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Background and Objective: Checkpoint inhibitor pneumonitis (CIP), caused by the anti‐programmed cell death‐1 (PD‐1)/programmed cell death ligand‐1 (PD‐L1) antibody, can be a fatal adverse event in cancer patients. However, no predictive biomarkers for CIP have been identified. Because high‐mobility group box 1 (HMGB1) can aggravate lung injury and potentially increase the immune response, it was investigated as a predictive blood marker. Methods: Blood samples, prospectively stored before anti‐PD‐1/PD‐L1 monotherapy between December 2015 and October 2020, were obtained at two university hospitals from 87 and 43 non‐small cell lung cancer (NSCLC) patients (discovery and validation cohorts, respectively). We retrospectively evaluated the association of serum HMGB1 levels with the incidence of CIP developed within 3 months of initiating anti‐PD‐1/PD‐L1 therapy. Results: CIP was observed in 9 (10.3%) and 6 (14.0%) patients in the discovery and validation cohorts, respectively. In each cohort, serum HMGB1 levels were significantly and reproducibly higher in patients with CIP. In the discovery cohort, an HMGB1 cut‐off level of 11.24 ng/ml was identified by receiver operating characteristic analysis. CIP incidence in the HMGB1high subgroup was significantly higher than that in the HMGB1low subgroup in the discovery (41.2% vs. 2.9%) and validation cohorts (36.4% vs. 6.3%). In an exploratory pooled analysis, three patients died of grade 5 CIP; a 19.29 ng/ml HMGB1 cut‐off level detected grade 5 CIP with 100% sensitivity and 96.85% specificity. Conclusion: Our results suggest that HMGB1 may be a potential blood marker to predict the development and severity of CIP in NSCLC patients. CIP incidence in the patients with high levels of serum HMGB1 (≥ 11.24 ng/ml) was significantly and reproducibly higher than in those with its low levels (< 11.24 ng/ml) in patients with NSCLC. Our results suggest that HMGB1 may be a potential blood marker for the prediction of CIP. [ABSTRACT FROM AUTHOR]

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]

Background: Mesenchymal-epithelial transition exon14 (METex14) skipping is one of the therapeutic driver oncogene mutations in non-small cell lung cancer (NSCLC), and can be treated with tepotinib and capmatinib. There is only one report on computed tomography (CT) findings of METex14 skipping-positive NSCLC, which shows that the primary tumor tends to have a large mass in the upper lobe, and extrathoracic metastases are common. This study examined the CT findings of METex14 skipping-positive NSCLC, focusing on the features of the margins and internal structures.Methods: We consecutively included patients with METex14 skipping-positive NSCLC who were diagnosed between January 2018 and December 2020 at four independent institutions. We retrospectively reviewed the patient demographics and CT findings for tumor margins (invasion into surrounding tissue, lobulation, pleural indentation, spicula, and ground-glass opacity) and internal structures (air bronchograms, cavitation and internal low-density area).Results: Fifteen patients with METex14 skipping-positive NSCLC were identified. Almost half of the patients were men (7/15; 46.7%), and their median age was 75.0 years. More than half were either current or former smokers (9/15; 60.0%). A vast majority of histological subtypes were adenocarcinoma (10/15; 66.7%), followed by pleomorphic carcinoma (3/15; 20.0%) and squamous cell carcinoma (2/15; 13.3%). With regard to CT findings, most primary tumors presented as masses larger than 30 mm (12/15; 80.0%) and were located in the upper lobes (12/15; 80.0%). Invasion into surrounding tissue and presence of internal low-density areas were observed in 60.0% (9/15) and 66.7% (10/15) of the primary tumors, respectively. Additionally, their frequencies increased to 72.7% (8/11) and 90.9% (10/11) in stage III/IV cases, respectively. In lymph node metastasis, internal low-density areas were observed in 8/10 cases (80.0%). Although these two CT features were rarely observed in distant metastases at diagnosis, they became apparent with progression of the metastatic tumor size.Conclusions: METex14 skipping-positive NSCLC tumors tend to invade surrounding tissue and possess internal low-density areas. These CT findings might be characteristic of METex14 skipping-positive NSCLC. [ABSTRACT FROM AUTHOR]

To predict grade ≥ 2 radiation pneumonitis (RP) in patients with locally advanced non-small cell lung cancer (NSCLC) using multi-region radiomics analysis. Data from 77 patients with NSCLC who underwent definitive radiotherapy between 2008 and 2018 were analyzed. Radiomic feature extraction from the whole lung (whole-lung radiomics analysis) and imaging- and dosimetric-based segmentation (multi-region radiomics analysis) were performed. Patients with RP grade ≥ 2 or < 2 were classified. Predictors were selected with least absolute shrinkage and selection operator logistic regression and the model was built with neural network classifiers. A total of 49,383 radiomics features per patient image were extracted from the radiotherapy planning computed tomography. We identified 4 features and 13 radiomics features in the whole-lung and multi-region radiomics analysis for classification, respectively. The accuracy and area under the curve (AUC) without the synthetic minority over-sampling technique (SMOTE) were 60.8%, and 0.62 for whole-lung and 80.1%, and 0.84 for multi-region radiomics analysis. These were improved 1.7% for whole-lung and 2.1% for multi-region radiomics analysis with the SMOTE. The developed multi-region radiomics analysis can help predict grade ≥ 2 RP. The radiomics features in the median- and high-dose regions, and the local intensity roughness and variation were important factors in predicting grade ≥ 2 RP. [ABSTRACT FROM AUTHOR]

The incidence of central nervous system metastasis is known to be high among patients with lung cancer. The frequency of brain metastasis and carcinomatous meningitis during the entire clinical course of non-small cell lung cancer is reported to be about 40% and 5%, respectively. In contrast, the incidence of cranial nerve metastasis is extremely rare, and detailed reports of its clinical course remain limited. Herein, we report 2 patients diagnosed with cranial nerve metastasis of lung adenocarcinoma and treated with radiotherapy and systemic chemotherapy. Both patients had cranial nerve symptoms, and brain magnetic resonance imaging showed cranial nerve enhancement. However, no evidence of carcinomatous meningitis was noted on magnetic resonance imaging and cerebrospinal fluid cytology. Based on these observations, these patients were diagnosed with cranial nerve metastasis of lung adenocarcinoma. Radiotherapy and chemotherapy were performed in both cases. In both cases, neurological symptoms had not worsened and imaging findings did not indicate any deteriorations. Therefore, radiotherapy and systemic chemotherapy should be considered when treating cranial nerve metastasis of lung adenocarcinoma. Early therapeutic intervention may lead to attenuation of the cranial nerve dysfunction resulting from cranial nerve metastasis. [ABSTRACT FROM AUTHOR]

Background: Anti-programmed cell death receptor (PD)-1 antibody treatment results in better prognosis than standard chemotherapy in patients with non-small cell lung cancer (NSCLC), especially those with high PD-ligand 1 (PD-L1) expression. However, several studies have reported a lack of antitumor effect of PD-1 antibody, even in patients with high PD-L1 expression. Therefore, reliable predictors of treatment response are urgently needed. The albumin–globulin ratio (AGR) is associated with prognosis in several cancers. We aimed to determine whether AGR is a predictive biomarker of anti-PD-1 antibody response in patients with NSCLC. Patients and methods: Seventy-four NSCLC patients treated with anti-PD-1 antibody were retrospectively enrolled. Patients with driver mutations were excluded. Results: The mean AGR was significantly higher in the disease control (DC) group than in the progressive disease (PD) group (p < 0.001). Receiver operating characteristic curve analysis revealed an AGR cutoff value for dividing patients into the DC or PD groups of 1.17. Multivariate logistic regression analysis showed that a high AGR (≥1.17, cutoff value) was an independent predictor of DC (p = 0.001). Progression-free survival (PFS) and overall survival (OS) were significantly longer in the high-AGR group than in the low-AGR group (p = 0.008, p = 0.002, respectively). Multivariate Cox regression analysis of PFS and OS showed that high AGR was an independent prognostic factor (p = 0.020, p < 0.001, respectively). Conclusion: Pretreatment serum AGR may be a useful predictor for DC and prognostic factor of anti-PD-1 antibody in patients with NSCLC. The clinical utility of AGR still needs to be confirmed in a prospective analysis. [ABSTRACT FROM AUTHOR]

S-1 is an oral fluoropyrimidine agent used for the treatment of non-small-cell lung cancer (NSCLC). Although S-1 monotherapy has been reported to exhibit lesser hematotoxicity compared with other third-generation chemotherapeutics, digestive toxicity was also frequently observed. Alternate-day administration of S-1 has shown a lower rate of severe digestive toxicity than the daily standard administration in patients with NSCLC. However, the safety of alternate-day S-1 therapy in elderly patients aged 75 years or older has not been investigated. The present study was a multi-center and prospective feasibility study aimed to evaluate the safety of alternate-day S-1 therapy in elderly patients with NSCLC. The patients received S-1 orally twice daily for 4 days (Monday, Wednesday, Friday, and Sunday) every week until disease progression or unacceptable toxicity. The primary endpoint was safety, which was evaluated as the number of grade ≥3 adverse events, and the secondary endpoints were progression-free survival (PFS), 1-year survival, and disease control rate (DCR). A total of 10 patients were enrolled, but 2 patients failed to initiate the treatment protocol. Finally, 8 patients were treated with the study protocol regimen. No grade 3 or higher adverse events were observed. Four (50%) and 1 (12.5%) patient had grade 2 or lower digestive symptoms such as anorexia, diarrhea, or stomatitis and grade 1 lacrimation, respectively. Moreover, 2 (25%), 1 (12.5%), and 1 (12.5%) patients had grade 2 renal dysfunction, grade 2 ileus, and elevated blood bilirubin, respectively. The median PFS was 1.5 months (95% confidence interval: 0.9–1.8), and the 1-year survival rate was 42.9%. The DCR was 12.5%. In conclusion, alternate-day S-1 administration can be a safe treatment regimen for elderly patients with NSCLC, but its therapeutic efficacy and safety for elderly patients with NSCLC should be compared against the standard S-1 administration in a large-scale study. [ABSTRACT FROM AUTHOR]

Objectives: Chemotherapy-related acute exacerbation (AE) of interstitial lung disease (ILD) is observed in certain patients with non-small cell lung cancer (NSCLC) who have ILD. Although the prognosis of AE-ILD is extremely poor, there are no established risk factors for its occurrence. Therefore, we retrospectively investigated whether high-resolution computed tomography (HRCT) findings could identify risk factors for AE-ILD.Materials and Methods: Between January 2005 and December 2016, 35 patients with NSCLC who received chemotherapy at Hiroshima University Hospital and were diagnosed with ILD on HRCT were enrolled. The extent of ground-glass attenuation (GGA), reticulation, honeycomb appearance, and emphysema, as well as the presence of micronodules, traction bronchiectasis, and consolidation were evaluated in five levels of the lung bilaterally. The HRCT scores of GGA, reticulation, honeycomb appearance, and emphysema were determined by the following formula: 100 × sum of the extent of the HRCT findings/lung area.Results: Thirty-five patients underwent various first- to fifth-line chemotherapy regimens. Nine patients (25.7%) developed AE-ILD. The median HRCT scores of GGA and reticulation were significantly higher in patients with AE-ILD than in those without. On univariate analysis, a GGA area score ≥ 24.8, reticulation area score ≥ 19.5, and KL-6 level ≥ 946 U/mL were significant risk factors. Multivariate logistic analysis revealed that only a GGA area score ≥ 24.8 was an independent risk factor of AE-ILD.Conclusions: The GGA area on HRCT is a risk factor for chemotherapy-related AE-ILD. Therefore, this parameter can be used to predict the risk of AE-ILD before administering chemotherapy. [ABSTRACT FROM AUTHOR]