title: Immunoregulatory Forkhead Box Protein p3-Positive Lymphocytes Are Associated with Overall Survival in Patients with Pancreatic Neuroendocrine Tumors.
abstract: BACKGROUND
  Forkhead box protein p3-positive (FoxP3(+)) regulatory T cells (Tregs) suppress host T-cell-mediated immune responses, limit surveillance against cancers, and have been associated with a poor prognosis.
  
  
  METHODS
  This study aims to identify the prognostic significance of FoxP3(+) Tregs in pancreatic neuroendocrine tumors (PNETs). Patients diagnosed with PNETs between 1992 and 2014 (n = 101) were included in this retrospective analysis. Clinical data, histopathology, and expression of FoxP3(+) Tregs and Ki-67 by immunohistochemistry were assessed. The association of these factors with survival was tested by log-rank test and in additional multivariable analysis.
  
  
  RESULTS
  A total of 101 patients were included in this study. Mean age was 58.0 years (range 18 to 87 years) and median tumor size was 25 mm (range 8 to 160 mm). The degree of infiltration of tumor by FoxP3(+) Tregs was graded as 0 (n = 75), 1 (n = 15), or 2 (n = 11). Median follow-up was 50 months (interquartile range 123 months; Q1 = 20 months and Q3 = 123 months). In univariate analyses, patient age older than 57 years, TNM stage III or IV, tumor size >25 mm, Ki-67 labeling index >20, and a high number of FoxP3(+) tumor-infiltrating lymphocytes were significantly associated with poorer overall survival. In multivariable analyses, FoxP3(+) expression score of 2 (hazard ratio = 6.9; 95% CI 1.4-34.4) was the only statistically significant predictor for overall mortality.
  
  
  CONCLUSIONS
  FoxP3(+) Treg expression is an independent prognostic factor in patients with PNETs, associated with statistically significant shorter overall survival. There is a role for additional research into the immune-mediated role of FoxP3(+) Tregs in PNETs.
authors.affiliation: Department of Gastrointestinal Surgery, Royal North Shore Hospital and North Shore Private Hospital, University of Sydney, New South Wales, Australia. Electronic address: Philipdereuver@gmail.com.
authors.forename: Philip R
authors.initials: PR
authors.lastname: de Reuver
authors.affiliation: Department of Gastrointestinal Surgery, Royal North Shore Hospital and North Shore Private Hospital, University of Sydney, New South Wales, Australia.
authors.forename: Shreya
authors.initials: S
authors.lastname: Mehta
authors.affiliation: Department of Gastrointestinal Surgery, Royal North Shore Hospital and North Shore Private Hospital, University of Sydney, New South Wales, Australia.
authors.forename: Preetjote
authors.initials: P
authors.lastname: Gill
authors.affiliation: Department of Anatomical Pathology, Royal North Shore Hospital, Cancer Diagnosis and Pathology Group Kolling Institute of Medical Research, University of Sydney, New South Wales, Australia.
authors.forename: Juliana
authors.initials: J
authors.lastname: Andrici
authors.affiliation: Department of Anatomical Pathology, Royal North Shore Hospital, Cancer Diagnosis and Pathology Group Kolling Institute of Medical Research, University of Sydney, New South Wales, Australia.
authors.forename: Lisa
authors.initials: L
authors.lastname: D'Urso
authors.affiliation: Department of Anatomical Pathology, Royal North Shore Hospital, Cancer Diagnosis and Pathology Group Kolling Institute of Medical Research, University of Sydney, New South Wales, Australia.
authors.forename: Adele
authors.initials: A
authors.lastname: Clarkson
authors.affiliation: Department of Gastrointestinal Surgery, Royal North Shore Hospital and North Shore Private Hospital, University of Sydney, New South Wales, Australia.
authors.forename: Anubhav
authors.initials: A
authors.lastname: Mittal
authors.affiliation: Department of Gastrointestinal Surgery, Royal North Shore Hospital and North Shore Private Hospital, University of Sydney, New South Wales, Australia.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Hugh
authors.affiliation: Department of Gastrointestinal Surgery, Royal North Shore Hospital and North Shore Private Hospital, University of Sydney, New South Wales, Australia; Macquarie University Hospital, Macquarie University, New South Wales, Australia.
authors.forename: Jaswinder S
authors.initials: JS
authors.lastname: Samra
authors.affiliation: Department of Anatomical Pathology, Royal North Shore Hospital, Cancer Diagnosis and Pathology Group Kolling Institute of Medical Research, University of Sydney, New South Wales, Australia.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Gill
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism*; D005260:Female; D005500:Follow-Up Studies; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D016246:Lymphocytes, Tumor-Infiltrating / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D018358:Neuroendocrine Tumors / Q000276:immunology* / Q000401:mortality / Q000601:surgery; D010180:Pancreatectomy; D010190:Pancreatic Neoplasms / Q000276:immunology* / Q000401:mortality / Q000601:surgery; D016577:Pancreaticoduodenectomy; D011379:Prognosis; D012189:Retrospective Studies; D016019:Survival Analysis; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism*; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors