Clinical significance of peripheral TCR and BCR repertoire diversity in EGFR/ALK wild-type NSCLC treated with anti-PD-1 antibody.

INTRODUCTION: TCR and BCR repertoire diversity plays a critical role in tumor immunity. Thus, analysis of TCR and BCR repertoires might help predict the clinical efficacy of anti-PD-1 treatment. METHODS: Blood samples from 30 patients with non-small cell lung cancer (NSCLC) treated with anti-PD-1 antibody were collected before and six weeks after treatment initiation. The clinical significance of TCR and BCR repertoire diversity in peripheral blood was evaluated in all the enrolled patients (n = 30) or in the subset with (n = 10) or without (n = 20) EGFR/ALK mutation. RESULTS: TCR and BCR diversity was significantly correlated at baseline (R = 0.65; P = 1.6 × 10-4) and on treatment (R = 0.72; P = 1.2 × 10-5). Compared to non-responders (SD or PD), responders (PR) showed significantly decreased TCR and BCR diversity after treatment in the EGFR/ALK wild-type subset (P = 0.0014 and P = 0.034, respectively), but not in all the enrolled patients. The post-treatment reduction in TCR and BCR repertoire diversity was also significantly associated with the occurrence of adverse events in the EGFR/ALK wild-type subset (P = 0.022 and P = 0.014, respectively). Patients with more reduced TCR diversity showed better progression-free survival (PFS) in the EGFR/ALK wild-type subset (P = 0.011) but not in the mutant subset. CONCLUSIONS: These findings suggest the clinical significance of changes in peripheral TCR and BCR repertoire diversity after anti-PD-1 treatment in patients with NSCLC without EGFR/ALK mutation. Monitoring of the peripheral TCR and BCR repertoires may serve as a surrogate marker for the early detection of EGFR/ALK wild-type NSCLC patients who would benefit from anti-PD-1 treatment.

Tissue surface area and tumor cell count affect the success rate of the Oncomine Dx Target Test in the analysis of biopsy tissue samples.

BACKGROUND: The Oncomine Dx Target Test (ODxTT) is a next-generation sequencing-based companion diagnostic test which has been recently developed; however, its analysis success rate could be improved, especially for small samples. The aim of this study was to identify the pathological factors associated with biopsy specimens that affect the analysis success rate of ODxTT. METHODS: We retrospectively investigated 119 cases subjected to ODxTT at Kanagawa Cancer Center. Data pertaining to the results of BRAF V600E mutation analysis in ODxTT and pathological factors based on microscope slides were collected. Pathological factors including tissue surface area, tumor cell count, and tumor content rate were assessed. We constructed receiver operating characteristic curves and determined the optimal cutoff values of each pathological factor. Multivariate logistic analysis was used to identify significant factors. RESULTS: A total of 98 of 119 samples were successfully analyzed (75.6%). The tissue surface area and tumor cell count were significantly higher in the group associated with analysis success (P < 0.001 and P = 0.011, respectively), and their optimal cutoff values were 1.04 mm2 and 375 cells, respectively. A tissue surface area > 1.04 mm2 and tumor cell count >375 cells had a positive effect on the analysis success rate of ODxTT (odds ratio [OR] 0.10; 95% confidence interval [CI]: 0.03-0.35; P < 0.001 and OR 0.25; 95% CI: 0.07-0.90; P = 0.033, respectively). CONCLUSIONS: Selecting samples with a tissue surface area > 1.04 mm2 and a tumor cell count >375 cells might improve the analysis success rate of ODxTT. KEY POINTS: Significant findings of the study: We found that a tissue surface area > 1.04 mm2 and tumor cell count >375 cells had a positive effect on the analysis success rate of ODxTT in the analysis of biopsy tissue samples. WHAT THIS STUDY ADDS: It is sometimes necessary to assess genetic alterations with a small biopsy sample in daily practice. The criteria mentioned above will help to determine which tests should be performed, ODxTT or multiple single-gene testing.

Tumor invasion in the central airway is a risk factor for early-onset checkpoint inhibitor pneumonitis in patients with non-small cell lung cancer.

BACKGROUND: Anti-programmed death-1 (PD-1) immunotherapy can cause immune-related pneumonitis, also known as checkpoint inhibitor pneumonitis (CIP). CIP that develops early after the initiation of anti-PD-1 immunotherapy is important because it is more severe than CIP that develops later. However, only a few studies have examined the risk factors for early-onset CIP. Previous studies have reported several risk factors for CIP, including imaging findings of airway obstruction adjacent to lung tumors. However, the utility of this factor is debatable. Therefore, we investigated potential risk factors for early-onset CIP, including tumor invasion in the central airway (TICA), in patients with non-small cell lung cancer (NSCLC) receiving anti-PD-1 therapy. METHODS: We retrospectively analyzed the medical records and chest computed tomography scans of patients with NSCLC treated with anti-PD-1 antibodies at the Kanagawa Cancer Center in Japan between 1 January 2016, and 30 June 2018. The clinical characteristics and imaging findings, including TICA, were compared between patients with and without early-onset CIP. RESULTS: Data from 181 eligible patients (114 receiving nivolumab and 67 receiving pembrolizumab) were analyzed. Early-onset CIP occurred in 13 of 79 patients (16.5%) with TICA and 2 of 102 patients (2.0%) without TICA. In multivariate analysis, the odds ratio of early-onset CIP for patients with TICA was 8.2 (95% confidence interval [CI]: 1.98-34.0, P = 0.0037). CONCLUSIONS: TICA was strongly associated with early-onset CIP in patients with NSCLC. Clinicians should carefully observe patients with TICA, especially within three months of anti-PD-1 antibody administration because of high CIP risk. KEY POINTS: Significant study findings Tumor invasion in the central airway (TICA) was a predictor of early-onset checkpoint inhibitor pneumonitis (CIP) TICA had good interobserver variability, indicating its utility in clinical practice Patients with TICA might have a higher immune status than patients without What this study adds This is the first study focusing on risk factors for CIP limited to early-onset CIP.

Analysis of targeted somatic mutations in pleomorphic carcinoma of the lung using next-generation sequencing technique.

BACKGROUND: Pleomorphic carcinoma (PC) of the lung is a rare type of lung cancer with aggressive characteristics and a poor prognosis. Because it is rare, the molecular characteristics of PC remain unclear. METHODS: A gene mutation analysis was performed using next-generation sequencing (NGS) in patients with PC of the lung who had undergone surgical resection. RESULTS: A total of nine patients were enrolled in the study. All the patients were male and eight had a history of smoking. Eight tumors contained spindle cells and three contained giant cells. Mutations considered significant were found in eight of the nine patients: in TP53 in five patients, in MET in two patients, and in ALK, ERBB2, PIK3CA, APC, NF1, and CDKN2A in one patient each. No EGFR mutation was detected in our analysis. Co-mutations were detected in three patients: TP53 with MET and NF1, TP53 with ERBB2, and PIK3CA with CDKN2A. CONCLUSIONS: TP53 mutations were detected most frequently in PC of the lung with NGS analysis. Different co-mutations were seen in several specimens. KEY POINTS: Significant findings of the study This study demonstrates that mutations in the TP53 gene are frequently found and co-mutations are sometimes found in pleomorphic carcinoma of the lung using genomic profiling analysis. What this study adds Our results will help to analogize the genetic characteristics and potential target of molecular-targeted agents of pleomorphic carcinoma of the lung.

Effect of epidermal growth factor receptor mutation on early-stage non-small cell lung cancer according to the 8th TNM classification.

OBJECTIVE: This study evaluated the effect of EGFR mutation on early-stage non-small cell lung cancer (NSCLC) based on the 8th TNM classification. MATERIALS AND METHODS: The study retrospectively examined 1231 patients who underwent curative resection for pathological stage 0-I (8th TNM classification) NSCLC and EGFR mutation analysis from January 2006 to December 2018 at Kanagawa Cancer Center. The disease-free survival (DFS), overall survival (OS) and disease-specific survival (DSS) of EGFR-mutant lung cancer (Mt) and EGFR wild-type lung cancer (Wt) patients at each stage were compared between two patient groups using the log-rank test. Cox regression analyses were performed to identify prognostic factors. RESULTS: The number of stage 0, IA1, IA2, IA3, and IB Mt/Wt patients was 79/92, 202/189, 145/144, 45/75, and 74/186, respectively. There was no statistically significant difference in DFS between Mt and Wt patients at any pathological stage. The 5-year OS of Mt/Wt patients was 96.9 %/98.5 % for stage 0 (p = 0.671), 92.2 %/92.2 % for stage IA1 (p = 0.997), 93.9 %/82.6 % for stage IA2 (p = 0.039), 87.3 %/91.4 % for stage IA3 (p = 0.768), and 85.3 %/69.3 % for stage IB (p = 0.017). The 5-year DSS of Mt/Wt patients was 95.7 %/95.4 % for stage IA2 (p = 0.684) and 93.2 %/77.5 % for stage IB (p = 0.016). In Cox regression analyses, Mt was not identified as a prognostic factor for OS among stage IA2 NSCLC patients (HR, 0.62; 95 % CI, 0.20-1.93; p = 0.413). However, Mt was a favorable prognostic factor for OS (HR, 0.44; 95 % CI, 0.19-1.00; p = 0.049) and DSS (HR, 0.38; 95 % CI, 0.17-0.87; p = 0.022) among stage IB NSCLC patients. CONCLUSION: EGFR mutation had no effect on the prognosis of stage 0-IA NSCLC but significantly affected the OS and DSS of stage IB NSCLC. Effect of EGFR mutations on postoperative prognosis of patients with stage 0-I NSCLC differed with each stage.

Phase II study of bevacizumab, cisplatin, and pemetrexed in advanced non-squamous non-small cell lung cancer (NS-NSCLC) with EGFR wild-type.

BACKGROUND: Continuation maintenance therapy with pemetrexed (PEM) and bevacizumab (BEV) following induction therapy with cisplatin (CDDP), PEM, and BEV is beneficial in advanced non-squamous non-small-cell lung cancer (NS-NSCLC), but the survival benefit of addition of BEV to CDDP/PEM as induction therapy is still unclear. The aim of this phase II study was to evaluate the feasibility and safety of a CDDP/PEM/BEV regimen in Japanese patients with EGFR wild-type NS-NSCLC. PATIENTS AND METHODS: This study included 25 patients who receive intravenous CDDP, PEM, and BEV (15 mg/kg) from August 2010 to February 2013. The primary endpoint of this study was the response rate (RR) and the secondary endpoint was progression free survival (PFS), overall survival (OS), and safety. RESULTS: The median cycles of induction chemotherapy were four (range 1-6). RR was 64%. Most patients (64%) transitioned to maintenance therapy. The median PFS was 9.7 months. Median OS was 21.6 months. Haematological adverse events reaching grade 3 to 4 were neutropenia (8%) without febrile neutropenia, thrombocytopenia (4%), and anemia (4%). BEV-related non-haematological toxicities of grade 3/4 were hypertension (16%), thrombosis (4%), and gastrointestinal perforation (4%). Each adverse events was controllable, and there were no treatment-related deaths. CONCLUSIONS: CDDP/PEM/BEV regimen is effective and tolerable in patients with EGFR wild-type advanced NS-NSCLC, but should be paid attention to some BEV-related toxicities.

Prognostic significance of blood and lymphatic vessel invasion in pathological stage IA lung adenocarcinoma in the 8th edition of the TNM classification.

OBJECTIVES: The prognostic significance of blood and lymphatic vessel invasion in the 8th edition of the Tumor, Node, Metastasis (TNM) classification remains unclear. Therefore, this study aimed to evaluate the prognostic significance of blood and lymphatic vessel invasion in p-stage IA lung adenocarcinoma in the 8th edition of the TNM classification. MATERIALS ANDMETHODS: We retrospectively examined patients with p-Stage 0-IA lung adenocarcinoma, reclassified according to the 8th edition of the TNM classification. Blood and lymphatic vessel invasion were evaluated using hematoxylin-eosin and Elastica van Gieson and hematoxylin-eosin and anti-podoplanin antibody staining, respectively. Combined blood and lymphatic vessel invasion constituted tumor vessel invasion (TVI). RESULTS: Overall, 306 patients were evaluated. The median follow-up period was 98.0 (range: 10-216) months. The 5-year recurrence-free survival differed significantly among patients with and without TVI in p-stage IA1 (TVI-: 100%, TVI+: 88.9%, P = 0.007) and IA2 (TVI-: 94.6%, TVI+: 80.8%, P = 0.012) but not in p-stage IA3 (TVI-: 66.7%, TVI+: 75.0%, P = 0.598). The 5-year lung cancer-specific survival also differed significantly among those with and without TVI in p-stage IA1 (TVI-: 100%, TVI+: 88.9%, P < 0.001) and IA2 (TVI-: 98.2%, TVI+: 88.7%, P = 0.043) but not in p-Stage IA3 (TVI-: 66.7%, TVI+: 75.0%, P = 0.858). No recurrence and lung cancer-specific deaths occurred in p-stage IA1 patients without TVI. On multivariate analysis, the presence of TVI was independently associated with recurrence and lung cancer-specific death in patients with p-stage IA1-2 lung adenocarcinoma. TVI did not affect the prognosis of those with p-stage IA3 adenocarcinoma. CONCLUSION: TVI is a prognostic factor in patients with p-stage IA1-2 lung adenocarcinoma. P-stage IA1 lung adenocarcinoma without TVI may therefore be classified as minimally invasive.

Multicenter study of zoledronic acid administration in non-small-cell lung cancer patients with bone metastasis: Thoracic Oncology Research Group (TORG) 1017.

Skeletal-related events (SREs) may occur at the time of first diagnosis in 20-30% of lung cancer patients with bone metastases. Several clinical trials have shown that zoledronic acid (ZA) is effective for decreasing SREs. The main objective of the present study was to discuss clinical data of ZA and compare the frequency of SREs with previous reports. All patients with non-small-cell lung cancer (NSCLC) with metastatic bone disease who were administered ZA at least twice between January 2008 and December 2009 were eligible for inclusion in the study. In total, 198 consecutive patients were identified. The median duration of ZA administration was 106 days [95% confidence interval (CI), 92-133 days], and the median number of ZA administrations was 4 (range, 2-41). The median time to first SRE in patients who experienced SRE following ZA treatment was 202 days (95% CI, 156-264 days). Among the 78 patients who had already experienced SRE prior to ZA treatment, 35 (45%) experienced SRE subsequently after starting ZA treatment. On the other hand, among the 120 patients without a history of SRE before starting ZA treatment, 42 (35%) experienced SRE after the start of ZA administration (P=0.16). No osteonecrosis of the jaw (ONJ) was reported in any of the patients. The present study revealed that ZA had a certain level of efficacy regardless of the presence or absence of prior SREs. However, the duration of ZA therapy was short in this study; further accumulation of data on the long-term prognosis and incidence rates of ONJ and other late complications of ZA therapy seems to be particularly important.

Two cases of lung neuroendocrine carcinoma with carcinoid morphology.

BACKGROUND: The category of grade 3 neuroendocrine tumor (NET G3) was newly introduced in the 2017 World Health Organization (WHO 2017) classification of neuroendocrine neoplasms of the pancreas. Pancreatic NET G3 shows a carcinoid-like morphology with high proliferative activity and the prognosis is intermediate between NET G2 and neuroendocrine carcinoma. There is no category corresponding to NET G3 in the current WHO 2015 classification of lung tumors. Herein, we report two cases of lung neuroendocrine carcinoma with carcinoid morphology that correspond to NET G3. CASE PRESENTATION: Case 1: An abnormal chest shadow was detected in a 78-year-old female never-smoker during a routine medical examination. She was asymptomatic. The radiological assessment revealed a mass in the peripheral S4 segment of the right lung. She underwent right middle lobectomy for the mass preoperatively diagnosed as non-small cell lung carcinoma. Postoperative histological examination revealed a neuroendocrine tumor with carcinoid morphology and a mitotic count of 15/2 mm2. Case 2: An abnormal chest shadow was detected in a 74-year-old female never-smoker undergoing follow-up for another disease. She was asymptomatic. The radiological assessment revealed a mass in the peripheral S3 segment of the right lung. She underwent right upper lobectomy for the mass suspected to be lung carcinoma. Postoperative histological examination revealed a neuroendocrine tumor with carcinoid morphology with mitotic count of 13/2 mm2. Both of these tumors showed carcinoid morphology but with a mitotic count exceeding 10/2 mm2; thus, we diagnosed them as small cell lung carcinomas according to the current WHO 2015 classification. CONCLUSIONS: Our tumors occurred in female never-smokers and their histology showed carcinoid morphology without extensive necrosis. Moreover, proliferative abilities of them were extremely low compared to small cell lung carcinoma. The clinical and pathological features of our tumors appeared to be different from those of small cell lung carcinoma. Although there is no category corresponding to NET G3 in the current classification of lung tumors, we consider that our tumors may correspond to NET G3 and identification of this subset is relevant for therapeutic management.

Should Pathologically Noninvasive Lung Adenocarcinoma Larger Than 3 cm Be Classified as T1a?

BACKGROUND: Adenocarcinoma in situ (AIS) is defined as noninvasive adenocarcinoma with a total tumor size including lepidic growth ≤3 cm; tumors >3 cm are classified as T1a. However, a tumor >3 cm that meets the histological criteria of AIS may have a prognosis equivalent to that of AIS. Here we examine the frequency and prognosis of noninvasive adenocarcinoma with a tumor >3 cm and the validity of the current definition of AIS tumor diameter. METHODS: The study was composed of patients with lung adenocarcinoma completely resected from January 2000 to December 2013 who met AIS histological criteria. Eligible patients were divided into 2 groups-the AIS group (tumor ≤3 cm) and the large AIS group (tumor >3 cm)-and the clinicopathologic characteristics and prognosis were retrospectively compared between the 2 groups. RESULTS: A total of 277 patients were analyzed and large AIS was found in 7.9% (22) of the patients. The 5-year overall survival was 98.3% in the AIS group and 95.5% in the large AIS group. No patient had recurrence. The consolidation size from computed tomography and pathologic alveolar collapse size were both significantly larger in the large AIS group. No significant differences between groups were found in the consolidation-tumor ratio or in the ratio of the pathologic alveolar collapse size to the pathological total tumor size. The prognosis of patients with pathologically noninvasive adenocarcinoma >3 cm was comparable to that of AIS. CONCLUSIONS: There is a possibility that tumor diameter need not be a consideration for AIS classification.

Efficacy of Platinum-Based Adjuvant Chemotherapy on Prognosis of Pathological Stage II/III Lung Adenocarcinoma based on EGFR Mutation Status: A Propensity Score Matching Analysis.

OBJECTIVE: This study aimed to retrospectively evaluate the efficacy of platinum-based adjuvant chemotherapy (PBAC) for patients with pathological II/III pulmonary adenocarcinoma after curative resection based on epidermal growth factor receptor (EGFR) mutation status using propensity score matching (PSM) analysis. METHODS: Among the 304 patients who underwent curative resection of the lung for pathological II/III pulmonary adenocarcinoma from 2002 to 2016 at the Kanagawa Cancer Center, 176 and 128 patients were wild-type EGFR (Wt) and mutant EGFR (Mt), respectively. Seventy-one Wt patients (40.3%) and 60 Mt patients (46.9%) received PBAC. The prognoses of Wt and Mt patients who did and did not receive PBAC were compared using PSM analysis to reduce bias. RESULTS: The overall survival (OS) of both Wt and Mt patients who received PBAC was significantly better than that of patients who did not receive PBAC before PSM. By multivariate analysis, PBAC was an independent prognostic factor for OS among Wt patients, as were age, carcinoembryonic antigen (CEA) level, pleural invasion, and lymph node metastasis. Although age and CEA level were independent factors for OS among Mt patients, PBAC was not a prognostic factor. After PSM, Wt patients who received PBAC had better OS than those who did not, although Mt patients who did and did not receive PBAC had no difference in OS. CONCLUSIONS: PBAC was associated with favorable prognosis after curative resection among Wt patients, but not among Mt patients. PBAC might not be necessary for Mt patients with pathological stage II/III pulmonary adenocarcinoma.

Which Window Setting Is Best for Estimating Pathologic Invasive Size and Invasiveness?

BACKGROUND: In the Eighth Edition of the Tumor Node Metastasis Classification System for Lung Cancer, the definitions of the clinical T and pathologic T descriptors have changed. Little has been reported on comparisons between the consolidation diameter in the lung window setting and the tumor diameter in the mediastinal window setting with respect to the correlations with pathologic invasive size (IS) and invasiveness. The present study was conducted to clarify which window setting was better for preoperatively estimating IS and invasiveness. METHODS: We retrospectively reviewed 1,167 consecutive patients with lung adenocarcinomas measuring 3 cm or less in diameter. We measured three high-resolution computed tomography variables and examined correlations of IS with these variables, factors predictive of an IS of 5 mm or less, and other variables related to invasiveness. RESULTS: On receiver operating characteristic curve analysis, the tumor diameter in the mediastinal window setting more strongly predicted IS than did the consolidation diameter in the lung window setting (p < 0.001), and the consolidation diameter in the lung window setting more strongly predicted IS than did the maximum tumor diameter in the lung window setting (p < 0.001). Lymphatic, vascular, and pleural invasion were best predicted by the tumor diameter in the mediastinal window setting. CONCLUSIONS: We can estimate IS and other variables related to invasiveness most precisely by measuring the tumor diameter in the mediastinal window setting. The tumor diameter in the mediastinal window setting is an important variable that we should measure preoperatively.

Association between soluble immune mediators and tumor responses in patients with nonsmall 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.

Impact of the epidermal growth factor receptor mutation status on the prognosis of recurrent adenocarcinoma of the lung after curative surgery.

BACKGROUND: The prognosis of patients with epidermal growth factor receptor (EGFR) mutant adenocarcinoma of the lung (Mt) and EGFR wild-type adenocarcinoma (Wt) after complete resection of the lung differ; however, the mechanisms responsible for these differences remain unclear. The present study examined the post-operative prognosis of recurrent pulmonary adenocarcinoma patients to evaluate the clinicopathological nature of Mt and contribution of EGFR - tyrosine kinase inhibitors (TKI) to the prognosis of patients. METHODS: The subjects were 237 patients with recurrent pulmonary adenocarcinoma who underwent EGFR mutation analysis, and consisted of 108 patients with recurrent Mt and 129 with recurrent Wt. Multivariate analyses were performed to investigate whether the EGFR status is a prognostic factor for relapse-free survival (RFS) and post-relapse survival (PRS). RESULTS: RFS was significantly better in Mt than in Wt patients; median RFS were 20.2 and 13.3 months, respectively (p < 0.001). The multivariate analysis identified EGFR mutation as an independent prognostic factor for a favorable RFS (hazard ratio = 0.68; 95% confidence interval, 0.52-0.89). Although, no significant differences were observed in PRS between Mt and Wt patients (median PRS were 33.9 and 28.2 months, respectively; p = 0.360), PRS was significantly better in Mt with EGFR - TKI than in Wt and Mt patients without EGFR - TKI (p = 0.008 and p < 0.001, respectively). PRS was also significantly better in Wt than in Mt patients without EGFR - TKI (p < 0.001). The multivariate analysis identified the administration of EGFR - TKI as an independent prognostic factor for PRS (hazard ratio = 0.60; 95% confidence interval, 0.40-0.89). CONCLUSIONS: EGFR mutation tumors were associated with a significantly better RFS for recurrent pulmonary adenocarcinoma after curative resection of the lung, which represented the less aggressive nature of Mt tumors. However, patients with Mt did not have a favorable prognosis after recurrence unless they received EGFR - TKI.

Phase II study of bevacizumab, cisplatin, and docetaxel plus maintenance bevacizumab as first-line treatment for patients with advanced non-squamous non-small-cell lung cancer combined with exploratory analysis of circulating endothelial cells: Thoracic Oncology Research Group (TORG)1016.

BACKGROUND: Preclinical studies have demonstrated that docetaxel and bevacizumab may act synergistically by decreasing endothelial cell proliferation and preventing circulating endothelial progenitor mobilization. The objective of this study was to assess the efficacy and safety of a combination therapy of bevacizumab, cisplatin, and docetaxel in chemotherapy-naive Japanese patients with advanced non-squamous non-small-cell lung cancer (NSCLC). METHODS: Eligible patients were chemotherapy-naive and had advanced/recurrent non-squamous NSCLC. The patients received 4 cycles of docetaxel (60 mg/m2), cisplatin (80 mg/m2), and bevacizumab (15 mg/kg) once every 3 weeks, followed by bevacizumab as maintenance therapy, every 3 weeks until disease progression or attainment of unacceptable toxicity level. The primary endpoint was objective response rate (ORR). The numbers of circulating endothelial cells (CEC) were also estimated on days 1 and 8 of the first cycle for the exploratory analysis of efficacy prediction. RESULTS: A total of 47 patients were enrolled from October 2010 to April 2012. Bevacizumab as maintenance therapy was administered to 41 patients (87.2%), and the median number of total treatment cycles was 9 (range: 1-36). ORR, median progression-free survival (PFS), and median overall survival of the patients were 74.5%, 9.0 months, and 27.5 months, respectively. The most common grade 3/4 adverse event was neutropenia (95.7%), followed by leukopenia (59.6%) and hypertension (46.8%). PFS was longer in patients with ≥10 count increase in CECs than that in patients with < 10 count increase in CECs (respective median PFS of 11.0 months versus 6.90 months) although the difference was not statistically significant (p = 0.074). CONCLUSIONS: A combination therapy of bevacizumab, cisplatin, and docetaxel, followed by bevacizumab as maintenance was highly effective in patients with non-squamous NSCLC despite the high incidence of grade 3/4 neutropenia. The increase in CEC count between days 1 and 8 may predict the efficacy of our bevacizumab-contained treatment regimen. TRIAL REGISTRATION: UMIN Clinical Trial Registry; UMIN000004368 . Registered date; October 11, 2010 (Retrospectively registered).

Anamorelin (ONO-7643) for the treatment of patients with non-small cell lung cancer and cachexia: Results from a randomized, double-blind, placebo-controlled, multicenter study of Japanese patients (ONO-7643-04).

BACKGROUND: Cachexia, described as weight loss (mainly in lean body mass [LBM]) and anorexia, is common in patients with advanced cancer. This study examined the efficacy and safety of anamorelin (ONO-7643), a novel selective ghrelin receptor agonist, in Japanese cancer patients with cachexia. METHODS: This double-blind clinical trial (ONO-7643-04) enrolled 174 patients with unresectable stage III/IV non-small cell lung cancer (NSCLC) and cachexia in Japan. Patients were randomized to daily oral anamorelin (100 mg) or a placebo for 12 weeks. The primary endpoint was the change from the baseline LBM (measured with dual-energy x-ray absorptiometry) over 12 weeks. The secondary endpoints were changes in appetite, body weight, quality of life, handgrip strength (HGS), and 6-minute walk test (6MWT) results. RESULTS: The least squares mean change (plus or minus the standard error) in LBM from the baseline over 12 weeks was 1.38 ± 0.18 and -0.17 ± 0.17 kg in the anamorelin and placebo groups, respectively (P < .0001). Changes from the baseline in LBM, body weight, and anorexia symptoms showed significant differences between the 2 treatment groups at all time points. Anamorelin increased prealbumin at weeks 3 and 9. No changes in HGS or 6MWT were detected between the groups. Twelve weeks' treatment with anamorelin was safe and well tolerated in NSCLC patients. CONCLUSIONS: Anamorelin significantly increased LBM and improved anorexia symptoms and the nutritional state, but not motor function, in Japanese patients with advanced NSCLC. Because no effective treatment for cancer cachexia is currently available, anamorelin can be a beneficial treatment option. Cancer 2018;124:606-16. © 2017 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Phase II study of nedaplatin and irinotecan as adjuvant chemotherapy for completely resected non-small cell lung cancer.

INTRODUCTION: Cisplatin-based chemotherapy is the standard adjuvant therapy for patients with completely resected stage II or III non-small cell lung cancer (NSCLC). However, the completion rate of four cycles of cisplatin-based chemotherapy is about 50%. This phase II study was conducted to evaluate the tolerability and efficacy of nedaplatin and irinotecan as adjuvant chemotherapy. METHODS: Patients with pathological stage II or III NSCLC who underwent complete resection were enrolled. Treatment consisted of four cycles of nedaplatin (50 mg/m2) and irinotecan (50 mg/m2) on days 1 and 8 every 4 weeks. The primary end-point was the completion rate of four cycles of nedaplatin and irinotecan. RESULTS: Between January 2009 and March 2012, 39 patients (23 males and 16 females; median age 68 years) were registered. Overall, 36/39 (92.3%) patients completed four cycles. The median clinical follow-up time was 56 months (range 11-88 months). There were no differences in adverse events between patients with UGT1A1 polymorphisms and patients with wild-type UGT1A1. The median disease-free survival (DFS) was 49.4 months (95% confidence interval 14.2-84.5 months). Median overall survival (OS) was not reached. There were no treatment-related deaths, and adverse events were acceptable. The 5-year DFS and OS rates were 43.1 and 69.8%, respectively. CONCLUSION: Nedaplatin and irinotecan is a tolerable regimen for adjuvant chemotherapy, and was associated with adequate 5-year DFS and OS rates.

Detection of tumor spread through airspaces by airway secretion cytology from resected lung cancer specimens.

It currently remains unclear whether tumor spread through airspaces (STAS) actually exist in vivo or are an artifact. The morphologies of STAS and tumor cell clusters in airway secretions collected from the segmental or lobar bronchus of resected lung adenocarcinomas and squamous cell carcinomas were compared among 48 patients. The EGFR status of tumor cell clusters in airway secretions was also compared with that of the main tumor in EGFR mutant adenocarcinomas. Tumor cell clusters were observed in the airway secretion cytology of ten patients (20.8%), and eight patients were adenocarcinoma (20.0% of adenocarcinoma). The morphology of STAS closely resembled that of tumor cell clusters detected in airway secretion cytology. The positive rates of airway secretion cytology were 83.3%, 100%, and 50% in papillary adenocarcinoma, micropapillary adenocarcinoma, and invasive mucinous adenocarcinoma, respectively. Among three EGFR mutant adenocarcinomas, the EGFR mutation subtypes of the main tumors in FFPE sections and tumor cell clusters in airway secretions were identical. These indicate that STAS may be detected in the airway secretion cytology. STAS is common in papillary or micropapillary adenocarcinoma and may spread as far as the segmental or lobar bronchus at the time of surgery.

A Hepatitis C Virus-Associated Cirrhotic Patient Developing Interstitial Pneumonia during the Course of Antiviral Therapy with Ombitasvir/Paritaprevir/Ritonavir.

Oral direct-acting antivirals (DAAs) are the main therapy for hepatitis C virus (HCV)-associated liver disease in Japan. Daclatasvir/asunaprevir is the first agent and sofosbuvir/ledipasvir is the secondary agent for HCV genotype 1b. More recently, ombitasvir/paritaprevir/ritonavir is also recommended as a potent therapy for HCV genotype 1b. Among the adverse events associated with these oral DAAs, interstitial pneumonia is one of the most severe ones. Regarding treatment with daclatasvir plus asunaprevir or sofosbuvir plus ledipasvir, a few cases have already been reported in a postmarketing surveillance. Recently, we have encountered a HCV-associated genotype 1b cirrhosis patient who developed interstitial pneumonia during treatment with ombitasvir/paritaprevir/ritonavir and who recovered after drug discontinuation without corticosteroid therapy. Interstitial pneumonia was confirmed by chest x-ray and chest computed tomography. The serum KL-6 level was elevated to 1,180 U/mL. The total duration of the drug administration was 7 weeks, and she achieved SVR24. This is the first detailed report in the literature on the development of interstitial pneumonia during treatment with ombitasvir/paritaprevir/ritonavir. When dry cough appeared in the treatment with DAAs, chest computed tomography and the evaluation of serum KL-6 level were recommended.

Nedaplatin and irinotecan with concurrent thoracic radiotherapy followed by docetaxel consolidation in patients with locally advanced non-small cell lung cancer.

OBJECTIVE: We conducted a phase II study of nedaplatin (NP) and irinotecan (CPT) with concurrent thoracic radiotherapy (TRT) followed by docetaxel for locally advanced non-small cell lung cancer (NSCLC) to determine the safety and efficacy of the treatment. Patients with stage IIIA or IIIB NSCLC were treated with 3 cycles of chemotherapy comprising NP at 50 mg/m2 and CPT at 50 mg/m2 on days 1 and 8 every 4 weeks with concurrent TRT (2 Gy/day, total 66 Gy) followed by 3 cycles of docetaxel at 60 mg/m2 on day 1 every 3 weeks. CONCLUSION: Fifteen patients were registered, and 8 were able to receive the entire treatment regimen. Grade 4 neutropenia and thrombocytopenia occurred in 6 and 1 patient, respectively, receiving NP and CPT with concurrent TRT. Major non-hematological toxicities were nausea, vomiting and fatigue. Grade 3 pneumonitis and esophagitis occurred in one patient each, and 4 patients developed febrile neutropenia. Docetaxel consolidation was associated with mild toxicities. Two patients died of late pulmonary failure 3 to 4 months after treatment completion, and the study was terminated. Twelve patients responded, and the median survival time, and the 1-year and 3-year survival rates were 39.3 months, 86.7% and 60.0%, respectively. In conclusion, NP and CPT with concurrent TRT is effective for patients with locally advanced NSCLC, but frequently induces pulmonary damage.