless, the cutoff value and utility of L1MI derived from low-dose chest CT (LDCT) remain unclear. Adults who received LDCT for health check-ups in 2017 were enrolled. The cutoff values of L1MI were established in subjects aged 20-60 years. The cutoff values were used in chronic obstructive pulmonary disease (COPD) patients to determine muscle quantity. A total of 1780 healthy subjects were enrolled. Subjects (n = 1393) aged 20-60 years were defined as the reference group. The sex-specific cutoff values of L1MI were 26.2 cm2/m2 for males and 20.9 cm2/m2 for females. Six subjects in the COPD group (6/44, 13.6%) had low L1MI. COPD subjects with low L1MI had lower forced expiratory volume in one second (0.81 ± 0.17 vs. 1.30 ± 0.55 L/s, p = 0.046) and higher COPD assessment test scores (19.5 ± 2.6 vs. 15.0 ± 4.9, p = 0.015) than those with normal L1MI. In conclusion, LDCT in health assessments may provide additional information on sarcopenia.

Clinicopathological Features and Survival Outcomes of Primary Pulmonary Invasive Mucinous Adenocarcinoma.

Pulmonary invasive mucinous adenocarcinoma (IMA) has unique histological patterns. This study aimed to comprehensively evaluate the clinicopathological features, prognosis, and survival outcomes of IMAs. We retrospectively identified 77 patients with pulmonary IMA and reviewed their clinical and pathological features. Another 520 patients with non-IMA-type ADC were retrieved for comparison with patients with IMA. A new two-tier grading system (high-grade and low-grade IMAs) modified from the pancreatic intraepithelial neoplasia classification system was used for survival analyses. Compared to patients with non-IMA-type ADC, patients with IMA tended to have never smoked (p = 0.01) and had early-stage IMA at initial diagnosis (p < 0.001). For stage I-II diseases, the five-year overall survival (OS) rates were 76% in IMAs and 50% in non-IMA-type ADCs, and a longer OS was observed in patients with IMA (p = 0.002). KRAS mutations were the most commonly detected driver mutations, which occurred in 12 of the 28 (43%) patients. High-grade IMAs were associated with a shorter recurrence-free survival (RFS) for stage I-IIIA diseases (p = 0.010) than low-grade IMAs but not for OS. In conclusion, patients with stage I and II IMA had better OS than those with non-IMA-type ADC. A new two-tier grading system might be useful for predicting RFS in stage I-IIIA IMAs.

Regional air trapping in acute exacerbation of obstructive lung diseases measured with electrical impedance tomography: a feasibility study.

BACKGROUND: Since bronchial abnormalities often exhibit spatial non-uniformity which may be not correctly assessed by conventional global lung function measures, regional information may help to characterize the disease progress. We hypothesized that regional air trapping during mechanical ventilation could be characterized by regional end-expiratory flow (EEF) derived from electrical impedance tomography (EIT). METHODS: Twenty-five patients suffering from chronic obstructive pulmonary disease (COPD grade 3 or 4) or severe asthma with acute exacerbation were examined prospectively. Patients were ventilated under assist-control mode. EIT measurements were conducted before and one hour after inhaled combined corticosteroid and long-acting ß2 agonist, on two consecutive days. Regional EEF was calculated as derivative of relative impedance for every image pixel in the lung regions. The results were normalized to global flow values measured by the ventilator. RESULTS: Regional and global EEF were highly correlated (P<0.00001) and regional effects of medication and disease progression were visible in the regional EEF maps. The sums of regional EEF in lung regions were 3.8 [2.0, 5.1] and 3.6 [1.9, 4.5] L/min in COPD patients before and after medication (median [lower, upper quartiles]; P=0.37). The corresponding values in asthma patients were 3.0 [2.5, 4.2] and 2.2 [1.7, 3.2] L/min (P<0.05). Histograms of regional EEF showed high spatial heterogeneity of EEF before medication. After one day of treatment, the histograms exhibited less heterogeneous and a decrease in EEF level. CONCLUSIONS: Regional EEF characterizes air trapping and intrinsic PEEP, which could provide diagnostic information for monitoring the disease progress during treatment.

miR-146b-5p Enhances the Sensitivity of NSCLC to EGFR Tyrosine Kinase Inhibitors by Regulating the IRAK1/NF-κB Pathway.

Although patients with non-small cell lung cancer harboring activating mutations in the epidermal growth factor receptor (EGFR) show good clinical response to EGFR tyrosine kinase inhibitors (TKIs), patients eventually develop acquired resistance. Previous studies have shown that several microRNAs (miRNAs) are involved in EGFR TKI resistance. Here, we aimed to investigate whether miR-146b-5p sensitizes the EGFR TKI-resistant lung cancer cells. Clinical analysis showed that miR-146b-5p expression in lung cancer cells isolated from pleural effusions of treatment-naive patients was significantly higher than that after acquiring resistance to EGFR TKI treatment. Ectopic expression of miR-146b-5p in EGFR TKI-resistant cells enhanced EGFR TKI-induced apoptosis. The same results were observed in EGFR-dependent and -independent osimertinib-resistant primary cancer cells (PE3479 and PE2988). Mechanically, miR-146b-5p suppressed nuclear factor κB (NF-κB) activity and NF-κB-related IL-6 and IL-8 production by targeting IRAK1. A negative correlation was observed between miR-146b-5p and IRAK1 in clinical specimens. In rescue experiments, restoration of IRAK1 expression reversed the effects of miR-146b-5p on EGFR TKI sensitivity and recovered NF-κB-regulated IL-6 and IL-8 production. In conclusion, miR-146b-5p/IRAK1/NF-κB signaling is important in promoting EGFR TKI resistance, and miR-146b-5p may be a useful tool for overcoming EGFR TKI resistance.

Lung cancer with epidermal growth factor receptor exon 20 mutations is associated with poor gefitinib treatment response.

PURPOSE: Clinical reports about responsiveness to gefitinib treatment in patients of non-small cell lung cancer (NSCLC) with mutations in exon 20 of epidermal growth factor receptor (EGFR) are limited. To increase understanding of the influence of exon 20 mutations on NSCLC treatment with gefitinib, we investigated the clinical features of lung cancer in patients with exon 20 mutations and analyzed the gefitinib treatment response. EXPERIMENTAL DESIGN: We surveyed the clinical data and mutational studies of NSCLC patients with EGFR exon 20 mutations in the National Taiwan University Hospital and reviewed the literature reports about EGFR exon 20 mutations and the gefitinib treatment response. RESULTS: Twenty-three patients with mutations in exon 20 were identified. Nine (39%) had coexisting mutations in EGFR exons other than exon 20. Sixteen patients received gefitinib treatment, and a response was noted in 4 patients. The gefitinib response rate of NSCLC with exon 20 mutations was 25%, far lower than those with deletions in exon 19 and L858R mutations. Interestingly, different exon 20 mutations and coexisting mutations seemed to have a different influence on gefitinib response. CONCLUSIONS: EGFR exon 20 mutations of NSCLC patients result in poorer responsiveness to gefitinib treatment, but variability exists between different individuals.

Radiotherapy in lung adenocarcinoma with brain metastases: effects of activating epidermal growth factor receptor mutations on clinical response.

PURPOSE: Whole-brain radiation therapy (WBRT) has been applied to inoperable brain metastases in lung adenocarcinoma. Recently, an in vitro study showed reduced clonogenic survival of mutant epidermal growth factor receptor (EGFR) lung cancer cell lines in response to ionizing radiation compared with that of the wild type. To elucidate the role of EGFR mutations in radiation treatment, we evaluated the clinical response to WBRT and survival of lung adenocarcinoma patients with brain metastases. EXPERIMENTAL DESIGN: This was a retrospective analysis of 63 patients with brain metastases from lung adenocarcinoma who were treated with WBRT. Demographic data, EGFR mutation status, response to WBRT, and survival data were collected. Clinical response was assessed 1 month after the start of WBRT. Univariate and logistic regression models were used to test potential predictive factors associated with clinical response. Log-rank test and Cox regression were analyzed to identify factors that affected survival. RESULTS: Clinical response to WBRT was observed in 29 patients (46%), with 34 nonresponder patients (54%). Patients with EGFR mutations had higher response rates to WBRT compared with those with the wild-type (54% versus 24%; P = 0.045). Both the administration of EGFR tyrosine kinase inhibitor (P = 0.034) and EGFR mutation (P = 0.029) were independently associated with response to WBRT. In Cox regression analysis, WBRT responder (P = 0.010) and absence of extracranial metastases (P = 0.002) were associated with better survival. CONCLUSIONS: Both the EGFR mutations and the administration of EGFR TKI during WBRT were independent predictors of response to WBRT in brain metastases of lung adenocarcinoma.

First- or second-line therapy with gefitinib produces equal survival in non-small cell lung cancer.

RATIONALE: Gefitinib is effective in treating patients with non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations. Deletions in exon 19 and L858R in exon 21 are the best-documented EGFR mutations that are associated with effective gefitinib responsiveness. OBJECTIVES: To clarify the influence of gefitinib timing, we conducted a study to compare the outcomes of different lines of gefitinib treatment in patients with exon 19 deletions or L858R. METHODS: We surveyed the clinical data and mutational studies of patients with NSCLC with EGFR mutations in the National Taiwan University Hospital (Taipei, Taiwan). MEASUREMENTS AND MAIN RESULTS: Three hundred and twenty-eight patients, who received gefitinib for stage IIIb or IV NSCLC, were adequately sequenced for EGFR mutations; 192 patients had mutant EGFR, including 77 patients with exon 19 deletions and 75 patients with L858R. The 152 patients with exon 19 deletions or L858R and who were receiving gefitinib were classified into a chemonaive group (91 patients) or a chemotherapy-treated group (61 patients). Chemonaive status before gefitinib and female sex were associated with clinical response to gefitinib (P = 0.006 and 0.053, respectively). Neither overall survival after the start of antitumor therapy nor progression-free survival after gefitinib therapy was significantly different between these two groups (P = 0.207 and 0.804, respectively). Clinical response to gefitinib was the only factor associated with better overall survival (P = 0.001). CONCLUSIONS: This study suggests that gefitinib is effective in patients with EGFR mutations. The gefitinib response rate in chemonaive patients is higher than in chemotherapy-treated patients; however, there is no difference in overall survival.

Validation of Immunohistochemistry for the Detection of BRAF V600E-Mutated Lung Adenocarcinomas.

BRAF V600E mutation, a missense mutation in exon 15 resulting in valine substitution for glutamate at position 600 within the kinase domain of BRAF oncogene, is found in a subset of lung adenocarcinoma (ADC). The usefulness of immunohistochemistry (IHC) as an alternative diagnostic tool has not been validated. Moreover, the clinical information of patients with BRAF V600E-mutated lung ADC is limited. We retrospectively identified 31 lung ADCs diagnosed with BRAF V600E mutation by standard molecular sequencing methods and reviewed their clinical characteristics and pathological features. An anti-BRAF V600E monoclonal VE1 antibody for IHC was used to confirm the expression patterns. The series was comprised of 99 cases, 29 with BRAF V600E mutation and 70 without BRAF V600E but with other types or undetected mutations. The majority of BRAF V600E-mutated biopsied tissues were poorly differentiated and micropapillary patterns. Application of the IHC VE1 assay was highly feasible in primary/metastatic sites or effusion blocks, yielding positive findings in 28 of 29 (96.6%) BRAF V600E-mutated tumors and negative results in 69 of 70 (98.6%) tumors harboring other types or undetected mutations. Patients who received pemetrexed/platinum-based rather than mutation-targeted chemotherapy as the first-line therapy for metastatic disease showed median overall survival of 15.5 months. Our findings indicated that VE1 antibody-based IHC analysis demonstrated high sensitivity and specificity to detect BRAF V600E-mutated lung ADCs in tissues from primary or metastatic sites.

Positive end-expiratory pressure titration with electrical impedance tomography and pressure-volume curve in severe acute respiratory distress syndrome.

BACKGROUND: The study objective was to compare titration of positive end-expiratory pressure (PEEP) with electrical impedance tomography (EIT) and with ventilator-embedded pressure-volume loop in severe acute respiratory distress syndrome (ARDS). METHODS: We have designed a prospective study with historical control group. Twenty-four severe ARDS patients (arterial oxygen partial pressure to fractional inspired oxygen ratio, PaO2/FiO2 < 100 mmHg) were included in the EIT group and examined prospectively. Data from another 31 severe ARDS patients were evaluated retrospectively (control group). All patients were receiving medical care under identical general support guidelines and protective mechanical ventilation. The PEEP level selected in the EIT group was the intercept point of cumulated collapse and overdistension percentages curves. In the control group, optimal PEEP was selected 2 cmH2O above the lower inflection point on the static pressure-volume curve. RESULTS: Patients in the EIT group were younger (P < 0.05), and their mean plateau pressure was 1.5 cmH2O higher (P < 0.01). No differences in other baseline parameters such as APACHE II score, PaO2/FiO2, initial PEEP, driving pressure, tidal volume, and respiratory system compliance were found. Two hours after the first PEEP titration, significantly higher PEEP, compliance, and lower driving pressure were found in the EIT group (P < 0.01). Hospital survival rates were 66.7% (16 of 24 patients) in the EIT group and 48.4% (15 of 31) in the control group. Identical rates were found regarding the weaning success rate: 66.7% in the EIT group and 48.4% in the control group. CONCLUSION: In severe ARDS patients, it was feasible and safe to guide PEEP titration with EIT at the bedside. As compared with pressure-volume curve, the EIT-guided PEEP titration may be associated with improved oxygenation, compliance, driving pressure, and weaning success rate. The findings encourage further randomized control study with a larger sample size and potentially less bias in the baseline data. Trial Registration NCT03112512.