Long COVID symptoms after 8-month recovery: persistent static lung hyperinflation associated with small airway dysfunction.

BACKGROUND: Limited research has investigated the relationship between small airway dysfunction (SAD) and static lung hyperinflation (SLH) in patients with post-acute sequelae of COVID-19 (PASC) especially dyspnea and fatigue. METHODS: 64 patients with PASC were enrolled between July 2020 and December 2022 in a prospective observational cohort. Pulmonary function tests, impulse oscillometry (IOS), and symptom questionnaires were performed two, five and eight months after acute infection. Multivariable logistic regression models were used to test the association between SLH and patient-reported outcomes. RESULTS: SLH prevalence was 53.1% (34/64), irrespective of COVID-19 severity. IOS parameters and circulating CD4/CD8 T-cell ratio were significantly correlated with residual volume to total lung capacity ratio (RV/TLC). Serum CD8 + T cell count was negatively correlated with forced expiratory volume in the first second (FEV1) and forced vital capacity (FVC) with statistical significance. Of the patients who had SLH at baseline, 57% continued to have persistent SLH after eight months of recovery, with these patients tending to be older and having dyspnea and fatigue. Post-COVID dyspnea was significantly associated with SLH and IOS parameters R5-R20, and AX with adjusted odds ratios 12.4, 12.8 and 7.6 respectively. SLH was also significantly associated with fatigue. CONCLUSION: SAD and a decreased serum CD4/CD8 ratio were associated with SLH in patients with PASC. SLH may persist after recovery from infection in a substantial proportion of patients. SAD and dysregulated T-cell immune response correlated with SLH may contribute to the development of dyspnea and fatigue in patients with PASC.

Real-world osimertinib pretreatment experience in patients with epidermal growth factor receptor T790M mutation-positive locally advanced or metastatic non-small cell lung cancer.

Osimertinib has demonstrated efficacy in patients with epidermal growth factor receptor (EGFR) T790M-positive non-small cell lung cancer (NSCLC) in clinical trials. However, real-world data on its effectiveness remain scarce. Taiwanese patients with T790M-positive locally advanced or metastatic NSCLC and progressive disease following treatment with at least one EGFR tyrosine kinase inhibitor (TKI) were enrolled from the osimertinib early access program. Of the 419 patients (mean age, 63 years; female, 67%), 53% were heavily pretreated (≥ third-line [3L]), making osimertinib a fourth-line (4L) intervention. The median progression-free survival (PFS) was 10.5 months (95% confidence interval [CI]: 8.95-11.41); the 18-month PFS rate was 26.5%. The median overall survival (OS) was 19.0 months (95% CI: 16.30-20.95); the 24-month OS rate was 40.9%. The objective response rate was 32.46%, and the disease control rate was 86.38%. The median time to treatment discontinuation of osimertinib monotherapy was 11.9 months (95% CI: 10.49-13.11). Subgroup analyses of median PFS and OS in the chemotherapy combination group vs. the osimertinib monotherapy group yielded no difference. Central nervous system (CNS) metastasis, number of prior lines of therapy, and types of initial EGFR-TKIs did not significantly impact outcomes. The median PFS values were 9.0 (95% CI: 5.18-11.34) and 10.9 (95% CI: 9.18-11.90) months with and without CNS metastasis, respectively, and 10.8 (95% CI: 8.59-12.69), 13.6 (95% CI: 10.89-16.3), and 9.2 (95% CI: 7.8-10.62) months for second-line (2L), 3L, and ≥4L therapy, respectively. In patients who received osimertinib as 2L therapy, the median PFS values in response to prior afatinib, erlotinib and gefitinib treatment were 11.2 (95% CI: 4.85-4.79), 10.5 (95% CI: 8.59-20.26) and 8.7 (95% CI: 7.21-16.79) months, respectively. Overall, real-world data from Taiwan support the clinical benefits of osimertinib in EGFR T790M -positive NSCLC.

Efficacy and safety of tepotinib in Asian patients with advanced NSCLC with MET exon 14 skipping enrolled in VISION.

BACKGROUND: Tepotinib, a MET inhibitor approved for the treatment of MET exon 14 (METex14) skipping NSCLC, demonstrated durable clinical activity in VISION (Cohort A + C; N = 313): objective response rate (ORR) 51.4% (95% CI: 45.8, 57.1); median duration of response (mDOR) 18.0 months (95% CI: 12.4, 46.4). We report outcomes in Asian patients from VISION (Cohort A + C) (cut-off: November 20, 2022). METHODS: Patients with advanced METex14 skipping NSCLC, detected by liquid or tissue biopsy, received tepotinib 500 mg (450 mg active moiety) once daily. PRIMARY ENDPOINT: objective response (RECIST 1.1) by independent review. Secondary endpoints included: DOR, progression-free survival (PFS), overall survival (OS), safety, and health-related quality of life (HRQoL). RESULTS: Across treatment lines in 106 Asian patients (39.6% female, 43.4% smoking history, 79.2% adenocarcinoma, 47.2% treatment-naive), ORR was 56.6% (95% CI: 46.6, 66.2), mDOR 18.5 months (10.4, ne), mPFS 13.8 months (10.8, 22.0), and mOS 25.5 months (19.3, 36.4). Consistent efficacy observed, regardless of baseline characteristics. HRQoL remained stable during treatment. Treatment-related adverse events (TRAEs) occurred in 95.3% of patients (39.6% Grade ≥3). Most common TRAEs: peripheral edema (62.3%), creatinine increase (38.7%). CONCLUSIONS: Tepotinib demonstrated robust and durable efficacy, with a manageable safety profile, in Asian patients with METex14 skipping NSCLC. CLINICAL TRIAL REGISTRATION: NCT02864992.

Influence of vaccination on critical COVID-19 patients with acute respiratory failure: a retrospective cohort study.

BACKGROUND: Despite vaccines' effectiveness in reducing COVID-19 infection rates and disease severity, their impact on critical patients presenting with acute respiratory failure is elusive. The aim of this study was to further investigate the influence of vaccination on mortality rates among severely ill COVID-19 patients experiencing acute respiratory failure. METHODS: This retrospective cohort study was carried out at a tertiary medical center in Taiwan. From April to September 2022, patients who tested positive for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) through reverse transcription polymerase chain reaction (RT-PCR) and subsequently experienced acute respiratory failure were included in the study. Baseline characteristics, including vaccination history, along with information regarding critical illness and clinical outcomes, were gathered and compared between patients who received the vaccine and those who did not. RESULTS: A total of 215 patients with COVID-19 exhibiting acute respiratory failure, as confirmed via RT‒PCR, were included in the analysis. Of this cohort, sixty-six (30.7%) patients died within 28 days. Neither administration of the vaccine nor achievement of primary series vaccination status had a significantly different effect on 28 day mortality, number of viral shedding events, acute respiratory distress syndrome (ARDS) incidence or other clinical outcomes. Patients who received the booster vaccine and completed the primary series showed a tendency of increased 28 days of ventilator-free status, though this difference was not statistically significant (p = 0.815). CONCLUSIONS: Vaccination status did not significantly influence mortality rates, the occurrence of ARDS, or the viral shedding duration in COVID-19 patients with acute respiratory failure.

Dynamic immune signatures of patients with advanced non-small-cell lung cancer for infection prediction after immunotherapy.

Background: Pulmonary infections are a crucial health concern for patients with advanced non-small-cell lung cancer (NSCLC). Whether the clinical outcome of pulmonary infection is influenced by immunotherapy(IO) remains unclear. By evaluating immune signatures, this study investigated the post-immunotherapy risk of pulmonary infection in patients with lung cancer and identified circulating biomarkers that predict post-immunotherapy infection. Methods: Blood specimens were prospectively collected from patients with NSCLC before and after chemotherapy(C/T) and/or IO to explore dynamic changes in immune signatures. Real-world clinical data were extracted from medical records for outcome evaluation. Mass cytometry and ELISA were employed to analyze immune signatures and cytokine profiles to reveal potential correlations between immune profiles and the risk of infection. Results: The retrospective cohort included 283 patients with advanced NSCLC. IO was associated with a lower risk of pneumonia (odds ratio=0.46, p=0.012). Patients receiving IO and remained pneumonia-free exhibited the most favorable survival outcomes compared with those who received C/T or developed pneumonia (p<0.001). The prospective cohort enrolled 30 patients. The proportion of circulating NK cells significantly increased after treatment in IO alone (p<0.001) and C/T+IO group (p<0.01). An increase in cell densities of circulating PD-1+CD8+(cytotoxic) T cells (p<0.01) and PD-1+CD4+ T cells (p<0.01) were observed in C/T alone group after treatment. In IO alone group, a decrease in cell densities of TIM-3+ and PD-1+ cytotoxic T cells (p<0.05), and PD-1+CD4+ T cells (p<0.01) were observed after treatment. In C/T alone and C/T+IO groups, cell densities of circulating PD-1+ cytotoxic T cells significantly increased in patients with pneumonia after treatment(p<0.05). However, in IO alone group, cell density of PD-1+ cytotoxic T cells significantly decreased in patients without pneumonia after treatment (p<0.05). TNF-α significantly increased after treatment with IO alone (p<0.05) but decreased after C/T alone (p<0.01). Conclusions: Our results indicate that the incorporation of immunotherapy into treatment regimens may potentially offer protective effects against pulmonary infection. Protective effects are associated with reduction of exhausted T-cells and augmentation of TNF-α and NK cells. Exhausted T cells, NK cells, and TNF-α may play crucial roles in immune responses against infections. These observations highlight the potential utility of certain circulating biomarkers, particularly exhausted T cells, for predicting post-treatment infections.

Detecting circulating microbial cell-free DNA by next-generation sequencing in patients with Mycobacterium avium complex-lung disease: A pilot study.

Objectives: Determining a diagnosis for non-Tuberculous mycobacterium (NTM)-lung disease (LD) remains difficult. The value of circulating cell-free DNA (cfDNA) secreted from microbes has been established in the detection of pathogens in septic patients. However, it is unknown whether NTM-derived cfDNA is detectable in plasma from patients with NTM-LD and whether this is associated with the disease status of NTM-LD, especially in patients with Mycobacterium avium complex (MAC)-LD. Materials and Methods: In this pilot study, from 2018 to 2019, we enrolled adult patients with MAC-LD at Taipei Veterans General Hospital in Taiwan for the detection of circulating cfDNA. We performed cfDNA extraction from plasma, next-generation sequencing (NGS) for nonhuman cfDNA, and sequence matching to a microbial database and then assessed the association between pathogen cfDNA and MAC-LD. Results: Two (40%) plasma samples from MAC-LD patients had detectable MAC-specific cfDNA, namely one instance of DNA polymerase III alpha subunit and one instance of ATP-binding cassette transporters permease. The plasma samples from the three other MAC-LD cases and the one tuberculosis control were negative for either NTM-derived cfDNA or tuberculosis-related cfDNA. In addition to MAC-specific cfDNA, Ralstonia solanacearum, Staphylococcus aureus, and Pasteurella multocida were the most observed bacteria in our patients. The two patients with MAC-cfDNA positivity yielded higher radiographic scores (P = 0.076) and presented a higher number of nonhuman reads than those without MAC-cfDNA positivity (P = 0.083). Conclusion: Using NGS method, we demonstrated MAC-cfDNA was detectable in patients with MAC-LD. Further large-scale research is warranted to assess the clinical value of detecting MAC-specific cfDNA in MAC-LD patients.

Clinical characteristics and outcomes among critically ill patients with cancer and COVID-19-related acute respiratory failure.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has affected individuals worldwide, and patients with cancer are particularly vulnerable to COVID-19-related severe illness, respiratory failure, and mortality. The relationship between COVID-19 and cancer remains a critical concern, and a comprehensive investigation of the factors affecting survival among patients with cancer who develop COVID-19-related respiratory failure is warranted. We aim to compare the characteristics and outcomes of COVID-19-related acute respiratory failure in patients with and without underlying cancer, while analyzing factors affecting in-hospital survival among cancer patients. METHODS: We conducted a retrospective observational study at Taipei Veterans General Hospital in Taiwan from May to September 2022, a period during which the omicron variant of the severe acute respiratory syndrome coronavirus 2 was circulating. Eligible patients had COVID-19 and acute respiratory failure. Clinical data, demographic information, disease severity markers, treatment details, and outcomes were collected and analyzed. RESULTS: Of the 215 enrolled critically ill patients with COVID-19, 65 had cancer. The patients with cancer were younger and had lower absolute lymphocyte counts, higher ferritin and lactate dehydrogenase (LDH) concentrations, and increased vasopressor use compared with those without cancer. The patients with cancer also received more COVID-19 specific treatments but had higher in-hospital mortality rate (61.5% vs 36%, P = 0.002) and longer viral shedding (13 vs 10 days, P = 0.007) than those without cancer did. Smoking [odds ratio (OR): 5.804, 95% confidence interval (CI): 1.847-39.746], elevated LDH (OR: 1.004, 95% CI: 1.001-1.012), vasopressor use (OR: 5.437, 95% CI: 1.202-24.593), and new renal replacement therapy (OR: 3.523, 95% CI: 1.203-61.108) were independent predictors of in-hospital mortality among patients with cancer and respiratory failure. CONCLUSION: Critically ill patients with cancer experiencing COVID-19-related acute respiratory failure present unique clinical features and worse clinical outcomes compared with those without cancer. Smoking, elevated LDH, vasopressor use, and new renal replacement therapy were risk factors for in-hospital mortality in these patients.

Clinical utility of immunohistochemical subtyping in patients with small cell lung cancer.

OBJECTIVES: Molecular subtyping of small cell lung cancer (SCLC) tumors based on the expression of four transcription factors (ASCL1, NEUROD1, POU2F3, and YAP1) using immunohistochemical (IHC) staining has recently emerged as a proposed approach. This study was aimed to examine this subtyping method in Asian patients with SCLC and investigate its correlation with treatment efficacy. MATERIALS AND METHODS: Seventy-two tumor samples from patients with SCLC, including de novo cases and those transformed from EGFR-mutant tumors, were analyzed. IHC staining was used to measure the expression of the four transcription factors and conventional SCLC markers. Subtypes were defined based on relative expression levels. The treatment response and outcome of patients receiving immune checkpoint inhibitors and chemotherapy were also reviewed. RESULTS: ASCL1 was the most common subtype, observed in 55.2 % of the samples, followed by NEUROD1 (26.9 %) and POU2F3 (9 %). No tumor exhibited predominant YAP1 positivity, while 41.8 % of the samples demonstrated positivity for two subtype markers. Approximately 50 % of the patients experienced a subtype switch after disease progression. Patients with the ASCL1/NEUROD1 (SCLC-A/N) subtype had similar progression-free survival (PFS) compared to non-SCLC-A/N patients after treatment with immune checkpoint inhibitors plus chemotherapy. Transformed SCLC patients had significantly worse PFS than de novo SCLC patients after chemoimmunotherapy. (2.1 vs. 5.4 months, P = 0.023) CONCLUSIONS: This study revealed the challenges associated with using IHC alone for molecular subtyping, highlighting the frequent co-expression of subtypes and temporal changes following treatment. Further research is warranted to explore the prognostic and therapeutic implications of IHC subtyping in patients with SCLC.

Low-dose CT screening among never-smokers with or without a family history of lung cancer in Taiwan: a prospective cohort study.

BACKGROUND: In Taiwan, lung cancers occur predominantly in never-smokers, of whom nearly 60% have stage IV disease at diagnosis. We aimed to assess the efficacy of low-dose CT (LDCT) screening among never-smokers, who had other risk factors for lung cancer. METHODS: The Taiwan Lung Cancer Screening in Never-Smoker Trial (TALENT) was a nationwide, multicentre, prospective cohort study done at 17 tertiary medical centres in Taiwan. Eligible individuals had negative chest radiography, were aged 55-75 years, had never smoked or had smoked fewer than 10 pack-years and stopped smoking for more than 15 years (self-report), and had one of the following risk factors: a family history of lung cancer; passive smoke exposure; a history of pulmonary tuberculosis or chronic obstructive pulmonary disorders; a cooking index of 110 or higher; or cooking without using ventilation. Eligible participants underwent LDCT at baseline, then annually for 2 years, and then every 2 years up to 6 years thereafter, with follow-up assessments at each LDCT scan (ie, total follow-up of 8 years). A positive scan was defined as a solid or part-solid nodule larger than 6 mm in mean diameter or a pure ground-glass nodule larger than 5 mm in mean diameter. Lung cancer was diagnosed through invasive procedures, such as image-guided aspiration or biopsy or surgery. Here, we report the results of 1-year follow-up after LDCT screening at baseline. The primary outcome was lung cancer detection rate. The p value for detection rates was estimated by the χ2 test. Univariate and multivariable logistic regression analyses were used to assess the association between lung cancer incidence and each risk factor. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of LDCT screening were also assessed. This study is registered with ClinicalTrials.gov, NCT02611570, and is ongoing. FINDINGS: Between Dec 1, 2015, and July 31, 2019, 12 011 participants (8868 females) were enrolled, of whom 6009 had a family history of lung cancer. Among 12 011 LDCT scans done at baseline, 2094 (17·4%) were positive. Lung cancer was diagnosed in 318 (2·6%) of 12 011 participants (257 [2·1%] participants had invasive lung cancer and 61 [0·5%] had adenocarcinomas in situ). 317 of 318 participants had adenocarcinoma and 246 (77·4%) of 318 had stage I disease. The prevalence of invasive lung cancer was higher among participants with a family history of lung cancer (161 [2·7%] of 6009 participants) than in those without (96 [1·6%] of 6002 participants). In participants with a family history of lung cancer, the detection rate of invasive lung cancer increased significantly with age, whereas the detection rate of adenocarcinoma in situ remained stable. In multivariable analysis, female sex, a family history of lung cancer, and age older than 60 years were associated with an increased risk of lung cancer and invasive lung cancer; passive smoke exposure, cumulative exposure to cooking, cooking without ventilation, and a previous history of chronic lung diseases were not associated with lung cancer, even after stratification by family history of lung cancer. In participants with a family history of lung cancer, the higher the number of first-degree relatives affected, the higher the risk of lung cancer; participants whose mother or sibling had lung cancer were also at an increased risk. A positive LDCT scan had 92·1% sensitivity, 84·6% specificity, a PPV of 14·0%, and a NPV of 99·7% for lung cancer diagnosis. INTERPRETATION: TALENT had a high invasive lung cancer detection rate at 1 year after baseline LDCT scan. Overdiagnosis could have occurred, especially in participants diagnosed with adenocarcinoma in situ. In individuals who do not smoke, our findings suggest that a family history of lung cancer among first-degree relatives significantly increases the risk of lung cancer as well as the rate of invasive lung cancer with increasing age. Further research on risk factors for lung cancer in this population is needed, particularly for those without a family history of lung cancer. FUNDING: Ministry of Health and Welfare of Taiwan.

A multiomic investigation of lung adenocarcinoma molecular subtypes.

BACKGROUND: Lung adenocarcinoma-an aggressive and life-threatening malignancy-is a type of non-small-cell lung cancer. Despite medical advancements, the prognosis of lung adenocarcinoma remains unfavorable, likely because of its heterogeneous nature. Furthermore, few subtype-specific treatments are available for lung adenocarcinoma. This study was conducted to explore the molecular subtypes of lung adenocarcinoma. METHODS: We performed a joint analysis of transcriptome and proteome data from East Asian patients with lung adenocarcinoma (nonsmokers, 86.5%). RESULTS: Four novel subtypes were identified based on distinct molecular characteristics: subtypes I, II, III, and IV. In patients with subtype I lung adenocarcinoma, eukaryotic translation initiation factor 4 gamma 1 activates cell proliferation; inhibiting this factor suppresses tumor growth, and reducing its level induces autophagy. Subtype II is characterized by Kristen rat sarcoma viral oncogene homolog-activating oncogenesis; the onset age of this subtype is the lowest among all subtypes. Subtype III manifests as an advanced disease at diagnosis; it is characterized by a core serum response-related oncogenic signature, which indicates poor overall survival in Western patients with lung cancer. Subtype IV is more common in men than in women; it has astroglial characteristics. A Connectivity Map analysis revealed that the oncogenic expression patterns corresponding to subtypes I, II, III, and IV can be reversed by the inhibitors of Inhibitor of κB (IκB) kinase (eg, withaferin A), mammalian target of rapamycin (eg, everolimus), Src proto-oncogene (Src) (eg, saracatinib), and Transforming Growth Factor (TGF)-ß/Smad (eg, LY-364947), respectively. CONCLUSION: This study introduced an innovative multiomics data analysis pipeline. Using this approach, we successfully identified four molecular subtypes of lung adenocarcinoma and their candidate therapeutic agents. The newly identified subtypes can be combined with the current biomarkers to generate a comprehensive roadmap for treatment decision-making.

Association of Late Radiographic Assessment of Lung Edema Score with Clinical Outcome in Patients with Influenza-Associated Acute Respiratory Distress Syndrome.

Background: Influenza virus infection leads to acute pulmonary injury and acute respiratory distress syndrome (ARDS). The Radiographic Assessment of Lung Edema (RALE) score has been proposed as a reliable tool for the evaluation of the opacity of chest X-rays (CXRs). This study aimed to examine the RALE scores and outcomes in patients with influenza-associated ARDS. Methods: Patients who were newly diagnosed with influenza-associated ARDS from December 2015 to March 2016 were enrolled. Two independent reviewers scored the CXRs obtained on the day of ICU admission and on days 2 and 7 after intensive care unit (ICU) admission. Results: During the study, 47 patients had influenza-associated ARDS. Five died within 7 days of ICU admission. Of the remaining 42, non-survivors (N = 12) had higher Sequential Organ Failure Assessment scores (SOFA) at ICU admission and higher day 7 RALE scores than survivors (N = 30). The day 7 RALE score independently related to late in-hospital mortality (aOR = 1.121, 95% CI: 1.014-1.240, p = 0.025). Conclusions: The RALE score for the evaluation of opacity on CXRs is a highly reproducible tool. Moreover, RALE score on day 7 was an independent predictor of late in-hospital mortality in patients with influenza-associated ARDS.

Management strategies for intracranial progression in ALK-positive non-small cell lung cancer: a real-world cohort study.

PURPOSE: ALK-positive NSCLC patients exhibit a particularly high propensity for the development of brain metastases. Current guidelines suggest transit to next-line therapy (SysTx) or local radiotherapy (RadTx) including whole-brain radiotherapy and radiosurgery. However, the clinical impact of these two strategies remains unclear. METHODS: We conducted a retrospective analysis focusing on patients with stage IV ALK-positive NSCLC who underwent first-line ALK TKI treatment. Patients with intracranial progression may receive two different treatment strategies: SysTx and RadTx. Our objective was to investigate the outcomes associated with these two distinct treatment pathways. RESULTS: A total 20 patients of ALK-positive NSCLC who received first-line ALK TKI therapy and subsequently developed intracranial progression were enrolled. About 55% of patients had brain metastasis initially. Nine patients (45%) were treated with crizotinib at first. Patients treated with crizotinib demonstrated a significantly shorter intracranial PFS1 (crizotinib: 8.27 months vs. others: 27.0 months, p = 0.006). Following intracranial progression, approximately 60% of patients transitioned to the next line of systemic treatment (SysTx), while the remaining 40% opted for local cranial radiotherapy (RadTx). Intriguingly, our analysis revealed no statistically significant difference in intracranial progression-free survival (PFS2) between these two distinct treatment strategies. (SysTx: 20.87 months vs. RadTx: 28.23 months, p = 0.461). CONCLUSION: The intracranial progression-free survival showed no difference between the two strategies suggesting that both local radiotherapy and systemic therapy may be valid options. Individualized strategy, molecular analysis, and multidisciplinary conferences may all play a pivotal role in decision-making.

Evaluating the Potential of Delta Radiomics for Assessing Tyrosine Kinase Inhibitor Treatment Response in Non-Small Cell Lung Cancer Patients.

Our study aimed to harness the power of CT scans, observed over time, in predicting how lung adenocarcinoma patients might respond to a treatment known as EGFR-TKI. Analyzing scans from 322 advanced stage lung cancer patients, we identified distinct image-based patterns. By integrating these patterns with comprehensive clinical information, such as gene mutations and treatment regimens, our predictive capabilities were significantly enhanced. Interestingly, the precision of these predictions, particularly related to radiomics features, diminished when data from various centers were combined, suggesting that the approach requires standardization across facilities. This novel method offers a potential pathway to anticipate disease progression in lung adenocarcinoma patients treated with EGFR-TKI, laying the groundwork for more personalized treatments. To further validate this approach, extensive studies involving a larger cohort are pivotal.

Analysis of the effect of cytomegalovirus infection in clinical outcomes and prolonged duration of SARS-CoV-2 shedding in intensive care unit patients with COVID-19 pneumonia.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is a global outbreak disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Cytomegalovirus (CMV) infection can occur in critical COVID-19 patients and is associated with adverse clinical outcomes. OBJECTIVE: The aim of this study was to explore the clinical characteristics and outcome of CMV infection in critical COVID-19 patients. DESIGN: This was a retrospective cohort study. METHODS: From May to September 2021, SARS-CoV-2 reverse transcription polymerase chain reaction (RT-PCR)-confirmed COVID-19 patients with intensive care unit (ICU) admission were enrolled. CMV infection was confirmed by PCR. Baseline characteristics, critical illness data and clinical outcomes were recorded and analyzed. RESULTS: Seventy-two RT-PCR-confirmed COVID-19 patients with ICU admission were included during the study period and 48 (66.7%) patients required mechanical ventilation (MV). Overall, in-hospital mortality was 19.4%. Twenty-one (29.2%) patients developed CMV infection. Patients with CMV infection had a higher likelihood of diabetes, higher lactate dehydrogenase and lactate levels, and higher proportions of MV, anticoagulant, and steroid use. Patients with CMV infection were associated with longer duration of SARS-CoV-2 shedding, longer ICU and hospital stay, and fewer ventilator-free days. The independent risk factor for development of CMV infection was a higher accumulative steroid dose. CONCLUSION: CMV infection adversely impacted the outcomes of critical COVID-19 patients, resulting in longer ICU stays, longer mechanical ventilation uses and prolonged shedding of SARS-CoV-2.

Comparison of clinical outcomes in critically ill COVID-19 patients on mechanical ventilation with nosocomial pneumonia between Alpha and Omicron variants.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), a pandemic that has resulted in millions of deaths worldwide. Critically ill COVID-19 patients who require intubation and develop nosocomial pneumonia, commonly caused by gram-negative bacilli, have a higher mortality rate than those without nosocomial pneumonia. OBJECTIVES: The aim of this study is to compare the clinical characteristics and outcomes and associated risk factors of Alpha and Omicron SARS-CoV-2 variants in critically ill patients on mechanical ventilation (MV) with nosocomial pneumonia. DESIGN: This is a retrospective single-center cohort study. METHODS: This observational study was conducted at Taipei Veterans General Hospital, Taiwan from May 2021 to September 2022. Critically ill patients who had confirmed SARS-CoV-2 infection and intubated on a MV with bacterial pneumonia were enrolled. Demographic data, laboratory results, and treatment information were collected and analyzed. In addition, clinical outcomes among different SARS-CoV-2 variants were examined. RESULTS: This study included 94 critically ill COVID-19 patients who required intubation and intensive care unit (ICU) admission. The Alpha group had a longer duration of SARS-CoV-2 viral shedding, MV days, and ICU stay, while the Omicron group had older age, more comorbidities, higher APACHE II scores, and higher in-hospital mortality (47.0% versus 25.0%, p = 0.047). However, independent risk factors for in-hospital mortality included malignancy, lower serum albumin levels, and lack of Remdesivir treatment, except for the SARS-CoV-2 variant. CONCLUSION: Our study discovered a higher in-hospital mortality rate in severe COVID-19 patients with MV and secondary pneumonia infected with the Omicron variant compared to the Alpha variant; however, real independent risk factors for in-hospital mortality are malignancy, lower serum albumin level, and lack of Remdesivir treatment.

Polygenic Risk Score, Environmental Tobacco Smoke, and Risk of Lung Adenocarcinoma in Never-Smoking Women in Taiwan.

Importance: Estimating absolute risk of lung cancer for never-smoking individuals is important to inform lung cancer screening programs. Objectives: To integrate data on environmental tobacco smoke (ETS), a known lung cancer risk factor, with a polygenic risk score (PRS) that captures overall genetic susceptibility, to estimate the absolute risk of lung adenocarcinoma (LUAD) among never-smokers in Taiwan. Design, Setting, and Participants: The analyses were conducted in never-smoking women in the Taiwan Genetic Epidemiology Study of Lung Adenocarcinoma, a case-control study. Participants were recruited between September 17, 2002, and March 30, 2011. Data analysis was performed from January 17 to July 15, 2022. Exposures: A PRS was derived using 25 genetic variants that achieved genome-wide significance (P < 5 × 10-8) in a recent genome-wide association study, and ETS was defined as never exposed, exposed at home or at work, and exposed at home and at work. Main Outcomes and Measures: The Individualized Coherent Absolute Risk Estimator software was used to estimate the lifetime absolute risk of LUAD in never-smoking women aged 40 years over a projected 40-year span among the controls by using the relative risk estimates for the PRS and ETS exposures, as well as age-specific lung cancer incidence rates for never-smokers in Taiwan. Likelihood ratio tests were conducted to assess an additive interaction between the PRS and ETS exposure. Results: Data were obtained on 1024 women with LUAD (mean [SD] age, 59.6 [11.4] years, 47.9% ever exposed to ETS at home, and 19.5% ever exposed to ETS at work) and 1024 controls (mean [SD] age, 58.9 [11.0] years, 37.0% ever exposed to ETS at home, and 14.3% ever exposed to ETS at work). The overall average lifetime 40-year absolute risk of LUAD estimated using PRS alone was 2.5% (range, 0.6%-10.3%) among women never exposed to ETS. When integrating both ETS and PRS data, the estimated absolute risk was 3.7% (range, 0.6%-14.5%) for women exposed to ETS at home or work and 5.3% (range, 1.2%-12.1%) for women exposed to ETS at home and work. A super-additive interaction between ETS and the PRS (P = 6.5 × 10-4 for interaction) was identified. Conclusions and Relevance: This study found differences in absolute risk of LUAD attributed to genetic susceptibility according to levels of ETS exposure in never-smoking women. Future studies are warranted to integrate these findings in expanded risk models for LUAD.

Treatment and survival of patients with small cell lung cancer and brain metastasis.

PURPOSE: To elucidate treatment patterns and their outcomes in patients with small cell lung cancer (SCLC) and brain metastasis (BM). METHODS: In this retrospective study, patients with SCLC and BM were stratified by treatment modality into three groups: those treated with systemic therapy only, those treated with stereotactic radiosurgery (SRS) and systemic therapy, and those treated with whole-brain radiotherapy (WBRT) and systemic therapy. The primary outcomes were overall survival (OS) and time to central nervous system progression (TTCP). RESULTS: The analysis included 149 patients. After BM diagnosis, 48 patients (32.2%) received systemic therapy alone, 33 received SRS with systemic therapy, and 68 received WBRT with systemic therapy. The median OS and TTCP were 7.2 months and 8.7 months, respectively. Patients receiving WBRT with systemic therapy exhibited better intracranial control, but not better OS, than did the other patients. Key prognostic factors affecting OS were age, BM lesion count, chemotherapy, and immunotherapy. Notably, the Eastern Cooperative Oncology Group performance status and BM lesion count significantly influenced intracranial control in patients treated with SRS and systemic therapy. CONCLUSION: Although WBRT combined with systemic therapy offer better intracranial control in patients with SCLC and BM, this approach is not superior to the other approaches in terms of OS benefits. Emerging systemic therapies, such as immunotherapy, may be used as alternative or adjunctive treatments for specific patient populations. Further studies are warranted to refine treatment selection.

Modifications of lipid pathways restrict SARS-CoV-2 propagation in human induced pluripotent stem cell-derived 3D airway organoids.

BACKGROUND: Modifications of lipid metabolism were closely associated with the manifestations and prognosis of coronavirus disease of 2019 (COVID-19). Pre-existing metabolic conditions exacerbated the severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection while modulations of aberrant lipid metabolisms alleviated the manifestations. To elucidate the underlying mechanisms, an experimental platform that reproduces human respiratory physiology is required. METHODS: Here we generated induced pluripotent stem cell-derived airway organoids (iPSC-AOs) that resemble the human native airway. Single-cell sequencing (ScRNAseq) and microscopic examination verified the cellular heterogeneity and microstructures of iPSC-AOs, respectively. We subjected iPSC-AOs to SARS-CoV-2 infection and investigated the treatment effect of lipid modifiers statin drugs on viral pathogenesis, gene expression, and the intracellular trafficking of the SARS-CoV-2 entry receptor angiotensin-converting enzyme-2 (ACE-2). RESULTS: In SARS-CoV-2-infected iPSC-AOs, immunofluorescence staining detected the SARS-CoV-2 spike (S) and nucleocapsid (N) proteins and bioinformatics analysis further showed the aberrant enrichment of lipid-associated pathways. In addition, SARS-CoV-2 hijacked the host RNA replication machinery and generated the new isoforms of a high-density lipoprotein constituent apolipoprotein A1 (APOA1) and the virus-scavenging protein deleted in malignant brain tumors 1 (DMBT1). Manipulating lipid homeostasis using cholesterol-lowering drugs (e.g. Statins) relocated the viral entry receptor angiotensin-converting enzyme-2 (ACE-2) and decreased N protein expression, leading to the reduction of SARS-CoV-2 entry and replication. The same lipid modifications suppressed the entry of luciferase-expressing SARS-CoV-2 pseudoviruses containing the S proteins derived from different SARS-CoV-2 variants, i.e. wild-type, alpha, delta, and omicron. CONCLUSIONS: Together, our data demonstrated that modifications of lipid pathways restrict SARS-CoV-2 propagation in the iPSC-AOs, which the inhibition is speculated through the translocation of ACE2 from the cell membrane to the cytosol. Considering the highly frequent mutation and generation of SARS-CoV-2 variants, targeting host metabolisms of cholesterol or other lipids may represent an alternative approach against SARS-CoV-2 infection.

Low-Dose Computed Tomography Screening in Relatives With a Family History of Lung Cancer.

INTRODUCTION: The role of a family history of lung cancer (LCFH) in screening using low-dose computed tomography (LDCT) has not been prospectively investigated with long-term follow-up. METHODS: A multicenter prospective study with up to three rounds of annual LDCT screening was conducted to determine the detection rate of lung cancer (LC) in asymptomatic first- or second-degree relatives of LCFH. RESULTS: From 2007 to 2011, there were 1102 participants enrolled, including 805 and 297 from simplex and multiplex families (MFs), respectively (54.2% women and 70.0% never-smokers). The last follow-up date was May 5, 2021. The overall LC detection rate was 4.5% (50 of 1102). The detection rate in MF was 9.4% (19 of 202) and 4.4% (4 of 91) in never-smokers and in those who smoked, respectively. The corresponding rates for simplex families were 3.7% (21 of 569) and 2.7% (6 of 223), respectively. Of these, 68.0% and 22.0% of cases with stage I and IV diseases, respectively. LC diagnoses within a 3-year interval from the initial screening tend to be younger, have a higher detection rate, and have stage I disease; thereafter, more stage III-IV disease and 66.7% (16 of 24) with negative or semipositive nodules in initial computed tomography scans. Within the 6-year interval, only maternal (modified rate ratio = 4.46, 95% confidence interval: 2.32-8.56) or maternal relative history of LC (modified rate ratio = 5.41, 95% confidence interval: 2.84-10.30) increased the risk of LC. CONCLUSIONS: LCFH is a risk factor for LC and is increased with MF history, among never-smokers, younger adults, and those with maternal relatives with LC. Randomized controlled trials are needed to confirm the mortality benefit of LDCT screening in those with LCFH.

Application of Radiomics in Prognosing Lung Cancer Treated with Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors: A Systematic Review and Meta-Analysis.

In the context of non-small cell lung cancer (NSCLC) patients treated with EGFR tyrosine kinase inhibitors (TKIs), this research evaluated the prognostic value of CT-based radiomics. A comprehensive systematic review and meta-analysis of studies up to April 2023, which included 3111 patients, was conducted. We utilized the Quality in Prognosis Studies (QUIPS) tool and radiomics quality scoring (RQS) system to assess the quality of the included studies. Our analysis revealed a pooled hazard ratio for progression-free survival of 2.80 (95% confidence interval: 1.87-4.19), suggesting that patients with certain radiomics features had a significantly higher risk of disease progression. Additionally, we calculated the pooled Harrell's concordance index and area under the curve (AUC) values of 0.71 and 0.73, respectively, indicating good predictive performance of radiomics. Despite these promising results, further studies with consistent and robust protocols are needed to confirm the prognostic role of radiomics in NSCLC.