Therapies targeted to the immune checkpoint mediated by PD-1 and PD-L1 show antitumor activity in a subset of patients with non-small cell lung cancer (NSCLC). We have now examined PD-L1 expression ...and its regulation in NSCLC positive for the EML4-ALK fusion gene.
The expression of PD-L1 at the protein and mRNA levels in NSCLC cell lines was examined by flow cytometry and by reverse transcription and real-time PCR analysis, respectively. The expression of PD-L1 in 134 surgically resected NSCLC specimens was evaluated by immunohistochemical analysis.
The PD-L1 expression level was higher in NSCLC cell lines positive for EML4-ALK than in those negative for the fusion gene. Forced expression of EML4-ALK in Ba/F3 cells markedly increased PD-L1 expression, whereas endogenous PD-L1 expression in EML4-ALK-positive NSCLC cells was attenuated by treatment with the specific ALK inhibitor alectinib or by RNAi with ALK siRNAs. Furthermore, expression of PD-L1 was downregulated by inhibitors of the MEK-ERK and PI3K-AKT signaling pathways in NSCLC cells positive for either EML4-ALK or activating mutations of the EGFR. Finally, the expression level of PD-L1 was positively associated with the presence of EML4-ALK in NSCLC specimens.
Our findings that both EML4-ALK and mutant EGFR upregulate PD-L1 by activating PI3K-AKT and MEK-ERK signaling pathways in NSCLC reveal a direct link between oncogenic drivers and PD-L1 expression.
The genetic backgrounds of the Japanese (or Asians) are, at least in part, different from those of Caucasians. It is necessary to recognize this difference to develop medicine that is both optimized ...and individualized. In particular, the consideration of ethnic differences is becoming increasingly important for lung cancer medicine. Japanese clinical practice guidelines indicate that some clinical biomarkers, such as epidermal growth factor receptor gene mutations, echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase fusion gene and uridine diphosphate glucuronosyltransferase genotypes should be determined in appropriate lung cancer patients. At the present time, tests for these biomarkers are covered by the Japanese national health-care programme, as is treatment with certain targeted drugs and cytotoxic agents. Therefore, most patients with lung cancer in Japan receive these tests as part of daily practice if their performance status and organ function are judged to be eligible. In addition, ethnic differences in bone marrow toxicity caused by cytotoxic drugs are reflected in treatment choice, and the requirements for the development of treatment modalities suitable for rare targeted populations are also increasing. To meet these requirements, many collaborative groups in Japan that have improved their infrastructure for investigator-initiated trials and conducted important activities need to provide further optimal treatment modalities for Japanese and Asian patients with lung cancer. Here, the characteristics of lung cancer in Japanese patients, general aspects of medical treatment and the care system in Japan, and representative studies on lung cancer in Japan are reviewed.
Immune checkpoint inhibitors (ICIs) play a central role in various cancers. ICIs can cause immune-related adverse events (irAEs). As severe irAEs can be life-threatening, biomarkers for estimating ...irAE onset are crucial. The neutrophils-to-lymphocytes ratio (NLR) reflects the systemic immune condition and known as a prognostic marker in ICI treatment. Our study evaluated if the NLR corresponded with irAEs, and its feasibility as a biomarker for irAE onset. We retrospectively analyzed 275 cancer patients treated with anti-PD-1 monotherapy. We observed 166 irAEs in 121 patients. The NLR was significantly elevated during irAEs. Patients experiencing interstitial pneumonitis showed NLR elevation 4 weeks before initial symptoms and diagnosis. Analyzing receiver operating characteristics curves revealed that elevated NLR distinguished subsequent pneumonitis severity with high accuracy (AUC 0.93, sensitivity 88.9%, specificity 88.2%, cut-off 2.37, p = 0.0004). After a severe irAE occurred, two NLR trends were observed. Patients who showed a prompt reduction in elevated NLRs had favorable progression-free survival (hazard ratio 0.32, 95% CI 0.10-1.01, p = 0.0140) and overall survival (hazard ratio 0.23, 95% CI 0.06-0.86, p = 0.0057) compared to the patients who maintained elevated NLRs. These findings suggest that continuous monitoring of NLR trends may predict irAE onset and severity and subsequent prognosis.
Recent clinical studies have suggested that inhalation of incense smoke (IS) may result in impaired lung function and asthma. However, there is little experimental evidence to link IS with airway ...hyperresponsiveness (AHR) and bronchial epithelial barrier function. Using mouse and cell culture models, we evaluated the effects of IS exposure on AHR, expression of multiple epithelial tight junction (TJ)- and adherens junction-associated mRNAs and proteins in the lungs, and the barrier function of bronchial epithelial cells assessed by transepithelial electronic resistance (TEER). Exposure of BALB/c mice to IS increased AHR and inflammatory macrophage recruitment to BALF; reduced claudin-1, -2, -3, -7, -10b, -12, -15, and -18, occludin, zonula occludens-1 ZO-1, and E-cadherin mRNA expression; and caused discontinuity of claudin-2 and ZO-1 protein immunostaining in lung tissue. IS extract dose-dependently decreased TEER and increased reactive oxygen species production in bronchial epithelial cell cultures. Treatment with N-acetyl-L-cysteine, but not glucocorticosteroids or long-acting β
-agonists, prevented the detrimental effects of IS. IS exposure can be problematic for respiratory health, as evidenced by AHR, increased recruitment of inflammatory macrophages and disruption of TJ proteins in the lung, and damage to epithelial barrier function. However, antioxidants may be useful for the treatment of IS-induced airway dysfunction.
Abstract
The liver is an essential organ for regulating innate and acquired immunity. We hypothesized that the pre-treatment hepatic function affects the clinical outcome of immune checkpoint ...inhibitors (ICIs) in non-small cell lung cancer (NSCLC). We analyzed 140 patients with NSCLC who received ICIs. We investigated the association between pre-treatment liver function, assessed using the albumin–bilirubin (ALBI) grade, and clinical outcomes in univariate, multivariate, and propensity score matching analyses. Patients were divided into four grades according to pre-treatment liver function. Eighty-eight patients had good hepatic reserve (ALBI grade 1 or 2a), whereas 52 patients had poor hepatic reserve (ALBI grade 2b or 3). In the univariate Kaplan–Meier analysis, the ALBI grade 1, 2a group had a significantly prolonged progression-free survival (PFS, 5.3 versus 2.5 months,
p
= 0.0019) and overall survival (OS, 19.6 vs. 6.2 months,
p
= 0.0002). These results were consistent, regardless of whether the analysis was performed in patients with a performance status of 0 or 1 at pre-treatment (N = 124) or in those selected using propensity score matching (N = 76). In the multivariate analysis, pre-treatment ALBI grade was an independent prognostic factor for both PFS (hazard ratio HR 0.57, 95% confidence interval 95% CI 0.38–0.86,
p
= 0.007) and OS (HR 0.45, 95% CI 0.29–0.72,
p
= 0.001). Our results suggest that pre-treatment hepatic function assessed by ALBI grade could be an essential biomarker for predicting the efficacy of treatment with ICIs in NSCLC.
Immune checkpoint inhibitors (ICPis) induce various immune-related adverse events (irAEs), despite their beneficial effects in treating various advanced cancers. ICPi-induced secondary adrenal ...insufficiency is described as a prevalent and serious ‘pituitary irAE.’ However, its precise mechanism remains unclear, and no definitive predictive markers have been reported.
We enrolled and studied 11 patients with advanced cancer (aged 39–70 years; 6 male patients) receiving nivolumab, pembrolizumab or ipilimumab who developed pituitary irAEs. Their clinical data, including endocrine functions, were retrospectively assessed and human leucocyte antigen (HLA) genotypes were determined to compare the HLA allele frequencies in these patients and healthy controls.
Among 11 patients, 7, 3 and 1 patients exhibited malignant melanoma, non–small-cell lung cancer and gastric cancer, respectively. HLA type screening results revealed that HLA-DR15, B52 and Cw12 were observed in 9, 7, and 7 patients with pituitary irAE, respectively. DR15, B52 and Cw12 were significantly more prevalent in our group than in the healthy control group from the Japanese HLA-haplotype database (this study vs healthy control group); DR15: 81.8% vs 33.5% (n = 11, P = 0.0014), B52: 63.6% vs 21.0% (n = 11, P = 0.0026) and Cw12: 70% vs 21.3% (n = 10, P = 0.0013).
HLA-DR15, B52 and Cw12 are possible predisposing factors for pituitary irAEs. HLA-DR15 is reportedly associated with autoimmune disease via interleukin-17 regulation, suggesting its involvement in pituitary irAE development. Using HLA haplotypes as pituitary irAE predictive markers, we could provide safe ICPi treatment and understand irAE pathogenesis.
•Specific human leucocyte antigen types were correlated with pituitary immune-related adverse events (irAEs).•This was seen especially in patients with secondary adrenal insufficiency.•This information may enable effective prediction of irAEs.•These data could enable safer treatment with immune checkpoint inhibitors.•This study provides clues regarding the aetiology of these adverse events.
Airway epithelial barrier function is maintained by the formation of tight junctions (TJs) and adherens junctions (AJs). Inhalation of cigarette smoke causes airway epithelial barrier dysfunction and ...may contribute to the pathogenesis of chronic lung diseases such as asthma and chronic obstructive pulmonary disease (COPD). We assessed the effects of cigarette smoke on barrier function and expression of multiple TJ and AJ proteins in the bronchial epithelium. We also examined whether treatment with glucocorticosteroids (GCSs), long-acting β
-agonists (LABAs), and human cathelicidin LL-37 can protect against cigarette smoke extract (CSE)-induced barrier dysfunction.
Calu-3 cells cultured at the air-liquid interface were pretreated with or without GCSs, LABAs, GCSs plus LABAs, or LL-37, and subsequently exposed to CSE. Barrier function was assessed by transepithelial electronic resistance (TEER) measurements. Gene and protein expression levels of TJ and AJ proteins were analyzed by quantitative PCR and western blotting, respectively. Immunofluorescence staining of TJ and AJ proteins was performed.
CSE decreased TEER and increased permeability in a concentration-dependent manner. CSE suppressed gene expression of claudin-1, claudin-3, claudin-4, claudin-7, claudin-15, occludin, E-cadherin, junctional adhesion molecule-A (JAM-A) and zonula occludens-1 (ZO-1) within 12 h post-CSE exposure, while suppressed protein expression levels of occludin at 12 h. CSE-treated cells exhibited discontinuous or attenuated immunostaining for claudin-1, claudin-3, claudin-4, occludin, ZO-1, and E-cadherin compared with untreated cells. GCS treatment partially restored CSE-induced TEER reduction, while LABA treatment had no effect. GCS and LABA combination treatment had no additive effect on CSE-induced TEER reduction and gene suppression of TJ and AJ proteins. Human cathelicidin LL-37 counteracted CSE-induced TEER reduction and prevented disruption of occludin and ZO-1. LL-37 also attenuated CSE-induced decreases in gene and protein expression levels of occludin.
CSE caused airway epithelial barrier dysfunction and simultaneously downregulated multiple TJ and AJ proteins. GCS and LABA combination treatment had no additive effect on CSE-induced TEER reduction. LL-37 counteracted CSE-induced TEER reduction and prevented disruption of occludin and ZO-1. Use of LL-37 to counteract airway epithelial barrier dysfunction may have significant benefits for respiratory diseases such as asthma and COPD.
Background
Many cancer patients suffer from the common side effect of chemotherapy-induced nausea and vomiting (CINV). Guidelines recommend a combination of two prophylactic antiemetics for ...moderately emetogenic chemotherapy (MEC) and three for highly emetogenic chemotherapy (HEC) and certain MEC regimens.
Methods
This multicenter, prospective, observational study analyzed data for 1,910 patients in Japan scheduled for MEC or HEC. Use of antiemetic prophylaxis in relation to type of chemotherapy, incidences of and risk factors for nausea, vomiting, and acute versus delayed CINV, and estimated incidence of CINV by staff were analyzed using Fisher’s exact test and multivariate logistic regression. The patients recorded the incidence of CINV and severity of nausea by visual analogue scales daily for 7 days after receiving chemotherapy.
Results
A total of 240 (20.1 %) HEC and 476 MEC patients (66.6 %) received 2 antiemetics, compared with 883 (73.9 %) and 200 (28.0 %), respectively, who received 3 antiemetics. Approximately 74 % of HEC and 95 % of MEC patients received antiemetic therapy in compliance with guidelines. Acute nausea and vomiting were well controlled, but high incidences of delayed nausea occurred in both HEC and MEC patients. Delayed vomiting (
p
< 0.0001) was significantly less frequent in patients receiving three compared with 2 antiemetics. Female sex was a major risk factor for CINV. Medical staff tended to overestimate the incidence of CINV. Among HEC regimens, the incidence of CINV and the degree of nausea on day 1 of anthracycline–cyclophosphamide combination therapy were higher than with a cisplatin-based regimen.
Conclusions
Adherence to antiemetic guidelines effectively controls vomiting but is less effective against delayed nausea in HEC and MEC patients. Identification of individual risk factors, such as female sex, will assist in the development of personalized treatments for CINV. More intensive antiemetic therapy or a different modality of prophylaxis should be considered for the control of acute CINV in an anthracycline–cyclophosphamide regimen.
The Japan Lung Cancer Society, the Japanese Association for Chest Surgery, and the Japanese Respiratory Society jointly established the Japanese Joint Committee for Lung Cancer Registration, which ...has regularly conducted lung cancer registries for surgical cases in 5-year periods. We analyzed data obtained in these registries to reveal the most recent surgical outcomes and trends related to lung cancer surgery in Japan.
Using data from the registry in 2010 for cases of surgery performed in 2004, demographics, surgical results, and stage-specific prognoses were analyzed. In addition, trends for those parameters over 10 years were assessed.
The 5-year survival rate for all cases (n = 11,663, 7369 males, mean age 66.7 years) was 69.6%. The 5-year survival rates by c-stage and p-stage were as follow: IA, 82.0% (n = 6295) and 86.8% (n = 4978); IB, 66.8% (n = 2339) and 73.9% (n = 2552); IIA, 54.5% (n = 819) and 61.6% (n = 941); IIB, 46.4% (n = 648) and 49.8% (n = 848); IIIA, 42.8% (n = 1216) and 40.9% (n = 1804); IIIB, 40.3% (n = 90) and 27.8% (n = 106); and IV, 31.4% (n = 256) and 27.9% (n = 434), respectively. The percentages of female patients, cases with adenocarcinoma, stage I or II disease, and tumors sized less than 2 cm were increased, while those of operative and hospital deaths were decreased. Furthermore, the prognoses of all cases and cases in each stage improved over the decade.
In Japanese cases of lung cancer surgery, demographics, surgical results, and stage-specific prognoses changed over the 10-year study period, while the 5-year survival rate for surgical cases improved to 69.6% in 2004.
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