Elements of End-of-Life Discussions Associated With Patients' Reported Outcomes and Actual End-of-Life Care in Patients With Pretreated Lung Cancer.

BACKGROUND: End-of-life discussions for patients with advanced cancer are internationally recommended to ensure consistency of end-of-life care with patients' values. This study examined the elements of end-of-life discussions associated with end-of-life care. MATERIALS AND METHODS: We performed a prospective observational study among consecutive patients with pretreated non-small cell lung cancer after the failure of first-line chemotherapy. We asked oncologists whether they had ever discussed "prognosis," "do not attempt resuscitation," "hospice," and "preferred place of death" with a patient at baseline. The quality of life (QOL) and depressive symptoms of patients were assessed using validated questionnaires at baseline and 3 months later. The end-of-life care that patients received was investigated using medical records. Oncologists' compassion and caregivers' preferences for hospice care were also assessed using questionnaires. Multiple regression analyses were conducted to examine the association between elements of end-of-life discussions and patient-reported outcomes as well as actual end-of-life care. RESULTS: We obtained 200 valid responses at baseline, 147 valid responses 3 months later, and 145 data points for medical care at the end-of-life stage. No element of the end-of-life discussion between the patient and their oncologist was significantly associated with patients' reported outcomes or actual end-of-life care. In addition, oncologists' compassion was significantly associated with improvement in both comprehensive QOL and depressive symptoms, and caregivers' preferences for hospice care and high educational level were significantly associated with hospice death. CONCLUSION: Oncologist-patient alliances and caregivers' involvement in end-of-life discussions may be influential in achieving optimal end-of-life care.

Efficacy of dupilumab for severe chronic rhinosinusitis with nasal polyps and asthma: A prospective study.

BACKGROUND: Dupilumab exerts clinical effects, including improved sinus opacification, olfactory function, and quality of life, in patients with severe chronic rhinosinusitis with nasal polyps (CRSwNP). Meanwhile, only a few studies have reported its effects on nasal airway resistance and olfactory function, particularly in the Japanese population. Predictors of response remain unclear. OBJECTIVE: In this prospective, observational study, we assessed the comprehensive efficacy and therapeutic response to dupilumab in severe CRSwNP patients with comorbid asthma. METHODS: In 16 adult severe CRSwNP patients with comorbid asthma, the efficacy of 48-week dupilumab treatment, including olfactory function measured by a T&T olfactometer, nasal airway resistance measured by rhinomanometry, nasal polyp score, Lund-Mackay computed tomography score (LMS), and 22-item Sinonasal Outcome Test (SNOT-22), was assessed. Regarding asthma, the annualized rate of exacerbations, 7-item Asthma Control Questionnaire (ACQ-7), and spirometry were assessed. Treatment responsiveness was analyzed. RESULTS: With 48-week dupilumab treatment, olfactory function, nasal airway resistance, nasal polyp score, LMS, and SNOT-22 scores improved significantly. Regarding comorbid asthma, the rate of exacerbations decreased, and ACQ-7 scores and lung function improved significantly. According to the European Position Paper on Rhinosinusitis and Nasal Polyps 2022/European Forum for Research and Education in Allergy and Airway Diseases criteria, 15 patients (94%) were moderate-to-excellent responders at 48 weeks of treatment. Patients with higher SNOT-22 scores, ACQ-7 scores, rates of asthma exacerbation in the previous year, and blood eosinophil counts benefited more from treatment. CONCLUSION: Dupilumab improved upper and lower airway outcomes especially in severe CRSwNP patients with comorbid, poorly controlled asthma.

Unrealistic expectations and disclosure of incurability in patients with non-small cell lung cancer.

PURPOSE: Determining whether patients' unrealistic expectations of chemotherapy as a cure were associated with their perception of the disclosure of incurability. METHODS: This prospective study included consecutive patients with pretreated non-small cell lung cancer from four study sites. Patients and their oncologists were asked whether they perceived the disclosure of cancer incurability. Patients were also asked if they thought that chemotherapy was curative. We followed up on whether the deceased patients received specialized palliative care 14 months after their last enrollment. Multiple regression analyses were conducted to examine the association between the expectation of chemotherapy as a cure and patient/oncologist-reported perceptions of the disclosure of incurability. RESULTS: We analyzed 200 patients, 77 (38.5%) of whom had unrealistic expectations of a cure. Based on patients' perceptions, incurability was disclosed to 138 (69.0%) patients, and based on their oncologists' perceptions, incurability was disclosed to 185 (92.5%) patients (patient/oncologist agreements, κ = 0.19). Patients without a perception of the oncologist's disclosure of incurability-regardless of their oncologist's perception-were more likely to have unrealistic expectations of a cure than patients for whom both patient and oncologist perceptions were present. Patients who had unrealistic expectations of chemotherapy as a cure were shown to be significantly less likely to have received specialized palliative care, after adjusting for covariates (adjusted OR, 0.45; 95% CI, 0.23-0.91; p = .027). CONCLUSION: Oncologists' disclosure of incurability was not fully recognized by patients, and expectations of chemotherapy as a cure were associated with patients' perception of the disclosure of incurability.

Efficacy of dupilumab for airway hypersecretion and airway wall thickening in patients with moderate-to-severe asthma: A prospective, observational study.

BACKGROUND: Dupilumab has clinical effects in patients with moderate-to-severe asthma. When considering interleukin (IL)-4 and IL-13 signaling, effects of dupilumab on airway mucus hypersecretion and airway remodeling are expected, but they have been reported in only a few short-term studies. Its efficacy for airway hyperresponsiveness (AHR) remains unknown. We comprehensively assessed the efficacy of dupilumab, especially for subjective and objective measures of airway mucus hypersecretion and airway dimensions in moderate-to-severe asthmatic patients. METHODS: In 28 adult patients with moderate-to-severe uncontrolled asthma, the comprehensive efficacy of 48-week dupilumab treatment, including the Cough and Sputum Assessment Questionnaire (CASA-Q), radiological mucus scores and airway dimensions on computed tomography (CT), was assessed prospectively. Treatment responsiveness to dupilumab was analyzed. RESULTS: With 48-week dupilumab treatment, all four cough and sputum domain scores of CASA-Q improved significantly. Radiological mucus scores and airway wall thickening on CT were significantly decreased. The decreases in mucus scores were significantly associated with improvements in Asthma Control Questionnaire scores, Asthma Quality of Life Questionnaire (AQLQ) overall scores, airway obstruction, and airway type 2 inflammation. When defined by > 0.5 improvement in AQLQ overall scores, 18 patients (64%) were identified as responders. CONCLUSIONS: Dupilumab reversed subjective and objective measures of airway mucus hypersecretion and some aspects of airway remodeling in patients with moderate-to-severe uncontrolled asthma.

Targeting the interleukin-5 pathway improves cough hypersensitivity in patients with severe uncontrolled asthma.

BACKGROUND: Capsaicin cough sensitivity (C-CS) reflects airway neuronal dysfunction and may be a significant biomarker of asthma. Although mepolizumab reduces cough in patients with severe uncontrolled asthma, it is unclear whether the cough reduction is associated with improved C-CS. OBJECTIVE: To clarify the effect of biologics on C-CS and cough-specific quality of life (QoL) in patients with severe uncontrolled asthma using our previous study cohort. METHODS: Overall, 52 consecutive patients who visited our hospital for severe uncontrolled asthma were included in the original study cohort, and 30 patients were eligible for this study. Changes in C-CS and cough-specific QoL were compared between patients treated with the anti-interleukin-5 (IL-5) pathway (n = 16) and those treated with other biologics (n = 14). The C-CS was measured as the concentration of capsaicin required to induce at least 5 coughs. RESULTS: Biologics significantly improved C-CS (P = .03). Anti-IL-5 pathway therapies significantly improved C-CS, whereas other biologics did not (P < .01 and P = .89, respectively). The C-CS improved significantly more in the anti-IL-5 pathway group than in the group treated with other biologics (P = .02). Changes in C-CS significantly correlated with improvements in cough-specific QoL in the anti-IL-5 pathway group (r = 0.58, P = .01) but not in the group treated with other biologics (r = 0.35, P = .22). CONCLUSION: Anti-IL-5 pathway therapies improve C-CS and cough-specific QoL, and targeting the IL-5 pathway may be a therapeutic strategy for cough hypersensitivity in patients with severe uncontrolled asthma.

Tiotropium for refractory cough in asthma via cough reflex sensitivity: A randomized, parallel, open-label trial.

BACKGROUND: We previously reported in an uncontrolled study that tiotropium alleviated chronic cough in asthma refractory to inhaled corticosteroids and long-acting ß2 agonists (ICS/LABA) by modulating capsaicin cough reflex sensitivity (C-CRS). OBJECTIVE: We sought to determine the antitussive effects of tiotropium for refractory cough in asthma in a randomized, parallel, open-label trial. METHODS: A total of 58 patients with asthma having chronic cough refractory to ICS/LABA were randomized in a 2:1 ratio to add tiotropium 5 µg (39 patients) or theophylline 400 mg (19 patients) for 4 weeks. Patients underwent workups, including capsaicin cough challenge test and subjective measures such as cough severity visual analog scales (VAS). We adopted C5, the lowest capsaicin concentration to induce at least 5 coughs, as an index of C-CRS. We also performed a posthoc analysis to identify factors predicting tiotropium responders, who found an improvement of at least 15 mm in cough severity VAS. RESULTS: A total of 52 patients (tiotropium, 38; theophylline, 14) completed the study. Both tiotropium and theophylline significantly improved cough severity VAS and cough-specific quality of life. Tiotropium, but not theophylline, significantly increased C5, whereas pulmonary function did not change in either group. In addition, changes in cough severity VAS correlated with changes in C5 values in the tiotropium group. A posthoc analysis revealed that heightened C-CRS (C5 ≤1.22 µM) before the addition of tiotropium was an independent predictor for tiotropium responders. CONCLUSION: Tiotropium may alleviate chronic cough in asthma refractory to ICS/LABA by modulating C-CRS. Heightened C-CRS may predict responsiveness to tiotropium for refractory cough in asthma. TRIAL REGISTRATION: Clinical Trials Registry ID: UMIN000021064 (https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000024253).

Overall survival analysis of patients enrolled in a randomized phase III trial comparing gefitinib and erlotinib for previously treated advanced lung adenocarcinoma (WJOG5108LFS).

BACKGROUND: Since the overall survival (OS) of patients enrolled in the first clinical phase III trial (WJOG5108L) was not recorded owing to time constraints, the present study (WJOG5108LFS) with a longer follow-up (66.6 months) aimed to compare OS of those treated with erlotinib (ER) and gefitinib (GE) for lung adenocarcinoma with epidermal growth factor receptor (EGFR) mutation. METHODS: Among 536 enrolled patients, 362 (67.5%) were EGFR mutation-positive, including 182 in the ER arm and 180 in the GE arm. Median survival time (MST) and progression-free survival (PFS) were calculated using Kaplan-Meier survival curves. OS and PFS were determined for patients with EGFR mutation. RESULTS: MSTs of ER (n = 182) and GE arms (n = 180) were 31.97 and 27.98 months, respectively (P = 0.3573, hazard ratio = 1.116). MSTs of exon 19 mutation patients in ER (n = 99) and GE arms (n = 89) were 37.49 and 28.91 months, respectively (P = 0.3791). MSTs of L858 mutation patients in ER (n = 82) and GE arms (n = 89) were 22.98 and 27.79 months, respectively (P = 0.7836). In patients with brain metastasis harboring mutation, response rates were 32.8% and 22.2% (P = 0.160), MSTs were 23.46 and 23.89 months (P = 0.7410), and PFS were 9.49 and 6.98 months (P = 0.1481) in the ER (n = 67) and GE arms (n = 72), respectively. CONCLUSIONS: No significant differences in OS were observed between the ER and GE arms in all patients with EGFR mutation and those with brain metastasis harboring EGFR mutation.

Functional gastrointestinal disorders are associated with capsaicin cough sensitivity in severe asthma.

BACKGROUND: Although sensory nerve dysfunction is related to the pathology of severe uncontrolled asthma and functional gastrointestinal disorders (FGIDs), the impact of comorbid FGIDs on the pathophysiology of severe uncontrolled asthma remains poorly understood. The aim was to clarify the physiological relationships between severe uncontrolled asthma and FGIDs. METHODS: Fifty-two patients with severe uncontrolled asthma who visited our hospital between September 2016 and August 2019 were retrospectively analyzed. Clinical characteristics, other comorbidities including gastroesophageal reflux disease (GERD), and biomarkers such as fractional nitric oxide (FeNO) and capsaicin cough sensitivity (C-CS) before the beginning of biologics or bronchial thermoplasty, were compared between patients with and without comorbid FGIDs. C-CS was evaluated by C5 (concentration of inhaled capsaicin that induced five or more coughs), and C5 ≤2.44 µM was defined as heightened C-CS. RESULTS: Seventeen patients had comorbid FGIDs. These patients had a lower FeNO level (21.9 ± 1.7 ppb vs. 33.9 ± 2.8 ppb, P = 0.04), a lower C5 threshold (2.24 ± 2.88 µM vs. 8.91 ± 5.5 µM, P < 0.001), a higher prevalence of comorbid GERD (64.7% vs. 31.7%, P = 0.03), and a higher prevalence of heightened C-CS (70.6% vs. 28.6%, P = 0.007) than those without FGIDs. Analysis of covariance showed a significant effect of FGIDs on C-CS in severe uncontrolled asthma without being affected by GERD. CONCLUSIONS: Comorbid FGIDs are associated with heightened C-CS in patients with severe uncontrolled asthma, and they may be an important extra-respiratory manifestation of the airway neuronal dysfunction phenotype of severe uncontrolled asthma.

Prognostic Awareness and Discussions of Incurability in Patients with Pretreated Non-Small Cell Lung Cancer and Caregivers: A Prospective Cohort Study.

BACKGROUND: Although patients with advanced cancer often have poor prognostic awareness, the most effective communication approach for improving prognostic awareness is unclear. In addition, the association between prognostic awareness and preferences for future medical treatment remains unexplored. MATERIALS AND METHODS: We performed a prospective observational study of consecutive patients with advanced or post-operative recurrent non-small cell lung cancer whose disease had progressed after first-line chemotherapy, and their caregivers. We evaluated patterns of clinical discussions about incurability, prognostic awareness, and preference for future medical treatment at baseline and 3 months later. RESULTS: We obtained 200 valid responses to the questionnaires at baseline and 147 valid responses 3 months later. In addition, 180 caregivers returned valid responses. A total of 54% of patients and 51% of caregivers had accurate awareness at baseline, and 52% of patients had accurate awareness 3 months later. Multiple logistic regression analysis revealed that patients who were informed about incurability in recent and past discussions were significantly more likely to have accurate awareness 3 months later, compared with those who were only informed recently (adjusted odds ratio 5.08; 95% CI, 1.31-19.78; P = .019). Accurate awareness at 3 months was significantly negatively associated with preference for life-prolonging treatment at 3 months after adjusting for covariates (adjusted odds ratio 0.39; 95% CI, 0.17-0.90; P = .028). CONCLUSION: Patients with advanced cancer who had both recent and past discussions about incurability with their oncologists have more accurate prognostic awareness. Improving prognostic awareness could reduce the preference for life-prolonging treatment.

Genetic variations in the ATP-binding cassette transporter ABCC10 are associated with neutropenia in Japanese patients with lung cancer treated with nanoparticle albumin-bound paclitaxel.

ABCC10/MRP7, an ATP-binding cassette (ABC) transporter, has been implicated in the extracellular transport of taxanes. Our group reported that the ABCC10 single nucleotide polymorphism (SNPs), rs2125739, influences docetaxel cytotoxicity in lung cancer cell lines as well as its side effects in clinical practice. In this study, we investigated whether the rs2125739 variant could affect paclitaxel (PTX) cytotoxicity in lung cancer cell lines. We also investigated the effect of rs2125739 on the efficacy and safety of nanoparticle albumin-bound PTX (nab-PTX) in clinical practice. The association between rs2125739 genotypes and the 50% inhibitory concentration (IC50) of PTX was investigated in 18 non-small cell lung cancer (NSCLC) cell lines, HeLa cells, and genome-edited HeLa cells. Next, blood samples from 77 patients with NSCLC treated with carboplatin plus nab-PTX were collected and analyzed for six SNPs, including rs2125739. The clinical outcomes among the different genotype groups were evaluated. In NSCLC cell lines, HeLa cells, and genome-edited HeLa cells, the IC50 was significantly higher in the ABCC10 rs2125739 T/T group than in the T/C and C/C groups. In 77 patients with NSCLC, there were no significant differences in clinical outcomes between the T/T and T/C groups. However, the rs2125739 T/T genotype was associated with a higher frequency of Grades 3/4 neutropenia. In contrast, there was no association between other SNPs and clinical efficacy or neutropenia. Our results indicate that the ABCC10 rs2125739 variant is associated with neutropenia in response to nab-PTX treatment.

Pretreatment Alveolar Nitric Oxide Levels Predict Improvement of Pulmonary Function 1 Year Following Anti-Asthma Treatments in Patients with Inhaled Corticosteroid-Naïve Asthma.

INTRODUCTION: Inhaled corticosteroids (ICS) are fundamental agents to subside airway inflammation and improve forced expiratory volume in 1 s (FEV1) among asthmatics. Alveolar concentrations of nitric oxide (CANO), as well as the classical fraction of exhaled nitric oxide (FeNO50), are associated with the pathophysiology of asthma. However, the association between pretreatment CANO levels and response to anti-asthma treatments, including ICS, remains unknown. METHODS: We retrospectively analyzed 107 patients newly diagnosed with asthma. ICS in combination with long-acting ß2-agonists (ICS/LABA) was initiated. FEV1 and FeNO levels were evaluated at diagnosis and were followed up at 6 and 12 months after the treatment intervention. CANO levels were estimated using various expiratory flows of FeNO measurements. Factors associated with annual changes in FEV1 (ΔFEV1) were analyzed. Patients with a ΔFEV1 <-20 mL were defined as "poor-responders." RESULTS: FEV1, FeNO50, and CANO levels significantly improved by anti-asthma treatments. The average ΔFEV1 was 85 (176) mL. Eighty-two patients continuously took ICS/LABA treatment. Higher pretreatment CANO levels and continuous use of LABA were independent predictive factors for the improvement of FEV1 on multivariate analysis. The decline in FeNO50 and CANO levels by the anti-asthma treatments was significantly greater in 81 responders than in 26 poor-responders. CANO, but not FeNO50, levels at 12 months were significantly higher in poor-responders than in responders (p = 0.009). CONCLUSION: Levels of CANO, but not FeNO50, predict changes in pulmonary function in ICS-naïve asthmatics. Meanwhile, persistently high levels of CANO may be related to poor responsiveness to treatments assessed by ΔFEV1.

Nasal polyp eosinophilia and FeNO may predict asthma symptoms development after endoscopic sinus surgery in CRS patients without asthma.

BACKGROUND: Asthma is a significant comorbidity of eosinophilic chronic rhinosinusitis (CRS). Type2-driven biomarkers such as sinus tissue eosinophilia and fractional nitric oxide (FeNO) may be utilized to detect high risk patients who develop asthma symptoms after endoscopic sinus surgery (ESS) in CRS patients. METHODS: Thirty-six CRS patients without asthma who agreed to undergo ESS between October 2015 and December 2017 were prospectively observed for 12 months following ESS. They were monitored for the development of typical asthma symptoms including dyspnea, wheezes, and cough which responded to anti-asthma medication. Biomarkers were compared between patients who developed asthma symptoms after ESS (asthma symptoms group) and those who did not (non-asthma group). Biomarker changes following ESS intervention were also evaluated. RESULTS: Six patients were lost to follow after ESS. Thus, 30 CRS patients [16 with nasal polyps (NPs) proved by surgery] were followed. Seven (23%) newly complained of asthma symptoms during follow-up. Levels of FeNO and the prevalence of eosinophilic NPs (eosinophils ≥ 70/high power fields) were significantly higher in the asthma symptom group than in non-asthma group [50.7 ppb vs 22.4 ppb for FeNO levels, and 100% (n = 3) vs 23% (n = 3) for eosinophilic NP prevalence, both p < 0.05]. Levels of sputum periostin decreased significantly by ESS in the non-asthma group. However, changes of biomarkers after ESS were comparable between the two groups. CONCLUSIONS: Eosinophils in NPs (≥70/high power fields) and preoperative FeNO may be significant biomarkers for predicting the development of asthma symptoms after ESS.

Tolerability, adverse events, and efficacy of treatment for Mycobacterium avium complex pulmonary disease in elderly patients.

INTRODUCTION: Although the number of patients with Mycobacterium avium complex (MAC) pulmonary disease has been increasing among the elderly individuals due to population aging in Japan, few studies have reported treatment in elderly patients with MAC pulmonary disease. We conducted a retrospective cohort study to evaluate differences in the tolerability of, adverse events associated with and efficacy of treatment for MAC pulmonary disease in elderly and nonelderly patients. METHODS: The medical records of 96 newly diagnosed MAC pulmonary disease patients at Nagoya City University Hospital between April 2014 and March 2019 were reviewed. RESULTS: Elderly patients ≥75 years old started multidrug treatment less frequently than nonelderly patients <75 years old (17 of 41 patients, 41.5% vs. 41 of 55 patients, 74.5%, P = 0.001). The treated elderly patients had more symptoms, more extensive radiological disease and a higher rate of positivity on sputum smear than the treated nonelderly patients. Eleven elderly patients and 19 nonelderly patients continued the initial multidrug regimen (64.7% vs. 46.3%, P = 0.26). Adverse events occurred in 6 elderly patients and 25 nonelderly patients (35.3% vs. 61.0%, P = 0.074). The rates of achievement of sputum conversion and radiological improvement after treatment for over 1 year were similar between the elderly and nonelderly patients (61.5% vs. 75.0%, P = 0.37; 76.9% vs. 78.1%, P = 1). CONCLUSIONS: The tolerability, adverse events, and efficacy of treatment in elderly patients with MAC pulmonary disease were not noticeably different from those in nonelderly patients.

Serum creatinine/cystatin C ratio is a surrogate marker for sarcopenia in patients with idiopathic pulmonary fibrosis.

BACKGROUND: The serum creatinine/cystatin C (Cr/CysC) ratio has attracted attention as a marker for sarcopenia, but has not been studied in patients with idiopathic pulmonary fibrosis (IPF). This study aimed to confirm the utility of the serum Cr/CysC ratio in predicting sarcopenia and investigate its clinical relevance. METHODS: This cross-sectional pilot study prospectively enrolled patients with stable IPF. IPF was diagnosed through multidisciplinary discussions according to the 2018 international guidelines, and sarcopenia was diagnosed according to the 2019 consensus report of the Asian Working Group for Sarcopenia. Patient-reported outcomes (PROs) were evaluated using the modified Medical Research Council (mMRC) dyspnea scale, chronic obstructive pulmonary disease assessment test (CAT), and King's Brief Interstitial Lung Disease (K-BILD) questionnaire. The associations between serum Cr/CysC ratio and the presence of sarcopenia and other clinical parameters, including PROs scores, were examined. RESULTS: The study enrolled 49 Japanese patients with IPF with a mean age of 73.0 ± 7.7 years and a mean percentage of predicted forced vital capacity of 80.4 ± 15.5%. Sarcopenia was diagnosed in 18 patients (36.7%), and the serum Cr/CysC ratio was 0.86 [0.76-0.94] (median [interquartile range]). The receiver operating characteristic curve analyses for the detection of sarcopenia according to the serum Cr/CysC showed that the area under the curve, optimal cutoff value, specificity, and sensitivity were 0.85, 0.88, 0.65, and 0.94, respectively. Sarcopenia was identified in 13% of patients with a high serum Cr/CysC ratio (≥ 0.88) and 60% of patients with a low serum Cr/CysC ratio (< 0.88) (P < 0.001). Multiple linear regression analysis showed that the serum Cr/CysC ratio was an independent predictive marker of worse PROs evaluated using mMRC (P < 0.05), CAT (P < 0.05), and K-BILD (P < 0.05). CONCLUSIONS: This study showed that the serum Cr/CysC ratio may be a surrogate marker of sarcopenia in patients with IPF. Furthermore, it is important to pay attention to the serum Cr/CysC ratio because a lower serum Cr/CysC ratio is associated with worse PROs. Further studies are required to validate these observations to determine whether the Cr/CysC ratio can be used to detect sarcopenia in patients with IPF.

Decreased peak expiratory flow rate associated with mortality in idiopathic pulmonary fibrosis: A preliminary report.

OBJECTIVES: The peak expiratory flow rate (PEFR) is known to decrease in patients with sarcopenia. However, little is known about the clinical impact of the PEFR in idiopathic pulmonary fibrosis (IPF). This study aimed to confirm whether a decrease in PEFR over 6 months was associated with survival in IPF patients. METHODS: Consecutive IPF patients who had been assessed at a single center were retrospectively analyzed. The relative decline in PEFR over 6 months was assessed. Survival analyses were performed by univariate and multivariate Cox proportional hazard models. RESULTS: A total of 61 eligible cases (average age 70 years) were examined, and 21 patients (34.4%) died. The univariate Cox regression analysis showed that the body mass index, baseline % predicted forced vital capacity (FVC), baseline % predicted PEFR, % predicted diffusion capacity for carbon monoxide (DLCO), relative decline in FVC, and relative decline in PEFR were prognostic factors. On multivariate analyses, relative decline in PEFR (hazard ratio [HR] 1.037, p < .05) and baseline % predicted FVC (HR 0.932, p < .001) were independent prognostic factors, whereas relative decline in FVC was not. CONCLUSION: A decrease in PEFR after 6 months may predict worse survival in patients with IPF.

Frequency and impact on clinical outcomes of sarcopenia in patients with idiopathic pulmonary fibrosis.

OBJECTIVES: Sarcopenia is a syndrome characterized by reduced muscle mass and function. It is well-recognized as a complication in chronic diseases such as chronic obstructive pulmonary disease. However, little is known about sarcopenia in patients with idiopathic pulmonary fibrosis (IPF). This study aimed to investigate the clinical characteristics of sarcopenia and the association between quality of life and sarcopenia in patients with IPF. METHODS: In this pilot cross-sectional study, 56 Japanese outpatients with IPF (49 men) were enrolled prospectively. Sarcopenia was diagnosed according to the criteria of the Asian Working Group for Sarcopenia 2019. Its associations with clinical parameters including age, pulmonary functions, physical performance, and patient-reported outcomes (PROs) were examined. RESULTS: The frequency of sarcopenia was 39.3% (n = 22) in this cohort. There were significant differences in St George's Respiratory Questionnaire (p = .005), modified Medical Research Council score (p = .004), and Hospital and Anxiety Depression Scale depression score (p = .030) between the sarcopenic and non-sarcopenic groups. On multivariate regression analysis, 6-min walk distance (6MWD) was an independent factor associated with sarcopenia (odds ratio 1.241, 95% confidence interval 1.016-1.515, p = .034). CONCLUSION: Sarcopenia was associated with PROs and physical performance in patients with IPF.

Reflux-related symptoms reflect poor asthma control and the presence of airway neuronal dysfunction.

BACKGROUND: Gastroesophageal reflux may be associated with the worsening of asthma by increasing cough reflex sensitivity. Hull Airway Reflux Questionnaire (HARQ) consists of 14 prevalent reflux-related symptoms. It may be useful in predicting the presence of cough reflex hypersensitivity in asthma. METHODS: From August 2018 to July 2020, 266 asthmatic patients completed the HARQ. They underwent blood analysis, spirometry, fraction of exhaled nitric oxide (FeNO) measurement, and the capsaicin cough challenge test. Patients were considered to have reflux-related symptoms if their HARQ scores were 13 points or higher. We evaluated the association between reflux-related symptoms and clinical asthma outcomes. Finally, we performed a multivariate analysis to determine the clinical significance of the HARQ for asthma. This study was registered in the University Hospital Medical Information Network (UMIN000040732). RESULTS: The mean HARQ scores were 13.1 (standard deviation 12.0). Patients in the high HARQ scores group (HARQ ≥13, n = 105) showed a lower prevalence of atopic predisposition, lower levels of FeNO, heightened capsaicin cough reflex sensitivity, poorer asthma control, and more frequent admissions due to asthma than those in the low HARQ groups (all p values < 0.05). The HARQ was useful in selecting patients with poor controlled asthma and those with severe cough when the cut-off value was set at 13. Multivariate analysis revealed that heightened capsaicin cough reflex sensitivity affected reflux-related symptoms, as well as lower levels of FeNO and younger age. CONCLUSIONS: Higher HARQ scores (≥13) may be useful in predicting not only poor asthma condition but also the presence of airway neuronal dysfunction in patients with asthma to some extent.

Clinical utility of liquid biopsy for EGFR driver, T790M mutation and EGFR amplification in plasma in patients with acquired resistance to afatinib.

BACKGROUND: Cell-free DNA (cfDNA) genotyping in plasma using the cobas EGFR Mutation Test v2 (cobas) is the first liquid biopsy as a companion diagnosis to identify the EGFR T790M mutation (T790M) after the failure of treatment of EGFR-tyrosine kinase inhibitors (TKIs) (1st generation, gefitinib [G] and erlotinib [E] and 2nd generation, afatinib [A]). This study investigated the clinical utility of a liquid biopsy for patients who acquired resistance to afatinib. METHODS: We prospectively collected plasma from 51 patients who had acquired resistance to afatinib between April 2015 and November 2016 to evaluate the frequency of T790M by cobas and digital droplet PCR (UMIN000025112). Additionally, we retrospectively reviewed 38 patients who tested by cobas in plasma after G/E failure to compare for T790M detection between A and with G/E. RESULTS: The detection rate of EGFR-driver and T790M in plasma in patients treated with A (A group) as a first-line EGFR-TKI was lower than with G/E followed by A (G/E→A group), although the differences were not significant (EGFR-driver: 41% [A] vs. 67% [G/E→A], P=0.1867; and T790M: 8% [A] vs. 17% [G/E→A], P=0.5798). In first-line setting, the detection rate for EGFR-driver and T790M in plasma by cobas was lower in A group than in G/E group, although there was no significant difference (EGFR-driver: 34% [A] vs. 52% [G/E], P=0.2072; and T790M: 10% [A] vs. 27% [G/E], P=0.1161). CONCLUSION: The detection of EGFR-driver and T790M in plasma by cobas in patients treated with afatinib might be lower than with G/E in a real-world setting.

The diagnostic utility of the frequency scale for the symptoms of gastroesophageal reflux disease questionnaire (FSSG) for patients with subacute/chronic cough.

BACKGROUND: The frequency scale for the symptoms of GERD (FSSG) questionnaire, which originally consists of acid-reflux and dysmotility symptom domains, is a succinct questionnaire to evaluate gastroesophageal reflux disease (GERD) symptoms. OBJECTIVES: To evaluate the utility of subjective questionnaire of GERD for the diagnosis of GERD-related cough by using FSSG questionnaire. METHODS: We recruited 256 patients with subacute/chronic cough between April 2012 and March 2018, who were analyzed using FSSG questionnaire and blood eosinophil counts. GERD-related cough was inferred through the presence of classic reflux symptoms including heartburn and/or typical coughing trigger (e.g. phonation, rising, lying, eating, and intake of certain food). The diagnosis was confirmed by response to specific treatments for GERD. Receiver operating characteristic curve analysis was performed to determine the cutoff score for the diagnosis. RESULTS: One-hundred ten patients (43%) were diagnosed as having GERD-related cough. FSSG questionnaire was relevant for diagnosing GERD-related cough, with the area under the curve (AUC) of 0.70 (p < 0.0001, cutoff score 7 points, sensitivity 75%, specificity 62%). When limited to patients with blood eosinophils of ≤150/µL or those with sputum eosinophils of ≤3%, sensitivity and specificity of the diagnosis was increased, respectively (sensitivity and specificity; 79% and 65% for blood eosinophils and 82% and 68% for sputum eosinophils. p < 0.0001, AUC 0.74 for both). CONCLUSIONS: The subjective questionnaire of GERD (FSSG) would be helpful in diagnosing GERD-related cough, particularly in patients with low blood or sputum eosinophil counts.

Increased Capsaicin Sensitivity in Patients with Severe Asthma Is Associated with Worse Clinical Outcome.

Rationale: Capsaicin cough reflex sensitivity (C-CS) is associated with poorly controlled asthma, although its association with severe asthma remains unknown.Objectives: To determine the clinical impact of C-CS on severe asthma.Methods: We prospectively enrolled 157 patients with asthma (including 122 patients with severe asthma who were in step 4 or 5 according to the Global Initiative for Asthma 2015 guidelines) between November 2016 and October 2019. A capsaicin cough challenge was performed along with spirometry and assessment of biomarkers. The concentration required to induce at least five coughs by capsaicin was adopted as an index of C-CS. An Asthma Control Test and comorbidities were also evaluated. Associations of biomarkers with four clinical features of severe asthma made by the European Respiratory Society/American Thoracic Society guidelines (poor control [Asthma Control Test < 20; n = 58], frequent exacerbations [≥2/yr; n = 28], admissions [≥1/yr; n = 17], and airflow limitation [FEV1% predicted < 80%; n = 30]) were assessed.Measurements and Main Results: Heightened C-CS was associated with poor asthma control, frequent exacerbations, and admissions, particularly in patients without atopy (n = 54). Meanwhile, C-CS was not related to airflow limitation. Multivariate regression analysis has revealed that heightened C-CS (at least five coughs by capsaicin ≤ 2.44 µM) was a significant risk for poor asthma control and frequent exacerbations. Regarding general factors and comorbidities, ex-smoking status, diabetes mellitus, and chronic rhinosinusitis were associated with clinical features of severe asthma (all P < 0.05).Conclusions: Heightened C-CS is a risk factor for severe asthma. The present study suggests the association of airway neuronal dysfunction with the pathophysiology of non-type 2 severe asthma.