Next-generation proteomics of serum extracellular vesicles combined with single-cell RNA sequencing identifies MACROH2A1 associated with refractory COVID-19.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic is widespread; however, accurate predictors of refractory cases have not yet been established. Circulating extracellular vesicles, involved in many pathological processes, are ideal resources for biomarker exploration. METHODS: To identify potential serum biomarkers and examine the proteins associated with the pathogenesis of refractory COVID-19, we conducted high-coverage proteomics on serum extracellular vesicles collected from 12 patients with COVID-19 at different disease severity levels and 4 healthy controls. Furthermore, single-cell RNA sequencing of peripheral blood mononuclear cells collected from 10 patients with COVID-19 and 5 healthy controls was performed. RESULTS: Among the 3046 extracellular vesicle proteins that were identified, expression of MACROH2A1 was significantly elevated in refractory cases compared to non-refractory cases; moreover, its expression was increased according to disease severity. In single-cell RNA sequencing of peripheral blood mononuclear cells, the expression of MACROH2A1 was localized to monocytes and elevated in critical cases. Consistently, single-nucleus RNA sequencing of lung tissues revealed that MACROH2A1 was highly expressed in monocytes and macrophages and was significantly elevated in fatal COVID-19. Moreover, molecular network analysis showed that pathways such as "estrogen signaling pathway," "p160 steroid receptor coactivator (SRC) signaling pathway," and "transcriptional regulation by STAT" were enriched in the transcriptome of monocytes in the peripheral blood mononuclear cells and lungs, and they were also commonly enriched in extracellular vesicle proteomics. CONCLUSIONS: Our findings highlight that MACROH2A1 in extracellular vesicles is a potential biomarker of refractory COVID-19 and may reflect the pathogenesis of COVID-19 in monocytes.

Quantitative evaluation of emphysema for predicting immunotherapy response in patients with advanced non-small-cell lung cancer.

The efficacy of immune checkpoint inhibitors (ICIs) in patients with advanced non-small-cell lung cancer (NSCLC) might depend on the presence of emphysema, but this association is not established. We aimed to investigate if quantitively and automatically measuring emphysema can predict the effect of ICIs. We retrospectively analyzed 56 patients with NSCLC who underwent immunotherapy at our hospital. We used the Goddard scoring system (GS) to evaluate the severity of emphysema on baseline CT scans using three-dimensional image analysis software. The emphysema group (GS ≥ 1) showed better progression-free survival (PFS) than the non-emphysema group (GS = 0) (6.5 vs. 2.3 months, respectively, p < 0.01). Multivariate analyses revealed that good performance status, GS of ≥ 1, and high expression of PD-L1 were independently associated with better PFS, while smoking status was not. In conclusion, quantitative evaluation of emphysema can be an objective parameter for predicting the therapeutic effects of ICIs in patients with NSCLC. Our findings can be used to generate hypotheses for future studies.

COVID-19 in a patient with sporadic lymphangioleiomyomatosis awaiting lung transplantation.

Coronavirus disease 2019 (COVID-19) is an emerging viral disease with a mortality that depends on the individual's condition. Underlying comorbidities are major risk factors for COVID-19-related morbidity and mortality. However, information regarding the clinical course of COVID-19 in patients with rare respiratory system diseases is lacking. Here, we present a case of severe COVID-19 in a patient with advanced sporadic lymphangioleiomyomatosis (LAM) who was awaiting lung transplantation. She experienced a marked worsening of her respiratory status despite the limited size of the infiltrations seen on chest computed tomography. She responded to treatment with dexamethasone and remdesivir, and did not require mechanical ventilation. She recovered her pre-COVID-19 respiratory function. This case illustrates that patients with severe lung parenchymal destruction due to advanced LAM are at risk of worsening hypoxemia, but may not have a bad outcome if managed appropriately. Prevention and early diagnosis of COVID-19 are crucial in patients with advanced LAM. Future studies are needed to improve understanding of the clinical features and optimal treatment of COVID-19 in patients with LAM.

Extracellular Water-to-total Body Water Ratio as an Objective Biomarker for Frailty in Lung Cancer Patients.

BACKGROUND/AIM: Our previous study revealed the association between extracellular water-to-total body water ratio (ECW/TBW) and the therapeutic durability of chemotherapy and/or immune checkpoint inhibitors in advanced lung cancer. We retrospectively examined the usefulness of ECW/TBW in detecting frailty compared to other bioelectrical impedance (BIA) parameters in a larger number of patients. PATIENTS AND METHODS: Lung cancer patients underwent BIA before anti-cancer therapy at our hospital between June 1, 2018 and July 31, 2020. RESULTS: Of 99 patients, 26 were assigned to ECW/TBW≥0.4 (higher group: HG) and 57 to ECW/TBW<0.4 (lower group: LG). ECW/TBW increased significantly with performance deterioration and ageing. HG patients had significantly shorter time-to-treatment failure (TTF) than LG patients. In patients with performance status 0-1, those in the HG had shorter TTF than those in the LG. ECW/TBW was the only independent predictor of TTF according to multivariate analysis. CONCLUSION: ECW/TBW is an objective biomarker for detecting frailty among lung cancer patients.

Transbronchial Cryobiopsy for Miliary Tuberculosis Mimicking Hypersensitivity Pneumonitis.

Miliary tuberculosis is a potentially lethal type of tuberculosis that results from the hematogenous dissemination of Mycobacterium tuberculosis bacilli. We herein describe the case of a 34-year-old man that presented with a one-month history of cough and fever, while his sputum smear results were negative. Chest computed tomography revealed bilateral centrilobular ground-glass opacification (GGO), suggestive of hypersensitivity pneumonitis; thus, bronchoscopy was performed. Cryobiopsy specimens revealed necrotic granulomas. A re-examination of sputum after bronchoscopy identified Mycobacterium tuberculosis, and miliary tuberculosis was diagnosed. A cryobiopsy might be useful for diagnosing miliary tuberculosis pathologically, particularly when miliary nodules may be masked by GGO.

Combined small cell lung carcinoma harboring ALK rearrangement: A case report and literature review.

Combined small cell lung cancer (c-SCLC) is a relatively rare subtype of SCLC and is defined by the combination of SCLC and any elements of non-small cell carcinoma (NSCLC). Standard chemotherapy for patients with c-SCLC has not yet been established. Gene mutations such as epidermal growth factor receptor (EGFR) mutations may be detected in patients with c-SCLC. However, little is known about anaplastic lymphoma kinase (ALK) rearrangement in c-SCLC patients. Here, we report a young female patient who was successfully treated with alectinib for ALK-positive c-SCLC after failure of immunochemotherapy for SCLC and cytotoxic chemotherapy for adenocarcinoma. Moreover, we performed a literature review of EGFR- or ALK-positive c-SCLC patients. Our report suggests that ALK testing may be justified in patients with SCLC that contain an adenocarcinoma component. KEY POINTS: SIGNIFICANT FINDINGS OF THE STUDY: • This is the first report describing the treatment course comprising immunochemotherapy and ALK-TKI in a patient with c-SCLC harboring ALK rearrangement. WHAT THIS STUDY ADDS: • Our case and literature review suggest that although ALK mutation is rare in patients with c-SCLC, its identification and treatment with ALK-TKIs may contribute to clinical benefits.

The Association Between Extracellular Water-to-Total Body Water Ratio and Therapeutic Durability for Advanced Lung Cancer.

BACKGROUND/AIM: Extracellular water-to-total body water ratio (ECW/TBW) measured by bioelectrical impedance analysis (BIA) reportedly predicts clinical outcomes of various diseases. The aim of this retrospective study was to examine the association between ECW/TBW and therapeutic durability of chemotherapy and/or immune checkpoint inhibitors in advanced lung cancer. PATIENTS AND METHODS: Patients with advanced lung cancer underwent BIA before chemotherapy and/or treatment with immune checkpoint inhibitors at our hospital between June 2018 and November 2019. RESULTS: Of 75 patients, 18 with ECW/TBW ≥0.4 were assigned to the overhydrated group (OH-G) and 57 patients ECW/TBW <0.4 were assigned to the non-overhydrated group (NOH-G). The median time-to-treatment failure was significantly shorter in the OH-G than in the NOH-G (p=0.003). Multivariate analysis revealed that ECW/TBW ≥0.4 predicted treatment failure [hazard ratio (HR)=2.508, 95% confidence interval (CI)=1.19-5.27; p=0.01]. CONCLUSION: The ECW/TBW may be an objective parameter for predicting therapeutic durability in advanced lung cancer.

Safety and efficacy of afatinib for the treatment of non-small-cell lung cancer following osimertinib-induced interstitial lung disease: A retrospective study.

Background Osimertinib is one of the first-line treatments for advanced non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations. However, the occurrence rate of osimertinib-induced interstitial lung disease (ILD) is particularly high in Japanese patients and little information on subsequent cancer treatment options after recovery from osimertinib-induced ILD is currently available. Thus, this study aims to determine the safety and efficacy of afatinib for the treatment of NSCLC following osimertinib-induced ILD. Methods We retrospectively investigated the clinical courses of all NSCLC patients with EGFR mutations at our facility between August 2018 and September 2019, who received osimertinib as first-line treatment and were subsequently treated with afatinib after developing osimertinib-induced ILD. Results Forty-two patients received osimertinib treatment at our facility during the study period, and four patients received afatinib after developing osimertinib-induced ILD. All events of ILD improved either spontaneously or with steroid therapy before the initiation of afatinib. For the four patients who were retrospectively reviewed, the overall response rate to afatinib therapy was 75%, and the disease control rate was 100%. During the study period, no ILD recurrence was observed in any of the four patients. Conclusions According to our study findings, afatinib treatment after osimertinib-induced ILD is considered safe and effective and it can be used as one of the treatment options for NSCLC following osimertinib-induced ILD.

Significance of Quantitative Interferon-gamma Levels in Non-small-cell Lung Cancer Patients' Response to Immune Checkpoint Inhibitors.

BACKGROUND/AIM: We aimed to study the association between the quantitative interferon-gamma (IFN-γ) levels and clinical outcomes in non-small-cell lung cancer (NSCLC) patients receiving immune checkpoint inhibitors (ICIs). PATIENTS AND METHODS: Sample collection for IFN-γ release assay (IGRA) was performed within 14 days before treatment (T1), on day 22±7 (T3), and on day 43±7 (T4). The stored specimens over 10 IU/ml in IGRA were re-examined using the dilution method (with saline as the dilution medium). The patients were classified into Lower and Higher groups by 7.06 IU/ml as a cut-off of IFN-γ levels at T1. RESULTS: Median progression-free survival in the Higher group was significantly longer than that in the Lower group. IFN-γ levels in the non-progression disease group were significantly higher than those in the progression disease group. IFN-γ levels at T1 in patients with immune-related adverse events were significantly lower compared to those at T3. CONCLUSION: IFN-γ could be a biomarker for NSCLC patients receiving ICIs.

Development of Severe Heart Failure in a Patient with Squamous Non-small-cell Lung Cancer During Nivolumab Treatment.

Cardiac side effects associated with immune checkpoint inhibitors (ICIs) are an uncommon but serious complication with a relatively high mortality. We experienced a case of cardiomyopathy induced by nivolumab. Echocardiography showed diffuse hypo-kinesis of the left ventricular cardiac wall and a significant decrease in the ejection fraction, like dilated cardiomyopathy. The myocardial biopsy showed non-inflammatory change; cardiac function gradually improved after treatment of acute heart failure without a corticosteroid. Although non-inflammatory left ventricular dysfunction induced by ICIs is rare, it is a reported cardiovascular toxicity. Physicians should consider this complication when treating patients with ICIs for malignant diseases.

Invasive Tracheobronchial Aspergillosis with Bronchial Ulcers Complicated by Nontuberculous Mycobacterial Disease.

Invasive tracheobronchial aspergillosis (ITBA) complicated by nontuberculous mycobacteria (NTM) is rare. An 88-year-old man was admitted for hemoptysis. Bronchoscopy revealed bronchial ulcers, and a tissue biopsy showed Aspergillus fumigatus. He was diagnosed with ITBA, which improved with voriconazole. During treatment, infiltrative shadows appeared in his lungs, and bronchoscopy was performed once again. A non-necrotic epithelioid granuloma and Mycobacterium intracellulare were detected in the biopsy specimen. He was diagnosed with NTM disease. It is important to note that tracheobronchial ulcers may cause hemoptysis and to identify the etiology and treat it appropriately when multiple bacteria are found.

The Levels of Interferon-gamma Release as a Biomarker for Non-small-cell Lung Cancer Patients Receiving Immune Checkpoint Inhibitors.

BACKGROUND/AIM: The present study aimed to prospectively examine the usefulness of interferon-gamma (IFN-γ) release (IGR) as a biomarker in non-small-cell lung cancer patients receiving immune checkpoint inhibitor treatment (ICI-Tx). PATIENTS AND METHODS: IGR was measured using enzyme-linked immunosorbent assay at four time points: within 14 days before ICI-Tx (T1), and 8±3 (T2), 22±7 (T3), and 43±7 (T4) days after ICI-Tx. RESULTS: Twenty-nine patients were divided into three groups based on IFN-γ levels in the IGR-positive control: Group-1 (n=8) with <10 IU/ml at T1, Group-2 (n=12) with a decrease in IFN-γ levels to <10 IU/ml at T3 and/or T4, and Group-3 (n=9) without changes in IFN-γ levels. Early progression and ICI-induced interstitial pneumonitis were frequently observed in Group-1 and Group-2, respectively. Group-3 exhibited more treatment cycles than the other groups. All three groups showed clear differences in clinical outcomes. CONCLUSION: IFN-γ levels could be a biomarker for ICI-Tx.

Comparison of the Utilities of Cryobiopsy and Forceps Biopsy for Peripheral Lung Cancer.

BACKGROUND/AIM: This study aimed to compare the efficacies of cryobiopsy and forceps biopsy for peripheral lung cancer detection. PATIENTS AND METHODS: A retrospective review of peripheral lung cancer cases between December 2017 and April 2019 was conducted. Forceps biopsy was performed followed by cryobiopsy using a guide sheath (GS). Diagnostic yields were compared between cryobiopsy and forceps biopsy. RESULTS: A total of 53 lung cancer lesions were evaluated. The diagnostic yields of forceps biopsy and cryobiopsy were 86.8% and 81.1%, respectively. Univariate and multivariate analyses indicated that cryobiopsy with a GS was significantly associated with increased diagnostic yield (odds ratio(OR)=11.6; p=0.044). Among the four patients who tested positive on cryobiopsy and negative on forceps biopsy, one had diffused pulmonary metastases and the others showed intratumoural air bronchograms. CONCLUSION: Cryobiopsy using a GS can significantly increase diagnostic yield and help identify lesions with intratumoural air bronchograms and external wall lesions.