Faculty Profiles - OHASHI Kadoaki

Papers - OHASHI Kadoaki

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Clinical significance of repeat rebiopsy in detecting the EGFR T790M secondary mutation in patients with non-small cell lung cancer. Reviewed International journal

Ichihara E, Hotta K, Kubo T, Higashionna T, Ninomiya K, Ohashi K, Tabata M, Maeda Y, Kiura K

Oncotarget 9 ( 50 ) 29525 - 29531 2018.6

Language：English Publishing type：Research paper (scientific journal)

Background: Osimertinib is an essential drug to treat non-small-cell lung cancer (NSCLC) harboring the epidermal growth factor receptor (EGFR) T790M mutation, and rebiopsy is necessary to detect this mutation. However, the significance of repeat rebiopsy in NSCLC patients whose first rebiopsy was T790M-negative remains unclear. We used a retrospective cohort to clarify this issue. Methods: We reviewed the medical records of patients with NSCLC harboring EGFR mutations who underwent EGFR tyrosine kinase inhibitor (TKI) treatment at Okayama University Hospital between January 2015 and January 2017. Results: Of 102 patients with EGFR-mutant NSCLC, 55 underwent rebiopsy after acquired resistance to prior EGFR TKIs. Pre-existing activating EGFR mutations were found in all 55 rebiopsied samples. Of the 55 samples, 25 were T790M-positive (45%). Among the remaining 30 patients (T790M-negative on the first rebiopsy), 21 underwent additional rebiopsies following interval therapy. Of the 21 patients, 11 were T790M-positive on the second rebiopsy and 1 on the third. We also evaluated the efficacy of osimertinib in patients who needed a repeat rebiopsy to detect the T790M mutation. Osimertinib showed good activity with an objective response rate of 50%. Conclusions: Repeat rebiopsy increases the ability to detect a secondary mutation (T790M) in EGFR.

DOI： 10.18632/oncotarget.25705

Second primary cancer in survivors of locally advanced non-small cell lung cancer treated with concurrent chemoradiation followed by surgery Reviewed

Go Makimoto, Toshio Kubo, Isao Oze, Kadoaki Ohashi, Katsuyuki Hotta, Masahiro Tabata, Junichi Soh, Shinichi Toyooka, Kuniaki Katsui, Nagio Takigawa, Mitsune Tanimoto, Katsuyuki Kiura

Japanese Journal of Clinical Oncology 48 ( 3 ) 287 - 290 2018.3

Language：English Publishing type：Research paper (scientific journal) Publisher：Oxford University Press

The standard treatment for patients with locally advanced non-small-cell lung cancer (LA-NSCLC) is chemoradiotherapy (CRT), but surgical resection following induction CRT can extend overall survival in a select population. However, patients who survive longer are at risk of developing a second primary cancer (SPC). This is the first report to determine the incidence of SPC in survivors with LA-NSCLC after trimodal therapy. Between October 1997 and October 2013, 112 Stage III NSCLC patients underwent trimodal therapy in our hospital. The 5-year overall survival rate was 71.8%. SPC developed in 10 of the 112 patients 0.60-15.0 (median 5.49) years after initiating CRT. The observed incidence of SPC was 1.8 per 100 patient-years. Although trimodal therapy can prolong patient survival, the estimated incidence of SPC does not increase. A large prospective study with a longer follow-up time is required to determine the effects of trimodal therapy, including the development of SPC.

DOI： 10.1093/jjco/hyy003

A Phase II Study of Trastuzumab Emtansine in HER2-Positive Non–Small Cell Lung Cancer Reviewed

Katsuyuki Hotta, Keisuke Aoe, Toshiyuki Kozuki, Kadoaki Ohashi, Kiichiro Ninomiya, Eiki Ichihara, Toshio Kubo, Takashi Ninomiya, Kenichi Chikamori, Daijiro Harada, Naoyuki Nogami, Taizo Hirata, Shiro Hinotsu, Shinichi Toyooka, Katsuyuki Kiura

Journal of Thoracic Oncology 13 ( 2 ) 273 - 279 2018.2

Language：English Publishing type：Research paper (scientific journal) Publisher：Elsevier Inc

Trastuzumab emtansine (T-DM1), an anti–erb-b2 receptor tyrosine kinase 2 (HER2) antibody-drug conjugate, has been shown to significantly improve survival in HER2-positive breast cancer. We report a phase II trial of T-DM1 monotherapy in relapsed NSCLC with documented HER2 positivity (an immunohistochemistry [IHC] score of 3+, both an IHC score of 2+ and fluorescence in situ hybridization positivity, or exon 20 mutation). This study was terminated early because of limited efficacy. The demographic characteristics in the 15 assessable patients were as follows: median age, 67 years
male sex, 47%
performance status of 0 to 1, 80%
HER2 status IHC 3+, 33%
HER status IHC 2+/fluorescence in situ hybridization–positive, 20%
and exon 20 mutation, 47%. The median number of delivered cycles was 3 (range 1–11). One patient achieved a partial response with an objective response rate of 6.7% (90% confidence interval: 0.2–32.0). With a median follow-up time of 9.2 months, the median progression-free survival time and median survival time were 2.0 and 10.9 months, respectively. Grade 3 or 4 adverse events included thrombocytopenia (40%) and hepatotoxicity (20%) without any treatment-related deaths. T-DM1 had a limited efficacy for HER2-positive NSCLC in our cohort. Applying the concept of precision medicine to tumors appears challenging
thus, additional molecular approaches are warranted.

DOI： 10.1016/j.jtho.2017.10.032

Potential influence of interleukin-6 on the therapeutic effect of gefitinib in patients with advanced non-small cell lung cancer harbouring EGFR mutations Reviewed

Tomoki Tamura, Yuka Kato, Kadoaki Ohashi, Kiichiro Ninomiya, Go Makimoto, Hiroko Gotoda, Toshio Kubo, Eiki Ichihara, Takehiro Tanaka, Koichi Ichimura, Yoshinobu Maeda, Katsuyuki Hotta, Katsuyuki Kiura

Biochemical and Biophysical Research Communications 495 ( 1 ) 360 - 367 2018.1

Language：English Publishing type：Research paper (scientific journal) Publisher：Elsevier B.V.

Although epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are a key therapy used for patients with EGFR-mutant non-small cell lung cancer (NSCLC), some of whom do not respond well to its therapy. Cytokine including IL-6 secreted by tumour cells is postulated as a potential mechanism for the primary resistance or low sensitivity to EGFR-TKIs. Fifty-two patients with advanced EGFR-mutant NSCLC who had received gefitinib were assessed retrospectively. The protein expression of IL-6 in the tumour cells was assessed by immunostaining and judged as positive if ≥ 50 of 100 tumour cells stained positively. Of the 52 patients, 24 (46%) and 28 (54%) were defined as IL-6-postitive (group P) and IL-6-negative (group N), respectively. Group P had worse progression-free survival (PFS) than that of group N, which was retained in the multivariate analysis (hazard ratio: 2.39
95 %CI: 1.00–5.68
p &lt
0.05). By contrast, the PFS after platinum-based chemotherapy did not differ between groups P and N (p = 0.47). In cell line-based model, the impact of IL-6 on the effect of EGFR-TKIs was assessed. The combination of EGFR-TKI and anti-IL-6 antibody moderately improved the sensitivity of EGFR-TKI in lung cancer cell with EGFR mutation. Interestingly, suppression of EGFR with EGFR-TKI accelerated the activation of STAT3 induced by IL-6. Taken together, tumour IL-6 levels might indicate a subpopulation of EGFR-mutant NSCLC that benefits less from gefitinib monotherapy.

DOI： 10.1016/j.bbrc.2017.10.175

Other Link： http://orcid.org/0000-0002-5180-3933

A phase I trial of afatinib and bevacizumab in chemo-naïve patients with advanced non-small-cell lung cancer harboring EGFR mutations: Okayama Lung Cancer Study Group Trial 1404 Reviewed

Takashi Ninomiya, Naoyuki Nogami, Toshiyuki Kozuki, Daijiro Harada, Toshio Kubo, Kadoaki Ohashi, Shoichi Kuyama, Kenichiro Kudo, Akihiro Bessho, Nobuaki Fukamatsu, Nobukazu Fujimoto, Keisuke Aoe, Takuo Shibayama, Keisuke Sugimoto, Nagio Takigawa, Katsuyuki Hotta, Katsuyuki Kiura

Lung Cancer 115 103 - 108 2018.1

Language：English Publishing type：Research paper (scientific journal) Publisher：Elsevier Ireland Ltd

Objective In advanced epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC), treatment with afatinib, a second-generation EGFR-tyrosine kinase inhibitor (TKI), confers a significant survival benefit over platinum-based chemotherapy. The first-generation EGFR-TKIs gefitinib and erlotinib in combination with bevacizumab have improved progression-free survival. We hypothesized that the combination of afatinib with bevacizumab would further improve efficacy, and conducted a phase I trial to test this hypothesis. Materials and methods Untreated patients with advanced EGFR-mutant NSCLC were enrolled. The primary endpoint was safety. Two doses of afatinib, 40 mg/day (level 0) and 30 mg/day (level −1), were evaluated in combination with 15 mg/kg bevacizumab every 3 weeks. Optimal dosing was determined by dose-limiting toxicity (DLT), with the concentration at which ≤4 of 12 patients experienced toxicity considered the recommended dose. Results Nineteen patients were enrolled (level 0:5, level −1:14). Three of the five patients at level 0 experienced a DLT, which indicated that this dose was unfeasible. Three patients at level −1 developed a DLT of grade 3 non-hematological toxicity, which was soon resolved. Grade 3 or worse adverse events were experienced by all five patients at dose level 0 (diarrhea in 2, skin rash in 1, hypoxia in 1, and paronychia in 1), and by three patients at level −1 (diarrhea in 2 and anorexia in 1). Among 16 evaluable patients, 1 had a complete response, 12 had partial responses, and 0 had progressive disease. Conclusion Afatinib plus bevacizumab (level −1) was well tolerated and showed evidence of favorable disease control. This combination therapy may represent a potent therapeutic option for patients with EGFR-mutant NSCLC.

DOI： 10.1016/j.lungcan.2017.11.025

Other Link： http://orcid.org/0000-0002-5180-3933

A phase II trial of carboplatin plus S-1 for elderly patients with advanced non-small-cell lung cancer with wild-type epidermal growth factor receptor: The Okayama Lung Cancer Study Group Trial 1202 Reviewed

Shoichi Kuyama, Nobuaki Ochi, Akihiro Bessho, Katsuyuki Hotta, Genyo Ikeda, Daizo Kishino, Toshio Kubo, Daijiro Harada, Nobukazu Fujimoto, Masamoto Nakanishi, Takahiro Umeno, Toshiaki Okada, Kenichi Chikamori, Tomoko Yamagishi, Kadoaki Ohashi, Eiki Ichihara, Nagio Takigawa, Mitsune Tanimoto, Katsuyuki Kiura

LUNG CANCER 112 188 - 194 2017.10

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER IRELAND LTD

Introduction: S-1 is an oral fluoropyrimidine-based combination of tegafur, gimeracil, and oteracil potassium. Although the combination of S-1 with carboplatin is a first-line chemotherapy regimen for advanced non-small cell lung cancer (NSCLC), the efficacy and safety of the regimen in the elderly remain unknown.
Methods: The patient inclusion criteria were previously untreated advanced NSCLC, wild-type epidermal growth factor receptor, aged 70 years or more, and a performance status (PS) of 0-2. The patients received oral S-1 (40 mg/m(2), twice daily) for 2 weeks and carboplatin (area under the curve: 5) on day 1 every 4 weeks as induction treatment. After four induction cycles, S-1 alone (40 mg/m(2), twice daily) was administered for 2 weeks every 4 weeks as a maintenance therapy until disease progression. The primary endpoint was the overall response rate (ORR), which was expected to exceed 20%, and the secondary endpoints included the disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and the toxicity profile. The associations between clinical outcomes and expression of genes such as thymidylate synthase and thymidine phosphorylase in the tumors were evaluated.
Results: Thirty-three patients were enrolled between March 2013 and June 2015. The median age was 78 (range 70-89) years, and 51.5% had a PS of 0. The ORR was 30.3% (95% confidence interval (CI): 14.6-46.0) and the DCR 57.6% (95% CI: 40.7-74.4). Grade 3/4 toxicities included thrombocytopenia (42.4%), neutropenia (33.3%), and anemia (27.3%). There was one treatment-related death due to aspiration pneumonia following febrile neutropenia. The median PFS and OS were 134 days (95% CI: 79-173) and 479 days (95% CI: 250-571), respectively. Low thymidine phosphorylase expression was associated with the DCR (P < 0.01).
Conclusion: This study met the predesigned primary endpoint, and the regimen seems to be a favorable treatment option.

DOI： 10.1016/j.lungcan.2017.08.010

Discomfort during bronchoscopy performed after endobronchial intubation with fentanyl and midazolam: a prospective study Reviewed

Daisuke Minami, Nagio Takigawa, Hirohisa Kano, Takashi Ninomiya, Toshio Kubo, Eiki Ichihara, Kadoaki Ohashi, Akiko Sato, Katsuyuki Hotta, Masahiro Tabata, Mitsune Tanimoto, Katsuyuki Kiura

JAPANESE JOURNAL OF CLINICAL ONCOLOGY 47 ( 5 ) 434 - 437 2017.5

Language：English Publishing type：Research paper (scientific journal) Publisher：OXFORD UNIV PRESS

Endobronchial intubation with fentanyl and midazolam might be recommended for an invasive bronchoscopic procedure.Although endobronchial intubation during a bronchoscopic examination is useful for invasive procedures, it is not routine practice in Japan. The present study evaluated discomfort due to endobronchial intubation using fentanyl and midazolam sedation during bronchoscopy.
Thirty-nine patients were enrolled prospectively from November 2014 to September 2015 at Okayama University Hospital. Fentanyl (20 A mu g) was administered to the patients just before endobronchial intubation, and fentanyl (10 A mu g) and midazolam (1 mg) were added as needed during the procedure. A questionnaire survey was administered 2 h after the examination. In the questionnaire, patient satisfaction was scored using a visual analog scale as follows: excellent (1 point), good (2 points), normal (3 points), uncomfortable (4 points) and very uncomfortable (5 points). An additional question ('Do you remember the bronchoscopic examination?') was also asked. Predefined parameters (blood pressure, heart rate, oxygen saturation and complications) were recorded.
The enrolled patients included 22 males and 17 females; their median age was 70 (range: 28-88) years. The patients received a mean dose of 47.9 A mu g of fentanyl (range: 30-90 A mu g) and 2.79 mg of midazolam (range: 1-7 mg). In total, 28 patients (71.7%) agreed to undergo a second bronchoscopic examination; the mean levels of discomfort and for the re-examination were 2.07 points each. About 41% of the patients remembered the bronchoscopic examination. No severe complications were reported.
Endobronchial intubation using fentanyl and midazolam sedation during an invasive bronchoscopic procedure might be recommended.
UMIN000015578 in the UMIN Clinical Trials Registry.

DOI： 10.1093/jjco/hyx022

Optimal method for quantitative detection of plasma EGFR T790M mutation using droplet digital PCR system Reviewed

Ken Suzawa, Hiromasa Yamamoto, Kadoaki Ohashi, Shinsuke Hashida, Shuta Tomida, Toshio Kubo, Yuho Maki, Junichi Soh, Kazunori Tsukuda, Katsuyuki Kiura, Shinichiro Miyoshi, Shinichi Toyooka

ONCOLOGY REPORTS 37 ( 5 ) 3100 - 3106 2017.5

Language：English Publishing type：Research paper (scientific journal) Publisher：SPANDIDOS PUBL LTD

Though patients with EGFR mutations are initially responsive to EGFR-tyrosine kinase inhibitors (TKIs), most tumors ultimately acquire resistance to EGFR-TKIs. The most frequently reported mechanism is EGFR T790M mutation. In this study, using a droplet digital PCR (ddPCR) system, we assessed optimal conditions for a mutation detection assay for EGFR T790M obtained from circulating cell-free DNA (cfDNA) in plasma. The advantages of locked nucleic acids (LNA) probe, short amplicon size, and blocking oligo using peptide nucleic acids (PNA) were assessed using control DNAs from cell lines to improve the sensitivity of mutation detection. T790M alleles were then analyzed using ddPCR in 59 plasma samples from 24 NSCLC patients with EGFR mutations, and compared to the T790M status which were determined thorough re-biopsies. The assessment of the optimal assay method revealed that the assay using the short amplicon can efficiently detect more fragmented-DNA. The LNA probe and PNA clamp contributed better separation between positive and negative droplets. This PNA-LNA-ddPCR clamp method can detect mutant alleles in the sample with a mutant allele content of 0.01%. In clinical plasma samples, T790M alleles were detected via ddPCR with a sensitivity of 42.8% and specificity of 97.3%. We established a highly-sensitive detection assay for the T790M allele using the PNA-LNA-ddPCR clamp method. ddPCR is a promising method for detecting non-invasive T790M mutation.

DOI： 10.3892/or.2017.5567

Trastuzumab Emtansine in HER2+Recurrent Metastatic Non-Small-Cell Lung Cancer: Study Protocol Reviewed

Kadoaki Ohashi, Katsuyuki Hotta, Taizo Hirata, Keisuke Aoe, Toshiyuki Kozuki, Kiichiro Ninomiya, Hiroe Kayatani, Hiroyuki Yanai, Shinichi Toyooka, Shiro Hinotsu, Minoru Takata, Katsuyuki Kiura

CLINICAL LUNG CANCER 18 ( 1 ) 92 - 95 2017.1

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal) Publisher：CIG MEDIA GROUP, LP

The treatment outcome has been unsatisfactory for patients with non small-cell lung cancer (NSCLC) refractory to standard first-line chemotherapy. Trastuzumab emtansine (T-DM1), an anti-HER2 antibody conjugated with a vinca alkaloid, has been approved for clinical use in HER2+ breast cancer in many countries. Approximately 5% of NSCLC tumors possess HER2 alterations, and T-DM1 has shown excellent antitumor effects against HER2+ lung cancer cell lines in preclinical models. Therefore, we hypothesized that T-DM1 could significantly inhibit the growth of HER2+ lung cancers. We have launched a nonrandomized phase II trial of T-DM1 monotherapy for patientg with HER2+ lung cancers. The major eligibility criteria are as follows: age >= 20 years, pathologically diagnosed NSCLC with documented HER2 positivity (immunohistochemistry 3+, both immunohistochemistry 2+ and fluorescence in situ hybridization positive, or exon 20 insertion mutation), and previous chemotherapy. Thirty patients will receive T-DM1 3.6 mg/kg every 3 weeks. The primary endpoint is the overall response rate. This trial will provide information on whether T-DM1 monotherapy is effective against HER2+ lung cancer. (C) 2016 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.cllc.2016.06.014

Safety And Discomfort During Bronchoscopy Performed Under Sedation With Fentanyl And Midazolam: A Prospective Study Reviewed

D. Minami, N. Takigawa, T. Ninomiya, T. Kubo, E. Ichihara, K. Ohashi, A. Sato, K. Hotta, T. Shibayama, N. Miyahara, M. Tabata, A. Kanehiro, K. Kiura

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE 195 ( 9 ) 871 - 874 2017

Potential influence of being overweight on the development of hepatic dysfunction in Japanese patients with EGFR-mutated non-small cell lung cancer undergoing gefitinib monotherapy: the Okayama Lung Cancer Study Group experience Reviewed

Naohiro Oda, Katsuyuki Hotta, Hiroshige Yoshioka, Kenichiro Kudo, Eiki Ichihara, Yuka Kato, Kiichiro Ninomiya, Daisuke Minami, Takashi Ninomiya, Toshio Kubo, Kadoaki Ohashi, Akiko Sato, Nagio Takigawa, Masahiro Tabata, Mitsune Tanimoto, Katsuyuki Kiura

CANCER CHEMOTHERAPY AND PHARMACOLOGY 78 ( 5 ) 941 - 947 2016.11

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER

Being overweight has been reported to induce hepatic dysfunction during cytotoxic chemotherapy. Severe hepatic dysfunction can also be observed during gefitinib monotherapy, leading to interrupted or discontinued treatment. However, whether being overweight is a risk factor during gefitinib therapy is unknown.
We retrospectively reviewed 183 Japanese patients with epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor-na < ve non-small cell lung cancer (NSCLC) harboring EGFR mutations, who received gefitinib monotherapy between July 2007 and February 2014. We defined being overweight as having a body mass index (BMI) aeyen 25 kg/m(2) and assessed its potential relationship with aeyengrade 2 hepatic dysfunction.
The patient demographics were as follows: 114 women; median age 72 years (range 42-95 years); BMI aeyen 25 kg/m(2), n = 32; performance status 0-1, n = 136; stage IIIB/IV, n = 141; and major EGFR mutations, n = 171. Hepatic dysfunction aeyengrade 2 during the gefitinib therapy was observed in 44 (24.0 %) patients, 22 (50.0 %) of whom interrupted or discontinued treatment. The median duration from gefitinib administration to the development of hepatic dysfunction was 56 days (range 6-1,352 days). Overweight patients were more likely to develop hepatic dysfunction aeyengrade 2 compared to non-overweight patients according to a multivariate analysis adjusted for several confounding factors (hazard ratio 2.24; 95 % confidence interval 1.01-4.95; p = 0.046).
These results suggest that being overweight may induce hepatic dysfunction during gefitinib monotherapy in Japanese patients with EGFR-mutated NSCLC.

DOI： 10.1007/s00280-016-3146-z

Protocol Design for the Bench to Bed Trial in Alectinib-Refractory Non-Small-Cell Lung Cancer Patients Harboring the EML4-ALK Fusion Gene (ALRIGHT/OLCSG1405) Reviewed

Hideko Isozaki, Katsuyuki Hotta, Eiki Ichihara, Nagio Takigawa, Kadoaki Ohashi, Toshio Kubo, Takashi Ninomiya, Kiichiro Ninomiya, Naohiro Oda, Hiroshige Yoshioka, Hirohisa Ichikawa, Masaaki Inoue, Ichiro Takata, Takuo Shibayama, Shoichi Kuyama, Keisuke Sugimoto, Daijiro Harada, Shingo Harita, Toshiaki Sendo, Mitsune Tanimoto, Katsuyuki Kiura

CLINICAL LUNG CANCER 17 ( 6 ) 602 - 605 2016.11

Language：English Publishing type：Research paper (scientific journal) Publisher：CIG MEDIA GROUP, LP

Based on our preclinical study results, which showed that the activation of the hepatocyte growth factor/MET pathway is a potential mechanism of acquired resistance to alectinib, we launched the ALRIGHT (OLCSG1405 [alectinib-refractory nonesmall-cell lung cancer patients harboring the EML4-ALK fusion gene]), a phase II trial of the anaplastic lymphoma kinase (ALK)/MET inhibitor crizotinib in patients with nonesmall-cell lung cancer refractory to alectinib and harboring the echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion gene. Patients with ALK-rearranged tumors who have developed disease progression during alectinib treatment will receive crizotinib monotherapy until disease progression or the occurrence of unacceptable toxicity. The primary endpoint is set as the objective response rate, assuming that a response in 50% of eligible patients will indicate potential usefulness and that 15% would be the lower limit of interest (1-sided a of 0.05, b of 0.20). The estimated accrual number of patients is 9. The secondary endpoints include progression-free survival, overall survival, adverse events, and patient-reported outcomes. We will also take tissue samples before crizotinib monotherapy to conduct an exploratory analysis of ALK and hepatocyte growth factor/MET expression levels and gene alterations (eg, mutations, amplifications, and translocations). We will obtain information regarding whether crizotinib, which targets not only ALK, but also MET, can truly produce efficacy with acceptable safety profiles in ALK(+) non-small-cell lung cancer even in the alectinibrefractory setting. (C) 2016 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.cllc.2016.05.005

Safety and discomfort during bronchoscopy performed under sedation with fentanyl and midazolam: a prospective study Reviewed

Daisuke Minami, Nagio Takigawa, Hiromi Watanabe, Takashi Ninomiya, Toshio Kubo, Kadoaki Ohashi, Akiko Sato, Katsuyuki Hotta, Masahiro Tabata, Mitsune Tanimoto, Katsuyuki Kiura

JAPANESE JOURNAL OF CLINICAL ONCOLOGY 46 ( 9 ) 871 - 874 2016.9

Language：English Publishing type：Research paper (scientific journal) Publisher：OXFORD UNIV PRESS

Objective: Although sedation with fentanyl and midazolam during bronchoscopic examination is widely accepted in the USA and Europe, it is not routine practice in Japan. The objective of the present study was to evaluate sedation with fentanyl and midazolam during bronchoscopy.
Methods: Thirty-seven patients were enrolled prospectively between November 2014 and July 2015 at Okayama University Hospital. Fentanyl (20 mu g) was administered to the patients just before the examination, and fentanyl (10 mu g) and midazolam (1mg) were added as needed during the procedure. A questionnaire was administered 2 hours after the examination. In the questionnaire, patient satisfaction was scored using a visual analog scale as follows: great (1 point), good (2 points), normal (3 points), uncomfortable (4 points) and very uncomfortable (5 points). An additional question ('Do you remember the bronchoscopic examination?') was also used. Predefined matters for investigation (e.g. blood pressure, heart rate, oxygen saturation and complications) were recorded.
Results: The enrolled patients included 13 males and 24 females; the median age was 67 (range: 31-87) years. The patients received a median dose of fentanyl of 45.4 mu g (range: 30-100 mu g) and midazolam of 2.56 mg (range: 1-10 mg). Twenty-six patients (70.2%) agreed to undergo a second bronchoscopic examination, and the average levels of discomfort and re-examination were 2.02 points for each. Only 37.8% of the patients remembered the bronchoscopic examination. No severe complications were reported.
Conclusions: Sedation with fentanyl and midazolam during bronchoscopic examination should be recommended for use in Japan.

DOI： 10.1093/jjco/hyw083

Activating alternative receptor tyrosine kinases induced alectinib-resistance in ALK rearranged non-small cell lung cancer cells Reviewed

Hideko Isozaki, Eiki Ichihara, Masayuki Yasugi, Nagio Takigawa, Kadoaki Ohashi, Toshio Kubo, Takashi Ninomiya, Nobuaki Ochi, Daisuke Minami, Kenichiro Kudo, Yuka Kato, Hiroe Kayatani, Tomoki Tamura, Kiichiro Ninonniya, Toshio Higo, Tsuyoshi Makimoto, Akiko Sato, Katsuyuki Hotta, Kunio Matsumoto, Toshiaki Sendo, Mitsune Tanimoto, Katsuyuki Kiura

CANCER RESEARCH 76 2016.7

Endobronchial ultrasound-guided transbronchial needle aspiration of hilar and mediastinal lymph nodes detected on F-18-fluorodeoxyglucose positron emission tomography/computed tomography Reviewed

Daisuke Minami, Nagio Takigawa, Naohiro Oda, Takashi Ninomiya, Toshio Kubo, Kadoaki Ohashi, Akiko Sato, Katsuyuki Hotta, Masahiro Tabata, Mitsumasa Kaji, Mitsune Tanimoto, Katsuyuki Kiura

JAPANESE JOURNAL OF CLINICAL ONCOLOGY 46 ( 6 ) 529 - 533 2016.6

Language：English Publishing type：Research paper (scientific journal) Publisher：OXFORD UNIV PRESS

Endobronchial ultrasound-guided transbronchial needle aspiration is of diagnostic value in hilar/mediastinal (N1/N2) lymph node staging. We assessed the utility of endobronchial ultrasound-guided transbronchial needle aspiration in lung cancer patients with N1/N2 lymph nodes detected on F-18-fluorodeoxyglucose positron emission tomography/computed tomography.
Fifty lung cancer patients with N1/N2 disease on F-18-fluorodeoxyglucose positron emission tomography/computed tomography underwent endobronchial ultrasound-guided transbronchial needle aspiration for pathological lymph nodes between November 2012 and April 2015. The diagnostic performance of endobronchial ultrasound-guided transbronchial needle aspiration, lymph node site and size, number of needle passes and complications were evaluated retrospectively from patients' medical records. Malignancy was defined as a maximum standardized uptake value (SUVmax) > 2.5.
The median longest diameter of the 61 lymph nodes (29 subcarinal, 21 right lower paratracheal, 6 left lower paratracheal, 4 right hilar and 1 upper paratracheal) was 23.4 mm (range: 10.4-45.7); the median number of needle passes was 2 (range: 1-5). There were no severe complications. A definitive diagnosis was made by endobronchial ultrasound-guided transbronchial needle aspiration in 39 patients (31 adenocarcinomas, 3 small-cell carcinomas, 2 squamous-cell carcinomas, 3 large-cell neuroendocrine carcinomas). In the remaining 11 patients, the diagnosis was indefinite: insufficient endobronchial ultrasound-guided transbronchial needle aspiration material was collected in two patients and non-specific lymphadenopathy was confirmed by endobronchial ultrasound-guided transbronchial needle aspiration or thoracotomy in the other nine patients. The mean lymph node SUVmax was 7.09 (range: 2.90-26.9) and was significantly higher in true-positive than in false-positive nodes (P < 0.05, t-test). Non-specific lymphadenopathy was diagnosed by expert visual interpretation of F-18-fluorodeoxyglucose positron emission tomography/computed tomography images in five of the nine patients.
Endobronchial ultrasound-guided transbronchial needle aspiration accurately diagnoses N1/N2 disease detected on F-18-fluorodeoxyglucose positron emission tomography/computed tomography.

DOI： 10.1093/jjco/hyw023

Non-Small Cell Lung Cancer Cells Acquire Resistance to the ALK Inhibitor Alectinib by Activating Alternative Receptor Tyrosine Kinases. Reviewed International journal

Hideko Isozaki, Eiki Ichihara, Nagio Takigawa, Kadoaki Ohashi, Nobuaki Ochi, Masayuki Yasugi, Takashi Ninomiya, Hiromichi Yamane, Katsuyuki Hotta, Katsuya Sakai, Kunio Matsumoto, Shinobu Hosokawa, Akihiro Bessho, Toshiaki Sendo, Mitsune Tanimoto, Katsuyuki Kiura

Cancer research 76 ( 6 ) 1506 - 16 2016.3

Language：English Publishing type：Research paper (scientific journal)

Crizotinib is the standard of care for advanced non-small cell lung cancer (NSCLC) patients harboring the anaplastic lymphoma kinase (ALK) fusion gene, but resistance invariably develops. Unlike crizotinib, alectinib is a selective ALK tyrosine kinase inhibitor (TKI) with more potent antitumor effects and a favorable toxicity profile, even in crizotinib-resistant cases. However, acquired resistance to alectinib, as for other TKIs, remains a limitation of its efficacy. Therefore, we investigated the mechanisms by which human NSCLC cells acquire resistance to alectinib. We established two alectinib-resistant cell lines that did not harbor the secondary ALK mutations frequently occurring in crizotinib-resistant cells. One cell line lost the EML4-ALK fusion gene, but exhibited increased activation of insulin-like growth factor-1 receptor (IGF1R) and human epidermal growth factor receptor 3 (HER3), and overexpressed the HER3 ligand neuregulin 1. Accordingly, pharmacologic inhibition of IGF1R and HER3 signaling overcame resistance to alectinib in this cell line. The second alectinib-resistant cell line displayed stimulated HGF autocrine signaling that promoted MET activation and remained sensitive to crizotinib treatment. Taken together, our findings reveal two novel mechanisms underlying alectinib resistance that are caused by the activation of alternative tyrosine kinase receptors rather than by secondary ALK mutations. These studies may guide the development of comprehensive treatment strategies that take into consideration the various approaches ALK-positive lung tumors use to withstand therapeutic insult.

DOI： 10.1158/0008-5472.CAN-15-1010

Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration Of Hilar And Mediastinal Lymph Nodes Detected On 18f-Fluorodeoxyglucose Positron Emission Tomography/computed Tomography

D. Minami, N. Takigawa, Y. Kato, T. Ninomiya, T. Kubo, K. Ohashi, K. Hotta, T. Shibayama, N. Miyahara, M. Tabata, A. Kanehiro, M. Tanimoto, K. Kiura

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE 193 ( 6 ) 529 - 533 2016

Downregulation of TBXAS1 in an iron-induced malignant mesothelioma model Reviewed

Daisuke Minami, Nagio Takigawa, Yuka Kato, Kenichiro Kudo, Hideko Isozaki, Shinsuke Hashida, Daijiro Harada, Nobuaki Ochi, Masanori Fujii, Toshio Kubo, Kadoaki Ohashi, Akiko Sato, Takehiro Tanaka, Katsuyuki Hotta, Masahiro Tabata, Shinichi Toyooka, Mitsune Tanimoto, Katsuyuki Kiura

CANCER SCIENCE 106 ( 10 ) 1296 - 1302 2015.10

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

Malignant mesothelioma is an aggressive and therapy-resistant neoplasm arising from mesothelial cells. Evidence suggests that the major pathology associated with asbestos-induced mesothelioma is local iron overload. In the present study, we induced iron-induced mesothelioma in rats based on previous reports. Ten Wistar rats were given ferric saccharate and nitrilotriacetate i.p. for 5 days a week. Five of the ten rats exhibited widespread mesotheliomas in the peritoneum and tunica vaginalis. The tumor cells showed positive immunostaining for calretinin, wilms tumor-1, podoplanin and the oxidative DNA marker 8-hydroxy-2-deoxyguanosine. In three of the five rats with mesothelioma, array-based comparative genomic hybridization analysis identified a common chromosomal deletion mapped to the chromosomal 4q31 locus, which encompasses the TBXAS1 gene. Downregulation of the TBXAS1 gene was confirmed using quantitative PCR. TBXAS1 gene expression was also reduced in three of four human malignant pleural mesothelioma cell lines compared with normal bronchial epithelial cells. Immunohistochemistry revealed that TBXAS1 expression was weakly positive and positive in five and three out of eight human malignant mesothelioma samples, respectively. In conclusion, TBXAS1 gene expression was downregulated in rats with iron-induced mesothelioma. The relationship between iron overload and TBXAS1 downregulation should be pursued further.

DOI： 10.1111/cas.12752

Other Link： http://orcid.org/0000-0002-5180-3933

Endobronchial ultrasound-guided transbronchial biopsy with or without a guide sheath for diagnosis of lung Cancer Reviewed

Daisuke Minami, Nagio Takigawa, Daisuke Morichika, Toshio Kubo, Kadoaki Ohashi, Akiko Sato, Katsuyuki Hotta, Masahiro Tabata, Mitsune Tanimoto, Katsuyuki Kiura

Respiratory Investigation 53 ( 3 ) 93 - 97 2015.5

Language：English Publishing type：Research paper (scientific journal) Publisher：Elsevier

Background: Endobronchial ultrasound-guided transbronchial biopsy with a guide sheath (EBUS-GS) is widely used for diagnosing lung cancers
however, the diagnostic yield varies widely. This study aimed to assess the efficiency of EBUS-GS. Methods: We retrospectively evaluated the results of 110 patients who underwent transbronchial biopsy (TBB) for diagnosis of peripheral lung cancer. Bronchoscopy with and without EBUS-GS was performed in 60 (group A) and 50 patients (group B), respectively
their medical records were examined, and results from the two groups were compared by using the unpaired Student t-test. Results: The diagnostic sensitivity for lung cancer was 83.3% in group A and 68% in group B ( P=0.066) while using at least one of the following procedures: TBB, cytological brushing, and bronchial washing. The diagnostic sensitivity for lesions ≥20. mm was 86.4% in group A and 76.7% in group B ( P=0.263). Moreover, the diagnostic sensitivity for lesions 10-20. mm was 60% in group A and 14.2% in group B ( P=0.0004)
the diagnostic sensitivity with TBB alone was 63.3% in group A and 44% in group B ( P=0.043). The diagnostic sensitivity with TBB alone for lesions ≥20. mm was 70.2% in group A and 44.8% in group B ( P=0.051). Moreover, the diagnostic sensitivity for lesions 10-20. mm in size was 45% in group A and 14.2% in group B with TBB alone ( P=0.115). Conclusion: EBUS-GS with TBB, brushing, and bronchial washing is effective in diagnosing lung cancers sized &lt
20. mm.

DOI： 10.1016/j.resinv.2014.10.003

Other Link： http://orcid.org/0000-0002-5180-3933

Magnitude of the Benefit of Progression-Free Survival as a Potential Surrogate Marker in Phase 3 Trials Assessing Targeted Agents in Molecularly Selected Patients with Advanced Non-Small Cell Lung Cancer: Systematic Review Reviewed

Katsuyuki Hotta, Yuka Kato, Natasha Leighl, Nagio Takigawa, Rabab Mohamed Gaafar, Hiroe Kayatani, Taizo Hirata, Kadoaki Ohashi, Toshio Kubo, Masahiro Tabata, Mitsune Tanimoto, Katsuyuki Kiura

PLOS ONE 10 ( 3 ) 2015.3

Language：English Publishing type：Research paper (scientific journal) Publisher：PUBLIC LIBRARY SCIENCE

Background
In evaluation of the clinical benefit of a new targeted agent in a phase 3 trial enrolling molecularly selected patients with advanced non-small cell lung cancer (NSCLC), overall survival (OS) as an endpoint seems to be of limited use because of a high level of treatment crossover for ethical reasons. A more efficient and useful indicator for assessing efficacy is needed.
Methods and Findings
We identified 18 phase 3 trials in the literature investigating EGFR-tyrosine kinase inhibitor (TKIs) or ALK-TKIs, now approved for use to treat NSCLC, compared with standard cytotoxic chemotherapy (eight trials were performed in molecularly selected patients and ten using an "all-comer" design). Receiver operating characteristic analysis was used to identify the best threshold by which to divide the groups. Although trials enrolling molecularly selected patients and all-comer trials had similar OS-hazard ratios (OS-HRs) (0.99 vs. 1.04), the former exhibited greater progression-free survival-hazard ratios (PFS-HR) (mean, 0.40 vs. 1.01; P < 0.01). A PFS-HR of 0.60 successfully distinguished between the two types of trials (sensitivity 100%, specificity 100%). The odds ratio for overall response was higher in trials with molecularly selected patients than in all-comer trials (mean: 6.10 vs. 1.64; P < 0.01). An odds ratio of 3.40 for response afforded a sensitivity of 88% and a specificity of 90%.
Conclusion
The notably enhanced PFS benefit was quite specific to trials with molecularly selected patients. A PFS-HR cutoff of similar to 0.6 may help detect clinical benefit of molecular targeted agents in which OS is of limited use, although desired threshold might differ in an individual trial.

DOI： 10.1371/journal.pone.0121211

Other Link： http://orcid.org/0000-0002-5180-3933

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