Prognostic Impact of Central Nervous System Recurrence After Surgery in Patients With Epidermal Growth Factor Receptor Mutation-positive Non-small-cell Lung Cancer.

BACKGROUND/AIM: Adjuvant therapy using third-generation tyrosine kinase inhibitors (TKI) demonstrated improved central nervous system (CNS) disease-free survival after surgery in patients with epidermal growth factor receptor (EGFR) mutation-positive lung cancer. However, the prognostic impact of CNS recurrence in surgical patients remains unknown. We evaluated the effect of CNS recurrence on post-recurrence survival (PRS) in patients with postoperatively recurrent NSCLC. PATIENTS AND METHODS: We assessed the prognostic impact of CNS recurrence using a cohort from a prospective observational study (Kyushu University Lung Surgery Group Study 2: KLSS-2). Based on data from 340 patients in whom EGFR mutations were assessed among 498 total patients in the KLSS-2 cohort, factors related to CNS recurrence and prognosis after postoperative recurrence were analyzed. RESULTS: We noted no marked differences in the presence of EGFR mutations (p=0.14) between patients with CNS recurrence and those without CNS recurrence. Among the patients tested for EGFR mutations with stage IV recurrences (n=219), survival analysis of patients with EGFR mutations showed that the CNS group had a significantly poorer PRS than the no-CNS group (MST: 36.8 vs. 43.9 months, p=0.035). In multivariate survival analysis of stage IV EGFR mutation-positive cases, recurrence in multiple organs and recurrence of brain metastases were independent poor prognostic factors (hazard ratio=2.2, p=0.029; hazard ratio=3.2, p=0.0006, respectively). CONCLUSION: Postoperative CNS recurrence was associated with a poor prognosis among patients with EGFR mutation-positive lung cancer in the period when third-generation EGFR-TKIs were not available. In EGFR mutation-positive lung cancer, prevention of CNS recurrence after surgery may improve post-recurrence prognosis.

Clinical benefit of platinum doublet combination therapy in older adults with advanced non-small cell lung cancer: A prospective multicenter study by the National Hospital Organization in Japan.

BACKGROUND: Previous trials suggest that older adults with non-small cell lung cancer (NSCLC) derive benefit from platinum doublet combination therapy, but its superiority is controversial. Although geriatric assessment variables are used to assess the individual risk of severe toxicity and clinical outcomes in older patients, the standard first-line treatment is still debated. Therefore, we aimed to identify the risk factors for clinical outcomes in older patients with NSCLC. METHODS: Patients aged ≥75 years with advanced NSCLC treated at any of 24 National Hospital Organization institutions completed a pre-first-line chemotherapy assessment, including patient characteristics, treatment variables, laboratory test values, and geriatric assessment variables. We evaluated whether these variables were the risk factors for progression-free survival (PFS) and overall survival (OS). RESULTS: A total of 148 patients with advanced NSCLC were treated with combination therapy (n = 90) or monotherapy (n = 58). Median PFS was 5.3 months and OS was 13.6 months. We identified that hypoalbuminemia (hazard ratio [HR] 2.570, 95% confidence interval [CI]: 1.117-5.913, p = 0.0264) was a risk factor for PFS and monotherapy (HR 1.590, 95% CI: 1.070-2.361, p = 0.0217), lactate dehydrogenase (HR 3.682, 95% CI: 1.013-13.39, p = 0.0478), and high C-reactive protein (HR 2.038, 95% CI: 1.141-3.642, p = 0.0161) were risk factors for OS. The median OS was significantly longer in patients treated with combination therapy than in those who received monotherapy (16.5 months vs. 10.3 months; HR 0.684, 95% CI: 0.470-0.995, p = 0.0453). DISCUSSION: Platinum doublet combination therapy may be beneficial in older patients with NSCLC. Identification of risk factors will assist in the development of a personalized treatment strategy.

Augmenting Granzyme B-Expressing NK Cells by Invariant NKT Ligand-Loaded APCs in Patients with Postoperative Early Stage Non-Small Cell Lung Cancer: Results of a Randomized Phase II Study.

NK cells are major effector cells involved in the elimination of early tumors and prevent metastasis. They often have an impaired function in patients with cancer. Preclinical studies have demonstrated NK cell activation as the adjunctive effect of invariant NKT (iNKT) cells. Activation of iNKT cells after administration of the glycolipid ligand α-galactosylceramide, loaded with CD1d-expressing human PBMC-derived APCs (APC/Gal), is an attractive cancer therapy to optimize the use of NK cells. However, the subsets of NK cells that are activated following iNKT cell activation as well as the period of NK cell activation remain unclear. In this study, we report that the granzyme B-expressing NK cell response in postoperative lung cancer patients was enhanced 49 d after administration of APC/Gal in a phase II study. We found maximum IFN-γ production on day 49 in 13 out of 27 APC/Gal-treated patients. On day 49, 14 out of 27 patients (51.9%) had higher IFN-γ production by iNKT cells (>6-fold higher than the baseline level). This increment significantly correlated with granzyme B-expressing NK cells. Although IFN-γ production was lower in patients in the nontreated group, we detected maximum IFN-γ production 12 mo after the resection of lung cancer (9 out of 29 patients [31%]). These findings suggest that elimination of cancer cells leads to increased NK cell function, which can be further enhanced by APC/Gal therapy.

Predicting systemic therapy toxicity in older adult patients with advanced non-small cell lung cancer: A prospective multicenter study of National Hospital Organization in Japan.

INTRODUCTION: Previous studies have developed risk stratification schemas to assess systemic therapy toxicity. However, it is controversial which geriatric assessment variables should be used to assess the individual risk of severe treatment-associated toxicity in older adult patients. MATERIALS AND METHODS: Patients aged ≥70 years with advanced non-small cell lung cancer (NSCLC) treated at 24 National Hospital Organization institutions completed a pre-first-line systemic therapy assessment, including patient characteristics, treatment variables, laboratory test values, and geriatric assessment variables. Patients were followed through one cycle of systemic therapy to assess grade 3 (severe) to grade 5 (death) adverse events according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. RESULTS: In total, 348 advanced NSCLC patients with a median age of 76 years (range, 70 to 95 years) joined this prospective study. Severe adverse events ≥grade 3 occurred in 136 patients (39.1%). Predictors of hematologic toxicity were treatment variables, body mass index, body weight loss, and limitation in daily living due to dementia. These predictors provided the predictive model of hematologic toxicity ≥grade 3; 0 point (22.2%), 1 point (33.8%), 2 points (59.6%), ≥3 points (73.3%). Sex, daily living independence level, and lactate dehydrogenase levels were associated with non-hematologic toxicity ≥grade 3 in multivariate analysis. A scoring system using these predictors distinguished the risk levels of non-hematologic toxicity ≥grade 3; 0 point (6.6%), 1 point (12.2%), 2 points (39.0%), 3 points (75.0%). DISCUSSION: A stratification using individual extracted risk factors may be useful to predict the vulnerability to systemic therapy in older adult NSCLC patients.

Prospective observational study of nutritional/immunologic indices as predictive biomarkers for the response to anti-PD-1 drugs in non-small cell lung cancer (ICI-PREDICT study).

Immune checkpoint inhibitors (ICIs) targeting programmed cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) have markedly improved the prognosis of many patients with advanced non-small cell lung cancer (NSCLC). However, the relationship between the patient's nutritional/immunologic status and the outcomes of ICI treatment remains unclear. In previous retrospective studies, we reported that the controlling nutritional status (CONUT) score, skeletal muscle area, and neutrophil-to-lymphocyte ratio were independent predictors of the response of NSCLC patients to anti-PD-1 drugs. The aim of this prospective multi-center study is to investigate the clinical impact of pre-treatment nutritional/immunologic indices and early post-treatment changes in the indices on treatment outcomes in advanced NSCLC. The main inclusion criteria are: (1) stage IV NSCLC, or stage III NSCLC not applicable for definitive chemoradiotherapy; (2) treatment with ICIs (monotherapy or combined with chemotherapy) as first-line therapy; and (3) available data on PD-L1 expression on tumor cells. A total of 300 patients will be enrolled prospectively. Enrollment will begin in 2020 and the final analyses will be completed by 2025.

Phase 2 Study of YS110, a Recombinant Humanized Anti-CD26 Monoclonal Antibody, in Japanese Patients With Advanced Malignant Pleural Mesothelioma.

INTRODUCTION: YS110, a humanized monoclonal antibody with a high affinity to CD26, exhibited promising antitumor activity and was generally well-tolerated in the phase 1 part of a phase 1 and 2 Japanese trial in patients with malignant pleural mesothelioma (MPM). Here we report the results of the phase 2 part of the study. METHODS: The patients included were aged 20 years and older, had histologically confirmed MPM, were refractory to or intolerant of existing antineoplastic agents, and were not candidates for standard therapy. YS110 6 mg/kg, determined in the phase 1 dose-determination part, was given in 6-weekly cycles (5 × once-weekly infusions, followed by a 1-wk rest). RESULTS: The study included 31 patients (median age = 68 y, 90.3% men); 64.5% had stage IV MPM, 90.3% had greater than or equal to 20% CD26 expression in tumor tissue, and 38.7% (12 patients) had previously received nivolumab. The 6-month disease control rate was 3.2%. The best overall response was partial response in one patient and stable disease in 14 patients. The median progression-free survival was 2.8 months (both in patients who had and had not previously received nivolumab-groups A and B, respectively). Respective progression-free survival rates at 6 months were 9.1% and 31.6% in groups A and B. The median overall survival was 9.7 months. A total of 30 patients (96.8%) had at least one adverse event. Common treatment-related adverse events were infusion-related reaction (16.1%), hiccups (9.7%), and interstitial lung disease (9.7%). There were no treatment-related deaths. CONCLUSIONS: The 6-month disease control rate did not exceed the predefined threshold, but YS110 revealed modest efficacy in response rate as salvage therapy in difficult-to-treat patients with MPM. YS110 was generally well tolerated.

Prognostic value of postoperative decrease in serum albumin on surgically resected early-stage non-small cell lung carcinoma: A multicenter retrospective study.

BACKGROUND: Preoperative nutritional status is an important host-related prognostic factor for non-small cell lung carcinoma (NSCLC); however, the significance of postoperative changes in nutritional status remains unclear. This study aimed to elucidate the significance of postoperative decreases in serum albumin (ΔAlb) on the outcomes of early-stage NSCLC. METHODS: We analyzed 443 training cohort (TC) and 642 validation cohort (VC) patients with pStage IA NSCLC who underwent surgery and did not recur within 1 year. We measured preoperative serum albumin levels (preAlb) and postoperative levels 1 year after surgery (postAlb), and calculated ΔAlb as (preAlb - postAlb)/preAlb × 100%. A cutoff value of 11% for ΔAlb was defined on the basis of the receiver operating characteristic curve for the TC. RESULTS: Patients were divided into ΔAlb-Decreased and ΔAlb-Stable groups, including 100 (22.6%) and 343 (77.4%) in the TC, and 58 (9.0%) and 584 (90.1%) in the VC. ΔAlb-Decreased was associated with male sex (p = 0.0490), smoking (p = 0.0156), and non-adenocarcinoma (p<0.0001) in the TC, and pT1b (p = 0.0169) and non-adenocarcinoma (p = 0.0251) in the VC. Multivariable analysis identified ΔAlb as an independent prognostic factor for disease-free survival (DFS) and overall survival (OS) in both cohorts (VC: DFS, HR = 1.9, 95%CI: 1.10-3.15, p = 0.0197; OS, HR = 2.0, 95%CI: 1.13-3.45, p = 0.0173). Moreover, subgroup analysis demonstrated that the prognostic value of ΔAlb was consistent for age, sex, smoking history, surgical procedure, and histological type. CONCLUSION: We demonstrated a negative impact of postoperative decrease of the serum albumin on the prognosis of patients with early-stage NSCLC. Postoperative changes in nutritional status might be important in NSCLC outcomes.

Paired analysis of tumor mutation burden for lung adenocarcinoma and associated idiopathic pulmonary fibrosis.

Genetic alterations underlying the development of lung cancer in individuals with idiopathic pulmonary fibrosis (IPF) have remained unclear. To explore whether genetic alterations in IPF tissue contribute to the development of IPF-associated lung cancer, we here evaluated tumor mutation burden (TMB) and somatic variants in 14 paired IPF and tumor samples from patients with IPF-associated lung adenocarcinoma. We also determined TMB for 22 samples of lung adenocarcinoma from patients without IPF. TMB for IPF-associated lung adenocarcinoma was significantly higher than that for matched IPF tissue (median of 2.94 vs. 1.26 mutations/Mb, P = 0.002). Three and 102 somatic variants were detected in IPF and matched lung adenocarcinoma samples, respectively, with only one pair of specimens sharing one somatic variant. TMB for IPF-associated lung adenocarcinoma was similar to that for lung adenocarcinoma samples with driver mutations (median of 2.94 vs. 2.51 mutations/Mb) and lower than that for lung adenocarcinoma samples without known driver mutations (median of 2.94 vs. 5.03 mutations/Mb, P = 0.130) from patients without IPF. Our findings suggest that not only the accumulation of somatic mutations but other factors such as inflammation and oxidative stress might contribute to the development and progression of lung cancer in patients with IPF.

Mutual checking system for assessing trainee skills of thoracic surgery.

BACKGROUND: Video-assisted surgery helps surgeons learn surgical skills efficiently. The aim of this study was to evaluate the effect of mutual evaluation of trainees' surgical techniques using tabulated common evaluation criteria. METHODS: We created a check sheet in which a standard pulmonary lobectomy procedure was divided into six parts and the checkpoints to note listed. Both the trainees and trainers used tabulated common evaluation criteria to evaluate lobectomies performed by the trainees. RESULTS: From September 2019 to March 2020, 30 lobectomies were performed by three trainees. The trainee's evaluations of their own procedures were relatively high at first, then decreased, then gradually increased; however, the trainers' evaluations showed no such tendency. CONCLUSIONS: Mutual evaluation of surgery using tabulated common evaluation criteria enables trainees to review their own surgery objectively and receive evaluations by trainers, thus helping them to avoid the Dunning-Kruger effect and efficiently acquire basic surgical skills.

Prognostic impact of primary cancer adjoining emphysematous bullae in non-small cell lung cancer patients treated with immune checkpoint inhibitors.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have become a standard therapy in non-small cell lung cancer (NSCLC). Although lung cancer adjoining emphysematous bullae (Ca-ADJ) were reported to express higher programmed cell death-ligand 1 (PD-L1), the predictive impact of Ca-ADJ on the response to ICIs is unknown. METHODS: Two hundred and fifty-seven advanced or recurrent NSCLC patients treated with ICI monotherapy at Kyushu University Hospital and National Hospital Organization Kyushu Cancer Center were analyzed. To minimize the bias arising from the patients' background, adjusted Kaplan-Meier survival curves and Cox proportional hazards regression analyses using inverse probability of treatment weights (IPTW) were performed. RESULTS: Of the 257 patients, 55 had Ca-ADJ. Patients with Ca-ADJ were significantly associated with younger age (P = 0.0343), male sex (P = 0.0070), and smoking (P = 0.0080). The objective response rate of cases with Ca-ADJ was significantly higher than that of those without Ca-ADJ (36.4% vs. 20.8%, respectively; P = 0.0167). The disease control rate of cases with Ca-ADJ was also significantly higher than tumors without Ca-ADJ (63.6% vs. 47.5%, respectively; P = 0.0341). The IPTW-adjusted Kaplan-Meier curves showed that patients with Ca-ADJ had significantly longer progression-free survival (PFS) and overall survival (OS) than those without Ca-ADJ (P = 0.0407 and P = 0.0126, respectively). On IPTW-adjusted Cox analysis, Ca-ADJ was an independent predictor of PFS and OS (P < 0.0001 and P < 0.0001, respectively). CONCLUSIONS: Patients with Ca-ADJ may be good candidates for ICIs. These findings should be validated prospectively.

Efficacy and safety of carboplatin with nab-paclitaxel versus docetaxel in older patients with squamous non-small-cell lung cancer (CAPITAL): a randomised, multicentre, open-label, phase 3 trial.

BACKGROUND: In Japan, docetaxel, a cytotoxic monotherapy, is the standard drug administered to older patients with advanced non-small-cell lung cancer (NSCLC). Carboplatin plus nab-paclitaxel has shown a high objective response rate in patients with squamous histology and was suggested to improve overall survival in patients aged 70 years and older. The CAPITAL trial aimed to assess the safety and efficacy of carboplatin plus nab-paclitaxel versus docetaxel as first-line therapy for patients aged 70 years and older with advanced squamous NSCLC. METHODS: This multicentre, open-label, randomised, phase 3 trial was carried out at 92 medical institutions in Japan. Eligible patients were aged 70 years and older, had advanced squamous NSCLC with no previous systemic chemotherapy, and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Using an electronic data capture system, patients were randomly assigned (1:1) to intravenous carboplatin (area under the concentration-time curve of 6 mg/mL per min for 30 min) on day 1 of a 21-day cycle and intravenous nab-paclitaxel (100 mg/m2 for 60 min) on days 1, 8, and 15 every 3 weeks or intravenous docetaxel (60 mg/m2 for 60 min) on day 1 every 3 weeks. Randomisation was computer-generated per participant and stratified by ECOG performance status, clinical stage, sex, age, and institution. The primary endpoint was overall survival, measured in the full analysis set and defined as the time from registration to the date of death due to any cause. Safety was assessed in all patients who received at least one dose of the trial treatment. This trial is registered with the UMIN Clinical Trials Registry, UMIN000019843, and the Japan Registry of Clinical Trials, jRCTs041180110. After the planned interim analysis in Aug 3, 2020, the independent data monitoring committee recommended that the trial be stopped early. This report represents the final analysis. FINDINGS: Between Feb 24, 2016, and Aug 11, 2020, 196 patients were enrolled and were randomly assigned to the carboplatin plus nab-paclitaxel group (n=98) or the docetaxel group (n=98). Of these patients, four (carboplatin plus nab-paclitaxel group, n=3; docetaxel group, n=1) did not receive any treatment and two patients in the docetaxel group were excluded from the full analysis set. Median overall survival in the full analysis set was 16·9 months (95% CI 12·6-25·4) in the carboplatin plus nab-paclitaxel group and 10·9 months (8·5-12·4) in the docetaxel group (hazard ratio 0·52 [90% CI 0·38-0·70]; p=0·0003). Grade 3-4 adverse events occurred in 79 (83%) patients in the carboplatin plus nab-paclitaxel group and 77 (79%) patients in the docetaxel group (p=0·63). The most common grade 3-4 adverse events in the carboplatin plus nab-paclitaxel group and the docetaxel group were leukopenia (44 [46%] vs 55 [57%]; p=0·20), neutropenia (60 [63%] vs 75 [77%]; p=0·046), febrile neutropenia (nine [10%] vs 19 [20%]; p=0·073), and anaemia (37 [39%] vs two [2%]; p<0·0001). Serious treatment-related adverse events of all grades occurred in 13 (14%) patients in the carboplatin plus nab-paclitaxel group and 11 (11%) patients in the docetaxel group. Treatment-related deaths occurred in two (2%; respiratory failure n=1, visceral arterial ischaemia n=1) patients in the carboplatin plus nab-paclitaxel group and one (1%; sepsis) patient in the docetaxel group. INTERPRETATION: Our study showed that overall survival was longer with carboplatin plus nab-paclitaxel than with docetaxel, suggesting that carboplatin plus nab-paclitaxel can be used as standard first-line treatment for patients aged 70 years and older with advanced squamous NSCLC. FUNDING: Taiho Pharmaceutical.

Prognostic Impact of Smoking Period in Patients with Surgically Resected Non-small Cell Lung Cancer.

BACKGROUND: The pack-year index, which is calculated by multiplying a smoking period by the number of cigarette packs smoked per day, is frequently used to investigate the risk of developing lung cancer. Notably, however, whether the smoking period or the number of packs per day is more predictive of postoperative prognosis remains unclear in non-small cell lung cancer (NSCLC) patients who receive curative lung resection. PATIENTS AND METHODS: Initial screening included 2055 consecutive lung cancer patients who had underwent curative lung resection between 2000 and 2016 at a single center in Japan. Data from 1134 NSCLC patients with smoking history were ultimately analyzed. Time-dependent areas under the curve (AUCs) were used to compare diagnostic accuracy. RESULTS: On univariate analysis, the number of packs smoked per day was not a significant predictor of disease-free survival (DFS; p = 0.2387) or overall survival (OS; p = 0.1357). On multivariable analysis, smoking period was an independent predictor of DFS and OS (both p < 0.0001). Time-dependent smoking period AUCs were superior to those of number of packs smoked per day. On subgroup analyses, patients with a smoking period ≥ 40 years had significantly shorter DFS and OS than those with a smoking period of < 40 years, independent of sex, clinical stage, and histological type. CONCLUSIONS: Smoking period was a significant prognostic indicator in NSCLC patients who underwent curative lung resection, which should be validated in further prospective and/or multicenter studies with large sample sizes.

Five-year follow-up results from phase II studies of nivolumab in Japanese patients with previously treated advanced non-small cell lung cancer: pooled analysis of the ONO-4538-05 and ONO-4538-06 studies.

BACKGROUND: Two phase II studies in Japan examined the efficacy and safety of nivolumab, a programmed cell death 1 receptor inhibitor, in patients with advanced squamous and non-squamous non-small cell lung cancer (ONO-4538-05 and ONO-4538-06). We examined the long-term efficacy and safety of nivolumab in these patients treated for up to 5 years. METHODS: Patients with squamous (N = 35) or non-squamous (N = 76) non-small cell lung cancer received nivolumab (3 mg/kg every 2 weeks) until disease progression/death. Overall survival and progression-free survival were assessed at 5 years after starting treatment in separate and pooled analyses. Safety was evaluated in terms of treatment-related adverse events. RESULTS: A total of 17 patients were alive at the database lock (26 July 2019). The median overall survival (95% confidence interval) and 5-year survival rate were 16.3 (12.4-25.2) months and 14.3% in squamous patients, 17.1 (13.3-23.0) months and 19.4% in non-squamous patients and 17.1 (14.2-20.6) months and 17.8% in the pooled analysis, respectively. Programmed death ligand-1 expression tended to be greater among 5-year survivors than in non-survivors (P = 0.0703). Overall survival prolonged with increasing programmed death ligand-1 expression, with 5-year survival rates of 11.8, 21.8 and 41.7% in patients with programmed death ligand-1 expression of <1, ≥1-<50 and ≥50%, respectively. Treatment-related adverse events in ≥10% of patients (pooled analysis) included rash (15.3%), malaise (14.4%), decreased appetite (14.4%), pyrexia (14.4%) and nausea (10.8%). CONCLUSIONS: Long-term survival with nivolumab was observed in patients with squamous or non-squamous non-small cell lung cancer. No new safety signals were reported after ≥5 years of follow-up.

A single-arm, phase 2 study of adjuvant chemotherapy with oral tegafur-uracil for pathologically lymphovascular invasion positive stage IA non-small cell lung cancer: LOGIK0602 study.

BACKGROUND: Lymphovascular invasion (LVI), which includes vascular or lymphatic invasions, is a representative prognostic factor even in patients with resected stage IA non-small cell lung cancer (NSCLC). Because tegafur-uracil is effective on cancers with LVI, we conducted a multi-center single-arm phase II study to estimate the efficacy of adjuvant tegafur-uracil in patients with LVI-positive stage IA NSCLC. METHODS: Patients with completely resected LVI-positive stage IA NSCLC were registered. LVI was diagnosed by consensus of two of three pathologists. Adjuvant chemotherapy consisted of 2 years of oral tegafur-uracil at 250 mg/m2/day. Fifty-five patients from 7 institutions were enrolled from June 2007 to September 2012. RESULTS: Among the 52 eligible patients, 36 (69.2%) completed the treatment course. There were 39 male and 13 female patients. The observation period was calculated as 562 to 3107 days using the reverse Kaplan-Meier method. The 5-year overall and relapse free survival rates were 94.2 and 88.5% respectively, which were significantly better than that of any other studies conducted on patients with LVI-positive stage IA NSCLC. Notably, the overall survival rate was 15% better than that of our prior retrospective study. The retrospective analysis of stage IA NSCLC patients who had received an operation in the same period revealed that the 5-year overall survival rate of the LVI positive group was 73.6% when adjuvant chemotherapy was not applied. Among 55 safety analysis sets, 4 cases of grade 3 hepatic function disorder (9.1%) and 5 cases of grade 2 anorexia (10.9%) were most frequently observed. No grade 4 adverse effects were encountered. CONCLUSION: A 2-year course of oral tegafur-uracil administration is feasible and might have a significant benefit in the adjuvant treatment of LVI-positive stage IA NSCLC. TRIAL REGISTRATION: UMIN identifier: UMIN000005921 ; Date of enrolment of the first participant to the trial: 19 June 2007; Date of registration: 5 July 2011 (retrospectively registered).

Clinical significance of preoperative inflammatory markers in non-small cell lung cancer patients: A multicenter retrospective study.

Inflammatory biomarkers have been associated with clinical outcomes in non-small cell lung cancer (NSCLC). However, the best prognostic marker(s) has not been identified, and the association between inflammatory markers and clinical characteristics is poorly understood. We selected 1,237 patients with resected NSCLC from Kyushu University (2003-2015) and Kyushu Cancer Center (2009-2015) in Japan. Pearson product-moment correlation coefficient among inflammatory markers and area under curve (AUC) of receiver operating characteristic (ROC) curve analyses for overall survival (OS) were calculated. We analyzed the associations between inflammatory markers and clinical factors using Student's t-test. Univariate and multivariate analyses with Cox proportional hazards regression analyses were performed to evaluate the relationship between survival and clinical factors. The cut-off values for neutrophil-lymphocyte ratio (NLR), lymphocyte-monocyte ratio (LMR), platelet-lymphocyte ratio, and derived NLR (dNLR) were determined by ROC curve analyses for OS. We found a strong positive correlation between NLR and dNLR (r = 0.9629). The AUC of LMR was the highest amongst the measured metrics, and the AUC of NLR was higher than dNLR. Levels of some inflammatory markers were associated with sex, smoking, squamous cell carcinoma, and pathological stage. LMR ≥ 5.11 and lactate dehydrogenase (LDH) concentration ≥ 222 (U/L) were independent predictors of both disease-free survival (DFS) and OS (LMR; P = 0.0009 and 0.0008, LDH; P = 0.0195 and 0.0187, respectively). Certain inflammatory markers, potentially linked to smoking, were associated with an advanced pathological stage in NSCLC. LMR and LDH were independent predictors of both DFS and OS.

Cohesion between pulmonary artery and bronchus after immune checkpoint inhibitor therapy in a lung cancer patient.

Immunotherapy targeting programmed death-1 or programmed death-ligand 1 has become the standard of care for advanced non-small cell lung cancer (NSCLC). Several recent clinical trials have investigated the efficacy of immune checkpoint inhibitors (ICIs) as neoadjuvant treatment for early NSCLC. However, the safety and feasibility of pulmonary resection after ICIs remain unclear. We herein report a patient in whom cohesion between the left main pulmonary artery and left upper bronchus was found during left upper lobectomy following neoadjuvant ICI combined with chemotherapy. After both central and peripheral sides of the left main pulmonary artery were clamped with the aim of controlling hemorrhage in case of vascular injury, the left main pulmonary artery and left upper bronchus were divided and individually cut with staplers. The thoracoscopic procedure was otherwise uneventful. The patient was discharged from our hospital with no postoperative complications. Thoracic surgeons should anticipate the possible need for management of cohesion between a pulmonary artery and bronchus in patients who have received immune checkpoint inhibitors preoperatively.

Development of adoptive immunotherapy with KK-LC-1-specific TCR-transduced γδT cells against lung cancer cells.

The present study analyzed the antitumor effect of γδT cells transduced with the TCR of cancer-specific CTLs to establish forceful cancer-specific adoptive immunotherapy. We cloned the TCRαß genes from CTLs showing HLA-B15 restricted recognition of Kita-Kyushu lung cancer antigen-1 (KK-LC-1), a cancer/germline gene antigen, identified in a lung adenocarcinoma case (F1121). The TCRαß and CD8 genes were transduced into γδT cells induced from PBLs of healthy volunteers stimulated with zoledronate and IL-2. The KK-LC-1-specific TCRαß-CD8 γδT cells showed cytotoxic activity against the KK-LC-1 positive lung cancer cell line F1121L and produced IFN-γ against F1121L and KK-LC-1 peptide-pulsed F1121 EBV-B cells. These responses were blocked by HLA class I and HLA-B/C antibodies. An in vivo assay using NOD/SCID mice with xenotransplantation of human lung cancer cells was performed, and the TCRαß-CD8 transduced γδT cells (TCRαß-CD8 γδT cells) were intravenously injected. Growth inhibition of KK-LC-1+ , HLA-B15+ lung cancer cells was confirmed in mice with injection of the TCRαß-CD8 γδT cells from 1 wk after xenotransplantation of cancer cells but not in those treated 2 wk after xenotransplantation. The resected specimens of the tumor, 2 wk after xenotransplantation, highly expressed FasL but not programmed death ligand-1 (PD-L1) by immunohistochemical staining. FasL highly expressed cancer cells xenotransplanted 2 wk ago were resistant to TCRαß-CD8 γδT cells injection. These results suggested that apoptosis of Fas-positive TCRαß-CD8 γδT cells may be induced by a Fas-mediated signal after interacting with FasL-positive cancer cells.

Erlotinib for Non-Small Cell Lung Cancer with Leptomeningeal Metastases: A Phase II Study (LOGIK1101).

LESSONS LEARNED: This phase II trial evaluated the efficacy of erlotinib for patients with non-small cell lung cancer with leptomeningeal metastasis. The 17 cerebrospinal fluid specimens that were available for epidermal growth factor receptor mutation analysis were all negative for the resistance-conferring T790M mutation. The cytological objective clearance rate was 30.0% (95% confidence interval: 11.9%-54.3%). The median time to progression was 2.2 months. The rate of cerebrospinal fluid penetration among these patients was equivalent to those in previous reports regarding leptomeningeal metastasis. BACKGROUND: Leptomeningeal metastases (LM) occur in approximately 5% of patients with non-small cell lung cancer (NSCLC) and are associated with a poor prognosis. However, no prospective study has identified an active chemotherapeutic drug in this setting. METHODS: Patients were considered eligible to receive erlotinib if they had NSCLC with cytologically confirmed LM. The objective cytological clearance rate, time to LM progression (TTP), overall survival (OS), quality of life outcomes, and pharmacokinetics were analyzed. This study was closed because of slow accrual at 21 of the intended 32 patients (66%). RESULTS: Between December 2011 and May 2015, 21 patients (17 with activating epidermal growth factor receptor [EGFR] mutations) were enrolled. The 17 cerebrospinal fluid specimens available were all negative for the T790M mutation, which confers erlotinib resistance. The clearance rate was 30.0% (95% confidence interval [CI]: 11.9%-54.3%), the median TTP was 2.2 months, and the median OS was 3.4 months. Significantly longer TTP and OS times were observed in patients with mutant EGFR (p = .0113 and p < .0054, respectively). The mean cerebrospinal fluid penetration rate was 3.31% ± 0.77%. There was a good correlation between plasma and cerebrospinal fluid (CSF) concentrations, although there was no clear correlation between pharmacokinetic parameters and clinical outcome. CONCLUSION: Erlotinib was active for LM and may be a treatment option for patients with EGFR-mutated NSCLC and LM.

Histological conversion from adenocarcinoma to small cell carcinoma of the lung after treatment with an immune checkpoint inhibitor: a case report.

The transformation of adenocarcinoma to small cell lung cancer has been reported as acquisition of resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors. We here report a patient who presented histologically confirmed transformation of adenocarcinoma to small cell lung cancer after treatment with immune checkpoint inhibitor. A 65-year-old man was treated with pembrolizumab as first-line therapy and achieved temporarily a stable disease with progression after six cycles of this agent. At that stage, a transbronchial biopsy showed small cell lung cancer, and he was found to have high serum concentrations of neuron-specific enolase despite concentrations of numerous tumor markers, including neuron-specific enolase, having been within normal limits at the time of presentation. The patient thereafter was treated as a small cell carcinoma patient using cisplatin plus irinotecan and amrubicin.