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Background First-line pembrolizumab monotherapy improves overall and progression-free survival in patients with untreated metastatic non-small-cell lung cancer with a programmed death ligand 1 (PD-L1) tumour proportion score (TPS) of 50% or greater. We investigated overall survival after treatment with pembrolizumab monotherapy in patients with a PD-L1 TPS of 1% or greater. Methods This randomised, open-label, phase 3 study was done in 213 medical centres in 32 countries. Eligible patients were adults (≥18 years) with previously untreated locally advanced or metastatic non-small-cell lung cancer without a sensitising EGFR mutation or ALK translocation and with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1, life expectancy 3 months or longer, and a PD-L1 TPS of 1% or greater. Randomisation was computer generated, accessed via an interactive voice-response and integrated web-response system, and stratified by region of enrolment (east Asia vs rest of world), ECOG performance status score (0 vs 1), histology (squamous vs non-squamous), and PD-L1 TPS (≥50% vs 1-49%). Enrolled patients were randomly assigned 1:1 in blocks of four per stratum to receive pembrolizumab 200 mg every 3 weeks for up to 35 cycles or the investigator's choice of platinum-based chemotherapy for four to six cycles. Primary endpoints were overall survival in patients with a TPS of 50% or greater, 20% or greater, and 1% or greater (one-sided significance thresholds, p=0·0122, p=0·0120, and p=0·0124, respectively) in the intention-to-treat population, assessed sequentially if the previous findings were significant. This study is registered at ClinicalTrials.gov, number NCT02220894. Findings From Dec 19, 2014, to March 6, 2017, 1274 patients (902 men, 372 women, median age 63 years [IQR 57-69]) with a PD-L1 TPS of 1% or greater were allocated to pembrolizumab (n=637) or chemotherapy (n=637) and included in the intention-to-treat population. 599 (47%) had a TPS of 50% or greater and 818 patients (64%) had a TPS of 20% or greater. As of Feb 26, 2018, median follow-up was 12·8 months. Overall survival was significantly longer in the pembrolizumab group than in the chemotherapy group in all three TPS populations (≥50% hazard ratio 0·69, 95% CI 0·56-0·85, p=0·0003; ≥20% 0·77, 0·64-0·92, p=0·0020, and ≥1% 0·81, 0·71-0·93, p=0·0018). The median surival values by TPS population were 20·0 months (95% CI 15·4-24·9) for pembrolizumab versus 12·2 months (10·4-14·2) for chemotherapy, 17·7 months (15·3-22·1) versus 13·0 months (11·6-15·3), and 16·7 months (13·9-19·7) versus 12·1 months (11·3-13·3), respectively. Treatment-related adverse events of grade 3 or worse occurred in 113 (18%) of 636 treated patients in the pembrolizumab group and in 252 (41%) of 615 in the chemotherapy group and led to death in 13 (2%) and 14 (2%) patients, respectively. Interpretation The benefit-to-risk profile suggests that pembrolizumab monotherapy can be extended as first-line therapy to patients with locally advanced or metastatic non-small-cell lung cancer without sensitising EGFR or ALK alterations and with low PD-L1 TPS. Funding Merck Sharp & Dohme.

Objective A subset analysis of the LETS study suggested that S-1 plus carboplatin was more beneficial than paclitaxel plus carboplatin in terms of the overall survival (OS) in squamous cell lung cancer. However, the benefit of maintenance therapy for squamous cell non-small cell lung cancer (NSCLC) patients is still unknown. We herein report a phase II study to evaluate the efficacy and safety of a tailored dose of S-1 plus carboplatin followed by maintenance S-1 in chemotherapy-naive advanced squamous cell NSCLC. Methods Patients received carboplatin on day 1 plus S-1 on days 1 to 14 every 21 days. The dose of S-1 was determined by the body surface area and creatinine clearance. After four cycles of induction, non-progressive patients continued to receive S-1 until disease progression or unacceptable toxicity occurred. The primary endpoint was an objective response rate (RR) with a threshold value of 15%. The secondary endpoints were the progression-free survival (PFS) and OS from enrollment, the PFS in the maintenance phase, and safety. Results In the 33 patients analyzed, the rate of patients who met the primary endpoint was 30.3% (95% confidence interval: 15.6-48.7%), and the disease control rate was 75.8%. The median PFS and OS were 3.5 and 11.3 months, respectively. Ten patients received maintenance S-1, and the median PFS from the beginning of induction treatment was 5.3 months. Grade 3/4 toxicities with a frequency of more than 5% were all controllable. Conclusion Tailored-dose S-1 plus carboplatin followed by maintenance S-1 is an effective and feasible treatment for advanced squamous cell NSCLC.

A retrospective study was conducted to investigate the efficacy and toxicity of single-agent nab-paclitaxel in 67 patients with platinum-resistant non-small cell lung cancer in Kansai Medical University Hospital from August 2013 to December 2015. Overall, 25% of patients experienced disease progression, 48% exhibited a partial response, 27% had stable disease and 0% had a complete response. The median progression-free survival (PFS) time was 4.8 months and the median overall survival time was 18.2 months. There was no statistically significant difference in PFS between patients with non-squamous carcinoma and squamous carcinoma, or between second-line use and post-second-line use. The most common severe adverse event was neutropenia, followed by interstitial lung disease, infection and fatigue. The results revealed that single agent nab-paclitaxel was associated with an acceptable level of toxicity and a favorable response. This regimen has been developed recently, thus it has not been sufficiently evaluated its toxicity and efficacy. Additional studies to evaluate these parameters in non-small cell lung cancer are warranted.

BACKGROUND Epidermal growth factor receptor tyrosine kinase inhibitors significantly prolong the progression-free survival of patients with non-squamous non-small cell lung cancer (NSCLC). However, most patients develop tumor regrowth and their prognosis remains poor. A new treatment strategy for NSCLC harboring EGFR mutation is therefore necessary. METHODS In phase I, eligible patients were administered oral erlotinib daily and intravenous pemetrexed, carboplatin, and bevacizumab every 3 weeks for four cycles with maintenance of pemetrexed and bevacizumab until progressive disease was observed. The dose of erlotinib was 100 mg for dose level 1 and 150 mg for dose level 2. The doses of pemetrexed, carboplatin, and bevacizumab were fixed at 500 mg/m2, area under the concentration-time curve of 6 mg/mL · min, and 15 mg/kg, respectively. The dose-limiting toxicities were grade 3/4 neutropenia with fever or infection, grade 4 leukopenia lasting for ≥7 days, grade 4 thrombocytopenia, grade 3/4 uncontrollable nonhematological toxicity, and delayed administration of the subsequent cycle by >2 weeks because of adverse events. RESULTS Six patients were enrolled in phase I (dose level 1, n = 3; dose level 2, n = 3). During the induction phase, grade 3 neutropenia without fever was observed in one patient at dose level 1 and two patients at dose level 2. Grade 3 anemia was reported in one patient at dose level 1 and grade 3 thrombocytopenia was reported in two patients at dose level 1 and dose level 2, respectively. CONCLUSION Four-drug combination therapy is a feasible and promising.

Bevacizumab(Avastin®), a humanized therapeutic monoclonal antibody that targets vascular endothelial growth factor, is widely used in cancer treatment. Patients who are treated with bevacizumab have an increased risk of developing systemic hypertension. However, the relationship between bevacizumab‐induced hypertension and clinical outcome remains unclear. We aimed to evaluate the effect of bevacizumab‐induced hypertension in terms of prognosis in patients with colorectal cancer and non‐small cell lung cancer. The study included 632 patients, 317 patients with non‐small cell lung cancer and 315 patients with colorectal cancer. All patients were treated with bevacizumab in combination with standard chemotherapy protocols, between April 2007 and December 2014. Blood pressure was measured before each treatment cycle. In the patient group with colorectal cancer, treated with bevacizumab, Grade 2–3 hypertension was present in 27.6%. In hypertensive patients with colorectal cancer, median overall survival was 42.6 months, compared with 20.6 months for normotensive patients in this group (P = 0.00071). In the patient group with non‐small cell lung cancer, treated with bevacizumab, Grade 2–3 hypertension was present in 20.5%. In hypertensive patients with non‐small cell lung cancer, median overall survival was 43.0 months, compared with 26.3 months for normotensive patients in this group (P = 0.00451). Patients who developed hypertension during treatment with bevacizumab for colorectal cancer and non‐small cell lung cancer had significantly prolonged overall survival when compared with normotensive patients. Bevacizumab‐induced hypertension may represent a biomarker for clinical benefit in cancer patients treated with bevacizumab.

Background: Bevacizumab-based chemotherapy has been shown to extend progression-free survival (PFS) of lung cancer, but its effect on overall survival (OS) remains unclear. However, bevacizumab beyond disease progression (BBP) significantly improved OS in patients with metastatic colorectal cancer. Methods: Therefore, we retrospectively analysed 22 patients with non-small cell lung cancer (NSCLC) who were treated with docetaxel plus BBP at the Department of Thoracic Oncology, Kansai Medical University Hirakata Hospital, between November 2009 and March 2013. Results: The response rate was 31.8% and the disease control rate was 86.4%. The median PFS was 4.5 months (95% confidence interval [CI], 2.5 - 8.7 months) and the median OS was 17.2 months (95% CI, 8.5 - 25.9 months). Grade 3 and 4 adverse events included leukocytopenia (68.2%), neutropenia (77.3%), fatigue (9.1%), proteinuria (9.1%), febrile neutropenia (4.5%), anemia (4.5%), and anorexia (4.5%). Conclusion: Docetaxel plus BBP was found to be generally well tolerated and effective.

The present study evaluated the efficacy and safety of pemetrexed, carboplatin and bevacizumab, followed by maintenance pemetrexed and bevacizumab, in chemotherapy-naive patients with stage IIIB/IV non-squamous non-small cell lung cancer (NSCLC). The patients were administered pemetrexed (500 mg/m 2 ), carboplatin (area under the concentration-time curve, 6.0 mg/ml x min) and bevacizumab (15 mg/kg) intravenously every three weeks for up to six cycles. Patients who did not experience tumor progression remained on maintenance pemetrexed and beva- cizumab until disease progression or unacceptable toxicity occurred. The primary endpoint was the overall response rate. Of the 26 patients enrolled between March 2010 and April 2011, three were excluded due to brain metastases, therefore the intention-to-treat (ITT) population consisted of 23 patients. The median age was 64 years (range, 40-74 years) and 15 patients were male. In total, six patients had a perfor- mance status of 0, and 20 had stage IV tumors. The response rate was 69.6% (95% confidence interval (CI), 47.1-86.8), the disease control rate was 100% and the time to response was 1.2 months (95% CI, 0.72-1.93). The median progression-free survival time was 8.6 months (95% CI, 5.9-10.9) and the median overall survival time was 18.6 months (95% CI, 12.9- 24.8). There were no grade 3 or worse hemorrhagic events and the feasibility was modest. Overall, pemetrexed and carboplatin plus bevacizumab, followed by maintenance pemetrexed and bevacizumab, was effective and tolerable in the patients with non-squamous NSCLC, and the time to response was relatively short.

A 61-year-old woman with lung cancer developed delayed transfusion-related acute lung injury (TRALI) syndrome after transfusion of plasma- and leukoreduced red blood cells (RBCs) for gastrointestinal bleeding due to intestinal metastasis. Acute lung injury (ALI) recurred 31 days after the first ALI episode. Both ALI episodes occurred 48 hours after transfusion. Laboratory examinations revealed the presence of various antileukocyte antibodies including antiplatelet antibody in the recipient's serum but not in the donors' serum. The authors speculate that antiplatelet antibodies can have an inhibitory effect in the recipient, which can modulate the bona fide procedure of ALI and lead to a delay in the onset of ALI. This case illustrates the crucial role of a recipient's platelets in the development of TRALI.

Although Bacillus Calmette-Guérin (BCG) has historically emerged as a potent adjuvant in cancer immunization through dendritic cell (DC) activation, the efficacy of its antitumor effect has been limited. Therefore, the strategy of adjuvant therapy using BCG needs to be improved by adding enhancers. Here we found that thymic stromal lymphopoietin (TSLP) acts as an enhancer for the BCG-mediated antitumor effect. While BCG-stimulated DCs induced CD8(+) T cell production of IFN-gamma without strong cell expansion, TSLP-stimulated DCs induced robust CD8(+) T cell expansion without high quantities of IFN-gamma production. Notably, DCs stimulated with both BCG and TSLP induced robust expansion of CD8(+) T cells that produced a large amount of IFN-gamma with a potent cytolytic activity related to granzyme B expression. Our data suggest that TSLP is a good adjuvant to enhance the BCG-mediated cytotoxic T cell effect through DC activation, and provide a functional basis for a novel strategy for antitumor immune-based therapy.

Atopic dermatitis is a major allergic disease that develops through dysregulation of Th2-mediated inflammation. Although dendritic cells (DCs) have been thought to play a critical role in the upstream phase of the allergic cascade, conventional drugs such as steroids and chemical mediator antagonists target the effector cells or factors in allergic inflammation. Recently, it has been demonstrated that interaction between thymic stromal lymphopoietin (TSLP) and human DCs plays an essential role in evoking inflammatory Th2 responses in allergy through OX40 ligand expression on DCs. In this study, we provide evidence that R848, an imidazoquinoline compound, which is a TLR ligand and a strong Th1 response-inducing reagent, is a potent adjuvant for the alteration of the Th2-inducing potency of human DCs activated by TSLP (TSLP-DCs). R848 inhibited the inflammatory Th2-inducing capacity of TSLP-DCs and redirected them to possessing an IL-10 and IFN-γ-producing regulatory Th1-inducing capacity. This functional alteration depended on both repression of OX40 ligand expression and induction of IL-12 production from DCs by the addition of R848. Additionally, R848 had the ability to inhibit the TSLP-mediated expansion and maintenance of the Th2 memory response. These findings suggest that imidazoquinoline may be a useful in the treatment of allergic diseases that are triggered by TSLP.

Allergic diseases such as atopic dermatitis and asthma develop as a consequence of dysregulated T(h)2 responses. Recently, it has been demonstrated that interaction between dendritic cells (DCs) and thymic stromal lymphopoietin (TSLP), an IL-7-like cytokine, is essential for evoking T(h)2 responses in allergy. In this study, we investigated whether Mycobacterium bovis Bacillus Calmette-Guérin (BCG), a strong T(h)1 response-inducing adjuvant, can alter the function of DCs activated by TSLP (TSLP-DCs). We demonstrated that BCG redirects TSLP-DCs away from inducing inflammatory T(h)2 cells that produce IL-4, IL-5, IL-13 and tumor necrosis factor (TNF)-alpha and toward regulatory T(h)1 cells that produce IFN-gamma and IL-10. We also demonstrated that this functional alteration of TSLP-DCs by BCG depended on both production of IL-12 from DCs and down-regulation of OX40 ligand, a member of the TNF family, on DCs. These findings suggest that BCG might be a useful adjuvant for the treatment of allergic diseases that are triggered by TSLP.

A recent report revealed that a large population of Hodgkin’s lymphoma-infiltrating lymphocytes (HLILs) consisted of regulatory T cells. In this study, we cocultured CD4+ naive T cells with KM-H2, which was established as a Hodgkin’s Reed-Sternberg cell line, to clarify their ability to induce CD25+Forkhead box P3+ (Foxp3+) T cells. The characteristic analyses of T cells cocultured with KM-H2 revealed the presence of CD4+CD25+ T cells. They expressed CTLA-4, glucocorticoid-induced TNFR family-related gene, and Foxp3 and could produce large amounts of IL-10. Conversely, KM-H2 also generated CD4+ CTLs, which expressed Granzyme B and T cell intracellular antigen-1 in addition to Foxp3+ T cells. They exhibit a strong cytotoxic effect against the parental KM-H2. In conclusion, KM-H2 promotes a bidirectional differentiation of CD4+ naive T cells toward Foxp3+ T cells and CD4+ CTLs. In addition to KM-H2, several cell lines that exhibit the APC function were able to generate Foxp3+ T cells and CD4+ CTLs. Conversely, the APC nonfunctioning cell lines examined did not induce both types of cells. Our findings suggest that the APC function of tumor cells is essential for the differentiation of CD4+ naive T cells into CD25+Foxp3+ T cells and CD4+ CTLs and at least partly explains the predominance of CD25+Foxp3+ T cells in HLILs and their contribution to a better prognosis. Therefore, in APC-functioning tumors, including classical Hodgkin lymphomas, which generate Foxp3+ T cells and CD4+ CTLs, these T cell repertories play a beneficial role synergistically in disease stability.

e20042Background: Concurrent platinum-based chemotherapy with thoracic radiation therapy (TRT) is well established with standard therapy in locally advanced NSCLC pts. Nanoparticle albumin-bound pa...

Statins, which are used as cholesterol-lowering agents, have pleiotropic immunomodulatory properties. Although beneficial effects of statins have been reported in autoimmune diseases, the mechanisms of these immunomodulatory effects are still poorly understood. Type I interferons (IFNs) and plasmacytoid dendritic cells (PDCs) represent key molecular and cellular pathogenic components in autoimmune diseases such as systemic lupus erythematosus (SLE). Therefore, PDCs may be a specific target of statins in therapeutic strategies against SLE. This study was undertaken to investigate the immunomodulatory mechanisms of statins that target the IFN response in PDCs.We isolated human blood PDCs by flow cytometry and examined the effects of simvastatin and pitavastatin on PDC activation, IFNalpha production, and intracellular signaling.Statins inhibited IFNalpha production profoundly and tumor necrosis factor alpha production modestly in human PDCs in response to Toll-like receptor ligands. The inhibitory effect on IFNalpha production was reversed by geranylgeranyl pyrophosphate and was mimicked by either geranylgeranyl transferase inhibitor or Rho kinase inhibitor, suggesting that statins exert their inhibitory actions through geranylgeranylated Rho inactivation. Statins inhibited the expression of phosphorylated p38 MAPK and Akt, and the inhibitory effect on the IFN response was through the prevention of nuclear translocation of IFN regulatory factor 7. In addition, statins had an inhibitory effect on both IFNalpha production by PDCs from SLE patients and SLE serum-induced IFNalpha production.Our findings suggest a specific role of statins in controlling type I IFN production and a therapeutic potential in IFN-related autoimmune diseases such as SLE.

Objective Statins, which are used as cholesterol-lowering agents, have pleiotropic immunomodulatory properties. Although beneficial effects of statins have been reported in autoimmune diseases, the mechanisms of these immunomodulatory effects are still poorly understood. Type I interferons (IFNs) and plasmacytoid dendritic cells (PDCs) represent key molecular and cellular pathogenic components in autoimmune diseases such as systemic lupus erythematosus (SLE). Therefore, PDCs may be a specific target of statins in therapeutic strategies against SLE. This study was undertaken to investigate the immunomodulatory mechanisms of statins that target the IFN response in PDCs. Methods We isolated human blood PDCs by flow cytometry and examined the effects of simvastatin and pitavastatin on PDC activation, IFNα production, and intracellular signaling. Results Statins inhibited IFNα production profoundly and tumor necrosis factor α production modestly in human PDCs in response to Toll-like receptor ligands. The inhibitory effect on IFNα production was reversed by geranylgeranyl pyrophosphate and was mimicked by either geranylgeranyl transferase inhibitor or Rho kinase inhibitor, suggesting that statins exert their inhibitory actions through geranylgeranylated Rho inactivation. Statins inhibited the expression of phosphorylated p38 MAPK and Akt, and the inhibitory effect on the IFN response was through the prevention of nuclear translocation of IFN regulatory factor 7. In addition, statins had an inhibitory effect on both IFNα production by PDCs from SLE patients and SLE serum–induced IFNα production. Conclusion Our findings suggest a specific role of statins in controlling type I IFN production and a therapeutic potential in IFN-related autoimmune diseases such as SLE.

A 28-year-old man had a 1-year history of hemoptysis. Consequently, he underwent a medical examination. A right pleural effusion, left hydropneumothorax, and multiple pulmonary nodular shadows were found on chest radiography. During a detailed interview, he reported that the hemoptysis began after eating "kejang" (a raw crab preparation) with a friend a year previously. His peripheral blood eosinophil count and serum IgE level were elevated. In addition, ova were detected in the sputum and bilateral pleural effusion. Morphological examination of the ova and immunoserological examination led to the diagnosis of Paragonimus westermani infection. The pleural effusion could be partially drained, and his symptoms and radiographic results showed improvement after treatment with Praziquantel administered at a dose of 75 mg/(kg x day) for 3 days. After one month, he and his friend ate seasoned raw crabs, Paragonimus was diagnosed in his friend. This case suggests that on encountering a paragonimus infection, everyone who ate food prepared in the same kitchen should be contacted because of possible infection with paragonimus.

e19132 Background: Randomized studies showed that the addition of bevacizumab to standard chemotherapy regimens significantly improved outcome in previously untreated patients with advanced non-squ...

e18081 Background: Until recently non–small-cell lung cancer was treated as a single disease with “platinum-based doublet chemotherapy” comprising first-line treatment for advanced disease. However, survival outcome of advanced non-squamous non–small-cell lung cancer are improving since the appearance of pemetrexed and bevacizumab. These drugs show a high effect especially to Adenocarcinoma, but there are few reports of the regimen which combined these both agents. Then, we designed this study to evaluate the efficacy and safety of pemetrexed, carboplatin, and bevacizumab followed by maintenance pemetrexed and bevacizumab in patients with chemotherapy-naïve Japanese stage IIIB or stage IV non-squamous non–small-cell lung cancer. Methods: Patients received pemetrexed 500 mg/m2, carboplatin area under the concentration-time curve of 6, and bevacizumab 15 mg/kg every 3 weeks for up to six cycles. For patients who is not progressed after pemetrexed, carboplatin and bevacizumab therapy, pemetrexed and bevacizumab were continued until disease progression or unacceptable toxicity. Primarity endpoint is response rate. Results: 23 patients were enrolled between March 2010 and April 2011 and treated. Median age was 64 (40-74), 15 patients were male, 6 patients were PS 0, 20 patients were Stage IV. Response rate was 69.5% and disease control rate was 100%. Median PFS was 8.5 months and median OS was not reached. Median time to response was 1.2 months. There were no grade 3 or worse hemorrhagic events. The feasibility was modest. Conclusions: Pemetrexed and carboplatin plus bevacizumab with maintenance pemetrexed and bevacizumab was efficacy and tolerable regimen in Japanese patients with non-squamous non-small-cell lung cancer. This regimen also has a trend of shorter period for response. It may contribute to the better QoL.