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Immunotherapy targeting programmed cell death-1 (PD-1) has become a standard pharmacological therapy. Although tumor mutation burden level was reported to depend on the tumor location in nonsmall cell lung cancer (NSCLC), predictive impact of the tumor location on the response to anti-PD-1 therapy is unknown. Two hundred and seventeen advanced or recurrent NSCLC patients treated with anti-PD-1 therapy 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. Of the 217 patients, 132, 27, and 58 had primary NSCLC in upper, middle, and lower lobes, respectively. Patients with NSCLC in upper lobe were significantly associated with younger age (P = .0070) and smoker (P = .0003). The epidermal growth factor receptor-wild type and tumor location in upper lobe were independent predictors of disease control (P = .0175 and P = .0425, respectively). The IPTW-adjusted Kaplan-Meier curves showed that patients with NSCLC in the upper lobes had significantly longer progression-free survival (PFS) and overall survival (OS) than those in middle/lower lobes (P = .0026 and P = .0015, respectively). On IPTW adjusted Cox analysis, NSCLC in the upper lobe was an independent predictor of PFS and OS (P = .0078 and P = .0034, respectively). Patients with primary NSCLC in the upper lobes may be good candidates for anti-PD-1 therapy. These findings should be validated prospectively., (© 2020 UICC.)

Background: Several serum markers have been associated with treatment response and clinical outcome in non-small cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors., Materials and Methods: We performed univariate and multivariate analyses on 226 patients with advanced or recurrent NSCLC treated with anti-programmed cell death-1 (PD-1) therapy. The cut-off values for body mass index (BMI), albumin (Alb), and serum inflammatory markers were determined by receiver operating characteristic curve analyses. Tumor response was assessed by computed tomography according to the Response Evaluation Criteria in Solid Tumors, version 1.1., Results: BMI ≥ 19.1 kg/m 2 and derived neutrophil-lymphocyte ratio (dNLR) < 2.79 were independent predictors of overall response, and Alb ≥ 3.5 g/dL and dNLR < 2.79 were independent predictors of disease control. Analyses of survival revealed that Alb < 3.5 g/dL, dNLR ≥ 2.79, lymphocyte-monocyte ratio < 2.12, and red blood cell distribution width ≥ 15.9 % were independent predictors of both progression-free and overall survival. Moreover, these markers tended to have a strong impact on survival, especially among patients with programmed cell death-ligand 1 tumor proportion score ≥ 50 %., Conclusions: dNLR might be the most important factor for predicting the efficacy in NSCLC patients treated with anti-PD-1 therapy., Competing Interests: Declaration of Competing Interest The authors have declared no conflicts of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

In patients with non-small cell lung cancer (NSCLC), stereotactic radiotherapy (SRT) is one of the standard therapies for those suffering with intracranial metastatic NSCLC. Radiation-induced necrosis (RIN) sometimes occurs as the result of the delayed effects of SRT. The magnetic resonance imaging (MRI) of RIN typically shows hypointense and hyperintense lesions on T1- and T2-weighted images, respectively. We herein report a patient with a growing brain cystic lesion mimicking RIN adjacent to a post-radiation brain metastasis from NSCLC harboring anaplastic lymphoma kinase rearrangement. The patient underwent surgical resection of the brain tumor because of the symptoms. The pathological diagnosis was cavernous hemangioma, and the pathological findings were an encapsulated nodular mass composed of dilated, cavernous vascular spaces with no residual tumor or recurrence. Clinicians should be aware of the possibility for the development of a brain cavernous hemangioma following SRT in NSCLC patients., (© 2020 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

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., (© The Author(s) 2020. Published by Oxford University Press.)

Background: To report the follow up data and clinical outcomes of the JME study (UMIN 000008177), a prospective, multicenter, molecular epidemiology examination of 876 surgically resected non-small-cell lung cancer (NSCLC) cases, and the impact of somatic mutations (72 cancer-associated genes) on recurrence-free survival (RFS) and overall survival (OS)., Methods: Patients were enrolled between July 2012 and December 2013, with follow up to 30th November 2017. A Cox proportional hazards model was used to assess the impact of gene mutations on RFS and OS, considering sex, smoking history, age, stage, histology, EGFR, KRAS, TP53, and number of coexisting mutations., Results: Of 876 patients, 172 had ≥2 somatic mutations. Median follow-up was 48.4 months. On multivariate analysis, number of coexisting mutations (≥2 vs 0 or 1, HR = 2.012, 95% CI: 1.488-2.695), age (≥70 vs <70 years, HR = 1.583, 95% CI: 1.229-2.049), gender (male vs female, HR = 1.503, 95% CI: 1.045-2.170) and pathological stage (II vs I, HR = 3.386, 95% CI: 2.447-4.646; ≥III vs I, HR = 6.307, 95% CI: 4.680-8.476) were significantly associated with RFS, while EGFR mutation (yes vs no, HR = 0.482, 95% CI: 0.309-0.736), number of coexisting mutations (≥2 vs 0 or 1, HR = 1.695, 95% CI: 1.143-2.467), age (≥70 vs <70 years, HR = 1.932, 95% CI: 1.385-2.726), and pathological stage (II vs I, HR = 2.209, 95% CI: 1.431-3.347; ≥III vs I, HR = 5.286, 95% CI: 3.682-7.566) were also significant for OS., Conclusion: A smaller number of coexisting mutations, earlier stage, and younger age were associated with longer RFS and OS, while EGFR mutations were significantly associated with improved OS., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Immunotherapy targeting programmed cell death-1 (PD-1) and programmed death-ligand 1 (PD-L1) has become the forefront strategy for systemic therapy in advanced non-small cell lung cancer (NSCLC) patients. PD-L1 expression on tumor cells has been reported as an eligible biomarker of response to such immunotherapies. However, useful biomarkers of response to atezolizumab, an anti PD-L1 antibody, are unestablished., Methods: We retrospectively analyzed clinicopathological characteristics including PD-L1 expression in NSCLC patients treated with atezolizumab from January 2018 at our department. In addition, we investigated the prognostic effect of the following pretreatment immune-inflammation-nutritional parameters: prognostic nutritional index (PNI), neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), and modified Glasgow prognostic score (mGPS)., Results: Twenty-four patients were enrolled in this study. The median age was 64.5 (range, 49-82) years, and 17 (70.8%) were men. Among this cohort, two patients showed high PD-L1 expression (≥50%), seven showed low (1-49%) expression, and the other 15 patients showed 0% or unknown expression. Survival analyses showed that low PNI was an independent predictor of short time to treatment failure (TTF) [hazard ratio (HR) =6.87, P=0.0052], and high NLR (HR =3.53, P=0.0375) and high mGPS (HR =23.2, P=0.0038) were independent prognostic factors for overall survival (OS) after atezolizumab. Furthermore, the NLR high/mGPS high group had far worse prognosis than the NLR low/mGPS low group., Conclusions: The therapeutic and prognostic effect of atezolizumab may depend on the host immune-nutritional status. This study provided novel but retrospective evidence, and thus further prospective studies are needed., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/jtd.2020.02.27). The authors have no conflicts of interest to declare., (2020 Journal of Thoracic Disease. All rights reserved.)

Thymic carcinoma is a rare epithelial tumor of the thymus with a poor prognosis, and multimodal approaches are important for its treatment. Recently, a number of studies have indicated that S-1 treatment is effective against thymic carcinoma. S-1 plus cisplatin with concurrent radiotherapy is a commonly used treatment for other malignancies, including non-small cell lung cancer (NSCLC). In addition, its safety has been confirmed, and it has been reported to have a marked effect against thymic carcinoma. Therefore, we conducted a phase II study of S-1 plus cisplatin with concurrent thoracic radiotherapy for locally advanced thymic carcinoma, in which the overall response rate was employed as the primary endpoint. The secondary endpoints were overall survival, progression-free survival, and safety., (© 2020 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Introduction: During treatment with immune checkpoint inhibitors, immune-related adverse events sometimes occur, and their management is a critical concern associated with such treatment. Encephalitis and meningitis are some of the critical immune-related adverse events. Atezolizumab is an immune checkpoint inhibitor that inhibits the programmed cell death-ligand. Encephalitis and meningitis were reported in 0.8% of the patients in the atezolizumab versus docetaxel in patients with previously treated NSCLC. However, none of the reports have clarified the details concerning atezolizumab-induced encephalitis and meningitis, including their background, time of onset, treatment, and therapeutic course. We herein report about three patients who experienced atezolizumab-induced meningitis in our department., Methods: Of the 29 patients who received atezolizumab in our department between October 2015 and September 2018, three developed aseptic meningitis. We retrospectively examined their clinical, radiologic, and cytologic features., Results: In all three cases, a depressed level of consciousness followed fever in cycle 1, days 15 and 16 after administration of atezolizumab. Cerebrospinal fluid examination revealed that the number of cells was not increased despite the protein level being high. No definite malignant cells were identified in the cerebrospinal fluid in any of the three cases. Only one patient exhibited abnormal enhancement along the lines of the corpus callosum on magnetic resonance imaging. On the basis of these findings, the patients were diagnosed with atezolizumab-induced meningitis. After the administration of methylprednisolone (1000 mg for 3 d), they promptly became conscious and alert., Conclusion: Atezolizumab-induced meningitis may have some specific features, such as a characteristic development period, findings in magnetic resonance imaging, and premonitory symptoms., (© 2020 The Authors.)

A 75-year-old woman was diagnosed with c-ros oncogene 1 ( ROS1 )-positive lung adenocarcinoma. She was treated with crizotinib 750 mg/day for 4.5 years, with partial tumor response. However, the patient subsequently presented with right hip pain and difficulty in walking. She underwent magnetic resonance imaging (MRI), which detected T2 prolongation in the right femoral bone head, synovial fluid retention, and bone joint fissure narrowing. The patient was diagnosed with rapidly destructive coxarthrosis (RDC) and received a total hip arthroplasty. This represents a rare case of RDC as a potential side effect of crizotinib in a patient with ROS1 -positive lung adenocarcinoma. MRI should therefore be recommended in patients receiving crizotinib who experience continuing severe hip pain and difficulty in walking. Further investigations are warranted to elucidate the pathogenesis of RDC associated with crizotinib treatment., Competing Interests: The authors report no conflicts of interest in this work., (© 2020 Takamori et al.)

Purpose: Regulatory T cells (Tregs) expressing CC chemokine receptor 4 (CCR4) can suppress antitumor immune responses and are associated with poor prognoses in several cancers. We assessed the safety and efficacy of combined mogamulizumab (anti-CCR4 antibody) and nivolumab [anti-programmed death-1 (PD-1) antibody] in immunotherapy-naïve patients with advanced/metastatic solid tumors., Patients and Methods: This study (NCT02476123) comprised dose-escalation (3+3 design) and expansion parts. Patients received nivolumab (3.0 mg/kg) every 2 weeks, with mogamulizumab (0.3 or 1.0 mg/kg in dose escalation, 1.0 mg/kg in expansion) once weekly for 4 weeks, then every 2 weeks, until progression or unacceptable toxicity. Primary objective was safety; secondary objectives were antitumor effects, pharmacokinetics, and immunogenicity. Exploratory biomarker analyses were conducted., Results: Ninety-six patients were enrolled (July 2015-November 2016): six patients in the dose-escalation part and 90 in the expansion part. No dose-limiting toxicities were observed in the dose-escalation part. Grade 3/4 treatment-related adverse events (TRAEs) occurred in 29% of patients in the expansion part (no grade 5 TRAEs). The most frequent TRAEs were rash (39%), rash maculopapular (20%), diarrhea (13%), stomatitis (12%), and pruritus (11%). There were four (27%) confirmed tumor responses among 15 patients with hepatocellular carcinoma, and one confirmed and two unconfirmed responses among 15 patients with pancreatic adenocarcinoma. During treatment, populations of effector Tregs (CD4 + CD45RA - FoxP3 high ) decreased and CD8 + T cells in tumor-infiltrating lymphocytes increased., Conclusions: Combining an anti-PD-1 antibody, nivolumab, with a Treg-depleting anti-CCR4 antibody, mogamulizumab, provides an acceptable safety profile, antitumor activity, and a potentially effective option in cancer immunotherapy., (©2019 American Association for Cancer Research.)

Background: We investigated the utility of the clinical T factor of the 8th edition of the TNM classification, which newly defines the consolidation size of the tumor, as a valuable predictor of pathologic lymph node metastasis (pN+) and the prognosis., Methods: We retrospectively reviewed 825 patients with surgically resected cN0 M0 non-small cell lung cancer of any T stage, focusing on the tumor's total size (7th edition) and consolidation size (8th edition) and examined pN+ and the prognosis., Results: No pN+ cases in the 7th or 8th edition groups had a tumor size of less than 1 cm, and in those sized 1 to 3 cm, the frequency of pN+ in the 7th and 8th edition groups was 10.3% and 13.4%, respectively. The frequency of pN+ in tumors without ground glass opacity (GGO-) was 5.5-times higher than that of tumors with GGO (GGO+). The frequency of pN+ in the GGO+ 8th edition group was twice that in the GGO+ 7th edition group. The frequency of pN+ in the GGO- 7th edition group was 4-times higher than that of the GGO+ 7th edition group. A multivariate analysis revealed that total size exceeding 2 cm, consolidation size exceeding 2 cm, and GGO- were significant predictors of a pN+ status, indicating that a consolidation size of more than 2 cm was a stronger predictor than a total size of more than 2 cm., Conclusions: A consolidation size of more than 2 cm and GGO- were predictors of pN+, and the clinical T factor of the 8th Edition was a stronger predictor of the pN+ status than that of the 7th edition., (Copyright © 2019 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Purpose: Malignant pleural mesothelioma (MPM) is a rare and aggressive malignancy with poor prognosis. Patients with MPM who do not respond to standard first-line chemotherapy have limited treatment options. We evaluated the efficacy and safety of nivolumab, an immune checkpoint inhibitor, for the treatment of advanced or metastatic MPM., Patients and Methods: Japanese patients with unresectable, advanced, or metastatic MPM resistant or intolerant to ≤2 regimens of chemotherapy and ≥1 measurable lesion(s) were enrolled. Patients received nivolumab 240 mg intravenously every 2 weeks until progressive disease or unacceptable toxicity. The primary endpoint was objective response rate by central assessment according to the Modified Response Evaluation Criteria in Solid Tumors. Adverse events (AEs) and treatment-related AEs (TRAEs) were evaluated., Results: Thirty-four patients were enrolled between July 2016 and October 2016. Median follow-up was 16.8 (range: 1.8-20.2) months. Ten (29%, 95% confidence interval, 16.8-46.2) patients showed a centrally assessed objective response. The objective response rates were 26% (7/27), 67% (2/3), and 25% (1/4) patients for epithelioid, sarcomatoid, and biphasic histologic subtypes, respectively. Median duration of response was 11.1 months with a 68% disease control rate. Median overall survival and progression-free survival were 17.3 and 6.1 months, respectively. The objective response rate was 40% with programmed death-ligand 1 expression ≥1% and 8% with <1%. Thirty-two patients (94%) experienced AEs and 26 (76%) experienced TRAEs., Conclusions: Nivolumab met the primary endpoint as second- or third-line treatment for patients with MPM and showed promising efficacy with manageable toxicity. See related commentary by Mansfield and Zauderer, p. 5438 ., (©2019 American Association for Cancer Research.)

Background: Pembrolizumab, an anti-programmed cell death-1 (PD-1) monoclonal antibody, has been shown to yield a durable response and significant survival benefit in some non-small cell lung cancer (NSCLC) patients. Recent studies have shown that the Controlling Nutritional Status (CONUT) score, a novel nutritional index, can be useful for predicting the prognosis in some malignancies. However, its usefulness in predicting the clinical outcome of immune-checkpoint inhibitor (ICI) treatment in patients with NSCLC has not been clarified. The aim of this study was to investigate the clinical significance of the CONUT score in NSCLC patients treated with pembrolizumab., Methods: We conducted a retrospective analysis of the clinical data of 32 patients with advanced NSCLC who received pembrolizumab monotherapy. A cut-off CONUT score of 2 was used to categorize patients into low and high CONUT groups. We evaluated the relation between the clinicopathological factors including CONUT score and neutrophil-to-lymphocyte ratio (NLR) and the prognosis., Results: Twenty-two patients were classified into the low CONUT score group, while 10 were classified into the high CONUT score group. In the univariate and multivariate analyses, the number of prior treatments and the CONUT score were found to independently predict progression-free survival (PFS) (P<0.05), while the CONUT score as well as NLR was an independent prognostic factor for overall survival (P<0.05). In addition, in patients who received pembrolizumab as a first-line treatment, a high CONUT score was associated with a significantly worse PFS and overall survival in comparison to a low CONUT score., Conclusions: The CONUT score has potential application as a predictor of the therapeutic effect and the prognosis of NSCLC patients treated with pembrolizumab. Our findings suggest that in addition to the programmed cell death ligand 1 expression level, the CONUT may also be a useful indicator for selecting NSCLC patients who may benefit from ICI treatment., Competing Interests: Conflicts of Interest: Dr. T Ohba reports personal fees from AstraZeneca, personal fees from Bristol-Myers Squibb, Chugai Pharmaceutical, and Nippon Boehringer Ingelheim. Dr. R Toyozawa reports personal fees from AstraZeneca, Bristol-Myers Squibb, Chugai Pharmaceutical, Eli Lilly Japan, Kyowa Hakko Kirin, MSD, Nippon Boehringer Ingelheim, Nippon Kayaku, Ono Pharmaceutical, and Taiho Pharmaceutical. Dr. K Nosaki reports personal fees from AstraZeneca, Bristol-Myers Squibb, Chugai Pharmaceutical, Eli Lilly Japan, Kyowa Hakko Kirin, Nippon Boehringer Ingelheim, Nippon Kayaku, Ono Pharmaceutical, Pfizer Japan, Taiho Pharmaceutical, and grants and personal fees from MSD, and Novartis Pharma. Dr. Miura reports personal fees from Ono Pharmaceutical. Dr. M Yamaguchi reports personal fees from Astellas Pharma, AstraZeneca, Chugai Pharmaceutical, Covidien Japan, Daiichi Sankyo, Eli Lilly Japan, Johnson & Johnson, Kyowa Hakko Kirin, Nippon Boehringer Ingelheim, Ono Pharmaceutical, and Taiho Pharmaceutical. Dr. K Taguchi reports personal fees from AstraZeneca, MSD, Ono Pharmaceutical, and Taiho Pharmaceutical. Dr. T Seto reports grants and personal fees from Astellas Pharma, AstraZeneca, Chugai Pharmaceutica, Eli Lilly Japan, Kissei Pharmaceutical, MSD, Nippon Boehringer Ingelheim, Novartis Pharma, Pfizer Japan, Takeda Pharmaceutical, and personal fees from Bristol-Myers Squibb, Kyowa Hakko Kirin, Nippon Kayaku, Ono Pharmaceutical, Roche Singapore, Taiho Pharmaceutical, Thermo Fisher Scientific, YakultHonsha, and grants from Bayer Yakuhin, Daiichi Sankyo, Eisai, LOXO Oncology, and Merck Serono. Dr. M Shimokawa reports consulting fee from Sysmex. Dr. M Takenoyama reports grants and personal fees from AstraZeneca, Bristol-Myers Squibb, Chugai Pharmaceutical, Covidien Japan, Eli Lilly Japan, Kyowa Hakko Kirin, MSD, Nippon Boehringer Ingelheim, Novartis Pharma, Ono Pharmaceutical, Taiho Pharmaceutical, and grants from Johnson & Johnson, Kaketsuken, and personal fees from Pfizer Japan. The other authors have no conflicts of interest to declare., (2019 Journal of Thoracic Disease. All rights reserved.)

Background: Nivolumab is a programmed cell death 1 (PD-1) receptor inhibitor antibody that enhances immune system antitumor activity. It is associated with longer overall survival (OS) than the standard treatment of docetaxel in patients with previously treated advanced squamous (SQ) and non-squamous (non-SQ) non-small cell lung cancer (NSCLC). We previously conducted two phase II studies of nivolumab in Japanese patients with SQ (ONO-4538-05) and non-SQ (ONO-4538-06) NSCLC, showing overall response rates (ORRs) (95% CI) of 25.7% (14.2-42.1) and 22.4% (14.5-32.9), respectively, with acceptable toxicity. In this analysis, we more precisely estimated the long-term safety and efficacy in patients with SQ and non-SQ NSCLC by pooling data from these two trials., Methods: SQ (N = 35) and non-SQ (N = 76) NSCLC patients received nivolumab (3 mg/kg, every 2 weeks) until progression or discontinuation. OS was estimated using the Kaplan-Meier method. A pooled analysis of SQ and non-SQ patients was also performed., Results: In SQ NSCLC patients, the median OS (95% CI) was 16.3 months (12.4-25.2), and the estimated 1-year, 2-year, and 3-year survival rates were 71.4% (53.4-83.5), 37.1% (21.6-52.7), and 20.0% (8.8-34.4), respectively. In non-SQ NSCLC patients, median OS was 17.1 months (13.3-23.0), and the estimated 1-, 2-, and 3-year survival rates were 68.0% (56.2-77.3), 37.4% (26.5-48.1), and 31.9% (21.7-42.5), respectively. When SQ NSCLC and non-SQ NSCLC data were pooled, the median OS was 17.1 months (14.2-20.6), and the estimated 1-, 2-, and 3-year survival rates were 69.1% (59.6-76.8), 37.3% (28.3-46.2), and 28.1% (20.0-36.7), respectively. Twenty (76.9%) of 26 responders lived for 3 or more years. Nivolumab was well tolerated and no new safety signals were found., Conclusion: Treatment with nivolumab improved long-term survival and was well tolerated in patients with SQ and non-SQ NSCLC., Trial Registration: JapicCTI-132072; JapicCTI-132073., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Most non-small cell lung cancer (NSCLC) patients relapse on anaplastic lymphoma kinase-tyrosine kinase inhibitor (ALK-TKI) therapy because of acquired resistance. Rebiopsy is recommended to provide optimal therapy after relapse for some ALK-TKI therapies; however, little clinical data exists on the clinical efficacy of ALK-TKI tailored to secondary mutation., Methods: A retrospective study was conducted to analyze the patterns of ALK-TKI treatment and clinical outcomes, including progression free survival (PFS), of ALK-positive NSCLC patients who received rebiopsy. Based on the rebiopsy results, secondary mutations in the ALK gene that were shown to be associated with the efficacy of ALK-TKI therapy in the preclinical or clinical setting were defined as "sensitive mutations (SM)"., Results: Among 71 patients who received ALK-TKI for NSCLC at our institution, 20 patients received rebiopsy, and secondary SM were found in eight patients. The objective response rate (ORR) of the cases with SM who received ALK-TKI therapy was 88.9%, while the ORR of the patients without SM who received ALK TKI or chemotherapy was 20.0%; however, the PFS of the patients with SM was relatively short (with SM vs. without SM: 5.6 months vs. 5.1 months)., Conclusions: The selection of ALK-TKI based on the rebiopsy result was associated with a high ORR and relatively short PFS. The mechanism responsible for the short PFS of sensitive ALK-TKI to secondary mutation should be clarified., (© 2019 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Objectives: Outcomes and prognostic factors remain obscure in patients with colorectal cancer after pulmonary metastasectomy who had previously received a curative hepatic metastasectomy., Methods: We collected data of 757 patients with pulmonary metastasis from colorectal cancer who underwent curative metastasectomy between 2004 and 2008 from 46 Japanese institutions, from which we extracted data on patients who previously received curative hepatic metastasectomy. Disease-free survival, overall survival, and prognostic factors were analyzed., Results: The subjects of this study were 160 patients, of whom 44% had primary rectal tumor, 73% had a single pulmonary metastasis, 11% had a bilateral pulmonary metastasis, and 39% had high (>5 ng/mL) serum carcinoembryonic antigen. Patients' median age was 66 years, and 58% were male. The median follow-up was 64 months. Five-year overall survival and disease-free survival were 65.2% (95% confidence interval, 56.8-72.5) and 33.5% (95% confidence interval, 26.1-41.0), respectively. In multivariable analyses, high prethoracotomy carcinoembryonic antigen level was an independent prognostic factor for overall survival (hazard ratio, 2.01; 95% confidence interval, 1.16-3.47) and disease-free survival (hazard ratio, 2.10; 95% confidence interval, 1.41-3.12). Five-year overall survival and disease-free survival of patients with normal prethoracotomy carcinoembryonic antigen level were 76.4% (95% confidence interval, 66.1-83.9) and 40.7% (95% confidence interval, 30.5-50.5), respectively., Conclusions: After pulmonary metastasectomy, approximately two thirds of patients with colorectal cancer with a history of curative hepatic metastasectomy survived for 5 years-half of them disease-free. Our results indicate that patients with colorectal cancer with pulmonary metastasis and a history of curative hepatic metastasectomy may benefit from sequential pulmonary metastasectomy, especially if prethoracotomy serum carcinoembryonic antigen levels are within normal range., (Copyright © 2019 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Purpose: We conducted a retrospective analysis to assess the practicality of pneumonectomy, especially after concurrent induction chemoradiotherapy (i-CRT), for locally advanced non-small cell lung cancer (LA-NSCLC). The operative risks vs. the survival benefit of this procedure for such patients is a subject of controversy., Methods: The subjects of this retrospective study were 71 consecutive LA-NSCLC patients with cStage IIIA-C NSCLC, who underwent i-CRT followed by curative intent pulmonary resection between February, 2001 and March, 2013., Results: Thirty-two patients underwent pneumonectomy (group P) and 39 patients underwent lobectomy (group L). In group P, 17 (54.8%) patients underwent right pneumonectomy. There was no 30-day postoperative mortality in either group and no significant difference in 90-day postoperative mortality between the groups (3.1% vs. 2.6% in groups P and L, respectively). The 5-year overall survival (OS) rate was 58.7% (95% CI: 41.5-75.9%) in group P and 57.3% (95% CI 41.2-73.4%) in group L, without a significant difference between the groups., Conclusion: Our findings suggest that i-CRT followed by pneumonectomy is feasible, with a similar survival benefit to lobectomy. Thus, pneumonectomy after i-CRT should not be avoided as it is a potentially curative intent strategy for carefully selected patients.

Objectives: This open-label, multicenter, phase 1b/2 study assessed necitumumab plus gemcitabine and cisplatin (GC + N) in patients with previously untreated squamous non-small cell lung cancer in Japan., Materials and Methods: The phase 1b part determined the gemcitabine dose for the phase 2 part, in which patients were randomized 1:1 to GC + N or gemcitabine and cisplatin (GC) (gemcitabine 1250 mg/m 2 on days 1 and 8; cisplatin 75 mg/m 2 on day 1 of maximum four 3-week cycles; nectimumab 800 mg on days 1 and 8 of a 3-week cycle continued until progressive disease or unacceptable toxicity). The primary endpoint of the phase 2 part was overall survival., Results: In the phase 2 part, 181 patients received GC + N (N = 90) or GC (N = 91). Overall survival was significantly improved with GC + N versus GC (median, 14.9 months vs 10.8 months; hazard ratio [HR] = 0.66, 95% CI: 0.47 - 0.93, p = 0.0161). Improvements were also observed in progression-free survival (median, 4.2 months vs 4.0 months; HR = 0.56; p = 0.0004) and objective response rate (51% vs 21%; p < 0.0001). Survival was also significantly prolonged with GC + N versus GC for patients with epidermal growth factor receptor-positive tumors. Grade ≥3 treatment-emergent adverse events at ≥5% higher incidence with GC + N than GC were neutrophil count decreased (42% vs 35%), febrile neutropenia (12% vs 3%), decreased appetite (11% vs 4%), and dermatitis acneiform (6% vs 0%)., Conclusion: GC + N is well tolerated and has significant and clinically meaningful treatment benefit in the first-line treatment of patients with squamous non-small cell lung cancer in Japan. Clinicaltrials.gov identifier: NCT01763788., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: Platinum-based combination chemotherapy is the standard postoperative adjuvant treatment for pathological stage II/III non-small cell lung cancer (NSCLC). Oral S-1 therapy has good efficacy and relatively low toxicity for the treatment of advanced NSCLC. We investigated whether long-term S-1 monotherapy is also useful as an adjuvant therapy after surgery in patients with NSCLC., Patients and Methods: We conducted a phase II randomized open-label multi-institutional study in patients with pathological stage II/IIIA NSCLC (7 th TNM classification) who underwent complete resection from 2009 to 2013. The primary endpoint, the 2-year disease-free survival (DFS) rate, was evaluated using the Bayesian method. Eligible patients were randomly assigned to two arms: oral S-1 monotherapy (S-1 arm) and S-1 plus cisplatin combination therapy followed by S-1 (S-1 plus cisplatin arm) both for a total of 1 year., Results: A total of 70 and 71 patients were enrolled in S-1 arm and S-1 plus cisplatin arm, respectively. The 2-year DFS rates were 52% (95% confidence interval [CI], 0.40-0.63) and 61% (95% CI, 0.48-0.70) for S-1 arm and S-1 plus cisplatin arm, respectively. Both arms met the primary endpoint. Neither DFS nor OS was significantly different between the arms (log-rank test: P =  0.1695 and P =  0.8684, respectively). The main G3/4 adverse events were loss of appetite and anemia (S-1 vs. S-1 plus cisplatin: 4.3% vs. 11.6% and 0% vs. 5.8%, respectively). The treatment completion rate did not differ between the two arms (S-1 vs. S-1 plus cisplatin: 45.7%, 95% CI, 41.9-66.3% vs. 43.5% 95% CI, 44.0-68.4%)., Conclusions: Long-term adjuvant chemotherapy with S-1 was a feasible and promising treatment for patients with completely resected NSCLC, regardless of cisplatin addition. S-1 monotherapy should be investigated further, based on its low toxicity and practical convenience., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Treatment with carboplatin (CBDCA) with weekly paclitaxel (PTX) has shown survival benefits compared with vinorelbine or gemcitabine in elderly patients with non-small-cell carcinoma (NSCLC). Docetaxel (DOC), however, remains a standard treatment in NSCLC. The 130-nm albumin-bound formulation of PTX (nab-PTX) has shown activity in NSCLC. Treatment with CBDCA with weekly nab-PTX showed significantly higher efficacy than CBDCA with PTX in patients with squamous histology and significantly increased overall survival (OS) in patients aged 70 years and older., Patients and Methods: This randomized, multicenter, phase III trial (UMIN000019843) was designed to compare the efficacy and safety of CBDCA with nab-PTX with DOC in patients aged 70 years and older with advanced squamous NSCLC. Elderly patients who have received no previous chemotherapy for advanced/metastatic squamous NSCLC with Eastern Cooperative Oncology Group performance status of 0 or 1 will be randomized 1:1 to DOC (60 mg/m 2 intravenous [I.V.] on day 1) or CBDCA (area under the blood concentration time curve 6 on day 1) with nab-PTX (100 mg/m 2 I.V. on days 1, 8, and 15) of each 21-day cycle. The primary end point is OS. Recruitment began in December 2015 and planned enrollment is 250 patients., Conclusion: If OS is greater in patients treated with CBDCA with nab-PTX than with DOC, this study will provide a new standard of care for elderly patients with squamous NSCLC., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Malignant pleural mesothelioma (MPM), a devastating neoplasm, is traditionally considered to be resistant to antitumor therapy. Identification of clinical prognostic indicators is therefore needed. Although the C-reactive protein/albumin ratio (CAR) has been used to predict the prognosis of many types of malignancy, its utility in patients with MPM is unknown., Methods: The data of 100 patients diagnosed as having MPM from 1995 to 2015 at the National Kyushu Cancer Center and Kyushu University were analyzed. The CAR was calculated as serum C-reactive protein concentration divided by albumin concentration. A cutoff for CAR was set at 0.58 according to a receiver operating characteristics curve for 1-year survival., Results: Thirty-five of the 100 (35.0%) patients were classified as having a high CAR. A high CAR was significantly associated with advanced clinical stage (p < 0.001) and chemotherapy alone (p = 0.002). Patients with a high CAR had significantly shorter overall survival (OS) (p < 0.001) and disease- or progression-free survival (DFS/PFS) (p < 0.001). These associations between CAR and prognosis remained significant after propensity score-matching. In multivariate analysis, a high CAR was an independent predictor of shorter OS and DFS/PFS (p = 0.003 and p = 0.008, respectively). Multivariate analyses of the subgroups of patients who had received chemotherapy and of patients who had undergone surgery also showed that a high CAR was an independent predictor of shorter OS and DFS/PFS., Conclusions: CAR is an independent predictor of prognosis in MPM patients. This prognostic index contributes to clinicians' ability to predict benefit from treatment. Further larger, prospective studies are necessary to validate these findings.

Objectives: We conducted a multi-institutional prospective observational study of elderly patients (≥ 75 years-old) with resected non-small cell lung cancer. In this report, we have followed the cohorts for 2 years after surgery and examined both the influence of preoperative comorbidity [Adult Comorbidity Evaluation-27 (ACE-27) index] on the postoperative survival and the change in the Karnofsky Performance Status (KPS)., Methods: From March 2014 to April 2015, 264 patients were prospectively registered from 22 hospitals affiliated with the National Hospital Organization. The mean age at the time of surgery was 79.3 years (range 75-90 years), and 41% of the patients were ≥ 80 years of age. A total of 26% underwent sublobar resection. The study endpoints were the postoperative overall survival (OS), its prognostic factors, and the changes in the postoperative KPS., Results: The 2-year OS was 85.3% (95% confidence interval 80.4-89.1%). Male gender, age ≥ 80, a smoking history, grade 2 of ACE-27, and an advanced disease stage were significantly poor prognostic factors for the OS in the univariate risk analysis. The multivariate analysis showed that male gender, age ≥ 80, an advanced disease stage and sublobar resection were significantly poor prognostic factors for the OS. In comparison with the preoperative KPS, no marked decline was observed in the postoperative chorological change of KPS., Conclusions: In the surgical treatment of elderly patients, the comorbidity as assessed by the ACE-27 index might affect the postoperative survival, and therefore should be taken into accounts in the preoperative evaluation of the surgical indications.

Background: In the global, Phase 3, ASCEND-5 study, ceritinib improved progression-free survival (PFS) vs chemotherapy in patients with anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) who had previously progressed on crizotinib and platinum-based chemotherapy. Here, we report efficacy and safety in a subset of Japanese patients from the ASCEND-5 study., Methods: Patients with advanced ALK-rearranged NSCLC received oral ceritinib 750 mg/day or chemotherapy (intravenous pemetrexed 500 mg/m2 or docetaxel 75 mg/m2 [investigator's choice], every 21 days)., Results: Among the 231 patients, 29 were Japanese, of which, 11 were treated with ceritinib and 18 were treated with chemotherapy (5 with pemetrexed and 13 with docetaxel). All the patients received prior crizotinib and one or two lines of prior chemotherapy for advanced disease. Median follow-up time was 16.6 months for ceritinib arm and 16.4 months for chemotherapy arm in the overall population. The median PFS by blinded independent review committee was 9.8 months (95% CI, 4.3-14.0) in ceritinib arm vs 1.6 months (95% CI, 1.4-3.0) in chemotherapy arm. Grade 3 or 4 adverse events, suspected to be study drug related, were reported in 36.4% of ceritinib arm and 72.2% of chemotherapy arm, respectively. No Grade 3 or 4 events of diarrhea, nausea and vomiting were reported in both the treatment arms. Adverse events leading to study drug discontinuation were reported in one patient in each arm: Grade 3 central-nervous system metastases in ceritinib-treated patient and Grade 3 febrile neutropenia in chemotherapy-treated patient., Conclusions: Consistent with overall population, ceritinib demonstrated better efficacy compared with the standard second-line chemotherapy in Japanese patients with crizotinib-resistant ALK+ NSCLC., Clinicaltrials.gov Identifier: NCT01828112.

We describe a 77-year-old Japanese woman who presented with three nodule shadows in three different lobes of the right lung, without evidence of lymph node metastasis or distant metastasis. All three tumors were surgically resected. The pathological diagnosis was synchronous multiple primary lung cancer: pT2aN0M0, pStageIB. Based on a differing epidermal growth factor receptor (EGFR) mutation status, no lymph node metastasis, and no distant metastasis, the tumors were characterized as synchronous triple primary rather than intrapulmonary metastases. At eight months after surgery, a new lesion emerged in the right lower lobe. Given that the most advanced tumor had an EGFR del-19 mutation, the patient was orally administered afatinib. Since then, the treatment response of the patient has been assessed as stable disease (SD) for about two years. This is a very rare case of resected triple synchronous primary lung cancer on the same lung side in which the lesions all had a different EGFR mutation status, and this report highlights the clinical utility of surgical resection of multifocal lung nodules without lymph node metastasis or distant metastasis in order to optimize therapy for patients with known driver mutations., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Background/aim: The aim of this study was to assess the appropriateness of pulmonary metastasectomy (MT), with a focus on the primary organ., Patients and Methods: The pathological status of the primary organ, outcome of the MT, disease-free interval, and overall survival were assessed., Results: The primary organ was the most significant prognostic factor analyzed, with a relative risk of 4.6 (95% confidence interval: 1.69-12.56, p=0.003). Patients with colorectal carcinoma had a better survival than those with another primary organ (p=0.003). The hazard ratios by primary organ in comparison to colorectal carcinoma were 3.2 for head and neck carcinoma, 3.5 for soft tissue sarcoma, 8.3 for hepatocellular carcinoma, and 8.9 for urinary carcinoma., Conclusion: Colorectal carcinoma is associated with a greater survival benefit than cancer of other primary organs. Colorectal carcinoma cases should be more aggressively considered for MT than other primary organ cases., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Objectives: Rovalpituzumab tesirine (Rova-T), an antibody-drug conjugate directed against Delta-like protein 3 (DLL3), is under development for patients with small cell lung cancer (SCLC) positive for this protein. However, the prevalence of DLL3 expression and its association with patient ethnicity and other characteristics have remained unclear., Materiais and Methods: Tumor samples from 63 patients with SCLC were subjected to immunohistochemical staining for DLL3. The relation of patient characteristics including sex, age, disease stage, and smoking history to DLL3 expression status was analyzed., Results and Conlusions: Fifty-two patients (83%) were positive for DLL3 expression, with 20 patients (32%) being positive in at least 50% of cancer cells (DLL3-high). DLL3 expression was not associated with any of the patient characteristics examined. In addition, overall survival did not differ between DLL3-high and DLL3-low patients. Our results reveal that DLL3 is expressed in tumor specimens from most patients with SCLC, and they should inform the undertaking of clinical trials of Rova-T including an ongoing phase I study (NCT03086239) in Japan as well as global phase III trials (NCT03061812 and NCT03033511)., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Some features found on chest computed tomography (CT), such as central tumor location, large pleural effusion, and the absence of a pleural tail, and a patient age of less than 60 years, have been suggested to be useful in predicting anaplastic lymphoma kinase (ALK) rearrangement in patients with non-small cell lung cancer (NSCLC).A 68-year-old female patient with a history of gynecological treatment was found to have a cavitary mass in the right lower lobe on an annual chest roentgenogram. The tumor was located in the peripheral area with a pleural tail showing no pleural effusion. In addition, two pure ground-glass-opacity nodules (p-GGNs) in the right upper lobe of the lung were detected on consecutive chest CT scans. The patient underwent right lower lobectomy, partial resection of the right upper lobe, and hilar mediastinal lymph node dissection for complete resection of each tumor. The pathological diagnosis was invasive mucinous adenocarcinoma with signet-ring cells for the cavitary mass in the right lower lobe and invasive adenocarcinoma for the rest of the p-GGNs; subcarinal lymph node metastasis was also detected. The ALK rearrangement was detected by fluorescence in situ hybridization from the cavitary mass. The patient underwent four cycles of cisplatin and vinorelbine chemotherapy as standard adjuvant chemotherapy for pStage III NSCLC. The ALK fusion gene status of NSCLC with atypical CT features should also be investigated.

Pure ground-glass opacity nodules (p-GGN) on high-resolution computed tomography (HRCT) generally have been considering typically associated with adenocarcinoma with less invasive nature. We herein reported a patient presenting focal p-GGN on middle lobe of the right lung who underwent surgical resection with its pathological diagnosis turned out to be typical carcinoid tumor.

Background: As the toxicity associated with the α-GalCer-pulsed dendritic cell (DC) therapy could be considered to be negligible, its addition to postoperative adjuvant chemotherapy would be expected to greatly improve the therapeutic effect, and could result in prolonged survival. The aim of the present study is to compare the therapeutic efficacy of alpha-galactosylceramide-pulsed DC therapy in patients who have undergone a complete resection of stage II-IIIA non-small-cell lung cancer (NSCLC) followed by postoperative adjuvant therapy with cisplatin plus vinorelbine, to that in patients who did not receive additional treatment (surgical resection plus postoperative adjuvant chemotherapy only)., Methods: Subsequent to the complete resection of NSCLC, followed by the administration of cisplatin plus vinorelbine dual-agent combination adjuvant chemotherapy, patients who satisfy the inclusion criteria will be randomly allocated to either the α-GalCer-pulsed DC immune therapy group, or the standard treatment group. In total, 56 patients will be included in the study. The primary endpoint is recurrence-free survival, and the secondary endpoints are natural killer T-cell-specific immune response, the frequency of toxic effects and safety, and overall survival., Discussion: In order to determine the efficacy of α-GalCer-pulsed DC therapy, the present study compares patients with stage II-III NSCLC who underwent complete surgical resection followed by postoperative adjuvant therapy with cisplatin plus vinorelbine, to those who did not receive additional treatment (surgical resection plus postoperative adjuvant chemotherapy only)., Trial Registration: UMIN000010386 ( R000012145 ). Registered on 1 April 2013. UMIN-CTR is officially recognized as a registration site which satisfies ICMJE criteria.

Spliced variant isoforms of CD44 (CD44v) are a marker of cancer stem cells in solid tumors. They stabilize the xCT subunit of the transporter system xc(-) and thereby promote synthesis of the antioxidant glutathione. Salazosulfapyridine (SASP) is an inhibitor of xCT and suppresses the proliferation of CD44v-positive cancer cells. Chemotherapy-naïve patients with advanced non-squamous non-small-cell lung cancer were enrolled in a dose-escalation study (standard 3 + 3 design) of SASP in combination with cisplatin and pemetrexed. The primary end-point was the percentage of patients who experience dose-limiting toxicity. Fifteen patients were enrolled in the study. Dose-limiting toxicity was observed in one of six patients at a SASP dose of 1.5 g/day (elevation of aspartate and alanine aminotransferase levels, each of grade 3), two of five patients at 3 g/day (hypotension or pneumonitis, each of grade 3), and two of three patients at 4.5 g/day (anorexia of grade 3). The maximum tolerated dose was thus 3 g/day, and the recommended dose was 1.5 g/day. The overall response rate was 26.7% and median progression-free survival was 11.7 months, much longer than that for cisplatin-pemetrexed alone in previous studies. Exposure to SASP varied markedly among individuals according to ABCG2 and NAT2 genotypes. The serum concentration of free CD44v protein was increased after the first cycle of treatment, possibly reflecting death of cancer stem cells. Salazosulfapyridine was thus given safely in combination with cisplatin-pemetrexed, with the addition of SASP tending to prolong progression-free survival. This trial is registered in the UMIN Clinical Trials Registry as UMIN000017854., (© 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Liposarcomas are the most common type of mesenchymal neoplasm in soft tissue sarcomas. Although they frequently develop at the lower limbs or retroperitoneum, cases arising from the mediastinum are rare. Furthermore, the incidence of the inflammatory subtype of well-differentiated liposarcoma is known to be low. We experienced a case of a middle mediastinal liposarcoma in a 68-year-old woman. The tumor, which was completely resected, was 92 mm in diameter. The tumor consisted of two different imaging components that showed different growth and which were diagnosed as the lipoma-like subtype and inflammatory subtype of well-differentiated liposarcoma. To the best of our knowledge, this is the first report of a well-differentiated inflammatory liposarcoma arising from the middle mediastinum., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Erlotinib is one of the treatment choices for patients with advanced non-small cell lung cancer (NSCLC), regardless of the epidermal growth factor receptor ( EGFR ) mutation status. However, its efficacy for the treatment of patients with NSCLC with EGFR wild type or who are beyond the usage of gefitinib remains controversial. The present study therefore retrospectively assessed the efficacy of erlotinib in patients with wild type EGFR who had previously undergone gefitinib therapy. A total of 222 patients with NSCLC who received chemotherapeutic treatment with erlotinib between July 2007 and February 2013 were evaluated. The background variables, response rates, progression-free survival (PFS) and overall survival rates were retrospectively analyzed. The male/female ratio of patients was 103/119, and patients had a median age of 63 years (range, 33-95 years). A total of 10 of the 222 patients had clinical stages IIIB/IV, 191 had adenocarcinoma, 5 had large cell carcinoma, 10 had squamous cell carcinoma and 6 had NSCLC of a variety not otherwise specified. The EGFR mutation was positive, wild type or unknown in 95, 52 and 75 patients, respectively. In the 52 patients with EGFR wild type, there were 3 partial responders, 25 with stable disease and 24 with progressive disease, for a response rate of 6% [95% confidence interval (CI), 1.3-15%]. The median PFS of EGFR wild type and positive were 1.1 months (95% CI, 1.04-1.16 months) and 5.42 months (95% CI, 5.43-5.68 months), respectively. The results of the study demonstrated that erlotinib is not sufficiently effective for patients with NSCLC who possess the EGFR wild type status.

Introduction: Malignant pleural mesothelioma (MPM) is a devastating neoplasm; however, some patients exhibit a good response to chemotherapy or multidisciplinary therapy, including surgery and chemotherapy. It is therefore important to discover the factors that can be used to select patients who will benefit from such treatment. Although the Controlling Nutritional Status (CONUT) score has been used to predict the prognosis in other types of malignancy, its utility in patients with MPM is unknown. The aim of this study was to clarify the clinical significance of the CONUT in patients with MPM., Methods: The data of 83 patients, who were treated with surgery, chemotherapy, or multidisciplinary therapy, were analyzed in the present study. A cut-off CONUT score of 2 was used to classify all of the patients into low or high CONUT groups., Results: Fifty-two of the 83 patients were classified into the low CONUT group. A high CONUT score was significantly correlated with chemotherapy alone (P = .011). The high CONUT group had significantly poorer overall survival (OS) (P < .001) and disease- or progression-free survival (DFS/PFS) (P < .001). The clinical stage and the CONUT score were found to be independent predictive factors for the OS: clinical stage, I/II and III/IV; P = .001 and CONUT score, ≥ 3 and ≤ 2; P = .011, respectively. The clinical stage and the CONUT score were also independent predictive factors for DFS/PFS: clinical stage, I/II and III/IV; P = .006 and CONUT score, ≥ 3 and ≤ 2; P = .013, respectively., Conclusions: The CONUT score was an independent predictor of a poor prognosis in the patients with MPM. This score provides useful information for selecting patients who will benefit from the treatment., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: We wanted to assess the efficacy of curative intent pulmonary resection for non-small cell lung cancer (NSCLC) patients with synchronous M1b-distant metastases in a single organ or lesion., Methods: Between 1995 and 2015, 23 consecutive synchronous M1b-cStage IV NSCLC patients who underwent any treatment for metastases and curative intent pulmonary resection were retrospectively analyzed., Results: Sixteen patients were men and 7 were women, with a median age of 56 years (range: 41 to 76 years). There were 17 adenocarcinoma, 4 large-cell carcinoma, 1 large-cell neuroendocrine cancer, and 1 carcinosarcoma. Thirteen patients had no lymph node metastasis. Fourteen patients received preoperative chemotherapy, and 10 received postoperative chemotherapy. The metastatic sites were the brain in 13 patients; bone in 3 patients; adrenal glands and extrathoracic lymph nodes in 2 patients each; and the liver, small intestine, and subcutaneous tissue in 1 patient each. Nineteen patients underwent lobectomy, and the other 4 patients underwent pneumonectomy. Seventeen patients experienced recurrence as follows: local recurrence in 3 patients, distant recurrence in 13 patients, and both in 1 patient. The 5-year progression-free survival rates in the 23 patients was14.5% (95% confidence interval: 0% to 30.6%), and the 5-year overall survival rate was 41.7% (95% confidence interval: 19.6% to 63.8%)., Conclusions: Some M1b-cStage IV NSCLC patients achieved longer survival than others with the same stage disease by using local treatment for distant metastases and curative intent pulmonary resection. Oligometastatic patients might have been inadvertently included in the present cohort. However, at present, the optimum method for patient selection remains unclear., (Copyright © 2017 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Limited treatment options are available for stage IIIB/IV non-small cell lung cancer (NSCLC). Nivolumab, a programmed cell death-1 immune checkpoint inhibitor antibody, has been shown to be effective for the treatment of NSCLC. The present study investigated the effectiveness and safety of nivolumab in Japanese patients with advanced or recurrent squamous NSCLC that progressed after platinum-containing chemotherapy. In this multicenter phase II study, patients were treated with nivolumab (3 mg/kg, i.v.) every 2 weeks until progressive disease or unacceptable toxicity was seen. Primary endpoint was overall response rate (ORR) assessed by independent radiology review committee (IRC) and secondary endpoints included a study site-assessed ORR, overall survival (OS), progression-free survival (PFS), duration of response, time to response, best overall response (BOR), and safety. The study included 35 patients from 17 sites in Japan. Patients had IRC-assessed ORR of 25.7% (95% CI 14.2, 42.1) and the study site-assessed ORR was 20.0% (95% CI 10.0, 35.9). Median OS, median time to response and median PFS were 16.3 (95% CI 12.4-25.4), 2.7 (range 1.2-5.5) and 4.2 (95% CI 1.4-7.1) months, respectively. The IRC-assessed BOR was partial response, stable disease, and progressive disease for 25.7%, 28.6%, and 45.7% of patients, respectively. Treatment-related adverse events were reported in 24 patients (68.6%), most of which resolved with appropriate treatment including steroid therapy or ‎discontinuation of nivolumab. Nivolumab was effective and well tolerated in Japanese patients with advanced or recurrent squamous NSCLC that progressed after platinum-containing chemotherapy., Clinical Trial Registration Number: JapicCTI-132072., (© 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Objective: Nivolumab is a fully human IgG4 programmed cell death 1 immune checkpoint inhibitor monoclonal antibody approved for the treatment of non-small cell lung cancer (NSCLC). The aim of this study was to evaluate the safety and efficacy of nivolumab in Japanese patients with advanced or recurrent non-squamous NSCLC., Methods: In this multicentre phase II study, patients with advanced or recurrent non-squamous NSCLC, which had progressed after platinum-containing chemotherapy, were treated with nivolumab 3 mg/kg, intravenously every 2 weeks until progressive disease or unacceptable toxicity was observed. The primary end point was independent radiology review committee (IRC) assessed overall response rate (ORR) and the secondary endpoints included ORR (investigator assessed), progression-free survival (PFS), overall survival (OS), duration of response, time to response, best overall response, and safety., Results: 76 patients were enrolled across 19 sites in Japan. The ORR (IRC assessed) was 22.4% (95% CI 14.5% to 32.9%). The median PFS and OS were 2.8 months (95% CI 1.4 to 3.4) and 17.1 months (95% CI 13.3 to 23.0), respectively. The OS rate at 1 year was 68.0% (95% CI 56.2% to 77.3%). Current/former smokers were more responsive to treatment than non-smokers (ORR 29.1% vs 4.8%). Patients with epidermal growth factor receptor (EGFR) mutation wild type/unknown showed higher ORR compared with EGFR mutation-positive patients (ORR 28.6% vs 5.0%) and programmed cell death ligand-1 (PD-L1) expression was likely associated with higher ORR, longer PFS and OS. Treatment-related adverse events of grade 3 or higher were reported in 17 patients; these events resolved or were resolving with appropriate treatment including steroid therapy or discontinuation of nivolumab., Conclusions: Nivolumab was well tolerated and showed clinical efficacy in Japanese patients with non-squamous NSCLC progressed after platinum-containing chemotherapy, especially in those with a history of smoking, wild type/unknown EGFR mutation status or positive PD-L1 expression., Trial Registration Number: JapicCTI-132073., Competing Interests: Competing interests: MN received honoraria from Pfizer, Bristol-Myers Squibb, Ono Pharmaceutical, Chugai Pharmaceutical, Eli Lilly, Taiho Pharmaceutical and AstraZeneca. MN also has been a consultant/advisor for Novartis, Ono Pharmaceutical, Chugai Pharmaceutical, Eli Lilly, Taiho Pharmaceutical, Pfizer, Bristol-Myers Squibb and Daiichi Sankyo, and received research funding from Novartis, Ono Pharmaceutical, Chugai Pharmaceutical, Bristol-Myers Squibb, Taiho Pharmaceutical, Eli Lilly, Pfizer, Astellas Pharma and AstraZeneca. THid received honoraria from Ono Pharmaceutical, Chugai Pharmaceutical, Eli Lilly, Novartis, Taiho Pharmaceutical, AstraZeneca, Boehringer Ingelheim, Pfizer, Bristol-Myers Squibb and Clovis. THid also received research funding from Ono Pharmaceutical, Chugai Pharmaceutical, Eli Lilly, Novartis, Taiho Pharmaceutical, AstraZeneca, Boehringer Ingelheim, Pfizer, Bristol-Myers Squibb, Clovis, Eisai, Takeda Pharmaceutical, Dainippon Sumitomo Pharma, Abbvie, Merck Serono, Kyowa Hakko Kirin, Daiichi Sankyo and Astellas Pharma. SA received honoraria from Chugai Pharmaceutical, Boehringer Ingelheim, AstraZeneca, Taiho Pharmaceutical, Eli Lilly, Ono Pharmaceutical, and Bristol-Myers Squibb. SA also received funding from AstraZeneca and Taiho Pharmaceutical for participating in a speakers' bureau. SA also received research funding from Chugai Pharmaceutical, Pfizer, Ono Pharmaceutical, Merck Serono, Boehringer Ingelheim, AstraZeneca, Taiho Pharmaceutical, Yakult and Eli Lilly. HSakai received honoraria and funding to participate in a speakers' bureau from Ono Pharmaceutical, Taiho Pharmaceutical, Chugai Pharmaceutical, Eli Lilly and Bristol-Myers Squibb. KN received honoraria from Astellas Pharma, AstraZeneca, EPS Holdings, Ono Pharmaceutical, Kyowa Hakko Kirin, Showa Yakuhin Kako, SymBio Pharmaceuticals, Daiichi Sankyo, Chugai Pharmaceutical, Boehringer Ingelheim, Eli Lilly, Pfizer and Bristol-Myers Squibb. KN also received research funding from Chugai Pharmaceutical, MSD, Ono Pharmaceutical, EPS Associates, Quintiles, Daiichi Sankyo, Japan Clinical Research Operations, Eisai, PPD-SNBL, Pfizer, Takeda Pharmaceutical, Boehringer Ingelheim, Taiho Pharmaceutical, Bristol-Myers Squibb, AstraZeneca, Kyowa Hakko Kirin and OncoTherapy Science. TTak received honoraria from AstraZeneca, Boehringer Ingelheim, Pfizer, Eli Lilly, Chugai Pharmaceutical and Ono Pharmaceutical. TTak also received research funding from AstraZeneca, Eli Lilly, Chugai Pharmaceutical, Ono Pharmaceutical, Pfizer, Takeda Pharmaceutical, Taiho Pharmaceutical and MSD. NN received honoraria from Astellas Pharma, AstraZeneca, Ono Pharmaceutical, Taiho Pharmaceutical, Chugai Pharmaceutical, Eli Lilly, Boehringer Ingelheim and Pfizer. HSaka received research funding from AstraZeneca, Daiichi Sankyo, Ono Pharmaceutical, Eli Lilly, Bayer, Taiho Pharmaceutical, MSD, Linical, Bristol-Myers Squibb and Sanofi. MT received honoraria from AstraZeneca, Chugai Pharmaceutical, Eli Lilly, Kyowa Hakko Kirin, Ono Pharmaceutical and Taiho Pharmaceutical. MT also received research funding from Bristol-Myers Squibb, Chugai Pharmaceutical, Eli Lilly, Boehringer Ingelheim, Novartis and Ono Pharmaceutical. MM received honoraria from AstraZeneca, Chugai Pharmaceutical, Pfizer, Ono Pharmaceutical, Bristol-Myers Squibb and Eli Lilly. MM also received research funding from Boehringer Ingelheim. YO’s immediate family member is an employee of Chugai Pharmaceutical. YO also has an immediate family member with an ownership of interest with Ono Pharmaceutical. YO received honoraria from AstraZeneca, Chugai Pharmaceutical, Eli Lilly, Ono Pharmaceutical, Bristol-Myers Squibb, Daiichi Sankyo, Nippon Kayaku, Boehringer Ingelheim, Bayer, Pfizer, MSD, Taiho Pharmaceutical, Clovis and Sanofi. YO has also been a consultant/advisor for AstraZeneca, Chugai Pharmaceutical Co., Eli Lilly, Ono Pharmaceutical and Novartis, and received funding from AstraZeneca, Chugai Pharmaceutical, Eli Lilly, Ono Pharmaceutical, Bristol-Myers Squibb, Kyorin Pharmaceutical, Dainippon Sumitomo Pharma, Pfizer, Taiho Pharmaceutical, Novartis and Merck Serono. YO has also been paid by AstraZeneca to provide expert testimony. HN received honoraria from AstraZeneca, Ono Pharmaceutical, Eli Lilly, Bristol-Myers Squibb and Chugai Pharmaceutical. HN also received research funding from Merck Serono, Pfizer, Taiho Pharmaceutical, Eisai, Chugai Pharmaceutical, Eli Lilly, Novartis, Daiichi Sankyo, GlaxoSmithKline, Yakult, Quintiles, Astellas Pharma, AstraZeneca, Boehringer Ingelheim and Ono Pharmaceutical. THir received research funding from MSD, AstraZeneca, Ono Pharmaceutical, Eisai, Daiichi Sankyo, Merck Serono, Eli Lilly, Taiho Pharmaceutical, Chugai Pharmaceutical, Kyowa Hakko Kirin and Takeda Pharmaceutical. HT received research funding from Eli Lilly, AstraZeneca, MSD, Ono Pharmaceutical, Takeda Pharmaceutical, Daiichi Sankyo, Pfizer, Chugai Pharmaceutical, Taiho Pharmaceutical and Boehringer Ingelheim. KT received honoraria from AstraZeneca, Ono Pharmaceutical, Eli Lilly, Chugai Pharmaceutical, Taiho Pharmaceutical, Boehringer Ingelheim, Daiichi Sankyo and Kyowa Hakko Kirin. KT also has been a consultant/advisor for AstraZeneca, Eli Lilly and Novartis, and received research funding from AstraZeneca, Chugai Pharmaceutical, Eisai, Bristol-Myers Squibb, Eli Lilly, Ono Pharmaceutical, Kyowa Hakko Kirin, Boehringer Ingelheim and Merck Serono. KG received honoraria from Daiichi Sankyo, Nippon Kayaku, Kyowa Hakko Kirin, Bristol-Myers Squibb, AstraZeneca, Pfizer, Chugai Pharmaceutical, Taiho Pharmaceutical, Ono Pharmaceutical, Novartis, Eli Lilly and Boehringer Ingelheim. KG also has been a consultant/advisor for Taiho Pharmaceutical, Chugai Pharmaceutical, and Daiichi Sankyo, and received research funding from MSD, AstraZeneca, Taiho Pharmaceutical, Chugai Pharmaceutical, Boehringer Ingelheim, Ono Pharmaceutical, GlaxoSmithKline, OxOnc, Dainippon Sumitomo Pharma, Takeda Pharmaceutical, Novartis, Daiichi Sankyo, Kyowa Hakko Kirin, Astellas Pharma, Eisai, Eli Lilly, Amgen Astellas BioPharma, Pizer, Riken Genesis and Bristol-Myers Squibb. MS received honoraria from Ono Pharmaceutical, Bristol-Myers Squibb, Chugai Pharmaceutical, Eli Lilly, AstraZeneca, Taiho Pharmaceutical, Pfizer, Boehringer Ingelheim Novartis and MSD. MS also received research funding from Ono Pharmaceutical, Bristol-Myers Squibb, Chugai Pharmaceutical, Eli Lilly, AstraZeneca, Pfizer, Novartis, MSD and Astellas Pharma. HI received funding to participate in a speakers' bureau from AstraZeneca, Bristol-Myers Squibb, Kyowa Hakko Kirin, Chugai Pharmaceutical and Boehringer Ingelheim. KM received research funding from Ono Pharmaceutical and Chugai Pharmaceutical. NS is an employee of Ono Pharmaceutical. TTam received honoraria from Ono Pharmaceutical, Bristol-Myers Squibb, Taiho Pharmaceutical, Chugai Pharmaceutical, Eli Lilly, Boehringer Ingelheim, Eisai, Yakult, Novartis, Daiichi Sankyo and Astellas Pharma.

In 2007, the rearrangement of anaplastic lymphoma kinase (ALK) was identified to be associated with the pathogenesis of a subset of patients with non-small-cell lung cancer (NSCLC). Surprisingly, approximately 4 years after the discovery of ALK rearrangement in lung cancer, the first-in-class ALK inhibitor (ALKi), crizotinib, was approved for metastatic ALK-rearranged NSCLC by the US Food and Drug Administration. Subsequently, next-generation ALKis, such as alectinib and ceritinib, have been developed, and some of them have been applied in the clinical setting. Furthermore, various resistance mechanisms against ALKis have been gradually elucidated, and treatment strategies according to such resistance have been proposed. In addition, novel ALKis exhibit good antitumor efficacy for brain metastases. Thus, we now know much about ALK-rearranged NSCLC; however, is it enough? Several concerns, such as the optimal sequence of ALKis, significance of antiangiogenic therapy, immune checkpoint therapy, and cytotoxic chemotherapy in ALK-rearranged NSCLC, should be clearly addressed, which would lead to the establishment of optimal treatment strategies and a more prolonged survival in patients with ALK rearrangement. Thus, we should w'ALK' into the next stage., (Copyright © 2016 Elsevier Inc. All rights reserved.)

We report herein a 70-year-old woman, with repeated thromboembolic events, including three cerebral embolisms and two venous thromboembolisms, despite adequate anticoagulant therapy. Trousseau syndrome was suspected, and she was diagnosed as having lung adenocarcinoma. Chemoradiotherapy was started, achieving improvements in the lung cancer, and thrombosis was also brought under control. Ten months later, the lung cancer relapsed, and second-line chemotherapy was performed. D-dimer levels, which had normalized after the first-line therapy, increased together with the relapse, but became negative again following the chemotherapy. In general, the prognosis of Trousseau syndrome is diverse. However, in this case, the course was good following the second lung cancer therapy: D-dimer levels did not increase, and there were no recurrences of thromboembolism. This experience reminds us the prognosis is most affected by whether the underlying disease is being effectively treated, and suggests that for Trousseau syndrome, despite adequate anticoagulant therapy, elevation of D-dimer levels should consider the recurrent cancer. < Learning objective: We report herein a case with repeated thromboembolic events as a result of Trousseau syndrome due to lung cancer. Chemotherapy achieved improvements, but the cancer relapsed and second-line chemotherapy was done. D-dimer levels, which had normalized, increased with the relapse before again becoming negative. This experience reminds us that prognosis is affected by treating underlying disease and suggests that elevation of D-dimer levels should consider the cancer recurrence.>.

Background: This study was designed to investigate potential molecules that predict chemosensitivity to pemetrexed (Alimta®) in surgically resected non-small cell lung cancer (NSCLC)., Materials and Methods: Chemosensitivity to ALM and other drugs was assessed by succinate dehydrogenase inhibition (SDI) test in 69 NSCLC samples (55 adenocarcinomas, and 14 squamous cell carcinomas). The mRNA expression levels of Alimta®-target enzymes [thymidylate synthase (TYMS); dihydrofolate reductase (DHFR) and glycinamide ribonucleotide formyltransferase (GARFT)], Alimta®-metabolizing enzymes [γ-glutamyl hydrase (GGH) and folylpolyglutamate synthase] and an Alimta® transporter [reduce folate carrier (RFC)] were measured and examined for potential correlations to chemosensitivity., Results: The squamous cell carcinoma samples showed higher TYMS expression and lower RFC expression than did the adenocarcinoma samples. In the adenocarcinoma sample analyses, GGH expression was inversely correlated to sensitivity., Conclusion: The histology-dependent differences in chemosensitivity to Alimta® may be attributed to the histology-dependent differences in TYMS and RFC expression. In adenocarcinomas, GGH potentially represents a marker for chemosensitivity to Alimta®., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background and Purpose: The EGFR, K-ras, EML4-ALK, and BRAF genes are oncogenic drivers of lung adenocarcinoma. We conducted this study to analyze the mutations of these genes in stage I adenocarcinoma., Methods: The subjects of this retrospective study were 256 patients with resected stage I lung adenocarcinoma. We analyzed mutations of the EGFR, K-ras, and BRAF genes, and the EML4-ALK fusion gene. We also assessed disease-free survival (DFS) to evaluate the prognostic value and overall survival (OS) to evaluate the predictive value of treatment after recurrence., Results: Mutations of the EGFR, K-ras, EML4-ALK, and BRAF genes were detected in 120 (46.8 %), 14 (5.5 %), 6 (2.3 %), and 2 (0.8 %) of the 256 tumors. Two tumors had double mutations (0.8 %). The incidence of EGFR mutations was significantly higher in women than in men. The EML4-ALK fusion gene was detected only in younger patients. The DFS and OS of the K-ras mutant group were significantly worse than those of the EGFR mutant group, the EML4-ALK fusion gene group, and the wild-type group. Six of the seven patients with the EML4-ALK fusion gene are still alive without recurrent disease., Conclusions: In patients with stage I adenocarcinoma, mutation of the K-ras gene was a poor prognostic factor for recurrence. The presence of a mutation of the EGFR or EML4-ALK gene was not a prognostic factor.

Background: Jumonji domain-containing 2B, JMJD2B, has been shown to play an important role in the pathogenesis of lung cancer cells. However, the significance of JMJD2B in patients with lung cancer remains to be elucidated., Patients and Methods: Seventy-eight patients with resected adenocarcinoma, whose data regarding oncogenic drivers in lung cancer were available, were included in the study. Immunohistochemical analysis was performed with a specific antibody for JMJD2B to investigate JMJD2B expression and the significance of JMJD2B expression in survival after surgery was evaluated., Results: Among the 78 patients, 50 (64%) exhibited JMJD2B immunopositivity. The overall survival (OS) of the 50 JMJD2B-positive patients after surgery was significantly inferior to that of the JMJD2B-negative patients (five-year survival=56.7% vs. 92.6%; log-rank: p=0.01). Multivariate analysis showed that JMJD2B positivity was an independent prognostic factor., Conclusion: JMJD2B may be a novel prognostic factor for resected lung adenocarcinoma., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)