title: Subclassification of prostate cancer circulating tumor cells by nuclear size reveals very small nuclear circulating tumor cells in patients with visceral metastases.
abstract: BACKGROUND
  Although enumeration of circulating tumor cells (CTCs) has shown some clinical value, the pool of CTCs contains a mixture of cells that contains additional information that can be extracted. The authors subclassified CTCs by shape features focusing on nuclear size and related this with clinical information.
  
  
  METHODS
  A total of 148 blood samples were obtained from 57 patients with prostate cancer across the spectrum of metastatic states: no metastasis, nonvisceral metastasis, and visceral metastasis. CTCs captured and enumerated on NanoVelcro Chips (CytoLumina, Los Angeles, Calif) were subjected to pathologic review including nuclear size. The distribution of nuclear size was analyzed using a Gaussian mixture model. Correlations were made between CTC subpopulations and metastatic status.
  
  
  RESULTS
  Statistical modeling of nuclear size distribution revealed 3 distinct subpopulations: large nuclear CTCs, small nuclear CTCs, and very small nuclear CTCs (vsnCTCs). Small nuclear CTCs and vsnCTC identified those patients with metastatic disease. However, vsnCTC counts alone were found to be elevated in patients with visceral metastases when compared with those without (0.36 ± 0.69 vs 1.95 ± 3.77 cells/mL blood; P<.001). Serial enumeration studies suggested the emergence of vsnCTCs occurred before the detection of visceral metastases.
  
  
  CONCLUSIONS
  There are morphologic subsets of CTCs that can be identified by fundamental pathologic approaches, such as nuclear size measurement. The results of this observational study strongly suggest that CTCs contain relevant information regarding disease status. In particular, the detection of vsnCTCs was found to be correlated with the presence of visceral metastases and should be formally explored as a putative blood-borne biomarker to identify patients at risk of developing this clinical evolution of prostate cancer.
authors.affiliation: Urologic Oncology Program and Uro-Oncology Research Laboratories, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California.
authors.forename: Jie-Fu
authors.initials: JF
authors.lastname: Chen
authors.affiliation: Department of Statistics, University of California at Los Angeles, Los Angeles, California.|Institute of Statistical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Hao
authors.initials: H
authors.lastname: Ho
authors.affiliation: Urologic Oncology Program and Uro-Oncology Research Laboratories, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California.
authors.forename: Jake
authors.initials: J
authors.lastname: Lichterman
authors.affiliation: Urologic Oncology Program and Uro-Oncology Research Laboratories, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California.
authors.forename: Yi-Tsung
authors.initials: YT
authors.lastname: Lu
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California at Los Angeles, Los Angeles, California.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California at Los Angeles, Los Angeles, California.
authors.forename: Mitch A
authors.initials: MA
authors.lastname: Garcia
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California at Los Angeles, Los Angeles, California.
authors.forename: Shang-Fu
authors.initials: SF
authors.lastname: Chen
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California at Los Angeles, Los Angeles, California.
authors.forename: An-Jou
authors.initials: AJ
authors.lastname: Liang
authors.affiliation: Urologic Oncology Program and Uro-Oncology Research Laboratories, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Hodara
authors.affiliation: Urologic Oncology Program and Uro-Oncology Research Laboratories, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California.
authors.forename: Haiyen E
authors.initials: HE
authors.lastname: Zhau
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California at Los Angeles, Los Angeles, California.
authors.forename: Shuang
authors.initials: S
authors.lastname: Hou
authors.affiliation: Urologic Oncology Program and Uro-Oncology Research Laboratories, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California.
authors.forename: Rafi S
authors.initials: RS
authors.lastname: Ahmed
authors.affiliation: Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Luthringer
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California at Los Angeles, Los Angeles, California.
authors.forename: Jiaoti
authors.initials: J
authors.lastname: Huang
authors.affiliation: Department of Statistics, University of California at Los Angeles, Los Angeles, California.|Institute of Statistical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Ker-Chau
authors.initials: KC
authors.lastname: Li
authors.affiliation: Urologic Oncology Program and Uro-Oncology Research Laboratories, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California.
authors.forename: Leland W K
authors.initials: LW
authors.lastname: Chung
authors.affiliation: Department of Pathology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
authors.forename: Zunfu
authors.initials: Z
authors.lastname: Ke
authors.affiliation: Institute of Statistical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Hsian-Rong
authors.initials: HR
authors.lastname: Tseng
authors.affiliation: Urologic Oncology Program and Uro-Oncology Research Laboratories, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California.
authors.forename: Edwin M
authors.initials: EM
authors.lastname: Posadas
mesh_terms: D002467:Cell Nucleus / Q000473:pathology*; D006801:Humans; D008297:Male; D009362:Neoplasm Metastasis / Q000473:pathology*; D009360:Neoplastic Cells, Circulating / Q000145:classification* / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000097:blood / Q000473:pathology*
keywords: NanoVelcro Chips; circulating tumor cells; nuclear size; prostate cancer; visceral metastasis