title: Transport properties of pancreatic cancer describe gemcitabine delivery and response.
abstract: BACKGROUND
  The therapeutic resistance of pancreatic ductal adenocarcinoma (PDAC) is partly ascribed to ineffective delivery of chemotherapy to cancer cells. We hypothesized that physical properties at vascular, extracellular, and cellular scales influence delivery of and response to gemcitabine-based therapy.
  
  
  METHODS
  We developed a method to measure mass transport properties during routine contrast-enhanced CT scans of individual human PDAC tumors. Additionally, we evaluated gemcitabine infusion during PDAC resection in 12 patients, measuring gemcitabine incorporation into tumor DNA and correlating its uptake with human equilibrative nucleoside transporter (hENT1) levels, stromal reaction, and CT-derived mass transport properties. We also studied associations between CT-derived transport properties and clinical outcomes in patients who received preoperative gemcitabine-based chemoradiotherapy for resectable PDAC.
  
  
  RESULTS
  Transport modeling of 176 CT scans illustrated striking differences in transport properties between normal pancreas and tumor, with a wide array of enhancement profiles. Reflecting the interpatient differences in contrast enhancement, resected tumors exhibited dramatic differences in gemcitabine DNA incorporation, despite similar intravascular pharmacokinetics. Gemcitabine incorporation into tumor DNA was inversely related to CT-derived transport parameters and PDAC stromal score, after accounting for hENT1 levels. Moreover, stromal score directly correlated with CT-derived parameters. Among 110 patients who received preoperative gemcitabine-based chemoradiotherapy, CT-derived parameters correlated with pathological response and survival.
  
  
  CONCLUSIONS
  Gemcitabine incorporation into tumor DNA is highly variable and correlates with multiscale transport properties that can be derived from routine CT scans. Furthermore, pretherapy CT-derived properties correlate with clinically relevant endpoints.
  
  
  BACKGROUND
  Clinicaltrials.gov NCT01276613.
  
  
  BACKGROUND
  Lustgarten Foundation (989161), Department of Defense (W81XWH-09-1-0212), NIH (U54CA151668, KCA088084).
authors.forename: Eugene J
authors.initials: EJ
authors.lastname: Koay
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Truty
authors.forename: Vittorio
authors.initials: V
authors.lastname: Cristini
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Thomas
authors.forename: Rong
authors.initials: R
authors.lastname: Chen
authors.forename: Deyali
authors.initials: D
authors.lastname: Chatterjee
authors.forename: Ya'an
authors.initials: Y
authors.lastname: Kang
authors.forename: Priya R
authors.initials: PR
authors.lastname: Bhosale
authors.forename: Eric P
authors.initials: EP
authors.lastname: Tamm
authors.forename: Christopher H
authors.initials: CH
authors.lastname: Crane
authors.forename: Milind
authors.initials: M
authors.lastname: Javle
authors.forename: Matthew H
authors.initials: MH
authors.lastname: Katz
authors.forename: Vijaya N
authors.initials: VN
authors.lastname: Gottumukkala
authors.forename: Marc A
authors.initials: MA
authors.lastname: Rozner
authors.forename: Haifa
authors.initials: H
authors.lastname: Shen
authors.forename: Jeffery E
authors.initials: JE
authors.lastname: Lee
authors.forename: Huamin
authors.initials: H
authors.lastname: Wang
authors.forename: Yuling
authors.initials: Y
authors.lastname: Chen
authors.forename: William
authors.initials: W
authors.lastname: Plunkett
authors.forename: James L
authors.initials: JL
authors.lastname: Abbruzzese
authors.forename: Robert A
authors.initials: RA
authors.lastname: Wolff
authors.forename: Gauri R
authors.initials: GR
authors.lastname: Varadhachary
authors.forename: Mauro
authors.initials: M
authors.lastname: Ferrari
authors.forename: Jason B
authors.initials: JB
authors.lastname: Fleming
mesh_terms: D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D001693:Biological Transport, Active; D021441:Carcinoma, Pancreatic Ductal / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism*; D018736:DNA Adducts / Q000378:metabolism; D004273:DNA, Neoplasm / Q000378:metabolism; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D033721:Equilibrative Nucleoside Transporter 1 / Q000378:metabolism; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D010190:Pancreatic Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism*; D011379:Prognosis; D011446:Prospective Studies; D014057:Tomography, X-Ray Computed; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D018736:DNA Adducts; D004273:DNA, Neoplasm; D033721:Equilibrative Nucleoside Transporter 1; C438649:SLC29A1 protein, human; D003841:Deoxycytidine; D000093542:Gemcitabine