Comparison of platinum combination chemotherapy plus pembrolizumab versus platinum combination chemotherapy plus nivolumab-ipilimumab for treatment-naive advanced non-small-cell lung cancer in Japan (JCOG2007): an open-label, multicentre, randomised, phase 3 trial.

BACKGROUND: The combination of platinum-based chemotherapy and an antibody to PD-1 or to its ligand PD-L1, with or without an antibody to CTLA-4, has improved the survival of individuals with metastatic non-small-cell lung cancer (NSCLC). However, no randomised controlled trial has evaluated the survival benefit of adding a CTLA-4 inhibitor to platinum-based chemotherapy plus a PD-1 or PD-L1 inhibitor. METHODS: This open-label, randomised, phase 3 trial was conducted at 48 hospitals in Japan. Eligible patients were aged 20 years or older with previously untreated advanced NSCLC and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients with known driver oncogenes were excluded. Participants were randomly assigned (1:1) to receive platinum-based chemotherapy (four cycles) plus pembrolizumab (pembrolizumab group) or platinum-based chemotherapy (two cycles) plus nivolumab-ipilimumab (nivolumab-ipilimumab group). The primary endpoint was overall survival and assessed in all randomly assigned patients on an intention-to-treat basis. The trial is registered in the Japan Registry for Clinical Trials, jRCTs031210013, and is now closed to new enrolment and is ongoing. FINDINGS: Between patient accrual initiation on April 6, 2021, and discontinuation of the trial on March 30, 2023, 11 (7%) of 148 patients in the nivolumab-ipilimumab group had a treatment-related death. Because of the high number of treatment-related deaths, patient accrual was terminated early, resulting in 295 patients (236 [80%] male and 59 [20%] female) enrolled; the primary analysis was done on the basis of 117 deaths (fewer than the required 329 deaths). By May 25, 2023 (data cutoff), overall survival did not differ significantly between the nivolumab-ipilimumab group and the pembrolizumab group (median 23·7 months [95% CI 17·6-not estimable] vs 20·5 months [17·6-not estimable], respectively; hazard ratio 0·98 [90% CI 0·72-1·34]; p=0·46). Non-haematological adverse events of grade 3 or worse occurred in 87 (60%) of 146 patients in the nivolumab-ipilimumab group and 59 (41%) of 144 patients in the pembrolizumab group. The pembrolizumab group tended to have a better quality of life compared with the nivolumab-ipilimumab group. INTERPRETATION: The safety and efficacy data suggest an unfavourable benefit-risk profile for nivolumab-ipilimumab combined with platinum-based chemotherapy relative to pembrolizumab combined with platinum-based chemotherapy as a first-line treatment for patients with advanced NSCLC, although a definitive conclusion awaits an updated analysis of overall survival. FUNDING: The National Cancer Center Research and Development Fund and Japan Agency for Medical Research and Development.

Soluble form of the MDA5 protein in human sera.

Viral double-stranded RNA (dsRNA) is sensed by toll-like receptor 3 (TLR3) and retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs), including melanoma differentiation-associated gene 5 (MDA5). MDA5 recognizes the genome of dsRNA viruses and replication intermediates of single-stranded RNA viruses. MDA5 also plays an important role in the development of autoimmune diseases, such as Aicardi-Goutieres syndrome and type I diabetes. Patients with dermatomyositis with serum MDA5 autoantibodies (anti-CADM-140) are known to have a high risk of developing rapidly progressive interstitial lung disease and poor prognosis. However, there have been no reports on the soluble form of MDA5 in human serum. In the present study, we generated in-house monoclonal antibodies (mAbs) against human MDA5. We then performed immunohistochemical analysis and sensitive sandwich immunoassays to detect the MDA5 protein using two different mAbs (clones H27 and H46). As per the immunohistochemical analysis, the MDA5 protein was moderately expressed in the alveolar epithelia of normal lungs and was strongly expressed in the cytoplasm of lymphoid cells in the tonsils and acinar cells of the pancreas. Interestingly, soluble MDA5 protein was detectable in the serum, but not in the urine, of healthy donors. Soluble MDA5 protein was also detectable in the serum of patients with dermatomyositis. Immunoblot analysis showed that human cells expressed a 120 kDa MDA5 protein, while the 60 kDa MDA5 protein increased in the supernatant of peripheral mononuclear cells within 15 min after MDA5 agonist/double-strand RNA stimulation. Hydrogen deuterium exchange mass spectrometry revealed that an anti-MDA5 mAb (clone H46) bound to the epitope (415QILENSLLNL424) derived from the helicase domain of MDA5. These results indicate that a soluble MDA5 protein containing the helicase domain of MDA5 could be rapidly released from the cytoplasm of tissues after RNA stimulation.

Obesity may be a risk factor for transbronchial lung cryobiopsy-related adverse events in Japanese patients with interstitial lung disease.

BACKGROUND: Transbronchial lung cryobiopsy (TBLC) is known to be associated with a high incidence of adverse events. However, few studies have investigated the correlation between obesity and the risk of TBLC-related adverse events, especially in Asians, who are known to have characteristic differences in height and weight as compared to individuals of other ethnicities. METHODS: We retrospectively assessed 102 Japanese patients who underwent TBLC for the diagnosis of interstitial lung disease to evaluate the correlation between patient characteristics and the occurrence of TBLC-related adverse events (hemorrhage, pneumothorax, and acute exacerbation of interstitial lung disease). RESULTS: TBLC-related adverse events occurred in 19 patients (18.6 %), with hemorrhage being the most common adverse event (in 14 patients, 13.7 %). There was no correlation between age, sex, or pulmonary function test results and the occurrence of adverse events. The body mass index (BMI) cut-off predicting the occurrence of all adverse events was 26.6 kg/m2 (sensitivity of 0.389 and specificity of 0.852), and that predicting the occurrence of adverse events of hemorrhage was 26.8 kg/m2 (sensitivity of 0.462 and specificity of 0.907). Among patients with a BMI >26.8 kg/m2, adverse events of hemorrhage occurred in 37.5 % of cases, which was higher than among those with a BMI <26.8 kg/m2. CONCLUSIONS: Obesity is a risk factor for the incidence of TBLC-related adverse events, particularly adverse events of hemorrhage, in Japanese patients. The BMI cut-off values that predicted an increased frequency of TBLC-related adverse events and hemorrhage specifically were 26.6 and 26.8 kg/m2, respectively.

A prospective cohort study of periostin as a serum biomarker in patients with idiopathic pulmonary fibrosis treated with nintedanib.

This study investigated the utility of periostin, a matricellular protein, as a prognostic biomarker in patients with idiopathic pulmonary fibrosis (IPF) who received nintedanib. Monomeric and total periostin levels were measured by enzyme-linked immunosorbent assay in 87 eligible patients who participated in a multicenter prospective study. Forty-three antifibrotic drug-naive patients with IPF described in previous studies were set as historical controls. Monomeric and total periostin levels were not significantly associated with the change in forced vital capacity (FVC) or diffusing capacity of the lungs for carbon monoxide (DLCO) during any follow-up period. Higher monomeric and total periostin levels were independent risk factors for overall survival in the Cox proportional hazard model. In the analysis of nintedanib effectiveness, higher binarized monomeric periostin levels were associated with more favorable suppressive effects on decreased vital capacity (VC) and DLCO in the treatment group compared with historical controls. Higher binarized levels of total periostin were associated with more favorable suppressive effects on decreased DLCO but not VC. In conclusion, higher periostin levels were independently associated with survival and better therapeutic effectiveness in patients with IPF treated with nintedanib. Periostin assessments may contribute to determining therapeutic strategies for patients with IPF.

Survival and acute exacerbation for patients with idiopathic pulmonary fibrosis (IPF) or non-IPF idiopathic interstitial pneumonias: 5-year follow-up analysis of a prospective multi-institutional patient registry.

OBJECTIVE: Few prospective cohort studies with relatively large numbers of patients with non-idiopathic pulmonary fibrosis (non-IPF) of idiopathic interstitial pneumonia (IIP) have been described. We aimed to assess disease progression and cause of death for patients with non-IPF IIPs or IPF under real-life conditions. METHODS: Data were analysed for a prospective multi-institutional cohort of 528 IIP patients enrolled in Japan between September 2013 and April 2016. Diagnosis of IPF versus non-IPF IIPs was based on central multidisciplinary discussion, and follow-up surveillance was performed for up to 5 years after patient registration. Survival and acute exacerbation (AE) were assessed. RESULTS: IPF was the most common diagnosis (58.0%), followed by unclassifiable IIPs (35.8%) and others (6.2%). The 5-year survival rate for non-IPF IIP and IPF groups was 72.8% and 53.7%, respectively, with chronic respiratory failure being the primary cause of death in both groups. AE was the second most common cause of death for both non-IPF IIP (24.1%) and IPF (23.5%) patients. The cumulative incidence of AE did not differ significantly between the two groups (p=0.36), with a 1-year incidence rate of 7.4% and 9.0% in non-IPF IIP and IPF patients, respectively. We found that 30.2% and 39.4% of non-IPF IIP and IPF patients, respectively, who experienced AE died within 3 months after an AE event, whereas 55.8% and 66.7% of such patients, respectively, died within 5 years after registration. CONCLUSION: Closer monitoring of disease progression and palliative care interventions after AE are important for non-IPF IIP patients as well as for IPF patients.

Periostin Is a Biomarker of Rheumatoid Arthritis-Associated Interstitial Lung Disease.

Periostin was investigated as a biomarker for rheumatoid arthritis-associated interstitial lung disease (RA-ILD). This prospective study measured serum monomeric and total periostin, Klebs von den Lungen-6 (KL-6), surfactant protein D (SP-D), and lactate dehydrogenase (LDH) in 19 patients with RA-ILD, 20 RA without ILD, and 137 healthy controls (HC). All biomarkers were higher in RA-ILD than HC or RA without ILD. KL-6 accurately detected ILD in RA patients (area under curve [AUC] = 0.939) and moderately detected SP-D and monomeric and total periostin (AUC = 0.803, =0.767, =0.767, respectively). Monomeric and total periostin were negatively correlated with normal lung area and positively correlated with honeycombing, reticulation, fibrosis score, and the traction bronchiectasis grade but not inflammatory areas. Serum levels of SP-D, KL-6, and LDH did not correlate with the extent of those fibrotic areas on high-resolution CT. Serum monomeric and total periostin were higher in patients with RA-ILD with definite usual interstitial pneumonia pattern compared with other ILD patterns. Immunohistochemical analyses of biopsy or autopsy lung tissues from RA-ILD during the chronic phase and acute exacerbation showed that periostin was expressed in fibroblastic foci but not inflammatory or dense fibrosis lesions. Periostin is a potential biomarker for diagnosis, evaluating fibrosis, and deciding therapeutic strategies for patients with RA-ILD.

Clinical significance of high monocyte counts for the continuous treatment with nintedanib.

BACKGROUND: Nintedanib is now widely used to treat interstitial lung disease (ILD). Adverse events, which occur in not a few patients, make it difficult to continue nintedanib treatment, but the risk factors for adverse events are not well understood. METHODS: In this retrospective cohort study, we enrolled 111 patients with ILDs treated with nintedanib and investigated the factors involved in starting dosage reduction, withdrawal, or discontinuation within 12 months, even with appropriate symptomatic treatment. We also examined the efficacy of nintedanib in reducing the frequency of acute exacerbations and the prevention of pulmonary function reduction. RESULTS: Patients with high monocyte counts (> 0.454 × 109/L) had a significantly higher frequency of treatment failure, such as dosage reduction, withdrawal, or discontinuation. High monocyte count was as significant a risk factor as body surface area (BSA). Regarding efficacy, there was no difference in the frequency of acute exacerbations or the amount of decline in pulmonary function within 12 months between the normal (300 mg) and reduced (200 mg) starting dosage groups. CONCLUSION: Our study results indicate that patients with higher monocyte counts (> 0.454 × 109/L) should very careful about side effects with regard to nintedanib administration. Like BSA, a higher monocyte count is considered a risk factor for nintedanib treatment failure. There was no difference in FVC decline and frequency of acute exacerbations between the starting doseage of nintedanib, 300 mg and 200 mg. Considering the risk of withdrawal periods and discontinuation, a reduced starting dosage may be acceptable in the patients with higher monocyte counts or small body sizes.

The Characteristic of Transbronchial Lung Cryobiopsy in the Pathological Diagnosis of Hypersensitivity Pneumonitis.

BACKGROUND: Transbronchial lung cryobiopsy (TBLC) has widely used for the diagnosis of diffuse lung disease. However, it remains unclear whether TBLC is useful for the diagnosis in hypersensitivity pneumonitis (HP). METHODS: We investigated 18 patients who underwent TBLC and were diagnosed with HP based on pathology or multidisciplinary discussion (MDD). Of the 18 patients, 12 had fibrotic HP (fHP), 2 had non-fibrotic HP (non-fHP) diagnosed with MDD. The remaining 4 patients were diagnosed with fHP by pathology but not by MDD because of clinical features. The radiology and pathology of these cases were compared. RESULTS: All patients with fHP showed radiological findings of inflammation, fibrosis, and airway disease. Conversely, pathology showed fibrosis and inflammation in 11 of 12 cases (92%), but airway disease was significantly less common with 5 cases (42%) (p = 0.014). Non-fHP showed inflammatory cell infiltration mainly in the centrilobule on pathology, which was consistent with radiology. Granulomas were found in 5 patients with HP (36%). In the non-HP group, airway-centered interstitial fibrosis was observed in 3 patients (75%) with pathology. CONCLUSIONS: The pathology with TBLC is difficult to evaluate airway disease of HP. We need to understand this characteristic of TBLC to make a MDD diagnosis of HP.

Impact of the pretreatment prognostic nutritional index on the survival after first-line immunotherapy in non-small-cell lung cancer patients.

BACKGROUND: Immunotherapy has become a standard-of-care for patients with non-small-cell lung cancer (NSCLC). Although several biomarkers, such as programmed cell death-1, have been shown to be useful in selecting patients likely to benefit from immune checkpoint inhibitors (ICIs), more useful and reliable ones should be investigated. The prognostic nutritional index (PNI) is a marker of the immune and nutritional status of the host, and is derived from serum albumin level and peripheral lymphocyte count. Although several groups reported its prognostic role in patients with NSCLC receiving a single ICI, there exist no reports which have demonstrated its role in the first-line ICI combined with or without chemotherapy. MATERIALS AND METHODS: Two-hundred and eighteen patients with NSCLC were included in the current study and received pembrolizumab alone or chemoimmunotherapy as the first-line therapy. Cutoff value of the pretreatment PNI was set as 42.17. RESULTS: Among 218 patients, 123 (56.4%) had a high PNI (≥42.17), while 95 (43.6%) had a low PNI (<42.17). A significant association was observed between the PNI and both the progression-free survival (PFS; hazard ratio [HR] = 0.67, 95% confidence interval [CI]: 0.51-0.88, p = 0.0021) and overall survival (OS; HR = 0.46, 95% CI: 0.32-0.67, p < 0.0001) in the entire population, respectively. The multivariate analysis identified the pretreatment PNI as an independent prognosticator for the PFS (p = 0.0011) and OS (p < 0.0001), and in patients receiving either pembrolizumab alone or chemoimmunotherapy, the pretreatment PNI remained an independent prognostic factor for the OS (p = 0.0270 and 0.0006, respectively). CONCLUSION: The PNI might help clinicians appropriately identifying patients with better treatment outcomes when receiving first-line ICI therapy.

Enhanced immune complex formation in the lungs of patients with dermatomyositis.

BACKGROUND: Interstitial lung disease is frequently comorbid with dermatomyositis and has a poor prognosis, especially in patients with the anti-melanoma differentiation-associated gene 5 (MDA5) autoantibody. However, the pathogenesis of dermatomyositis-related interstitial lung disease remains unclear. METHODS: We examined 18 and 19 patients with dermatomyositis-related interstitial lung disease and idiopathic pulmonary fibrosis (control), respectively. Lung tissues obtained from these patients were semi-quantitatively evaluated by immunohistochemical staining with in-house anti-human MDA5 monoclonal antibodies, as well as anti-human immunoglobulin (Ig) G, IgM, IgA, and complement component 3(C3) antibodies. We established human MDA5 transgenic mice and treated them with rabbit anti-human MDA5 polyclonal antibodies, and evaluated lung injury and Ig and C3 expression. RESULTS: MDA5 was moderately or strongly expressed in the lungs of patients in both groups, with no significant differences between the groups. However, patients with dermatomyositis-related interstitial lung disease showed significantly stronger expression of C3 (p < 0.001), IgG (p < 0.001), and IgM (p = 0.001) in the lungs than control. Moreover, lung C3, but IgG, IgA, nor IgM expression was significantly stronger in MDA5 autoantibody-positive dermatomyositis-related interstitial lung disease (n = 9) than in MDA5 autoantibody-negative dermatomyositis-related interstitial lung disease (n = 9; p = 0.022). Treatment with anti-MDA5 antibodies induced lung injury in MDA5 transgenic mice, and strong immunoglobulin and C3 expression was observed in the lungs of the mice. CONCLUSION: Strong immunoglobulin and C3 expression in the lungs involve lung injury related to dermatomyositis-related interstitial lung disease. Enhanced immune complex formation in the lungs may contribute to the poor prognosis of MDA5 autoantibody-positive dermatomyositis-related interstitial lung disease.

Characteristics of Postoperative Patients with Breast Cancer Aged 65 Years and Older.

Objective: This study aimed to compare postoperative patients with breast cancer aged ≥65 years with those aged <65 years and clarify the characteristics of postoperative patients with breast cancer aged ≥65. Methods: In total, 376 patients in whom we were able to evaluate survey items one month after surgery were included in the study. Comorbidity, including diabetes mellitus and hypertension, shoulder range of motion (ROM), upper-limb function, and psychological problems, was evaluated. Results: Hypertension and diabetes mellitus were significantly higher in patients aged ≥65 years (the elderly group) than in those aged <65 years (the non-elderly group) (p < 0.05). Preoperative shoulder flexion ROM was significantly restricted in the elderly group compared with the non-elderly group (p < 0.05). Preoperative shoulder abduction ROM was significantly restricted in the elderly group compared with the non-elderly group (p < 0.05). At one month after surgery, upper-limb function was more impaired in the non-elderly group than in the elderly group (p < 0.05). In both groups, both ROM and upper-limb function were significantly impaired one month after surgery compared with before surgery (p < 0.05). Conclusions: Postoperative patients with breast cancer aged ≥65 years should be careful about risk management and intervention during rehabilitation. Preoperative evaluation of shoulder ROM should be performed because patients aged ≥65 years have limited ROM before surgery.

Nintedanib in Asian patients with progressive fibrosing interstitial lung diseases: Results from the INBUILD trial.

BACKGROUND AND OBJECTIVE: In the INBUILD trial in patients with progressive fibrosing interstitial lung diseases (ILDs), nintedanib reduced the rate of decline in forced vital capacity (FVC) with an adverse event profile characterized mainly by gastrointestinal events. We analysed the effects of nintedanib in the subset of Asian subjects. METHODS: Subjects with fibrosing ILDs other than idiopathic pulmonary fibrosis who had shown progression of ILD at any time within the prior 24 months despite management deemed appropriate in clinical practice were randomized to receive nintedanib or placebo. We analysed the rate of decline in FVC (ml/year) over 52 weeks in all Asian subjects and in Asian subjects with a usual interstitial pneumonia (UIP)-like fibrotic pattern on high-resolution computed tomography (HRCT). RESULTS: One hundred sixty-four subjects in the INBUILD trial were of Asian race. The rate of decline in FVC (ml/year) over 52 weeks in this subgroup was -116.8 in the nintedanib group and -207.9 in the placebo group (difference: 91.0 [95% CI: 8.1, 173.9]; nominal p = 0.03). In Asian subjects with a UIP-like fibrotic pattern on HRCT, the rate of decline in FVC (ml/year) over 52 weeks was -130.1 in the nintedanib group and -224.2 in the placebo group (difference: 94.1 [5.5, 182.7]; nominal p = 0.04). Adverse events led to treatment discontinuation in 19.0% of the nintedanib group and 13.8% of the placebo group. CONCLUSION: In Asian patients with progressive fibrosing ILDs, nintedanib reduced the rate of decline in FVC with adverse events that were manageable for most patients.

Phase II study of durvalumab (MEDI 4736) plus carboplatin and etoposide in elderly patients with extensive stage small cell lung cancer: Study protocol of turtle study (LOGIK 2003).

BACKGROUND: Recently, the addition of antiprogrammed cell death-ligand 1 (PD-L1) monoclonal antibodies, including durvalumab and atezolizumab to platinum-based chemotherapy, has demonstrated clinical benefits in patients with untreated advanced small cell lung cancer (SCLC). However, these clinical trials comprised small populations of elderly patients with SCLC. Therefore, the safety of anti-PD-L1 immunotherapy plus platinum and etoposide in elderly patients remains unclear. METHODS: This prospective, multicenter, single-arm study was designed to evaluate the safety and efficacy of durvalumab plus carboplatin and etoposide in untreated elderly patients (aged > 75) with extensive stage (ES) SCLC. A total of 40 patients were recruited. Patients received up to four cycles of durvalumab 1500 mg and carboplatin at a dose equivalent to an area under the curve of 5 on day 1, and etoposide 80 mg/m2 on days 1 to 3 every 3 weeks as induction treatment, followed by durvalumab maintenance treatment every 4 weeks. The primary endpoint was safety as measured by adverse events according to the Common Terminology Criteria for Adverse Events version 5.0, laboratory analyses, vital signs, and physical examination. Key secondary endpoints were objective response rate, median progression-free survival, 12-month overall survival rate, and the completion rate for four cycles of induction chemotherapy. DISCUSSION: The present study was designed to evaluate the safety of durvalumab plus carboplatin and etoposide in elderly patients with ES-SCLC.

Sensitivity of transbronchial lung cryobiopsy in the diagnosis of different interstitial lung diseases.

The accuracy of transbronchial lung cryobiopsy (TBLC) in each disease for pathological and multidisciplinary discussion (MDD) diagnosis is not yet established. METHOD: We investigated 431 patients who were classified by MDD diagnosis and were grouped into the disease categories. For each category or disease, we used TBLC samples to calculate the sensitivities of the pathological diagnosis compared with MDD diagnoses. Further, we compared these sensitivities to pathological diagnoses with all clinical/radiological information. RESULT: The sensitivity for diagnosing idiopathic interstitial pneumonia (IIPs) with TBLC was higher than connective tissue disease associated ILD (CTD-ILD). Idiopathic nonspecific interstitial pneumonia (iNSIP), fibrotic hypersensitivity pneumonitis, and some CTD-ILDs were diagnosed with lower sensitivities compared to IPF. The sensitivity of pathological diagnosis with all clinical/radiological information in IPF was higher than in iNSIP, but not significantly different from other diseases. The overall sensitivity of the pathological diagnosis with clinical/radiological information was 69.0%, significantly higher than without clinical/radiological information. CONCLUSION: The sensitivity of pathological diagnosis with TBLC was low for some diseases except IPF. The addition of all clinical/radiological information increased the sensitivity of pathology diagnosis by TBLC, which was no less sensitive than IPF for all diseases except iNSIP.

Gut microbiota diversity and specific composition during immunotherapy in responders with non-small cell lung cancer.

Cancer immunotherapy including immune checkpoint inhibitors (ICI) has revolutionized non-small cell lung cancer (NSCLC) therapy. Recently, the microbiota status "before" initiation of ICI therapy has been emphasized as a predictive biomarker in patients undergoing ICI therapy. However, the microbiota diversity and composition "during" ICI therapy is unknown. This multicenter, prospective observational study analyzed both saliva and feces from 28 patients with NSCLC. We performed 16S ribosomal RNA gene sequencing, then analyzed associations of oral and gut microbiota diversity or composition with ICI response. At the genus level, the alpha diversity of the gut microbiota was significantly greater in responders (n = 17) than in non-responders (n = 11) (Chao 1, p = 0.0174; PD whole tree, p = 0.0219; observed species, p = 0.0238; Shannon, p = 0.0362), while the beta diversity of the gut microbiota was significantly different (principal coordinates analysis, p = 0.035). Compositional differences in the gut microbiota were observed between the two groups; in particular, g_Blautia was enriched in responders, whereas o_RF32 order unclassified was enriched in non-responders. The progression-free survival (PFS) of patients enriched gut microbiota of g_Blautia was significantly longer [median survival time (MST): not reached vs. 549 days, p = 0.0480] and the PFS of patients with gut microbiota of o_RF32 unclassified was significantly shorter (MST: 49 vs. 757 days, p = 0.0205). There were no significant differences between groups in the oral microbiota. This study revealed a strong association between gut microbiota diversity and ICI response in NSCLC patients. Moreover, specific gut microbiota compositions may influence the ICI response. These findings might be useful in identifying biomarkers to predict ICI response.

Positive Autoantibody Is Associated with Malignancies in Patients with Idiopathic Interstitial Pneumonias.

Various autoantibodies are associated with clinical outcomes in patients with idiopathic interstitial pneumonias (IIPs). We retrospectively analyzed the association between autoantibodies and malignancies in IIP patients. Comprehensive analyses of autoantibodies were performed using immunoprecipitation and enzyme-linked immunosorbent assays in 193 consecutive IIP patients. Cancer-related factors were analyzed using logistic regression analysis. In total, 22 of 193 patients (11.4%) with IIP had malignant disease. In univariate analysis, positivity for any autoantibody (odds ratio (OR), 3.1; 95% confidence interval (CI), 1.2-7.7; p = 0.017) and antinuclear antibody titer ≥1:320 (OR, 3.4; CI, 1.2-9.8; p = 0.024) were significantly associated with malignancies. Positive anti-aminoacyl tRNA synthetase (ARS) (OR, 3.7; CI, 0.88-15.5; p = 0.074) and anti-Ro52 antibody (OR, 3.2; CI, 0.93-11.2; p = 0.065) tended to be associated with malignancies. In multivariate analysis, independent risk factors were male sex (OR, 3.7; CI, 1.0-13.5; p = 0.029) and positivity for any autoantibody (OR, 3.9; CI, 1.5-10.1; p = 0.004) in model 1, and male sex (OR, 3.9; CI, 1.0-15.3; p = 0.049), antinuclear antibody titer ≥1:320 (OR, 4.2; CI, 1.4-13.3; p = 0.013), and positivity for anti-ARS antibody (OR, 6.5; CI, 1.2-34.1; p = 0.026) in model 2. Positivity for any autoantibody, antinuclear and anti-ARS antibodies, and male sex were independent risk factors for malignancies in IIP patients. Testing autoantibodies in IIP patients might help the early diagnosis of malignancies.

Nationwide retrospective observational study of idiopathic dendriform pulmonary ossification: clinical features with a progressive phenotype.

BACKGROUND: Diffuse pulmonary ossification is a specific lung condition that is accompanied by underlying diseases. However, idiopathic dendriform pulmonary ossification (IDPO) is extremely rare, and the clinical features remain unclear. In this study, we aimed to report the clinical characteristics of IDPO. METHODS: We conducted a nationwide survey of patients with IDPO from 2017 to 2019 in Japan and evaluated the clinical, radiological, and histopathological findings of patients diagnosed with IDPO. RESULTS: Twenty-two cases of IDPO were identified. Most subjects (82%) were male, aged 22-56 years (mean (SD), 37.9 (9.1)) at diagnosis. Nearly 80% of the subjects were asymptomatic, and the condition was discovered during a medical check-up. However, 36% of the subjects showed a decline in forced vital capacity (%FVC) predicted <80% at diagnosis. The typical radiological features of high-resolution CT (HRCT) are calcified branching structures that are predominantly distributed in the lower lung fields without any other conspicuous finding. Histopathological analysis also showed dendriform ossified lesions from the intraluminal areas to interstitial areas. Notably, during the follow-up period of 20 years, disease progression was found in 88% on HRCT and more than 50% on pulmonary function tests (FVC and/or forced expiratory volume in 1 s). Two cases with rapid decline of 10% /year in %FVC predicted were observed.)) at diagnosis. Nearly 80% of the subjects were asymptomatic, and the condition was discovered during a medical check-up. However, 36% of the subjects showed a decline in forced vital capacity (%FVC) predicted <80% at diagnosis. The typical radiological features of high-resolution CT (HRCT) are calcified branching structures that are predominantly distributed in the lower lung fields without any other conspicuous finding. Histopathological analysis also showed dendriform ossified lesions from the intraluminal areas to interstitial areas. Notably, during the follow-up period of 20 years, disease progression was found in 88% on HRCT and more than 50% on pulmonary function tests (FVC and/or forced expiratory volume in 1 s). Two cases with rapid decline of 10% /year in %FVC predicted were observed. CONCLUSIONS: IDPO develops at a young age with gradually progressive phenotype. Further research and long-term (>20 years) follow-up are required to clarify the pathogenesis and clinical findings in IDPO.

Effects of nintedanib on disease progression and safety in Japanese patients with progressive fibrosing interstitial lung diseases: Further subset analysis from the whole INBUILD trial.

BACKGROUND: A previous subgroup analysis of data from the INBUILD trial showed that nintedanib reduced the annual rate of decline in forced vital capacity (FVC) in Japanese patients with progressive fibrosing interstitial lung diseases (PF-ILDs). The safety profile of nintedanib over 52 weeks in Japanese patients was similar to that of the overall population. METHODS: Using data from 108 Japanese patients with PF-ILDs who had received at least 1 dose of study medication in the INBUILD trial, we evaluated the effect of nintedanib on disease progression and assessed the safety profile over the whole trial period (i.e., a longer duration than the prior analysis) compared with placebo. ILD progression was defined as an absolute decline in FVC ≥10% predicted vs baseline. RESULTS: Over the whole trial, in Japanese patients with PF-ILDs, nintedanib numerically lowered the risk of progression of ILD or death (hazard ratio [HR], 0.66; 95% confidence intervals [CI]: 0.37, 1.16), acute exacerbation of ILD or death (HR, 0.28; 95% CI: 0.09, 0.83), and death (HR, 0.41; 95% CI: 0.11, 1.51). The most common adverse event over the whole trial in nintedanib-treated Japanese patients was diarrhea, which was manageable for most patients by dose reduction and interruption. The safety profile of nintedanib in this longer duration analysis was consistent with that previously reported. CONCLUSIONS: In this analysis of data from Japanese patients with PF-ILDs, nintedanib nominally reduced the risk of clinically meaningful outcomes reflecting disease progression, including death, over the whole trial, and no new safety concerns were observed. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT02999178.

IgG4-related lung disease with a desquamative interstitial pneumonia pattern radiologically and pathologically.

A man in his 60s exhibited persistent dry cough and dyspnoea, which persisted even after smoking cessation. Chest high-resolution CT showed diffuse ground-glass opacities in the subpleural areas of both lungs. He underwent bronchoscopy, but no definitive diagnosis could be made. Histopathological analysis of the specimen obtained by surgical lung biopsy showed a desquamative interstitial pneumonia (DIP) pattern, with lymphocyte and plasma cell infiltrates in the alveolar septa; the ratio of IgG and IgG4-positive cells was more than 90%. He quit smoking, but the radiological findings worsened. Based on the pathological findings, we diagnosed the patient with DIP due to IgG4-related lung disease. Prednisolone was initiated, and the symptoms and radiological findings improved.

Prognostic implication of IgG4 and IgG1-positive cell infiltration in the lung in patients with idiopathic interstitial pneumonia.

Immunoglobulin (Ig) G4-positive cells are rarely observed in the lungs of patients with idiopathic interstitial pneumonias (IIPs). IgG1 may be more pathogenic than IgG4, with IgG4 having both pathogenic and protective roles in IgG4-related disease (IgG4-RD). However, the role of both IgG1 and IgG4 in IIPs remains unclear. We hypothesized that patients with IgG4-positive interstitial pneumonia manifest different clinical characteristics than patients with IgG4-RD. Herein, we identified the correlation of the degree of infiltration of IgG1- and IgG4-positive cells with IIP prognosis, using a Japanese nationwide cloud-based database. We included eighty-eight patients diagnosed with IIPs after multidisciplinary discussion, from April 2009 to March 2014. IgG4-positive cell infiltration was identified in 12/88 patients with IIPs and 8/41 patients with idiopathic pulmonary fibrosis (IPF). Additionally, 31/88 patients with IIPs and 19/41 patients with IPF were diagnosed as having IgG1-positive cell infiltration. IgG4-positive IIPs tended to have a better prognosis. Conversely, overall survival in cases with IgG1-positive IPF was significantly worse. IIPs were prevalent with IgG1- or IgG4-positive cell infiltration. IgG1-positive cell infiltration in IPF significantly correlated with a worse prognosis. Overall, evaluating the degree of IgG1-positive cell infiltration may be prognostically useful in cases of IPF.