Background
This study assesses different technologies for detecting epidermal growth factor receptor (EGFR) mutations from circulating tumor DNA in patients with EGFR T790M‐positive advanced ...non–small cell lung cancer (NSCLC) from the AURA3 study (NCT02151981), and it evaluates clinical responses to osimertinib and platinum‐pemetrexed according to the plasma T790M status.
Methods
Tumor tissue biopsy samples were tested for T790M during screening with the cobas EGFR Mutation Test (cobas tissue). Plasma samples were collected at screening and at the baseline and were retrospectively analyzed for EGFR mutations with the cobas EGFR Mutation Test v2 (cobas plasma), droplet digital polymerase chain reaction (ddPCR; Biodesix), and next‐generation sequencing (NGS; Guardant360, Guardant Health).
Results
With cobas tissue test results as a reference, the plasma T790M positive percent agreement (PPA) was 51% (110 of 215 samples) by cobas plasma, 58% (110 of 189) by ddPCR, and 66% (136 of 207) by NGS. Plasma T790M detection was associated with a larger median baseline tumor size (56 mm for T790M‐positive vs 39 mm for T790M‐negative; P < .0001) and the presence of extrathoracic disease (58% for M1b‐positive vs 39% for M0‐1a‐positive; P = .002). Progression‐free survival (PFS) was prolonged in randomized patients (tissue T790M‐positive) with a T790M‐negative cobas plasma result in comparison with those with a T790M‐positive plasma result in both osimertinib (median, 12.5 vs 8.3 months) and platinum‐pemetrexed groups (median, 5.6 vs 4.2 months).
Conclusions
PPA was similar between ddPCR and NGS assays; both were more sensitive than cobas plasma. All 3 test platforms are suitable for routine clinical practice. In patients with tissue T790M‐positive NSCLC, an absence of detectable plasma T790M at the baseline is associated with longer PFS, which may be attributed to a lower disease burden.
This exploratory analysis of the AURA3 study demonstrates that plasma‐based platforms (cobas EGFR Mutation Test v2, next‐generation sequencing, and droplet digital polymerase chain reaction) are suitable for epidermal growth factor receptor mutation detection in routine clinical practice. In patients with tissue T790M‐positive non–small cell lung cancer, the absence of detectable plasma T790M is associated with longer progression‐free survival, which may be attributed to a lower disease burden.
Reactivation of T cell immunity by PD-1/PD-L1 immune checkpoint blockade has been shown to be a promising cancer therapeutic strategy. However, PD-L1 immunohistochemical readout is inconsistent with ...patient response, which presents a clinical challenge to stratify patients. Because PD-L1 is heavily glycosylated, we developed a method to resolve this by removing the glycan moieties from cell surface antigens via enzymatic digestion, a process termed sample deglycosylation. Notably, deglycosylation significantly improves anti-PD-L1 antibody binding affinity and signal intensity, resulting in more accurate PD-L1 quantification and prediction of clinical outcome. This proposed method of PD-L1 antigen retrieval may provide a practical and timely approach to reduce false-negative patient stratification for guiding anti-PD-1/PD-L1 therapy.
Display omitted
•N-linked glycosylation of PD-L1 hinders its recognition by PD-L1 antibodies•Removal of glycosylation enhances anti-PD-L1 signal in a variety of bioassays•Patient sample deglycosylation prevents false-negative detection of PD-L1•Deglycosylated PD-L1 is a more reliable biomarker to guide immunotherapy
Histological detection of PD-L1 may guide therapy with anti-PD-1/PD-L1 antibodies but some PD-L1-negative tumors respond to these treatments. Lee et al. show that enzymatic deglycosylation of tissue sections improves PD-L1 detection and its predictive value, and could potentially impact patient stratification.
There are several publications reported that obstructive sleep apnea (OSA) was associated with asthma. However, large-scaled, population-based cohort study has been limited. We aimed to examine the ...risk of OSA among adult patients with asthma in an Asian population.
We conducted a retrospective cohort study using data from the National Health Insurance (NHI) of Taiwan. The asthma cohort included 38,840 newly diagnosed patients between 2000 and 2010. The date of diagnosis was defined as the index date. Each patient was randomly matched with four people without asthma according to gender, age, and the index year as the comparison cohort. The occurrence of OSA was followed up until the end of 2011. The risk of OSA was estimated using the Cox proportional hazard model after adjusting for gender, age, and comorbidities.
The overall incidence of OSA was 2.51-fold greater in the asthma cohort than in the comparison cohort (12.1 versus 4.84 per 1000 person-years). Compared to non-asthma subjects, the adjusted hazard ratio (aHR) of OSA increased to 1.78 for asthma patients with one or less annual emergency room (ER) visit, and 23.8 for those who visited ER more than once per year. In addition, aHR in patients with inhaled steroid treatment compared to those without steroid treatment was 1.33 (95% CI = 1.01-1.76).
Patients with asthma have a significantly higher risk of developing OSA than the general population. The results suggest that the risk of OSA is proportional to asthma control and patients with inhaled steroid treatment have a higher risk for OSA than those without steroid treatment.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The study aimed to investigate comorbidities, major adverse respiratory events, and mortality in patients with idiopathic pulmonary fibrosis (IPF). We established an IPF cohort and a comparative ...cohort matched for sex, age, and the date of IPF diagnosis. We recorded the most frequent comorbidities, the proportions, and time durations to the episode of major adverse respiratory events and death. Both cohorts were followed up to the end of 2016. We included 921 patients in the IPF cohort and 3,677 individuals in the comparative cohort. Comorbidities associated with IPF included pulmonary hypertension, chronic obstructive pulmonary disease, heart failure, asthma, and gastroesophageal reflux disease. The IPF cohort was more likely to have pneumonia (47.6 vs 12.0%), acute respiratory failure (17.8 vs 4.30%), chronic respiratory failure (4.23 vs 0.63%), and death (36.3 vs 15.0%) than the comparative cohort. The time durations to the first episode of pneumonia, acute respiratory failure, chronic respiratory failure, and death were 2.09 ± 2.98, 3.12 ± 3.62, 3.20 ± 4.03, and 3.27 ± 3.03 years in the IPF cohort. In conclusion, patients with IPF had significant comorbidities, particularly pulmonary and cardiovascular comorbidities. The duration from diagnosis to the major adverse respiratory events or death was short.
There is a demonstrated association between asthma and irritable bowel syndrome (IBS). In this study, we examined the bidirectional association between asthma and IBS using a nationwide database.
We ...conducted two retrospective cohort studies using data obtained from the National Health Insurance of Taiwan. Study 1 included 29,648 asthma patients newly diagnosed between 2000 and 2010. Study 2 included 29,875 IBS patient newly diagnosed between 2000 and 2010. For each study, four subjects without asthma and IBS were selected, respectively, frequency-matched by sex, age, and the diagnosis date. All four cohorts were followed up until the end of 2011 to estimate incident IBS for Study 1 and incident asthma for study 2. Adjusted hazard ratios (aHRs) were estimated using the Cox proportional hazards model after controlling for sex, age and comorbidities.
The incidence of IBS was 1.89 times higher in the asthma cohort than in the comparison cohort (8.26 vs. 4.36 per 1,000 person-years), with an aHR of 1.57 95% confidence interval (CI) = 1.47-1.68. The aHRs remained significant in all subgroups measured by sex, age and the presence of comorbidities. In contrast, the incidence of asthma was 1.76 times higher in the IBS cohort than the comparison cohort (7.09 vs. 4.03 per 1,000 person-years), with an aHR of 1.54 (95% CI = 1.44-1.64). Similarly, aHRs remained significant in all subgroups measured by sex, age and the presence of comorbidities.
The present study suggests a bidirectional association between asthma and IBS. Atopy could be a shared pathophysiology underlying this association, deserving a further investigation.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Asthma is an inflammatory disease and interleukin 12 (IL-12) may play a regulatory role in allergen-induced inflammation. The aim of this study was to investigate the association of polymorphisms in ...IL-12A/IL-12B with asthma. The asthma group included 198 adult patients and the control group included 453 individuals without asthma that were frequency-matched by gender and age. The distribution of genotypic and allelic frequencies of IL-12A rs568408 demonstrated significant differences between case and control groups. Specifically, the percentages of AA genotype of IL-12A rs568408 was significantly higher among asthmatic patients in Taiwan than healthy controls, compared to GG genotype. No significant difference was observed among the IL-12A rs2243115 and IL-12B rs3212227 genotypes between case and control groups. In addition, the A allele at IL-12A rs568408 was associated with more severe symptoms (P = 0.0085) among asthmatic patients. These results suggest that IL-12A rs568408 may contribute to the etiology and symptoms severity of asthma, indicating its usefulness as a predictive and diagnostic biomarker of asthma.
Summary Background Afatinib is an irreversible ErbB-family blocker with preclinical activity in non-small-cell lung cancer (NSCLC) with EGFR mutations. We aimed to assess the efficacy of afatinib in ...patients with lung adenocarcinoma and EGFR mutations. Methods In this phase 2 study, we enrolled patients from 30 centres in Taiwan and the USA with lung adenocarcinoma (stage IIIb with pleural effusion or stage IV) with EGFR mutations, who had no more than one previous chemotherapy regimen for advanced disease, an Eastern Cooperative Oncology Group performance status of 0–2, and no previous treatment with EGFR tyrosine-kinase inhibitors. We tested two afatinib starting doses: 50 mg daily and subsequently 40 mg daily, introduced to establish whether tolerability could be improved with retention of anti-tumour activity. The primary endpoint was the proportion of patients with a confirmed objective response (complete response or partial response), on the basis of Response Evaluation Criteria in Solid Tumors 1.0 (independent review). This study is registered with ClinicalTrials.gov , number NCT00525148. Findings 129 patients were treated with afatinib, 99 with a starting dose of 50 mg and 30 with a starting dose of 40 mg. 79 (61%) of 129 patients had an objective response (two complete responses, 77 partial responses). 70 (66%) of the 106 patients with the two common activating EGFR mutations (deletion 19 or L858R) had an objective response, as did nine (39%) of 23 patients with less common mutations. Similar proportions of patients had an objective response when analysed by starting dose (18 60% of 30 patients at 40 mg vs 61 62% of 99 patients at 50 mg). Of the two most common adverse events (diarrhoea and rash or acne), grade 3 events were more common in patients receiving a 50 mg starting dose (22 22% of 99 patients for diarrhoea and 28 28% of 99 patients for rash or acne) than they were in those receiving a 40 mg starting dose (two 7% of 30 patients for both diarrhoea and rash or acne); possibly treatment-related serious adverse events were also less common in patients receiving a 40 mg starting dose (two of 30 patients vs 14 of 99 patients). We recorded one possibly drug-related death (interstitial lung disease). Interpretation Afatinib shows activity in the treatment of patients with advanced lung adenocarcinoma with EGFR mutations, especially in patients with deletion 19 or L858R mutations. The efficacy of afatinib 40 mg should be compared with chemotherapy or other EGFR tyrosine-kinase inhibitors in EGFR-mutation-positive NSCLC. Funding Boehringer Ingelheim Inc.
The coronavirus disease (COVID-19) pandemic has resulted in an increasing population that is experiencing a wide range of long-lasting symptoms after recovery from the acute infection. Long COVID ...refers to this specific condition and is associated with diverse symptoms, such as fatigue, myalgias, dyspnea, headache, cognitive impairment, neurodegenerative symptoms, anxiety, depression, and a sense of despair. The potential of hyperbaric oxygen therapy (HBOT) to improve chronic fatigue, cognitive impairments, and neurological disorders has been established; therefore, the use of HBOT to treat long COVID has also been studied. We conducted a literature search between 1 January 2019 and 30 October 2023, focusing on the clinical efficacy and utility of HBOT for treating long COVID and found ten clinical studies that fit the review topic, including one case report, five one-group pretest-posttest design studies, one safety report from a randomized controlled trial (RCT), and three complete reports of RCTs. Most studies found that HBOT can improve quality of life, fatigue, cognition, neuropsychiatric symptoms, and cardiopulmonary function. Although HBOT has shown some benefits for long COVID symptoms, further rigorous large-scale RCTs are required to establish precise indications, protocols, and post-treatment evaluations.
Background: Studies have reported an association between asthma and oral diseases, including periodontal diseases. The aim of this retrospective study is to investigate risk of periodontal diseases ...for patients with asthma.
Methods: Using the claims data of National Health Insurance of Taiwan and patients without a history of periodontal diseases, 19,206 asthmatic patients, who were newly diagnosed from 2000 through 2010, were identified. For each case, four comparison individuals without history of asthma and periodontal disease were randomly selected from the general population and frequency matched (categorical matched) by sex, age, and year of diagnosis (n = 76,824). Both cohorts were followed to the end of 2011 to monitor occurrence of periodontal diseases. Adjusted hazard ratios (aHRs) of periodontal disease were estimated using Cox proportional hazards regression analysis.
Results: Overall incidence of periodontal diseases was 1.18‐fold greater in the asthma cohort than in the comparison cohort (P <0.001). Patients with at least three emergency visits annually had an aHR of 55.9 (95% confidence interval CI = 50.6 to 61.7) for periodontal diseases compared with those with a mean of less than one visit. Patients with at least three admissions annually also had a similar aHR (51.8) for periodontal disease. In addition, asthmatic patients on inhaled corticosteroid (ICS) therapy had greater aHRs than non‐users (aHR = 1.12; 95% CI = 1.03 to 1.23).
Conclusions: In the studied population, asthmatic patients are at an elevated risk of developing periodontal diseases. The risk is much greater for those with emergency medical demands or hospital admissions and those on ICS treatment.
Background
This study aimed to examine the clinical characteristics of bone metastasis (BoM) in patients with non‐small cell lung cancer (NSCLC) who have an epidermal growth factor receptor (EGFR) ...mutation and to identify the most effective treatment strategy using EGFR–tyrosine kinase inhibitors (TKIs).
Methods
The study included patients with stage IV EGFR‐mutated NSCLC who were receiving first‐line treatment with EGFR–TKIs between January 2014 and December 2020. These patients were divided into two groups based on the presence or absence of BoM at the time of initial diagnosis. The BoM group was further subdivided based on whether they received denosumab or not.
Results
The final analysis included 247 patients. Those with BoM at initial diagnosis had shorter progression‐free survival (12.6 vs. 10.5 months, p = 0.002) and overall survival (OS) (49.7 vs. 30.9 months, p = 0.002) compared to those without BoM. There was a difference in the location of metastatic sites between the two groups, with a higher incidence of extrathoracic metastasis in the BoM group (p < 0.001). The incidence of T790M was higher in patients with BoM than in those without (47.4% vs. 33.9%, p = 0.042). Multivariate Cox regression analysis revealed that sequential osimertinib treatment and the addition of antiangiogenic therapy (AAT) and denosumab therapy improved OS in patients with BoM.
Conclusions
The presence of BoM is a negative prognostic factor for NSCLC patients with an EGFR mutation, possibly due to the presence of extrathoracic metastases. However, adding AAT and denosumab, along with sequential osimertinib, to the treatment regimen for patients with BoM can improve survival outcomes.
PDF
