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Background: High-mobility group box 1 (HMGB1) is a pro-inflammatory protein associated with the pathophysiology of lung injury and lung tumorigenesis. Here, we investigated the predictive potential of serum HMGB1 levels for radiation pneumonitis in patients with lung cancer. Methods: This was a retrospective biomarker study of 73 patients with non-small cell lung cancer treated with definitive thoracic radiotherapy between August 2007 and January 2021. We measured HMGB1 levels in serum stored before treatment, and analyzed its association with the development of grade ≥ 2 or grade ≥ 3 radiation pneumonitis. Additionally, baseline characteristics affecting HMGB1 levels were identified. Results: Of the 73 patients, 21 (28.8%) and 6 (8.2%) patients experienced grade 2 and ≥ 3 radiation pneumonitis, respectively. Univariate and multivariate logistic regression analyses revealed that higher baseline levels of serum HMGB1 were significantly associated with a higher risk of grade ≥ 3, but not grade ≥ 2, radiation pneumonitis. The incidence of grade ≥ 3 radiation pneumonitis was higher in patients with HMGB1 levels ≥ 6.2 ng/mL than in those with levels < 6.2 ng/mL (25.0% vs. 3.5%, p = 0.019). Baseline serum levels of HMGB1 were independently and positively associated with gross tumor volume. Conclusions: Higher serum HMGB1 levels were significantly associated with the risk of grade ≥ 3 radiation pneumonitis in patients with lung cancer, and therefore, HMGB1 could be a potential blood biomarker for predicting severe radiation pneumonitis. [ABSTRACT FROM AUTHOR]

Purpose: Cytotoxic chemotherapy-induced lung injury is a fatal complication in patients with lung cancer and interstitial lung disease (ILD). We aimed to evaluate the association between hyperglycemia and this form of lung injury in patients with lung cancer concomitant with ILD. Methods: From 1147 patients with advanced lung cancer, we retrospectively enrolled 98 patients with ILD whose hemoglobin A1c (HbA1c) levels were measured, and investigated the association between HbA1c levels and cytotoxic chemotherapy-induced lung injury. In 73 patients whose serum samples were retained, we measured serum levels of advanced glycation end products (AGE) and assessed the association of AGE levels with HbA1c levels and cytotoxic chemotherapy-induced lung injury. Results: The incidence of cytotoxic chemotherapy-induced lung injury was significantly higher in patients with HbA1c levels ≥ 5.8% than in those with HbA1c levels < 5.8%, but not in those with HbA1c levels ≥ 6.5% than in those with HbA1c levels < 6.5%. The multivariate logistic regression model revealed that HbA1c level ≥ 5.8% was a significant risk factor for this complication [odds ratio 3.178 (95% confidence interval 1.057–9.556), P = 0.040]. In addition, serum AGE levels were significantly higher in patients with HbA1c levels ≥ 5.8% than in those with HbA1c levels < 5.8% [median (interquartile range); 0.129 (0.023–0.290) and 0.474 (0.213–1.109) μg/mL, P = 0.001]. Conclusion: Glucose intolerance (e.g., HbA1c level ≥ 5.8%) may be a risk factor of cytotoxic chemotherapy-induced lung injury, which might be associated with elevated AGE production due to hyperglycemia. [ABSTRACT FROM AUTHOR]

Postoperative acute exacerbation of interstitial lung disease (AE-ILD) can be fatal in patients with lung cancer concomitant with ILD. We aimed to elucidate the predictive potential of high-mobility group box 1 (HMGB1), which is associated with the development and severity of lung injury, for evaluating the risk of this complication. We included 152 patients with lung cancer and ILD who underwent radical surgery between January 2011 and August 2019. We evaluated the preoperative levels of serum HMGB1 and its predictive potential for postoperative AE-ILD. Postoperative AE-ILD developed in 17 patients. Serum levels of HMGB1 were significantly higher in patients with postoperative AE-ILD than in those without (median [interquartile range]: 5.39 [3.29–11.70] ng/mL vs. 3.55 [2.07–5.62] ng/mL). Univariate and multivariate logistic regression analyses revealed that higher HMGB1 levels were significantly associated with the development of postoperative AE-ILD in entire studied patients (n = 152). In the subgroup analysis, higher HMGB1 levels were associated with a significantly increased risk of this complication in patients who underwent lobectomy (n = 77) than in those who underwent sublobar resection (n = 75). Serum HMGB1 could be a promising marker for evaluating the risk of postoperative AE-ILD, specifically in patients who underwent lobectomy. [ABSTRACT FROM AUTHOR]

Objectives: Bronchoscopy is frequently performed for patients suspected of having lung cancer; however, we sometimes fail to make a definitive diagnosis, resulting in additional invasive testing. Many studies indicate that microRNAs (miRs) are abnormally expressed in cancers. We examined the diagnostic value of 4 miRs (miR-21, miR-31, miR-182, and miR-183) extracted from liquid-based cytology (LBC) samples and validated whether they were diagnostically useful.Methods: We collected 18 surgically resected tissue samples and 136 LBC specimens obtained during bronchoscopic examination at Hiroshima University Hospital. We extracted RNA from these samples and compared the expression of 4 miRs by reverse transcription-quantitative polymerase chain reaction.Results: We confirmed that expression of the 4 miRs was significantly higher in cancer tissues than in tumor-adjacent normal tissues. We examined the expression of these miRs in 125 (cancer cases, 83; noncancer cases, 42) of 136 cytologic samples. Expression of all 4 miRs was significantly higher in patients with lung cancer than in those without lung cancer. Among samples judged as benign or indeterminate, levels of these miRs were also significantly higher in patients with lung cancer than in those without lung cancer.Conclusions: The analysis of miR expression in LBC samples might be helpful for primary lung cancer diagnosis. [ABSTRACT FROM AUTHOR]

Pneumatosis intestinalis (PI) is a rare disease that forms emphysema lesions under the mucosa and serosa of the gastrointestinal tract. We present the first case of PI following radiation-induced esophagitis during chemoradiotherapy (CRT) for lung cancer. A 74-year-old man with severe chronic obstructive pulmonary disease (COPD) was treated with CRT for lung cancer. During the treatment, he presented with vomiting and abdominal distention. CT showed pneumatosis from the esophagus to the small intestine. Severe radiation-induced esophagitis was observed, and gastrointestinal endoscopy revealed a circumferential esophageal ulcer. From these observations, this case was diagnosed as PI following severe esophagitis. A nasogastric tube was inserted, and conservative treatment with fasting, fluid replacement, and antibiotic was performed. Four days after the onset of PI, CT showed marked improvement of the pneumatosis. When CRT is performed for lung cancer patients, we should not only consider esophagitis but also PI. The presence of COPD may be considered a specific factor for the development of severe esophagitis and the consequent PI in this case. [ABSTRACT FROM AUTHOR]

Background: The prognosis of patients with lung cancer accompanied by interstitial pneumonia is poorer than that of patients with lung cancer but without interstitial pneumonia. Moreover, the available therapeutic interventions for lung cancer patients with interstitial pneumonia are limited. Therefore, a new treatment strategy for these patients is required. The aim of the present study was to investigate the pathophysiological relationship between interstitial pneumonia and lung cancer and explore potential therapeutic agents. Methods: A novel hybrid murine model of lung cancer with interstitial pneumonia was established via bleomycin-induced pulmonary fibrosis followed by orthotopic lung cancer cell transplantation into the lungs. Changes in tumor progression, lung fibrosis, RNA expression, cytokine levels, and tumor microenvironment in the lung cancer with interstitial pneumonia model were investigated, and therapeutic agents were examined. Additionally, clinical data and samples from patients with lung cancer accompanied by interstitial pneumonia were analyzed to explore the potential clinical significance of the findings. Results: In the lung cancer with interstitial pneumonia model, accelerated tumor growth was observed based on an altered tumor microenvironment. RNA sequencing analysis revealed upregulation of the hypoxia-inducible factor 1 signaling pathway. These findings were consistent with those obtained for human samples. Moreover, we explored whether ascorbic acid could be an alternative treatment for lung cancer with interstitial pneumonia to avoid the disadvantages of hypoxia-inducible factor 1 inhibitors. Ascorbic acid successfully downregulated the hypoxia-inducible factor 1 signaling pathway and inhibited tumor progression and lung fibrosis. Conclusions: The hypoxia-inducible factor 1 pathway is critical in lung cancer with interstitial pneumonia and could be a therapeutic target for mitigating interstitial pneumonia-mediated lung cancer progression. [ABSTRACT FROM AUTHOR]

Nailfold capillary abnormalities are typically observed in patients with systemic sclerosis and are also often found in patients with polymyositis (PM) and dermatomyositis (DM). Nailfold capillary abnormalities in some patients with PM/DM were found to improve with immunosuppressant treatment. However, the short-term changes in nailfold capillaries and their associations with disease activity have not been established yet. Additionally, there have been no reports on whether nailfold capillary abnormalities can change during the progression of malignant tumours. A man in his 60s with anti-transcriptional intermediate factor 1γ (anti-TIF-1γ) antibody-positive DM complicated with small cell lung carcinoma was treated with prednisolone (PSL) 70 mg, carboplatin (CBDCA) and etoposide (VP-16). His nailfold capillary abnormalities improved rapidly, and the tumour size decreased with treatment. Although chemotherapy was continued, abnormalities in the nailfold capillaries gradually recurred. The worsening of the capillary abnormalities prompted us to examine computed tomography scans, which showed the recurrence of lung cancer. After switching to second-line chemotherapy, the change in the nailfold capillary abnormalities was again in a parallel course with the disease status of lung cancer. Changes in nailfold capillaries may be useful not only for the diagnosis but also for the evaluation of the recurrence of malignant tumours with DM. [ABSTRACT FROM AUTHOR]

• Osimertinib cannot be used for T790M-negative NSCLC after 1st/2nd generation EGFR-TKI. • This study was initiated at the request of a dedicated network for patients with lung cancer in Japan. • We demonstrated that osimertinib had modest antitumor activity against those patients. Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that is an established standard treatment option for chemotherapy-naive patients with EGFR mutation-positive non–small cell lung cancer (NSCLC). However, of such patients who have received prior treatment with a first- or second-generation EGFR TKI, only approximately half are eligible for osimertinib therapy because its indication as second-line treatment and beyond is limited to metastatic NSCLC that is positive for the T790M resistance mutation of the EGFR gene. This study was initiated at the request of a dedicated network for patients with lung cancer in Japan. We conducted a phase II study to assess the efficacy of osimertinib in patients with EGFR mutation-positive NSCLC in whom systemic disease (T790M-negative) progressed after treatment with first- or second-generation EGFR TKIs and platinum-based chemotherapy. The primary end point was response rate (assessed by a central imaging reviewer). From August 2020 to February 2021, 55 patients from 15 institutions were enrolled in the study. The overall response for primary analysis was achieved in 16 patients (29.1 %; 95 % CI, 17.6–42.9), which exceeded the threshold response rate necessary for analysis. Stable disease was found in 16 patients (29.1 %), and progressive disease, in 18 (32.7 %). The median length of progression-free survival (PFS) was 4.07 months (95 % CI 2.10–4.30), and the rate of 12-month PFS was 17.3 %. Osimertinib demonstrated modest antitumor activity against progressive EGFR T790M-negative disease. [ABSTRACT FROM AUTHOR]

Simple Summary: Osimertinib is widely employed in patients with epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC). Most EGFR-mutated NSCLC cells are killed within a few days after osimertinib treatment; however, surviving cells remain detectable and are called drug-tolerant cells. Avoiding drug tolerance would maintain the long-term efficacy of osimertinib. We showed that the expression of PAI-1 and mesenchymal genes in EGFR-mutated cancer cell lines was upregulated after developing tolerance to EGFR-TKIs in vitro. In addition, PAI-1 inhibition limited the proliferation and mesenchymal gene expression of EGFR-TKI-tolerant cells. These results indicate that PAI-1 is involved in drug tolerance to EGFR-TKIs via epithelial–mesenchymal transition. Furthermore, we demonstrated that the combination of osimertinib with a PAI-1 inhibitor prevented the regrowth of osimertinib-treated tumors composed of EGFR-mutated cancer cells in in vivo experiments. Based on these observations, PAI-1 may prove to be a potential therapeutic target for overcoming tolerance to osimertinib. Most epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC) cells are killed within a few days after osimertinib treatment; however, surviving cells remain detectable and are called drug-tolerant cells. Plasminogen activator inhibitor-1 (PAI-1) was reported to be involved in chemotherapeutic or radiotherapeutic resistance. The purpose of the present study was to investigate whether PAI-1 is involved in osimertinib tolerance and whether it could be a therapeutic target for overcoming this tolerance. We showed that the PAI-1 mRNA expression levels and mesenchymal gene expression levels were significantly higher in drug-tolerant EGFR-mutated NSCLC cells than in control cells after 7 days of in vitro osimertinib treatment. Additionally, an RNA microarray analysis revealed upregulation of the integrin-induced EMT pathway in osimertinib-tolerant cells. Furthermore, we observed that PAI-1 inhibitors suppressed proliferation and the degree of epithelial–mesenchymal transition (EMT) in tolerant cells. Finally, in a subcutaneous tumor model, we showed that combining osimertinib with a PAI-1 inhibitor prevented the regrowth of tumors comprising EGFR-mutated cancer cells. The present study is the first to show PAI-1 to be involved in tolerance to osimertinib via EMT. [ABSTRACT FROM AUTHOR]

Context: The Dyspnea-12 questionnaire is a simple tool to assess dyspnea using qualitative descriptors that include both physical and emotional domains. However, the reliability and validity of the Japanese version in patients with lung cancer have not been assessed.Objective: To determine the reliability and validity of the Japanese version of the Dyspnea-12 questionnaire in patients with lung cancer.Methods: The assessment was based on the numerical rating scale (NRS), cancer dyspnea scale (CDS), and hospital anxiety and depression scale (HADS). Spearman's correlation assessed the convergent validity of Dyspnea-12 using these three scales. Exploratory factor analysis examined the construct validity. The reliability was verified using Cronbach's alpha. Anxiety, depression, clinical dyspnea, presence of chronic obstructive pulmonary disease (COPD), and patient status were identified by discriminating performance.Results: The analysis included 113 patients with lung cancer. A significant positive correlation was found between Dyspnea-12 and NRS, CDS, and HADS scores. Similar to the original version, factor analysis clearly classified Dyspnea-12 into two components (physical and emotional), thereby confirming its construct validity. Cronbach's alpha values for the total Dyspnea-12 and its physical and emotional components were 0.97, 0.95, and 0.96, respectively. Patients with anxiety, depression, and clinical dyspnea and those in the palliative phase had significantly higher Dyspnea-12 scores than their respective counterparts. The Dyspnea-12 scores of patients with and without COPD were similar.Conclusion: The Japanese version of the Dyspnea-12 questionnaire is a useful and reliable tool to assess the multi-dimensional aspects of dyspnea in patients with lung cancer. [ABSTRACT FROM AUTHOR]

Background: Pembrolizumab is the recommended first‐line therapy for patients with advanced non‐small‐cell lung cancer (NSCLC) and a programmed death ligand‐1 (PD‐L1) tumor proportion score (TPS) of ≥50% without driver mutations. However, its efficacy and safety for patients ≥75 years have not been prospectively investigated; this was the aim of this study. Methods: This multicenter and open‐label single‐arm phase II study was conducted at 12 institutions. Chemotherapy‐naïve patients with advanced NSCLC and a PD‐L1 TPS of ≥50% without EGFR mutations or translocation of the ALK received pembrolizumab every 3 weeks. The primary endpoint was progression‐free survival (PFS) with a threshold of 4.3 months. The secondary endpoints were overall survival (OS), objective response rate (ORR), disease control rate (DCR), safety, and quality of life. Results: Twenty‐six patients were enrolled between October 2017 and March 2020. The median PFS was 9.6 (95% confidence interval [CI] 2.1–20.6) months. The lower limit of the 95% CI did not exceed the target. The median OS was 21.6 months. The ORR and DCR were 41.7% and 70.8%, respectively. The proportion of patients with grade ≥3 treatment‐related adverse events was 15.4%. The quality of life score did not change significantly during treatment. Conclusion: While this study showed that pembrolizumab was a tolerable treatment for elderly patients, the safety requires further confirmation in a larger study. Although the primary endpoint, the median PFS (9.6 months), was slightly shorter than that (10.3 months) of the previous phase III study (KEYNOTE‐024 study), the median PFS did not achieve the expected value. [ABSTRACT FROM AUTHOR]

Osimertinib is the standard treatment for non‐small cell lung cancer (NSCLC) with an active epidermal growth factor receptor (EGFR) mutation and a T790M mutation—present in cases of acquired resistance. However, there have been no reports on the efficacy of osimertinib in patients with EGFR G719S and de novo T790M mutations. Here, we present the case of a 71‐year‐old woman who received first‐line osimertinib for lung adenocarcinoma with G719S and de novo T790M mutations. A partial response was observed after osimertinib initiation; however, the disease progressed 5 months after. Next‐generation sequencing using a rebiopsy sample from the brain metastases revealed no newly acquired resistance mutations, including EGFR C797S. From experience, the efficacy of osimertinib in NSCLC with G719S and T790M compound mutations may be poor. Therefore, optimal treatment for these cases should be determined. [ABSTRACT FROM AUTHOR]

Severe leukopenia, thrombocytopenia, and bi-cytopenia due to nivolumab have been reported. In this report, we present the first case of nivolumab-induced severe pancytopenia in a patient with lung adenocarcinoma. A 56-year-old Japanese man with lung adenocarcinoma received nivolumab therapy as second-line treatment. After 3 cycles of this therapy, although computed tomography (CT) showed a reduced tumor size, laboratory findings revealed pancytopenia and a bone marrow biopsy showed a severely hypoplastic marrow. The pancytopenia was diagnosed as an adverse effect of nivolumab; filgrastim (75 μg/day), steroid-pulse therapy (intravenous methylprednisolone: 500 mg/day), and subsequently intravenous prednisolone (50 mg/day) were administered. Furthermore, intravenous administration of immunoglobulins was also performed. However, these treatments were ineffective. He was further diagnosed with fungal pneumonia and a catheter-related bloodstream infection. Anti-bacterial chemotherapy was administered. Two months after hospitalization, the neutrophil count improved to 1000/μL, but multiple red blood cell and platelet transfusions were needed. Therefore, further chemotherapy for lung adenocarcinoma could not be initiated, and the patient died due to progression of lung cancer 118 days after the onset of pancytopenia. The possibility of severe pancytopenia as an immune-related adverse event should be considered as a mandatory prerequisite for nivolumab therapy. [ABSTRACT FROM AUTHOR]