title: Membrane Localization of Human Equilibrative Nucleoside Transporter 1 in Tumor Cells May Predict Response to Adjuvant Gemcitabine in Resected Cholangiocarcinoma Patients.
abstract: The use of gemcitabine as an adjuvant modality for cholangiocarcinoma (CC) is increasing, but limited data are available on predictive biomarkers of response. Human equilibrative nucleoside transporter 1 (hENT-1) is the major transporter involved in gemcitabine intracellular uptake. This study investigated the putative predictive role of hENT-1 localization in tumor cells of CC patients undergoing treatment with adjuvant gemcitabine.
  
  
  
  Seventy-one consecutive patients with resected CC receiving adjuvant gemcitabine at our center were retrospectively analyzed by immunohistochemistry for hENT-1 localization in tumor cells. The main outcome measure was disease-free survival (DFS). Hazard ratios (HRs) of relapse and associated 95% confidence intervals (CIs) were obtained from proportional hazards regression models stratified on quintiles of propensity score.
  
  
  
  Twenty-three (32.4%) cases were negative for hENT-1, 22 (31.0%) were positive in the cytoplasm only, and 26 (36.6%) showed concomitant cytoplasm/membrane staining. Patients with membrane hENT-1 had a longer DFS (HR 0.49, 95% CI 0.24-0.99, p = .046) than those who were negative or positive only in the cytoplasm of tumor cells. Notably, the association between DFS and membrane hENT-1 was dependent on the number of gemcitabine cycles (one to two cycles: HR 0.96, 95% CI 0.34-2.68; three to four cycles: HR 0.99, 95% CI 0.34-2.90; five to six cycles: HR 0.27, 95% CI 0.10-0.77).
  
  
  
  hENT-1 localization on tumor cell membrane may predict response to adjuvant gemcitabine in CC patients receiving more than four cycles of chemotherapy. Further prospective randomized trials on larger populations are required to confirm these preliminary results, so that optimal gemcitabine-based chemotherapy may be tailored for CC patients in the adjuvant setting.
  
  
  
  Gemcitabine is becoming an increasingly used adjuvant modality in cholangiocarcinoma (CC), but limited data are available on predictive biomarkers of response. In this study, patients receiving more than four cycles of adjuvant gemcitabine and harboring Human equilibrative nucleoside transporter 1 (hENT-1, the major transporter involved in gemcitabine intracellular uptake) on tumor cell membrane had a longer disease-free survival compared with patients negative or positive for hENT-1 only in the cytoplasm of tumor cells. Overall these results may lay the basis for further prospective randomized trials based on a larger population of patients and may prove useful for tailoring appropriate gemcitabine-based chemotherapy for CC patients in the adjuvant setting.
authors.affiliation: Department of Experimental, Diagnostic, and Specialty Medicine, S. Orsola-Malpighi University Hospital, Bologna, Italy "G. Prodi" Interdepartmental Center for Cancer Research, University of Bologna, Bologna, Italy giovanni.brandi@unibo.it.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Brandi
authors.affiliation: Department of Experimental, Diagnostic, and Specialty Medicine, S. Orsola-Malpighi University Hospital, Bologna, Italy Center for Applied Biomedical Research, S. Orsola-Malpighi University Hospital, Bologna, Italy.
authors.forename: Marzia
authors.initials: M
authors.lastname: Deserti
authors.affiliation: "F. Addarii" Institute of Oncology and Transplantation Pathology, S. Orsola-Malpighi University Hospital, Bologna, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Vasuri
authors.affiliation: Department of Medical and Surgical Sciences, S. Orsola-Malpighi University Hospital, Bologna, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Farioli
authors.affiliation: "F. Addarii" Institute of Oncology and Transplantation Pathology, S. Orsola-Malpighi University Hospital, Bologna, Italy.
authors.forename: Alessio
authors.initials: A
authors.lastname: Degiovanni
authors.affiliation: Department of Experimental, Diagnostic, and Specialty Medicine, S. Orsola-Malpighi University Hospital, Bologna, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Palloni
authors.affiliation: Department of Experimental, Diagnostic, and Specialty Medicine, S. Orsola-Malpighi University Hospital, Bologna, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Frega
authors.affiliation: Department of Experimental, Diagnostic, and Specialty Medicine, S. Orsola-Malpighi University Hospital, Bologna, Italy.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Barbera
authors.affiliation: Department of Experimental, Diagnostic, and Specialty Medicine, S. Orsola-Malpighi University Hospital, Bologna, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: de Lorenzo
authors.affiliation: Department of Experimental, Diagnostic, and Specialty Medicine, S. Orsola-Malpighi University Hospital, Bologna, Italy.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Garajova
authors.affiliation: Department of Experimental, Diagnostic, and Specialty Medicine, S. Orsola-Malpighi University Hospital, Bologna, Italy.
authors.forename: Mariacristina
authors.initials: M
authors.lastname: Di Marco
authors.affiliation: Division of Surgery and Transplantation, S. Orsola-Malpighi University Hospital, Bologna, Italy.
authors.forename: Antonio D
authors.initials: AD
authors.lastname: Pinna
authors.affiliation: Division of Surgery and Transplantation, S. Orsola-Malpighi University Hospital, Bologna, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Cescon
authors.affiliation: Division of Surgery and Transplantation, S. Orsola-Malpighi University Hospital, Bologna, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Cucchetti
authors.affiliation: Division of Surgery and Transplantation, S. Orsola-Malpighi University Hospital, Bologna, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Ercolani
authors.affiliation: "F. Addarii" Institute of Oncology and Transplantation Pathology, S. Orsola-Malpighi University Hospital, Bologna, Italy.
authors.forename: Antonietta
authors.initials: A
authors.lastname: D'Errico-Grigioni
authors.affiliation: Department of Experimental, Diagnostic, and Specialty Medicine, S. Orsola-Malpighi University Hospital, Bologna, Italy.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Pantaleo
authors.affiliation: Department of Experimental, Diagnostic, and Specialty Medicine, S. Orsola-Malpighi University Hospital, Bologna, Italy "G. Prodi" Interdepartmental Center for Cancer Research, University of Bologna, Bologna, Italy.
authors.forename: Guido
authors.initials: G
authors.lastname: Biasco
authors.affiliation: Department of Experimental, Diagnostic, and Specialty Medicine, S. Orsola-Malpighi University Hospital, Bologna, Italy Center for Applied Biomedical Research, S. Orsola-Malpighi University Hospital, Bologna, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Tavolari
mesh_terms: D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D001650:Bile Duct Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000401:mortality / Q000601:surgery; D017024:Chemotherapy, Adjuvant; D018281:Cholangiocarcinoma / Q000737:chemistry / Q000188:drug therapy* / Q000401:mortality / Q000601:surgery; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D018572:Disease-Free Survival; D033721:Equilibrative Nucleoside Transporter 1 / Q000032:analysis*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D033721:Equilibrative Nucleoside Transporter 1; C438649:SLC29A1 protein, human; D003841:Deoxycytidine; D000093542:Gemcitabine
keywords: Adjuvant gemcitabine; Cholangiocarcinoma; Human equilibrative nucleoside transporter 1; Predictive biomarkers of response to chemotherapy