Urinary cadmium concentration is associated with the severity and clinical outcomes of COVID-19: a bicenter observational cohort study.

BACKGROUND: Cadmium and nickel exposure can cause oxidative stress, induce inflammation, inhibit immune function, and therefore has significant impacts on the pathogenesis and severity of many diseases. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can also provoke oxidative stress and the dysregulation of inflammatory and immune responses. This study aimed to assess the potential associations of cadmium and nickel exposure with the severity and clinical outcomes of patients with coronavirus disease 2019 (COVID-19). METHODS: We performed a retrospective, observational, bicenter cohort analysis of patients with SARS-CoV-2 infection in Taiwan between June 2022 and July 2023. Cadmium and nickel concentrations in blood and urine were measured within 3 days of the diagnosis of acute SARS-CoV-2 infection, and the severity and clinical outcomes of patients with COVID-19 were analyzed. RESULTS: A total of 574 patients were analyzed and divided into a severe COVID-19 group (hospitalized patients) (n = 252; 43.9%), and non-severe COVID-19 group (n = 322; 56.1%). The overall in-hospital mortality rate was 11.8% (n = 68). The severe COVID-19 patients were older, had significantly more comorbidities, and significantly higher neutrophil/lymphocyte ratio, C-reactive protein, and interleukin-6 than the non-severe COVID-19 patients (all p < 0.05). Blood and urine cadmium and urine nickel concentrations were significantly higher in the severe COVID-19 patients than in the non-severe COVID-19 patients. Among the severe COVID-19 patients, those in higher urine cadmium/creatinine quartiles had a significantly higher risk of organ failure (i.e., higher APACHE II and SOFA scores), higher neutrophil/lymphocyte ratio, lower PaO2/FiO2 requiring higher invasive mechanical ventilation support, higher risk of acute respiratory distress syndrome, and higher 60-, 90-day, and all-cause hospital mortality (all p < 0.05). Multivariable logistic regression models revealed that urine cadmium/creatinine was independently associated with severe COVID-19 (adjusted OR 1.643 [95% CI 1.060-2.547], p = 0.026), and that a urine cadmium/creatinine value > 2.05 µg/g had the highest predictive value (adjusted OR 5.349, [95% CI 1.118-25.580], p = 0.036). CONCLUSIONS: Urine cadmium concentration in the early course of COVID-19 could predict the severity and clinical outcomes of patients and was independently associated with the risk of severe COVID-19.

Comparison of prone positioning and extracorporeal membrane oxygenation in acute respiratory distress syndrome: A multicenter cohort study and propensity-matched analysis.

BACKGROUND/PURPOSE: Both prone positioning and extracorporeal membrane oxygenation (ECMO) are used as rescue therapies for severe hypoxemia in patients with acute respiratory distress syndrome (ARDS). This study compared outcomes between patients with severe influenza pneumonia-related ARDS who received prone positioning and those who received ECMO. METHODS: This retrospective cohort study included eight tertiary referral centers in Taiwan. All patients who were diagnosed as having influenza pneumonia-related severe ARDS were enrolled between January and March 2016. We collected their demographic data and prone positioning and ECMO outcomes from medical records. RESULTS: In total, 263 patients diagnosed as having ARDS were included, and 65 and 53 of them received prone positioning and ECMO, respectively. The baseline PaO2/FiO2 ratio, Acute Physiology and Chronic Health Evaluation II score and Sequential Organ Failure Assessment score did not significantly differ between the two groups. The 60-day mortality rate was significantly higher in the ECMO group than in the prone positioning group (60% vs. 28%, p = 0.001). A significantly higher mortality rate was still observed in the ECMO group after propensity score matching (59% vs. 36%, p = 0.033). In the multivariate Cox regression analysis, usage of prone positioning or ECMO was the single independent predictor for 60-day mortality (hazard ratio: 2.177, p = 0.034). CONCLUSION: While the patients receiving prone positioning had better outcome, the causality between prone positioning and the prognosis is unknown. However, the current data suggested that patients with influenza-related ARDS may receive prone positioning before ECMO support.

The Clinical Experience of Mycobacterial Culture Yield of Pleural Tissue by Pleuroscopic Pleural Biopsy among Tuberculous Pleurisy Patients.

Background and Objectives: Tuberculous pleurisy is a common extrapulmonary TB that poses a health threat. However, diagnosis of TB pleurisy is challenging because of the low positivity rate of pleural effusion mycobacterial culture and difficulty in retrieval of optimal pleural tissue. This study aimed to investigate the efficacy of mycobacterial culture from pleural tissue, obtained by forceps biopsy through medical pleuroscopy, in the diagnosis of TB pleurisy. Materials and Methods: This study retrospectively enrolled 68 TB pleurisy patients. Among them, 46 patients received semi-rigid pleuroscopy from April 2016 to March 2021 in a tertiary hospital. We analyzed the mycobacterial culture from pleural tissue obtained by forceps biopsy. Results: The average age of the study participants was 62.8 years, and 64.7% of them were men. In the pleuroscopic group, the sensitivity of positive Mycobacterium tuberculosis (M. TB) cultures for sputum, pleural effusion, and pleural tissue were 35.7% (15/42), 34.8% (16/46), and 78.3% (18/23), respectively. High sensitivities of M. TB culture from pleural tissue were up to 94.4% and 91.7% when pleural characteristic patterns showed adhesion lesions and both adhesion lesions and presence of micronodules, respectively. Conclusions: M. TB culture from pleural tissue should be considered a routine test when facing unknown pleural effusion during pleuroscopic examination.

Mechanical power during extracorporeal membrane oxygenation and hospital mortality in patients with acute respiratory distress syndrome.

BACKGROUND: Mechanical power (MP) refers to the energy delivered by a ventilator to the respiratory system per unit of time. MP referenced to predicted body weight (PBW) or respiratory system compliance have better predictive value for mortality than MP alone in acute respiratory distress syndrome (ARDS). Our objective was to assess the potential impact of consecutive changes of MP on hospital mortality among ARDS patients receiving extracorporeal membrane oxygenation (ECMO). METHODS: We performed a retrospective analysis of patients with severe ARDS receiving ECMO in a tertiary care referral center in Taiwan between May 2006 and October 2015. Serial changes of MP during ECMO were recorded. RESULTS: A total of 152 patients with severe ARDS rescued with ECMO were analyzed. Overall hospital mortality was 53.3%. There were no significant differences between survivors and nonsurvivors in terms of baseline values of MP or other ventilator settings. Cox regression models demonstrated that mean MP alone, MP referenced to PBW, and MP referenced to compliance during the first 3 days of ECMO were all independently associated with hospital mortality. Higher MP referenced to compliance (HR 2.289 [95% CI 1.214-4.314], p = 0.010) was associated with a higher risk of death than MP itself (HR 1.060 [95% CI 1.018-1.104], p = 0.005) or MP referenced to PBW (HR 1.004 [95% CI 1.002-1.007], p < 0.001). The 90-day hospital mortality of patients with high MP (> 14.4 J/min) during the first 3 days of ECMO was significantly higher than that of patients with low MP (≦ 14.4 J/min) (70.7% vs. 46.8%, p = 0.004), and the 90-day hospital mortality of patients with high MP referenced to compliance (> 0.53 J/min/ml/cm H2O) during the first 3 days of ECMO was significantly higher than that of patients with low MP referenced to compliance (≦ 0.53 J/min/ml/cm H2O) (63.6% vs. 29.7%, p < 0.001). CONCLUSIONS: MP during the first 3 days of ECMO was the only ventilatory variable independently associated with 90-day hospital mortality, and MP referenced to compliance during ECMO was more predictive for mortality than was MP alone.

Increased Death of Peripheral Blood Mononuclear Cells after TLR4 Inhibition in Sepsis Is Not via TNF/TNF Receptor-Mediated Apoptotic Pathway.

BACKGROUND: Apoptosis is one of the causes of immune depression in sepsis. Pyroptosis also occurs in sepsis. The toll-like receptor (TLR) 4 and receptor for advanced glycation end products (RAGE) have been shown to play important roles in apoptosis and pyroptosis. However, it is still unknown whether TLR4 inhibition decreases apoptosis in sepsis. METHODS: Stimulated peripheral blood mononuclear cells (PBMCs) with or without lipopolysaccharides (LPS) and high-mobility group box 1 (HMGB1) were cultured with or without TLR4 inhibition using monoclonal antibodies from 20 patients with sepsis. Caspase-3, caspase-8, and caspase-9 activities were measured. The expression of B cell lymphoma 2 (Bcl2) and Bcl2-associated X (Bax) was measured. The cell death of PBMCs was detected using a flow cytofluorimeter. RESULTS: After TLR4 inhibition, Bcl2 to Bax ratio elevated both in LPS and HMGB1-stimulated PBMCs. The activities of caspase-3, caspase-8, and caspase-9 did not change in LPS or HMGB1-stimulated PBMCs. The cell death of LPS and HMGB1-stimulated CD8 lymphocytes and monocytes increased after TLR4 inhibition. The cell death of CD4 lymphocytes was unchanged. CONCLUSION: The apoptosis did not decrease, while TLR4 was inhibited. After TLR4 inhibition, there was an unknown mechanism to keep cell death in stimulated PBMCs in patients with sepsis.

Elevated Monocytic Interleukin-8 Expression under Intermittent Hypoxia Condition and in Obstructive Sleep Apnea Patients.

Obstructive sleep apnea (OSA) is a disease with great cardiovascular risk. Interleukin-8 (IL-8), an important chemokine for monocyte chemotactic migration, was studied under intermittent hypoxia condition and in OSA patients. Monocytic THP-1 cells were used to investigate the effect of intermittent hypoxia on the regulation of IL-8 by an intermittent hypoxic culture system. The secreted protein and mRNA levels were studied by means of enzyme-linked immunosorbent assay and RT/real-time PCR. The chemotactic migration of monocytes toward a conditioned medium containing IL-8 was performed by means of the transwell filter migration assay. Peripheral venous blood was collected from 31 adult OSA patients and RNA was extracted from the monocytes for the analysis of IL-8 expression. The result revealed that intermittent hypoxia enhanced the monocytic THP-1 cells to actively express IL-8 at both the secreted protein and mRNA levels, which subsequently increased the migration ability of monocytes toward IL-8. The ERK, PI3K and PKC pathways were demonstrated to contribute to the activation of IL-8 expression by intermittent hypoxia. In addition, increased monocytic IL-8 expression was found in OSA patients, with disease severity dependence and diurnal changes. This study concluded the monocytic IL-8 gene expression can be activated by intermittent hypoxia and increased in OSA patients.

Blood Cadmium Levels and Oxygen Desaturation during the 6-Minute Walk Test in Patients with Chronic Obstructive Pulmonary Disease.

Background and Objectives: chronic obstructive pulmonary disease (COPD) is characterized by persistent airflow limitation and a history of exposure to noxious stimuli. Cigarette smoking is the most important causal factor for developing COPD. Cadmium, a minor metallic element, is one of the main inorganic components in tobacco smoke. Inhaled cadmium was associated with a decline in lung function, gas exchange impairment, and the development of obstructive lung disease. Patients with COPD who had oxygen desaturation during the 6-min walk test (6MWT) had a significantly worse prognosis than non-desaturation in COPD patients. Nonetheless, few studies have addressed the influence of blood cadmium levels on exercise-induced oxygen desaturation in COPD patients. Our objective was to assess the potential impact of blood cadmium levels on oxygen desaturation during the 6MWT among COPD patients. Materials and Methods: we performed a retrospective analysis of patients with COPD who were examined for blood cadmium levels in a tertiary care referral center in Taiwan, between March 2020 and May 2021. The 6-min walk test was performed. Normal control subjects who had no evidence of COPD were also enrolled. Results: a total of 73 COPD patients were analyzed and stratified into the high-blood cadmium group (13 patients) and low-blood cadmium group (60 patients). A total of 50 normal control subjects without a diagnosis of COPD were enrolled. The high-blood cadmium group had a significantly higher extent of desaturation than the low-blood cadmium group. The frequency of desaturation during 6MWT revealed a stepwise-increasing trend with an increase in blood cadmium levels. A multivariable logistic regression model revealed that blood cadmium levels were independently associated with desaturation during the 6MWT (odds ratio 12.849 [95% CI 1.168-141.329]; p = 0.037). Conclusions: our findings indicate that blood cadmium levels, within the normal range, were significantly associated with desaturation during 6MWT in patients with COPD.

Outcomes of severe H1N1 pneumoniae: A retrospective study at intensive care units.

BACKGROUND: The incidence of acute respiratory distress syndrome (ARDS) and the mortality rate of H1N1 influenza pneumonia are unclear. The aim of this study is to investigate the clinical features and outcomes of adult patients admitted to intensive care units (ICUs) with H1N1 pneumonia related ARDS. METHODS: This retrospective study included patients with confirmed H1N1 influenza pneumonia admitted to the ICUs of a medical center between July 2009 and May 2014. We investigated the patients' characteristics, clinical presentations, illness severities, and outcomes. RESULTS: Sixty-six patients were confirmed to have H1N1 influenza pneumonia requiring mechanical ventilation. Fifty-four of those patients (82%) developed ARDS, while their hospital mortality rate was 33% (22/66). There were no significant differences in the ICU and hospital mortality rates of the ARDS and non-ARDS patients. Among the ARDS patients, there were higher rates of solid malignant disease (22.8% vs. 2.8%, p = 0.038) and sepsis (66.7% vs. 33.3%, p = 0.020) and a higher mean tidal volume (8.9 ± 1.8 vs. 7.8 ± 1.9 ml/kg, p = 0.032) in the non-survivors than the survivors. Logistic regression analysis revealed that a high tidal volume (odds ratio = 1.448, 95 % CI = 1.033-2.030; p = 0.032) and sequential organ failure assessment (SOFA) score (odds ratio = 1.233, 95% CI = 1.029-1.478; p = 0.023) were the risk factors of hospital mortality. CONCLUSION: For H1N1 influenza pneumonia patients admitted to ICUs with mechanical ventilation, there is a high probability of developing ARDS with a modest mortality rate. For patients with ARDS due to H1N1 influenza pneumonia, the tidal volume and SOFA score are the predictors of hospital mortality.

Attenuation of ventilation-induced diaphragm dysfunction through toll-like receptor 4 and nuclear factor-κB in a murine endotoxemia model.

Mechanical ventilation (MV) is often used to maintain life in patients with sepsis and sepsis-related acute lung injury. However, controlled MV may cause diaphragm weakness due to muscle injury and atrophy, an effect termed ventilator-induced diaphragm dysfunction (VIDD). Toll-like receptor 4 (TLR4) and nuclear factor-κB (NF-κB) signaling pathways may elicit sepsis-related acute inflammatory responses and muscle protein degradation and mediate the pathogenic mechanisms of VIDD. However, the mechanisms regulating the interactions between VIDD and endotoxemia are unclear. We hypothesized that mechanical stretch with or without endotoxin treatment would augment diaphragmatic structural damage, the production of free radicals, muscle proteolysis, mitochondrial dysfunction, and autophagy of the diaphragm via the TLR4/NF-κB pathway. Male C57BL/6 mice, either wild-type or TLR4-deficient, aged between 6 and 8 weeks were exposed to MV (6 mL/kg or 10 mL/kg) with or without endotoxemia for 8 h. Nonventilated mice were used as controls. MV with endotoxemia aggravated VIDD, as demonstrated by the increases in the expression levels of TLR4, caspase-3, atrogin-1, muscle ring finger-1, and microtubule-associated protein light chain 3-II. In addition, increased NF-κB phosphorylation and oxidative loads, disorganized myofibrils, disrupted mitochondria, autophagy, and myonuclear apoptosis were also observed. Furthermore, MV with endotoxemia reduced P62 levels and diaphragm muscle fiber size (P < 0.05). Endotoxin-exacerbated VIDD was attenuated by pharmacologic inhibition with a NF-κB inhibitor or in TLR4-deficient mice (P < 0.05). Our data indicate that endotoxin-augmented MV-induced diaphragmatic injury occurs through the activation of the TLR4/NF-κB signaling pathway.

Maternal and neonatal outcomes of respiratory failure during pregnancy.

BACKGROUND: Obstetric patients comprise a limited portion of intensive care unit patients, but they often present with unfamiliar conditions and exhibit the potential for catastrophic deterioration. This study evaluated the maternal and neonatal outcomes of respiratory failure during pregnancy. METHODS: Information on 71 patients at >25 weeks gestation in the ICU with respiratory failure was recorded between 2009 and 2013. The characteristics and outcomes of mothers and fetuses were determined through a retrospective chart review and evaluated using Student's t test, chi-square test, and Fisher's exact test. RESULTS: The leading causes of respiratory failure were postpartum hemorrhage and severe preeclampsia in the obstetric causes group and pneumonia in the nonobstetric causes group during pregnancy and the peripartum period. The non-obstetric causes group exhibited a higher incidence of acute respiratory distress syndrome and renal replacement therapy as well as requiring more ventilator days. The patients in the obstetric causes group showed significant improvement after delivery in the partial pressure of arterial oxygen to the fraction of inspired oxygen and peak inspiratory pressure decrease. Both groups exhibited high incidences of neonatal respiratory distress syndrome. Neonatal complications resulting from meconium aspiration syndrome (MAS) and sepsis were more common in the non-obstetric causes group; however, neurological development impairment was more common in the obstetric causes group. CONCLUSION: Obstetric cause was associated with longer ventilator free days and fewer episodes of ARDS after delivery. Neonatal complications resulting from different etiologies of respiratory failure were found to differ.

Activation of Src-dependent Smad3 signaling mediates the neutrophilic inflammation and oxidative stress in hyperoxia-augmented ventilator-induced lung injury.

BACKGROUND: Mechanical ventilation and concomitant administration of hyperoxia in patients with acute respiratory distress syndrome can damage the alveolar epithelial and capillary endothelial barrier by producing inflammatory cytokines and reactive oxygen species. The Src tyrosine kinase and Smad3 are crucial inflammatory regulators used for ventilator-induced lung injury (VILI). The mechanisms regulating interactions between high-tidal-volume mechanical ventilation, hyperoxia, and acute lung injury (ALI) are unclear. We hypothesized that high-tidal-volume mechanical stretches and hyperoxia augment lung inflammation through upregulation of the Src and Smad3 pathways. METHODS: Wild-type or Src-deficient C57BL/6 mice, aged between 6 and 8 weeks, were exposed to high-tidal-volume (30 mL/kg) ventilation with room air or hyperoxia for 1-4 h after 2-mg/kg Smad3 inhibitor (SIS3) administration. Nonventilated mice were used as control subjects. RESULTS: We observed that the addition of hyperoxia to high-tidal-volume mechanical ventilation further induced microvascular permeability, neutrophil infiltration, macrophage inflammatory protein-2 and matrix metalloproteinase-9 (MMP-9) production, malondialdehyde, nicotinamide adenine dinucleotide phosphate oxidase activity, MMP-9 mRNA expression, hypoxemia, and Src and Smad3 activation (P < 0.05). Hyperoxia-induced augmentation of VILI was attenuated in Src-deficient mice and mice with pharmacological inhibition of Smad3 activity by SIS3 (P < 0.05). Mechanical ventilation of Src-deficient mice with hyperoxia further reduced the activation of Smad3. CONCLUSIONS: Our data suggest that hyperoxia-increased high-tidal-volume ventilation-induced ALI partially depends on the Src and Smad3 pathways.

Clinical outcomes and molecular typing of heterogenous vancomycin-intermediate Staphylococcus aureus bacteremia in patients in intensive care units.

BACKGROUND: Staphylococcus aureus is one of most common pathogens in humans. Methicillin-resistant S. aureus (MRSA) accounts for 64 % of S. aureus bacteremia isolated in intensive care units (ICUs), and heteroresistant vancomycin-intermediates S. aureus (hVISA) is a phenotype of MRSA. However, studies focusing on the hVISA impact on critically ill patients are scarce. METHODS: This was a retrospective study conducted in a tertiary medical center from January 2009 to December 2010. All adult patients in ICUs with MRSA bloodstream infection were eligible. A modified population analysis profile and area under the curve method was applied to all isolates to confirm hVISA phenotype. Multilocus sequence typing (MLST), staphylococcal cassette chromosome mec (SCCmec) and the accessory gene regulator (agr) typing were performed individually. Clinical outcomes including in-hospital mortality, length of stay in intensive care unit and hospital after MRSA bacteremia of the patients were also analyzed. RESULTS: A total of 48 patients were enrolled and 14 patients were confirmed to have the hVISA phenotype. The prevalence of hVISA was 29.2 %. There was no difference in the age, sex, comorbidity, Charlson's comorbidity score and previous vancomycin therapy between the hVISA and VSSA groups. The hVISA group had a significantly higher in-hospital mortality than the VSSA group (13/14 versus 22/34; p = 0.046). All of the 14 hVISA patients had an MIC = 2 mg/L by E-test and this represented a significant association between high MIC and the development of hVISA (p < 0.001). MLST analysis showed all the isolates in the hVISA group were ST239, while ST239 (14/34; 41.2 %) and ST5 (12/34; 35.3 %) were predominant in the VSSA group (p = 0.007). A comparison of the survivor and non-survivor group showed that the hVISA phenotype (OR 11.8; 95 % CI 1.1-126.99; p = 0.042) and sequential organ failure assessment (SOFA) score (OR 1.39; 95 % CI 1.07-1.81; p = 0.014) were independent factors significantly associated with in-hospital mortality. CONCLUSIONS: Patients in ICUs with MRSA bacteremia may have a higher in-hospital mortality if they have the hVISA phenotype. SOFA score is also predictor of mortality.

Diffuse alveolar damage associated mortality in selected acute respiratory distress syndrome patients with open lung biopsy.

INTRODUCTION: Diffuse alveolar damage (DAD) is the pathological hallmark of acute respiratory distress syndrome (ARDS), however, the presence of DAD in the clinical criteria of ARDS patients by Berlin definition is little known. This study is designed to investigate the role of DAD in ARDS patients who underwent open lung biopsy. METHODS: We retrospectively reviewed all ARDS patients who met the Berlin definition and underwent open lung biopsy from January 1999 to January 2014 in a referred medical center. DAD is characterized by hyaline membrane formation, lung edema, inflammation, hemorrhage and alveolar epithelial cell injury. Clinical data including baseline characteristics, severity of ARDS, clinical and pathological diagnoses, and survival outcomes were analyzed. RESULTS: A total of 1838 patients with ARDS were identified and open lung biopsies were performed on 101 patients (5.5 %) during the study period. Of these 101 patients, the severity of ARDS on diagnosis was mild of 16.8 %, moderate of 56.5 % and severe of 26.7 %. The hospital mortality rate was not significant difference between the three groups (64.7 % vs 61.4 % vs 55.6 %, p = 0.81). Of the 101 clinical ARDS patients with open lung biopsies, 56.4 % (57/101) patients had DAD according to biopsy results. The proportion of DAD were 76.5 % (13/17) in mild, 56.1 % (32/57) in moderate and 44.4 % (12/27) in severe ARDS and there is no significant difference between the three groups (p = 0.113). Pathological findings of DAD patients had a higher hospital mortality rate than non-DAD patients (71.9 % vs 45.5 %, p = 0.007). Pathological findings of DAD (odds ratio: 3.554, 95 % CI, 1.385-9.12; p = 0.008) and Sequential Organ Failure Assessment score on the biopsy day (odds ratio: 1.424, 95 % CI, 1.187-1.707; p<0.001) were significantly and independently associated with hospital mortality. The baseline demographics and clinical characteristics were not significantly different between DAD and non-DAD patients. CONCLUSIONS: The correlation of pathological findings of DAD and ARDS diagnosed by Berlin definition is modest. A pathological finding of DAD in ARDS patients is associated with hospital mortality and there are no clinical characteristics that could identify DAD patients before open lung biopsy.

Factors associated with prolonged progression-free survival of patients treated with first-line afatinib for advanced epidermal growth factor receptor-mutated non-small cell lung cancer.

BACKGROUND: This study aimed to investigate the factors associated with prolonged progression-free survival (PFS) (>36 months) of advanced non-small cell lung cancer (NSCLC) patients harboring epidermal growth factor receptor (EGFR) mutations treated with first-line afatinib. METHODS: We performed a retrospective analysis of data of patients with advanced EGFR-mutated NSCLC receiving first-line afatinib at two tertiary care referral centers, Linkou and Kaohsiung Chang Gung Memorial Hospital, in Taiwan between June 2014 and April 2022. RESULTS: The data of 546 treatment-naïve EGFR-mutated advanced NSCLC patients were analyzed. Median PFS and overall survival were 14.5 months and 27.2 months, respectively. The PFS of 462 patients (84.6%) was less than 36 months and of 84 patients (15.4%) was more than 36 months. The PFS > 36 months group had a significantly higher percentage of patients with uncommon mutations (p = 0.002). The PFS ≤36 months group had significantly higher incidences of bone, liver, and adrenal metastases (all p < 0.05) and a higher rate of multiple distant metastases. Multivariate logistic regression analysis showed that liver metastasis was negatively and independently associated with prolonged PFS (adjusted odds ratio = 0.246 [95% CI: 0.067-0.908], p = 0.035). The median overall survival of the PFS >36 months group was 46.0 months and that of the PFS ≤36 months group was 22.9 months (log-rank test, p < 0.001). CONCLUSIONS: We found that EGFR-mutated NSCLC patients receiving first-line afatinib were prone to shorter PFS if they had distant organ metastasis, especially liver metastasis.

A Clinical Analysis of Anti-Programmed Death-Ligand 1 (PD-L1) Immune Checkpoint Inhibitor Treatments Combined with Chemotherapy in Untreated Extensive-Stage Small-Cell Lung Cancer.

Real-world clinical experience of using anti-programmed death-ligand 1 (PD-L1) immune checkpoint inhibitors (ICIs) combined with chemotherapy in the first-line treatment of extensive-stage small-cell lung cancer (SCLC) patients has rarely been reported. In this study, we aimed to perform a retrospective multicenter clinical analysis of extensive-stage SCLC patients receiving first-line therapy with anti-PD-L1 ICIs combined with chemotherapy. Between November 2018 and March 2022, 72 extensive-stage SCLC patients receiving first-line atezolizumab or durvalumab in combination with chemotherapy, according to the cancer center databases of Linkou, Chiayi, and Kaohsiung Chang Gung Memorial Hospitals, were retrospectively included in the analysis. Twenty-one patients (29.2%) received atezolizumab and fifty-one (70.8%) received durvalumab. Objective response (OR) and disease control (DC) rates of 59.7% and 73.6%, respectively, were observed with first-line ICI plus chemotherapy. The median progression-free survival (PFS) was 6.63 months (95% confidence interval (CI), 5.25-8.02), and the median overall survival (OS) was 16.07 months (95% CI, 15.12-17.0) in all study patients. A high neutrophil-to-lymphocyte ratio (NLR; >4) and a high serum lactate dehydrogenase (LDH) concentration (>260 UL) were identified as independent unfavorable factors associated with shorter OS in the multivariate analysis. Regarding safety, neutropenia was the most common grade 3 treatment-related adverse event (AE), but no treatment-related deaths occurred in the study patients. First-line anti-PD-L1 ICIs combined with chemotherapy are effective and safe for male extensive-stage SCLC patients. Further therapeutic strategies may need to be developed for patients with unfavorable outcomes (e.g., baseline high NLR and serum LDH level).

Case Report: High-dose steroid and IVIG successful treatment in a case of COVID-19-associated autoimmune encephalitis: a literature review.

Autoimmune encephalitis is a rare but critical complication of COVID-19. The management of COVID-19-associated autoimmune encephalitis includes the use of steroids, intravenous immunoglobulin (IVIG), plasmapheresis, and monoclonal antibody therapy. This study presented a patient with critical COVID-19 autoimmune encephalitis who rapidly recovered after the initiation of corticosteroids and IVIG therapy. This study reviewed the current literature on the pathophysiological mechanisms, diagnosis, and management of COVID-19-associated autoimmune encephalitis.

Predicting Inhaled Drug Dose Generated by Mesh Nebulizers.

Background: The lung dose of nebulized drugs for spontaneous breathing is influenced by breathing patterns and nebulizer performance. This study aimed to develop a system for measuring breath patterns and a formula for estimating inhaled drugs, and then to validate the hypothesized prediction formula. Methods: An in vitro model was first used to determine correlations among the delivered dose, breath patterns, and doses deposited on the accessories and reservoirs testing with a breathing simulator to generate 12 adult breathing patterns (n = 5). A pressure sensor was developed to measure breathing parameters and used along with a prediction formula that accounted for the initial charge dose, respiratory pattern, and dose on the accessory and reservoir of a nebulizer. Three brands of nebulizers were tested by placing salbutamol (5.0 mg/2.5 mL) in the drug holding chamber. Ten healthy individuals participated in the ex vivo study to validate the prediction formula. The agreement between the predicted and inhaled doses was analyzed using the Bland-Altman plot. Results: The in vitro model showed that the inspiratory time to total respiratory cycle time (Ti/Ttotal; %) was significantly directly correlated with the delivered dose among the respiratory factors, followed by inspiratory flow, respiratory rate, and tidal volume. The ex vivo model showed that Ti/Ttotal was significantly directly correlated with the delivered dose among the respiratory factors, in addition to the nebulization time and accessory dose. The Bland-Altman plots for the ex vivo model showed similar results between the two methods. Large differences in inhaled dose measured at the mouth were observed among the subjects, ranging from 12.68% to 21.68%; however, the difference between the predicted dose and inhaled dose was lower, at 3.98%-5.02%. Conclusions: The inhaled drug dose could be predicted with the hypothesized estimation formula, which was validated by the agreement between the inhaled and predicted doses of breathing patterns of healthy individuals.

Clinical outcome analysis of non-small cell lung cancer patients with brain metastasis receiving metastatic brain tumor resection surgery: a multicenter observational study.

Brain metastasis is most common in primary non-small cell lung cancer (NSCLC), and some patients require neurosurgical resection for intracranial disease control. Because advances in systemic therapies for metastatic NSCLC have been developed in the past decade, we aimed to analyze and determine clinical factors associated with the postresection survival of NSCLC patients with brain metastasis who underwent neurosurgery followed by systemic therapy. Between January 2017 and December 2021, data for 93 NSCLC patients with brain metastasis treated with neurosurgery followed by systemic therapy at Linkou, Kaohsiung and Chiayi Chang Gung Memorial Hospitals were retrospectively retrieved for analysis. For all study patients, median postresection survival was 34.36 months (95% confidence interval (CI), 28.97-39.76), median brain metastasis (BM)-free survival was 26.90 months (95% CI, 22.71-31.09), and overall survival (OS) was 41.13 months (95% CI, 34.47-47.52). In multivariate analysis, poor performance status (Eastern Cooperative Oncology Group performance status (ECOG PS) ≥2) and concurrent liver metastasis were identified as independent unfavorable factors associated with significantly shortened postresection survival (P<0.001). The histological type adenocarcinoma was associated with significantly longer postresection survival (P = 0.001). The median postresection survival for adenocarcinoma and nonadenocarcinoma patients was 36.23 and 10.30 months, respectively (hazard ratio (HR) = 0.122; 95% CI, 0.035-0.418; P<0.001); that for patients with and without concurrent liver metastasis was 11.43 and 36.23 months, respectively (HR = 22.18; 95% CI, 5.827-84.459; P<0.001). Patients with preserved ECOG PS, adenocarcinoma histology type and no concurrent liver metastasis appeared to have better postresection survival than nonadenocarcinoma patients. Our results provide counseling and decision-making references for neurosurgery feasibility in NSCLC patients with brain metastasis.

Afatinib in Untreated Stage IIIB/IV Lung Adenocarcinoma with Major Uncommon Epidermal Growth Factor Receptor (EGFR) Mutations (G719X/L861Q/S768I): A Multicenter Observational Study in Taiwan.

BACKGROUND: Real-world clinical experience with afatinib as a treatment for advanced lung adenocarcinoma harboring uncommon epidermal growth factor receptor (EGFR) mutations (G719X, L861Q and S768I) has rarely been reported. OBJECTIVE: We aimed to perform a retrospective multicenter study to analyze afatinib therapy in untreated advanced lung adenocarcinoma harboring uncommon EGFR mutations. PATIENTS AND METHODS: Between May 2014 and June 2021, the data of 90 stage IIIB/IV lung adenocarcinoma patients with uncommon EGFR mutations (G719X/L861Q/S768I) treated with first-line afatinib from the cancer center database of Linkou, Tucheng, and Kaohsiung Chang Gung Memorial Hospitals were retrospectively retrieved and analyzed. RESULTS: Afatinib had an objective response rate (ORR) of 63.3% and a disease control rate (DCR) of 86.7%. The median progression-free survival (PFS) with first-line afatinib therapy was 17.3 months (95% confidence interval (CI), 12.07-22.53), and the median overall survival (OS) was 28.5 months (95% CI, 20.22-36.77) in all study patients. In the multivariate analysis, poor performance (Eastern Cooperative Oncology Group performance status (ECOG PS) ≥ 2) and brain and liver metastases were independent predictors of unfavorable PFS. The G719X mutation (alone+compound) was an independent predictor of favorable PFS (hazard ratio (HR) = 0.578; 95% CI, 0.355-0.941; P = 0.027). Most afatinib-related adverse events (AEs) were limited to grades 1 and 2 and were manageable. CONCLUSIONS: First-line afatinib therapy is effective and safe for advanced lung adenocarcinoma harboring uncommon EGFR mutations. The G719X mutation was an independent factor associated with a favorable outcome. Poor performance (ECOG PS ≥ 2), brain metastasis, and liver metastasis were predictive factors of shorter PFS with first-line afatinib therapy.

Sequential treatment in advanced epidermal growth factor receptor-mutated lung adenocarcinoma patients receiving first-line bevacizumab combined with 1st/2nd-generation EGFR-tyrosine kinase inhibitors.

Introduction: The clinical outcomes of sequential treatment of advanced epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) patients with first-line bevacizumab combined with 1st/2nd-generation EGFR-TKIs are unclear. Thus, we aimed to analyze the outcomes of these patients. Methods: Between January 2015 and December 2020, data for 102 advanced EGFR-mutated lung adenocarcinoma patients receiving first-line bevacizumab combined with erlotinib or afatinib followed by treatments at multiple institutions were retrospectively analyzed. All patients with progressive disease (PD) after first-line therapy underwent secondary T790M mutation detection. Results: The secondary T790M mutation positive rate of all study patients was 57.9%. First-line erlotinib use and progression-free survival (PFS) after first-line therapy > 12 months were positively associated with the T790M mutation (P <0.05). The response rates (RRs) to second-line treatments were 51.7% and 22.7% for the osimertinib and nonosimertinib groups, respectively (P = 0.001). The median PFS associated with second-line osimertinib and nonosimertinib therapy was 13.7 and 7.1 months, respectively (hazard ratio (HR) = 0.38; 95% confidence interval (CI), 0.23-0.63; P< 0.001). Patients with a secondary T790M mutation receiving second-line osimertinib treatment had a median overall survival (OS) of 54.3 months, and the median OS was 31.9 months for non-T790M-mutated patients receiving second-line nonosimertinib treatments (HR = 0.36; CI: 0.21-0.62, P < 0.001). Conclusion: The majority of acquired resistance to first-line bevacizumab combined with 1st/2nd-generation EGFR-TKIs is associated with the T790M mutation. Sequential osimertinib treatment in patients with positive secondary T790M mutation is associated with better outcomes among these patients.