Olanzapine Plus Triple Antiemetic Therapy for the Prevention of Carboplatin-Induced Nausea and Vomiting: A Randomized, Double-Blind, Placebo-Controlled Phase III Trial.

PURPOSE: We evaluated the efficacy and safety of antiemetic therapy with olanzapine, a neurokinin-1 receptor antagonist (RA), a 5-hydroxytryptamine-3 (5-HT3) RA, and dexamethasone for preventing chemotherapy-induced nausea and vomiting in patients receiving carboplatin-containing chemotherapy. PATIENTS AND METHODS: Chemotherapy-naïve patients scheduled to receive carboplatin (AUC ≥5) were randomly assigned to receive either olanzapine 5 mg once daily (olanzapine group) or placebo (placebo group) in combination with aprepitant, a 5-HT3 RA, and dexamethasone. The primary end point was the complete response (CR; no vomiting and no rescue therapy) rate in the overall phase (0-120 hours). Secondary end points included the proportion of patients free of nausea and safety. RESULTS: In total, 355 patients (78.6% male, median age 72 years, 100% thoracic cancer), including 175 and 180 patients in the olanzapine and placebo groups, respectively, were evaluated. The overall CR rate was 86.9% in the olanzapine group versus 80.6% in the placebo group. The intergroup difference in the overall CR rate was 6.3% (95% CI, -1.3 to 13.9). The proportions of patients free of chemotherapy-induced nausea in the overall (88.6% in the olanzapine group v 75.0% in the placebo group) and delayed (89.7% v 75.6%, respectively) phases were significantly higher in the olanzapine group than in the placebo group (both P < .001). Somnolence was observed in 43 (24.6%) and 41 (22.9%) patients in the olanzapine and placebo groups, respectively, and no events were grade ≥3 in severity. CONCLUSION: The addition of olanzapine was not associated with a significant increase in the overall CR rate. Regarding the prevention of nausea, adding olanzapine provided better control in patients receiving carboplatin-containing chemotherapy, which needs further exploration.

Neutrophil-lymphocyte ratio being associated with mortality risk in patients receiving antifibrotic therapy.

BACKGROUND: Antifibrotic therapy is widely used for patients with progressive fibrotic interstitial lung disease (ILD), regardless of etiology. There is an urgent need for a simple, inexpensive, and repeatable biomarker to evaluate disease severity and mortality risk. METHODS: This retrospective multicohort study assessed the neutrophil-lymphocyte ratios (NLRs) of 416 patients with ILD who received antifibrotic therapy (Hamamatsu cohort, n = 217; Seirei cohort, n = 199). The mortality risk vs. NLR relationship was evaluated at therapy initiation and 1 year. The optimal NLR cutoff of 2.7 was selected according to the mortality risk. RESULTS: Survival was shorter in patients with high NLR than with low NLR (median: 2.63 vs. 4.01 years). The NLR classification results (cutoff: 2.7) were longitudinally preserved in >70 % of the patients, and patients with consistently high NLR had a higher risk of mortality than others (median, 2.97 vs. 4.42 years). In multivariate analysis, high NLR was significantly associated with mortality independent of age, sex, forced vital capacity, lung diffusing capacity for carbon monoxide (DLCO), or the gender-age-physiology (GAP) index. A combined GAP index-NLR assessment classified mortality risk into four groups. Subset analyses revealed that NLR assessment was more applicable to patients without advanced disease, not taking steroids, and with idiopathic pulmonary fibrosis (IPF) than to patients with advanced disease, taking steroids, and patients with Non-IPF. CONCLUSION: High NLR was associated with an increased mortality risk in patients with ILDs receiving antifibrotic therapy. Assessment of NLR may help predict disease severity and mortality risk in antifibrotic therapy.

Association of the lung immune prognostic index with the survival of patients with idiopathic interstitial pneumonias.

BACKGROUND AND OBJECTIVE: The lung immune prognostic index (LIPI), a simple index calculated from the blood lactate dehydrogenase level and derived neutrophil-to-lymphocyte ratio, is thought to be associated with host immune status. However, the utility of LIPI in patients with idiopathic interstitial pneumonias (IIPs) is unknown. METHODS: In this multicentre, retrospective, observational study, an association between LIPI and the survival of patients with IIPs was evaluated. RESULTS: Exploratory and validation cohorts consisting of 460 and 414 patients with IIPs, respectively, were included (159 and 159 patients had idiopathic pulmonary fibrosis [IPF], and 301 and 255 had non-IPF, respectively). In the exploratory cohort, patients with IPF and a low LIPI had significantly better survival than those with a high LIPI (median of 5.6 years vs. 3.9 years, p = 0.016). The predictive ability of LIPI for the survival of patients with IPF was validated in the validation cohort (median of 8.5 years vs. 4.4 years, p = 0.003). In a multivariate Cox proportional hazard analysis, LIPI was selected as an independent predictive factor for the survival of IPF patients. There was no significant association between LIPI and survival of non-IPF patients in the exploratory and validation cohorts. CONCLUSION: The LIPI was a predictive factor for the survival of patients with IPF and could aid the management of IPF.

Prognostic Role of Interferon-λ3 in Anti-Melanoma Differentiation-Associated Gene 5-Positive Dermatomyositis-Associated Interstitial Lung Disease.

OBJECTIVE: Interferon-λ3 (IFNλ3) is a cytokine with antiviral functions on barrier surfaces, and it is associated with disease activity in autoimmune diseases. This study assessed the clinical significance of serum IFNλ3 levels in polymyositis/dermatomyositis (PM/DM)-associated interstitial lung disease (ILD). METHODS: We measured serum IFNλ3 levels in 221 patients with PM/DM-ILD (155 in the derivation cohort, 66 in the validation cohort) and 38 controls. We evaluated factors associated with mortality risk among 79 patients with anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive DM-ILD. RESULTS: Serum IFNλ3 levels at diagnosis were significantly higher in patients with PM/DM-ILD than in healthy controls. Remarkably, serum IFNλ3 levels were specifically increased in patients with anti-MDA5 antibody-positive DM-ILD in both the derivation and validation cohorts. In anti-MDA5 antibody-positive DM-ILD, patients with high IFNλ3 levels (>120 pg/mL) had significantly lower survival rates than those with low IFNλ3 levels (≤120 pg/mL). A multivariate analysis revealed that high IFNλ3 levels, as well as old age and low Pao2, were significantly associated with poor prognoses in patients with anti-MDA5 antibody-positive DM-ILD. In a classification analysis of patients with anti-MDA5 antibody-positive DM-ILD based on age, IFNλ3 level, and Pao2, patients with old age (>53 years), high IFNλ3 levels (>120 pg/mL), and low Pao2 (<75 mm Hg) had the worst survival. In lung pathologic analyses, IFNλ3-positive staining was observed in macrophages, airway epithelial cells, the pleural region, and intrapulmonary veins in patients with anti-MDA5 antibody-positive DM-ILD. CONCLUSION: Serum IFNλ3 is a promising biomarker for identifying patients at high risk of poor outcomes in anti-MDA5 antibody-positive DM-ILD.

A predictive model for acute exacerbation of idiopathic interstitial pneumonias.

BACKGROUND: Acute exacerbation of idiopathic interstitial pneumonias (AE-IIPs) induces permanent pulmonary dysfunction and is potentially lethal. The unpredictable occurrence of AE-IIPs remains an important clinical issue in the management of IIPs. METHODS: In this multicentre, retrospective, observational study, a predictive score for AE-IIPs was designed using clinical factors based on multivariate Fine-Gray analysis in patients with IIPs. RESULTS: Based on multivariate Fine-Gray analysis in an exploratory cohort of 487 patients with IIPs, the predictive score for AE-IIPs was determined as follows: 1 point each was added for honeycombing on high-resolution computed tomography (H), age >75 years (A) and lactate dehydrogenase level >222 U·L-1 (L); the total score ranged from 0 to 3 (HAL score). The HAL score discriminated the risk of AE-IIPs with a C-index of 0.62 (95% CI 0.56-0.67); this discrimination was verified in a validation cohort of 402 patients with IIPs with a C-index of 0.67 (95% CI 0.60-0.73). In a combined cohort, the estimated cumulative risks for AE-IIPs at 1, 2, 3, 5 and 10 years were 1.9%, 3.5%, 5.1%, 7.7% and 12.9%, respectively, in the total score 0 group; 4.7%, 8.3%, 12.0%, 17.7% and 28.4%, respectively, in the total score 1 group; and 8.0%, 14.2%, 19.7%, 28.7% and 43.0%, respectively, in the total score ≥2 group. Subgroup analysis revealed that the HAL score was applicable to patients with and without idiopathic pulmonary fibrosis. CONCLUSIONS: The HAL score discriminated the risk of AE-IIPs and could aid in the management of IIPs.

Frequency, proportion of PF-ILD, and prognostic factors in patients with acute exacerbation of ILD related to systemic autoimmune diseases.

BACKGROUND: Acute exacerbation (AE) of systemic autoimmune disease-related interstitial lung diseases (SAID-ILD) is less common than AE of idiopathic pulmonary fibrosis (IPF) and the details of AE-SAID-ILD have not been elucidated, but the prognosis is similarly devastating. This study was undertaken to determine the incidences of AE-ILD in each SAID and to elucidate the proportion of progressive fibrosing (PF)-ILD in AE-SAID-ILD. METHODS: We retrospectively analysed data for patients with SAID-ILD who were diagnosed and observed at our hospital between 1999 and 2020. RESULTS: Two hundred and thirty-two patients with SAID-ILD were enrolled, with a mean observation period of 100.2 months. AE-SAID-ILD was found in 25 patients (10.78%), mainly in patients with RA (17 patients, 68%) and elderly male patients with a smoking history. The overall incidence of AE-SAID-ILD was 1.29%/person-year, and the incidence for each SAID was as follows: RA 2.193, microscopic polyarteritis (MPA) 3.203, systemic sclerosis (SSc) 2.277, primary Sjögren syndrome 0.426, and polymyositis/dermatomyositis 0.222. The incidence of AE of RA/MPA/SSc-ILD was significantly higher than that of other AE-SAID-ILD (p < 0.001). Five of 25 patients (20%) fulfilled the criteria for PF-ILD. The 90-day survival rate was 48.0%, and a higher neutrophil count at AE (HR 13.27, 95%CI 2.447-246, p = 0.001) and early commencement of long-duration direct haemoperfusion with a polymyxin B-immobilised fibre column (HR 0.105, 95%CI 0.005-0.858, p = 0.035) were significant prognostic factors. CONCLUSIONS: The incidence of AE-SAID-ILD was significantly higher in patients with RA, MPA, or SSc than in patients with other SAID. Furthermore, even in patients with AE-SAID-ILD, the proportion of PF-ILD just before AE was not high (20%).

Impact of antifibrotic therapy on lung cancer development in idiopathic pulmonary fibrosis.

Patients with idiopathic pulmonary fibrosis (IPF) are at a high risk of lung cancer (LC). Antifibrotic therapy slows disease progression and possibly prolongs survival. However, whether antifibrotic therapy affects LC development in patients with IPF remains unknown. This multicentre retrospective study evaluated 345 patients with IPF. The incidence and prevalence of LC were significantly lower in patients with IPF receiving antifibrotic therapy than those not receiving. Subsequently, LC-related mortality was significantly lower in patients with IPF receiving antifibrotic therapy. These results suggest that antifibrotic therapy was possibly associated with a reduced risk of LC development in patients with IPF, which may be partly associated with its survival benefit.

Increased serum cholesterol and long-chain fatty acid levels are associated with the efficacy of nivolumab in patients with non-small cell lung cancer.

BACKGROUND: Lipids have immunomodulatory functions and the potential to affect cancer immunity. METHODS: The associations of pretreatment serum cholesterol and long-chain fatty acids with the objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were evaluated in 148 patients with non-small cell lung cancer who received nivolumab. RESULTS: When each lipid was separately evaluated, increased low-density lipoprotein (LDL)-cholesterol (P < 0.001), high-density lipoprotein (HDL)-cholesterol (P = 0.014), total cholesterol (P = 0.007), lauric acid (P = 0.015), myristic acid (P = 0.022), myristoleic acid (P = 0.035), stearic acid (P = 0.028), linoleic acid (P = 0.005), arachidic acid (P = 0.027), eicosadienoic acid (P = 0.017), dihomo-γ-linolenic acid (P = 0.036), and behenic acid levels (P = 0.032) were associated with longer PFS independent of programmed death ligand 1 (PD-L1) expression. Meanwhile, increased LDL-cholesterol (P < 0.001), HDL-cholesterol (P = 0.009), total cholesterol (P = 0.036), linoleic acid (P = 0.014), and lignoceric acid levels (P = 0.028) were associated with longer OS independent of PD-L1 expression. When multiple lipids were evaluated simultaneously, LDL-cholesterol (P = 0.003), HDL-cholesterol (P = 0.036), and lauric acid (P = 0.036) were independently predictive of PFS, and LDL-cholesterol (P = 0.008) and HDL-cholesterol (P = 0.031) were predictive of OS. ORR was not associated with any serum lipid. CONCLUSIONS: Based on the association of prolonged survival in patients with increased serum cholesterol and long-chain fatty acid levels, serum lipid levels may be useful for predicting the efficacy of immune checkpoint inhibitor therapy.

Combined assessment of the GAP index and body mass index at antifibrotic therapy initiation for prognosis of idiopathic pulmonary fibrosis.

Antifibrotic therapy (AFT) slows disease progression in patients with idiopathic pulmonary fibrosis (IPF). The Gender-Age-Physiology (GAP) index, was developed based on data at IPF diagnosis before the introduction of AFT and has not been evaluated in the AFT context. Further, recent advances have revealed the importance of body-composition factors in prognosis of IPF treated with AFT. This multi-centre, retrospective study aimed to evaluate the GAP index and body mass index (BMI) at the time of AFT initiation for predicting prognosis in patients with IPF. This study included two patient cohorts of IPF receiving AFT, Hamamatsu cohort (n = 110) and Seirei cohort (n = 119). The distribution of GAP stages I, II, and III was 38.2%, 43.6%, and 18.2%, respectively, in Hamamatsu cohort; in Seirei cohort, it was 41.2%, 50.4%, and 8.4%, respectively. In both cohorts, the GAP index distinctly classified prognosis into three groups (log-rank test). Interestingly, a lower BMI showed prognostic value independent of the GAP index in multivariate analyses. Subsequently, combining the GAP index with BMI at AFT initiation successfully divided the patients with IPF into four distinct prognoses. Assessment of the GAP index and BMI measurement at AFT initiation are important for predicting prognosis in patients with IPF.

Clinical Significance of Cold-Inducible RNA-Binding Protein in Idiopathic Pulmonary Fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is associated with a poor prognosis with variable clinical course. Early identification of patients at high risk for disease progression and death would lead to early therapeutic intervention and thereby improvement of outcomes. Cold-inducible RNA-binding protein (CIRBP) is produced in response to cellular stresses, which is implicated in multiple biological processes, including cell survival and proliferation. RESEARCH QUESTION: Is CIRBP a useful biomarker for predicting the outcomes of patients with IPF? STUDY DESIGN AND METHODS: This study included 95 and 93 patients with IPF from two independent hospitals (derivation and validation cohorts, respectively). The associations of serum CIRBP level on IPF diagnosis with disease progression within 1 year after diagnosis (ie, ≥10% relative decline in percent predicted FVC or death) and all-cause mortality were retrospectively analyzed. Discrimination performances for predicting these outcomes were evaluated using the c-index. RESULTS: Serum and lung tissue CIRBP levels were higher in patients with IPF than in control subjects. In the derivation cohort, the CIRBPhigh subgroup had significantly higher 1-year disease progression rates and lower cumulative survival rates than the CIRBPlow subgroup, and the results were replicated in the validation cohort. In multivariate analyses, high serum CIRBP level was independently associated with higher 1-year disease progression and all-cause mortality rates in both cohorts. Combining the Gender-Age-Physiology (GAP) and serum CIRBP models improved the c-indexes for predicting 1-year disease progression and all-cause mortality compared with that of each model alone. The c-indexes of serum CIRBP were particularly high in patients with GAP stage I. INTERPRETATION: This study successfully validated that serum CIRBP level was an independent predictor of 1-year disease progression and all-cause mortality in IPF. CIRBP is a promising biomarker that can help identify high-risk patients with IPF, especially in the early stage.

Switching antifibrotics in patients with idiopathic pulmonary fibrosis: a multi-center retrospective cohort study.

BACKGROUND: Currently, there are two antifibrotics used to treat idiopathic pulmonary fibrosis (IPF): pirfenidone and nintedanib. Antifibrotics slow disease progression by reducing the annual decline of forced vital capacity (FVC), which possibly improves outcomes in IPF patients. During treatment, patients occasionally switch antifibrotic treatments. However, prognostic implication of changing antifibrotics has not yet been evaluated. METHODS: This multi-center retrospective cohort study examined 262 consecutive IPF patients who received antifibrotic therapy. Antifibrotic agents were switched in 37 patients (14.1%). The prognoses were compared between the patient cohort that switched antifibrotics (Switch-IPF) and those without (Non-Switch-IPF) using propensity-score matched analyses. RESULTS: The median period between the initiation of antifibrotic therapy and the drug switch was 25.8 (12.7-35.3) months. The most common reasons for the switch were disease progression (n = 17) followed by gastrointestinal disorders (n = 12). Of the 37 patients that switched antifibrotics, only eight patients disrupted switched antifibrotics by their adverse reactions. The overall prognosis of the Switch-IPF cohort was significantly better than the Non-Switch-IPF cohort (median periods: 67.2 vs. 27.1 months, p < 0.0001). In propensity-score matched analyses that were adjusted to age, sex, FVC (%), history of acute exacerbation, and usage of long-term oxygen therapy, the Switch-IPF cohort had significantly longer survival times than the Non-Switch-IPF group (median 67.2 vs. 41.3 months, p = 0.0219). The second-line antifibrotic therapy showed similar survival probabilities than those in first-line antifibrotic therapy in multistate model analyses. CONCLUSION: Switching antifibrotics is feasible and may improve prognosis in patients with IPF. A further prospective study will be required to confirm clinical implication of switching the antifibrotics.

Cluster analysis-based clinical phenotypes of idiopathic interstitial pneumonias: associations with acute exacerbation and overall survival.

BACKGROUND: The precise classification of idiopathic interstitial pneumonia (IIP) is essential for selecting treatment as well as estimating clinical outcomes; however, this is sometimes difficult in clinical practice. Therefore, cluster analysis was used to identify the clinical phenotypes of IIPs, and its usefulness for predicting clinical outcomes was evaluated. METHODS: Cluster analysis was performed using clinical features including patients' demographics; histories; pulmonary function test data; and laboratory, physical and radiological findings. RESULTS: In 337 patients with IIPs, four clusters were identified: Cluster I, in which > 80% of the patients had autoimmune features; Cluster II, which had the lowest rate of smoking, the lowest percent predicted forced vital capacity (%FVC) and the lowest body mass index (BMI); Cluster III, which had the highest rate of smoking, the highest rate of dust exposure, the second lowest %FVC and normal BMI; and Cluster IV, which exhibited maintenance of %FVC and normal BMI. Cluster IV had significantly longer overall survival than Clusters II and III. Clusters I and III had significantly longer overall survival than Cluster II. Clusters II and III had a significantly higher cumulative incidence of acute exacerbation than Cluster IV. CONCLUSION: Cluster analysis using clinical features identified four clinical phenotypes of IIPs, which may be useful for predicting the risk of acute exacerbation and overall survival.

Extrinsic compression of the left main coronary artery: A rare cause of cardiogenic shock.

A left main coronary artery (LMCA) stenosis due to extrinsic compression by mediastinal tumor is a rare finding. In this case reports, we present a 63-year-old woman, who was transferred to the emergency department with chief complains of persistent chest and back pain. An electrocardiogram revealed diffuse ST-segment depression (elevation in lead aVR). Contrast-enhanced computed tomography (CT) showed a huge cystic mass above the left atrium. After the CT examination, she was temporarily in shock. Compression of the LMCA was evident on the CT angiography and a diagnosis of acute myocardial infarction due to compression of the LMCA by a tumor was made. An emergent resection of the tumor was performed. Histopathological assessment of the resected cyst revealed that it was a schwannoma. She made an uneventful postoperative recovery. A follow-up 3-dimensional CT scan performed after the operation confirmed no evidence of LMCA compression.

Palliative Care for Idiopathic Pulmonary Fibrosis Patients: Pulmonary Physicians' View.

CONTEXT: Although idiopathic pulmonary fibrosis (IPF) has worse outcomes compared with most malignancies, patients with IPF receive poor access to optimal palliative care. OBJECTIVES: This study aimed to characterize the practice of pulmonologists regarding palliative care and end-of-life communication for patients with IPF and identify perceived difficulties and barriers thereto. METHODS: Self-administered questionnaires were sent by mail to representative pulmonologists from Shizuoka prefecture, Japan. Physician-reported practice, difficulties, timing of end-of-life communication, and barriers related to palliative care were investigated. RESULTS: Among the 135 participants, 130 (96%) completed the questionnaire. Most of the participants reported that patients with IPF complained of dyspnea and cough. However, less morphine was prescribed for IPF than for lung cancer. The participants experienced greater difficulty in providing palliative care for IPF than for lung cancer. Moreover, actual end-of-life discussions in patients with IPF were conducted later than the physician-perceived ideal timing. Among the barriers identified, few established treatment and difficulty in predicting prognosis (odds ratio [OR] 2.0; P = 0.04), discrepancies in understanding and care goals among patients, family, and medical staff (OR 2.2; P = 0.03), and inadequate communication about goal of care (OR 2.3; P = 0.003) were significantly associated with the physician-perceived difficulties in providing palliative care for patients with IPF. CONCLUSION: Pulmonologists experienced greater difficulty in providing palliative care to patients with IPF than to those with lung cancer. Clinical studies on the optimal palliative care for patients with IPF are urgently required.

Acute exacerbation of idiopathic interstitial pneumonias related to chemotherapy for lung cancer: nationwide surveillance in Japan.

BACKGROUND: Chemotherapy-induced acute exacerbation (AEx) of idiopathic interstitial pneumonias (IIPs) seriously compromises the success of treatment of Japanese lung cancer patients. Here, we conducted a nationwide surveillance to clarify the risk of AEx and compare it with the survival benefit of chemotherapy for this population. METHODS: Advanced nonsmall cell lung cancer (NSCLC) or small cell lung cancer (SCLC) patients with IIPs were retrospectively analysed. For the surveillance of first-line chemotherapy in 2009, we gathered clinical data from 396 patients who received chemotherapy at 19 institutions between January 1990 and July 2009. In a consecutive retrospective study in 2012, we analysed data from 278 patients from 17 institutions who received second-line chemotherapy between April 2002 and March 2012. RESULTS: Of the 396 patients analysed, 13.1% developed chemotherapy-related AEx. Combination chemotherapies of carboplatin plus paclitaxel (CP) or carboplatin plus etoposide (CE) were frequently used as first-line treatments. The lowest incidence of AEx was 3.7% in CE, followed by 8.6% in CP. In the retrospective study, 16.2% of the 278 patients developed a second-line chemotherapy-related AEx. The overall response rate by second-line chemotherapy was 7.4% in NSCLC and 25.7% in SCLC. The median overall survival from second-line and first-line chemotherapy was 8.0 and 14.3 months in NSCLC, and 8.7 and 16.0 months in SCLC, respectively. CONCLUSION: Combination chemotherapies consisting of CP or CE are candidates for standard first-line treatments for patients with advanced lung cancer accompanied by IIP. Second-line chemotherapy should be considered for patients remaining fit enough to receive it.

Assessment of Immune-Related Interstitial Lung Disease in Patients With NSCLC Treated with Immune Checkpoint Inhibitors: A Multicenter Prospective Study.

INTRODUCTION: Programmed cell death protein 1 immune checkpoint inhibitors (ICIs) have been reported to improve the survival of patients with NSCLC. On the expansion of clinical administration for a variety of cancers, immune-related adverse events have been typically recognized to be associated with ICIs, therefore, necessitating the monitoring and management of these patients. Among immune-related adverse events, immune-related interstitial lung disease (ir-ILD) is a serious complication that interrupts treatment and can occasionally be fatal. However, no prospective studies have investigated the incidence of ir-ILD and associated risk factors for its development in the clinical setting. METHODS: This is a prospective cohort study consisting of patients with NSCLC treated with ICIs. Baseline characteristics, including laboratory data, pulmonary function tests, daily symptoms of dyspnea defined by the modified Medical Research Council, and antitumor response were assessed. RESULTS: Among the 138 patients with NSCLC who received anti-programmed cell death protein 1 monotherapy, 20 patients (14.5%) had ir-ILD within median 51.5 days (interquartile range: 29-147). This was approximately three times higher than those in clinical trials. A total of 11 patients (55.0%), including all eight patients with high-grade ir-ILD (≥grade 3), developed ir-ILD within 60 days. Impaired spirometry, decreased forced vital capacity and forced expiratory volume in 1 second, and daily symptoms of dyspnea measured using the modified Medical Research Council scale were identified as risk factors for ir-ILD development. In addition, combination assessment of forced vital capacity and forced expiratory volume in 1 second successfully classified patients at risk for ir-ILD development. CONCLUSIONS: The incidence of ir-ILD was substantially higher in the clinical setting. Assessment of spirometry and daily dyspneic symptoms before ICI treatment may be useful in monitoring and managing patients with NSCLC.

Intravoxel incoherent motion magnetic resonance imaging for predicting the long-term efficacy of immune checkpoint inhibitors in patients with non-small-cell lung cancer.

OBJECTIVES: Conventional evaluation of anti-tumor activity on the basis of tumor size is inadequate for immune checkpoint inhibitors (ICIs). We therefore aimed to assess the usefulness of intravoxel incoherent motion magnetic resonance imaging (IVIM-MRI) for evaluation of the therapeutic efficacy of ICIs. MATERIALS AND METHODS: A chest IVIM-MRI was performed before and 2, 4, and 8 weeks after administration of ICIs in patients with advanced non-small-cell lung cancer. Apparent diffusion coefficient (ADC), skewness of ADC (ADCskew), kurtosis of ADC (ADCkurt), true diffusion coefficient (D), pseudodiffusion coefficient (D*), and perfusion fraction (f) were evaluated at each evaluation point and changes from the baseline (Δ). RESULTS: Twenty patients were enrolled in this study. An increased ADC 8 weeks and decreased ADCkurt and ΔADCkurt 4 weeks after ICIs was associated with objective responses and longer progression-free survival (PFS). A decreased ΔADCskew at 4 weeks was associated with objective responses, disease control, and longer PFS and overall survival. There was no correlation between the efficacy of ICIs and D, D* and f. All of three patients who had pseudoprogression had decreased ΔADCskew at 4 weeks and two of them had decreased ΔADCkurt at 4 weeks. Inversely, all five patients who had progressive disease (PD) did not have increased ΔADCskew at 4 weeks and only one of them had decreased ΔADCkurt at 4 weeks. CONCLUSIONS: Changes in histograms of ADC may be useful for predicting long-term efficacy and distinguishing between pseudoprogression and actual PD after ICIs.

Heterogeneity analysis of PD-L1 expression and copy number status in EBUS-TBNA biopsy specimens of non-small cell lung cancer: Comparative assessment of primary and metastatic sites.

OBJECTIVES: Most patients with non-small cell lung cancer (NSCLC) are diagnosed at advanced stages where small biopsy specimens obtained through endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) are sometimes the only available samples for diagnosis. We aimed to determine whether EBUS-TBNA specimens are suitable for the evaluation of PD-L1 protein expression and copy number alterations (CNAs). MATERIALS AND METHODS: PD-L1 protein expression and CNAs in 71 EBUS-TBNA specimens of NSCLC were assessed. Sixty-eight corresponding transbronchial biopsy (TBB) specimens from primary sites, thirteen resected primary tumors, and six resected metastases were comparatively analyzed. PD-L1 expression in tumor cells was assessed by immunohistochemistry (E1L3N). Positivity of ≥1% was used as the cutoff. PD-L1 CNAs were assessed with fluorescent in situ hybridization and were classified into three categories: amplification, polysomy, and disomy. Concordance between EBUS-TBNA and other specimens was calculated. RESULTS: The cohort comprised 48 men (67.6%), 15 never-smokers (21.1%), and 39 adenocarcinomas (54.9%). The concordance of PD-L1 positivity between EBUS-TBNA and other specimens was moderate; κ = 0.63 for EBUS-TBNA vs. TBB, κ = 0.68 for EBUS-TBNA vs. resected primary tumors, and κ = 1.0 for EBUS-TBNA vs. resected metastases. The concordance of PD-L1 CNA status was comparable with that of PD-L1 expression: κ = 0.60 for EBUS-TBNA vs. TBB and κ = 0.74 for EBUS-TBNA vs. resected primary tumors. When PD-L1 copy number was assessed as a continuous variable, the correlation of PD-L1 CNAs was superior to that of PD-L1 expression. Intratumorally, PD-L1 copy number was less heterogeneous than protein expression in whole sections of resected tumors. CONCLUSION: EBUS-TBNA specimens can be used to assess PD-L1 CNAs and protein expression. Although spatial heterogeneity should be considered for accurate interpretation, the evaluation of PD-L1 CNAs provides more reproducible results than that of protein expression levels especially with regard to intratumoral heterogeneity.

The influence of frailty under direct oral anticoagulant use in patients with atrial fibrillation.

BACKGROUND: Frailty is a prognostic factor in patients with atrial fibrillation (AF). However, there is no report on the associations between frailty and clinical adverse events in patients with AF taking direct oral anticoagulants (DOAC). The factors related to the occurrence of clinical adverse events are still under discussion. Therefore, we examined the associations between frailty and clinical adverse events in patients with AF taking DOAC in daily clinical practice. METHODS: We retrospectively evaluated 240 consecutive patients with AF who had been newly prescribed DOAC in our hospital from April 2016 through May 2017. Data collected included Clinical Frailty Scale (CFS) scores, laboratory results and basic demographic information. RESULTS: During the mean follow-up period of 13.4 months, 20 patients died (7.6 per 100 person-years), stroke or systemic embolism occurred in seven patients (2.6 per 100 person-years) and major bleeding occurred in 11 patients (4.2 per 100 person-years). We defined these adverse events as composite end points, and we estimated adjusted HRs and 95% CIs for risk factors using the Cox proportional hazard regression model. Frailty (defined as a CFS score of 5 or more; HR: 3.71; 95% CI: 1.59 to 8.65), female sex (HR: 3.49; 95% CI: 1.73 to 7.07), serum albumin level (HR: 0.47; 95% CI: 0.28 to 0.79) and malignancy (HR: 4.02; 95% CI: 1.83 to 8.84) were independent predictors of the composite end points. CONCLUSIONS: Frailty, female sex, hypoalbuminaemia and malignancy were associated with clinical adverse events in patients with AF who were prescribed DOAC.

Nationwide cloud-based integrated database of idiopathic interstitial pneumonias for multidisciplinary discussion.

Multidisciplinary discussion (MDD) requiring close communication between specialists (clinicians, radiologists and pathologists) is the gold standard for the diagnosis of idiopathic interstitial pneumonias (IIPs). However, MDD by specialists is not always feasible because they are often separated by time and location. An online database would facilitate data sharing and MDD. Our aims were to develop a nationwide cloud-based integrated database containing clinical, radiological and pathological data of patients with IIPs along with a web-based MDD system, and to validate the diagnostic utility of web-based MDD in IIPs.Clinical data, high-resolution computed tomography images and lung biopsy slides from patients with IIPs were digitised and uploaded to separate servers to develop a cloud-based integrated database. Web-based MDD was performed using the database and video-conferencing to reach a diagnosis.Clinical, radiological and pathological data of 524 patients in 39 institutions were collected, uploaded and incorporated into the cloud-based integrated database. Subsequently, web-based MDDs with a pulmonologist, radiologist and pathologist using the database and video-conferencing were successfully performed for the 465 cases with adequate data. Overall, the web-based MDD changed the institutional diagnosis in 219 cases (47%). Notably, the MDD diagnosis yielded better prognostic separation among the IIPs than did the institutional diagnosis.This is the first study of developing a nationwide cloud-based integrated database containing clinical, radiological and pathological data for web-based MDD in patients with IIPs. The database and the web-based MDD system that we built made MDD more feasible in practice, potentially increasing accurate diagnosis of IIPs.