Faculty Profiles - ARAKI Motoo

Synergistic effects of the immune checkpoint inhibitor CTLA-4 combined with the growth inhibitor lycorine in a mouse model of renal cell carcinoma Reviewed

Xiezhao Li, Peng Xu, Chongshan Wang, Naijin Xu, Abai Xu, Yawen Xu, Takuya Sadahira, Motoo Araki, Koichiro Wada, Eiji Matsuura, Masami Watanabe, Junxia Zheng, Pinghua Sun, Peng Huang, Yasutomo Nasu, Chunxiao Liu

ONCOTARGET 8 ( 13 ) 21177 - 21186 2017.3

Language：English Publishing type：Research paper (scientific journal) Publisher：IMPACT JOURNALS LLC

Renal cell carcinoma (RCC) management has undergone a major transformation over the past decade; immune checkpoint inhibitors are currently undergoing clinical trials and show promising results. However, the effectiveness of immune checkpoint inhibitors in patients with metastatic RCC (mRCC) is still limited. Lycorine, an alkaloid extracted from plants of the Amaryllidaceae family, is touted as a potential anti-cancer drug because of its demonstrative growth inhibition capacity (induction of cell cycle arrest and inhibition of vasculogenic mimicry formation). Moreover, T cell checkpoint blockade therapy with antibodies targeting cytotoxic T-lymphocyte associated protein 4 (CTLA-4) has improved outcomes in cancer patients. However, the anti-tumor efficacy of combined lycorine and anti-CTLA-4 therapy remains unknown. Thus, we investigated a combination therapy of lycorine hydrochloride and anti-CTLA-4 using a murine RCC model. As a means of in vitro confirmation, we found that lycorine hydrochloride inhibited the viability of various RCC cell lines. Furthermore, luciferase-expressing Renca cells were implanted in the left kidney and the lung of BALB/c mice to develop a RCC metastatic mouse model. Lycorine hydrochloride and anti-CTLA-4 synergistically decreased tumor weight, lung metastasis, and luciferin-staining in tumor images. Importantly, the observed anti-tumor effects of this combination were dependent on significantly suppressing regulatory T cells while upregulating effector T cells; a decrease in regulatory T cells by 31.43% but an increase in effector T cells by 31.59% were observed in the combination group compared with those in the control group). We suggest that a combination of lycorine hydrochloride and anti-CTLA-4 is a viable therapeutic option for RCC patients.

DOI： 10.18632/oncotarget.15505

Efficacy and safety of 3 day versus 7 day cefditoren pivoxil regimens for acute uncomplicated cystitis: multicentre, randomized, open-label trial. Reviewed International journal

Takuya Sadahira, Koichiro Wada, Motoo Araki, Ayano Ishii, Atsushi Takamoto, Yasuyuki Kobayashi, Masami Watanabe, Toyohiko Watanabe, Yasutomo Nasu, Hiromi Kumon

The Journal of antimicrobial chemotherapy 72 ( 2 ) 529 - 534 2017.2

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

BACKGROUND: Fluoroquinolone-non-susceptible Escherichia coli isolated from patients with acute uncomplicated cystitis are a matter of increasing concern. Cefditoren pivoxil is an oral, β-lactamase-stable, extended-spectrum cephalosporin that is effective against fluoroquinolone-non-susceptible bacteria. OBJECTIVES: To evaluate the clinical and microbiological efficacies of cefditoren pivoxil against acute uncomplicated cystitis and to determine the optimal duration of cefditoren pivoxil treatment. METHODS: We compared 3 and 7 day regimens of cefditoren pivoxil in a multicentre, randomized, open-label study. RESULTS: A total of 104 female patients with acute uncomplicated cystitis were enrolled and randomized into 3 day (n = 51) or 7 day (n = 53) treatment groups. At first visit, 94 bacterial strains were isolated from the 104 participants of which 81.7% (85/104) were E. coli. Clinical and microbiological efficacies were evaluated 5-9 days following administration of the final dose of cefditoren pivoxil. The clinical efficacies of the 3 and 7 day groups were 90.9% (40/44) and 93.2% (41/44), respectively (P = 1.000). The microbiological efficacies of the 3 and 7 day groups were 82.5% (33/40) and 90.2% (37/41), respectively (P = 0.349). There were no adverse events due to cefditoren pivoxil treatment, with the exception of a mild allergic reaction in one patient, after which the cefditoren pivoxil was exchanged for another antimicrobial. CONCLUSIONS: Cefditoren pivoxil is safe and effective for uncomplicated cystitis, with no significant differences in clinical and microbiological efficacies between 3 and 7 day regimens.

DOI： 10.1093/jac/dkw424

The Prostate in Female? Clear Cell Adenocarcinoma in a Female Urethral Diverticulum Reviewed

Takuya Sadahira, Yuuki Maruyama, Motoo Araki, Yasuyuki Kobayashi, Toyohiko Watanabe, Yasutomo Nasu

UROLOGY 99 E25 - E26 2017.1

Language：English Publisher：ELSEVIER SCIENCE INC

Urethral diverticular clear cell adenocarcinoma in a female patient is extremely rare. This tumor sometimes displays a characteristic image on magnetic resonance imaging, surrounding the urethra like the prostate does in men. We report a patient with this tumor who underwent cystourethrectomy and ileal conduit diversion. We think that imaging studies could be useful to make the appropriate diagnosis. UROLOGY 99: e25-e26, 2017. (C) 2016 Elsevier Inc.

DOI： 10.1016/j.urology.2016.10.021

URETEROLYSIS WITH OMENTAL WRAP FOR BILATERAL HYDRONEPHROSIS SECONDARY TO RETROPERITONEAL FIBROSIS : A CASE REPORT Reviewed

79 ( 1 ) 12 - 15 2017

Value of percutaneous needle biopsy of small renal tumors in patients referred for cryoablation Reviewed

Toshihiro Iguchi, Takao Hiraki, Hideo Gobara, Hiroyasu Fujiwara, Jun Sakurai, Yusuke Matsui, Motoo Araki, Yasutomo Nasu, Susumu Kanazawa

MINIMALLY INVASIVE THERAPY & ALLIED TECHNOLOGIES 26 ( 2 ) 86 - 91 2017

Language：English Publishing type：Research paper (scientific journal) Publisher：TAYLOR & FRANCIS LTD

Purpose: To retrospectively evaluate the safety and diagnostic yield of needle biopsy of small renal tumors, and the clinical consequences of performing needle biopsy in patients referred for percutaneous cryoablation before their treatment.
Material and methods: Biopsy was performed for 120 tumors (mean diameter, 2.2 cm) in 119 patients. All procedures were divided into diagnostic and non-diagnostic biopsies. Various variables were compared between the two groups. All cryoablation procedures were divided into two groups: procedures with or without simultaneous biopsy. The rates of benign or non-diagnostic tumors in each group were compared.
Results: After performing 120 initial and eight repeat biopsies, Grade 1 bleedings occurred in 44 cases. Six tumors were non-diagnostic and 114 were pathologically diagnosed. There were no significant variables between the diagnostic and non-diagnostic biopsies. Unnecessary cryoablation was avoided in nine benign lesions by performing biopsy in advance. Cryoablation performed simultaneously with biopsy included significantly more benign or non-diagnostic tumors than cryoablation performed after biopsy (15.2% vs. 1.4%; p =.01).
Conclusions: Percutaneous biopsy of small renal tumors referred for cryoablation was a safe procedure with high diagnostic yield. The confirmation of pathological diagnosis prior to cryoablation is necessary because patients with benign tumors can avoid unnecessary treatment.

DOI： 10.1080/13645706.2016.1249889

Adenovirus vector carrying REICIDKK-3 gene: neoadjuvant intraprostatic injection for high-risk localized prostate cancer undergoing radical prostatectomy Reviewed

H. Kumon, Y. Ariyoshi, K. Sasaki, T. Sadahira, M. Araki, S. Ebara, H. Yanai, M. Watanabe, Y. Nasu

CANCER GENE THERAPY 23 ( 11 ) 400 - 409 2016.11

Language：English Publishing type：Research paper (scientific journal) Publisher：NATURE PUBLISHING GROUP

As the First-In-Human study of in situ gene therapy using an adenovirus vector carrying the human REIC (reduced expression in immortalized cell)/Dkk-3 gene (Ad-REIC), we conducted neoadjuvant intraprostatic injections in patients with high-risk localized prostate cancer undergoing radical prostatectomy (RP). Patients with recurrence probability of 35% or more within 5 years following RP, as calculated by Kaftan's nomogram, were enrolled. Patients received two ultrasound-guided intratumoral injections at 2-week intervals, followed by RP 6 weeks after the second injection. After confirming the safety of the therapeutic interventions with initially planned three escalating doses of 1.0 x 10(10), 1.0 x 10(11) and 1.0 x 10(12) viral particles (vp) in 1.0-1.2 ml (n=3, 3 and 6), an additional higher dose of 3.0 x 10(12) vp in 3.6 ml (n=6) Was further studied. All four DLs including the additional dose level-4 (DL-4) were feasible with no adverse events, except for grade 1 or 2 transient fever. Laboratory toxicities were grade 1 or 2 elevated aspartate transaminase/alanine transaminase (n=4). Regarding antitumor activities, cytopathic effects (tumor degeneration With cytolysis and pyknosis) and remarkable tumor-infiltrating lymphocytes in the targeted tumor areas were detected in a clear dose-dependent manner. Consequently, biochemical recurrence-free survival in DL-4 was significantly more favorable than in patient groups DL-1+2+2:

DOI： 10.1038/cgt.2016.53

The Efficacy of Rituximab in High-risk Renal Transplant Recipients. Reviewed

Motoo Araki, Koichiro Wada, Yosuke Mitsui, Risa Kubota, Takashi Yoshioka, Yuichi Ariyoshi, Yasuyuki Kobayashi, Masashi Kitagawa, Katsuyuki Tanabe, Hiroshi Sugiyama, Jun Wada, Masami Watanabe, Toyohiko Watanabe, Katsuyuki Hotta, Yasutomo Nasu

Acta medica Okayama 70 ( 4 ) 295 - 7 2016.8

Authorship：Lead author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Okayama University Medical School

Although graft survival following renal transplantation (RTx) has improved, outcomes following highrisk RTx are variable. Preexisting antibodies, including donor-specific antibodies (DSA), play an important role in graft dysfunction and survival. We have designed a study to investigate the safety and efficacy of anti-CD20 monoclonal antibodies (rituximab) in high-risk RTx recipients. Major eligibility criteria include: 1) major and minor ABO blood group mismatch, 2) positive DSA. Thirty-five patients will receive 200 mg/body of rituximab. The primary endpoint is the incidence of B cell depletion. This study will clarify whether rituximab is efficacious in improving graft survival in high-risk RTx recipients.

DOI： 10.18926/AMO/54507

Clinical analysis of bacterial strain profiles isolated from urinary tract infections: A 30-year study. Reviewed International journal

Koichiro Wada, Shinya Uehara, Masumi Yamamoto, Takuya Sadahira, Ritsuko Mitsuhata, Motoo Araki, Yasuyuki Kobayashi, Ayano Ishii, Reiko Kariyama, Toyohiko Watanabe, Yasutomo Nasu, Hiromi Kumon

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy 22 ( 7 ) 478 - 82 2016.7

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE BV

OBJECTIVES: We analyzed bacterial strains isolated from urine samples of patients with urinary tract infections (UTI) at Okayama University Hospital over a 30-year period to characterize trends in species and antimicrobial susceptibilities. METHODS: Clinical isolates were collected from in- and out-patients with pyuria and bacteriuria who were treated between 1984 and 2014 (one episode per patient and plural isolates were counted in polymicrobial infection). We examined these isolates to identify pathogens and tested for antimicrobial susceptibility. RESULTS: Isolates from complicated UTI over a 30-year period revealed Pseudomonas aeruginosa (P. aeruginosa) was the most frequently isolated in the first decade (1984-1994), MRSA in the second decade (1995-2004), and Escherichia coli (E. coli) in the latest decade (2005-2014). In uncomplicated UTI examined over 20 years, E. coli was the most frequently isolated species accounting for 47-94% of isolates. Fluoroquinolone (FQs)-insusceptible E. coli were first isolated in 1994 and increased to about 35% in 2013 in patients with complicated UTI. CONCLUSIONS: Complicated UTI involving P. aeruginosa and MRSA decreased over the last 10 years. Our data suggest that several factors such as shorter hospitalizations, shorter indwelling catheter use, and appropriate antimicrobial use has decreased colonization of P. aeruginosa and MRSA with relative increases in isolation of E. coli including FQs-insusceptible strains. We must continue our surveillance of antimicrobial-resistant bacteria isolated from urine samples and evaluate antibiograms, since their persistence in the urinary tract would be problematic.

DOI： 10.1016/j.jiac.2016.04.004

Effectiveness and Safety of Ureteroscopic Holmium Laser Lithotripsy for Upper Urinary Tract Calculi in Elderly Patients Reviewed

Takashi Yoshioka, Hideo Otsuki, Shinya Uehara, Toshihiro Shimizu, Wataru Murao, Koji Fujio, Kei Fujio, Koichiro Wada, Motoo Araki, Yasutomo Nasu

ACTA MEDICA OKAYAMA 70 ( 3 ) 159 - 166 2016.6

Language：English Publishing type：Research paper (scientific journal) Publisher：OKAYAMA UNIV MED SCHOOL

Upper urinary tract calculi are common; however, there is no recommended treatment selection for elderly patients. Ureteroscopic holmium laser lithotripsy (URS lithotripsy) is minimally invasive, and it provides a high stone-free rate (SFR) treatment for upper urinary tract calculi. Here, we retrospectively evaluated the surgical outcomes of URS lithotripsy after dividing the 189 cases into 3 groups by patient age: the '< 65 group' (< 65 years old, n=108), the '65-74 group' (65-74 years old, n=42), and the '>= 75 group' (>= 75 years old, n=39). The patients 'characteristics, stone status, and perioperative outcomes were assessed. The 65-74 group and the >= 75 group had a significantly higher prevalence of hypertension compared to the < 65 group. Compared to the < 65 group, the 65-74 group had a significantly higher prevalence of hyperlipidemia, and the >= 75 group had significantly higher the American Society of Anesthesiologists (ASA) scores. Despite these preoperative risk factors, SFR and postoperative pyelonephritis in the 65-74 group and the >= 75 group were similar to those of the < 65 group. In conclusion, URS lithotripsy is the preferred treatment for upper urinary tract calculi, even for elderly patients who have multiple preoperative risk factors.

DOI： 10.18926/AMO/54414

A Case of Metastatic Urachal Cancer Including a Neuroendocrine Component Treated with Gemcitabine, Cisplatin and Paclitaxel Combination Chemotherapy Reviewed

Shin Ebara, Yasuyuki Kobayashi, Katsumi Sasaki, Motoo Araki, Morito Sugimoto, Koichirou Wada, Kei Fujio, Atsushi Takamoto, Toyohiko Watanabe, Hiroyuki Yanai, Yasutomo Nasu

ACTA MEDICA OKAYAMA 70 ( 3 ) 223 - 227 2016.6

Language：English Publishing type：Research paper (scientific journal) Publisher：OKAYAMA UNIV MED SCHOOL

The present case report describes a case of recurrent and advanced urachal carcinoma including neuroendocrine features with iliac bone metastasis after partial cystectomy and adjuvant chemotherapy consisting of irinotecan and cisplatin in a 32-year-old man. He received gemcitabine/cisplatin/paclitaxel (GCP) combination chemotherapy, consisting of gemcitabin (1,000mg/m(2)) on day 1, 8, cisplatin (70mg/m(2)) on day 1, and paclitaxel (80mg/m(2)) on day 1 and 8. After three cycles of chemotherapy, PET-CT showed complete regression of the disease. So the patient underwent total cystoure-threctomy, and histological examination showed an almost complete pathological response. External beam radiation therapy was also given to the ileac bone metastasis regions. However, PET-CT taken 17 months after the external beam radiation showed multiple lung metastases. He received GCP chemotherapy again, which resulted in a complete response again after three cycles of chemotherapy. This is the first report on GCP chemotherapy used not only as a salvage chemotherapy but also as a rechallenge regimen for metastatic urachal cancer including a neuroendocrine component.

DOI： 10.18926/AMO/54423

The induction of antigen-specific CTL by in situ Ad-REIC gene therapy Reviewed

Y. Ariyoshi, M. Watanabe, S. Eikawa, C. Yamazaki, T. Sadahira, T. Hirata, M. Araki, S. Ebara, Y. Nasu, H. Udono, H. Kumon

GENE THERAPY 23 ( 5 ) 408 - 414 2016.5

Language：English Publishing type：Research paper (scientific journal) Publisher：NATURE PUBLISHING GROUP

An adenovirus vector carrying the human Reduced Expression in Immortalized Cell (REIC)/Dkk-3 gene (Ad-REIC) mediates simultaneous induction of cancer-selective apoptosis and augmentation of anticancer immunity. In our preclinical and clinical studies, in situ Ad-REIC gene therapy showed remarkable direct and indirect antitumor effects to realize therapeutic cancer vaccines. We herein aimed to confirm the induction of tumor-associated antigen-specific cytotoxic T lymphocytes (CTLs) by Ad-REIC. Using an ovalbumin (OVA), a tumor-associated antigen, expressing E.G7 tumor-bearing mouse model, we investigated the induction and expansion of OVA-specific CTLs responsible for indirect, systemic effects of Ad-REIC. The intratumoral administration of Ad-REIC mediated clear antitumor effects with the accumulation of OVA-specific CTLs in the tumor tissues and spleen. The CD86-positive dendritic cells (DCs) were upregulated in the tumor draining lymph nodes of Ad-REIC-treated mice. In a dual tumor-bearing mouse model in the left and right back, Ad-REIC injection in one side significantly suppressed the tumor growth on both sides and significant infiltration of OVA-specific CTLs into non-injected tumor was also detected. Consequently, in situ Ad-REIC gene therapy is expected to realize a new-generation cancer vaccine via anticancer immune activation with DC and tumor antigen-specific CTL expansion.

DOI： 10.1038/gt.2016.7

Factors Predicting Adhesion between Renal Capsule and Perinephric Adipose Tissue in Partial Nephrectomy Reviewed

Yasuyuki Kobayashi, Hiroaki Kurahashi, Yuko Matsumoto, Koichiro Wada, Katsumi Sasaki, Motoo Araki, Shin Ebara, Toyohiko Watanabe, Yasutomo Nasu

ACTA MEDICA OKAYAMA 70 ( 2 ) 69 - 74 2016.4

Language：English Publishing type：Research paper (scientific journal) Publisher：OKAYAMA UNIV MED SCHOOL

In minimally invasive partial nephrectomy (MIPN), it is important to preoperatively predict the degree of difficulty of tumor resection. When severe adhesions occur between the renal capsule and perinephric adipose tissue, detachment can be difficult. Preoperative prediction of adhesion is thought to be useful in the selection of surgical procedure. Subjects were 63 patients of a single surgeon who had received MIPN between April 2008 and August 2013 at Okayama University Hospital. Of these patients, this study followed 47 in whom the presence or absence of adhesions between the renal capsule and perinephric adipose tissue was confirmed using intraoperative videos. Data collected included: sex, BMI, CT finding (presence of fibroids in perinephric adipose tissue), comorbidities and lifestyle. Adhesion was observed in 7 patients (14.9). The mean operative time was 291.6min in the adhesion group, and 226.3min in the group without. The increased time in the adhesions group was significant (p<0.05). Predictive factors were a positive CT finding for fibroid structure and comorbidity of hypertension (p<0.05). In MIPN, difficulty of surgery can be affected by the presence of adhesion of the perinephric adipose tissue. Predicting such adhesion from preoperative CT is thus important.

DOI： 10.18926/AMO/54185

ADVANCED TWO-STEP TRANSCRIPTIONAL AMPLIFICATION AS A NOVEL SYSTEM FOR DETECTING VIABLE BLADDER CANCER CELLS

Takuya Sadahira, Masami Watanabe, Motoo Araki, Shin Ebara, Toyohiko Watanabe, Yasutomo Nasu

JOURNAL OF UROLOGY 195 ( 4 ) E610 - E610 2016.4

The gender specific risk factors for prolonged hospitalization due to acute pyelonephritis in a Japanese tertiary emergency center Reviewed

Risa Muneishi, Ryuta Tanimoto, Koichiro Wada, Philip Hsiao, Jun Eguchi, Motoo Araki, Toyohiko Watanabe, Yasutomo Nasu, Naoki Akebi

JOURNAL OF INFECTION AND CHEMOTHERAPY 22 ( 1-2 ) 108 - 111 2016.1

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE BV

Objectives: The aim of this study is to characterize the potential differences between male and female patients with acute pyelonephritis (AP) and to predict the severity of AP based on the length of hospital stay.
Methods: We conducted a retrospective medical chart review of 172 consecutive adult patients who were hospitalized in Tsuyama Central Hospital due to AP from January 2007 through June 2012. We analyzed the length of hospital stay by the proportional hazard model.
Results: A total of 172 patients were identified who were admitted to our hospital with a diagnosis of AP. Of them, 62% (106/172) were female. Except for urological malignancy, there was no significant difference between men and women in underlying disease. Out of 26 variables, univariate analysis in male showed that only urolithiasis (OR 1.75, p = 0.0294) was significantly associated with longer hospital stay, while septic shock (OR 3.18, P = 0.003), urological malignancy (OR 2.94, P = 0.002), age over 65 (OR 1.66, p = 0.018) and neurogenic bladder (OR 1.92, p = 0.014) were all associated with longer hospital stay in female patients.
Conclusions: This is the first report to identify the risk factors for prolonged hospital stay for the patients who were admitted with AP in the Japanese population. The risk factors causing prolonged hospital stay were totally different between males and females. Reviewing the medical history based on sex gender might enable a clinician to predict the severity of acute pyelonephritis during the initial evaluation. (C) 2015, Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.jiac.2015.11.007

Feasibility of Neoadjuvant Ad-REIC Gene Therapy in Patients with High-Risk Localized Prostate Cancer Undergoing Radical Prostatectomy. International journal

Hiromi Kumon, Katsumi Sasaki, Yuichi Ariyoshi, Takuya Sadahira, Motoo Araki, Shin Ebara, Hiroyuki Yanai, Masami Watanabe, Yasutomo Nasu

Clinical and translational science 8 ( 6 ) 837 - 40 2015.12

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

In a phase I/IIa study of in situ gene therapy using an adenovirus vector carrying the human REIC/Dkk-3 gene (Ad-REIC), we assessed the inhibitory effects of cancer recurrence after radical prostatectomy (RP), in patients with high risk localized prostate cancer (PCa). After completing the therapeutic interventions with initially planned three escalating doses of 1.0 × 10(10) , 1.0 × 10(11) , and 1.0 × 10(12) viral particles (VP) in 1.0-1.2 mL (n = 3, 3, and 6), an additional higher dose of 3.0 × 10(12) VP in 3.6 mL (n = 6) was further studied. Patients with recurrence probability of 35% or more within 5 years after RP as calculated by Kattan's nomogram, were enrolled. They received two ultrasound-guided intratumoral injections at 2-week intervals, followed by RP 6 weeks after the second injection. Based on the findings of MRI and biopsy mapping, as a rule, one track injection to the most prominent cancer area was given to initial 12 patients and 3 track injections to multiple cancer areas in additional 6 patients. As compared to the former group, biochemical recurrence-free survival of the latter showed a significantly favorable outcome. Neoadjuvant Ad-REIC, mediating simultaneous induction of cancer selective apoptosis and augmentation of antitumor immunity, is a feasible approach in preventing cancer recurrence after RP. (199).

DOI： 10.1111/cts.12362