Norikazu Matsuo

Predictive relevance of PD-L1 expression combined with CD8+ TIL density in stage III non-small cell lung cancer patients receiving concurrent chemoradiotherapy.

BACKGROUND Expression of programmed cell death-ligand 1 (PD-L1) is known to be a mechanism whereby cancer can escape immune surveillance, but little is known about factors predictive of efficacy in patients with locally advanced non-small cell lung cancer (NSCLC). We investigated the predictive relevance of PD-L1 expression and CD8+ tumour-infiltrating lymphocytes (TILs) density in patients with locally advanced NSCLC receiving concurrent chemoradiotherapy (CCRT). METHODS We retrospectively reviewed 74 consecutive patients with stage III NSCLC who had received CCRT. PD-L1 expression and CD8+ TIL density were evaluated by immunohistochemical analysis. RESULTS Univariate and multivariate analyses demonstrated that CD8+ TIL density was an independent and significant predictive factor for progression-free survival (PFS) and OS, whereas PD-L1 expression was not correlated with PFS and OS. Sub-analysis revealed that the PD-L1+/CD8 low group had the shortest PFS (8.6 months, p = 0.02) and OS (13.9 months, p = 0.11), and that the PD-L1-/CD8 high group had the longest prognosis (median PFS and OS were not reached) by Kaplan-Meier curves of the four sub-groups. CONCLUSIONS Among stage III NSCLC patients who received CCRT, there was a trend for poor survival in those who expressed PD-L1. Our analysis indicated that a combination of lack of PD-L1 expression and CD8+ TIL density was significantly associated with favourable survival in these patients. It is proposed that PD-L1 expression in combination with CD8+ TIL density could be a useful predictive biomarker in patients with stage III NSCLC.

Association of EGFR Exon 19 Deletion and EGFR-TKI Treatment Duration with Frequency of T790M Mutation in EGFR-Mutant Lung Cancer Patients

The most common event responsible for resistance to first- and second-generation (1st and 2nd) epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) is acquisition of T790M mutation. We examined whether T790M is related to clinicopathologic or prognostic factors in patients with relapse of EGFR mutant non-small cell lung cancer (NSCLC) after treatment with 1st or 2nd EGFR-TKIs. We retrospectively reviewed the T790M status and clinical characteristics of 73 patients with advanced or recurrent NSCLC who had been treated with EGFR-TKIs and undergone rebiopsy at Kurume University Hospital between March 2005 and December 2015. T790M mutation was more frequent in patients with EGFR exon 19 deletion mutation (63%, 26/41) than in those with L858R mutation (38%, 12/32) (p = 0.035). The median total duration of 1st or 2nd EGFR-TKI treatment was significantly longer in patients with T790M mutation than in those without (15.3 months vs 8.1 months, p < 0.001). Multivariate analysis revealed that the type of EGFR mutation and the total duration of EGFR-TKI treatment were significantly associated with T790M prevalence. Patients with EGFR exon 19 deletion mutation who receive long-term EGFR-TKI therapy show a high prevalence of T790M mutation. The present data are potentially important for clinical decision-making in NSCLC patients with EGFR mutation.

Clinical features of usual interstitial pneumonia with anti-neutrophil cytoplasmic antibody in comparison with idiopathic pulmonary fibrosis.

Myeloperoxidase anti‐neutrophil cytoplasmic antibody (MPO‐ANCA) is occasionally positive in patients with usual interstitial pneumonia (UIP). However, the differences from idiopathic pulmonary fibrosis (IPF/UIP) have not been well documented. We aimed to clarify the clinical, radiological and pathological features of UIP associated with MPO‐ANCA (ANCA/UIP).

Programmed cell death-ligand 1 expression and immunoscore in stage II and III non-small cell lung cancer patients receiving adjuvant chemotherapy

Programmed cell death 1 (PD-1) receptor-ligand interaction is a major pathway that is often hijacked by tumors to suppress immune control. Immunoscore (IS), a combinational index of CD3 and CD8 tumor-infiltrating lymphocyte (TIL) density in the tumors center and invasive margin, is a new prognostic tool suggested to be superior to conventional tumor-staging methods in various tumors. This retrospective study aimed to investigate the prevalence and prognostic roles of PD-ligand 1 (PD-L1) expression and IS in non-small cell lung cancer (NSCLC) patients receiving adjuvant chemotherapy. PD-L1 expression and TIL density were evaluated by immunohistochemical analysis in 36 patients with stage II and III NSCLC. Tumors with staining in over 1% of their cells were scored as positive for PD-L1 expression, and we determined the median number of CD3- and CD8-positive TILs as the cutoff point for TIL density. To determine IS, each patient was given a binary score (0 for low and 1 for high) for CD3 and CD8 density in both the tumor center and invasive margin region. PD-L1 expression in tumor cells was observed in 61.1% (22/36) of patients. PD-L1 expression was significantly associated with high IS, and highest IS tended to have a favorable disease-free survival.Programmed cell death 1 (PD-1) receptor–ligand interaction is a major pathway that is often hijacked by tumors to suppress immune control. Immunoscore (IS), a combinational index of CD3 and CD8 tumor-infiltrating lymphocyte (TIL) density in the tumor’s center and invasive margin, is a new prognostic tool suggested to be superior to conventional tumor-staging methods in various tumors. This retrospective study aimed to investigate the prevalence and prognostic roles of PD-ligand 1 (PD-L1) expression and IS in non-small cell lung cancer (NSCLC) patients receiving adjuvant chemotherapy. PD-L1 expression and TIL density were evaluated by immunohistochemical analysis in 36 patients with stage II and III NSCLC. Tumors with staining in over 1% of their cells were scored as positive for PD-L1 expression, and we determined the median number of CD3- and CD8-positive TILs as the cutoff point for TIL density. To determine IS, each patient was given a binary score (0 for low and 1 for high) for CD3 and CD8 density in both the tumor center and invasive margin region. PD-L1 expression in tumor cells was observed in 61.1% (22/36) of patients. PD-L1 expression was significantly associated with high IS, and highest IS tended to have a favorable disease-free survival.

Accuracy of transbronchial biopsy as a rebiopsy method for patients with relapse of advanced non-small-cell lung cancer after systemic chemotherapy

Introduction Rebiopsy in patients with advanced non-small-cell lung cancer (NSCLC) resistant to systemic chemotherapy may yield information on the mechanisms of resistance and planning of subsequent treatment. Transbronchial biopsy (TBB) using a flexible bronchoscope has been commonly used for establishing the initial diagnosis of lung cancer. The aim of this study was to assess the accuracy and safety of TBB in patients with NSCLC relapse, and the factors affecting its diagnostic yield. Methods We retrospectively screened patients with advanced NSCLC who underwent TBB for rebiopsy after developing resistance to systemic chemotherapy at Kurume University Hospital between January 2012 and June 2016. A positive diagnostic result obtained by TBB was defined as malignancy determined on the basis of histological features that were adequate for mutational analysis or immunohistochemistry. Severe postprocedural complications were defined as those requiring invasive medical procedures or prolonged hospitalisation. Results 109 patients were enrolled in this retrospective study. Adequate tumour samples were collected from 88 of these patients, giving a high diagnostic yield of 80.7%. The diagnostic yield of TBB was not associated with tumour mutational status, the previous treatment regimen, or efficacy of the previous treatment. There were no severe postprocedural complications such as pneumothorax or serious haemorrhage. Conclusions TBB is considered one of the safest and most useful procedures for rebiopsy of NSCLC that has relapsed after chemotherapy, regardless of patient background and treatment history.

Prognostic stratification of patients with nasopharyngeal carcinoma based on tumor immune microenvironment

Little is known about immune‐related prognostic factors in patients with nasopharyngeal carcinoma (NPC).

Phase II Trial of Carboplatin and Pemetrexed Plus Bevacizumab with Maintenance Bevacizumab as a First-line Treatment for Advanced Non-squamous Non-small Cell Lung Cancer in Elderly Patients

Background/Aim: The combination of platinum-doublet chemotherapy with bevacizumab has been established as a first-line treatment option in non-elderly patients with non-squamous (non-sq) non-small cell lung cancer (NSCLC). However, the safety and efficacy of this regimen have not yet been fully established in elderly patients. Patients and Methods: Chemo-naïve patients with non-sq NSCLC, aged ≥75 years, having a good performance status (Eastern Cooperative Oncology Group performance status 0-1) and adequate organ function were considered eligible. Patients received carboplatin (area under the curve=5 mg/ml/min), pemetrexed (500 mg/m2), and bevacizumab (15 mg/kg) every 3 weeks for up to 4 cycles, followed by maintenance bevacizumab. The primary endpoint was the objective response rate (ORR; target=50%, threshold=30%; Simons two-stage design), and the secondary endpoints were safety, progression-free survival (PFS), and overall survival (OS). Results: Twelve patients were enrolled from June 2013 to July 2017. The study was closed because of slow patient accrual. The median patient age was 80 years. Eleven patients (92%) completed 4 cycles of induction chemotherapy. Seven patients achieved a partial response (PR), yielding an ORR of 58%. The median PFS was 8.4 [95% confidence interval (CI)=4.4-10.5] months, and the median OS was 33.9 (95%CI=13.2-43.3) months. Toxicities were generally mild and consistent with previous reports. There were no treatment-related deaths. Conclusion: A regimen comprising carboplatin and pemetrexed plus bevacizumab followed by maintenance bevacizumab is feasible and potentially efficacious in elderly patients with non-sq NSCLC.

A Case of Lung Cancer with a Small Cell Carcinoma Component Diagnosed from Pleural Effusion and a Squamous Cell Carcinoma Component Diagnosed from the Tumor

There have been few reports on the accuracy of the diagnosis of small-cell carcinoma based on a cytological examination of malignant pleural effusion, so whether or not such a diagnosis is possible using this approach alone remains unclear. We herein report a 76-year-old Japanese man in whom small-cell carcinoma was diagnosed cytopathologically from pleural effusion and squamous cell carcinoma was diagnosed histopathologically from a transbronchial biopsy. Tumor shrinkage was achieved by treatment with docetaxel, but the efficacy of carboplatin plus etoposide was inadequate. If small-cell carcinoma is detected on the basis of pleural fluid cytopathology alone, it is extremely important to perform a histopathological examination to rule out the possibility of other malignancies.

Pulmonary pleomorphic carcinoma: A case harboring EGFR mutation treated with EGFR-TKIs: Pleomorphic carcinoma with EGFR mutation

Pulmonary pleomorphic carcinoma (PPC) is a very rare type of primary lung cancer with an aggressive clinical course. Few reports have documented therapeutic options for PPC with EGFR mutations. Herein, we report a case of PPC with EGFR mutation treated with EGFR‐tyrosine kinase inhibitors (TKIs). A 65‐year‐old Japanese woman was diagnosed with stage IV lung adenocarcinoma with L858R point mutation in exon 21. Despite treatment with erlotinib, the patient died after two weeks as a result of rapid disease progression. Postmortem examination indicated that the thoracic tumors consisted primarily of spindle/sarcomatous components, while expression of the mutated EGFR protein was only observed in adenocarcinoma components. We speculate that the tumor was not driven by EGFR mutation. Clinicians should bear in mind the possibility of pleomorphic carcinoma if EGFR‐TKI treatment fails to achieve a clinical response for adenocarcinoma harboring an activating EGFR mutation diagnosed on the basis of small biopsy specimens.

Association between soluble immune mediators and tumor responses in patients with non-small cell lung cancer treated with anti-PD-1 inhibitor: Association between soluble immune mediators and tumor responses in patients with non-small cell lung cancer treated with anti-PD-1 inhibitor

Although programmed death (PD)‐1 immune checkpoint therapies target the immune system, the relationship between inflammatory factors and the clinical outcome of anti‐PD‐1 therapy for nonsmall cell lung cancer (NSCLC) is not fully understood. Here we examined the association between soluble immune mediators and the outcome of treatment with PD‐1 inhibitors in patients with advanced/recurrent NSCLC. In two independent cohorts, we assessed the levels of 88 different soluble immune mediators in peripheral blood before and after anti‐PD‐1 treatment, and evaluated their associations with clinical outcomes. In the training cohort, the plasma levels of chitinase 3‐like‐1 and GM‐CSF before treatment (p = 0.006 and p = 0.005, respectively) and changes in the plasma levels of CXCL2, VEGF, IFNα2, and MMP2 after treatment (p < 0.001, p = 0.019, p = 0.019, and p = 0.012, respectively) were significantly correlated with PFS. The change in the plasma CXCL2 level was also significantly associated with treatment‐related AEs (p = 0.017). In the validation cohort, however, only the changes in the plasma levels of CXCL2 and MMP2 after treatment were associated with PFS (p = 0.003 and p = 0.006, respectively), and these changes were maintained during the course of anti‐PD‐1 therapy in patients who showed better clinical outcomes, even in those with tumor pseudoprogression. Since CXCL2 and MMP2 can be easily measured by minimally invasive blood sampling, they could be useful for monitoring of clinical outcomes in NSCLC patients receiving PD‐1 inhibitor therapy.