Publications by authors named "Hiroshi Isobe"

75 Publications

Prognostic factors in patients with advanced non-small cell lung cancer after long-term Anti-PD-1 therapy (HOT1902).

Lung Cancer 2021 Apr 15;156:12-19. Epub 2021 Apr 15.

Department of Respiratory Medicine, KKR Sapporo Medical Center, Sapporo, Japan.

Objectives: Limited information is available on the appropriate treatment duration of immune checkpoint inhibitors (ICIs). We aimed to identify candidates who would benefit from ICI discontinuation after one year of treatment for metastatic non-small cell lung cancer (NSCLC).

Materials And Methods: This retrospective multi-institutional observational study examined medical records of all consecutive patients with advanced or recurrent NSCLC, who started ICI monotherapy at 15 institutions in Japan between December 2015 and December 2017. Patients who received initial ICI therapy for >1 year without progressive disease were defined as the long-term treatment (LT) group; others were defined as the non-long-term treatment (NLT) group. Primary outcomes included the prognostic factors in the LT group, whereas secondary outcomes included efficacy of ICI rechallenge, safety, and survival outcomes in the overall population.

Results: In total, 676 patients were enrolled, and 114 (16.9 %) were assigned to the LT group. The median time interval from the start of initial ICI administration to data cutoff was 34.3 months (range, 24.1-47.8); thus, all surviving patients were followed-up for at least 2 years from the start of initial ICI. Median progression-free survival (PFS) was longer in the LT than in the NLT group (33.6 months vs. 2.7 months; p < 0.001). On multivariate analysis, significantly better PFS was associated with smoking (hazard ratio [HR]=0.36, p = 0.04), and complete response (CR; HR=uncomputable, p < 0.001) in the LT group. Thirty-seven patients (5.5 %) received ICI rechallenge, including 10 in the LT group. Among patients receiving rechallenge treatment, the median PFS was 2.2 months, with no difference between the LT and NLT groups.

Conclusions: In the LT group, smoking and achieving CR were significantly associated with better PFS. Since rechallenge treatment was not effective, careful consideration is required for discontinuing ICI. However, these prognostic factors are helpful in considering candidates for ICI discontinuation.

Trial Registration: UMIN ID, UMIN000041403.
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http://dx.doi.org/10.1016/j.lungcan.2021.04.011DOI Listing
April 2021

Delta-like 1 homolog (DLK1) as a possible therapeutic target and its application to radioimmunotherapy using I-labelled anti-DLK1 antibody in lung cancer models (HOT1801 and FIGHT004).

Lung Cancer 2021 03 14;153:134-142. Epub 2021 Jan 14.

Department of Respiratory Disease, Sapporo City General Hospital, Sapporo, Japan.

Objectives: Delta-like 1 homolog (DLK1) is a non-canonical Notch ligand known to be expressed in several cancers but whose role in lung cancer is not yet fully understood. We sought to confirm DLK1 expression in small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC), and to examine DLK1's clinical significance. Furthermore, we examined the possible utility of DLK1 as a novel target in radioimmunotherapy (RIT).

Methods: We retrospectively assessed the correlation between clinical features and DLK1 expression by immunohistochemistry in resected specimens from 112 patients with SCLC and 101 patients with NSCLC. Moreover, we performed cell and animal experiments, and examined the possibility of RIT targeting DLK1 in SCLC using iodine-125 (I) -labeled anti-DLK1 antibody, knowing that I can be replaced with the alpha-particle-emitter astatine-211 (At).

Results: In SCLC and NSCLC, 20.5 % (23/112) and 16.8 % (17/101) of patients (respectively) had DLK1-positive tumors. In NSCLC, DLK1 expression was associated with recurrence-free survival (P < 0.01) but not with overall survival. In SCLC, there was no association between DLK1 expression and survival. In addition, I-labeled anti-DLK1 antibody specifically targeted DLK1 on human SCLC tumor cell lines. Furthermore, I-labeled anti-DLK1 antibody was incorporated into tumor tissue in a mouse model.

Conclusion: A proportion of SCLC and NSCLC exhibits DLK1 expression. As a clinical feature, DLK1 expression could be a promising prognostic factor for recurrence in patients with resected NSCLC. In addition, DLK1 could serve as a new therapeutic target, including RIT, as suggested by our pilot study using a radiolabeled anti-DLK1 antibody in SCLC.
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http://dx.doi.org/10.1016/j.lungcan.2021.01.014DOI Listing
March 2021

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

Jpn J Clin Oncol 2021 Jan;51(1):106-113

Thoracic Center, St. Luke's International Hospital, Tokyo, Japan.

Background: Two phase II studies in Japan examined the efficacy and safety of nivolumab, a programmed cell death 1 receptor inhibitor, in patients with advanced squamous and non-squamous non-small cell lung cancer (ONO-4538-05 and ONO-4538-06). We examined the long-term efficacy and safety of nivolumab in these patients treated for up to 5 years.

Methods: Patients with squamous (N = 35) or non-squamous (N = 76) non-small cell lung cancer received nivolumab (3 mg/kg every 2 weeks) until disease progression/death. Overall survival and progression-free survival were assessed at 5 years after starting treatment in separate and pooled analyses. Safety was evaluated in terms of treatment-related adverse events.

Results: A total of 17 patients were alive at the database lock (26 July 2019). The median overall survival (95% confidence interval) and 5-year survival rate were 16.3 (12.4-25.2) months and 14.3% in squamous patients, 17.1 (13.3-23.0) months and 19.4% in non-squamous patients and 17.1 (14.2-20.6) months and 17.8% in the pooled analysis, respectively. Programmed death ligand-1 expression tended to be greater among 5-year survivors than in non-survivors (P = 0.0703). Overall survival prolonged with increasing programmed death ligand-1 expression, with 5-year survival rates of 11.8, 21.8 and 41.7% in patients with programmed death ligand-1 expression of <1, ≥1-<50 and ≥50%, respectively. Treatment-related adverse events in ≥10% of patients (pooled analysis) included rash (15.3%), malaise (14.4%), decreased appetite (14.4%), pyrexia (14.4%) and nausea (10.8%).

Conclusions: Long-term survival with nivolumab was observed in patients with squamous or non-squamous non-small cell lung cancer. No new safety signals were reported after ≥5 years of follow-up.
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http://dx.doi.org/10.1093/jjco/hyaa157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7767981PMC
January 2021

Detection of somatic mutation in surgically resected small-cell lung cancer by targeted exome sequencing: association with longer relapse-free survival.

Heliyon 2020 Jul 13;6(7):e04439. Epub 2020 Jul 13.

Department of Medical Oncology, KKR Sapporo Medical Center, Sapporo 062-0931, Japan.

Objectives: Few reports have explored clinical biomarkers, including those identified by targeted exome sequencing (TES) of surgically resected small-cell lung cancer (SCLC) and correlation with patient survival.

Patients And Methods: We collected formalin-fixed paraffin-embedded tumor samples from 127 patients with SCLC who had undergone surgery and analysed nonsynonymous somatic gene mutation profiles by TES of 26 cancer-related genes using next-generation sequencing (NGS) and web databases (UMIN Registration No. 000010117).

Results: We detected 38 nonsynonymous somatic () mutations in 43 (54.4%) patients. Among these lesions, we identified clinically relevant mutations including those encoding Y220C, R248W, R249M, M237I, and R273L substitutions in the p53 protein. These mutations have been reported to be associated with certain clinical outcomes or biology in other types of malignancies but not in SCLC. Moreover, nonsynonymous somatic mutations of were positively associated with relapse-free survival (RFS) (median, 17.33 months [95% confidence interval (CI), 3.86-30.79] in a mutation-positive group vs 10.39 months (6.96-13.82) in a mutation-negative group, p = 0.042). Multivariate analysis revealed that nonsynonymous somatic mutation was an independent factor of prolongation of RFS (hazard ratio: 0.51, 95% CI: 0.29-0.89, p = 0.019) but not overall survival (OS).

Conclusion: These data suggested that TES may play a critical role for promoting reverse-translational studies, including investigations of the biology of mutations in different stages of SCLC. Accumulation of the data using cancer panels with a broader range of genes, including , is expected to be useful for future clinical applications for patients with SCLC.
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http://dx.doi.org/10.1016/j.heliyon.2020.e04439DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7358392PMC
July 2020

A randomized phase II trial of cisplatin plus gemcitabine versus carboplatin plus gemcitabine in patients with completely resected non-small cell lung cancer: Hokkaido Lung Cancer Clinical Study Group Trial (HOT0703).

Cancer Chemother Pharmacol 2020 07 20;86(1):117-127. Epub 2020 Jun 20.

First Department of Medicine, Hokkaido University Hospital, Sapporo, Japan.

Purpose: This study evaluated the efficacy and safety of platinum plus gemcitabine (P/G) combinations as postoperative adjuvant chemotherapies for non-small cell lung cancer.

Methods: Patients with postoperative stage IB-IIIA non-small cell lung cancer were randomly assigned to receive either cisplatin plus gemcitabine (GP arm) or carboplatin plus gemcitabine (GC arm) every 3 weeks for four cycles. The primary endpoint was 2-year disease-free survival (DFS). Secondary endpoints were safety, feasibility, overall survival (OS), and biomarker analyses.

Results: A total of 102 patients were randomized (stage IB, 22%; II, 36%; IIIA, 42%; histology: 74% adenocarcinoma). Of the 51 patients in each arm, 37 (73%) completed 4 cycles. During follow-up (median 5.8 years; range 0.1-9.7 years), estimated DFS and OS rates at 2 years were 59.6% and 86.3% with GP and 68.0% and 86.3% with GC, respectively. No significant difference in DFS was noted between arms (P = 0.163), although 3-, 4-, and 5-year DFS rates were higher with GC. Hematological toxic effects were comparable and non-hematological toxic effects were infrequent. DFS was significantly higher in the excision repair cross-complementation group 1 (ERCC1)-low group than in the ERCC1-high group for the GP arm (P = 0.045).

Conclusion: Both P/G combination regimens were feasible and well-tolerated, and thus may represent valid options for postoperative adjuvant treatment of non-small cell lung cancer. Although no significant differences in DFS were evident between regimens, the present data favor the adoption of GC for further evaluation.

Clinical Trial Registration: UMIN-CTR ( https://www.umin.ac.jp/ctr/ ) identifier: UMIN000000913.
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http://dx.doi.org/10.1007/s00280-020-04104-1DOI Listing
July 2020

A prospective phase II study of carboplatin and nab-paclitaxel in patients with advanced non-small cell lung cancer and concomitant interstitial lung disease (HOT1302).

Lung Cancer 2019 12 30;138:65-71. Epub 2019 Sep 30.

Department of Respiratory Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.

Objectives: Patients with concomitant advanced non-small cell lung cancer (NSCLC) and interstitial lung disease (ILD) are excluded from most clinical chemotherapy trials because of the high risk of exacerbating the latter condition. This study prospectively investigated the efficacy and safety of albumin-bound paclitaxel (nab-paclitaxel) in combination with carboplatin in patients with both advanced NSCLC and ILD.

Patients And Methods: The enrolled patients had treatment-naïve, advanced NSCLC with ILD. Patients received 100 mg/mnab-paclitaxel weekly and carboplatin at an area under the concentration-time curve of 6 once every 3 weeks for 4-6 cycles. The primary endpoint was the overall response rate (ORR); secondary endpoints included toxicity, progression-free survival (PFS), and overall survival (OS).

Results: Thirty-six patients were enrolled between April 2014 and September 2017. Sixteen patients (44.4%) had adenocarcinoma, 15 (41.7%) had squamous cell carcinoma (Sq), and 5 (13.9%) had non-small cell carcinoma. The median number of cycles administered were 4 (range: 1-6). The ORR was 55.6% (95% confidence interval [CI]: 39.6-70.5). The median PFS and OS were 5.3 months (95% CI: 3.9-8.2) and 15.4 months (95% CI: 9.4-18.7), respectively. A greater proportion of patients with Sq experienced improvements than did those with non-Sq: ORRs, 66.7% (95% CI: 41.7-84.8) vs. 47.6% (95% CI: 28.3-67.6) (P = 0.254); median PFS, 8.2 months (95% CI: 4.0-10.2) vs. 4.1 months (95% CI: 3.3-5.4) (HR, 0.60 [95% CI, 0.30-1.20]; P = 0.15); and median OS, 16.8 months (95% CI: 9.8-not reached) vs. 11.9 months (95% CI: 7.3-17.4) (HR, 0.56 [95% CI, 0.24-1.28]; P = 0.17). Two patients (5.6%) experienced grade ≥2 pneumonitis and 1 patient (2.8%) died.

Conclusion: Weekly nab-paclitaxel combined with carboplatin showed favorable efficacy with acceptable toxicity in patients with both advanced NSCLC and ILD.
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http://dx.doi.org/10.1016/j.lungcan.2019.09.020DOI Listing
December 2019

An oxyl/oxo mechanism for oxygen-oxygen coupling in PSII revealed by an x-ray free-electron laser.

Science 2019 10 17;366(6463):334-338. Epub 2019 Oct 17.

Research Institute for Interdisciplinary Science and Graduate School of Natural Science and Technology, Okayama University, 3-1-1 Tsushima Naka, Okayama 700-8530, Japan.

Photosynthetic water oxidation is catalyzed by the MnCaO cluster of photosystem II (PSII) with linear progression through five S-state intermediates (S to S). To reveal the mechanism of water oxidation, we analyzed structures of PSII in the S, S, and S states by x-ray free-electron laser serial crystallography. No insertion of water was found in S, but flipping of D1 Glu upon transition to S leads to the opening of a water channel and provides a space for incorporation of an additional oxygen ligand, resulting in an open cubane MnCaO cluster with an oxyl/oxo bridge. Structural changes of PSII between the different S states reveal cooperative action of substrate water access, proton release, and dioxygen formation in photosynthetic water oxidation.
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http://dx.doi.org/10.1126/science.aax6998DOI Listing
October 2019

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

Cancer Med 2019 Sep 29;8(11):5183-5193. Epub 2019 Jul 29.

Thoracic Center, St. Luke's International Hospital, Tokyo, Japan.

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.
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http://dx.doi.org/10.1002/cam4.2411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6718542PMC
September 2019

Phase II trial of S-1 plus cisplatin combined with bevacizumab for advanced non-squamous non-small cell lung cancer (TCOG LC-1202).

Jpn J Clin Oncol 2019 Aug;49(8):749-754

Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo.

Background: S-1 plus cisplatin is a standard chemotherapy regimen for advanced non-small cell lung cancer (NSCLC). The addition of bevacizumab has been shown to significantly improve overall survival (OS) in patients with advanced non-squamous (NSq) NSCLC who received carboplatin plus paclitaxel, however, failed to show an OS advantage in patients who received cisplatin plus gemcitabine.

Methods: Chemotherapy-naive patients with Stage IIIB, IV or recurrent non-SQ NSCLC were treated with a 3-week cycle of S-1 80 mg/m2 on days 1-14, cisplatin 60 mg/m2 on day 8 and bevacizumab 15 mg/kg on day 8 for 4-6 cycles. Patients without progressive disease (PD) received maintenance bevacizumab 15 mg/kg on day 1 with a 3-week cycle and S-1 80 mg/m2 every other day. The primary endpoint was progression-free survival (PFS). Secondary endpoints were objective response rate (ORR), OS, toxicity profile and Quality of life (QOL).

Results: From June 2013 to January 2015, 39 eligible patients were enrolled from eight institutions. Thirty-one patients (79%) completed four cycles of induction chemotherapy, and maintenance chemotherapy was initiated in 23 patients (59%). Median PFS, OS and ORR were 7.3 months (95% CI: 5.9-8.7), 21.4 months (95% CI: 14.7-not reached) and 64%, respectively. The most common grade 3/4 toxicities were leukopenia (12.8%), neutropenia (23.0%) and hypertension (28.2%). QOL analyses showed detrimental effects after initiation of the regimen.

Conclusions: S-1 plus cisplatin in combination with bevacizumab met the primary endpoint in patients with advanced NSq-NSCLC. RR was anticipated to be high with acceptable toxicities.
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http://dx.doi.org/10.1093/jjco/hyz064DOI Listing
August 2019

Analysis of DLL3 and ASCL1 in Surgically Resected Small Cell Lung Cancer (HOT1702).

Oncologist 2019 11 8;24(11):e1172-e1179. Epub 2019 May 8.

Department of Medical Oncology, KKR Sapporo Medical Center, Sapporo, Japan.

Background: Delta-like protein 3 (DLL3) is a Notch ligand that has an important role in the tumorigenesis of small cell lung cancer (SCLC). Recently, rovalpituzumab tesirine (Rova-T), a DLL3-targeted antibody-drug conjugate, has been developed for treating SCLC. DLL3 is a transcriptional target of the achaete-scute homolog-1 (ASCL1) transcription factor, which is involved in pulmonary neuroendocrine cell development. However, the relationship between DLL3 and/or ASCL1 expression and the clinical features of SCLC remains unknown, especially for early-stage resected SCLC. This study aimed to investigate the expression of DLL3 and ASCL1 in resected SCLC samples using immunohistochemical analysis.

Materials And Methods: We collected 95 surgically resected SCLC samples, which were formalin fixed and paraffin embedded. Immunohistochemistry staining was performed to investigate the correlation between the expression of either DLL3 or ASCL1 and clinicopathological features of study patients.

Results: Seventy-seven (83%) of 93 immunohistochemically evaluable samples were positive for DLL3 (expression in ≥1% of tumor cells), and DLL3-high expression (≥75%) was observed in 44 samples (47%). Sixty-one (64%) of 95 samples were positive for ASCL1 (expression in ≥5% of tumor cells). A positive correlation was observed between DLL3 and ASCL1 expression. DLL3 and ASCL1 expression were not associated with survival in SCLC patients. DLL3 was more prevalent in patients with advanced clinical disease.

Conclusion: DLL3 and ASCL1 were highly expressed in patients with surgically resected SCLC. DLL3 and ASCL1 may be targets for the treatment of SCLC.

Implications For Practice: This article examines the relationship between delta-like protein 3 (DLL3) and achaete-scute homolog-1 (ASCL1) protein expression with the clinical features of 95 surgically resected small cell lung cancer (SCLC). DLL3 is attracting attention because rovalpituzumab tesirine (Rova-T), a DLL3-targeted antibody-drug conjugate, was developed recently. DLL3 and ASCL1 were highly expressed in patients with surgically resected SCLC. DLL3 and ASCL1 may be targets for the treatment of early-stage SCLC, including with Rova-T.
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http://dx.doi.org/10.1634/theoncologist.2018-0676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6853124PMC
November 2019

Spin, Valence, and Structural Isomerism in the S State of the Oxygen-Evolving Complex of Photosystem II as a Manifestation of Multimetallic Cooperativity.

J Chem Theory Comput 2019 Apr 11;15(4):2375-2391. Epub 2019 Mar 11.

Institute for NanoScience Design , Osaka University , Toyonaka , Osaka 560-0043 , Japan.

Photosynthetic water oxidation is catalyzed by a MnCaO-cluster in photosystem II through an S-state cycle. Understanding the roles of heterogeneity in each S-state, as identified recently by the EPR spectroscopy, is very important to gain a complete description of the catalytic mechanism. We performed herein hybrid DFT calculations within the broken-symmetry formalism and associated analyses of Heisenberg spin models to study the electronic and spin structures of various isomeric structural motifs (hydroxo-oxo, oxyl-oxo, peroxo, and superoxo species) in the S state. Our extensive study reveals several factors that affect the spin ground state: (1) (formal) Mn oxidation state; (2) metal-ligand covalency; (3) coordination geometry; and (4) structural change of the Mn cluster induced by alternations in Mn···Mn distances. Some combination of these effects could selectively stabilize/destabilize some spin states. We found that the high spin state ( S = 6) of the oxyl-oxo species can be causative for catalytic function, which manifests through mixing of the metal-ligand character in magnetic orbitals at relatively short O5···O6 distances (<2.0 Å) and long Mn···O5 distances (>2.0 Å). These results will serve as a basis to conceptually identify and rationalize the physicochemical synergisms that can be evoked by the unique "distorted chair" topology of the cluster through cooperative Jahn-Teller effects on multimetallic centers.
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http://dx.doi.org/10.1021/acs.jctc.8b01055DOI Listing
April 2019

Theoretical and computational investigations of geometrical, electronic and spin structures of the CaMn O (X = 5, 6) cluster in the Kok cycle S (i = 0-3) of oxygen evolving complex of photosystem II.

Physiol Plant 2019 May 4;166(1):44-59. Epub 2019 Apr 4.

Department of Chemistry, Graduate School of Science, Osaka University, Suita, Osaka 560-0043, Japan.

The optimized geometries of the CaMn O (X = 5, 6) cluster in the oxygen evolving complex (OEC) of photosystem II (PSII) by large-scale quantum mechanics (QM) and molecular mechanics (MM) calculations are compared with recent serial femtosecond crystallography (SFX) results for the S (i = 0-3) states. The valence states of four Mn ions by the QM/MM calculations are also examined in relation to the experimental results by the X-ray emission spectroscopy (XES) for the S intermediates. Geometrical and valence structures of right-opened Mn-hydroxide, Mn-oxo and Mn-peroxide intermediates in the S state are investigated in detail in relation to recent SFX and XES experiments for the S state. Interplay between theory and experiment indicates that the Mn-oxo intermediate is a new possible candidate for the S state. Implications of the computational results are discussed in relation to possible mechanisms of the oxygenoxygen bond formation for water oxidation in OEC of PSII.
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http://dx.doi.org/10.1111/ppl.12960DOI Listing
May 2019

Synthesis of Pd-Fe System Alloy Nanoparticles by Pulsed Plasma in Liquid.

Nanomaterials (Basel) 2018 Dec 18;8(12). Epub 2018 Dec 18.

Faculty of Science, Kumamoto University, Kumamoto 860-0862, Japan.

We synthesized Pd-Fe series nanoparticles in solid solution using pulsed plasma in liquid with Pd-Fe bulk mixture electrodes. The Pd-Fe atomic percent ratios were 1:3, 1:1, and 3:1, and the particle size was measured to be less than 10 nm by high-resolution transmission electron microscopy (HR-TEM). The nanoparticles showed face-centered cubic structure. The lattice parameter increased with increasing Pd content and followed Vegard's law, and energy-dispersive X-ray spectra were consistent with the ratios of the starting samples, which showed a solid solution state. The solid solution structure and local structure were confirmed by HR-TEM and X-ray absorption fine structure.
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http://dx.doi.org/10.3390/nano8121068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6315479PMC
December 2018

Molecular testing and treatment patterns for patients with advanced non-small cell lung cancer: PIvOTAL observational study.

PLoS One 2018 27;13(8):e0202865. Epub 2018 Aug 27.

Hospital Universitario La Paz (IDIPAZ), Madrid, Spain.

Background: The goals of this multinational retrospective study were to describe treatment patterns and survival outcomes by receipt of molecular testing and molecular status of patients with advanced non-small cell lung cancer (NSCLC).

Methods: This chart review study, conducted in Italy, Spain, Germany, Australia, Japan, Korea, Taiwan, and Brazil, included 1440 patients with newly diagnosed advanced (stage IIIB/IV) NSCLC initiating systemic therapy from January 2011 through June 2013, with follow-up until July 2016. We evaluated treatment patterns and survival by histology, line of therapy, molecular testing, and test results for epidermal growth factor receptor (EGFR) mutation and/or anaplastic lymphoma kinase (ALK) rearrangement. Country-specific data were analyzed descriptively and presented as ranges (lowest to highest country). Overall survival (OS) was estimated using Kaplan-Meier method.

Results: Patients with ≥1 molecular test varied from 43% (Brazil) to 85% (Taiwan). Numerically greater proportions of patients who were female, Asian, or never/former-smokers, and those with nonsquamous histology or stage-IV NSCLC, received a test. Testing was common for nonsquamous NSCLC (54%, Brazil, to 91%, Taiwan), with positive EGFR and ALK tests from 17% (Brazil and Spain) to 67% (Taiwan) and from 0% (Brazil) to 60% (Taiwan), respectively. First-line treatment regimens for nonsquamous NSCLC with positive EGFR/ALK tests included targeted therapy for 30% (Germany) to 89% (Japan); with negative/inconclusive test results, platinum-based combinations for 88% (Japan) to 98% (Brazil); and if not tested, platinum-based combinations for 80% (Australia) to 95% (Japan), except in Taiwan, where 44% received single agents. Median OS from first-line therapy initiation was 10.0 (Japan) to 26.7 (Taiwan) months for those tested and 7.6 (Australia/Brazil) to 19.3 (Taiwan) months for those not tested.

Conclusions: We observed substantial variation among countries in testing percentages, treatment patterns, and survival outcomes. Efforts to optimize molecular testing rates should be implemented in the context of each country's health care scenario.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0202865PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6110501PMC
February 2019

A phase II study of carboplatin, pemetrexed, and bevacizumab followed by erlotinib and bevacizumab maintenance for non-squamous non-small cell lung cancer with wild-type EGFR (HOT1101).

Int J Clin Oncol 2018 Dec 19;23(6):1060-1069. Epub 2018 Jul 19.

First Department of Medicine, Hokkaido University Hospital, North 15, West 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan.

Background: This study evaluated the efficacy and safety of switch maintenance erlotinib and bevacizumab after induction therapy with carboplatin/pemetrexed/bevacizumab for non-squamous non-small cell lung cancer (NSCLC) with wild-type EGFR.

Methods: Enrolled patients had treatment-naïve, advanced non-squamous NSCLC with wild-type EGFR. Carboplatin [area under the curve (AUC) 5.0], pemetrexed (500 mg/m2) and bevacizumab (15 mg/kg) were administered on day 1 every 3 weeks for 4-6 cycles. Maintenance therapy with erlotinib (150 mg/body) on day 1 through 21 plus bevacizumab on day 1 every 3 weeks was continued until disease progression or unacceptable toxicity. The primary endpoint was 6-month progression-free survival (PFS); secondary endpoints included overall survival (OS), overall response rate (ORR), toxicity, and quality of life (QOL).

Results: Fifty-one patients were enrolled between September 2011 and June 2014. The median number of cycles for induction and maintenance therapy was 4 (range 1-6) and 4 (range 1-20). Twenty-nine patients (58%) received maintenance therapy. The 6-month PFS rate was 59.5% [95% confidence interval (CI) 45.0-72.6%]. The ORR was 48.0% (95% CI 34.8-61.5%), and disease control rate was 86.0% (95% CI 73.8-93.0%). The median PFS and OS were 6.5 months (95% CI 5.8-7.2 months) and 21.4 months (95% CI 15.9-26.9 months), respectively. Although grades ≥ 3 adverse events were observed in 33 patients (66.0%), most were hematologic; there was no febrile neutropenia. QOL was maintained throughout treatment.

Conclusions: Carboplatin/pemetrexed/bevacizumab followed by erlotinib and bevacizumab maintenance showed modest efficacy and was well tolerated in non-squamous NSCLC patients with wild-type EGFR.

Trial Registration: UMIN000005872.
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http://dx.doi.org/10.1007/s10147-018-1318-zDOI Listing
December 2018

Characteristics and outcomes of patients with EGFR-mutation positive non-small-cell lung cancer receiving gefitinib beyond radiological progression.

Expert Opin Pharmacother 2018 Jul 21;19(10):1049-1056. Epub 2018 Jun 21.

r Department of Medical Oncology , Japanese Red Cross Medical Center , Tokyo , Japan.

Background: This study aimed to analyze the characteristics and outcomes of patients suffering from non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor mutations (EGFRm+) receiving gefitinib who remained clinically stable following confirmation of progressive disease (PD) using Response Evaluation Criteria in Solid Tumors (RECIST) (R-PD) and identify those who benefited from tyrosine kinase inhibitor therapy beyond PD.

Research Design And Methods: The clinical courses of patients with EGFRm+ advanced NSCLC who received first-line gefitinib were investigated. Clinical PD (C-PD) was defined as one or more of the following: (1) symptomatic PD, (2) worsening performance status resulting from PD, (3) threat to a major organ(s), or (4) unequivocal multiorgan PD.

Results: Of 529 patients, 258 experienced R-PD without C-PD. Among 258 patients, 91 received gefitinib beyond R-PD. Females were more likely to receive gefitinib beyond R-PD and exhibit a longer time from R-PD to C-PD than males (median days, 175 vs. 79.5). Survival beyond R-PD tended to be longer for elderly patients who received gefitinib beyond PD than for those who did not (median days, 458 vs. 336), but this was not the case for non-elderly patients (median days, 481 vs. 487).

Conclusions: Some patients may benefit from continuation of gefitinib beyond PD.
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http://dx.doi.org/10.1080/14656566.2018.1484903DOI Listing
July 2018

Concerted Mechanism of Water Insertion and O Release during the S to S Transition of the Oxygen-Evolving Complex in Photosystem II.

J Phys Chem B 2018 06 15;122(25):6491-6502. Epub 2018 Jun 15.

Institute for NanoScience Design , Osaka University , Toyonaka , Osaka 560-0043 , Japan.

The O release of the oxygen-evolving complex of the photosystem II (PSII) is one of the essential processes responsible for the highly efficient O production. Despite its importance, the detailed molecular mechanism is still unsolved. In the present study, we show that the O release is directly coupled with water insertion into the Mn cluster based on the quantum mechanics/molecular mechanics (QM/MM) calculations. In this mechanism, the O molecule first dissociates from the Mn sites in order, that is, the O atom coordinating to the Mn3 (O5a) first dissociates, then the other O atom coordinating to the Mn1 (O5d) dissociates in the next step in the late S state (1 → 2). Next, the O migrates to a space surrounded by the Val185 and His332 side chains as one water molecule coordinating to the Ca ion (W3) comes into the O bonded site (2 → 3). Finally, a pre-S state (4) is formed after a proton transfer from the inserted water to the other proton acceptor site (W2) (3 → 4). The highest activation barrier during these reactions was found at the O release step (2 → 3) that only requires E = 12.7 kcal mol ( G = 10.4 kcal mol). A series of the reactions (2 → 3) look like a chain crash of billiard balls because the W3 is inserted into the catalytic center from the water-abundant side (Ca ion side), and then the O moiety is pushed out to the opposite side (Val185 side). The hydrophobic residue of Val185 covers the active O5 site and forms an O-specific permeation tunnel. The present sequential reactions clearly demonstrate the efficient removal of the toxic O from the catalytic center and implications of the essential roles of Val185, Ca ions and water molecules, which are all present in the active site of PSII as the indispensable constituents.
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http://dx.doi.org/10.1021/acs.jpcb.8b03465DOI Listing
June 2018

Understanding Two Different Structures in the Dark Stable State of the Oxygen-Evolving Complex of Photosystem II: Applicability of the Jahn-Teller Deformation Formula.

ChemPhotoChem 2018 03 27;2(3):257-270. Epub 2017 Dec 27.

Riken Advanced Institute for Computational Science, Chuo-Ku Kobe, Hyogo 650-0047Japan.

Tanaka et al. (., , , 1718) recently reported the three-dimensional (3D) structure of the oxygen evolving complex (OEC) of photosystem II (PSII) by X-ray diffraction (XRD) using extremely low X-ray doses of 0.03 and 0.12 MGy. They observed two different 3D structures of the CaMnO cluster with different hydrogen-bonding interactions in the S state of OEC keeping the surrounding polypeptide frameworks of PSII the same. Our Jahn-Teller (JT) deformation formula based on large-scale quantum mechanics/molecular mechanics (QM/MM) was applied for these low-dose XRD structures, elucidating important roles of JT effects of the Mn ion for subtle geometric distortions of the CaMnO cluster in OEC of PSII. The JT deformation formula revealed the similarity between the low-dose XRD and damage-free serial femtosecond X-ray diffraction (SFX) structures of the CaMnO cluster in the dark stable state. The extremely low-dose XRD structures were not damaged by X-ray irradiation. Implications of the present results are discussed in relation to recent SFX results and a blue print for the design of artificial photocatalysts for water oxidation.
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http://dx.doi.org/10.1002/cptc.201700162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5861676PMC
March 2018

Updated survival outcomes of NEJ005/TCOG0902: a randomised phase II study of concurrent versus sequential alternating gefitinib and chemotherapy in previously untreated non-small cell lung cancer with sensitive mutations.

ESMO Open 2018 23;3(2):e000313. Epub 2018 Feb 23.

Japan Anti-Tuberculosis Association, Tokyo, Japan.

Background: The North-East Japan Study Group (NEJ) 005/Tokyo Cooperative Oncology Group (TCOG) 0902 study has reported that first-line concurrent and sequential alternating combination therapies of an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (gefitinib) plus platinum-based doublet chemotherapy (carboplatin/pemetrexed) offer promising efficacy with predictable toxicities for patients with -mutant non-small cell lung cancer. However, overall survival (OS) data were insufficient in the primary report because of the lack of death events.

Patients And Methods: Progression-free survival (PFS) and OS were re-evaluated at the final data cut-off point (March 2017) for the entire population (n=80).

Results: At the median follow-up time of 35.6 months, 88.8% of patients had progressive disease and 77.5% of patients had died. Median PFS was 17.5 months for the concurrent regimen and 15.3 months for the sequential alternating regimen (P=0.13). Median OS was 41.9 and 30.7 months, respectively (P=0.036). Updated response rates were similar in both groups (90.2% and 82.1%, respectively; P=0.34). Patients with Del19 tumours displayed relatively better OS (median: 45.3 vs 33.3 months, respectively) than those with L858R (31.4 vs 28.9 months, respectively). No severe adverse events, including interstitial lung disease, occurred in the period since the primary report.

Conclusions: This updated analysis confirms that PFS is improved with first-line combination therapy compared with gefitinib monotherapy and that the concurrent regimen, in particular, offers an OS benefit of 42 months in the -mutated setting. Our ongoing NEJ009 study will clarify whether this combination strategy can be incorporated into routine clinical practice.

Trial Registration Number: UMIN C000002789, Post-results.
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http://dx.doi.org/10.1136/esmoopen-2017-000313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5844373PMC
February 2018

Health care resource use among patients with advanced non-small cell lung cancer: the PIvOTAL retrospective observational study.

BMC Health Serv Res 2018 03 1;18(1):147. Epub 2018 Mar 1.

Medical Oncology Service, Hospital Universitario La Paz (IDIPAZ), Madrid, Spain.

Background: Data are scarce regarding real-world health care resource use (HCRU) for non-small cell lung cancer (NSCLC). An understanding of current clinical practices and HCRU is needed to provide a benchmark for rapidly evolving NSCLC management recommendations and therapeutic options. The objective of this study was to describe real-world HCRU for patients with advanced NSCLC.

Methods: This multinational, retrospective chart review study was conducted at academic and community oncology sites in Italy, Spain, Germany, Australia, Japan, South Korea, Taiwan, and Brazil. Deidentified data were drawn from medical records of 1440 adults (≥18 years old) who initiated systemic therapy (2011 to mid-2013) for a new, confirmed diagnosis of advanced or metastatic (stage IIIB or IV) NSCLC. We summarized HCRU associated with first and subsequent lines of systemic therapy for advanced/metastatic NSCLC.

Results: The proportion of patients who were hospitalized at least once varied by country from 24% in Italy to 81% in Japan during first-line therapy and from 22% in Italy to 84% in Japan during second-line therapy; overall hospitalization frequency was 2.5-11.1 per 100 patient-weeks, depending on country. Emergency visit frequency also varied among countries (overall from 0.3-5.9 per 100 patient-weeks), increasing consistently from first- through third-line therapy in each country. The outpatient setting was the most common setting of resource use. Most patients in the study had multiple outpatient visits in association with each line of therapy (overall from 21.1 to 59.0 outpatient visits per 100 patient-weeks, depending on country). The use of health care resources showed no regular pattern associated with results of tests for activating mutations of the epidermal growth factor receptor (EGFR) gene or anaplastic lymphoma kinase (ALK) gene rearrangements.

Conclusions: HCRU varied across countries. These findings suggest differing approaches to the clinical management of advanced NSCLC among the eight countries. Comparative findings and an understanding of country-specific clinical practices can help to identify areas of need and guide future resource allocation for patients with advanced NSCLC. Further studies evaluating the costs associated with resource use are warranted.
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http://dx.doi.org/10.1186/s12913-018-2946-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5831211PMC
March 2018

Rikkunshito for Preventing Chemotherapy-Induced Nausea and Vomiting in Lung Cancer Patients: Results from 2 Prospective, Randomized Phase 2 Trials.

Front Pharmacol 2017 16;8:972. Epub 2018 Jan 16.

First Department of Medicine, Hokkaido University Hospital, Sapporo, Japan.

The herbal medicine rikkunshito has the potential to improve chemotherapy-induced nausea and vomiting (CINV) by stimulating ghrelin secretion. We aimed to evaluate the efficacy and safety of rikkunshito in preventing CINV for patients with lung cancer. Two separate prospective, randomized, phase II parallel design studies were conducted in patients with lung cancer. Fifty-eight and sixty-two patients scheduled to receive highly emetogenic chemotherapy (HEC) and moderately emetogenic chemotherapy (MEC), respectively, were randomized 1:1 to receive either standard antiemetic therapy in accordance with international guidelines (S group) or standard antiemetic therapy plus oral rikkunshito (R group). The primary endpoint was overall complete response (CR)-that is, no emesis and rescue medication in the first 120 h post-chemotherapy. Secondary endpoints included CR in the acute (0-24 h) and delayed (>24-120 h) phases and safety. Fifty-seven patients (S group, 28; R group, 29) receiving HEC and sixty-two patients (S group, 30; R group, 32) receiving MEC with comparable characteristics were evaluated. The CR rates were similar across the S and R groups for the HEC study in the overall (67.9% vs. 62.1%), acute (96.4% vs. 89.6%), and delayed (67.9% vs. 62.1%) phases, respectively, and for the MEC study in the overall (83.3% vs. 84.4%), acute (100% vs. 100%), and delayed (83.3% vs. 84.4%) phases, respectively. No severe adverse events were observed. Although rikkunshito was well tolerated, it did not demonstrate an additional preventative effect against CINV in lung cancer patients receiving HEC or MEC. This study is registered with the University Hospital Medical Information Network (UMIN) Clinical Trial Registry, identification numbers UMIN 000014239 and UMIN 000014240.
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http://dx.doi.org/10.3389/fphar.2017.00972DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5776023PMC
January 2018

Real-world practice patterns for patients with advanced non-small cell lung cancer: multicenter retrospective cohort study in Japan.

Lung Cancer (Auckl) 2017 24;8:191-206. Epub 2017 Oct 24.

Department of Respiratory Medicine, Kanagawa Cardiovascular and Respiratory Center, Kanagawa, Japan.

Background: Recommended therapies for advanced/metastatic non-small cell lung cancer (NSCLC) have changed with the advent of targeted therapies. The objectives of this retrospective chart review study were to describe treatment patterns, biomarker testing practices, and health care resource use for advanced NSCLC at 5 sites in Japan.

Patients And Methods: We studied anonymized medical record data of patients aged ≥18 years who initiated systemic therapy for newly diagnosed stage IIIB or IV NSCLC from January 2011 through June 2013. Data were analyzed descriptively by histology and mutation status. Overall survival was estimated using the Kaplan-Meier method.

Results: We studied 175 patients, including 43 (25%), 129 (74%), and 3 (2%) with squamous, nonsquamous, and unknown NSCLC histology, respectively; 83% had stage IV NSCLC. Overall, 123 patients (70%) were male; the median age was 70 years (range, 47-86); and 33 (19%) were never-smokers. In the nonsquamous cohort, 105 (81%) and 25 (19%) of patients were tested for epidermal growth factor receptor () mutation and anaplastic lymphoma kinase () rearrangement, respectively; 44 (42%) had -positive NSCLC and 2 (8%) had -positive NSCLC, including 26/46 (57%) women and 21/46 (46%) never-smokers. In the squamous cohort, 17 (40%) and 4 (9%), respectively, were tested; 1 -positive tumor was detected. After first-line therapy, 105 (60%) patients received second-line, and 54/105 (51%; or 31% overall) received third-line therapy. tyrosine kinase inhibitors were most commonly prescribed for -positive NSCLC across all lines. In the nonsquamous /-negative/unknown cohort, most received first-line platinum combinations, particularly younger patients (78% ≥75 years vs 93% <75 years old). The average hospitalization was 21 days/admission. The median (95% CI) overall survival from start of first-line therapy was 9.9 months (7.6-11.7) for all patients and 17.9 months (9.9-24.4) for patients with /-positive status.

Conclusion: Biomarker testing is common for nonsquamous NSCLC at the 5 Japanese study sites. Treatment is personalized by mutation status and age, per guideline recommendations.
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http://dx.doi.org/10.2147/LCTT.S140491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5661576PMC
October 2017

Continuing EGFR-TKI beyond radiological progression in patients with advanced or recurrent, EGFR mutation-positive non-small-cell lung cancer: an observational study.

ESMO Open 2017 14;2(4):e000214. Epub 2017 Sep 14.

Department of Medical Oncology, Japanese Red Cross Medical Center, Tokyo, Japan.

Background: Some patients with advanced or recurrent, epidermal growth factor receptor (EGFR) mutation-positive (EGFR M+) non-small-cell lung cancer (NSCLC) continue to receive EGFR tyrosine kinase inhibitors (TKIs) beyond radiological progression.

Methods: We analysed a cohort of 577 patients with EGFR M+ NSCLC, who had received a first-line EGFR-TKI. We classified patients according to clinical course and treatment patterns at Response Evaluation Criteria in Solid Tumors (RECIST) progressive disease (PD). We evaluated the period from RECIST PD to TKI discontinuation or clinical PD and also evaluated survival after RECIST PD and compared it between groups.

Results: RECIST PD was documented in 451 cases, of which 283 (62.7%) were clinically stable. 186 (65.7%) discontinued and 97 (34.3%) continued the EGFR-TKI. In those who continued EGFR-TKI, median time between RECIST PD and clinical PD or TKI discontinuation was 5.1 months. Median survival after RECIST PD in patients who discontinued and continued EGFR-TKI after clinically stable RECIST PD was 14.6 and 15.3 months (p=0.5489), respectively. In multivariate analysis, continuing EGFR-TKI therapy, female gender, better performance status and exon 19 deletion subtype were likely positive predictive factors for survival after clinically stable RECIST PD.

Conclusion: Our study suggests that some patients could benefit from receiving an EGFR-TKI beyond radiological progression.
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http://dx.doi.org/10.1136/esmoopen-2017-000214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5604715PMC
September 2017

A randomized phase II trial of erlotinib vs. S-1 as a third- or fourth-line therapy for patients with wild-type EGFR non-small cell lung cancer (HOT1002).

Cancer Chemother Pharmacol 2017 Nov 13;80(5):955-963. Epub 2017 Sep 13.

First Department of Medicine, Hokkaido University Hospital, North 15, West 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan.

Purpose: A high proportion of patients with wild-type EGFR non-small cell lung cancer (NSCLC) receive third-line therapy and beyond, with no prospective randomized trials addressing the issue. This study aimed to select the most suitable regimen as a third- or fourth-line therapy for wild-type EGFR NSCLC.

Methods: This multicenter, randomized phase II study in Japan included patients with recurrent or advanced NSCLC with wild-type or unknown EGFR, who progressed after two or three previous chemotherapies. The patients were randomly assigned to erlotinib (150 mg/day, days 1-21) or S-1 (80-120 mg/day, days 1-14) every 3 weeks until disease progression or unacceptable toxicity. The primary endpoint was disease control rate (DCR). The secondary endpoints included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), toxicity, and quality of life (QOL).

Results: From 2011 to 2016, 37 patients were randomly assigned to receive erlotinib (E arm, n = 19) and S-1 (S arm, n = 18). This study was terminated prematurely because of poor patient accrual. DCR/ORR were 42.1%/15.8% in the E arm and 66.7%/16.7% in the S arm. Median PFS/OS were 1.6 months/8.0 months in the E arm and 3.3 months/12.2 months in the S arm. In both groups, the most commonly reported grade 3-4 toxicities were fatigue, anorexia, and nausea. One grade 5 pneumonitis occurred in the S arm. No significant difference was seen in QOL.

Conclusions: S-1 as a third- or fourth-line therapy for wild-type EGFR NSCLC showed numerically better clinical outcomes than erlotinib.

Clinical Trial Registration No: UMIN000005308.
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http://dx.doi.org/10.1007/s00280-017-3432-4DOI Listing
November 2017

Multicentre phase II study of nivolumab in Japanese patients with advanced or recurrent non-squamous non-small cell lung cancer.

ESMO Open 2016 7;1(4):e000108. Epub 2017 Mar 7.

Thoracic Center, St. Luke's International Hospital, Tokyo, Japan.

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.
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http://dx.doi.org/10.1136/esmoopen-2016-000108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5566979PMC
March 2017

Large-scale QM/MM calculations of the CaMnO cluster in the S state of the oxygen evolving complex of photosystem II. Comparison between water-inserted and no water-inserted structures.

Faraday Discuss 2017 06;198:83-106

Center for Computational Sciences, University of Tsukuba, Tennodai 1-1-1, Tsukuba, Ibaraki 305-8577, Japan.

Large-scale QM/MM calculations were performed to elucidate an optimized geometrical structure of a CaMnO cluster with and without water insertion in the S state of the oxygen evolving complex (OEC) of photosystem II (PSII). The left (L)-opened structure was found to be stable under the assumption of no hydroxide anion insertion in the S state, whereas the right (R)-opened structure became more stable if one water molecule is inserted to the MnCa cluster. The optimized Mn-Mn distance determined by QM/MM was about 5.0 Å for the S structure without an inserted hydroxide anion, but this is elongated by 0.2-0.3 Å after insertion. These computational results are discussed in relation to the possible mechanisms of O-O bond formation in water oxidation by the OEC of PSII.
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http://dx.doi.org/10.1039/c6fd00230gDOI Listing
June 2017

Efficacy and safety of nivolumab in Japanese patients with advanced or recurrent squamous non-small cell lung cancer.

Cancer Sci 2017 May 26;108(5):1000-1006. Epub 2017 Apr 26.

St. Luke's International Hospital, Tokyo, Japan.

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.
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http://dx.doi.org/10.1111/cas.13225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5448646PMC
May 2017

Expression of Notch1 and Numb in small cell lung cancer.

Oncotarget 2017 Feb;8(6):10348-10358

Department of Thoracic Surgery, Kanazawa Medical University, Uchinada, Japan.

Notch signaling in tumorigenesis functions as an oncogene or tumor suppressor according to the type of malignancy. Numb represses intracellular Notch signaling. Previous studies have demonstrated that Notch signaling suppresses the proliferation of small cell lung cancer (SCLC) cell lines. However, in SCLC, the association between Notch1 and Numb expression and clinicopathological factors or prognosis has remained unclear. In this study, we evaluated the expression of Notch1 and Numb in SCLC. We immunohistochemically assessed 125 SCLCs that were surgically resected at 16 institutions participating in either the Hokkaido Lung Cancer Clinical Study Group Trial (HOT) or the Fukushima Investigative Group for Healing Thoracic Malignancy (FIGHT) between 2003 and 2013. Correlations between Notch1 or Numb expression and various clinicopathological features were evaluated. Notch1 expression was associated with ECOG performance status. Numb expression was associated with age, sex, and pathological histology (SCLC or Combined SCLC). Analysis of cellular biological expression did not demonstrate a significant correlation between the expression of Notch1 and of Numb. Multivariate Cox regression analysis showed that high Notch1 expression was an independent favorable prognostic factor for SCLC(hazard ratio = 0.503, P = 0.023). High Notch1 expression, but not Numb expression, is associated with favorable prognosis in SCLC.
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http://dx.doi.org/10.18632/oncotarget.14411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5354663PMC
February 2017

Immunohistochemical profiling of receptor tyrosine kinases, MED12, and TGF-βRII of surgically resected small cell lung cancer, and the potential of c-kit as a prognostic marker.

Oncotarget 2017 Jun;8(24):39711-39726

Department of Pulmonary Medicine, Fukushima Medical University, Fukushima, Japan.

The limited number of available treatments for patients with small-cell lung cancer (SCLC) has prompted us to further investigate the biology of SCLC by molecular profiling. We collected formalin-fixed paraffin-embedded tumor samples from 127 patients with SCLC, who had undergone surgery at 16 institutions between January 2003 and January 2013, and analyzed the association between disease-specific survival and protein expression of c-kit, c-Met, epidermal growth factor receptor, human EGFR-related 2, vascular endothelial growth factor receptor II, anaplastic lymphoma kinase, mediator complex subunit 12 (MED12), and transforming growth factor beta receptor II (TGF-βRII) by immunohistochemistry (IHC). Of the 125 evaluable samples, all tumors expressed MED12, and 123 samples (98.4%) expressed TGF-βRII. MED12 was highly expressed in the nucleus in 92% of the positive samples while TGF-βRII was highly expressed in the cytoplasm in 55% of the positive samples. High c-kit expression was an independent favorable prognostic marker confirmed by multivariate analysis (hazard ratio: 0.543, 95% confidence interval: 0.310-0.953, p = 0.033). Both the relapse free-survival and overall survival of patients who underwent adjuvant chemotherapy were statistically longer in those with high c-kit expression (n = 38) than those with intermediate, low, or no c-kit expression (n = 19) (not reached vs 11.6 months, p = 0.021; not reached vs 25.9 months, p = 0.028). IHC for c-kit may offer a prognostic marker for early-stage SCLC, and the results for MED12 and TGF-βRII may suggest the biological characteristics of SCLC. Further investigation of the roles of their related molecules in early stage SCLC is required.
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http://dx.doi.org/10.18632/oncotarget.14410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5503646PMC
June 2017

Geometric and electronic structures of the synthetic Mn₄CaO₄ model compound mimicking the photosynthetic oxygen-evolving complex.

Phys Chem Chem Phys 2016 Apr;18(16):11330-40

Institute for NanoScience Design, Osaka University, Toyonaka, Osaka 560-0043, Japan and Handairigaku Techno-Research (NPO), Toyonaka, Osaka 560-0043, Japan.

Water oxidation by photosystem II (PSII) converts light energy into chemical energy with the concomitant production of molecular oxygen, both of which are indispensable for sustaining life on Earth. This reaction is catalyzed by an oxygen-evolving complex (OEC) embedded in the huge PSII complex, and its mechanism remains elusive in spite of the extensive studies of the geometric and electronic structures. In order to elucidate the water-splitting mechanism, synthetic approaches have been extensively employed to mimic the native OEC. Very recently, a synthetic complex [Mn4CaO4(Bu(t)COO)8(py)(Bu(t)COOH)2] (1) closely mimicking the structure of the native OEC was obtained. In this study, we extensively examined the geometric, electronic and spin structures of 1 using the density functional theory method. Our results showed that the geometric structure of 1 can be accurately reproduced by theoretical calculations, and revealed many similarities in the ground valence and spin states between 1 and the native OEC. We also revealed two different valence states in the one-electron oxidized state of 1 (corresponding to the S2 state), which lie in the lower and higher ground spin states (S = 1/2 and S = 5/2), respectively. One remarkable difference between 1 and the native OEC is the presence of a non-negligible antiferromagnetic interaction between the Mn1 and Mn4 sites, which slightly influenced their ground spin structures (spin alignments). The major reason causing the difference can be attributed to the short Mn1-O5 and Mn1-Mn4 distances in 1. The introduction of the missing O4 atom and the reorientation of the Ca coordinating ligands improved the Mn1-O5 and Mn1-Mn4 distances comparable to the native OEC. These modifications will therefore be important for the synthesis of further advanced model complexes more closely mimicking the native OEC beyond 1.
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http://dx.doi.org/10.1039/c5cp07226cDOI Listing
April 2016