Mechanistic insights into cardiovascular effects of ultrafine particle exposure: A longitudinal panel study.

BACKGROUND: Ultrafine particle (UFP) has been linked with higher risks of cardiovascular diseases; however, the biological mechanisms remain to be fully elucidated. OBJECTIVES: This study aims to investigate the cardiovascular responses to short-term UFP exposure and the biological pathways involved. METHODS: A longitudinal panel study was conducted among 32 healthy, non-smoking young adults in Shanghai, China, who were engaged in five rounds of follow-ups between December 2020 and November 2021. Individual exposures were calculated based on the indoor and outdoor real-time measurements. Blood pressure, arterial stiffness, targeted biomarkers, and untargeted proteomics and metabolomics were examined during each follow-up. Linear mixed-effect models were applied to analyze the exposure and health data. The differential proteins and metabolites were used for pathway enrichment analyses. RESULTS: Short-term UFP exposure was associated with significant increases in blood pressure and arterial stiffness. For example, systolic blood pressure increased by 2.10 % (95 % confidence interval: 0.63 %, 3.59 %) corresponding to each interquartile increase in UFP concentrations at lag 0-3 h, while pulse wave velocity increased by 2.26 % (95 % confidence interval: 0.52 %, 4.04 %) at lag 7-12 h. In addition, dozens of molecular biomarkers altered significantly. These effects were generally present within 24 h after UFP exposure, and were robust to the adjustment of co-pollutants. Molecular changes detected in proteomics and metabolomics analyses were mainly involved in systemic inflammation, oxidative stress, endothelial dysfunction, coagulation, and disturbance in lipid transport and metabolism. DISCUSSION: This study provides novel and compelling evidence on the detrimental subclinical cardiovascular effects in response to short-term UFP exposure. The multi-omics profiling further offers holistic insights into the underlying biological pathways.

Pathogenic variants in the NLRP3 LRR domain at position 861 are responsible for a boost-dependent atypical CAPS phenotype.

BACKGROUND: Cryopyrin-associated periodic syndrome (CAPS) is associated with NLRP3 pathogenic variants, mostly located in the NACHT (neuronal apoptosis inhibitor protein, MHC class 2 transcription activator, incompatibility locus protein from Podospora anserina, telomerase-associated protein) domain. Cold-induced urticarial rash is among the main clinical features. However, this study identified a series of 14 patients with pathogenic variants of the Y861 residue (p.Tyr861) of the LRR domain of NLRP3 and minimal prevalence of cold-induced urticarial rash. OBJECTIVES: This study aimed to address a possible genotype/phenotype correlation for patients with CAPS and to investigate at the cellular levels the impact of the Y861C substitution (p.Tyr861Cys) on NLRP3 activation. METHODS: Clinical features of 14 patients with CAPS and heterozygous substitution at position 861 in the LRR domain of NLRP3 were compared to clinical features of 48 patients with CAPS and pathogenic variants outside the LRR domain of NLRP3. IL-1ß secretion by PBMCs and purified monocytes from patients and healthy donors was evaluated following LPS and monosodium urate crystal stimulation. RESULTS: Patients with substitution at position 861 of NLRP3 demonstrated a higher prevalence of sensorineural hearing loss while being less prone to skin urticarial. In contrast to patients with classical CAPS, cells from patients with a pathogenic variant at position 861 required an activation signal to secrete IL-1ß but produced more IL-1ß during the early and late phase of secretion than cells from healthy donors. CONCLUSIONS: Pathogenic variants of Y861 of NLRP3 drive a boost-dependent oversecretion of IL-1ß associated with an atypical CAPS phenotype.

Successful treatment of JAK1-associated inflammatory disease.

BACKGROUND: Gain-of-function variants of JAK1 drive a rare immune dysregulation syndrome associated with atopic dermatitis, allergy, and eosinophilia. OBJECTIVES: This study sought to describe the clinical and immunological characteristics associated with a new gain-of-function variant of JAK1 and report the therapeutic efficacy of Janus kinase (JAK) inhibition. METHODS: The investigators identified a family affected by JAK1-associated autoinflammatory disease and performed clinical assessment and immunological monitoring on 9 patients. JAK1 signaling was studied by flow and mass cytometry in patients' cells at basal state or after immune stimulation. A molecular disease signature in the blood was studied at the transcriptomic level. Patients were treated with 1 of 2 JAK inhibitors: either baricitinib or upadacitinib. Clinical, cellular, and molecular response were evaluated over a 2-year period. RESULTS: Affected individuals displayed a syndromic disease with prominent allergy including atopic dermatitis, ichthyosis, arthralgia, chronic diarrhea, disseminated calcifying fibrous tumors, and elevated whole blood histamine levels. A variant of JAK1 localized in the pseudokinase domain was identified in all 9 affected, tested patients. Hyper-phosphorylation of STAT3 was found in 5 of 6 patients tested. Treatment of patients' cells with baricitinib controlled most of the atypical hyper-phosphorylation of STAT3. Administration of baricitinib to patients led to rapid improvement of the disease in all adults and was associated with reduction of systemic inflammation. CONCLUSIONS: Patients with this new JAK1 gain-of-function pathogenic variant displayed very high levels of blood histamine and showed a variable combination of atopy with articular and gastrointestinal manifestations as well as calcifying fibrous tumors. The disease, which appears to be linked to STAT3 hyperactivation, was well controlled under treatment by JAK inhibitors in adult patients.

Front-line therapy for brain metastases and non-brain metastases in advanced epidermal growth factor receptor-mutated non-small cell lung cancer: a network meta-analysis.

BACKGROUND: The brain is a common metastatic site in patients with non-small cell lung cancer (NSCLC), resulting in a relatively poor prognosis. Systemic therapy with epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) is recommended as the first-line treatment for EGFR -mutated, advanced NSCLC patients. However, intracranial activity varies in different drugs. Thus, brain metastasis (BM) should be considered when choosing the treatment regimens. We conducted this network meta-analysis to explore the optimal first-line therapeutic schedule for advanced EGFR -mutated NSCLC patients with different BM statuses. METHODS: Randomized controlled trials focusing on EGFR-TKIs (alone or in combination) in advanced and EGFR -mutant NSCLC patients, who have not received systematic treatment, were systematically searched up to December 2021. We extracted and analyzed progression-free survival (PFS) and overall survival (OS). A network meta-analysis was performed with the Bayesian statistical model to determine the survival outcomes of all included therapy regimens using the R software. Hazard ratios (HRs) and 95% confidence intervals (CIs) were used to compare intervention measures, and overall rankings of therapies were estimated under the Bayesian framework. RESULTS: This analysis included 17 RCTs with 5077 patients and 12 therapies, including osimertinib + bevacizumab, aumolertinib, osimertinib, afatinib, dacomitinib, standards of care (SoC, including gefitinib, erlotinib, or icotinib), SoC + apatinib, SoC + bevacizumab, SoC + ramucirumab, SoC + pemetrexed based chemotherapy (PbCT), PbCT, and pemetrexed free chemotherapy (PfCT). For patients with BM, SoC + PbCT improved PFS compared with SoC (HR = 0.40, 95% CI: 0.17-0.95), and osimertinib + bevacizumab was most likely to rank first in PFS, with a cumulative probability of 34.5%, followed by aumolertinib, with a cumulative probability of 28.3%. For patients without BM, osimertinib + bevacizumab, osimertinib, aumolertinib, SoC + PbCT, dacomitinib, SoC + ramucirumab, SoC + bevacizumab, and afatinib showed superior efficacy compared with SoC (HR = 0.43, 95% CI: 0.20-0.90; HR = 0.46, 95% CI: 0.31-0.68; HR = 0.51, 95% CI: 0.34-0.77; HR = 0.50, 95% CI: 0.38-0.66; HR = 0.62, 95% CI: 0.43-0.89; HR = 0.64, 95% CI: 0.44-0.94; HR = 0.61, 95% CI: 0.48-0.76; HR = 0.71, 95% CI: 0.50-1.00), PbCT (HR = 0.29, 95% CI: 0.11-0.74; HR = 0.31, 95% CI: 0.15-0.62; HR = 0.34, 95% CI: 0.17-0.69; HR = 0.34, 95% CI: 0.18-0.64; HR = 0.42, 95% CI: 0.21-0.82; HR = 0.43, 95% CI: 0.22-0.87; HR = 0.41, 95% CI: 0.22-0.74; HR = 0.48, 95% CI: 0.31-0.75), and PfCT (HR = 0.14, 95% CI: 0.06-0.32; HR = 0.15, 95% CI: 0.09-0.26; HR = 0.17, 95% CI: 0.09-0.29; HR = 0.16, 95% CI: 0.10-0.26; HR = 0.20, 95% CI: 0.12-0.35; HR = 0.21, 95% CI: 0.12-0.39; HR = 0.20, 95% CI: 0.12-0.31; HR = 0.23, 95% CI: 0.16-0.34) in terms of PFS. And, SoC + apatinib showed relatively superior PFS when compared with PbCT (HR = 0.44, 95% CI: 0.22-0.92) and PfCT (HR = 0.21, 95% CI: 0.12-0.39), but similar PFS to SoC (HR = 0.65, 95% CI: 0.42-1.03). No statistical differences were observed for PFS in patients without BM between PbCT and SoC (HR = 1.49, 95% CI: 0.84-2.64), but both showed favorable PFS when compared with PfCT (PfCT vs. SoC, HR = 3.09, 95% CI: 2.06-4.55; PbCT vs. PfCT, HR = 0.14, 95% CI: 0.06-0.32). For patients without BM, osimertinib + bevacizumab was most likely to rank the first, with cumulative probabilities of 47.1%. For OS, SoC + PbCT was most likely to rank first in patients with and without BM, with cumulative probabilities of 46.8%, and 37.3%, respectively. CONCLUSION: Osimertinib + bevacizumab is most likely to rank first in PFS in advanced EGFR -mutated NSCLC patients with or without BM, and SoC + PbCT is most likely to rank first in OS.

Large scale controlled Fab exchange GMP process to prepare bispecific antibodies.

Objective: Bispecific antibodies (BsAbs) have demonstrated significant therapeutic impacts for the treatment of a broad spectrum of diseases that include oncology, auto-immune, and infectious diseases. However, the large-scale production of clinical batches of bispecific antibodies still has many challenges that include having low yield, poor stability, and laborious downstream purification processes. To address such challenges, we describe the optimization of the controlled Fab arm exchange (cFAE) process for the efficient generation of BsAbs. Methods: The process optimization of a large-scale good manufacturing practice (GMP) cFAE strategy to prepare BsAbs was based on screening the parameters of temperature, reduction, oxidation, and buffer exchange. We include critical quality standards for the reducing agent cysteamine hydrochloride. Results: This large-scale production protocol enabled the generation of bispecific antibodies with >90% exchange yield and at >95% purity. The subsequent downstream processing could use typical mAb procedures. Furthermore, we demonstrated that the bispecific generation protocol can be scaled up to ∼60 L reaction scale using parental monoclonal antibodies that were expressed in a 200 L bioreactor. Conclusion: We presented a robust development strategy for the cFAE process that can be used for a larger scale GMP BsAb production.

Maximum Somatic Allele Frequency-Adjusted Blood-Based Tumor Mutational Burden Predicts the Efficacy of Immune Checkpoint Inhibitors in Advanced Non-Small Cell Lung Cancer.

INTRODUCTION: Recent studies exhibited the unstable prediction ability of blood-based tumor mutational burden (bTMB) when predicting the response of immune checkpoint inhibitors (ICIs) therapy in patients with non-small cell lung cancer (NSCLC). Circulating tumor DNA (ctDNA) abundance, usually represented by maximum somatic allele frequency (MSAF), was one possible confounding factor influencing bTMB ability in ICIs response prediction. METHODS: MSAF-adjusted bTMB (Ma-bTMB) was established and validated in patients with advanced NSCLC among Geneplus Cancer Genome Database (GCGD, n = 1679), Zhuo (n = 35), Wang (n = 45), POPLAR (NCT01903993, n = 211) and OAK (NCT02008227, n = 642) cohorts. RESULTS: MSAF demonstrated a modest positive correlation with bTMB and a negative one with survival benefit. Improved survival outcomes of ICIs therapy have been observed among patients with high-Ma-bTMB compared to those with low-Ma-bTMB in Zhuo and Wang cohorts. In addition, compared to low-Ma-bTMB, high-Ma-bTMB was associated with more positive clinical benefits from ICIs therapy than chemotherapy both in POPLAR and OAK cohorts. Further exploration suggested that Ma-bTMB could precisely identify more potential ICIs beneficiaries compared to bTMB and LAF-bTMB, complementary to PD-L1 expression. CONCLUSIONS: We developed Ma-bTMB, a convenient, readily available, non-invasive predictive biomarker effectively differentiates beneficiaries of ICIs therapy in advanced NSCLC, warranting future clinical trials.

Correlations of switch/sucrose nonfermentable complex mutations with clinical outcomes in advanced non-small cell lung cancer.

BACKGROUND: The switch/sucrose nonfermentable complex mutations (SWI/SNF-mut) are common in non-small cell lung cancer (NSCLC). However, the association of SWI/SNF-mut with the clinical outcomes of immune checkpoint inhibitors (ICIs), particularly of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), has not been established. METHODS: We retrospectively collected data of patients at Cancer Hospital Chinese Academy of Medical Sciences. Patients with advanced NSCLC who received programmed cell death protein-1 or programmed cell death ligand 1 (PD-[L]1) inhibitors were included in cohort 1 and those with EGFR mutations (EGFR-mutant) received EGFR-TKIs monotherapy were included in cohort 2. Two reported Memorial Sloan-Kettering Cancer Center (MSKCC) cohorts received immunotherapy alone used as the validation for cohort 1. We analyzed the relationship between SWI/SNF alterations and clinical outcomes in each cohort. RESULTS: In total, 1162 patients were included, of which 230 patients (19.8%) were identified as SWI/SNF-mut with the most common genetic alterations being ARID1A (33.4%) and SMARCA4 (28.3%). In cohort 1 (n = 146), patients with co-mutations of SWI/SNF and Kirsten rat sarcoma oncogene (KRAS) (SWI/SNFmutKRASmut, n = 18) had significantly prolonged progression-free survival (PFS) (8.6 m vs. 1.9 m; hazard ratio [HR],  0.31; 95% confidence intervals [CI], 0.11-0.83; p = 0.032) to PD-(L)1 inhibitors monotherapy, which was consistent with the MSKCC cohorts (not reach [NR] vs. 6.3 m; HR, 0.36, 95% CI, 0.15-0.82; p = 0.016). In cohort 2 (n = 205), ARID1A-mut (n = 16) was associated with improved PFS after EGFR-TKIs (20.6 m vs. 11.2 m; HR, 0.47, 95% CI, 0.27-0.94; p = 0.023). CONCLUSIONS: In advanced NSCLC, patients with SWI/SNFmutKRASmut seem to benefit more from ICIs. Furthermore, ARID1A-mut may provide a protective effect to EGFR-TKIs in EGFR-mutant patients. However, this is a retrospective single-institution analysis that requires further validation by large prospective studies.

PD-1 inhibitors plus chemotherapy in EGFR/ALK-positive NSCLC patients with brain metastases and disease progression after EGFR/ALK-TKIs therapy.

BACKGROUND: Resistance to epidermal growth factor receptor (EGFR)/anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitors (TKIs) is a pervasive barrier in TKIs therapy for EGFR/ALK-positive non-small cell lung cancer (NSCLC) patients. Immune checkpoint inhibitor (ICI) monotherapy has exhibited an encouraging anti-tumor activity in high-selected EGFR/ALK-positive NSCLC patients with acquired resistance to TKI therapy. However, the effect of ICI plus chemotherapy therapy on those with brain metastases in this subset of patients is still unknown. METHODS: From April 2019 to August 2021, EGFR-mutated or ALK-rearranged NSCLC patients who progressed after previous EGFR/ALK-TKIs with brain metastases and received ICI plus chemotherapy ± bevacizumab at Cancer Hospital of the Chinese Academy of Medical Sciences (CAMS) were included. We retrospectively analyzed the efficacy, toxicity and progression site after ICI treatment. RESULTS: A total of 19 patients were included in the study, including 16 (84.4%) patients with EGFR mutations, 2 (10.5%) with ALK translocations and 1 (5.3%) with RET rearrangement. All of the patients progressed after previous TKI therapy and had brain metastatic lesions when received ICI combination therapy. The overall response rate (ORR) and disease control rate (DCR) were 15.8 and 57.9%, respectively. The median progression-free survival (PFS) and overall survival (OS) were 4.7 months (95% confidence interval CI 0.43-8.96) and 19.2 months (95% CI 15.08-23.29), respectively. The intracranial ORR was 10.5% and extracranial ORR was 15.8%, and the intracranial and extracranial DCR were 68.4 and 63.2%, respectively. The most common progression pattern was extracranial failure, and primary lesions enlargement rather than new sites metastases accounted for the vast majority of progressions. The most common grade 3-4 adverse event (AE) was leukopenia (31.6%), followed by neutropenia (26.3%), thrombocytopenia (10.5%) and rash (5.3%) successively. No grade 5 AE and discontinuation of ICI therapy for severe AEs were observed. CONCLUSIONS: ICI combined with chemotherapy ± bevacizumab might be effective and safe for EGFR/ALK-positive NSCLC patients who progressed after previous TKI therapy, and synergistic anti-tumor activity for brain metastases was also observed.

[Current Progress and Future Developments of Antibody Drug Conjugates 
in Lung Cancer].

Antibody drug conjugates (ADCs) are a novel class of anti-cancer drugs, which combined the specificity of monoclonal antibodies with the cytotoxic palyload via the linkers. Many ADCs have not only verified impressive activity in a variety of cancers, including breast cancer and hematological system tumors, but also in lung cancer. The aim of this study was to provide informations for practice by summarizing the mechanism of action, clinical application and problems and challenges of ADCs.
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Disease monitoring of epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer patients treated with tyrosine kinase inhibitors via EGFR status in circulating tumor DNA.

OBJECTIVE: Circulating tumor DNA (ctDNA) monitoring proves to be a promising approach to assess response and predict survival in epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC) patients treated with tyrosine kinase inhibitors (TKIs). However, whether the dynamic changes in ctDNA EGFR mutation status have the same predictive value as ctDNA remains unknown. This study aims to explore the predictive value of dynamic changes in both ctDNA and ctDNA EGFR status. METHODS: A retrospective analysis was performed using 91 ctDNA samples from a cohort of 28 patients who were diagnosed with EGFR-mutated NSCLC and treated with EGFR-TKIs, including 14 patients treated with first-/second-generation TKIs and 14 treated with osimertinib. Blood samples at baseline (BL), within 4 weeks after TKI initiation (Week4), within 12 weeks before progression (pre-PD), and at progression were collected. The relationship alternatives in ctDNA status, ctDNA EGFR status and response to EGFR-TKIs as well as progression-free survival (PFS) were analyzed. RESULTS: We categorized 20 BL-ctDNA positive patients with available Week4-ctDNA into two groups: ctDNA-clearance (N = 7, 35%) and ctDNA-non-clearance (N = 13, 65%). The ctDNA-clearance group had better PFS than the ctDNA-non-clearance group (ctDNA-clearance vs. ctDNA-non-clearance, p = 0.091, hazard ratio [HR] = 0.42, 95% confidence interval [CI] = 0.15-1.19). According to Week4-EGFR status, we observed that PFS was significantly longer in EGFR-clearance patients than EGFR-non-clearance groups, (p = 0.011, HR = 0.23, 95% CI = 0.08-0.72). We then categorized patients into three subgroups according to Week4-ctDNA and Week4-EGFR status: non-clearance (N = 9), only-EGFR-clearance (concomitant alterations non-clearance) (N = 4), and all-clearance (N = 7). The nonclearance group had a significantly worse PFS than the all-clearance group (median PFS = 5.07 vs. 11.40 months, p = 0.029, HR = 3.45, 95% CI = 1.05-11.49). The only-EGFR-clearance group had a similar PFS to the all-clearance group (p = 0.607), which was longer than that of the non-clearance group (median PFS = 9.20 vs. 5.07 months, p = 0.060, HR = 0.25, 95% CI = 0.05-1.18). We found that the all-clearance group had a similar objective response rate (ORR) to the only-EGFR-clearance group (p = 1.000) and a higher ORR than the non-clearance group (p = 0.012). CONCLUSION: Monitoring of EGFR clearance in ctDNA is promising and cost-effective in assessing response and predicting survival in EGFR-mutated NSCLC patients treated with EGFR-TKIs, with similar predictive value to ctDNA surveillance.

Efficacy of first-line treatments in the elderly and non-elderly patients with advanced epidermal growth factor receptor mutated, non-small cell lung cancer: a network meta-analysis.

OBJECTIVE: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are the current standard of care for advanced or metastatic non-small cell lung cancer (NSCLC) patients harboring EGFR activating mutations. However, the optimal strategy for elderly NSCLC patients is still under debate. This study was designed to explore the optimal first-line regimens by comparing diverse strategies for elderly and non-elderly EGFR-mutated NSCLC patients. METHODS: A systematic review was conducted to summarize all available randomized controlled trials (RCTs) from PubMed, EMBASE, Cochrane Central Register of Controlled Trials databases, and international conferences before September 30, 2020. The primary outcome was progression free survival (PFS), and the secondary outcome was overall survival (OS). A network meta-analysis (NMA) was constructed using the Bayesian statistical model to synthesize the survival outcomes of all the treatments. RESULTS: In total, 12 RCTs were deemed eligible for inclusion with 3779 patients who have received 10 diverse treatments including EGFR-TKIs. Results from the Bayesian ranking suggested that osimertinib was most likely to rank the first in overall population and in elderly patients in PFS, with the cumulative probabilities of 42.20% and 31.46%, respectively. In non-elderly group (younger than 65 years old), standard of care (SoC, representing first-generation EGFR-TKIs in this NMA) + chemotherapy ranked the first (31.66%). As for OS, SoC + chemotherapy ranked first in all patients (64.33%), patients younger than 65 years old (61.98%), or older than 65 years old (34.45%). CONCLUSION: The regimen of osimertinib is associated with the most favorable PFS in elderly advanced EGFR-mutated NSCLC patients, while SoC + chemotherapy is the optimal strategy in PFS for non-elderly NSCLC patients harboring EGFR activating mutations, and in OS for both elderly and non-elderly EGFR-mutated advanced NSCLC patients. TRIAL REGISTRATION: INPLASY protocol 2020100061 https://doi.org/10.37766/inplasy2020.20.0061 .

Non-optimum ambient temperature may decrease pulmonary function: A longitudinal study with intensively repeated measurements among asthmatic adult patients in 25 Chinese cities.

BACKGROUND: Non-optimum ambient temperature has not been widely perceived as an important environmental risk factor for asthma, and the association between ambient temperature and pulmonary function is rarely explored. Our study aimed to investigate the associations between non-optimum ambient temperature and pulmonary function among asthmatic adult patients. METHODS: We performed a longitudinal study among 4,992 eligible adult asthmatic patients in 25 cities of China from 2017 to 2020. The patients were required to complete pulmonary function test every day in the morning and evening. Linear mixed-effects models and distributed lag non-linear models were used to evaluate the associations between ambient temperature and pulmonary function. RESULTS: We evaluated 298,396 records of pulmonary function tests. We found inversely J-shaped exposure-response relationship curves for ambient temperature and pulmonary function. The effects of extreme low temperature occurred at lag 0 h and vanished at lag 72 h (almost 3 days). Compared with referent temperature (29.5 °C), extreme low temperature (-9.4 °C) was associated with decreases of 60.4 mL in FEV1, 299.7 mL/s in PEF, and 101.5 mL in FVC. Extreme high temperature (34.2 °C) was associated with decreases of 26.0 mL in FEV1, 35.8 mL/s in PEF, and 23.4 mL in FVC. Patients of male, overweight, and elder ages were vulnerable populations, and cold effects were more prominent in the south and in areas without central heating. CONCLUSIONS: Both extreme low and high ambient temperatures were associated with decreased pulmonary function in adult asthmatic patients. The effect could last for almost 3 days and low temperature was more harmful.

Establishment of prognostic nomograms for predicting the progression free survival of EGFR-sensitizing mutation, advanced lung cancer patients treated with EGFR-TKIs.

BACKGROUND: There is a lack of clinically available predictive models for patients with epidermal growth factor receptor (EGFR) mutation positive, advanced non-small cell lung cancer (NSCLC) treated with EGFR-tyrosine kinase inhibitors (TKIs). METHODS: The clinical data of patients at the Cancer Hospital, Chinese Academy of Medical Sciences between from January 2016 to January 2021 were retrospectively retrieved as training set. The patients from BENEFIT trial were for the validation cohort. The nomogram was built based on independent predictors identified by univariate and multivariate Cox regression analyses. The discrimination and calibration of the nomogram were evaluated by C-index and calibration plots. RESULTS: A total of 502 patients with complete clinical data and follow-up information were enrolled in this study. Five independent prognostic factors, including The Eastern Cooperative Oncology Group Performance Status scale (ECOG PS), EGFR mutation subtype, EGFR co-mutation, liver metastasis and malignant pleural effusion (p < 0.05). The C-indexes of the nomogram were 0.694 (95% confidence interval [CI], 0.663-0.725) for the training set and 0.653 (95% CI, 0.610-0.696) for the validation set. The calibration curves for the probabilities of 9-, 12- and 18-month progression-free survival (PFS) revealed satisfactory consistency in both the internal and external validations. Additionally, the patients were divided into two groups according to risk (high-risk, low-risk), and significant differences in PFS were observed between the groups in the training and external validation cohorts (p < 0.001). CONCLUSIONS: We constructed and validated a convenient nomogram that have the potential to become an accurate and reliable tool for patients with EGFR mutation positive, advanced NSCLC to individually predict their potential benefits from EGFR-TKIs, and facilitate clinical decision-making.

Hourly concentrations of fine and coarse particulate matter and dynamic pulmonary function measurements among 4992 adult asthmatic patients in 25 Chinese cities.

The short-term associations of fine particulate matter (PM2.5) and coarse particulate matter (PM2.5-10) with pulmonary function were inconsistent and rarely evaluated by dynamic measurements. Our study aimed to investigate the associations of PM2.5 and PM2.5-10 with real-time pulmonary function. We conducted a longitudinal study based on dynamic pulmonary function measurements among adult asthmatic patients in 25 cities of 19 provincial regions of China from 2017 to 2020. Linear mixed-effects models combined with polynomial distributed lag models were used for statistical analysis. A total of 298,396 records among 4,992 asthmatic patients were evaluated. We found generally inverse associations of PM2.5 and PM2.5-10 with 16 pulmonary function indicators that were independent of gaseous pollutants. The associations occurred at lag 1 d, became the strongest at lag 4 d, and vanished a week later. PM2.5-10 had stronger associations than PM2.5, especially in southern China. Nationally, an interquartile increase in PM2.5-10 (28.0 µg/m3) was significantly associated with decreases in forced expiratory volume in 1 s (FEV1, 41.6 mL), the ratio of FEV1 in forced vital capacity (1.1%), peak expiratory flow (136.9 mL/s), and forced expiratory flow at 25-75% of forced vital capacity (54.3 mL/s). We observed stronger associations in patients of male, BMI ≥ 25 kg/m2, age ≥ 45 years old, and during warm seasons. In conclusion, this study provided robust evidence for impaired pulmonary function by short-term exposure to PM2.5 and PM2.5-10 in asthmatic patients using the largest dataset of dynamic monitoring. The associations can last for one week and PM2.5-10 may be more hazardous.

Front-Line Therapy in EGFR Exon 19 Deletion and 21 Leu858Arg Mutations in Advanced Non-Small Cell Lung Cancer: A Network Meta-Analysis.

OBJECTIVE: This study aimed to compare the efficacy of different first-line strategies based on different EGFR mutation types (19 deletion and 21 Leu858Arg mutations). METHODS: We conducted a systematic review and network meta-analysis (NMA) by searching and analyzing RCTs on PubMed, Embase, Cochrane Library, ASCO.org, and ESMO.org, from inception to September 30th, 2020. RESULTS: Nineteen RCTs involving 5450 patients were finally included in this study, covering 10 different treatment strategies. The Bayesian ranking results suggested that, in terms of PFS, in the overall population and in patients with 19del mutation, osimertinib was most likely to rank the first, with the cumulative probabilities of 41.89% and 45.73%, respectively, while for patients with 21 Leu858Arg mutation, standard of care (SoC, represents first-generation EGFR-TKIs in this NMA) + chemotherapy was most likely to rank the first, with the cumulative probabilities of 30.81% in PFS. Moreover, SoC + chemotherapy provided the best overall survival benefit for the overall population and patients with 19del, with the cumulative probabilities of 57.85% and 33.51%, respectively. In contrast, for patients with 21 Leu858Arg mutation, dacomitinib showed the most favorable overall survival, with the cumulative probabilities of 36.73%. CONCLUSIONS: In this NMA, osimertinib and SoC combined with chemotherapy would be the optimal first-line treatment options for advanced NSCLC patients harboring EGFR 19 deletion mutation and 21 Leu858Arg mutation, respectively. This finding is likely to be adopted in clinical practice and provide guidance for future clinical study design. Systematic review registration: INPLASY2020100059.

[Clinical Features of EGFR Mutation Negative in Patients 
with Non-small Cell Lung Cancer and Brain Metastases].

In addition to rare incidence of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 receptor kinase (ROS1) positive patients, patients with brain metastases of non-small cell lung cancer (NSCLC) without epidermal growth factor receptor (EGFR) sensitive mutation have no effective systemic therapy at present, and the overall prognosis is poor. Since the low blood-brain barrier permeability of chemotherapy drugs, the local treatment plays an important role in brain metastases. To understand the clinical characteristics and treatment of brain parenchymal metastases in patients with NSCLC and EGFR mutation negative, we reviewed the incidence, onset time, site, numbers, size, symptom, therapeutic effect and disease evolution in them, which can provide reference for interventional timing and local treatment technology selection of local treatment for brain parenchymal metastases.
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The Downregulation of lncRNA pgm5-as1 Inhibits the Proliferation and Metastasis Via Increasing miR-484 Expression in Colorectal Cancer.

Background: Bioinformatics showed that long non-coding RNA (lncRNA) pgm5-as1 was regulated in patients with colorectal cancer (CRC), and miR-484 was also regulated in CRC. We aimed at determining the modulatory pathway of lncRNA pgm5-as1 in CRC cells, and whether miR-484 was involved in the pathway. Materials and Methods: The target gene of pgm5-as1 was predicted by bioinformatics and verified by dual luciferase assay. Transcription levels of pgm5-as1 and miR-484 were determined by quantitative real-time polymerase chain reaction. Viability, migration rate, invasion, and growth of SW480 and HCT116 cells were determined by Cell Counting Kit-8 (CCK-8), wound healing assay, transwell, and colony formation assay, respectively. Results: pgm5-as1 was upregulated in CRC tissues and cell lines; however, its downregulation contributed to the decreasing of cell viability, growth, migration, and invasion of SW480 and HCT116 cells. Moreover, miR-484 was predicted as the target of pgm5-as1, and the downregulation of pgm5-as1 partially restored the elevated cell viability, growth, migration, and invasion that were induced by the inhibition of miR-484 expression in SW480 and HCT116 cells. Conclusions: The loss of miR-484 expression in CRC might be involved in the promotion and metastasis of CRC, which may be caused by the overexpression of pgm5-as1. Hence, the downregulation of pgm5-as1 could be a therapeutic target in the prevention or intervention of CRC.

Clinicopathological features and prognostic analysis of 247 small cell lung cancer with limited-stage after surgery.

The objective of this study was to analyze the clinical and pathological characteristics of patients with small cell lung cancer (SCLC) after curative surgery and to explore prognostic factors for disease-free survival (DFS) and overall survival (OS). Clinical data of 247 patients were collected, and clinicopathological features were retrieved, including gender, age, smoking history, tumor location, and distant metastasis. Histopathological features were also reviewed by three pathologists, including primary tumor (T), lymph node metastasis (N), pleural invasion, bronchial invasion, nerve invasion, spread through air spaces (STAS), tumor thrombosis, major cell shape (round Vs. spindle), tumor necrosis, stromal fibrosis, and tumor-infiltrating lymphocytes (TILs). Immunohistochemical staining of neuroendocrine markers (CD56, synapsin, chromogranin A) was also reviewed. All patients were followed up for recurrence, distant metastasis, and survival. Kaplan-Meier curves and log-rank tests were applied for survival analysis. The median DFS was 98 months, and the 1-year, 3-year, and 5-year DFS rates were 70.9%, 54.4%, and 52.2%, respectively. The median OS was not reached, and the 1-year, 3-year, and 5-year survival rates were 94.2%, 72.3%, and 65.4%, respectively. Univariate analysis revealed clinicopathological features with DFS (gender, smoking history, primary tumor, regional lymph node metastasis, major cell shape, and TILs) and OS (age, primary tumor, regional lymph node metastasis, distant metastasis, nerve invasion, major cell shape, and TILs). Multivariate analysis revealed DFS-related factors (smoking history, regional lymph node metastasis and major cell shape) and OS-related factors (age, primary tumor, distant metastasis in the brain, liver, bone, nerve invasion, and TILs). Age more than 65 years, smoking, advanced stage (T and N), distant metastasis, nerve invasion, major cell shape as spindle and TILs >30% were negatively correlated with survival. Neuroendocrine immunostaining markers showed no correlation with survival. Of interest, spindle cell type and TILs >30% are revealed as independent negative prognostic factors, and further molecular mechanisms need to be explored.

Nab-paclitaxel in combination with Bevacizumab in patients with non-squamous non-small cell lung cancer after failure of at least one prior systemic regimen.

Background: Most patients with non-small cell lung cancer (NSCLC) experience disease progression after first-line treatment. The efficacy and safety of the nab-paclitaxel (nab-PTX) and bevacizumab combination as the second or further line of treatment in patients with advanced NSCLC have not been reported yet. Objective: To evaluate the efficacy and safety of the nab-PTX and bevacizumab combination in patients with advanced non-squamous (NSQ) NSCLC after failure of at least one prior systemic regimen. Methods: Patients with advanced (stage IV) NSQ NSCLC who received the nab-PTX and bevacizumab combination as the second or further line treatment between February 2012 and December 2018 at the Cancer Hospital of the Chinese Academy of Medical Sciences (Beijing, China) were included in this retrospective study. The main outcomes included the objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety. Results: Thirty-four patients received 1-27 cycles (median, four cycles) of treatment; 67.6% (23/34) patients had undergone at least two lines of previous treatment. The ORR and disease control rates were 26.5% (9/34) and 82.4% (28/34), respectively. The median PFS and OS were 6.0 (95% CI=2.9-7.2) and 11.0 (95% CI=7.8-18.7) months, respectively. The multivariable analyses indicated that the combined use of other drugs and pleural metastasis were respectively associated with better PFS (hazard ratio=0.354, 95% CI=0.134-0.935, P=0.036) and OS (hazard ratio=0.540, 95% CI=0.118-0.980, P=0.046). The most frequent grade 3-4 adverse events (AEs) were neutropenia 20.6% (7/34), leukopenia 8.8% (3/34), and anemia 5.9% (2/34). No grade 5 AE occurred. Conclusion: Combined nab-PTX and bevacizumab might be an effective treatment regimen for patients with advanced NSQ NSCLC after failure of at least one prior systemic regimen, but studies have to validate those findings.