SFTPB in serum extracellular vesicles as a biomarker of progressive pulmonary fibrosis.

Progressive pulmonary fibrosis (PPF), defined as the worsening of various interstitial lung diseases (ILDs), currently lacks useful biomarkers. To identify novel biomarkers for early detection of patients at risk of PPF, we performed a proteomic analysis of serum extracellular vesicles (EVs). Notably, the identified candidate biomarkers were enriched for lung-derived proteins participating in fibrosis-related pathways. Among them, pulmonary surfactant-associated protein B (SFTPB) in serum EVs could predict ILD progression better than the known biomarkers, serum KL-6 and SP-D, and it was identified as an independent prognostic factor from ILD-gender-age-physiology index. Subsequently, the utility of SFTPB for predicting ILD progression was evaluated further in 2 cohorts using serum EVs and serum, respectively, suggesting that SFTPB in serum EVs but not in serum was helpful. Among SFTPB forms, pro-SFTPB levels were increased in both serum EVs and lungs of patients with PPF compared with those of the control. Consistently, in a mouse model, the levels of pro-SFTPB, primarily originating from alveolar epithelial type 2 cells, were increased similarly in serum EVs and lungs, reflecting pro-fibrotic changes in the lungs, as supported by single-cell RNA sequencing. SFTPB, especially its pro-form, in serum EVs could serve as a biomarker for predicting ILD progression.

Short sleep duration and smoking initiation in university students: a retrospective cohort study.

PURPOSE: The aim of this study was to clarify an association between short sleep duration and smoking initiation. METHODS: Participants eligible for this retrospective cohort study were university students who were admitted to a single national university in Japan between 2007 and 2015. Baseline sleep duration and smoking status were measured using general questionnaires at health checkups at admission. During a 6-year observation period, smoking initiation was assessed using general questionnaires at annual health checkups. Cox proportional hazards models adjusted for clinically relevant factors were used to assess the association between sleep duration and smoking initiation. RESULTS: Of 17,493 men, including 540, 5,568, 8,458, 2,507, and 420 men with sleep duration of < 5, 5-6, 6-7, 7-8, and ≥ 8 h, respectively, smoking initiation was observed in 16.1%, 12.5%, 11.2%, 10.0%, and 11.7%, respectively, during a median observation period of 3.0 years. Men with shorter sleep duration were at a higher risk of smoking initiation (adjusted hazard ratio 1.49 [95% confidence interval 1.19-1.85], 1.11 [1.01-1.22], 1.00 [reference], 0.92 [0.80-1.06], and 1.00 [0.75-1.34], respectively). Of 8,880 women, including 267, 3,163, 4,220, and 1,230 women with sleep duration of < 5, 5-6, 6-7, and ≥ 7 h, respectively, smoking initiation was observed in 4.9%, 2.3%, 2.0%, and 2.2%, respectively, during a median observation period of 3.0 years. A similar dose dependent association was ascertained in women (2.50 [1.39-4.49], 1.18 [0.86-1.62], 1.00 [reference], and 1.22 [0.79-1.89], respectively). CONCLUSION: This study clarified that university students with short sleep duration were vulnerable to smoking initiation.

Galectin-10 in serum extracellular vesicles reflects asthma pathophysiology.

BACKGROUND: Novel biomarkers (BMs) are urgently needed for bronchial asthma (BA) with various phenotypes and endotypes. OBJECTIVE: We sought to identify novel BMs reflecting tissue pathology from serum extracellular vesicles (EVs). METHODS: We performed data-independent acquisition of serum EVs from 4 healthy controls, 4 noneosinophilic asthma (NEA) patients, and 4 eosinophilic asthma (EA) patients to identify novel BMs for BA. We confirmed EA-specific BMs via data-independent acquisition validation in 61 BA patients and 23 controls. To further validate these findings, we performed data-independent acquisition for 6 patients with chronic rhinosinusitis without nasal polyps and 7 patients with chronic rhinosinusitis with nasal polyps. RESULTS: We identified 3032 proteins, 23 of which exhibited differential expression in EA. Ingenuity pathway analysis revealed that protein signatures from each phenotype reflected disease characteristics. Validation revealed 5 EA-specific BMs, including galectin-10 (Gal10), eosinophil peroxidase, major basic protein, eosinophil-derived neurotoxin, and arachidonate 15-lipoxygenase. The potential of Gal10 in EVs was superior to that of eosinophils in terms of diagnostic capability and detection of airway obstruction. In rhinosinusitis patients, 1752 and 8413 proteins were identified from EVs and tissues, respectively. Among 11 BMs identified in EVs and tissues from patients with chronic rhinosinusitis with nasal polyps, 5 (including Gal10 and eosinophil peroxidase) showed significant correlations between EVs and tissues. Gal10 release from EVs was implicated in eosinophil extracellular trapped cell death in vitro and in vivo. CONCLUSION: Novel BMs such as Gal10 from serum EVs reflect disease pathophysiology in BA and may represent a new target for liquid biopsy approaches.

Balloon Dilatation for Bronchoscope Delivery in a Swine Model: A Novel Technique for Ultra-Peripheral Lung Field Access and Accurate Biopsy.

INTRODUCTION: In transbronchial biopsy of peripheral pulmonary lesions, the bronchoscope can reach only a limited depth due to the progressive narrowing of bronchi, which may reduce the diagnostic rate. This study examined the balloon dilatation for bronchoscope delivery (BDBD) technique, employing a novel balloon device to enhance bronchoscopy into the peripheral lung areas. METHODS: Anaesthetised swine served as our primary model. Using computed tomography (CT) scans, we positioned virtual targets characterised by a positive bronchus sign and a diameter of 20 mm beneath the pleura. The bronchoscope was navigated along the pathways determined from the CT images. We performed balloon dilatation when bronchial narrowing obstructed progress to assess whether balloon dilatation would enable the bronchoscope to enter further into the periphery. RESULTS: We established 21 virtual targets on the CT scans. An average of 12.1 branches were identified along the pathways on the CT scans; however, bronchoscopy without BDBD only allowed access to an average of 6.7 branches. Based on 72 balloon dilatations with 3.0-mm or 4.0-mm ultra-thin bronchoscopes, there was an average increased access of 3.43 and 5.14 branches per route, respectively, with no significant BDBD complications. The bronchoscope was able to reach the planned location along all pathways, and the mean final bronchoscopic endpoints were at an average distance of 14.7 mm from the pleura. Post-procedure CT confirmed biopsy accuracy. CONCLUSION: The BDBD technique can enhance access of a flexible bronchoscope into the peripheral lung fields, which could potentially allow more accurate transbronchial interventions for peripheral targets.

Cancer-associated SNRPD3 mutation confers resistance to hypoxia, which is attenuated by DRP1 inhibition.

RNA splicing is a fundamental cellular mechanism performed by spliceosomes that synthesise multiple mature RNA isoforms from a single gene. The association between spliceosome abnormality and solid cancers remains largely unknown. Here, we demonstrated that Sm proteins, which are common components of the spliceosomes and constitute the Sm ring, were overexpressed in multiple cancers and their expression levels were correlated with clinical prognosis. In a pan-cancer mutational hotspot in the Sm ring at SNRPD3 G96V, we found that the G96V substitution confers resistance to hypoxia. RNA-seq detected numerous differentially spliced events between the wild-type and mutation-carrying cells cultured under hypoxia, wherein skipping exons and mutually exclusive exons were frequently observed. This was observed in DNM1L mRNA, which encodes the DRP1 protein that regulates mitochondrial fission. The mitochondria of cells carrying this mutation were excessively fragmented compared with those of wild-type cells. Furthermore, treatment with a DRP1 inhibitor (Mdivi-1) recovered the over-fragmented mitochondria, leading to the attenuation of hypoxia resistance in the mutant cells. These results propose a novel correlation between the cancer-related spliceosome abnormality and mitochondrial fission. Thus, targeting SNRPD3 G96V with a DRP1 inhibitor is a potential treatment strategy for cancers with spliceosome abnormalities.

Real-world outcomes of nivolumab plus ipilimumab and pembrolizumab with platinum-based chemotherapy in advanced non-small cell lung cancer: a multicenter retrospective comparative study.

INTRODUCTION: Nivolumab plus ipilimumab with chemotherapy (NICT) and pembrolizumab with chemotherapy (PCT) are commonly used in patients with advanced non-small cell lung cancer (NSCLC). Compared with immune checkpoint inhibitor (ICI) monotherapy, ICI combination therapy can increase immune-related toxicity instead of prolonging survival. This study aimed to compare the efficacy and safety of NICT and PCT to decide on the favorable treatment. METHODS: We conducted a multi-center retrospective cohort study on patients who underwent NICT or PCT between December 2018 and May 2022. Propensity score matching (PSM) was performed with the variables age, sex, smoking status, performance status, stage, histology, and programmed cell death ligand-1 (PD-L1). The Kaplan-Meier method was used to compare survival for the matched patients. RESULTS: Six hundred consecutive patients were included. After PSM, 81 and 162 patients were enrolled in the NICT and PCT groups, respectively. The baseline characteristics were well-balanced. The median progression-free survival was equivalent (11.6 vs. 7.4 months; P = 0.582); however, the median overall survival (OS) was significantly longer in the NICT group than in the PCT group (26.0 vs. 16.8 months; P = 0.005). Furthermore, OS was better in PD-L1-negative patients who underwent NICT than in those who underwent PCT (26.0 vs. 16.8 months; P = 0.045). Safety profiles did not differ significantly in terms of severe adverse event and treatment-related death rates (P = 0.560, and 0.722, respectively). CONCLUSIONS: Real-world data suggests that NICT could be a favorable treatment option compared with PCT for patients with advanced NSCLC. Further follow-up is needed to determine the long-term prognostic benefit.

Living Arrangements Predict Frequent Alcohol Consumption Among University Students: A Retrospective Cohort Study.

PURPOSE: This study aimed to confirm the clinical impact of living arrangements on incidence of frequent alcohol consumption in university students. DESIGN: A retrospective cohort study. SETTING: A national university in Japan. SUBJECTS: 17,774 university students. MEASURES: The association between living arrangements on admission and the incidence of frequent alcohol consumption (≥4 days/week) was assessed using multivariable-adjusted Cox proportional-hazards models. RESULTS: Among 5,685, 692, and 5,151 male students living with family, living in the dormitory, and living alone, 5.0%, 6.2%, and 5.8% reported frequent alcohol consumption during the median observational period of 3.0 years, respectively. Living in the dormitory and living alone were identified as significant predictors of frequent alcohol consumption (multivariable-adjusted hazard ratios: 1.00 [reference], 1.39 [1.01-1.92], and 1.21 [1.03-1.42], respectively). On the contrary, living arrangements were not associated with the incidence of frequent alcohol consumption among of 6,091 female students, partly because of low incidence of frequent alcohol consumption (2.3%, 1.4%, and 2.6%, respectively). CONCLUSIONS: Living arrangements predicted frequent alcohol consumption among male university students, whereas not among female university students.

Pneumonitis During Durvalumab Consolidation Therapy Affects Survival in Stage III NSCLC.

Introduction: Durvalumab consolidation therapy is the standard of care after concurrent chemoradiotherapy (CRT) for stage III NSCLC. Immune-related pneumonitis during durvalumab treatment is potentially fatal; however, information is lacking regarding the impact of pneumonitis on patient survival. This study investigates the effect of pulmonary and nonpulmonary immune-related adverse events (irAEs) on the efficacy of durvalumab treatment in patients with stage III NSCLC. Methods: We retrospectively assessed 158 patients who received durvalumab after CRT at nine Japanese institutions between July 2018 and March 2020. Survival outcomes were compared between patients who developed pneumonitis with those who developed irAEs other than pneumonitis. Patients who survived for less than 3 months were excluded to reduce immortal time bias. Results: Among 158 evaluated patients, 76 (48%) experienced grade less than or equal to one irAEs, whereas 82 (52%) experienced grade greater than or equal to two irAEs. Among the patients with grade greater than or equal to two irAEs, those with grade greater than or equal to two pneumonitis (n = 55) were compared with those with grade greater than or equal to two irAEs other than pneumonitis (n = 27). Patients with grade greater than or equal to two pneumonitis exhibited a significantly worse overall survival than those with grade greater than or equal to two irAEs that excluded pneumonitis. Multivariate analysis revealed that grade greater than or equal to two pneumonitis (hazard ratio = 3.71; 95% confidence interval, 1.85-7.45; p < 0.001) and squamous histology (hazard ratio = 2.64; 95% confidence interval, 1.29-5.42; p = 0.008) were independently associated with worse overall survival. Conclusions: After minimizing immortal time bias, pneumonitis grade two or greater and squamous histology were poor prognostic factors in patients who received consolidation durvalumab after CRT.

Association of secondhand smoke exposure and health-related lifestyle behaviors among male university employees in Japan.

Secondhand smoke (SHS) exposure causes various health problems associated with an unhealthy lifestyle. However, the lifestyles of individuals exposed to SHS have not been characterized extensively. Therefore, this cross-sectional study aimed to investigate the association between SHS exposure and lifestyle behaviors. The participants were 2379 healthy male employees at Osaka University who underwent health examinations. Physical and biochemical parameters and lifestyle behavior data were obtained from all the participants. Participants with SHS exposure had significantly higher body mass index, waist circumference, and serum levels of triglycerides and uric acid than that of those without SHS exposure. SHS exposure was significantly correlated with several lifestyle behaviors, including TV time, frequency of breakfast consumption and fried food consumption, vegetable and fruit intake, alcohol consumption frequency and daily alcohol intake, and smoking status. Thus, SHS exposure may be associated with an unhealthy lifestyle. The lifestyle behaviors of the smoke-excluded population were assessed further; however, SHS exposure was still associated with dietary and drinking habits. Since participants with SHS exposure are likely to have an unhealthy life and combined unhealthy lifestyle behaviors, the confounding effect of these factors should be considered when assessing the impact of SHS exposure on health.

Impact of Lymphopenia Recovery After Chemoradiotherapy on Durvalumab Consolidation Therapy in Stage III NSCLC.

Introduction: Durvalumab maintenance therapy after definitive concurrent chemoradiotherapy (CRT) is the standard treatment modality for stage III NSCLC. Although severe treatment-related lymphopenia (TRL) during CRT may impair the efficacy of subsequent durvalumab therapy, data on the effect of TRL recovery on consolidation durvalumab therapy are lacking. Methods: This retrospective study evaluated patients with unresectable stage III NSCLC treated with durvalumab after concurrent CRT. The patients were enrolled across nine institutes throughout Japan between August 2018 and March 2020. The effect of TRL recovery on survival was evaluated. The patients were divided into two groups on the basis of their lymphocyte recovery status: the recovery group involved patients who did not experience severe TRL or experienced TRL but exhibited lymphocyte count recovery at durvalumab initiation, and the nonrecovery group involved patients who experienced severe TRL and did not exhibit lymphocyte count recovery on durvalumab initiation. Results: Among the 151 patients evaluated, 41 (27%) and 110 (73%) patients were classified into the recovery and the nonrecovery groups, respectively. The nonrecovery group had significantly worse progression-free survival than the recovery group (21.9 mo versus not reached, p = 0.018). Recovery from TRL (p = 0.027) and high pre-CRT lymphocyte count (p = 0.028) independently influenced progression-free survival. Conclusions: Baseline lymphocyte count and recovery from TRL at the start of durvalumab therapy were predictive factors for survival outcomes in patients with NSCLC treated with durvalumab consolidation after concurrent CRT.

A cancer-associated METTL14 mutation induces aberrant m6A modification, affecting tumor growth.

The methyltransferase-like 3 (METTL3)-/METTL14-containing complex predominantly catalyzes N6-methyladenosine (m6A) modification, which affects mRNA stability. Although the METTL14 R298P mutation is found in multiple cancer types, its biological effects are not completely understood. Here, we show that the heterozygous R298P mutation promotes cancer cell proliferation, whereas the homozygous mutation reduces proliferation. Methylated RNA immunoprecipitation sequencing analysis indicates that the R298P mutation reduces m6A modification at canonical motifs. Furthermore, this mutation induces m6A modification at aberrant motifs, which is evident only in cell lines harboring the homozygous mutation. The aberrant recognition of m6A modification sites alters the methylation efficiency at surrounding canonical motifs. One example is c-MET mRNA, which is highly methylated at canonical motifs close to the aberrantly methylated sites. Consequently, c-MET mRNA is severely destabilized, reducing c-Myc expression and suppressing cell proliferation. These data suggest that the METTL14 R298P mutation affects target recognition for m6A modification, perturbing gene expression patterns and cell growth.

Impact of minocycline on outcomes of EGFR-mutant non-small cell lung cancer patients treated with EGFR-TKIs.

Minocycline is often administered prophylactically or therapeutically to non-small cell lung cancer (NSCLC) patients receiving epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) for skin rash as an adverse event. We examined the effects of minocycline on the outcomes of EGFR-mutant NSCLC treated with first-line EGFR-TKIs based on a single-center retrospective analysis. In this retrospective cohort study, data were collected on NSCLC patients treated with first-line EGFR-TKIs between January 2010 and June 2021. The treatment efficacy of first-line EGFR-TKIs was compared between patients who received minocycline and those who did not. Median progression-free survival (PFS) with first-line EGFR-TKIs was significantly longer in the minocycline group (N = 32) than in the control group (N = 106); 714 (95% confidence interval CI 411-1247) days vs. 420 (95% CI 343-626) days, p = 0.019. A multivariate analysis including skin rash as a variable confirmed that the administration of minocycline for 30 days or longer correlated with good PFS and overall survival (OS) with first-line EGFR-TKIs (HR 0.44 [95% CI 0.27-0.73], p = 0.0014 and HR 0.50 [95% CI 0.27-0.92], p = 0.027, respectively). The administration of minocycline influenced good treatment efficacy with first-line EGFR-TKIs independently of skin rash.

Tumor-derived semaphorin 4A improves PD-1-blocking antibody efficacy by enhancing CD8+ T cell cytotoxicity and proliferation.

Immune checkpoint inhibitors (ICIs) have caused revolutionary changes in cancer treatment, but low response rates remain a challenge. Semaphorin 4A (Sema4A) modulates the immune system through multiple mechanisms in mice, although the role of human Sema4A in the tumor microenvironment remains unclear. This study demonstrates that histologically Sema4A-positive non-small cell lung cancer (NSCLC) responded significantly better to anti-programmed cell death 1 (PD-1) antibody than Sema4A-negative NSCLC. Intriguingly, SEMA4A expression in human NSCLC was mainly derived from tumor cells and was associated with T cell activation. Sema4A promoted cytotoxicity and proliferation of tumor-specific CD8+ T cells without terminal exhaustion by enhancing mammalian target of rapamycin complex 1 and polyamine synthesis, which led to improved efficacy of PD-1 inhibitors in murine models. Improved T cell activation by recombinant Sema4A was also confirmed using isolated tumor-infiltrating T cells from patients with cancer. Thus, Sema4A might be a promising therapeutic target and biomarker for predicting and promoting ICI efficacy.

Virtual fluoroscopic preprocedural planning using Ziostation2 for transbronchial biopsy: A prospective self-controlled study.

BACKGROUND: Bronchoscopes cannot reach the periphery of the lung because the bronchi are tapered. Therefore, selectively advancing a device-e.g., an endobronchial ultrasonography (EBUS) probe-to the targets can be challenging. Virtual fluoroscopic preprocedural planning (VFPP) is a method in which the route to the target is superimposed on an X-ray fluoroscopy-like image reconstructed from CT images, facilitating the advancement of the EBUS probe to the target. The VFPP method was integrated into the Ziostation2 bronchoscopic navigation system (Ziosoft, Inc., Tokyo, Japan) in 2018. Here, we prospectively examined the feasibility of the VFPP method using Ziostation2 (Zio-VFPP). METHODS: Thirty-six patients who had pulmonary lesions with long axes ≤30 mm and who underwent thin-slice CT with ≤0.625-mm thickness were enrolled. We initiated bronchoscopy using EBUS with a guide sheath (EBUS-GS) while referring to Ziostation2 bronchoscopic navigation. When the probe was not "within" a lesion, we attempted to correct its position based on Zio-VFPP. EBUS findings before and after Zio-VFPP were compared. RESULTS: Zio-VFPP was performed in 24 patients, and EBUS findings improved in nine patients. Before Zio-VFPP, 18 patients were "outside," but after Zio-VFPP, the number decreased to ten. Statistically, this difference was significant (p = 0.0392). There were no cases in which EBUS findings worsened with Zio-VFPP. CONCLUSION: Zio-VPFPP improves EBUS findings and significantly reduces "outside" cases. However, further investigation is necessary to verify its effectiveness.

Proposal of a novel pipeline involving precise bronchoscopy of distal peripheral pulmonary lesions for genetic testing.

Next-generation sequencing (NGS) has become increasingly more important for lung cancer management. We now expect biopsies to be sensitive, safe, and yielding sufficient samples for NGS. In this study, we propose ultraselective biopsy (USB) with sample volume adjustment (SVA) as a novel method that integrates an ultrathin bronchoscope, radial probe endobronchial ultrasound, and the direct oblique method for ultraselective navigation, and adjustment of sample volume for NGS. Our purpose was to estimate the diagnostic potential and the applicability of USB-SVA for amplicon-based NGS analysis. The diagnostic yield of bronchoscopy in forty-nine patients with malignant peripheral pulmonary lesions (PPLs) was retrospectively analyzed, and amplicon-based NGS analysis was performed on samples from some patients using USB. The diagnostic yields of distal PPLs in the USB group were significantly higher than those in the non-USB group (90.5% vs. 50%, respectively, p = 0.015). The extracted amounts of nucleic acids were at least five times the minimum requirement and the sequence quality met the criteria for the Oncomine™ Target Test. Only the tumor cell content of some samples was insufficient. The feasibility of the pipeline for USB, SVA, and amplicon-based NGS in distal PPLs was demonstrated.

Impact of treatment line on risks and benefits of immune checkpoint inhibitor in patients with advanced non-small cell lung cancer and interstitial lung disease: a systematic review and meta-analysis of cohort studies.

Background: There is no clear consensus regarding the safety and efficacy of immune checkpoint inhibitors (ICIs) in patients with advanced non-small cell lung cancer (NSCLC) and pre-existing interstitial lung disease (ILD). We aimed to elucidate the impact of ICIs on pre-existing ILD. Methods: We systematically queried PubMed-MEDLINE, Embase-Scopus, and ISI Web of Science databases up to January 10, 2022. The pooled any-grade and grade 3-5 ICI-associated pneumonitis (ICIP) rate and objective response rate (ORR) in patients with pre-existing ILD were mainly evaluated. The relative risk (RR) was also evaluated for pre-existing ILD and usual interstitial pneumonia (UIP) patterns. Sensitivity and subgroup analyses were performed to assess the heterogeneity. Results: In total, 17 studies involving 5,529 patients were included in the meta-analysis. The pooled ICIP rate was 30% [95% confidence interval (CI): 24-36%]; it was found to be significantly higher in patients with pre-existing ILD relative to those without (RR =3.05, 95% CI: 2.53-3.69; I2=0.0%). The pooled grade 3-5 ICIP rate was 12% (95% CI: 9-15%); this was also significantly higher in patients with pre-existing ILD (RR =3.19, 95% CI: 2.32-4.38; I2=0.0%). According to subgroup analysis, these ICIP rates were not significantly different among the treatment lines (first, ≥ second, and mixed) (P=0.33) whereas the pooled ORR was 36% (95% CI: 24-48%; I2=53.7%) with a significant difference among the treatment lines (P=0.027). The pooled ICIP rate was independent of the UIP pattern (RR =1.06, 95% CI: 0.86-1.32; I2=0.0%). Conclusions: Overall, ICIs should be administered cautiously in patients with pre-existing ILD, regardless of the treatment line. Moreover, the risks of ICIP may outweigh ICI benefits, especially in second-or later-line treatment. These results need to be further confirmed by meta-analyses including more observational cohort studies in clinical setting.

Peripheral T cell cytotoxicity predicts the efficacy of anti-PD-1 therapy for advanced non-small cell lung cancer patients.

Anti-programmed cell death-1 (PD-1) therapy exerts beneficial effects in a limited population of cancer patients. Therefore, more accurate diagnostics to predict the efficacy of anti-PD-1 therapy are desired. The present study investigated whether peripheral T cell cytotoxicity predicts the efficacy of anti-PD-1 therapy for advanced non-small cell lung cancer (NSCLC) patients. Advanced NSCLC patients treated with anti-PD-1 monotherapy (nivolumab or pembrolizumab) were consecutively enrolled in the present study. Peripheral blood samples were subjected to an analysis of peripheral T cell cytotoxicity and flow cytometry prior to the initiation of anti-PD-1 therapy. Peripheral T cell cytotoxicity was assessed using bispecific T-cell engager (BiTE) technology. We found that progression-free survival was significantly longer in patients with high peripheral T cell cytotoxicity (p = 0.0094). In the multivariate analysis, treatment line and peripheral T cell cytotoxicity were independent prognostic factors for progression-free survival. The analysis of T cell profiles revealed that peripheral T cell cytotoxicity correlated with the ratio of the effector memory population in CD4+ or CD8+ T cells. Furthermore, the results of flow cytometry showed that the peripheral CD45RA+CD25+/CD4+ T cell ratio was higher in patients with than in those without severe adverse events (p = 0.0076). These results indicated that the peripheral T cell cytotoxicity predicted the efficacy of anti-PD-1 therapy for advanced NSCLC patients.

Fragment size and dynamics of EGFR-mutated tumor-derived DNA provide prognostic information regarding EGFR-TKI efficacy in patients with EGFR-mutated NSCLC.

Circulating tumor DNA (ctDNA)-based next-generation sequencing (NGS) is a complementary and alternative test to tissue-based NGS. We performed NGS analysis of ctDNA samples collected from patients with EGFR-mutated non-small cell lung cancer (NSCLC) who received osimertinib; the samples were collected after second-line treatment, before osimertinib treatment, one week and one month after osimertinib treatment, and at the time of resistance formation. We examinedthe correlation with osimertinib efficacy. From January to December 2018, 34 patients with EGFR-mutated NSCLC harboring EGFR T790M mutations were enrolled, and a total of 132 peripheral blood samples were collected. The fragment sizes of EGFR-mutated ctDNAs were significantly shorter than that of their corresponding normal fragments. Osimertinib treatment of patients with shorter EGFR-mutated ctDNA fragments resulted in shorter progression-free survival (PFS). The disappearance time of EGFR-mutated fragment fractions and clonal evolution patterns (new driver mutation group, additional mutation group vs. attenuation group) were each associated with the PFS achieved with osimertinib treatment; however,multivariate analysis revealed that only shorter EGFR-mutated ctDNA fragments were associated with the PFS resulting from osimertinib treatment. EGFR-mutated ctDNA fragment size, time of disappearance of these fragments, and clonal evolution pattern were related to the effects of osimertinib. In particular, short EGFR-mutated ctDNA fragmentation may be closely related to osimertinib efficacy prediction.

Soluble angiotensin-converting enzyme 2 association with lipid metabolism.

Increased expression of angiotensin-converting enzyme 2 (ACE2) is one of the likely explanations for disease severity in patients with coronavirus disease 2019 (COVID-19). In this study, we aimed to test whether soluble ACE2 (sACE2) levels are correlated to known risk factors of severe COVID-19 including biochemical parameters, body mass index and smoking habits. We cross-sectionally evaluated serum sACE2 levels in obese or tobacco-smoking populations and compared them to those in non-obese and non-smoking healthy participants. Additionally, fibroblast growth factor-21 (FGF21) was investigated as a candidate regulator of sACE2. A total of 220 male participants aged 30-59 years undergoing an annual health checkup were enrolled in this study: 59 obese, 80 smokers, and 81 healthy. Serum sACE2 levels were significantly higher in obese participants but not in tobacco-smoking participants when compared to healthy participants. sACE2 levels were significantly correlated with total cholesterol and triglycerides but not with body mass index. Furthermore, no regulatory relationship was found between FGF21 and sACE2. Lipid metabolism disorders accompanied by upregulation of serum sACE2 may be underlying mechanisms of COVID-19 aggravation and might be a novel breakthrough treatment target.