Predicting dupilumab effectiveness with Type-2 biomarkers: A real-world study of severe asthma.

BACKGROUND: The therapeutic effectiveness of dupilumab for severe asthma in real-world settings is yet to be prospectively investigated across multiple institutions, and uncertainties persist regarding predictive factors for its effectiveness. We aimed to assess the effectiveness of dupilumab and identify predictors of its effectiveness in real-world settings using two type-2 biomarkers: FeNO concentration and blood eosinophil count. METHODS: This prospective multicenter study included 103 patients with severe asthma. Exacerbations and respiratory functions were monitored for 24 weeks. Asthma control was evaluated using the Asthma Control Questionnaire-5. Clinical symptoms and their impact on cough and sputum were assessed using the Cough and Sputum Assessment Questionnaire (CASA-Q). Subgroup analyses of type-2 biomarkers were conducted based on FeNO levels and blood eosinophil counts at baseline. RESULTS: Treatment with dupilumab led to a reduction in exacerbations and enhancement in asthma control, FEV1, and CASA-Q scores. FEV1 improvement was correlated with enhancement in the sputum domain of the CASA-Q. Patients exhibiting elevated FeNO levels and blood eosinophil counts demonstrated more significant enhancements in FEV1. CASA-Q sputum domain scores were significantly higher in the group with elevated eosinophil counts. Regression analysis revealed that FeNO levels and blood eosinophil counts are significant predictors of FEV1 improvement, with blood eosinophil counts also predicting sputum improvement in patients treated with dupilumab. CONCLUSIONS: Type-2 biomarkers may act as indicators of improvement in FEV1 and sputum outcomes among patients with severe asthma undergoing dupilumab treatment in real-world settings.

Combination effect of Mepolizumab and Endobronchial Watanabe Spigot (EWS) in drug-induced eosinophilic pneumonia complicated by refractory pneumothorax.

Few reports have described the treatment of eosinophilic pneumonia (EP) complicated by refractory pneumothorax. A 62-year-old man with a medical history of ulcerative colitis who was undergoing maintenance treatment presented with fever, cough, and diffuse bilateral consolidation on chest radiography. Laboratory findings showed peripheral eosinophilia, and he was hospitalized with a diagnosis of drug-induced EP and started on corticosteroid therapy. During the course, he developed refractory pneumothorax, and it was difficult to control the air leakage. As it was necessary to control the eosinophilic inflammation and air leakage, mepolizumab, a humanized anti-interleukin-5 monoclonal antibody, and an endobronchial Watanabe spigot (EWS), were introduced. After EWS insertion, the leakage of the refractory pneumothorax disappeared. The patient continued to have no recurrence of EP or pneumothorax after the removal of the EWS. The combination of mepolizumab and an EWS may be effective in cases of EP complicated by refractory pneumothorax.

The influence of 4G/5G polymorphism in the plasminogen-activator-inhibitor-1 promoter on COVID-19 severity and endothelial dysfunction.

Introduction: Plasminogen activator inhibitor-1 (PAI-1) is linked to thrombosis and endothelial dysfunction in severe COVID-19. The +43 G>A PAI-1 and 4G/5G promoter polymorphism can influence PAI-1 expression. The 4G5G PAI-1 promoter gene polymorphism constitutes the 4G4G, 4G5G, and 5G5G genotypes. However, the impact of PAI-1 polymorphisms on disease severity or endothelial dysfunction remains unclear. Methods: Clinical data, sera, and peripheral blood mononuclear cells (PBMCs) of COVID-19 patients were studied. Results: Comorbidities and clinical biomarkers did not correlate with genotypes in either polymorphism. However, differences between fibrinolytic factors and interleukin-1ß (IL-1ß) were identified in genotypes of the 4G/5G but not the 43 G>A PAI polymorphism. Patients with the 4G4G genotype of the 4G/5G polymorphism showed high circulating PAI-1, mainly complexed with plasminogen activators, and low IL-1ß and plasmin levels, indicating suppressed fibrinolysis. NFκB was upregulated in PBMCs of COVID-19 patients with the 4G4G genotype. Discussion: Mechanistically, IL-1ß enhanced PAI-1 expression in 4G4G endothelial cells, preventing the generation of plasmin and cleavage products like angiostatin, soluble uPAR, and VCAM1. We identified inflammation-induced endothelial dysfunction coupled with fibrinolytic system overactivation as a risk factor for patients with the 5G5G genotype.

Differences between oscillometry measurements obtained by MostGraph-01 and MasterScreen-IOS in patients with asthma.

BACKGROUND: Oscillometry devices (also termed forced oscillation technique) devices such as MasterScreen-IOS® (Jaeger, Hochberg, Germany) and MostGraph-01® (Chest, Tokyo, Japan) are useful for obtaining physiological assessments in patients with obstructive lung diseases, including asthma. However, as oscillometry measurements have not been fully compared between MasterScreen-IOS® and MostGraph-01® in patients with asthma, it is unknown whether there are differences in the measurements between the devices. This study aimed to determine whether there is any difference in oscillometry measurements obtained using the two devices in patients with asthma. METHODS: Oscillometry measurements obtained using MasterScreen-IOS® and MostGraph-01® were retrospectively evaluated in 95 patients with asthma at Juntendo University Hospital between October 2009 and November 2009. RESULTS: There was a strong positive correlation in the measurements between the two devices. However, the values of R5, R20, ALX and Fres were lower when measured with MostGraph-01® than with MasterScreen-IOS®, and vice versa for the values of X5. The results were used in correction equations to convert oscillometry parameters measured using MasterScreen-IOS® to those measured using MostGraph-01®. CONCLUSIONS: To our knowledge, this is the first report to compare MostGraph-01® and MasterScreen-IOS® devices using practical clinical data obtained in patients with asthma. The values obtained by both devices can be interpreted in a similar way, although there is slight variation. The conversion equations produced in this study may assist to compare the oscillometry measurements obtained by each of the two devices.

Anti-Müllerian hormone type II receptor protein expression in non-small cell lung cancer and the effect of AMH/AMHR2 signaling on cancer cell proliferation.

BACKGROUND: Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths worldwide despite advances in cancer therapeutics. In several gynecological cancers, anti-Müllerian hormone receptor type 2 (AMHR2) mediates AMH-induced growth inhibition and is expressed at high levels. Furthermore, 5%-8% of NSCLCs exhibit high AMHR2 expression, suggesting that AMH may inhibit the progression of some lung cancers. However, the clinical relevance of AMHR2 expression and its role in lung cancer is not fully clarified. METHODS: Immunostaining was performed on 79 surgical specimens of NSCLC. The Cancer Genome Atlas RNA-seq data for lung adenocarcinoma were analyzed, and gene ontology and gene set enrichment analyses were performed. In cellular experiments, AMHR2-overexpressing NSCLC cell lines were established, and the role of the AMH-AMHR2 pathway in cell proliferation with recombinant human AMH protein treatment was examined. RESULTS: A total of 13 cases (16.5%) were positive for immunostaining in lung adenocarcinoma tissues; no positive signals were detected in lung squamous carcinoma tissues. Gene expression variation analysis using The Cancer Genome Atlas data showed that the expression of genes related to the cell cycle was downregulated in the AMHR2-high group. Cellular experiments showed that activation of the AMH-AMHR2 pathway suppressed cell proliferation. CONCLUSION: In lung adenocarcinoma tissues with high expression of AMHR2, activation of the AMH-AMHR2 pathway may suppress cell proliferation.

Corrigendum: SARS-CoV-2 evolution among patients with immunosuppression in a nosocomial cluster of a Japanese medical center during the Delta (AY.29 sublineage) surge.

[This corrects the article DOI: 10.3389/fmicb.2023.944369.].

Antimicrobial susceptibility analysis of isepamicin combination treatments in Mycobacterium abscessus species.

This study evaluated the antimicrobial potency of the combination of isepamicin (ISP) for Mycobacterium abscessus species (MABS). 34 clinical MABS strains were isolated from clinical samples. Of them, 11 (32.4 %) were M. abscessus subsp. abscessus (Mab), 22 (64.7 %) were M. abscessus subsp. massiliense (Mma), and one (2.9 %) was M. abscessus subsp. bolletii (Mbo). We compared susceptibility to sitafloxacin (STFX)-ISP and clarithromycin (CLR)-ISP combinations with those of the antimicrobial agents alone, and synergistic effects were observed in 41.2 % and 17.6 % when treated with STFX-ISP and CLR-ISP. By hierarchical cluster analysis, the isolates divided into treatment-sensitive and treatment-resistant groups. Non-Mma or rough colony isolates were significantly likely to belong to the treatment-sensitive group (p = 0.024, p < 0.001, respectively). These results suggest that the ISP-containing combination could be a new therapeutic strategy for MABS, especially in cases of non-Mma: treatment-refractory subspecies, and rough morphotypes: high-virulence morphotypes.

Clinical potential of SKP2 as diagnostic marker and therapeutic target in small cell lung cancer.

BACKGROUND: Small cell lung cancer (SCLC) is the most aggressive type of lung cancer. The overall survival has not improved significantly over the last decades because no major therapeutic breakthroughs have been achieved for over 15 years. METHODS: We analyzed a genome-wide loss-of-function screening database to identify vulnerabilities in SCLC for the development of urgently needed novel therapies. RESULTS: We identified SKP2 (encoding S-phase kinase-associated protein 2) and CKS1B (encoding CDC28 protein kinase regulatory subunit 1B) as the two most essential genes in that order in SCLC. Notably, SKP2 and CKS1B comprise the p27 binding pocket of the E3 ubiquitin ligase SCFSKP2 complex. Immunohistochemistry on tissue microarrays revealed that SKP2 was expressed in >95% of samples at substantially higher levels than that observed for commonly used neuroendocrine markers. As expected, SCLC cell lines were sensitive to SKP2 inhibition. Furthermore, SKP2 or CKS1B knockdown induced apoptosis in RB1 mutant cells, whereas it induced senescence in RB1 wild-type cells. CONCLUSION: Although the mechanism underlying SKP2 knockdown-induced growth inhibition differs between RB1-wild-type and -mutant SCLC, SKP2 can be considered a novel therapeutic target for patients with SCLC regardless of the RB1 mutation status. Our findings indicate that SKP2 is a potential novel clinical diagnostic marker and therapeutic target in SCLC.

Ancestry-, Sex-, and Age-Based Differences of Gene Alterations in NSCLC: From the Real-World Data of Cancer Genomic Profiling Tests.

BACKGROUND: Some genomic alterations in non-small cell lung cancer (NSCLC) are known to differ according to race, sex, or age. These studies have been limited in sample size and thus they cannot detect the differences precisely and comprehensively. METHODS: Tissue-based comprehensive genomic profiling was performed on 75,362 patients with NSCLC from the United States during routine clinical care. Additionally, we examined data of a Japanese NSCLC cohort with 1,019 patients. In the US cohort, 296 genes were examined for pathogenic alterations. Predominant genetic ancestry was inferred using a SNP-based approach, and patients were categorized into European (EUR), African (AFR), East Asian (EAS), Admixed American (AMR), and South Asian (SAS) ancestry groups. Patients were additionally stratified by histologic type, age (<40/≥40 years, <75/≥75 years), and sex. The prevalence of high tumor mutational burden (TMB-High) and microsatellite instability status was also calculated. RESULTS: Stratified by ancestry, EGFR alterations were significantly enriched in EAS versus other ancestry groups. The prevalence of ALK was significantly higher in the AMR, EAS, and SAS patients than in AFR and EUR patients. KRAS and STK11 were enriched in EUR and AFR patients versus other groups. TMB-High was significantly enriched in AFR patients versus all other groups. An analysis based on sex revealed differences in prevalence of alterations in 80 genes and TMB-High status. For example, EGFR, ALK, BRAF, and KRAS alterations were significantly enriched in females, whereas TP53, STK11, KEAP1, and TMB-High were significantly enriched in males. With respect to age, the prevalence of alterations in 41 genes, including ALK, RET, MET, EGFR, STK11, KEAP1, BRAF, and KRAS, as well as TMB-High, were significantly different between patients aged <40 years and those aged ≥40 years. CONCLUSIONS: Comprehensive analysis from a large real-world dataset revealed ancestry-associated differences in genomic alterations in NSCLC. Age- and sex-related differences in prevalence of genomic alterations and TMB-High status were also observed.

Trophoblast Cell Surface Antigen 2 Expression in Thymic Carcinoma: Brief Report.

Introduction: Trophoblast cell surface antigen 2 (TROP2) is a transmembrane glycoprotein overexpressed in various cancer types. Although TROP2-targeting therapy is currently attracting attention, little is known about TROP2 expression in thymic carcinoma. Methods: TROP2 gene expression in thymic epithelial tumors was analyzed using RNA-sequencing (RNA-seq) data for 122 cases obtained from The Cancer Genome Atlas. Immunohistochemistry (IHC) staining with anti-TROP2 antibody (SP295) was performed in 26 cases of thymic carcinoma tissues surgically resected at Juntendo University. Results: RNA-seq data analysis from The Cancer Genome Atlas revealed that TACSTD2 (gene encoding TROP2) expression was significantly higher in thymic carcinoma than in thymoma (adjusted p = 6.64e-05). There was also a trend of increasing expression in the order of thymoma type B1, B2, B3, and thymic carcinoma. As for IHC in thymic carcinoma, TROP2 expression was localized to the membrane of cancer cells. Intensity 0, 1, and 2 was observed in six (23.1%), 11 (42.3%), and nine (34.6%) cases, respectively, leading to TROP2 positivity in 20 cases (76.9%). The median proportion of TROP2-positive tumor cells and the median H-score were 25.0% (range: 0%-100%) and 25.0 (range: 0-200), respectively. No relevant factors were identified in the analysis of TROP2 expression and patient background. Although not significant, high TROP2 expression (H-score ≥ 50) tended to be associated with shorter survival. Conclusions: TROP2 expression in thymic carcinoma was confirmed by both RNA-seq and IHC, with high expression observed in IHC for intensity (76.9%) and proportion. TROP2 could be a potential target in thymic carcinoma.

Risk and survival of patients with non-small cell lung cancer and pre-existing autoimmune disorders receiving immune checkpoint blockade therapy: Survival analysis with inverse probability weighting from a nationwide, multi-institutional, retrospective study (NEJ047).

BACKGROUND: The risk and survival of patients with non-small cell lung cancer (NSCLC) with pre-existing autoimmune disorders (AIDs) receiving immune checkpoint blockade (ICB) therapy have not been clearly established. PATIENTS AND METHODS: This multi-institutional, retrospective cohort study was conducted in collaboration with 20 centers in Japan. RESULTS: In total, 229 patients with advanced or recurrent NSCLC and pre-existing AID, with or without ICB treatment from January 2010-February 2020, were included and analyzed. Among 69 patients who received ICB, 2 received two lines of ICBs with a total of 71 ICB treatments; 57 (80.3 %) and 14 (19.7 %) patients received ICB monotherapy and combination therapy, respectively. AID flares were observed in 18 patients (25.4 %, 95 % confidence interval [CI], 15.8-37.1 %) receiving ICB. AID exacerbations were more likely when NSCLC was diagnosed less than 1 year after the AID diagnosis (odds ratio 5.26 [95 % CI, 1.40-21.61]; P = 0.016). Immune-related adverse events were observed in 32 patients (45.1 %, 95 % CI, 33.2-57.3 %); 17 had grade 3 or higher. The safety profile of combination immunotherapy was not significantly different from that of the monotherapy. After inverse probability weighting, the use of ICB prolonged survival (hazard ratio 0.43 [95 % CI, 0.26-0.70]; P = 0.0006). CONCLUSIONS: These findings revealed a novel risk factor for AID flares following ICB treatment, that is the diagnosis of NSCLC within 1 year of AID diagnosis, and showed that ICBs may improve survival in this population. These results support the utilization of ICB in patients with NSCLC and pre-existing AID.

Effects of weight loss rate on myostatin and follistatin dynamics in patients with obesity.

Background: Exercise-induced cytokines involved in controlling body composition include myostatin (MST) and follistatin (FST), both of which are influenced by physical activity. This study investigated changes in body composition and physical activity during a weight loss program, as well as the impact on serum MST and FST levels at various weight loss rates. Methods: A total of 126 patients with obesity who completed a 6-month weight loss program were divided into three groups based on weight loss rate (%): low (< 3%), middle (3-10%), and high (≥10%). The International Physical Activity Questionnaire was used for assessing physical activity, whereas dual X-ray absorptiometry was used to determine body composition. Serum MST and FST levels were measured using the enzyme-linked immunosorbent assay. Results: The middle and high groups showed a significant decrease in percent body fat and a significant increase in percent lean body mass and physical activity. Serum MST levels increased significantly in all three groups, although FST levels reduced significantly only in the middle group. After adjusting for sex and body composition, changes in peak oxygen intake (ß = -0.359) and serum FST levels (ß = -0.461) were identified as independent factors for the change in MST levels in the low group. Sex (ß = -0.420) and changes in MST levels (ß = -0.525) were identified as independent factors for the change in serum FST levels in the low group, whereas in the high group, sitting time (ß = -0.600) during the weight loss program was identified as an independent factor for change in serum FST levels. Conclusion: Serum MST levels in patients with obesity increased significantly following the weight loss program, independent of weight loss rate. In contrast, serum FST levels reduced significantly only in the 3-10% weight loss group. These findings indicate that MST and FST secretion dynamics may fluctuate in response to physical activity, while also reflecting feedback regulation of body composition and metabolism during weight reduction.

A 53-year-old Man with Idiopathic Bilateral Chylothorax Refractory to Lymphaticovenular Anastomosis: A Case Report.

A 53-year-old man with chronic dyspnea and bilateral pleural effusion was subsequently diagnosed with idiopathic chylothorax. Lymphatic scintigraphy confirmed lymphatic fluid leakage at the left venous angle, prompting management with lymphaticovenular anastomosis (LVA). Although the left pleural effusion was controlled, the right pleural effusion continued to increase, resulting in bilateral leg lymphedema that was refractory to LVA. Approximately three years and three months after the presentation, the patient succumbed to CO2 narcosis and renal failure. It is crucial to study additional cases in order to uncover new causes and develop pathology-based treatments for this condition.

A case of middle-aged central sleep apnea due to Joubert syndrome with different treatment effects of oxygen and acetazolamide.

We report a case of severe central sleep apnea incidentally diagnosed during polysomnography for suspected obstructive sleep apnea. Characteristic clinical features included episodic hyperventilation followed by apnea from hypocapnia, which did not follow a Cheyne-Stokes pattern. Combined with the identification of cerebellar and brainstem malformations known as the "molar tooth sign" on a brain MRI, developmental delay, and motor coordination problems, Joubert syndrome (a congenital disease) was first diagnosed at the age of 50 years. Central apneas were also observed during wakefulness, although not continuously. During sleep, continuous positive airway pressure and adaptive servo-ventilation were ineffective at the referring clinic and at our hospital. Supplemental oxygen decreased the frequency of central apneas and significantly shortened the duration of each central sleep apnea compared with room air. In contrast, the opposite response was observed with acetazolamide administration.

The inciting factor for bradycardia in COVID-19 patients: a potential harm of steroid treatment.

Background: The coronavirus disease 2019 (COVID-19) is a condition caused by the novel severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2). Although several papers have reported the presence bradycardia in patients with COVID-19, the pathophysiology behind this remains unclear. Therefore, we investigated the presence of bradycardia in patients with COVID-19. Methods: We conducted a retrospective cohort study in a total of 153 patients with COVID-19 and 90 patients with influenza who were hospitalized in our hospital from January 1, 2020 to December 31, 2021 and from January 1, 2014 to December 31, 2021, respectively. Data were collected from patient medical records, which included sex, age, duration of hospitalization, pneumonia complications, supplemental oxygen therapy, antiviral treatment, past history, and vital signs. Results: After adjustment, the incidence of bradycardia and steroid use in patients with COVID-19 were significantly higher than those in patients with influenza (P=0.007 and P<0.001, respectively). We then compared the detailed characteristics of patients with COVID-19 to evaluate risk factors for bradycardia. Multivariate logistic regression analysis revealed that steroid use was significantly related to bradycardia [P=0.031; odds ratio (OR): 3.67; 95% confidence interval (CI): 1.12-11.96]. Overall, results showed a higher incidence of bradycardia in patients with COVID-19 who received steroid treatment. Conclusions: Our results showed that steroid treatment in patients with COVID-19 may be associated with the incidence of bradycardia.

Multicenter Pharmacokinetic and Pharmacodynamic Study of Pembrolizumab for Non-small-Cell Lung Cancer in Patients Aged 75 Years and Older.

Pembrolizumab is a major treatment for recurrent or advanced non-small-cell lung cancer (NSCLC). However, data on its use and pharmacokinetics (PK) in older patients are limited. This open-label, multicenter, observational study evaluated real-world data on the safety, efficacy, and PK of pembrolizumab in older patients with NSCLC. In 99 patients aged ≥75 years, PK was determined by liquid chromatography-mass spectrometry on pretreatment samples. Performance status (PS), geriatric assessment (GA), overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) were evaluated. The median age was 78 (75-87) years. PS was 2-3 in 14 patients. The median ORR, PFS, and OS were 47.5%, 8.0, and 20.5 months, respectively. Although PK and ORR were not significantly associated, patients with the lowest Cycle 1-trough quartile (Q1) experienced poorer PFS (Q1 vs. Q2-4; 3.4 vs. 11.8 months, P = 0.006) and OS (Q1 vs. Q2-4; 9.9 vs. 21.7 months, P = 0.005) than in other quartiles overall, and even in the PD-L1 ≥50% subset (PFS, Q1 vs. Q2-4; 4.1 vs. 14.7 months, P = 0.005; OS, Q1 vs. Q2-4; 9.4 vs. 22.1 months, P = 0.010). The Q1 subgroup was characterized by poor PS and lower albumin, and more frequent "weight loss ≥ 10%" on the GA. Pembrolizumab therapy had similar PK and efficaciousness in older as well as younger patients. In patients with PS ≥2, low albumin, and vulnerable GA, early increases in PK levels are less likely, potentially diminishing efficacy even when PD-L1 ≥50%.

Acute exacerbation predicting poor outcomes in idiopathic interstitial pneumonia and advanced lung cancer patients undergoing cytotoxic chemotherapy.

Effective treatment for advanced lung cancer and idiopathic interstitial pneumonia (IIP) remains an unmet medical need. The relationship between chemotherapy's effectiveness in advanced lung cancer and the risk of acute exacerbation of IIP is poorly investigated. There is limited evidence that patients who experience an acute exacerbation of IIPs during cytotoxic chemotherapy have poorer outcomes than those who do not. Among 1004 patients with advanced lung cancer and IIPs enrolled in our published multi-centre retrospective study from 110 Japanese institutions, 708 patients (male: female, 645:63; mean age, 70.4) received first-line chemotherapy. The occurrence of chemotherapy-triggered acute exacerbations of IIPs and overall survival (OS) were analysed. The OS between groups of patients with and without the occurrence of acute exacerbation was compared at four landmark time points (30, 60, 90, and 120 days), starting from the first-line chemotherapy, using the landmark method. The incidence of acute exacerbation in patients who received first-line chemotherapy with small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) was more frequent in NSCLC patients than in SCLC (4.2% vs 12.6%; odds ratio [OR]: 3.316; 95% confidence interval [CI] 1.25-8.8). Median survival time was 9.9 months (95% CI 9.2-10.7). Patients who experienced acute exacerbation had significant worse survival outcomes than those who did not at various time points (30 days, hazard ratio [HR]: 5.191, 95% CI 2.889-9.328; 60 days, HR: 2.351, 95% CI 1.104-5.009; 90 days, HR: 2.416, 95% CI 1.232-4.739; and 120 days, HR: 2.521, 95% CI 1.357-4.681). Acute exacerbation during first-line chemotherapy can predict poor survival.Trial Registration number: UMIN000018227.

Suppression of Type I Interferon Signaling in Myeloid Cells by Autoantibodies in Severe COVID-19 Patients.

PURPOSE: Auto-antibodies (auto-abs) to type I interferons (IFNs) have been identified in patients with life-threatening coronavirus disease 2019 (COVID-19), suggesting that the presence of auto-abs may be a risk factor for disease severity. We therefore investigated the mechanism underlying COVID-19 exacerbation induced by auto-abs to type I IFNs. METHODS: We evaluated plasma from 123 patients with COVID-19 to measure auto-abs to type I IFNs. We performed single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells from the patients with auto-abs and conducted epitope mapping of the auto-abs. RESULTS: Three of 19 severe and 4 of 42 critical COVID-19 patients had neutralizing auto-abs to type I IFNs. Patients with auto-abs to type I IFNs showed no characteristic clinical features. scRNA-seq from 38 patients with COVID-19 revealed that IFN signaling in conventional dendritic cells and canonical monocytes was attenuated, and SARS-CoV-2-specific BCR repertoires were decreased in patients with auto-abs. Furthermore, auto-abs to IFN-α2 from COVID-19 patients with auto-abs recognized characteristic epitopes of IFN-α2, which binds to the receptor. CONCLUSION: Auto-abs to type I IFN found in COVID-19 patients inhibited IFN signaling in dendritic cells and monocytes by blocking the binding of type I IFN to its receptor. The failure to properly induce production of an antibody to SARS-CoV-2 may be a causative factor of COVID-19 severity.

Lymphangioleiomyomatosis as a potent lung cancer risk factor: Insights from a Japanese large cohort study.

BACKGROUND AND OBJECTIVE: Lymphangioleiomyomatosis (LAM) is a rare neoplastic disease associated with the functional tumour suppressor genes TSC1 and TSC2 and causes structural destruction in the lungs, which could potentially increase the risk of lung cancer. However, this relationship remains unclear because of the rarity of the disease. METHODS: We investigated the relative risk of developing lung cancer among patients diagnosed with LAM between 2001 and 2022 at a single high-volume centre in Japan, using data from the Japanese Cancer Registry as the reference population. Next-generation sequencing (NGS) was performed in cases where tumour samples were available. RESULTS: Among 642 patients diagnosed with LAM (sporadic LAM, n = 557; tuberous sclerosis complex-LAM, n = 80; unclassified, n = 5), 13 (2.2%) were diagnosed with lung cancer during a median follow-up period of 5.13 years. All patients were female, 61.5% were never smokers, and the median age at lung cancer diagnosis was 53 years. Eight patients developed lung cancer after LAM diagnosis. The estimated incidence of lung cancer was 301.4 cases per 100,000 person-years, and the standardized incidence ratio was 13.6 (95% confidence interval, 6.2-21.0; p = 0.0008). Actionable genetic alterations were identified in 38.5% of the patients (EGFR: 3, ALK: 1 and ERBB2: 1). No findings suggested loss of TSC gene function in the two patients analysed by NGS. CONCLUSION: Our study revealed that patients diagnosed with LAM had a significantly increased risk of lung cancer. Further research is warranted to clarify the carcinogenesis of lung cancer in patients with LAM.

Hyperprogressive disease under anti-PD-1 rechallenge after initial response to anti-PD-1 treatment for non-small cell lung cancer: a case report.

Background: Hyperprogressive disease is an unexpected response pattern observed in immune checkpoint therapy and associated with poor prognosis. The rechallenge of programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) inhibitors can be a treatment option in non-small cell lung cancer (NSCLC) patients who once responded to them. Here, we reported the hyperprogressive phenomenon after PD-1/PD-L1 rechallenge in a patient with NSCLC. Case Description: This case report described a patient with recurrent large cell lung cancer undergoing hyperprogressive disease with pleural and pericardial dissemination shortly after the pembrolizumab rechallenge, although he had a favorable response to the initial pembrolizumab treatment. A lower ratio of CD8+ T cells to Foxp3+ regulatory T cells was distributed in the cell blocks of pleural and pericardial effusion which were taken after hyperprogressive disease, compared to the resected tumor microenvironment. Neutrophil-to-lymphocyte ratio (NLR) was lower in peripheral blood when the disease was controlled and it rose when the disease progressed. Notably, NLR increased dramatically when hyperprogression occurred. Conclusions: For the first time, we reported that a patient who showed a favorable response to initial anti-PD-1 treatment underwent hyperprogressive disease when rechallenging the same immunotherapy. The increased Foxp3+ regulatory T cells in the tumor microenvironment and the longitudinal change of NLRs in peripheral blood were suggested to be associated with hyperprogressive disease.