Attenuation of PI3K-Akt-mTOR Pathway to Reduce Cancer Stemness on Chemoresistant Lung Cancer Cells by Shikonin and Synergy with BEZ235 Inhibitor.

Lung cancer is considered the number one cause of cancer-related deaths worldwide. Although current treatments initially reduce the lung cancer burden, relapse occurs in most cases; the major causes of mortality are drug resistance and cancer stemness. Recent investigations have provided evidence that shikonin generates various bioactivities related to the treatment of cancer. We used shikonin to treat multi-resistant non-small lung cancer cells (DOC-resistant A549/D16, VCR-resistant A549/V16 cells) and defined the anti-cancer efficacy of shikonin. Our results showed shikonin induces apoptosis in these ABCB1-dependent and independent chemoresistance cancer sublines. Furthermore, we found that low doses of shikonin inhibit the proliferation of lung cancer stem-like cells by inhibiting spheroid formation. Concomitantly, the mRNA level and protein of stemness genes (Nanog and Oct4) were repressed significantly on both sublines. Shikonin reduces the phosphorylated Akt and p70s6k levels, indicating that the PI3K/Akt/mTOR signaling pathway is downregulated by shikonin. We further applied several signaling pathway inhibitors that have been used in anti-cancer clinical trials to test whether shikonin is suitable as a sensitizer for various signaling pathway inhibitors. In these experiments, we found that low doses shikonin and dual PI3K-mTOR inhibitor (BEZ235) have a synergistic effect that inhibits the spheroid formation from chemoresistant lung cancer sublines. Inhibiting the proliferation of lung cancer stem cells is believed to reduce the recurrence of lung cancer; therefore, shikonin's anti-drug resistance and anti-cancer stem cell activities make it a highly interesting molecule for future combined lung cancer therapy.

Primary tumor consolidative therapy improves the outcomes of patients with advanced EGFR-mutant lung adenocarcinoma treated with first-line osimertinib.

Background: Patients with advanced epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma (LAD) inevitably experience drug resistance following treatment with EGFR-tyrosine kinase inhibitors (TKIs). Objectives: We aimed to analyze the effect of primary tumor consolidative therapy (PTCT) on patients treated with first-line osimertinib. Design and methods: This retrospective cohort study was conducted in patients with advanced stage III or stage IV LAD with EGFR-sensitizing mutations (exon 19 deletion or L858R mutation) with disease control after first-line osimertinib. A curative dose of primary tumor radiotherapy or primary tumor resection was classified as PTCT. We compared the progression-free survival (PFS) and overall survival (OS) of patients with and without PTCT. Results: This study included 106 patients with a median age of 61.0 years, and of those, 42% were male and 73.6% were never-smokers. Exon 19 deletion was observed in 67.9%, 30.2% had a programmed cell death ligand 1 (PD-L1) tumor proportion score <1%, 33.0% had brain metastasis, and 40.6% had oligometastasis. In all, 53 (50%) patients underwent PTCT. Patients who underwent PTCT demonstrated significantly better PFS [30.3 (95% confidence interval (CI), 24.1-36.4) versus 18.2 (95% CI, 16.1-20.2) months; p = 0.005] and OS [not reached versus 36.7 (95% CI, 32.5-40.9) months; p = 0.005] than patients who did not. A multivariate analysis showed that PTCT was an independent factor associated with better PFS [hazard ratio (HR), 0.22; 95% CI, 0.10-0.49; p < 0.001] and OS [HR, 0.10; 95% CI, 0.01-0.82; p = 0.032]. The PFS benefits of PTCT were consistent across subgroups, and the HR tended to be lower in patients aged <65 years, males, smokers, stage IVB disease, L858R, PD-L1 expression ⩾1%, non-oligometastasis, and brain metastasis. Conclusion: Of the patients with advanced EGFR-mutant LAD, those who underwent PTCT had a significantly better survival outcome than those who did not. The survival benefits were consistent across different subgroups.

Outcome of Thromboembolic Events and Its Influence on Survival Time of Advanced NSCLC Patients Treated with Antiangiogenic Therapy.

Background: Antiangiogenetic therapy and lung cancer, per se, are associated with an increased risk of thromboembolic events (TE). We aim to evaluate the pattern and outcome of TE as well as its influence on survival time of advanced non-small cell lung cancer (NSCLC) patients receiving antiangiogenic therapy. Methods: This was a retrospective cohort study, which included advanced NSCLC patients receiving antiangiogenic therapy. All TE were confirmed by objective image studies. We disclosed the presentation and risk factors of TE and evaluated its influence on outcome. Results: A total of 427 patients were included. TE occurred in 43 patients (10.1%). Deep vein thrombosis (DVT) was the most common TE (n = 20). Up to 46.2% of DVT did not occur in the typical lower extremities. Two patients died of TE. Among patients with continuous use or reuse of antiangiogenetic therapy, 18.2% had recurrent TE events. At the occurrence of TE, 28 patients experienced progressive disease (TE with PD), while tumor status remained stable in another 15 patients (TE without PD). The post-TE survival of patients without and with PD were 8.9 months (95% CI 3.9-13.9) vs 2.2 months (95% CI 0.1-4.3), P = 0.012. As compared with patients without TE (31.4 months [95% CI 27.1-35.7]), TE with PD patients experienced a significantly shorter overall survival (20.1 months [95% CI 15.5-24.6]), but TE without PD patients had comparable survival time (32.7 months [95% CI 7.4-28.1]) (P = 0006). The use of hormone analogue and proteinuria predicted the events among TE with PD group (aOR 2.79 [95% CI 1.13=6.92]; P = 0.027) and TE without PD group (aOR 4.30 [95% CI 1.13-16.42]; P = 0.033), respectively. Conclusion: Owing to the different risk factors and influences on the survival time, TE with and without PD may be two different disease entities.

Injectable gelatin/glucosamine cryogel microbeads as scaffolds for chondrocyte delivery in cartilage tissue engineering.

In this study, we fabricate squeezable cryogel microbeads as injectable scaffolds for minimum invasive delivery of chondrocytes for cartilage tissue engineering applications. The microbeads with different glucosamine concentrations were prepared by combining the water-in-oil emulsion and cryogelation through crosslinking of gelatin with glutaraldehyde in the presence of glucosamine. The physicochemical characterization results show the successful preparation of cryogel microbeads with uniform shape and size, high porosity, large pore size, high water uptake capacity, and good injectability. In vitro analysis indicates proliferation, migration, and differentiated phenotype of rabbit chondrocytes in the cryogel scaffolds. The seeded chondrocytes in the cryogel scaffold can be delivered by injecting through an 18G needle to fully retain the cell viability. Furthermore, the incorporation of glucosamine in the cryogel promoted the differentiated phenotype of chondrocytes in a dose-dependent manner, from cartilage-specific gene expression and protein production. The in vivo study by injecting the cryogel microbeads into the subcutaneous pockets of nude mice indicates good retention ability as well as good biocompatibility and suitable biodegradability of the cryogel scaffold. Furthermore, the injected chondrocyte/cryogel microbead constructs can form ectopic functional neocartilage tissues following subcutaneous implantation in 21 days, as evidenced by histological and immunohistochemical analysis.

The Role of Neutrophil-to-Lymphocyte Ratio in Advanced EGFR-Mutant NSCLC Patients Treated with First-Line Osimertinib.

Purpose: Although serum neutrophil-to-lymphocyte ratio (NLR) is correlated with the outcome of various cancer types, its role in treatment-naïve, advanced, epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) patients treated with osimertinib remains uncertain. We have the intention to use this biomarker to evaluate the outcomes in NSCLC. Patients and Methods: Advanced EGFR-mutant NSCLC patients receiving osimertinib as the first-line treatment were included. We evaluated the prognostic role of baseline NLR and explored its association with patients' characteristics. A high NLR was defined as pretreatment serum NLR ≥ 5. Results: A total of 112 eligible patients were included. The objective response rate was 83.7%. The median progression-free survival (PFS) and overall survival (OS) were 20.5 months (95% CI 14.5-26.5) and 47.3 months (95% CI 36.7-58.2), respectively. A high NLR predicted an inferior PFS (HR 1.90 [95% CI 1.02-3.51], P = 0.042) and OS (HR 3.85 [95% CI 1.39-10.66], P = 0.009). Patients with stage IVB disease were more likely to have a high baseline NLR than those with stage IIIB-IVA (33.9% vs 15.1%, P = 0.029). Other patients' characteristics did not correlate with the baseline NLR significantly. Patients with a high NLR had significantly more metastatic organs than those with a low NLR (2.5 ± 1.3 vs 1.8 ± 0.9, P = 0.012), particularly brain, liver, and bone metastasis. There was no significant association between NLR and intrathoracic metastasis. Conclusion: Baseline serum NLR could act as an important prognostic marker for EGFR-mutant NSCLC patients receiving first-line osimertinib. A high NLR was associated with higher metastatic burden, more extrathoracic metastases, and therefore, a worse outcome.

Adjuvant chemotherapy compared with observation in patients with T2aN0 stage IB lung adenocarcinoma.

Introduction: For patients with T2aN0 stage IB lung adenocarcinoma, benefits of adjuvant chemotherapy remain controversial. Here, we aimed to evaluate such benefits. Methods: This retrospective cohort study was conducted on the database of the National Taiwan Cancer Registry. We analyzed patients with T2aN0 stage IB lung adenocarcinoma (re-classified by AJCC 8th edition) diagnosed during the period from January 2011 to December 2017. They were divided into two groups: (1) group 1: tumor <=3 cm with visceral pleural invasion (VPI); (2) group 2: tumor >3 cm, but <=4 cm. Overall survival (OS) and cancer specific survival (CSS) were evaluated. Risk factors for survival were determined. Results: A total of 2,100 patients with T2aN0 stage IB lung adenocarcinoma (1,265 in group 1 and 835 in group 2) were enrolled for study. The proportions of patients receiving adjuvant chemotherapy in group 1 and 2 were 39.1% and 68.6%, respectively. Amongst group 1 patients, adjuvant chemotherapy was not an independent risk factor for OS and CSS. Amongst group 2 patients, high-grade histologic findings and receiving sublobar resection were two risk factors for poorer survival. Adjuvant chemotherapy was also associated with an OS (adjusted hazard ratio (aHR), 0.52; 95% confidence interval (CI), 0.38-0.72; P<0.001) and CSS (aHR, 0.54; 95% CI, 0.37-0.78; p=0.001) benefit regardless of the presence or absence of risk factors. Conclusion: For patients with T2aN0 stage IB lung adenocarcinoma, adjuvant chemotherapy improved OS and CSS in those with tumors >3 cm, but <=4 cm.For patients with tumors <=3 cm with VPI, adjuvant chemotherapy had no survival benefit.

Sensing Antibiotics in Wastewater Using Surface-Enhanced Raman Scattering.

Rapid and cost-effective detection of antibiotics in wastewater and through wastewater treatment processes is an important first step in developing effective strategies for their removal. Surface-enhanced Raman scattering (SERS) has the potential for label-free, real-time sensing of antibiotic contamination in the environment. This study reports the testing of two gold nanostructures as SERS substrates for the label-free detection of quinoline, a small-molecular-weight antibiotic that is commonly found in wastewater. The results showed that the self-assembled SERS substrate was able to quantify quinoline spiked in wastewater with a lower limit of detection (LoD) of 5.01 ppb. The SERStrate (commercially available SERS substrate with gold nanopillars) had a similar sensitivity for quinoline quantification in pure water (LoD of 1.15 ppb) but did not perform well for quinoline quantification in wastewater (LoD of 97.5 ppm) due to interferences from non-target molecules in the wastewater. Models constructed based on machine learning algorithms could improve the separation and identification of quinoline Raman spectra from those of interference molecules to some degree, but the selectivity of SERS intensification was more critical to achieve the identification and quantification of the target analyte. The results of this study are a proof-of-concept for SERS applications in label-free sensing of environmental contaminants. Further research is warranted to transform the concept into a practical technology for environmental monitoring.

Decoding the metabolic response of Escherichia coli for sensing trace heavy metals in water.

Heavy metal contamination due to industrial and agricultural waste represents a growing threat to water supplies. Frequent and widespread monitoring for toxic metals in drinking and agricultural water sources is necessary to prevent their accumulation in humans, plants, and animals, which results in disease and environmental damage. Here, the metabolic stress response of bacteria is used to report the presence of heavy metal ions in water by transducing ions into chemical signals that can be fingerprinted using machine learning analysis of vibrational spectra. Surface-enhanced Raman scattering surfaces amplify chemical signals from bacterial lysate and rapidly generate large, reproducible datasets needed for machine learning algorithms to decode the complex spectral data. Classification and regression algorithms achieve limits of detection of 0.5 pM for As3+ and 6.8 pM for Cr6+, 100,000 times lower than the World Health Organization recommended limits, and accurately quantify concentrations of analytes across six orders of magnitude, enabling early warning of rising contaminant levels. Trained algorithms are generalizable across water samples with different impurities; water quality of tap water and wastewater was evaluated with 92% accuracy.

Integrative pathway and network analysis provide insights on flooding-tolerance genes in soybean.

Soybean is highly sensitive to flooding and extreme rainfall. The phenotypic variation of flooding tolerance is a complex quantitative trait controlled by many genes and their interaction with environmental factors. We previously constructed a gene-pool relevant to soybean flooding-tolerant responses from integrated multiple omics and non-omics databases, and selected 144 prioritized flooding tolerance genes (FTgenes). In this study, we proposed a comprehensive framework at the systems level, using competitive (hypergeometric test) and self-contained (sum-statistic, sum-square-statistic) pathway-based approaches to identify biologically enriched pathways through evaluating the joint effects of the FTgenes within annotated pathways. These FTgenes were significantly enriched in 36 pathways in the Gene Ontology database. These pathways were related to plant hormones, defense-related, primary metabolic process, and system development pathways, which plays key roles in soybean flooding-induced responses. We further identified nine key FTgenes from important subnetworks extracted from several gene networks of enriched pathways. The nine key FTgenes were significantly expressed in soybean root under flooding stress in a qRT-PCR analysis. We demonstrated that this systems biology framework is promising to uncover important key genes underlying the molecular mechanisms of flooding-tolerant responses in soybean. This result supplied a good foundation for gene function analysis in further work.

Thoracic radiotherapy may improve the outcome of extensive stage small cell lung carcinoma patients treated with first-line immunotherapy plus chemotherapy.

OBJECTIVE: Immunotherapy plus etoposide and platinum (EP)-based chemotherapy is the standard of care for patients with extensive stage-small cell lung carcinoma (ES-SCLC). In the era of immunotherapy, the role of thoracic radiotherapy for ES-SCLC remains unclear. METHODS: We retrospectively included ES-SCLC patients treated with first-line EP-based chemotherapy plus atezolizumab or durvalumab at Taichung Veterans General Hospital to evaluate the prognostic role and safety of thoracic radiotherapy. RESULTS: A total of 22 patients were included. The median age was 64 years and most of them were male and smokers. Sixteen patients (72.7%) received durvalumab, while the other 6 patients (27.3%) underwent atezolizumab treatment. Among these patients, 11 (50.0%) had a history of thoracic radiotherapy. There was no significant difference in baseline characteristics between patients with and without thoracic radiotherapy. In the overall population, the objective response rate to immunotherapy plus chemotherapy was 73.7%. The progression-free survival and overall survival were 6.0 months (95% CI: 4.0-7.9) and 13.8 months (95% CI: 8.0-19.6), respectively. The overall survival was significantly longer in patients with thoracic radiotherapy (not-reached [NR] [95% CI NR-NR] vs. 9.6 months [95% CI 2.5-16.6]), respectively ( P value by log-rank test <0.001). Both multivariate analysis and subgroup analysis specifically comparing patients with consolidative thoracic radiotherapy and patients with clinical benefits to systemic therapy who did not undergo thoracic radiotherapy indicated that thoracic radiotherapy improved survival. CONCLUSION: The real-world efficacy of EP-based chemotherapy plus atezolizumab or durvalumab was comparable with that of clinical trials. Thoracic radiotherapy may improve the outcome of ES-SCLC.

A multiple phenotype imputation method for genetic diversity and core collection in Taiwanese vegetable soybean.

Establishment of vegetable soybean (edamame) [Glycine max (L.) Merr.] germplasms has been highly valued in Asia and the United States owing to the increasing market demand for edamame. The idea of core collection (CC) is to shorten the breeding program so as to improve the availability of germplasm resources. However, multidimensional phenotypes typically are highly correlated and have different levels of missing rate, often failing to capture the underlying pattern of germplasms and select CC precisely. These are commonly observed on correlated samples. To overcome such scenario, we introduced the "multiple imputation" (MI) method to iteratively impute missing phenotypes for 46 morphological traits and jointly analyzed high-dimensional imputed missing phenotypes (EC impu ) to explore population structure and relatedness among 200 Taiwanese vegetable soybean accessions. An advanced maximization strategy with a heuristic algorithm and PowerCore was used to evaluate the morphological diversity among the EC impu . In total, 36 accessions (denoted as CC impu ) were efficiently selected representing high diversity and the entire coverage of the EC impu . Only 4 (8.7%) traits showed slightly significant differences between the CC impu and EC impu . Compared to the EC impu , 96% traits retained all characteristics or had a slight diversity loss in the CC impu . The CC impu exhibited a small percentage of significant mean difference (4.51%), and large coincidence rate (98.1%), variable rate (138.76%), and coverage (close to 100%), indicating the representativeness of the EC impu . We noted that the CC impu outperformed the CC raw in evaluation properties, suggesting that the multiple phenotype imputation method has the potential to deal with missing phenotypes in correlated samples efficiently and reliably without re-phenotyping accessions. Our results illustrated a significant role of imputed missing phenotypes in support of the MI-based framework for plant-breeding programs.

Various impacts of driver mutations on the PD-L1 expression of NSCLC.

We aimed to evaluate whether different driver mutations have varying impacts on the programmed cell death-ligand 1 (PD-L1) expression of non-small cell lung cancer (NSCLC), and whether the prognostic roles of PD-L1 amongst our patients were divergent. This was a single-institute study that included patients with NSCLC. Six driver mutations, PD-L1 status, and the outcomes of treatment were assessed. A total of 1,001 NSCLC patients were included for analysis. Overall, the PD-L1 positive (TPS ≥ 1%) and strong positive (TPS ≥ 50%) rates were 52.2% and 17.3%, respectively. As compared with wild type lung adenocarcinoma, EGFR-mutant and HER2-mutant patients had similarly low PD-L1 and strong PD-L1 positive rates. BRAF-mutant patients had numerically higher PD-L1 and strong PD-L1 positive rates. Patients with fusion mutation (ALK and ROS1) (aOR 2.32 [95% CI 1.10-4.88], P = 0.027 and 2.33 [95% CI 1.11-4.89], P = 0.026), KRAS mutation (aOR 2.58 [95% CI 1.16-5.75], P = 0.020 and 2.44 [95% CI 1.11-5.35], P = 0.026), and non-adenocarcinoma histology (aOR 2.73 [95% CI 1.72-4.34], P < 0.001 and 1.93 [95% CI 1.13-3.30], P = 0.016) all had significantly higher PD-L1 and strong PD-L1 positive rates. A trend towards longer survival was noted in ROS-1 rearranged and KRAS-mutant patients with strong PD-L1 expression who had received crizotinib and chemotherapy, respectively. In conclusion, individual driver mutations had various impacts on the PD-L1 expression of NSCLC patients. The prognostic role of PD-L1 may also be divergent amongst patients harboring different driver mutations.

Histological Transformation after Acquired Resistance to the Third-Generation EGFR-TKI in Patients with Advanced EGFR-Mutant Lung Adenocarcinoma.

Background and Objectives: Third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) is one of the standard-of-care therapies in patients with EGFR-mutant lung adenocarcinoma; however, acquired resistance inevitably developed. Despite the proposition of histological transformation being one of the resistance mechanisms, its incidence and influence on outcome remain unclear. Materials and Methods: This was a retrospective study conducted at Taichung Veterans General Hospital on patients with advanced EGFR-mutant lung adenocarcinoma receiving the third-generation EGFR-TKI. Only patients receiving rebiopsy were included in the analysis. Results: A total of 55 patients were studied. Eight patients (14.5%) showed histological transformation, including three small cell carcinoma, three squamous cell carcinoma, one large cell neuroendocrine carcinoma, and one with a mixture of adenocarcinoma and squamous cell carcinoma components. The median treatment duration of the third-generation EGFR-TKI before rebiopsy was numerically longer in patients with histological transformation than those without (16.0 vs. 10.9 months). Both the overall survival time from the start of third-generation EGFR-TKI initiation (30.8 vs. 41.2 months) and from rebiopsy (6.6 vs. 12.9 months) to mortality were numerically shorter amongst the transformed population. All patients in the transformed group did not respond to the next line of systemic treatment. One patient with histological transformation receiving local treatment for the metastatic site had a longer overall survival. Conclusions: Repeating biopsy to identify histological transformation should be considered in patients with progression to the third-generation EGFR-TKI. Histological transformations could contribute to the acquired resistance with the implication of a worse prognosis. Further studies are needed to determine the optimal therapy for these patients.

Curcumin Induces Apoptosis of Chemoresistant Lung Cancer Cells via ROS-Regulated p38 MAPK Phosphorylation.

This study aimed to challenge chemoresistance by curcumin (CUR) with drug-selected human lung cancer A549 sublines that continuously proliferate in the present of docetaxel (DOC) and vincristine (VCR). Their sensitivities to CUR were measured by MTT assay and the particular intracellular reactive oxygen species (ROS) was detected by fluorescence activated cell sorting (FACS) analysis. Apoptosis was analyzed by Annexin V assay of the flow cytometry. Inhibitors and RNA interference were used to examine the signaling pathway regulated by the kinases. The obtained data demonstrated that CUR induces chemoresistant cell apoptosis by generating ROS and application of N-acetylcysteine (NAC) blocks ROS production, resulting in apoptosis suppression. Phosphorylation of extracellular regulated kinase (ERK), p38 MAPK, and eIF-2α were increased but c-Jun N-terminal kinase (JNK) did not increase when chemoresistant cells were treated with CUR. Downregulation of ERK and p38 MAPK phosphorylation by their inhibitors had no effect on CUR-induced apoptosis. Interestingly, the knockdown of p38 MAPK with shRNA significantly reduced CUR-induced apoptosis on the chemoresistant sublines. Phosphorylation of the eIF-2α protein was inhibited when p38 MAPK was knocked down in DOC-resistant A549 cells, but a high level of phosphorylated eIF-2α protein remained on the VCR-resistant A549 cells when p38 MAPK was knocked down. These data confirmed that CUR-augmented ROS potently induced apoptosis via upregulated p38 MAPK phosphorylation. Therefore, activated p38 MAPK is considered a pro-apoptotic signal for CUR-induced apoptosis of chemoresistant human lung cancer cells.

Influence of the Timing of Leptomeningeal Metastasis on the Outcome of EGFR-Mutant Lung Adenocarcinoma Patients and Predictors of Detectable EGFR Mutations in Cerebrospinal Fluid.

BACKGROUND: We aim to evaluate the influence of the timing of leptomeningeal metastasis (LM) occurrence on the outcome of EGFR-mutant lung adenocarcinoma and to explore the predictors of detectable EGFR mutation in the cerebrospinal fluid (CSF). METHODS: EGFR-mutant lung adenocarcinoma patients with cytologically confirmed LM were included for analysis. EGFR mutation in CSF was detected by MALDI-TOF MS plus PNA. RESULTS: A total of 43 patients was analyzed. Of them, 8 (18.6%) were diagnosed with LM prior to first-line EGFR-TKI treatment (early onset), while 35 patients (81.4%) developed LM after first-line EGFR-TKI treatment (late onset). Multivariate analysis suggested that both late-onset LM (aHR 0.31 (95% CI 0.10-0.94), p = 0.038) and a history of third-generation EGFR-TKI treatment (aHR 0.24 (95% CI 0.09-0.67), p = 0.006) independently predicted a favorable outcome. EGFR mutation detection sensitivity in CSF was 81.4%. The radiological burden of LM significantly correlated with CSF tumor cell counts (p = 0.013) with higher CSF tumor cell counts predicting a higher detection sensitivity of EGFR mutation (p = 0.042). CONCLUSIONS: Early onset LM was an independently poor prognostic factor. A higher radiological severity score of LM could predict higher tumor cell counts in CSF, which in turn were associated with a higher detection rate of EGFR mutation.

Characteristics and immune checkpoint inhibitor effects on non-smoking non-small cell lung cancer with KRAS mutation: A single center cohort (STROBE-compliant).

ABSTRACT: Kirsten rat sarcoma (KRAS) mutation (KRASm) is associated with poor prognosis in non-small cell lung cancer (NSCLC) patients. We have aimed to survey NSCLC patients harboring KRASm in Taiwan, where never-smoking lung adenocarcinoma predominates, and analyze the immune checkpoint inhibitor effect on NSCLC harboring KRASm.NSCLC patients with KRASm were enrolled and tested on programmed death-ligand 1 (PD-L1) expression using available tissue. We analyzed their clinical features, PD-L1 status, responses to ICIs, and overall survival (OS).We studied 93 patients with a median age 66.0 years, 23.7% of whom were women, and 22.6% were never-smokers. The results showed that G12C (36.6%) was the most common KRASm. In 47 patients with available tissue for PD-L1 testing, PD-L1 expression was positive in 66.0% of patients, while PD-L1 ≥50% was higher in ever-smokers (P = .038). Among 23 patients receiving ICI treatment, those with PD-L1 ≥50% experience a 45.5% response rate to ICI. There were benefits from ICI treatment on OS compared with no ICI treatment (median OS 35.6 vs 9.8 months, P = .002) for all of our patients, and for patients with PD-L1 ≥50% (median OS not-reached vs 8.4 months, P = .008). There were no differences in survival across different KRAS subtypes (P = .666).Never-smokers composed more than one-fifth of KRASm in NSCLC in Taiwan. A high PD-L1 expression was related to smoking history and responded well to ICI. ICI treatment improved the OS in NSCLC patients with KRASm, particularly those with PD-L1 ≥50%.

PD-L1 strong expressions affect the clinical outcomes of osimertinib in treatment naïve advanced EGFR-mutant non-small cell lung cancer patients.

The impact of strong Programmed Death-ligand 1 (PD-L1) expression on the clinical outcomes of osimertinib in treatment naïve advanced Epidermal Growth Factor Receptor (EGFR)-mutant Non-small Cell Lung Cancer (NSCLC) patients remains uncertain. We enrolled advanced NSCLC patients who harbored sensitizing EGFR mutation and were treated first-line with osimertinib between 2017 and 2021. The PD-L1 expression level was also tested. A total of 85 patients were included. The objective response rate to osimertinib was 78.9%, with the disease control rate being 90.8%. Median Progression-free Survival (PFS) was 22.1 months, while median Overall Survival (OS) was not reached (NR). Patients with the exon 19 deletion experienced better PFS than those with the exon 21 L858R mutation (NR vs 12.4 months, aHR 0.24 (95% CI, 0.10 to 0.57); p = 0.001). Seventy-one of these 85 patients had reported on their PD-L1 expression. Patients with a PD-L1 < 50% experienced longer PFS than patients with a PD-L1 ≧50% (26.5 vs 9.7 months, aHR 0.19 (95% CI, 0.06 to 0.67); p = 0.009). Additionally, patients with a PD-L1 < 50% experienced better OS than those with a PD-L1 ≧50% (NR vs 25.4 months, aHR 0.09 (95% CI, 0.01 to 0.70); p = 0.021). Strong expressions of PD-L1 in treatment naïve advanced EGFR-mutant NSCLC patients were associated with poor prognoses in those undergoing treatment with osimertinib as first-line therapy.

The Difference in Clinical Outcomes Between Osimertinib and Afatinib for First-Line Treatment in Patients with Advanced and Recurrent EGFR-Mutant Non-Small Cell Lung Cancer in Taiwan.

BACKGROUND: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors are the standard first-line treatment for patients with advanced and recurrent EGFR-positive non-small cell lung cancer. OBJECTIVE: The main objective of the present study was to compare the clinical efficacies between osimertinib and afatinib as first-line treatment in patients with EGFR-mutant non-small cell lung cancer. METHODS: We retrospectively analyzed patients with advanced and recurrent non-small cell lung cancer who harbored an exon 19 deletion or an exon 21 L858R mutation and were being given either osimertinib or afatinib as first-line treatment from January 2018 to December 2020. RESULTS: A total of 128 patients were selected for this study. The osimertinib group included 47 patients, while 81 patients received afatinib. The median follow-up time was 20.1 months in the osimertinib group and 22.7 months in the afatinib group. The median progression-free survival was 18.8 months and 13.1 months in the osimertinib and afatinib groups, respectively (hazard ratio 0.75 [95% confidence interval 0.48-1.18]). The median overall survival was not reached in the osimertinib group and was 41.7 months in the afatinib group (hazard ratio 0.79 [95% confidence interval 0.36-1.72]). In patients without brain metastasis, the median progression-free survival was 17.9 months and 17.2 months in the osimertinib and afatinib groups, respectively (hazard ratio 1.02 [95% confidence interval 0.56-1.85]). In patients with brain metastasis at baseline, the median progression-free survival was 22.1 months in the osimertinib group, and 10.9 months in the afatinib group (adjusted hazard ratio 0.45 [95% confidence interval 0.21-0.96]). CONCLUSIONS: Our research demonstrates that there was no strong evidence showing that patients taking osimertinib as first-line treatment experienced longer median progression-free survival and overall survival than patients treated with afatinib. However, there was a statistical significance revealing that osimertinib provided better median progression-free survival than afatinib in patients with brain metastasis at baseline.

Association of Smoking With Patient Characteristics and Outcomes in Small Cell Lung Carcinoma, 2011-2018.

Importance: Small cell lung carcinoma (SCLC) is uncommon in individuals who have never smoked (never-smokers). The related epidemiologic factors and prognosis remain unclear. Objective: To assess the epidemiologic factors, clinical characteristics, and outcomes of SCLC in never-smokers. Design, Setting, and Participants: A retrospective cohort study was conducted using data from the national Taiwan Cancer Registry, which was inaugurated in 1979 and maintains standardized records of patients' characteristics and clinical information for all individuals with cancer. Patients with cytologically or pathologically proven lung cancer were included for analysis. The study obtained data on patients from January 1, 1996, to December 31, 2018; data analysis was conducted from January 1, 1996, to December 31, 2019. Exposures: Clinical characteristics and outcomes of smokers and never-smokers with SCLC. Main Outcomes and Measures: Clinical characteristics for comparison included age at diagnosis, sex, performance status, tumor stage, and treatment. The main outcome parameter was overall survival of patients with SCLC from 2011 to 2018. Results: From 1996 to 2018, a total of 225 788 patients had diagnosed lung cancer; 141 654 patients (62.7%) were men; mean (SD) age was 67.55 (12.58) years. The numbers of both patients with newly diagnosed lung cancer and those with SCLC increased until 2009 by 111.5% for lung cancer and 118.5% for SCLC. Thereafter, lung cancer cases grew in number, but SCLC cases did not; hence, the percentage of patients with SCLC decreased from 9.3% in 2009 to 6.3% in 2018. From 2011 to 2018, the percentage of never-smokers increased significantly among all patients with lung cancers (from 49.9% in 2011 to 60.2% in 2018) and among those with lung adenocarcinomas (from 64.1% in 2011 to 70.9% in 2018) (both P < .001). However, the percentage of never-smokers appeared to vary little in the SCLC population: 15.5% in 2011 and 16.1% in 2018 (P = .28). The median overall survival was significantly longer in patients with adenocarcinoma vs SCLC (adjusted hazard ratio, 0.32; 95% CI, 0.31-0.33; P < .001). Compared with smokers with SCLC, never-smokers with SCLC tended to include more older patients (age ≥70 years: 492 [57.3%] vs 2242 [44.8%]), more women (274 [31.9%] vs 322 [6.4%]), more individuals with a poor performance status (Eastern Cooperative Oncology Group performance status ≥2: 284 [33.1%] vs 1261 [25.2%]) and stage IV cancer (660 [76.9%] vs 3590 [71.8%]), and more patients without treatment (203 [23.7%] vs 626 [12.5%]). Furthermore, never-smokers, particularly men, experienced a shorter survival rate (adjusted hazard ratio, 1.10; 95% CI, 1.00-1.20; P = .04) compared with the other groups. Conclusions and Relevance: The findings of this cohort study suggest that the decrease in the percentage of patients with SCLC was associated with increased lung cancers of other histologic types, with no substantial decrease in the number of those with SCLC.