A case of autoimmune pulmonary alveolar proteinosis during the course of treatment of rapidly progressive interstitial pneumonia associated with anti-MDA5 antibody-positive dermatomyositis.

BACKGROUND: Autoimmune pulmonary alveolar proteinosis (APAP) is a diffuse lung disease that causes abnormal accumulation of lipoproteins in the alveoli; however, its pathogenesis remains unclear. Recently, APAP cases have been reported during the course of dermatomyositis. The combination of these two diseases may be coincidental; however, it may have been overlooked because differentiating APAP from a flare-up of interstitial pneumonia associated with dermatomyositis is challenging. This didactic case demonstrates the need for early APAP scrutiny. CASE PRESENTATION: A 50-year-old woman was diagnosed with anti-melanoma differentiation-associated gene 5 (anti-MDA5) antibody-positive dermatitis and interstitial pneumonia in April 2021. The patient was treated with corticosteroids, tacrolimus, and cyclophosphamide pulse therapy for interstitial pneumonia complicated by MDA5 antibody-positive dermatitis, which improved the symptoms and interstitial pneumonia. Eight months after the start of treatment, a new interstitial shadow appeared that worsened. Therefore, three additional courses of cyclophosphamide pulse therapy were administered; however, the respiratory symptoms and interstitial shadows did not improve. Respiratory failure progressed, and 14 months after treatment initiation, bronchoscopy revealed turbid alveolar lavage fluid, numerous foamy macrophages, and numerous periodic acid-Schiff-positive unstructured materials. Blood test results revealed high anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) antibody levels, leading to a diagnosis of APAP. The patient underwent whole-lung lavage, and the respiratory disturbance promptly improved. Anti-GM-CSF antibodies were measured from the cryopreserved serum samples collected at the time of diagnosis of anti-MDA5 antibody-positive dermatitis, and 10 months later, both values were significantly higher than normal. CONCLUSIONS: This is the first report of anti-MDA5 antibody-positive dermatomyositis complicated by interstitial pneumonia with APAP, which may develop during immunosuppressive therapy and be misdiagnosed as a re-exacerbation of interstitial pneumonia. In anti-MDA5 antibody-positive dermatomyositis, APAP comorbidity may have been overlooked, and early evaluation with bronchoalveolar lavage fluid and anti-GM-CSF antibody measurements should be considered, keeping the development of APAP in mind.

Glasgow prognostic score and body mass index predict short-term discontinuation of the antifibrotic agents pirfenidone and nintedanib.

BACKGROUND: The antifibrotic agents pirfenidone and nintedanib have been shown to be effective in patients with idiopathic pulmonary fibrosis (IPF). However, discontinuation of antifibrotic drugs is a major clinical concern because of the lack of alternative treatment options. Therefore, we identified factors that may be useful for predicting the termination of antifibrotic agents. METHODS: We retrospectively recruited 280 IPF patients treated with antifibrotic drugs between 2009 and 2018 from seven regional core hospitals in Gunma prefecture, Japan. RESULTS: At four months, the short-term discontinuation group exhibited a significantly worse prognosis in the pirfenidone group and a poorer prognosis in the nintedanib group compared to that in the continuation group. The discontinuation group of pirfenidone at 4 months exhibited lower albumin and higher C-reactive protein (CRP) levels in the sera compared to the group that continued treatment for more than 4 months. In multivariate analysis, the Glasgow prognostic score (GPS), well known as a predictor of cancer prognosis, which comprises serum CRP and albumin levels, predicted early discontinuation and prognosis in the pirfenidone group, whereas the body mass index (BMI) predicted early discontinuation of nintedanib. A high GPS, with both albumin <3.5 g/dL and CRP >1.0 mg/dL, was associated with a poorer prognosis in the pirfenidone group. CONCLUSION: GPS and BMI were significant factors for short-term pirfenidone and nintedanib discontinuation, respectively. Initial evaluation of GPS and BMI prior to antifibrotic therapy may contribute to less interrupted IPF management, thus leading to better prognostic outcomes in patients with IPF.

Japanese clinical practice guide 2022 for hypersensitivity pneumonitis.

Considering recently published two guidelines for the diagnosis of hypersensitivity pneumonitis (HP), the Japanese Respiratory Society (JRS) has now published its own Japanese clinical practice guide for HP. Major types of HP in Japan include summer-type, home-related, bird-related, farmer's lung, painter's lung, humidifier lung, and mushroom grower's lung. Identifying causative antigens is critical for increasing diagnostic confidence, as well as improving prognosis through appropriate antigen avoidance. This guide proposes a comprehensive antigen questionnaire including the outbreak sources reported in Japan. Drawing on the 2021 CHEST guideline, this guide highlights the antigen identification confidence level and adaptations for environmental surveys. The detection of specific antibodies against causative antigens is an important diagnostic predictor of HP. In Japan, the assessments of bird-specific IgG (pigeons, budgerigars) and the Trichosporon asahii antibody are covered by medical insurance. Although this guide adopts the 2020 ATS/JRS/ALAT guideline diagnostic criteria based on the combination of imaging findings, exposure assessment, bronchoalveolar lavage lymphocytosis, and histopathological findings, it added some annotations to facilitate the interpretation of the content and correlate the medical situation in Japan. It recommends checking biomarkers; seasonal changes in the KL-6 concentration (increase in winter for bird-related HP/humidifier lung and in summer for summer-type HP) and high KL-6 concentrations providing a basis for the suspicion of HP. Antigen avoidance is critical for disease management of HP. This guide also addresses the pharmacological management of HP, highlighting the treatment strategy for fibrotic HP including combination therapies with anti-inflammatory/immunosuppressive and antifibrotic drugs.

The oncogenic role of LGR6 overexpression induced by aberrant Wnt/ß-catenin signaling in lung cancer.

BACKGROUND: Molecular abnormalities in the Wnt/ß-catenin pathway confer malignant phenotypes in lung cancer. Previously, we identified the association of leucine-rich repeat-containing G protein-coupled receptor 6 (LGR6) with oncogenic Wnt signaling, and its downregulation upon ß-catenin knockdown in non-small cell lung cancer (NSCLC) cells carrying CTNNB1 mutations. The aim of this study was to explore the mechanisms underlying this association and the accompanying phenotypes. METHODS: LGR6 expression in lung cancer cell lines and surgical specimens was analyzed using quantitative RT-PCR and immunohistochemistry. Cell growth was assessed using colony formation assay. Additionally, mRNA sequencing was performed to compare the expression profiles of cells subjected to different treatments. RESULTS: LGR6 was overexpressed in small cell lung cancer (SCLC) and NSCLC cell lines, including the CTNNB1-mutated NSCLC cell lines HCC15 and A427. In both cell lines, LGR6 knockdown inhibited cell growth. LGR6 expression was upregulated in spheroids compared to adherent cultures of A427 cells, suggesting that LGR6 participates in the acquisition of cancer stem cell properties. Immunohistochemical analysis of lung cancer specimens revealed that the LGR6 protein was predominantly overexpressed in SCLCs, large cell neuroendocrine carcinomas, and lung adenocarcinomas, wherein LGR6 overexpression was associated with vascular invasion, the wild-type EGFR genotype, and an unfavorable prognosis. Integrated mRNA sequencing analysis of HCC15 and A427 cells with or without LGR6 knockdown revealed LGR6-related pathways and genes associated with cancer development and stemness properties. CONCLUSIONS: Our findings highlight the oncogenic roles of LGR6 overexpression induced by aberrant Wnt/ß-catenin signaling in lung cancer.

Effective treatment with mepolizumab in a patient with severe eosinophilic granulomatosis with polyangiitis complicated with small intestine perforation.

Eosinophilic granulomatosis with polyangiitis (EGPA) is systemic vasculitis caused by eosinophilia affecting small to medium-sized blood vessels, which damages the organs. Antineutrophil cytoplasmic antibody-associated vasculitis EGPA treatment guidelines added anti-interleukin-5 antibody mepolizumab to the standard treatment protocol for active-non-severe EGPA based on the MIRRA study. Nevertheless, the role of mepolizumab in treating patients with active severe EGPA has not been established. We treated a patient with EGPA complicated with small intestine perforation using steroid pulse intravenous, high-dose glucocorticoids, intravenous high-dose immunoglobulin therapy, and mepolizumab without immunosuppression agents; the patient went into remission, suggesting that mepolizumab is an effective therapeutic agent that could lead to remission in severe EGPA.

Sustained antitumor response to lenvatinib with weekend-off and alternate-day administration in chemotherapy-refractory thymic carcinoma: a case report.

Lenvatinib is a multitargeted kinase inhibitor and maintaining its dose intensity has been shown to be beneficial in patients with thyroid and hepatocellular carcinomas. However, most patients require lenvatinib interruption and dose reduction due to the high incidence of adverse events (AEs). Lenvatinib was recently approved in Japan for patients with unresectable thymic carcinoma; however, real-world evidence of its clinical benefit is limited. Here, we report the case of chemotherapy-refractory thymic carcinoma in a patient who was administered a starting dose of lenvatinib using a 5-day on/2-day off (weekend-off) protocol, followed by alternate-day administration after fatigue onset derived from overt or subclinical hypothyroidism. Consequently, the patient exhibited a durable response to lenvatinib, with a 17-month progression-free survival without any severe or intolerable AEs. The present case suggests that maintaining lenvatinib dose intensity using such alternative administration regimens contributes to favorable clinical outcomes in thymic carcinoma.

Effect of the Inspiratory Method and Timing of Voluntary Cough on Peak Cough Flow.

OBJECTIVE: To define the effect of the inspiratory method and cough timing on peak cough flow (PCF). METHODS: We investigated the effect of measurement conditions on PCF in healthy subjects (n=10). We then compared obstructive and restrictive pulmonary diseases (n=20) to assess for similar results in respiratory diseases. The PCF was measured under four conditions: before coughing, without maneuver 1 or with maneuver 2 a temporary respiratory pause (4-6 seconds) after rapid inspiration, and without maneuver 3 or with maneuver 4 a temporary respiratory pause after slow inspiration. After the measurements were completed, the PCF between the four conditions was compared for each subject group, and the effect size was calculated. RESULTS: PCF of maneuvers 1 and 3 were significantly higher than maneuver 4 in healthy subjects (476.34±102.05 L/min and 463.44±107.14 L/min vs. 429.54±116.83 L/min, p<0.01 and p<0.05, respectively) and patients with restrictive pulmonary disease (381.96±145.31 L/min, 354.60±157.36 L/min vs. 296.94±137.49 L/min, p<0.01 and p<0.05, respectively). In obstructive pulmonary disease, maneuver 1 was significantly higher than maneuver 4 (327.42±154.73 L/min vs. 279.48±141.10 L/min, p<0.05). The largest effect sizes were shown by maneuvers 4 and 1. CONCLUSION: PCF depends on changes in inspiratory speed before coughing and on temporary respiratory pauses after maximal inspiration. It will become necessary to unify the measurement methods for coughing strength and present appropriate coughing methods.

Long-term Safety and Efficacy of Benralizumab for Eosinophilic Granulomatosis with Polyangiitis Complicated with Severe Neuropathy.

The efficacy of benralizumab, as well as mepolizumab, to granulomatosis with polyangiitis (EGPA) involved with mononeuritis multiplex remains unclear. We experienced a case of EGPA presenting neuropathy with severe asthma. Muscle weakness due to neuropathy involved with gait disturbance was partly ameliorated by intravenous immunoglobulin therapy. Mepolizumab (100 mg/day) did not promote further improvement of neuropathy. However, the administration of benralizumab instead of mepolizumab improved neuropathy quickly and enabled walking alone. The efficacy of benralizumab for EGPA and its complication has been maintained for over four years. Benralizumab may be a possible treatment for EGPA presenting neuropathy with severe asthma.

A pregnant woman with severe dyspnoea.

Preterm delivery is a feasible option in the third trimester of pregnancy in the treatment of pregnant women with acute respiratory distress syndrome due to miliary tuberculosis with respiratory failure https://bit.ly/3stKOzj.

Durable response to afatinib rechallenge in a long-term survivor of non-small cell lung cancer harboring EGFR L858R and L747V mutations.

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors are standard therapeutic agents for non-small cell lung cancer (NSCLC) patients with major EGFR mutations such as exon 19 deletions and a L858R mutation, whereas treatment strategies for cases with uncommon EGFR mutations remain to be fully established. Here, we report a long-term (≥20 years from initial diagnosis) NSCLC survivor carrying EGFR L858R and L747V mutations. The patient received gefitinib monotherapy, systemic chemotherapy/chemoimmunotherapy, and local consolidative therapies for oligometastatic lesions, and responded to afatinib rechallenge with a progression-free survival of 12 months. The current case suggests that afatinib is effective in NSCLC patients with EGFR L858R and L747V mutations and that a therapeutic approach combining appropriately timed systemic therapies with local consolidative therapies for oligometastatic lesions improves long-term survival.

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.

Treatment strategies with alternative treatment options for patients with Mycobacterium avium complex pulmonary disease.

Diseases caused by Mycobacterium avium complex (MAC) infection in the lungs are increasing worldwide. The recurrence rate of MAC-pulmonary disease (PD) has been reported to be as high as 25-45%. A significant percentage of recurrences occurs because of reinfection with a new genotype from the environment. A focus on reducing exposure to MAC organisms from the environment is therefore an essential component of the management of this disease as well as standard MAC-PD treatment. A macrolide-containing three-drug regimen is recommended over a two-drug regimen as a standard treatment, and azithromycin is recommended rather than clarithromycin. Both the 2007 and 2020 guidelines recommend a treatment duration of MAC-PD of at least one year after the culture conversion. Previous clinical studies have reported that ethambutol could prevent macrolide resistance. Furthermore, the concomitant use of aminoglycoside, amikacin liposomal inhalation, clofazimine, linezolid, bedaquiline, and fluoroquinolone with modification of guideline-based therapy has been studied. Long-term management of MAC-PD remains challenging because of the discontinuation of multi-drug regimens and the acquisition of macrolide resistance. Moreover, the poor compliance of guideline-based therapy for MAC-PD treatment worldwide is concerning since it causes macrolide resistance. Therefore, in this review, we focus on MAC-PD treatment and summarize various treatment options when standard treatment cannot be maintained, with reference to the latest ATS/ERS/ESCMID/IDSA clinical practice guidelines revised in 2020.

Design and Synthesis of Cyclopropane Congeners of Resolvin E3, an Endogenous Pro-Resolving Lipid Mediator, as Its Stable Equivalents.

Resolvins are pro-resolving lipid mediators with highly potent anti-inflammatory effects. Because of their polyunsaturated structures, however, they are unstable to oxygen as a drug prototype. To address this issue, we designed and synthesized CP-RvE3 as oxidatively stable congeners of RvE3 by replacing the cis-olefin with a cis-cyclopropane to avoid the unstable bisallylic structure. Although the oxidative stabilities of CP-RvE3 were not improved, ß-CP-RvE3 was 3.7 times more metabolically stable than RvE3. Thus, we identified ß-CP-RvE3 as a metabolically stable equivalent.

Role of Neuron-Specific Enolase in the Diagnosis and Disease Monitoring of Sarcoidosis.

Sarcoidosis is a systemic granulomatous disease of unknown etiology. The diagnosis of sarcoidosis is based on clinicopathologic findings accompanied by the formation of granulomas in multiple organs, including the lung. Although angiotensin-converting enzyme (ACE) and soluble interleukin 2 receptor (sIL-2R) are traditionally used for the diagnosis of sarcoidosis, specific diagnostic markers remain to be determined. In the current study, we found that serum neuron-specific enolase (NSE) levels were elevated in patients with sarcoidosis. Serum NSE levels were positively correlated with serum ACE and sIL-2R levels. The sensitivity of NSE alone was modest, but its combination with sIL-2R and ACE had the highest sensitivity compared to those of each single marker. When comparing serum NSE and pro-gastrin-releasing peptide (ProGRP) levels in SCLC patients with those in patients with sarcoidosis and nonsarcoidotic benign diseases, serum NSE could be used to distinguish SCLC from sarcoidosis and nonsarcoidosis by setting at a cutoff value of 17.0 ng/ml with a sensitivity of 73.5% and a specificity of 90.2%, which were comparable to those of ProGRP. Serum NSE levels were associated with organ involvement and were higher in sarcoidosis patients who had been treated with oral corticosteroid (OCS) than in those who had never received OCS therapies; there was a positive association between elevated serum NSE levels and OCS use. Increased concentrations of serum NSE in patients at the nonremission phase decreased after spontaneous remission, whereas serum NSE levels fluctuated in accordance with serum ACE or sIL-2R levels during the follow-up period in patients with sarcoidosis. These findings suggest that NSE could be a marker for the diagnosis and monitoring of the clinical outcome of patients with sarcoidosis.

The Relationship between Tumor Development and Sarcoidosis in Aspects of Carcinogenesis before and after the Onset of Sarcoidosis.

Background and Objectives: It is still unclear whether sarcoidosis is likely to be associated with tumors. In addition, the use of an immune checkpoint inhibitor has been reported to initiate the onset of sarcoidosis. We retrospectively analyzed tumor development before and after the diagnosis of sarcoidosis and examined the impact of having a history of tumors on the activity or the severity of sarcoidosis. Materials and Methods: We recruited 312 consecutive cases of sarcoidosis and analyzed the tumor development before and after the onset of sarcoidosis. Results: Among them, 25 cases were diagnosed with malignant tumor after diagnosis of sarcoidosis. In the analysis of the tumor-development group after diagnosis of sarcoidosis, both serum angiotensin I-converting enzyme and mediastinal lymph node size were significantly reduced at the time of malignant tumor diagnosis compared to at the onset of sarcoidosis, indicating that the decreasing activity of sarcoidosis may be partly associated with tumor development. Furthermore, we examined 34 cases having tumor history before the onset of sarcoidosis and analyzed the effect of tumor history on the severity of sarcoidosis. Cases with a malignant tumor in the past were older and had less complicated organs of sarcoidosis than cases without malignant tumors in the past. Oral corticosteroid therapy was administrated more frequently in cases without malignant tumors in the past, indicating that the history of a malignant tumor may influence the severity of sarcoidosis. Conclusion: These results indicate that tumor development may be partly associated with the activity or severity of sarcoidosis.

Perspectives on the Efficacy of Benralizumab for Treatment of Eosinophilic Granulomatosis With Polyangiitis.

Two types of interleukin (IL)-5 antibody biologics, anti-IL-5 antibodies (mepolizumab) and anti-IL-5α receptor antibodies (benralizumab), are indicated for severe asthma. While high-dose mepolizumab is also indicated for EGPA, benralizumab is indicated only for severe asthma. Benralizumab is characterized by antibody-dependent cell-mediated cytotoxicity activity, giving them specific and rapid anti-IL-5α receptor binding abilities and the ability to target a high number of eosinophils in tissues as well as peripheral blood. Recently, reports on the efficacy of benralizumab as a treatment for EGPA have been published, along with reports on some cases that are difficult to treat with existing oral corticosteroids and mepolizumab. Therefore, we focus on the perspective of the efficacy and safety of benralizumab as a treatment for EGPA patients with steroid dependence in this review. A total of 41 patients with EGPA were treated with benralizumab. After the introduction of benralizumab, oral corticosteroids could be reduced to 10 mg/day or less in all cases and to less than 5 mg/day in 80% or more of the cases. Discontinuation of oral corticosteroids was achieved in more than 40% of patients with EGPA. Benralizumab was effective in patients with mepolizumab-refractory EGPA and intractable cardiac and neuropathy complications. Efficient elimination of eosinophils is expected to improve the remission rate of EGPA with benralizumab treatment. Although the total number of patients was small, benralizumab was safe and tolerable in a wide range of age groups, suggesting efficacy in severe cases with EGPA.

Resolvin E3 ameliorates high-fat diet-induced insulin resistance via the phosphatidylinositol-3-kinase/Akt signaling pathway in adipocytes.

Obesity-associated type 2 diabetes mellitus is associated with the development of insulin resistance. Among several metabolites, resolvins that are metabolites of eicosapentaenoic acid have been shown to exert insulin-sensitizing effects; however, the role of resolvin E3 (RvE3) in glucose metabolism has not been studied. In this study, the effect of RvE3 on glucose metabolism in mice with high-fat diet-induced obesity and 3T3L1 adipocytes was studied. C57BL/6 mice fed a high-fat diet were administered RvE3, for which insulin tolerance, oral glucose tolerance tests, and the homeostasis model assessment of insulin resistance, were performed. RvE3 treatment significantly improved insulin sensitivity and glucose tolerance and regulated protein kinase B (Akt) phosphorylation in the adipose tissue. Moreover, RvE3 treatment enhanced the insulin-stimulated glucose transporter 4 (Glut4) translocation, glucose uptake, phosphatidylinositol-3-kinase (PI3K) activity, and Akt phosphorylation in 3T3L1 adipocytes, whereas a PI3K inhibitor inhibited the enhanced insulin-stimulated glucose uptake induced by RvE3. These findings indicate that RvE3 likely improves insulin sensitivity, resulting in the upregulation of glucose uptake in adipocytes by activating the PI3K/Akt signaling pathways. Collectively, the findings of this study show that RvE3 may play a role in glucose homeostasis and could be used as a potential therapeutic target for developing treatments for obesity-associated diabetes.

First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in advanced non-small cell lung cancer: a subanalysis of Asian patients in CheckMate 9LA.

BACKGROUND: CheckMate 9LA, a phase 3, randomized, open-label study in first-line advanced non-small cell lung cancer (NSCLC), showed significantly improved overall survival (OS) with nivolumab plus ipilimumab combined with 2 cycles of chemotherapy versus chemotherapy alone (4 cycles). We present results for the Asian subpopulation enrolled in Japan and China. METHODS: Patients aged ≥ 18 years with treatment-naive, histologically confirmed stage IV or recurrent NSCLC, Eastern Cooperative Oncology Group performance status 0-1 and no sensitizing EGFR/ALK mutations were randomized 1:1 to nivolumab [360 mg every 3 weeks (Q3W)] plus ipilimumab (1 mg/kg Q6W) combined with chemotherapy (Q3W for 2 cycles), or chemotherapy alone (Q3W for 4 cycles). Primary endpoint was OS; secondary endpoints included progression-free survival (PFS) and objective response rate (ORR). RESULTS: Twenty-eight patients received nivolumab plus ipilimumab combined with chemotherapy and 30 received chemotherapy. At a minimum follow-up of 12.7 months, median OS was not reached with nivolumab plus ipilimumab combined with chemotherapy versus 13.3 months with chemotherapy [hazard ratio (HR) 0.33; 95% confidence interval (CI) 0.14-0.80]. Median PFS was 8.4 versus 5.4 months (HR 0.47; 95% CI 0.24-0.92) and ORR was 57% versus 23%, respectively. Grade 3-4 treatment-related adverse events were observed in 57% versus 60% of patients, respectively. CONCLUSION: Consistent with results in the all randomized population, nivolumab plus ipilimumab combined with chemotherapy improved efficacy in the Asian subpopulation versus chemotherapy alone and had a manageable safety profile, supporting its use as first-line treatment for advanced NSCLC in Asian patients.

Differential Discontinuation Profiles between Pirfenidone and Nintedanib in Patients with Idiopathic Pulmonary Fibrosis.

Antifibrotic agents have been widely used in patients with idiopathic pulmonary fibrosis (IPF). Long-term continuation of antifibrotic therapy is required for IPF treatment to prevent disease progression. However, antifibrotic treatment has considerable adverse events, and the continuation of treatment is uncertain in many cases. Therefore, we examined and compared the continuity of treatment between pirfenidone and nintedanib in patients with IPF. We retrospectively enrolled 261 consecutive IPF patients who received antifibrotic treatment from six core facilities in Gunma Prefecture from 2009 to 2018. Among them, 77 patients were excluded if the antifibrotic agent was switched or if the observation period was less than a year. In this study, 134 patients treated with pirfenidone and 50 treated with nintedanib were analyzed. There was no significant difference in patient background, discontinuation rate of antifibrotic treatment over time, and survival rate between the two groups. However, the discontinuation rate due to adverse events within one year of antifibrotic treatment was significantly higher in the nintedanib group than in the pirfenidone group (76% vs. 37%, p < 0.001). Furthermore, the discontinuation rate due to adverse events in nintedanib was higher than that of pirfenidone treatment throughout the observation period (70.6% vs. 31.2%, p = 0.016). The pirfenidone group tended to be discontinued due to acute exacerbation or transfer to another facility. The results of this study suggest that better management of adverse events with nintedanib leads to more continuous treatment that prevents disease progression and acute exacerbations, thus improving prognosis in patients with IPF.