Treatment Strategies for Non-Small-Cell Lung Cancer with Comorbid Respiratory Disease; Interstitial Pneumonia, Chronic Obstructive Pulmonary Disease, and Tuberculosis.

Non-small cell lung cancer (NSCLC) patients are often complicated by other respiratory diseases, including interstitial pneumonia (IP), chronic obstructive pulmonary disease (COPD), and pulmonary tuberculosis (TB), and the management of which can be problematic. NSCLC patients with IP sometimes develop fatal acute exacerbation induced by pharmacotherapy, and the establishment of a safe treatment strategy is desirable. For advanced NSCLC with IP, carboplatin plus nanoparticle albumin-bound paclitaxel is a relatively safe and effective first-line treatment option. Although the safety of immune checkpoint inhibitors (ICIs) for these populations remains controversial, ICIs have the potential to provide long-term survival. The severity of COPD is an important prognostic factor in NSCLC patients. Although COPD complications do not necessarily limit treatment options, it is important to select drugs with fewer side effects on the heart and blood vessels as well as the lungs. Active TB is complicated by 2-5% of NSCLC cases during their disease course. Since pharmacotherapy, especially ICIs, reportedly induces the development of TB, the possibility of developing TB should always be kept in mind during NSCLC treatment. To date, there is no coherent review article on NSCLC with these pulmonary complications. This review article summarizes the current evidence and discusses future prospects for treatment strategies for NSCLC patients complicated with IP, severe COPD, and TB.

KRASG12C Inhibitor as a Treatment Option for Non-Small-Cell Lung Cancer with Comorbid Interstitial Pneumonia.

Non-small-cell lung cancer (NSCLC) with comorbid interstitial pneumonia (IP) is a population with limited treatment options and a poor prognosis. Patients with comorbid IP are at high risk of developing fatal drug-induced pneumonitis, and data on the safety and efficacy of molecularly targeted therapies are lacking. KRAS mutations have been frequently detected in patients with NSCLC with comorbid IP. However, the low detection rate of common driver gene mutations, such as epidermal growth factor receptor and anaplastic lymphoma kinase, in patients with comorbid IP frequently results in inadequate screening for driver mutations, and KRAS mutations may be overlooked. Recently, sotorasib and adagrasib were approved as treatment options for advanced NSCLC with KRASG12C mutations. Although patients with comorbid IP were not excluded from clinical trials of these KRASG12C inhibitors, the incidence of drug-induced pneumonitis was low. Therefore, KRASG12C inhibitors may be a safe and effective treatment option for NSCLC with comorbid IP. This review article discusses the promise and prospects of molecular-targeted therapies, especially KRASG12C inhibitors, for NSCLC with comorbid IP, along with our own clinical experience.

Favorable treatment response of bevacizumab-combined chemotherapy for advanced or recurrent invasive mucinous adenocarcinoma of the lung: A retrospective observational study.

Invasive mucinous adenocarcinoma (IMA) of the lung is a rare variant of adenocarcinoma characterized by abundant intracytoplasmic mucin within the tumor. Although IMA has poor sensitivity to conventional chemotherapy regimens used for non-small cell lung cancer, we observed a better response to the bevacizumab (BEV) regimen. In this retrospective study, we aimed to investigate the response to BEV-combined regimens in patients with IMA. Among 16 consecutive patients diagnosed with IMA between January 2016 and December 2020 at our institution and treated with systemic chemotherapy, seven patients were treated with BEV-combined regimens. The overall response rate to BEV-combined regimens was 85.7%, with six patients showing a partial response. The median progression-free survival was 6.1 months. One patient experienced respiratory failure, which was improved after administration of BEV-combined regimen. BEV-combined systemic therapy may have a favorable effect on advanced or recurrent IMA of the lung.

Autophagy Inhibition-induced Cytosolic DNA Sensing Combined with Differentiation Therapy Induces Irreversible Myeloid Differentiation in Leukemia Cells.

Accumulating evidence indicates that various oncogenic mutations interfere with normal myeloid differentiation of leukemogenic cells during the early process of acute myeloid leukemia (AML) development. Differentiation therapy is a therapeutic strategy capable of terminating leukemic expansion by reactivating the differentiation potential; however, the plasticity and instability of leukemia cells counteract the establishment of treatments aimed at irreversibly inducing and maintaining their differentiation states. On the basis of our previous observation that autophagy inhibitor treatment induces the accumulation of cytosolic DNA and activation of cytosolic DNA-sensor signaling selectively in leukemia cells, we herein examined the synergistic effect of cytosolic DNA-sensor signaling activation with conventional differentiation therapy on AML. The combined treatment succeeded in inducing irreversible differentiation in AML cell lines. Mechanistically, cytosolic DNA was sensed by absent in melanoma 2 (AIM2), a cytosolic DNA sensor. Activation of the AIM2 inflammasome resulted in the accumulation of p21 through the inhibition of its proteasomal degradation, thereby facilitating the myeloid differentiation. Importantly, the combined therapy dramatically reduced the total leukemia cell counts and proportion of blast cells in the spleens of AML mice. Collectively, these findings indicate that the autophagy inhibition-cytosolic DNA-sensor signaling axis can potentiate AML differentiation therapy. SIGNIFICANCE: Clinical effects on AML therapy are closely associated with reactivating the normal myeloid differentiation potential in leukemia cells. This study shows that autophagosome formation inhibitors activate the cytosolic DNA-sensor signaling, thereby augmenting conventional differentiation therapy to induce irreversible differentiation and cell growth arrest in several types of AML cell lines.

Immune checkpoint inhibitors in patients with lung cancer having chronic interstitial pneumonia.

Background: In interstitial pneumonia (IP)-associated lung cancer, immune checkpoint inhibitor pneumonitis (ICIP) is common with immune checkpoint inhibitor (ICI) treatment. The purpose of the present study was to clarify the safety and efficacy of ICI treatment for patients with lung cancer with IP. Methods: This multicentre retrospective observational study was conducted from June 2016 to December 2020 in patients with primary lung cancer with IP who received ICI treatment. Results: A total of 200 patients (median age 70 years; male/female, 176/24) were enrolled from 27 institutions. ICIP occurred in 61 patients (30.5%), pneumonitis grades 3-5 in 32 patients (15.5%) and death in nine patients (4.5%). The common computed tomography pattern of ICIP was organising pneumonia in 29 patients (47.5%). Subsequently, diffuse alveolar damage (DAD) pattern was observed in 19 patients (31.1%) who had a significantly worse prognosis than those with a non-DAD pattern (median progression-free survival (PFS) 115 days versus 226 days, p=0.042; median overall survival (OS) 334 days versus 1316 days, p<0.001). Immune-related adverse events (irAEs) occurred in approximately 50% of patients. Patients with irAEs (n=100) had a better prognosis than those without irAEs (n=100) (median PFS 200 days versus 77 days, p<0.001; median OS 597 days versus 390 days p=0.0074). The objective response rate and disease control rate were 41.3% and 68.5%, respectively. Conclusions: Although ICI treatment was effective for patients with lung cancer with IP, ICIP developed in approximately 30% of patients. Patients with irAEs had a significantly better PFS and OS than those without irAEs.

Bilateral Pneumothorax after a Transbronchial Lung Cryobiopsy for Interstitial Lung Disease.

We herein report a case of bilateral pneumothorax after a unilateral transbronchial lung cryobiopsy (TBLC). A 73-year-old man with no history of cardiothoracic surgery underwent a TBLC for the reevaluation of interstitial lung disease. Five hours later, he developed bilateral pneumothorax, pneumomediastinum, and subcutaneous emphysema. He underwent bilateral chest drainage and was discharged 18 days later. The lung biopsy specimens obtained from the TBLC contained visceral pleura and bronchial cartilage, suggesting bronchial injury as the cause of the bilateral pneumothorax.

Concordance between transbronchial lung cryobiopsy and surgical lung biopsy in patients with idiopathic multicentric Castleman disease: A report of four cases.

BACKGROUND: Idiopathic multicentric Castleman disease (iMCD) is a rare polyclonal lymphoproliferative disease often associated with pulmonary involvement. Recently, transbronchial lung cryobiopsy (TBLC) has been reported to be useful for the diagnosis of diffuse interstitial lung disease. However, there have been no reports of pathological assessment of TBLC for iMCD. METHOD: To clarify the efficacy of TBLC in the diagnosis of iMCD, we retrospectively reviewed four iMCD patients who had undergone both TBLC and surgical lung biopsy (SLB). RESULTS: The median age was 44 years; 2 males and 2 females. Two or three TBLC specimens were taken from each patient. All patients had no complications other than minimal bleeding. The size of the TBLC specimens was approximately 5-6 × 3-4 mm, and the alveolar region, and centrilobular and perilobular areas were adequately sampled. As with SLB, the extent of lung lesions and inflammatory cell infiltration could be sufficiently evaluated by TBLC. The presence of lymphoid follicles could also be assessed by TBLC; however, the germinal centers with lymphoid follicles were difficult to evaluate. The TBLC specimens could also be evaluated for immunostaining, especially IgG4 immunostaining, to rule out IgG4-related lung disease. Pulmonary pathological grading showed a high concordance rate between major pathological findings of TBLC and SLB. The pathologist's confidence level of TBLC for the diagnosis of iMCD was high in all cases. CONCLUSIONS: TBLC exhibits a high concordance rate with SLB in the pathological evaluation of iMCD, which may be useful for the diagnosis of iMCD.

Clinical and imaging features of interstitial lung disease in cancer patients treated with trastuzumab deruxtecan.

BACKGROUND: Interstitial lung disease/pneumonitis (ILD/pneumonitis) has been identified as a drug-related adverse event of special interest of trastuzumab deruxtecan (T-DXd), but there were a few reports of T-DXd-related ILD/pneumonitis in clinical practice. METHODS: Between May 25, 2020 (the launch of T-DXd in Japan) and February 24, 2022, there were 287 physician-reported potential ILD/pneumonitis cases from the Japanese post-marketing all-case surveillance. By February 27, 2022, an independent adjudication committee assessed 138 cases and adjudicated 130 cases as T-DXd-related ILD/pneumonitis. The clinical features and imaging characteristics of these cases were evaluated. RESULTS: The majority of adjudicated T-DXd-related ILD/pneumonitis cases were grade 1 or 2 (100/130, 76.9%). The most common radiological pattern types observed were organizing pneumonia patterns (63.1%), hypersensitivity pneumonitis patterns (16.9%), and diffuse alveolar damage (DAD) patterns (14.6%). Eleven cases (8.5%) from 130 resulted in death; the majority of these (8/11, 72.7%) had DAD patterns. The overall proportion of recovery (including the outcomes of recovered, recovered with sequelae, and recovering) was 76.9%, and the median time to recovery was 83.5 days (interquartile range: 42.25-143.75 days). Most cases (59/71, 83.1%) that were treated with corticosteroids were considered responsive to treatment. CONCLUSIONS: This is the first report to evaluate T-DXd-related ILD/pneumonitis cases in clinical practice. Our findings are consistent with previous reports and suggest that patients with DAD patterns have poor outcomes. Evaluation of a larger real-world dataset may further identify predictors of clinical outcome.

Short-term inhalation of sargramostim with concomitant high-dose steroids does not hasten recovery in moderate COVID-19 pneumonia: a double-blind, randomised, placebo-controlled trial.

BACKGROUND: Granulocyte-macrophage colony stimulating factor (GM-CSF) inhalation may alleviate pulmonary inflammation caused by viral pneumonia. To investigate this, we evaluated its efficacy on COVID-19 pneumonia. METHODS: This double-blind, randomised, placebo-controlled study (ClinicalTrials.gov: NCT04642950) evaluated patients in the first half of 2021 at seven Japanese hospitals. Hospitalised patients with COVID-19 pneumonia with moderate hypoxaemia inhaled sargramostim or placebo for 5 days. The primary endpoint was days to achieve a ≥ 2-category improvement from baseline on a modified 7-category ordinal scale. Secondary endpoints included degree of oxygenation, defined by amount of oxygen supply, and serum CCL17 level. RESULTS: Seventy-five patients were randomly assigned in a 2:1 ratio to receive sargramostim or placebo, of which 47 and 23 were analysed, respectively. No difference was observed between groups regarding the primary endpoint (8.0 and 7.0 days for sargramostim and placebo, respectively) or in the secondary endpoints, except for CCL17. A post hoc sub-analysis indicated that endpoint assessments were influenced by concomitant corticosteroid therapy. When the cumulative corticosteroid dose was ≤500 mg during Days 1-5, recovery and oxygenation were faster in the sargramostim group than for placebo. Bolus dose corticosteroids were associated with temporarily impaired oxygenation and delayed clinical recovery. The increase in serum CCL17, a candidate prognostic factor, reflected improvement with sargramostim inhalation. The number of adverse events was similar between groups. Two serious adverse events were observed in the sargramostim group without causal relation. CONCLUSIONS: Inhaled sargramostim was likely to be effective for COVID-19 pneumonia unless the concomitant corticosteroid dose was high.

Acute Exacerbation and Proposed Criteria for Progressive Pulmonary Fibrosis in Patients with Fibrotic Hypersensitivity Pneumonitis and Idiopathic Pulmonary Fibrosis.

BACKGROUND: Acute exacerbation (AE) occasionally develops in the course of fibrotic hypersensitivity pneumonitis (HP). OBJECTIVE: The aim of the study was to compare AE of fibrotic HP with that of idiopathic pulmonary fibrosis (IPF). METHODS: Consecutive patients with pathologically confirmed fibrotic HP and IPF diagnosed based on a multidisciplinary discussion were included in the analysis. AE in patients with fibrotic HP and IPF was evaluated retrospectively. RESULTS: This study included 309 and 160 patients with fibrotic HP and IPF, respectively. Their 50% survival times were 96.1 and 78.0 months, respectively (hazard ratio [HR]: 0.54 [95% confidence interval, CI: 0.36-0.77], log-rank test; p < 0.001). Notably, the cumulative AE rates of fibrotic HP were 3% at 1 year and 10% at 3 years. Moreover, the corresponding rates of IPF were 8% at 1 year and 20% at 3 years (HR: 0.66 [95% CI: 0.45-0.93], log-rank test; p = 0.034). The 90-day survival rates from the AE onset of fibrotic HP and IPF were 75% and 64%, respectively (HR: 0.51 [95% CI: 0.31-0.83], log-rank test; p = 0.006). The respiratory function test on the physiological criteria of progressive pulmonary fibrosis (PPF) was a predictor of AE in fibrotic HP. However, the high-resolution CT (HRCT) changes in the criteria of PPF were not. Nevertheless, both the physiological and radiological criteria of PPF were a predictor of AE of IPF. CONCLUSION: AE of fibrotic HP has a lesser prognostic effect than that of IPF. HRCT criteria for PPF were not a risk factor for AE in patients with fibrotic HP.

Concordance between transbronchial lung cryobiopsy and surgical lung biopsy for interstitial lung disease in the same patients.

BACKGROUND: The diagnostic accuracy and safety of transbronchial lung cryobiopsy (TBLC) via a flexible bronchoscope under sedation compared with that of surgical lung biopsy (SLB) in the same patients is unknown. METHODS: Retrospectively the data of fifty-two patients with interstitial lung diseases (median age: 63.5 years; 21 auto-antibody positive) who underwent TBLC followed by SLB (median time from TBLC to SLB: 57 days) was collected. The samples from TBLC and SLB were randomly labelled to mask the relationship between the two samples. Diagnosis was made independently by pathologists, radiologists, and pulmonary physicians in a stepwise manner, and a final diagnosis was made at multidisciplinary discussion (MDD). In each diagnostic step the specific diagnosis, the diagnostic confidence level, idiopathic pulmonary fibrosis (IPF) diagnostic guideline criteria, and treatment strategy were recorded. RESULTS: Without clinical and radiological information, the agreement between the histological diagnoses by TBLC and SLB was 42.3% (kappa [κ] = 0.23, 95% confidence interval [CI]: 0.08-0.39). However, the agreement between the TBLC-MDD and SLB-MDD diagnoses and IPF/non-IPF diagnosis using the two biopsy methods was 65.4% (κ = 0.57, 95% CI: 0.42-0.73) and 90.4% (47/52), respectively. Out of 38 (73.1%) cases diagnosed with high or definite confidence at TBLC-MDD, 29 had concordant SLB-MDD diagnoses (agreement: 76.3%, κ = 0.71, 95% CI: 0.55-0.87), and the agreement for IPF/non-IPF diagnoses was 97.4% (37/38). By adding the pathological diagnosis, the inter-observer agreement of clinical diagnosis improved from κ = 0.22 to κ = 0.42 for TBLC and from κ = 0.27 to κ = 0.38 for SLB, and the prevalence of high or definite diagnostic confidence improved from 23.0% to 73.0% and from 17.3% to 73.0%, respectively. Of all 383 TBLC performed during the same period, pneumothorax occurred in 5.0% of cases, and no severe bleeding, acute exacerbation of interstitial lung disease, or fatal event was observed. CONCLUSIONS: TBLC via a flexible bronchoscope under deep sedation is safely performed, and the TBLC-MDD diagnosis with a high or definite confidence level is concordant with the SLB-MDD diagnosis in the same patients.

Successful tepotinib treatment of adenocarcinoma with MET exon 14 skipping and discordant results between Oncomine Dx target test and ArcherMET: A case report.

Patients with non-small cell lung cancer (NSCLC) are often positive for oncogenic driver mutations, such as EGFR, ALK, BRAF, RET and MET exon 14 skipping mutations (METex14 skipping). Recently, METex14 skipping has become a functional biomarker for NSCLC with the approval of MET kinase inhibitors. Tepotinib is an oral MET kinase inhibitor. Its overall response rate is 46%, and the median duration of the response is 11.1 months. In Japan, companion diagnostics for tepotinib are limited with the ArcherMET and AmoyDx test, but not with Oncomine Dx target test. The present study reports the case of a 60-year-old male patient with lung adenocarcinoma harboring METex14 skipping, which was positive on Oncomine DxTT, but not on ArcherMET. In his sample used for Oncomine DxTT, the read count of MET(13)-MET(15) products was only 46. He was treated with various chemotherapeutic agents, but developed cardiac tamponade due to the progression of the disease of mediastinal lymph node metastases. Tepotinib was administered following pericardial drainage, resulting in an immediate response in all lesions. The majority of the discordant samples between Oncomine DxTT and ArcherMET had read counts <800, and the patient described herein had only 46. Therefore, the results of the present study indicate that the use of tepotinib should be considered even in patients whose METex14 skipping results were negative with ArcherMET, yet positive on Oncomine DxTT, particularly relatively with low lead counts.

Radiological and Pathological Features of Cyst Formation in Idiopathic Multicentric Castleman Disease.

INTRODUCTION: Idiopathic multicentric Castleman disease (MCD) has been reported to form lung cysts at a relatively high rate. However, the radiological and pathological features of cystic formation in MCD are unclear. METHODS: To clarify these questions, we retrospectively investigated the radiological and pathological findings of cysts in MCD patients. Eight consecutive patients who underwent surgical lung biopsies in our center from 2000 to 2019 were included. RESULTS: The median age was 44.5 years, with three males and five females. On the initial computed tomography, cyst formation was found in seven patients (87.5%). All of the cysts were multiple, round, and thin walled, accompanying ground-glass attenuation (GGA) around cysts. In six patients (75%), cysts increased during their clinical courses, and the new cysts had emerged from GGA, although GGA was improved by treatment. In all four cases, whose pulmonary cysts could be pathologically evaluated, a marked plasma cell infiltration around the cyst wall, and loss of elastic fibers of the alveolar wall were observed. CONCLUSIONS: Pulmonary cysts emerged in the area of GGA pathologically consistent with plasma cell infiltration. Cysts in MCD may be formed by the loss of elastic fibers due to marked plasma cell infiltration and may be considered irreversible changes.

Cumulative Incidence of Thromboembolism and Prognostic Impact of Stroke in BRAF V600E-mutant Non-small-cell Lung Cancer.

BACKGROUND/AIM: Cancer and ischemic stroke are closely associated. Thromboembolism susceptibility in lung cancer may differ depending on oncogenic alterations. However, the clinical characteristics of thromboembolism in patients with BRAF-mutant non-small-cell lung cancer remain unknown. Thus, this study aimed to evaluate the cumulative incidence of thromboembolism in this population and describe such cases in detail. PATIENTS AND METHODS: We retrospectively investigated consecutive patients with BRAF V600E-mutant non-small-cell lung cancer. Cumulative incidence was calculated using a competing risk analysis. RESULTS: Of 10 patients with BRAF-V600E mutant lung cancer, five developed a total of seven thromboembolic events, showing a 1-year cumulative incidence of 43% (95% confidence interval=11-72%). These events consisted of four cancer-related stroke (CRS) events and three venous events including deep vein thrombosis or pulmonary embolism. Of note, most of the early thrombotic events were CRS. Two patients with CRS had multiple brain infarctions during anticancer drug therapy, characterized by high D-dimer levels, resulting in short-term mortality (13 and 22 days after stroke onset). CONCLUSION: A substantial proportion of patients with BRAF V600E-mutant lung cancer experienced thromboembolism during their disease course. CRS of undetermined source may predict a worse prognosis in this population.

Design and rationale of the Japanese Idiopathic Interstitial Pneumonias (JIPS) Registry.

BACKGROUND: Numerous studies investigated patients with IPF; however, only a few examined patients with idiopathic interstitial pneumonias (IIPs). METHODS: The Japanese Idiopathic Interstitial Pneumonias (JIPS) Registry, which was initiated in December 2016, is a multicenter prospective observational study of patients newly diagnosed with IIPs from 86 facilities treating ILDs. The plan is to enroll more than 600 new patients during the 2-year enrolment period and to follow their progress for 3 years after the last case enrolment. If additional consent is obtained, the study will continue for another 2 years. Research questions mainly focus on identifying the frequency by IIP classification, patient background, and diagnostic methods during enrolment, survival, acute exacerbation rate, changes in high-resolution CT imaging, forced vital capacity, and interstitial pneumonia markers over time. Other research questions, including those regarding disease behavior in patients with progressive fibrosing-ILD and new biomarkers associated with genetic predispositions, will be investigated. DISCUSSION: The JIPS Registry will provide a comprehensive description of the disease progression, prognosis, treatment status, new biomarkers, and validity of guidelines and central multidisciplinary decisions for IPF and similar diseases that can be differentiated from IPF among IIPs. ETHICS AND DISSEMINATION: Ethical approval was obtained from the institutional review board of Kanagawa Cardiovascular and Respiratory Center (KCRC-16-0005), and that of Jichi Medical University approved the biobank part (I18-005). Results will be published in peer-reviewed journals and will be presented at national and international conferences. TRIAL REGISTRATION: ClinTrials.gov Registry (NCT03041623, first posted on February 3, 2017).

Impact of antigen avoidance test for fibrotic hypersensitivity pneumonitis in stable phase.

BACKGROUND: The antigen avoidance has been used in the diagnosis and treatment of hypersensitivity pneumonitis (HP); however, its usefulness in stable fibrotic HP is controversial. OBJECTIVE: To investigate the usefulness of the antigen avoidance test in patients with fibrotic HP in stable phase. METHODS: The antigen avoidance test was conducted during a 2-week hospitalization comparing clinical parameters at admission and before discharge. A retrospective review of patients who underwent surgical lung biopsy or transbronchial lung cryobiopsy, who were diagnosed with fibrotic HP by multi-disciplinary discussion, and whose disease progression was stable for more than two months before the antigen avoidance test was done. RESULTS: Between 2016 and 2021, 40 patients met the criteria, and 17 (43%) patients had a positive antigen avoidance test. The patients with positive in the antigen avoidance test had significantly greater annual forced vital capacity (FVC) decline than those with negative before the test (- 6.5% vs. - 0.3%, p = 0.045). The patients with positive antigen avoidance test had less annual FVC decline than those with negative in the year following the test (0.8% vs. - 5.0%, p = 0.048). The differences in annual improvement were found for serum Krebs von den Lungen-6 between the positive and negative patients in the year following the test (- 27% vs. - 5%, p = 0.049). In multivariate Cox hazard regression analysis, a negative result of the antigen avoidance test was a risk factor for death or acute exacerbation of fibrotic HP (HR = 0.26 [95% CI: 0.07-0.90], p = 0.034). CONCLUSIONS: In fibrotic HP patients in stable phase, the antigen avoidance test under a 2-week hospitalization was valuable in predicting prognosis.

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.

Validation of inhalation challenge test and serum immunoglobulin G test for bird-related fibrotic hypersensitivity pneumonitis.

BACKGROUND: The inhalation challenge test is considered to be the item for diagnosis of hypersensitivity pneumonitis (HP) and identifying the causative antigen in patients with fibrotic HP. However, the inhalation challenge test is not widely used. OBJECTIVE: To evaluate the values of the inhalation challenge test by comparing with serum immunoglobulin (Ig)G test. METHODS: This was a single-center, retrospective study. The patients with fibrotic HP were diagnosed pathologically by surgical lung biopsy or transbronchial lung cryobiopsy and were assumed to have bird-related fibrotic HP if they had a history of obvious avian exposure. RESULTS: On the basis of pathologic findings and history of avian exposure, 43 of 86 patients were diagnosed with having bird-related fibrotic HP. In 43 patients with bird-related fibrotic HP, 15 (35%) were positive for anti-bird IgG antibody and 36 (84%) were positive for the inhalation challenge test; in addition, the specificity of the inhalation challenge test was 67%. Patients with both positive results from inhalation challenge test and anti-bird IgG antibodies had a 2.7% decline in annual forced vital capacity (FVC) before the inhalation (P = .02). In patients with positive result from inhalation challenge test and negative result from anti-bird IgG antibodies, the annual FVC decreased by 5.8% (P = .03). FVC was not consistent in patients with positive result from the anti-bird IgG antibodies. CONCLUSION: The inhalation challenge test for bird-related fibrotic HP was more sensitive than the anti-bird IgG antibodies. Furthermore, the inhalation challenge test could select patients with similar disease progression.

Disease activity of lung cancer at the time of acute exacerbation of interstitial lung disease during cytotoxic chemotherapy.

BACKGROUND: The prognosis of lung cancer patients with interstitial lung disease (ILD) is poor, and acute exacerbation (AE) of ILD can occur during chemotherapy as a fatal adverse event. Although AE-ILD development is correlated with various factors, no reports are investigating the disease activity of lung cancer at the time of AE-ILD development. METHODS: All consecutive lung cancer patients with ILD who developed chemotherapy-related AE-ILD within 28 days after the last administration of cytotoxic chemotherapy between 2011 and 2020 were retrospectively reviewed. RESULTS: Among 206 lung cancer patients with ILD who were treated with cytotoxic chemotherapy, 30 patients were included. The median age was 72 years and all patients were men with smoking history. Usual interstitial pneumonia (UIP) and non-UIP patterns of ILD was observed in 17 and 13 patients. Most of AE-ILD occurred during second- or later-line (22/30, 73.3%) and developed within first or second courses during chemotherapy (19/30, 63.3%). Regarding tumor response to chemotherapy at AE-ILD development, majority of patients (18 patients, 60.0%) experienced progressive disease and only one patient (3.3%) experienced a partial response. Notably, 27 patients (90.0%) did not exhibit any tumor shrinkage of the thoracic lesions. CONCLUSION: Lung cancer was uncontrolled with cytotoxic chemotherapy at the time of AE-ILD development. Although AE-ILD during chemotherapy has been generally discussed in terms of drug-specific adverse effects, uncontrolled lung cancer may be also correlated with AE-ILD development.