title: Circulating and tumor-infiltrating myeloid cells predict survival in human pleural mesothelioma.
abstract: BACKGROUND
  Malignant pleural mesothelioma (MPM) tumor cells produce copious amounts of myeloid cell-stimulating factors. The current study examined the prognostic significance of circulating monocytes and tumor-infiltrating macrophages on overall survival in patients with MPM.
  
  
  METHODS
  The authors retrospectively reviewed 667 patients with MPM who underwent cytoreductive surgery at the Brigham and Women's Hospital in Boston, Massachusetts between 1989 and 2009. Kaplan-Meier and Cox proportional hazards models were used to determine the impact of preoperative circulating monocytes on overall survival. Immunohistochemical staining for CD68 was performed on a tissue microarray of MPM tumors from 52 patients undergoing cytoreductive surgery. The phenotype of circulating monocytes and tumor-infiltrating macrophages in 7 additional patients was determined by flow cytometry.
  
  
  RESULTS
  The median survival for all patients was 13.4 months, and 35% of patients had tumors of nonepithelial histology. For patients with nonepithelial compared with epithelial tumors, survival was significantly worse (9.3 months vs 16.6 months; P < .0001), the number of monocytes was significantly higher (580 ± 20 cells/μL vs 520 ± 10 cells/μL; P = .002), and higher monocyte counts were associated with higher tumor stage. Increasing monocyte counts were correlated with poor survival for all patients with MPM. Within MPM tumors, macrophages comprised 27% ± 9% of the tumor area and demonstrated an immunosuppressive phenotype with high expression of CD163, CD206, and interleukin-4 receptor α. The degree of macrophage infiltration was found to be negatively correlated with survival in patients with nonepithelial (P = .008) but not those with epithelial (P = .7) MPM, independent of disease stage.
  
  
  CONCLUSIONS
  Higher numbers of circulating monocytes are associated with poor survival in all patients with MPM and higher densities of tumor-infiltrating macrophages are associated with poor survival in patients with nonepithelial MPM. Both may enable a novel target for immunotherapy.
authors.affiliation: Division of Thoracic Surgery, The Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Bryan M
authors.initials: BM
authors.lastname: Burt
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Rodig
authors.forename: Tamara R
authors.initials: TR
authors.lastname: Tilleman
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Elbardissi
authors.forename: Raphael
authors.initials: R
authors.lastname: Bueno
authors.forename: David J
authors.initials: DJ
authors.lastname: Sugarbaker
mesh_terms: D000368:Aged; D005260:Female; D006801:Humans; D008264:Macrophages / Q000473:pathology; D008297:Male; D008654:Mesothelioma / Q000401:mortality* / Q000473:pathology*; D008875:Middle Aged; D022423:Myeloid Cells / Q000473:pathology*; D009360:Neoplastic Cells, Circulating / Q000473:pathology*; D010997:Pleural Neoplasms / Q000401:mortality* / Q000473:pathology*; D011379:Prognosis; D015996:Survival Rate