No abstract

Background/Aim: The present study aimed to prospectively examine the usefulness of interferon-gamma (IFNγ) release (IGR) as a biomarker in non-small-cell lung cancer patients receiving immune checkpoint inhibitor treatment (ICI-Tx). Patients and Methods: IGR was measured using enzymelinked immunosorbent assay at four time points: within 14 days before ICI-Tx (T1), and 8±3 (T2), 22±7 (T3), and 43±7 (T4) days after ICI-Tx. Results: Twenty-nine patients were divided into three groups based on IFN-γ levels in the IGR-positive control: Group-1 (n=8) with <10 IU/ml at T1, Group-2 (n=12) with a decrease in IFN-γ levels to <10 IU/ml at T3 and/or T4, and Group-3 (n=9) without changes in IFN-γ levels. Early progression and ICI-induced interstitial pneumonitis were frequently observed in Group-1 and Group-2, respectively. Group-3 exhibited more treatment cycles than the other groups. All three groups showed clear differences in clinical outcomes. Conclusion: IFN-γ levels could be a biomarker for ICI-Tx. After the programmed cell death-1 (PD-1) gene was cloned (1), an anti-PD-1 antibody (2) was rapidly developed as an immune checkpoint inhibitor (ICI). ICIs have since become very important anticancer agents (3-5). However, there is currently no other biomarker for non-small-cell lung cancer (NSCLC) than programmed deathligand 1 (PD-L1) (6). Recently, we have reported on NSCLC patients who developed pulmonary Mycobacterium tuberculosis (MTB) infection while receiving nivolumab (7). We have shown that the development of this paradoxical response closely resembles that of pseudo progression after ICI treatment. Furthermore, several studies (8-10) have indicated that the PD-1/PD-L1 axis and interferon-gamma (IFN-γ) are very important for cellular immunity to MTB. The interferon-gamma release assay (IGRA) is widely used as a diagnostic method for latent MTB infection (11). The QuantiFERON ®-TB Test is an IGRA that can measure IFN-γ released from T lymphocytes by whole bloodbased enzyme-linked immunosorbent assay (ELISA). We hypothesized that changes in the PD-1/PD-L1 axis by ICI treatment affect IFN-γ release by T lymphocytes. Thus, the aim of the present prospective observational study was to verify our hypothesis and to examine the usefulness of monitoring IFNγ as a biomarker in patients with NSCLC who are receiving ICI treatment. Patients and Methods Ethics. This study was approved by our institutional review board (approval no.: 884). All patients who participated in this study were enrolled after providing their written informed consent. Furthermore, this study was registered in the University Hospital Medical Information Network Clinical Trials Registry (UMIN000031881).

Background/Aim: Extracellular water-to-total body water ratio (ECW/TBW) measured by bioelectrical impedance analysis (BIA) reportedly predicts clinical outcomes of various diseases. The aim of this retrospective study was to examine the association between ECW/TBW and therapeutic durability of chemotherapy and/or immune checkpoint inhibitors in advanced lung cancer. Patients and Methods: Patients with advanced lung cancer underwent BIA before chemotherapy and/or treatment with immune checkpoint inhibitors at our hospital between June 2018 and November 2019. Results: Of 75 patients, 18 with ECW/TBW ≥0.4 were assigned to the overhydrated group (OH-G) and 57 patients ECW/TBW <0.4 were assigned to the non-overhydrated group (NOH-G). The median time-to-treatment failure was significantly shorter in the OH-G than in the NOH-G (p=0.003). Multivariate analysis revealed that ECW/TBW ≥0.4 predicted treatment failure [hazard ratio (HR)=2.508, 95% confidence interval (CI)=1.19-5.27; p=0.01]. Conclusion: The ECW/TBW may be an objective parameter for predicting therapeutic durability in advanced lung cancer.

Background/Aim: We aimed to study the association between the quantitative interferon-gamma (IFNγ) levels and clinical outcomes in non-small-cell lung cancer (NSCLC) patients receiving immune checkpoint inhibitors (ICIs). Patients and Methods: Sample collection for IFN-γ release assay (IGRA) was performed within 14 days before treatment (T1), on day 22±7 (T3), and on day 43±7 (T4). The stored specimens over 10 IU/ml in IGRA were re-examined using the dilution method (with saline as the dilution medium). The patients were classified into Lower and Higher groups by 7.06 IU/ml as a cut-off of IFN-γ levels at T1. Results: Median progression-free survival in the Higher group was significantly longer than that in the Lower group. IFN-γ levels in the nonprogression disease group were significantly higher than those in the progression disease group. IFN-γ levels at T1 in patients with immune-related adverse events were significantly lower compared to those at T3. Conclusion: IFN-γ could be a biomarker for NSCLC patients receiving ICIs.Immune checkpoint Inhibitors (ICIs) are widely used as immunotherapy for a number of cancers. Cytotoxic Tlymphocyte-associated antigen 4 antibodies for melanoma were the first ICIs used in a clinical situation (1). After the programmed cell death-1 (PD-1) gene was cloned (2), an anti-PD-1 antibody (3) was also rapidly developed as one of the ICIs. Apart from treating melanomas, ICIs are being approved for different types of cancers, such as lymphomas (4) and gastric cancers (5).Non-small cell lung cancer (NSCLC) is one of the cancers usually treated with ICIs (6, 7). Programmed death-ligand 1 (PD-L1) is highly expressed in NSCLC and is the only biomarker that is used in the clinical practice to predict response to ICIs (8). However, this biomarker is not ideal because in some patients ICIs were less effective, even when PD-L1 expression level was high. In previous studies, many factors have been reported as biomarkers for ICIs response (9). However, none of the biomarkers were more effective than PD-L1. In our recent study (10), we examined the association between clinical outcomes of ICIs and levels of interferongamma (IFN-γ) release. We concluded that changes in the PD-1/PD-L1 axis by ICI treatment affected IFN-γ release by T lymphocytes, and IFN-γ levels could be a biomarker for the early detection of severe immune-related adverse events (irAEs), such as ICI-induced interstitial pneumonitis (ICI-IP), and for patient selection for ICI treatment. However, in our previous study (10) IFN-γ was examined qualitatively with an upper cut-off level of 10 IU/ml, while quantitative levels of IFN-γ in response to ICI are still unknown. As a result, the patients enrolled in our previous study were classified into three groups according to the IFN-γ levels at pre-treatment and on treatment, because the cut-off level of interferon-gamma release assay (IGRA) was 10 IU/ml. Because of this limitation in our previous study, we herein quantitatively re-examined the levels of IFN-γ >10 IU/ml using the diluti...

Immune checkpoint inhibitors (ICIs) improved the prognosis of patients with advanced lung cancers. The combination therapy of cytotoxic drugs and ICI is approved as first-line chemotherapy in non-small-cell lung cancer (NSCLC) and extensive disease small-cell lung cancer (ED-SCLC). It has been reported various immune-related adverse events (irAEs). We herein report a 65-year-old man with NSCLC who developed hepatitis and pancreatitis simultaneously during the combination immunochemotherapy. In the treatment of hepatitis and pancreatitis, the clinical course was different. In this report, the importance of accurate diagnosis through detailed examination and treatment priority depending on the severity of the symptoms is indicated.