title: The acceleration of glucose accumulation in renal cell carcinoma assessed by FDG PET/CT demonstrated acquisition of resistance to tyrosine kinase inhibitor therapy.
abstract: Tyrosine-kinase inhibitor (TKI) targeting angiogenesis improves the prognosis of patients with metastatic renal cell carcinoma (RCC), but its effect is temporary. In order to understand the mechanism by which RCC acquires resistance to TKI, we investigated the change of glucose accumulation in RCC by FDG PET/CT when they demonstrated progression disease (PD) against TKI.
  
  
  
  We monitored the FDG accumulation in RCC of 38 patients treated with TKI by 162 PET/CT sequentially until they were judged to demonstrate PD. Standardized uptake value (SUV), a simplified index of tissue FDG accumulation rate, was measured, and the sequential changes of max SUVmax (the highest SUV in an individual patient) was analyzed. Additionally, the expression of glucose transporter 1 (GLUT-1) and associated proteins in 786-O cells cultured under hypoxia were analyzed.
  
  
  
  The 10 patients with RCC which FDG accumulation was accelerated after beginning of TKI treatment demonstrated PD soon. The other 28 patients with RCC which FDG accumulation was suppressed by TKI showed longer progression-free survival (3.6 months vs 6.5 months, P = 0.0026), but this suppression in most cases (96%) was temporary and FDG accumulation was accelerated when tumor demonstrated PD. Interestingly, the FDG accumulation at PD was higher than that before TKI treatment in the half cases. The acceleration of FDG accumulation was suppressed by following treatment by mammalian target of rapamycin (mTOR) inhibitor. Additionally, in vitro assay demonstrated that the expression of GLUT-1 was increased in the RCC cells surviving under hypoxia condition via mTOR pathway.
  
  
  
  The acceleration of glucose accumulation dependent on mTOR in RCC assessed by FDG PET/CT demonstrated acquisition of resistance to TKI. FDG PET/CT had potential as an assessment method monitoring not only the initial response but also following status of RCC during TKI treatment.
  
  
  
  UMIN0000008141 , 11 Jun 2012. This trial was retrospectively registered.
authors.affiliation: Department of Urology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura Kanazawaku, Yokohama, 236-0004, Japan. nakaigan@med.yokohama-cu.ac.jp.
authors.forename: Noboru
authors.identifier: 0000-0002-7228-3447
authors.initials: N
authors.lastname: Nakaigawa
authors.affiliation: Department of Urology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura Kanazawaku, Yokohama, 236-0004, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Kondo
authors.affiliation: Department of Urology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura Kanazawaku, Yokohama, 236-0004, Japan.
authors.forename: Daiki
authors.initials: D
authors.lastname: Ueno
authors.affiliation: Department of Urology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura Kanazawaku, Yokohama, 236-0004, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Namura
authors.affiliation: Department of Urology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura Kanazawaku, Yokohama, 236-0004, Japan.
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Makiyama
authors.affiliation: Department of Urology, Yokosuka Kyosai Hospital, Yokosuka, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Kobayashi
authors.affiliation: Department of Urology, Yokosuka Kyosai Hospital, Yokosuka, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Shioi
authors.affiliation: Department of Urology, Yokohama Minami kyosai Hospital, Yokohama, Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Ikeda
authors.affiliation: Department of Urology, Kanagawa Cancer Center, Yokohama, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kishida
authors.affiliation: Department of Radiology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kaneta
authors.affiliation: Department of Radiology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Ryogo
authors.initials: R
authors.lastname: Minamimoto
authors.affiliation: Department of Radiology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Ukihide
authors.initials: U
authors.lastname: Tateishi
authors.affiliation: Department of Radiology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Tomio
authors.initials: T
authors.lastname: Inoue
authors.affiliation: Department of Urology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura Kanazawaku, Yokohama, 236-0004, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yao
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002291:Carcinoma, Papillary / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D002292:Carcinoma, Renal Cell / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D005260:Female; D019788:Fluorodeoxyglucose F18 / Q000378:metabolism*; D005500:Follow-Up Studies; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D007680:Kidney Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D000072078:Positron Emission Tomography Computed Tomography / Q000379:methods*; D011379:Prognosis; D011446:Prospective Studies; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D019275:Radiopharmaceuticals / Q000378:metabolism; D015996:Survival Rate
chemical_list: D047428:Protein Kinase Inhibitors; D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18; D005947:Glucose
keywords: FDG PET/CT; Renal cell carcinoma; Resistance acquisition; Standardized uptake value; Tyrosine kinase inhibitor