Immunotherapy With Radiotherapy for Brain Metastases in Patients With NSCLC: NEJ060.

Introduction: Immune checkpoint inhibitor (ICI)-based treatment has become standard treatment for patients with advanced NSCLC. We aimed to determine the survival benefit of upfront radiotherapy for brain metastases (BMs) in patients with NSCLC who received ICI alone (ICI-alone) or with chemotherapy (ICI-chemo). Methods: This study included consecutive patients with NSCLC having BMs who received ICI alone or ICI-chemo at 50 institutes between February 2017 and September 2021. The presence of BMs was confirmed by imaging before treatment. Treatment outcomes were compared between patients who did and did not receive upfront radiotherapy for BMs. Potential confounding factors were adjusted between the groups through inverse probability treatment weighting (IPTW) analysis and overlap weighting (OW) analysis with propensity scores. Results: Patients were grouped as ICI-alone cohort, 224 patients (upfront-radiotherapy group, 135 patients; no-radiotherapy group, 89 patients) and ICI-chemo cohort, 367 patients (upfront-radiotherapy group, 212 patients; no-radiotherapy group, 155 patients). In the ICI-alone cohort, the overall survival of the upfront-radiotherapy group was significantly longer than that of the no-radiotherapy group (IPTW-adjusted hazards ratio [HR] = 0.45 [95% confidence interval [CI]: 0.29-0.72], OW-adjusted HR = 0.52 [95% CI: 0.35-0.77]). In contrast, in the ICI-chemo cohort, the OS of the upfront-radiotherapy group was not significantly different from that of the no-radiotherapy group (IPTW-adjusted HR = 1.02 [95% CI: 0.70-1.48], OW-adjusted HR = 0.93 [95% CI: 0.65-1.33]). Conclusions: Upfront radiotherapy for BMs was associated with longer overall survival in patients with NSCLC who received ICI alone; however, it did not exhibit survival benefits in the patients who received ICI-chemo.

Real-World Data on Subsequent Therapy for First-Line Osimertinib-Induced Pneumonitis: Safety of EGFR-TKI Rechallenge (Osi-risk Study TORG-TG2101).

BACKGROUND: Although osimertinib is a promising therapeutic agent for advanced epidermal growth factor receptor (EGFR) mutation-positive lung cancer, the incidence of pneumonitis is particularly high among Japanese patients receiving the drug. Furthermore, the safety and efficacy of subsequent anticancer treatments, including EGFR-tyrosine kinase inhibitor (TKI) rechallenge, which are to be administered after pneumonitis recovery, remain unclear. OBJECTIVE: This study investigated the safety of EGFR-TKI rechallenge in patients who experienced first-line osimertinib-induced pneumonitis, with a primary focus on recurrent pneumonitis. PATIENTS AND METHODS: We retrospectively reviewed the data of patients with EGFR mutation-positive lung cancer who developed initial pneumonitis following first-line osimertinib treatment across 34 institutions in Japan between August 2018 and September 2020. RESULTS: Among the 124 patients included, 68 (54.8%) patients underwent EGFR-TKI rechallenge. The recurrence rate of pneumonitis following EGFR-TKI rechallenge was 27% (95% confidence interval [CI] 17-39) at 12 months. The cumulative incidence of recurrent pneumonitis was significantly higher in the osimertinib group than in the first- and second-generation EGFR-TKI (conventional EGFR-TKI) groups (hazard ratio [HR] 3.1; 95% CI 1.3-7.5; p = 0.013). Multivariate analysis revealed a significant association between EGFR-TKI type (osimertinib or conventional EGFR-TKI) and pneumonitis recurrence, regardless of severity or status of initial pneumonitis (HR 3.29; 95% CI 1.12-9.68; p = 0.03). CONCLUSIONS: Osimertinib rechallenge after initial pneumonitis was associated with significantly higher recurrence rates than conventional EGFR-TKI rechallenge.

Transcutaneous gas monitoring is a useful tool to detect respiratory depression during bronchoscopy performed under propofol sedation.

BACKGROUND: Bronchoscopy is a relatively invasive procedure where patients are often sedated. However, adequate sedation is not always achieved. Propofol is often used for difficult-to-sedate patients undergoing bronchoscopy despite a potential risk of respiratory depression. Transcutaneous carbon dioxide (tcpCO2) monitoring, introduced recently, is recognized as a convenient surrogate method for continuous monitoring of the partial pressure of arterial carbon dioxide (PaCO2). This study examined the safety of switching to propofol during bronchoscopy by using transcutaneous carbon dioxide monitoring. METHODS: Patients in whom transcutaneous gas monitoring had been performed during bronchoscopy were included in this study. The participants were divided into two groups: 1) the midazolam + fentanyl group (MF group), and 2) the group in which midazolam was switched to propofol owing to inadequate sedation obtained with midazolam + fentanyl (MFP group). We retrospectively analyzed the transcutaneous gas measurement data collected in patients under propofol sedation for bronchoscopy. RESULTS: This study included 61 (MF, n = 41; MFP, n = 20) patients. The duration of elevated tcpCO2 (>50 mm Hg) was greater in the MFP group (MF 8.5 min vs. MFP 22.1 min, p = 0.042). CONCLUSION: Switching midazolam to propofol during bronchoscopy was significantly associated with a higher risk of elevated tcpCO2, which is indicative of respiratory depression. Therefore, continuous tcpCO2 monitoring is required to ensure the safety of patients under propofol sedation for bronchoscopy.

Changing patterns of pulmonary abnormalities in rheumatoid arthritis.

BACKGROUND: As a first step in identifying the developmental pathways of pulmonary abnormalities in rheumatoid arthritis (RA), we sought to determine the existing and changing patterns of pulmonary abnormalities. METHODS: We conducted a retrospective cohort study of consecutive patients with RA who underwent high-resolution computed tomography before and during biologic therapy. The presence of 20 pulmonary abnormalities and the changes in those abnormalities were recorded. Patterns of pre-existing and changing abnormalities were examined via cluster analysis, and their relationship was also assessed using the Kaplan-Meier method and log-rank test. RESULTS: A total of 208 subjects were included. Pulmonary abnormalities were observed in 70% of patients: 39% had interstitial lung disease, and 55% had airway disease (AD). Several different pulmonary abnormalities were commonly found to co-exist in several patterns in the same patient. In most patients with pulmonary abnormalities, AD was present alone or in combination with other abnormalities. During the observation period (mean 3.2 years), 172 pulmonary abnormalities had changed in 91 patients: 115 pulmonary abnormalities newly emerged, whereas 42 worsened and 25 demonstrated improvement. Pulmonary abnormalities changed in several patterns. Correlations were observed between pre-existing and new/worsening abnormalities at individual and regional levels, such as new ground-glass opacity (GGO) and pre-existing AD, small nodular patterns, and honeycombing. AD was a possible initial abnormality. CONCLUSIONS: Pulmonary abnormalities occurred and changed in several patterns, which suggests the existence of developmental pathways of pulmonary abnormalities. AD may play an important role in the development of these abnormalities, including GGO.

Carboplatin plus nab-paclitaxel for recurrent small cell lung cancer: A phase II study.

BACKGROUND: We conducted a phase II study of carboplatin plus nab-paclitaxel for the treatment of small cell lung cancer (SCLC) after the failure of a prior standard chemotherapy containing platinum, etoposide, irinotecan, and amrubicin if indicated. Patients with interstitial pneumonia complications were included in the study. METHODS: Patients received 100 mg/m2 of nab-paclitaxel weekly (on days 1, 8, and 15) and an AUC 5 of carboplatin on day 1. The study treatment was repeated every 3 weeks until disease progression or the appearance of unacceptable toxicities. The primary endpoint was the objective response rate. RESULTS: A total of 21 patients were enrolled, all of whom were eligible for inclusion in the analysis. Twelve patients had pre-existing interstitial pneumonia. The overall response rate was 19.0% (90% confidence interval [CI]: 6.8%-38.4%). The lower limit of the 90% CI for the response rate did not exceed the prespecified threshold value of 10%. Among the 12 patients with pre-existing interstitial pneumonia, the response rate was 25%. The median progression-free survival time was 2.5 months (95% CI: 1.5-3.4 months), and the median survival time was 5.1 months (95% CI: 2.1-8.1 months). Two patients developed interstitial lung disease; both of these patients had pre-existing interstitial pneumonia. One of the patients died from interstitial lung disease. CONCLUSION: Combination chemotherapy with carboplatin plus nab-paclitaxel for recurrent SCLC had a modest activity, although the primary study endpoint was not met. Further investigation of this regimen for patients with recurrent SCLC and interstitial pneumonia is warranted.

Clinical Significance of Tumor Markers for Advanced Thymic Carcinoma: A Retrospective Analysis from the NEJ023 Study.

The optimal tumor marker for predicting the prognosis of advanced thymic carcinoma (ATC) remains unclear. We conducted a multi-institutional retrospective study of patients with ATC. A total of 286 patients were treated with chemotherapy. Clinicopathological information, including serum tumor markers, was evaluated to determine the overall survival (OS) and progression-free survival (PFS). The carcinoembryonic antigen, cytokeratin-19 fragment, squamous cell carcinoma (SCC) antigen, progastrin-releasing peptide, neuron-specific enolase (NSE), and alpha-fetoprotein levels were evaluated. In the Kaplan-Meier analysis, the OS was significantly shorter in the patients with elevated NSE levels than in those with normal NSE levels (median, 20.3 vs. 36.8 months; log-rank test p = 0.029; hazard ratio (HR), 1.55; 95% confidence interval (CI), 1.05-2.31 (Cox proportional hazard model)); a similar tendency regarding the PFS was observed (median, 6.4 vs. 11.0 months; log-rank test p = 0.001; HR, 2.04; 95% CI, 1.31-3.18). No significant differences in the OS and PFS were observed among the other tumor markers. In both univariate and multivariate analyses of the patients with SCC only, the NSE level was associated with the OS and PFS. Thus, the NSE level may be a prognostic tumor marker for thymic carcinoma, regardless of histology.

Auto-antibody evaluation in idiopathic interstitial pneumonia and worse survival of patients with Ro52/TRIM21auto-antibody.

Some patients with interstitial pneumonia (IP) have auto-antibodies, but do not fit the criteria for specific connective tissue diseases. Examination of auto-antibodies is recommended for diagnosis idiopathic pulmonary fibrosis. A prospective cohort study was performed in 285 patients with IP. Eleven auto-antibodies were assessed and patients were followed for 2 years. All 285 patients underwent the myositis panel test (MPT) for 11 auto-antibodies. Among them, 23.5% (67/285) of the patients had a positive MPT and 14.7% (42/285) had connective tissue diseases. Among the 49 MPT positive patients without connective tissue diseases, 29 patients (59.2%) were positive for Ro52, including 17 patients with Ro52 mono-positivity. Among interstitial pneumonia patients without connective tissue diseases, the Ro52 mono-positive patients showed worse at 2-years survival than those who were Ro52 negative (p = 0.022, HR = 5.88, 95% CI 1.29-26.75). Most of the Ro52 positive patients also showed a low titer of anti-nucleolar antibody. About 20% of IP patients had auto-antibodies detectable by the MPT, and Ro52 positive patients accounted for more than half of the MPT positive patients without connective tissue diseases. Detection of Ro52 auto-antibodies may be useful for assessing the risk of progression in idiopathic interstitial pneumonia patients without connective tissue diseases and a low anti-nucleolar antibody titer.

A case of spindle cell dominant histiocytic sarcoma showing a complete remission after first-line chemotherapy with doxorubicin and ifosfamide.

Histiocytic sarcoma (HS), an extremely rare malignancy, usually follows a progressive time course, and patients die within two years of diagnosis. At present, there is no consensus for effective chemotherapy. We report the case of a 54-year-old man who presented with low back pain and left hip joint pain. Imaging for the pain revealed multiple lesions in the mediastinum, vertebral bodies, and left ilium. Biopsies of the mediastinal and vertebral lesions yielded a diagnosis of soft tissue sarcoma. He received standard chemotherapy for sarcoma with doxorubicin and ifosfamide, as the initial pathological diagnosis was soft tissue sarcoma. This is called AI therapy and commonly used for soft tissue sarcoma. Palliative radiation therapy to the left iliac lesion was added for pain control. Complete remission (CR) was achieved after two courses of AI therapy. Subsequent immunopathological examination revealed that the tumor was spindle cell dominant HS. CR was maintained for more than three years. To the best of our knowledge, this is the first report that a CR was achieved by AI therapy as first-line treatment for spindle cell dominant HS, combined with focal bone palliative irradiation. AI therapy could be an effective option as chemotherapy for HS.

Osimertinib, a third-generation EGFR tyrosine kinase inhibitor: A retrospective multicenter study of its real-world efficacy and safety in advanced/recurrent non-small cell lung carcinoma.

BACKGROUND: Osimertinib is recommended for T790M mutation-positive advanced non-small cell lung cancer (NSCLC) resistant to first- and second-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs). Recently, some reports exist on the real-world use of osimertinib; however, reports involving third/later-line use are few. Hence, this study was conducted to evaluate the efficacy and safety of osimertinib used in various treatment lines for T790M-positive NSCLC patients. METHODS: This retrospective, observational, multicenter study included T790M-positive advanced/recurrent NSCLC patients treated with osimertinib from May 2016 to March 2018. The clinical characteristics, efficacy, and adverse events were retrospectively investigated. The Kaplan-Meier method was used to analyze progression-free survival (PFS) and overall survival (OS). PFS-associated clinical characteristics were evaluated using the Cox proportional hazards model. RESULTS: The objective response rate (ORR) and disease control rate (DCR) were 60.7% and 91.1%, respectively; the median PFS was 11.0 months. There were no significant differences in the median PFS for patients treated with osimertinib as second-line and third-/later-line (14.5 vs. 11.0 months respectively, P = 0.327). Analysis using the Cox proportional hazards model for clinical features affecting PFS also revealed no significant factors. Adverse events of grade ≥ 3 were reported in 15 patients (26.8%); the most common were anemia (n = 3) and cutaneous toxicity (n = 3). Grade 4 neutropenia was observed in one patient; any-grade pneumonitis was observed in six patients (10.7%), including one with grade 3 pneumonitis. CONCLUSIONS: Osimertinib demonstrated efficacy even when administered as third-/later-line treatment to NSCLC patients. Osimertinib-related pneumonitis was observed more frequently than previously reported. KEY POINTS: Significant findings of the study Osimertinib shows efficacy even as later-line treatment in T790M mutation-positive NSCLC patients previously treated with EGFR-TKIs. However, the incidence of ≥ grade 3 adverse events, especially pneumonitis, was higher than that previously reported by other studies. What this study adds Osimertinib was approved for previously EGFR-TKI-treated EGFR T790M-positive NSCLC. With the increasing frequency of its use as first-line treatment, this study provides valuable evidence for the efficacy and safety of osimertinib for previously EGFR-TKI-treated NSCLC.

Lipid Accumulation in Peripheral Blood Dendritic Cells and Anticancer Immunity in Patients with Lung Cancer.

We studied the subsets of peripheral blood dendritic cells (DCs) and lipid accumulation in DCs to investigate the involvement of DCs in the decreased anticancer immunity of advanced lung cancer patients. We analyzed the population of DC subsets in peripheral blood using flow cytometry. We then determined lipid accumulation in the DCs using BODIPY 650/665, a fluorophore with an affinity for lipids. Compared with healthy controls, the number of DCs in the peripheral blood of treatment-naive cancer patients was significantly reduced. In patients with stage III + IV disease, the numbers of myeloid DCs (mDCs) and plasmacytoid DCs were also significantly reduced. Lipid accumulation in DCs evaluated based on the fluorescence intensity of BODIPY 650/665 was significantly higher in stage III + IV lung cancer patients than in the controls. In the subset analysis, the fluorescence was highest for mDCs. The intracellularly accumulated lipids were identified as triglycerides. A decreased mixed leukocyte reaction was observed in the mDCs from lung cancer patients compared with those from controls. Taken together, the results show that lung cancer patients have a notably decreased number of peripheral blood DCs and their function as antigen-presenting cells is decreased due to their high intracellular lipid accumulation. Thereby, anticancer immunity is suppressed.

Prognostic Factors and Efficacy of First-Line Chemotherapy in Patients with Advanced Thymic Carcinoma: A Retrospective Analysis of 286 Patients from NEJ023 Study.

BACKGROUND: The prognostic factors and the efficacy of first-line chemotherapy remain unclear in patients with advanced thymic carcinoma. MATERIALS AND METHODS: We conducted a multi-institutional retrospective study named NEJ023 for patients with advanced thymic carcinoma. All patients without any indication of curative treatment were treated with chemotherapy from 1995 to 2014 at 40 institutions of the North East Japan Study Group. RESULTS: A total of 286 patients with advanced thymic carcinoma were analyzed. First-line chemotherapy included platinum-based doublets in 62.2% of the patients, monotherapy in 3.5%, and other multidrug chemotherapy (e.g., cisplatin, doxorubicin, vincristine, and cyclophosphamide [ADOC]) in 34.3%. The median follow-up period was 55.5 months, and the median overall survival (OS) from the start of first-line chemotherapy was 30.7 months (95% confidence interval, 25.9-35.9 months). There was no significant difference in OS among different first-line chemotherapy regimens (e.g., between carboplatin/paclitaxel and ADOC, median OS: 27.8 vs. 29.9 months). Masaoka-Koga stage IVa and volume reduction surgery were favorable prognostic factors for OS in the multivariate analysis using the Cox proportional hazards model. CONCLUSION: The efficacy of each first-line chemotherapy regimen for advanced thymic carcinoma did not vary significantly. Our results might support the adequacy of the use of carboplatin/paclitaxel as first-line chemotherapy for these patients. IMPLICATIONS FOR PRACTICE: Because of its rarity, there is limited information about prognostic factors and efficacy of chemotherapy in patients with advanced thymic carcinoma. This is the largest data set for those patients treated with chemotherapy. This study suggests there is no significant difference in efficacy between carboplatin/paclitaxel and cisplatin/doxorubicin/vincristine/cyclophosphamide for advanced thymic carcinoma. This result can support the adequacy of the selection of platinum doublets as treatment for those patients, rather than anthracycline-based multidrug regimen.

Riluzole-induced lung injury in two patients with amyotrophic lateral sclerosis.

Riluzole has recently been proven as the first effective drug for the treatment of amyotrophic lateral sclerosis (ALS). We report two rare cases of lung injury caused by riluzole therapy in patients with ALS. Chest radiographs showed bilateral lower lobe, dorsal-dominant ground glass opacity, and/or consolidation. A drug lymphocyte stimulation test (DLST) of peripheral blood or bronchoalveolar lavage cells was positive for riluzole. Histopathological examination of lung biopsy specimens revealed lung injury without fungoid granuloma, vasculitis, or diffuse alveolar damage. To the best of our knowledge, this is the first report of riluzole-induced lung injury with positive DLST results.

Relationship between sensitivity to dyspnea and fluctuating peak expiratory flow rate in the absence of asthma symptoms.

BACKGROUND: Exacerbation of asthma has a negative impact on quality of life and increases the risk of fatal asthma. One of the known risk factors for patients with a history of near-fatal asthma is reduced sensitivity to dyspnea. OBJECTIVE: We aimed to identify patients with such risk before they experienced severe exacerbation of asthma. METHODS: We analyzed asthma symptoms and peak expiratory flow rate (PEFR) values of 53 patients recorded daily in a diary over a mean period of 274 days. Patients matched their symptoms to one of eight categories ranging in severity from 'absent' to 'severe attack'. We then analyzed the relationship between PEFR and asthma symptoms by dividing the PEFR value by the values of clinical parameters, including asthma symptom level. RESULTS: Average PEFR was 75.2% (50.5-100%) in the 'absent' symptom category, 64.5% (36.6-92.6%) in 'wheeze', 57.3% (25.0-94.7%) in 'mild attack' and 43.6% (20.4-83.1%) in 'moderate attack', with the personal best reading taken as 100%. Thus, differences in PEFR in patients in the same symptom category varied widely. PEFR in wheeze, mild attack and moderate attack did not correlate significantly with duration of asthma, forced expiratory volume in one second or proportion of personal best to standard predicted PEFR values. These PEFRs showed no significant difference in groups divided by type of regular treatment, but showed a significant negative correlation with the coefficient of variation (CV) of PEFR when asthma symptoms were absent. CV for absent symptoms should be between +4.0 and -4.0% when using regression analysis to measure PEFR if the decreased PEFR is in agreement with guidelines. CONCLUSION: To determine which patients have reduced sensitivity to dyspnea, CV of PEFR should be considered when asthma symptoms are reported as absent. When patients present with more than 8% fluctuation in PEFR, we should intervene in their treatment, even when they claim to be stable.