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A new type of catalyst for reactions via σ-bond activation is Rh(PAlP): Rh-Al heterobimetallic complex of diphosphine-based tridentate pincer-type PAlP ligand bearing an aluminyl moiety at the center coordination site. This work reports results of theoretical and computational studies of the unique Rh–Al direct bond, flexible behavior of Rh(PAlP) for substrate coordination, and new catalytic functions of Rh(PAlP) via the C–H and C–F σ-bond activations. It is particularly interesting that the Rh-Al bond exhibits an unusual Rhδ−–Alδ+ polarization of the Rh–Al σ-bonding MO, opposite to Mδ+–Lδ− polarization of the usual coordinate bond. The other characteristic feature of PAlP is its strong trans-influence, which is as strong as that of SiMe3 ligand but much stronger than that of CH3 ligand. Because the Al atom of PAlP plays a role of a Lewis acid in Rh(PAlP), Rh(PAlP) has three coordination sites: Al site, Rh axial site, and Rh equatorial site. There, NH3 coordinates to the Al site and the Rh axial site with similar stability, whereas CO coordinates to the Rh axial site and C2H4 coordinates to the Rh equatorial site. Electrostatic interaction plays a crucially important role in the NH3 coordination to the Al site. Rh(PAlP) catalyses conversion of fluorobenzene to benzoic acid via C–F σ-bond cleavage and C(2)-regioselective alkylation of pyridine with alkene via C–H σ-bond activation. Theoretical studies show clearly that the Rh and Al sites participate cooperatively in C–F and C–H σ-bond activations. The unusual Rhδ−–Alδ+ polarization and coordination flexibility play important roles in these catalytic reactions.

We have synthesized rhodium complexes that bear X-type PBP and PGaP pincer ligands. X-ray diffraction analysis and IR spectroscopy of the PBP– and PGaP–Rh(CO)2 complexes showed that the σ-donicity ...

Background Immune checkpoint inhibitors (ICIs) are essential for treatment of various malignancies, including non–small-cell lung cancer (NSCLC). Recently, several studies have shown that the gut microbiome plays an important role in ICI treatment of solid cancers, and antibiotic (ATB) use had a negative impact on the outcomes of ICI treatment via dysbiosis in the gut. However, whether this is applicable to NSCLC remains unclear. The impact of ATBs based on PD-L1 expression also remains unclear. Methods We retrospectively reviewed the medical records of patients with NSCLC who received ICI monotherapy (anti–PD-1 or anti–PD-L1 antibody) at nine institutions from December 2015 to May 2018. Outcomes with use of ATBs during the 2 months before or a month after initiation of ICI treatment, including progression-free survival (PFS) and overall survival (OS), were investigated using the Kaplan-Meier method. Multivariate analysis was also conducted using a Cox proportional hazards model. Results A total of 531 patients were included in this study, among whom 98 (18.5%) received ATBs before or after ICI treatment. ATB use was significantly associated with a shorter median OS (11.7 months in the ATB group vs. 16.1 months in the non-ATB group; p = 0.028), whereas the difference in PFS was not significant (3.5 months in both the groups; p = 0.287). We next investigated the association based on PD-L1 expression in the 265 patients for whom PD-L1 expression was determined. There was no significant difference in the median OS or PFS between patients with NSCLC and PD-L1 expression Conclusions Our results indicate that the impact of ATB use on the efficacy of ICIs differed based on PD-L1 expression in patients with advanced NSCLC. A negative impact of ATB use was found in patients with NSCLC and PD-L1 expression ≥50% but not in those with PD-L1 expression

The recently synthesized rhodium-aluminum bimetallic complex Rh(PAlP) 1 (PAlP = pincer-type diphosphino-aluminyl ligand Al{[N(C6H4)]2NMe}[CH2P(iPr)2]2) containing a unique Rh-Al direct bond exhibits coordination flexibility because Rh and Al can play the role of coordination site for the substrate. DFT calculations of NH3, CO, and C2H4 adducts with 1 show that the Rh atom is favorable for all these substrate but the Al atom is as favorable as the Rh atom for NH3 and unfavorable for CO and C2H4. NH3 and CO prefer the coordination at the Rh-axial (Ax) site to the Rh-equatorial (Eq) site, but C2H4 prefers coordination at the Rh-Eq site to the Rh-Ax site. Consequently, two CO and C2H4 molecules coordinate with 1 at the Rh-Ax and Rh-Eq sites to afford trigonal bipyramidal complexes Rh(PAlP)(CO)2 and Rh(PAlP)(C2H4)2, which is consistent with the experimental observation of Rh(PAlP)(CO)2. Energy decomposition analysis reveals that an electrostatic term plays an important role for NH3 coordination with the Al atom of 1, because Al has a significantly large positive charge and NH3 has a much negatively charged N atom and exhibits a considerably negative electrostatic potential at the Al position. In B and Ga analogues Rh(PBP) 2 and Rh(PGaP) 3, B and Ga atoms are not good for CO and C2H4 like the Al atom in 1. NH3 adducts with 2 and 3 at the B and Ga sites are less stable than those adducts at the Rh-Ax site unlike the NH3 adduct with 1 at the Al site. This difference in the NH3 adduct between Rh(PAlP) and others (Rh(PBP) and Rh(PGaP)) arises from much less positive charges of B and Ga and a smaller atomic size of B than that of Al. These results indicate that the significantly large electropositive nature and appropriate atomic size of Al are responsible for the characteristic coordination flexibility of Rh(PAlP).

Increasing research has been conducted about patients’ preferences for their role in treatment decision making. Nowadays, a patient-centred approach, so-called ‘shared decision making,’ emphasises ...

The unique Rh-Al bond in recently synthesized Rh(PAlP) 1 {PAlP = pincer-type diphosphino-aluminyl ligand Al[NCH2(P iPr2)]2(C6H4)2NMe} was investigated using the DFT method. Complex 1 has four doubly occupied nonbonding d orbitals on the Rh atom and one Rh d orbital largely participating in the Rh-Al bond which exhibits considerably large bonding overlap between Rh and Al atoms like in a covalent bond. Interestingly, Rhδ--Alδ+ polarization is observed in the bonding MO of 1, which is reverse to Rhδ+-Eδ- (E = coordinating atom) polarization found in a usual coordinate bond. This unusual polarization arises from the presence of the Al valence orbital at significantly higher energy than the Rh valence orbital energy. Characteristic features of 1 are further unveiled by comparing 1 with similar Rh complexes RhL(PMe3)2 (2 for L = AlMe2, 3 for L = Al(NMe2)2, 4 for L = BMe2, 5 for L = SiMe3, 6 for L = SiH3, 7 for L = CH3, 8 for L = OMe, and 9 for L = Cl). As expected, 7, 8, and 9 exhibit usual Rhδ+-Eδ- polarization (E = coordinating atom) in the Rh-E bonding MO. On the other hand, the reverse Rhδ--Eδ+ polarization is observed in the Rh-E bonding MOs of 2-5 like in 1, while the Rh-Si bond is polarized little in 6. These results are clearly understood in terms of the valence orbital energy of the ligand. Because the LUMO of 1 mainly consists of the Rh 4dσ, 5s, and 5p orbitals and the Al 3s and 3p orbitals, both Rh and Al atoms play the role of coordinating site for a substrate bearing a lone pair orbital. For instance, NH3 and pyridine coordinate to both Al and Rh atoms with considerably large binding energy. PAlP exhibits significantly strong trans influence, which is as strong as that of SiMe3 but moderately weaker than that of BMe2. The trans influence of these ligands is mainly determined by the valence orbital energy of the ligand and the covalent bond radius of the coordinating E atom.

We have developed a C2-selective mono-silylation of a variety of pyridines using a Rh–Al complex. Both the site- and mono-selectivity are controlled via the pyridine coordination to the Lewis-acidic Al center prior to the activation of the pyridine C(2)–H bond at the proximal Rh center. A reaction mechanism is proposed based on several mechanistic studies, including the isolation of a (2-pyridyl)silylrhodium intermediate.

We report the catalytic reduction of a C-O bond and the borylation by a rhodium complex bearing an X-type PAlP pincer ligand. We have revealed the reaction mechanism based on the characterization of the reaction intermediate and deuterium-labeling experiments. Notably, this novel catalytic system shows steric-hindrance-dependent chemoselectivity that is distinct from conventional Ni-based catalysts and suggests a new strategy for selective C-O bond activation by heterobimetallic catalysis.

Molecular agents targeting the epidermal growth factor receptor (EGFR)‐, anaplastic lymphoma kinase (ALK)‐ or c‐ros oncogene 1 (ROS1) alterations have revolutionized the treatment of oncogene‐driven non‐small‐cell lung cancer (NSCLC). However, the emergence of acquired resistance remains a significant challenge, limiting the wider clinical success of these molecular targeted therapies. In this study, we investigated the efficacy of various molecular targeted agents, including erlotinib, alectinib, and crizotinib, combined with anti‐vascular endothelial growth factor receptor (VEGFR) 2 therapy. The combination of VEGFR2 blockade with molecular targeted agents enhanced the anti‐tumor effects of these agents in xenograft mouse models of EGFR‐, ALK‐, or ROS1‐altered NSCLC. The numbers of CD31‐positive blood vessels were significantly lower in the tumors of mice treated with an anti‐VEGFR2 antibody combined with molecular targeted agents compared with in those of mice treated with molecular targeted agents alone, implying the antiangiogenic effects of VEGFR2 blockade. Additionally, the combination therapies exerted more potent antiproliferative effects in vitro in EGFR‐, ALK‐, or ROS1‐altered NSCLC cells, implying that VEGFR2 inhibition also has direct anti‐tumor effects on cancer cells. Furthermore, VEGFR2 expression was induced following exposure to molecular targeted agents, implying the importance of VEGFR2 signaling in NSCLC patients undergoing molecular targeted therapy. In conclusion, VEGFR2 inhibition enhanced the anti‐tumor effects of molecular targeted agents in various oncogene‐driven NSCLC models, not only by inhibiting tumor angiogenesis but also by exerting direct antiproliferative effects on cancer cells. Hence, combination therapy with anti‐VEGFR2 antibodies and molecular targeted agents could serve as a promising treatment strategy for oncogene‐driven NSCLC., We found that VEGFR2 blockade augmented the anti‐tumor effects of molecular targeted agents in oncogene‐driven NSCLC, particularly in EGFR/ALK/ROS1‐driven NSCLC. We also identified 2 mechanisms underlying the synergistic effects of anti‐VEGFR2 therapy with molecular targeted agents. VEGFR2 blockade not only inhibited tumor angiogenesis but also exerted direct antiproliferative effects on cancer cells.

The recently synthesized rhodium-aluminum bimetallic complex Rh(PAlP)

Objectives Studies investigating the association between radiation therapy and the efficacy of immune checkpoint inhibitors in advanced non-small-cell lung cancer have provided inconsistent results, likely due to relatively small cohort sizes. This study investigated the effect of previous thoracic radiation therapy on the efficacy of immune checkpoint inhibitor therapy in a large non-small-cell lung cancer cohort. Patients and methods We conducted a retrospective cohort study using data from 531 non-small-cell lung cancer patients who received monotherapy with programmed cell death protein 1/programmed death-ligand 1 inhibitors at nine institutions. The effects of thoracic radiation therapy on the efficacy of immune checkpoint inhibitors were investigated. Results A total of 531 non-small-cell lung cancer patients treated with immune checkpoint inhibitors were included in this study. The progression-free survival period was significantly longer in patients that had received thoracic radiation therapy before immune checkpoint inhibitor therapy compared to those without previous thoracic radiation therapy (median progression-free survival 5.0 vs. 3.0 months, P = 0.0013). A multivariate analysis showed that thoracic radiation therapy was an independent predictive factor of improved progression-free survival (hazard ratio of progression-free survival: 0.79, P = 0.049). In contrast, extra-thoracic radiation therapy was associated with inferior outcomes (median progression-free survival 3.0 vs. 4.2 months, P = 0.0008). Conclusion Previous thoracic radiation therapy, but not prior extra-thoracic radiation therapy, enhanced the efficacy of anti-programmed cell death protein 1/programmed death-ligand 1 therapy in non-small-cell lung cancer patients.

Most clinical trials of non‐small‐cell lung cancer (NSCLC) exclude patients with poor ECOG performance status (PS). Thus, the efficacy of immune checkpoint inhibitors (ICIs) in patients with poor PS remains unclear. Herein, we used data from a retrospective cohort to assess the potential clinical benefits of ICIs in NSCLC patients with poor PS. Data from NSCLC patients who received ICI monotherapy at 9 institutions between December 2015 and May 2018 were retrospectively analyzed. After excluding 4 patients who lacked PS data, a total of 527 ICI‐treated patients, including 79 patients with PS 2 or higher, were used for our analyses. The progression‐free survival (PFS) and overall survival (OS) of patients with PS 2 or higher were significantly shorter compared with those of PS 0‐1 patients (median PFS, 4.1 vs 2.0 months; P, A total of 527 immune checkpoint inhibitor (ICI)‐treated patients, including 79 patients with an ECOG performance status (PS) of 2 or higher, were retrospectively analyzed. Although poor PS was significantly associated with worse outcomes in non‐small‐cell lung cancer (NSCLC) patients treated with ICIs, pembrolizumab given as a first‐line treatment in NSCLC patients expressing high levels of programmed cell death protein‐ligand 1 could provide a clinical benefit, even in patients rated PS 2.

Exon 18 delE709_T710insD is an extremely rare mutation in epidermal growth factor receptor (EGFR) in non-small-cell lung cancer (NSCLC); the efficacy of EGFR tyrosine kinase inhibitors against this mutation remains unclear. In this case report, we report a case of NSCLC harboring EGFR exon 18 delE709_T710insD that was not detected by a commercially available assay, but was detected by a next-generation sequencing cancer panel. A 56-year old female patient with advanced NSCLC was diagnosed as EGFR-mutation-negative using the PNAClamp method. ALK rearrangement was also absent and she received cytotoxic chemotherapies. Clinical characteristics, including adenocarcinoma histology and no history of smoking, implied the presence of a driver mutation, so a next-generation-sequencing Oncomine® Cancer Research Panel was conducted in the patient’s clinical course and the EGFR exon 18 delE709_T710insD mutation was detected. The patient started afatinib as sixth-line treatment and her pulmonary lesion significantly decreased in size. Afatinib was continued for 7 months until disease progressed.

A C2- and mono-selective alkylation of various pyridines and azines with unactivated alkenes and vinylarenes using a heterobimetallic Rh–Al catalyst is reported. The use of aliphatic alkenes exclusively affords the linear alkylation products, while vinylarenes mainly afford branched alkylation products. The details of the reaction mechanism are revealed by DFT calculations: the reductive elimination of the products is rate-determining, which is consistent with the experimental results. The origin of the linear/branched selectivity is elucidated based on deformation/interaction analysis.

Immune checkpoint inhibitors (ICIs) are less effective in non-small-cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations. However, a small percentage of patients with EGFR-mutant NSCLC do respond, and the characteristics of these patients are not known. Here, we identify the characteristics of patients who may respond to ICI therapy for EGFR-mutant NSCLC. The medical records of NSCLC patients with EGFR mutations who received PD-1/PD-L1 antibody monotherapy at nine institutions were reviewed. In total, 58 patients with EGFR-mutant NSCLC were analyzed. Various clinical factors such as smoking history and EGFR mutation type were not associated with progression-free survival (PFS) of ICIs, while the PFS of prior EGFR tyrosine kinase inhibitors (TKIs) was inversely associated with that of ICIs. Patients who responded to prior EGFR TKIs for > 10 months exhibited a significantly shorter response to ICIs compared to those who had responded for ≤ 10 months (PFS of ICI: 1.6 vs. 1.9 months; hazard ratio: 2.54; 95% confidence interval 1.26–5.12; p = 0.009). However, patients who responded to ICIs for > 6 months responded to prior EGFR TKIs for significantly shorter periods compared to those who responded to ICIs for ≤ 6 months (PFS of prior EGFR TKI: 5.3 vs. 12.1 months; log-rank test: p = 0.0025). The duration of response to prior EGFR TKIs could be a predictive marker of ICI therapy in EGFR-mutant NSCLC patients.

Aim Evidence is lacking on the best standard method for forced diuresis to prevent cisplatin-induced nephrotoxicity. We compared the cisplatin-induced nephrotoxicity prevention effect of furosemide or mannitol in patients with advanced non-small cell lung cancer. Methods Patients with advanced non-small cell lung cancer suitable to receive cisplatin-containing regimen were randomly assigned to receive furosemide or mannitol with appropriate hydration. The primary endpoint was the proportion of ≥ grade 1 serum creatinine elevation in the first cycle. Results The trial was terminated early with 44 (22 per arm) of the planned 66 patients because of slow accrual. Patients' characteristics were well balanced with median baseline creatinine clearance of 98.0 and 95.1 mL/min in the furosemide and mannitol arms, respectively. In the first cycle, two (9%) and four (18%) patients developed grade 1 creatinine elevation (P = .66), respectively, despite no ≥ grade 2 toxicity. The median times to develop the worst creatinine score were 10 and 8 days, respectively. For all cycles, median times to recover to grade 0 were 56 and 20 days, respectively. The furosemide arm was characterized by relatively high urine output after cisplatin administration (900 vs 550 mL/h), low frequency of unplanned additional hydration (14% vs 32%), and high incidence of hyponatremia (18% and 5%) compared with the mannitol arm. Both arms showed similar progression-free survival and overall survival. Conclusion The preventive effect of the two forced diuretics on cisplatin-induced nephrotoxicity was not significantly different. However, the two diuretics have some distinct types of clinical presentations.

Objectives : Body mass index (BMI) is reported to be associated with the efficacy of immune checkpoint inhibitors (ICIs) in solid tumors such as melanomas. However, it remains unclear whether such a relationship exists in non-small cell lung cancer (NSCLC) treated with programmed cell death protein 1 (PD-1)/ programmed death-ligand 1(PD-L1) inhibitors. The purpose of this study was to investigate the relationship between BMI and the efficacy of ICI treatment in patients with advanced NSCLC. Materials and methods : The medical records of NSCLC patients who received PD-1/PD-L1 antibody monotherapy at nine institutions between December 2015 and May 2018 were reviewed retrospectively. The effect of BMI was investigated in two cohorts. Cohort 1 included patients with NSCLCs with high PD-L1 expression (≥ 50 %) treated with pembrolizumab as first-line therapy, and cohort 2 included patients with NSCLCs treated with nivolumab/pembrolizumab/atezolizumab as second- or later-line treatment. Results : A total of 513 from nine institutions were analyzed (84 in cohort 1, 429 in cohort 2). Using a BMI cut-off value of 22 kg/m2, which is an ideal BMI in our country (high BMI:22.0 and low BMI:22.0), there was no significant difference in the PFS or OS between the high and low BMI patients in cohort 1. However, in cohort 2, survival was significantly longer in patients with a high versus low BMI (PFS: 3.7 vs. 2.8 months, p = 0.036; OS: 15.4 vs. 13.5 months, p = 0.021). Conclusion : BMI was significantly associated with the efficacy of ICIs in patients with NSCLC treated with second- or later-line PD-1/PD-L1 inhibitors in our cohort.

Palladium complexes with pincer-type ligands containing a Z-type aluminum moiety are synthesized by the reaction of palladium(0) precursors with aluminum-containing diphosphine ligands. Chlorine on the aluminum center can be substituted by methyl and triflate groups to control the electronic and steric properties of the aluminum ligands.

We report rhodium complexes bearing PAlP pincer ligands with an X-type aluminyl moiety. IR spectroscopy and single-crystal X-ray diffraction analysis of a carbonyl complex exhibit the considerable σ-donating ability of the aluminyl ligand, whose Lewis acidity is confirmed through coordination of pyridine to the aluminum center. The X-type PAlP–Rh complexes catalyze C2-selective monoalkylation of pyridine with alkenes.

Chronic inflammation plays a key role in the pathogenesis of malignant pleural mesothelioma (MPM) as a result of asbestos exposure. Several inflammation-based prognostic scores including the lymphocyte-to-monocyte ratio (LMR), Glasgow Prognostic Score (GPS), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) reportedly predict survival in many malignancies, while the role of LMR in MPM remains unclear. The aim of this study was to evaluate the clinical value of LMR and to compare the prognostic value of these inflammation-based scores in predicting overall survival (OS) in MPM.One hundred and fifty patients with histologically proven MPM were included in this retrospective study. Kaplan-Meier curves and multivariate Cox-regression analyses were calculated for OS. The area under the receiver operating characteristics curve (AUC) was calculated to compare the discriminatory ability of each scoring system.An elevated LMR was significantly associated with prolonged OS. Patients with LMR2.74 had significantly poor survival compared with LMR ≥2.74 (median, 5.0 versus 14.0 months; p=0.000). The LMR consistently had a higher AUC value at 6 months (0.722), 12 months (0.712), and 24 months (0.670), compared with other scores. Multivariate analysis showed that the LMR was independently associated with OS.The LMR is an independent prognostic marker for OS in patients with MPM and is superior to other inflammation-based prognostic scores with respect to prognostic ability.

Background: Non-small cell lung cancers (NSCLCs) harboring driver oncogene such as epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) rearrangement are sensitive to the corresponding molecular targeted tyrosine kinase inhibitors (TKIs). However, acquired resistance inevitably develops, and more effective treatment strategies are needed. Anti-vascular endothelial growth factor (VEGF) antibody bevacizumab significantly prolongs progression free survival when added to first-generation EGFR TKIs in EGFR mutant NSCLC. However, it remains unknown whether anti-VEGF receptor (VEGFR) antibody enhances the efficacy of molecular targeted agents as well. In this study, we investigated combinations with an anti-VEGFR antibody and EGFR or ALK TKIs in preclinical models Materials and Methods: We treated mice bearing subcutaneous tumor cell lines harboring EGFR mutation (PC-9, H3255) or ALK rearrangement (ABC-11, H3122) using combinations of anti-mouse VEGFR antibody DC101 and erlotinib (EGFR TKI) /alectinib (ALK TKI). Neovascularization of the tumors were determined by CD31 immunostaining. To determine the effects of VEGFR antibody on cancer cell itself, we also examined the efficacy of the combinations in vitro. Results: Combination therapy demonstrated significantly better tumor inhibition compared to erlotinib or alectinib alone in all the examined xenograft tumors. CD31 positive blood vessel staining was significantly reduced in the tumors treated with combination therapy. Mutant EGFR transfection in HEK293T cells increased VEGF expression in the cell culture supernatant. Furthermore, MTT assay showed significantly enhanced cell growth inhibition when anti-human VEGFR antibody ramucirumab combined with erlotinib (against PC-9 or H3255 cells) or alectinib (against ABC-11 or H3122 cells) suggesting that anti-VEGFR antibody affects not only on tumor vasculature but cancer cell itself. Consistent with this finding, combination with siVEGFR and erlotinib also inhibited the cell proliferation significantly better than erlotinib alone in PC-9 cells. Conclusion: A significant combination benefit was observed with anti-VEGFR2 antibody and EGFR or ALK TKI both in vivo and in vitro, suggesting anti-VEGFR antibody inhibits not only the blood vessels but may also exert direct anticancer effects. Combination therapy of erlotinib or alectinib and anti-VEGFR2 antibody could be a promising treatment strategy for oncogene addicted NSCLC. Citation Format: Hiromi Watanabe, Eiki Ichihara, Hiroe Kayatani, Hisao Higo, Go Makimoto, Hirohisa Kano, Kazuya Nishii, Naofumi Hara, Kiichiro Ninomiya, Toshio Kubo, Kadoaki Ohashi, Kammei Rai, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura. Significant combination benefit of anti-VEGFR antibody and oncogene-targeted agents in EGFR or ALK mutant NSCLC cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2131.

Background: Anti-Programed cell death 1 (PD-1) antibodies such as nivolumab or pembrolizumab show promising treatment effects in smoking-related lung cancer. However, anti-PD-1 antibodies have very little effect on epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC). EGFR mutations are the most frequent oncogenic drivers in non-smoking related NSCLC. Therefore, we aimed to explore the mechanism underlying tumor immunoediting in a lung cancer mouse model harboring EGFR mutations. Methods: We previously established two strains of transgenic lung cancer mouse (C57BL/6) harboring a mouse Egfr exon 19-deletion (mDEL) or a human EGFR L858R (hLR) mutation, driven by a surfactant protein (SP)-C promoter (Ohashi, Cancer Sci. 2008; Ohashi, Cancer Res. 2009). These mice developed EGFR-dependent multifocal lung adenocarcinomas from type II pneumocytes. We modified the two models by transplanting lung tumors subcutaneously into C57BL/6 (Ohashi, AACR. 2018). Evaluation of mice tumor lymphocyte profile was done through flow cytometry or immunohistochemistry (IHC). Effects of T cell depletion or anti-mouse PD-1 antibody (4H2) in vivo were also assessed. Comprehensive analysis of mRNA expression of immuno-checkpoint molecules in the tumors was performed using PanCancer Immune Profiling Panel (NanoString Technologies). Results: CD4+ T cells and/or CD8+ T cells were depleted in the subcutaneously transplanted tumor model followed by treatment with gefitinib (50 mg/kg/day, 5 days/week) for 2 weeks. As a result, after gefitinib discontinuation, rapid regrowth was seen in the tumors from groups with depletion of CD8+ T cells; depletion of CD4+ T cells had little effect on tumor regrowth, and tumor inhibition continued for 2 weeks after cessation of gefitinib. IHC showed relatively increased numbers of CD4+ T cells in the mice tumors whereas a decrease in the number of CD8+ T cells or Foxp3 positive cells was noted. PD-L1 expression was not observed in the tumors. Consistently, 4H2 showed little effect on tumor growth in vivo. The cancer immune panel showed increased expression of immune mediators such as Ccl6, Clec4n, and Lcn2. Conclusions: Our results suggest that CD8+ T cells can recognize mice tumors in vivo. New immuno-checkpoint molecules regulating CD8+ T cells from PanCancer Immune Profiling Panel were evaluated. Further, we plan to evaluate the efficacy of various immuno-checkpoint inhibitors in vivo. Citation Format: Kazuya Nishii, Kadoaki Ohashi, Kiichiro Ninomiya, Go Makimoto, Hiromi Watanabe, Hirohisa Kano, Naofumi Hara, Heiichiro Udono, Katsuyuki Kiura. Tumor immunoediting in a lung cancer mouse model harboring EGFR mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 582.

An 81-year-old woman visited a local clinic due to chest pain and a skin induration on the right precordia. She had a history of right breast cancer, and she had undergone a mastectomy and radiation therapy 10 years prior. Computed tomography (CT) imaging of the chest demonstrated a lobular mass that involved the right anterior thoracic wall and partially extruded from the thoracic cavity into the subcutaneous tissue. The tumor was surgically excised, and pathological analyses yielded a diagnosis of angiosarcoma. Five months after the operation, CT imaging showed multiple masses on the right pleura, indicating a local relapse and pleural dissemination of the angiosarcoma. Systemic chemotherapy composed of nanoparticle albumin-bound paclitaxel (nab-PTX) (80 mg/m(2)) was delivered weekly. After 4 courses of chemotherapy, the tumors regressed remarkably. Nab-PTX may be an effective treatment option for recurrent or metastatic angiosarcoma.

The Rapid Appearance and Disappearance of Dendriform Pulmonary Ossification after Diffuse Alveolar Hemorrhage Tomoko Yamagishi, Nobukazu Fujimoto, Yosuke Miyamoto, Naofumi Hara, Michiko Asano, Yasuko Fuchimoto, Sae Wada, Kenichi Kitamura, Shinji Ozaki, Hideyuki Nishi, and Takumi Kishimoto Department of Respiratory Medicine, Department of Medical Oncology, Department of Surgery, and Department of Internal Medicine, Okayama Rosai Hospital, Okayama, Japan