Research ArticleCancer Diagnostics

Nondestructive tissue analysis for ex vivo and in vivo cancer diagnosis using a handheld mass spectrometry system

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Science Translational Medicine  06 Sep 2017:
Vol. 9, Issue 406, eaan3968
DOI: 10.1126/scitranslmed.aan3968
  • Fig. 1. Schematic representation of the MasSpec Pen system and operational steps.

    (A) The pen-sized handheld device is directly integrated into a laboratory-built MS interface through PTFE tubing. The integrated MS interface houses the pinch valves, microcontroller, and tubing to connect the system to the mass spectrometer inlet. The system is triggered by the user through a foot pedal. (B) The MasSpec Pen (handheld device) is designed with a PDMS tip and three PTFE conduits, which provide incoming water (1) and gas (2) to the tip and an outgoing conduit for the water droplet (3). (C) The tip contacts the tissue for analysis. Inset shows the three conduits (1 to 3) and solvent reservoir (4) within the tip. When the system is triggered (t = 0 s) by using the foot pedal, the syringe pump delivers a controlled volume of water to the reservoir. The discrete water droplet interacts with the tissue to extract the molecules (t = 2 s). After 3 s of extraction, the vacuum and the gas conduits are concomitantly opened (arrows) to transport the droplet from the MasSpec Pen to the mass spectrometer through the tubing system for molecular analysis.

  • Fig. 2. MasSpec Pen analysis of PTC and normal thyroid tissue sections.

    (A) A representative negative ion mode MasSpec Pen mass spectra obtained from a normal human thyroid tissue section (average of n = 5 mass spectra) and (B) a PTC tissue section (average of n = 4 mass spectra) are shown. Identification of the most abundant molecular ions is provided. Insets shows an optical image of the H&E-stained tissue sections evaluated by histopathology.

  • Fig. 3. Nondestructive molecular analysis of human tissue samples using the MasSpec Pen.

    (A) Optical images show a lung adenocarcinoma tissue sample before, during, and after the MasSpec Pen analysis. A magnification of the tissue specimen (inset) shows no macroscopic damage to the tissue region analyzed by the MasSpec Pen. (B) Negative ion mode mass spectrum obtained for the tissue region analyzed including the identification of the most abundant molecular ions.

  • Fig. 4. PCA of the data obtained from human tissue samples using the MasSpec Pen.

    A total of 253 patient tissue samples were analyzed including breast (n = 45), thyroid (n = 56), ovary (n = 57), and lung (n = 96) cancer and normal tissue samples. 3D PCA (PC1, PC2, and PC3) score plots are shown for each tissue type. The first three PCs explain the 77, 69, 51, and 87% of the total variance of breast, thyroid, lung, and ovarian data sets, respectively.

  • Fig. 5. MasSpec Pen analysis of an HGSC tissue sample with mixed histologic composition.

    (A) Optical image shows the tissue sample that was analyzed at the demarcated regions (1 to 5) using a 1.5-mm-diameter MasSpec Pen. After the MasSpec Pen analysis, the tissue sample was frozen, sectioned, and H&E-stained. An optical image of the H&E-stained tissue section obtained at region 3 is shown (inset), presenting a mixed histologic composition including cancer and adjacent normal stroma tissue. (B) The MasSpec Pen negative ion mode mass spectra are shown for regions 1 (normal stroma; average of n = 3 mass spectra), 3 (mixture of normal stroma and cancer; average of n = 3 mass spectra), and 5 (cancer; average of n = 3 mass spectra). (C) Table listing the pathologic diagnosis of the five regions analyzed and the Lasso prediction results.

  • Fig. 6. Intraoperative analysis of tumor and normal tissues in a murine model.

    (A) Experiments were performed in vivo in mice under anesthesia. Optical images show the animal under anesthesia and before, during, and after the MasSpec Pen analysis. (B) Representative negative ion mode mass spectra show distinct molecular profiles from normal (average of n = 3 mass spectra) and tumor (average of n = 3 mass spectra) tissues.

  • Table 1. Human tissue sample details and results obtained using the MasSpec Pen.

    Pathological diagnosis, number of patient samples, and the Lasso prediction sensitivity, specificity, accuracy, and AUC obtained using a leave-one-out cross-validation approach are shown.

    OrganPathologic evaluationNumber of patientsLasso prediction
    DiagnosisHistologic typeSensitivitySpecificityAccuracyAUC
    BreastNormal2987.5%100.0%95.6%1.00
    CancerDuctal carcinoma16
    Lung*Normal4797.9%95.7%96.8%0.97
    CancerAdenocarcinoma1788.2%93.6%92.2%0.98
    Squamous cell1788.2%95.7%93.8%0.93
    Others14
    OvaryNormal29100.0%89.7%94.7%0.98
    CancerHigh-grade serous28
    ThyroidNormal27
    TumorPapillary carcinoma1894.4%100.0%97.8%0.99
    Follicular adenoma1190.9%96.3%94.7%0.93

    *Lasso prediction results for lung are shown for normal versus all cancer tissues (first row), followed by normal versus lung adenocarcinoma (middle row) and normal versus squamous cell carcinoma (last row).

    †Lasso prediction results for thyroid are shown for normal versus malignant papillary carcinoma and normal versus benign follicular adenoma.

    Supplementary Materials

    • www.sciencetranslationalmedicine.org/cgi/content/full/9/406/eaan3968/DC1

      Materials and Methods

      Fig. S1. Effect of MasSpec Pen contact time on the mass spectra obtained.

      Fig. S2. Effect of MasSpec Pen tip diameter on the mass spectra obtained.

      Fig. S3. MasSpec Pen analysis of a mouse brain tissue section.

      Fig. S4. Positive ion mode analysis using the MasSpec Pen.

      Fig. S5. Comparison between MasSpec Pen and DESI-MSI mass spectra.

      Fig. S6. Effect of MasSpec Pen solvent systems on the mass spectra obtained.

      Fig. S7. MasSpec Pen detection of protein ions.

      Fig. S8. PCA of the data obtained for the human tissue sections including normal and tumor thyroid and breast tissue sections.

      Fig. S9. Comparison between the MasSpec Pen mass spectra obtained from the tissue section and fresh tissue piece.

      Fig. S10. MasSpec Pen analysis of an HGSC tissue sample with mixed histologic composition.

      Fig. S11. Intraoperative analysis of tumor and normal tissues in a murine model.

      Fig. S12. MasSpec Pen analysis of the same tissue sample in vivo and ex vivo.

      Table S1. Data obtained for the identification of selected negative ion mode molecular ions from mouse brain tissue.

      Table S2. Data obtained for the identification of selected negative ion mode molecular ions from human thyroid tissue.

      Table S3. Data obtained for the identification of selected negative ion mode molecular ions from human ovarian tissue.

      Table S4. Data obtained for the identification of selected negative ion mode molecular ions from human lung tissue.

      Table S5. Data obtained for the identification of selected negative ion mode molecular ions from human breast tissue.

      Table S6. Patient demographics of the 253 human tissue samples used in this study.

      Movie S1. Simulation demonstrating the use of the MasSpec Pen for routine intraoperative diagnosis.

    • Supplementary Material for:

      Nondestructive tissue analysis for ex vivo and in vivo cancer diagnosis using a handheld mass spectrometry system

      Jialing Zhang, John Rector, John Q. Lin, Jonathan H. Young, Marta Sans, Nitesh Katta, Noah Giese, Wendong Yu, Chandandeep Nagi, James Suliburk, Jinsong Liu, Alena Bensussan, Rachel J. DeHoog, Kyana Y. Garza, Benjamin Ludolph, Anna G. Sorace, Anum Syed, Aydin Zahedivash, Thomas E. Milner, Livia S. Eberlin*

      *Corresponding author. Email: liviase{at}utexas.edu

      Published 6 September 2017, Sci. Transl. Med. 9, eaan3968 (2017)
      DOI: 10.1126/scitranslmed.aan3968

      This PDF file includes:

      • Materials and Methods
      • Fig. S1. Effect of MasSpec Pen contact time on the mass spectra obtained.
      • Fig. S2. Effect of MasSpec Pen tip diameter on the mass spectra obtained.
      • Fig. S3. MasSpec Pen analysis of a mouse brain tissue section.
      • Fig. S4. Positive ion mode analysis using the MasSpec Pen.
      • Fig. S5. Comparison between MasSpec Pen and DESI-MSI mass spectra.
      • Fig. S6. Effect of MasSpec Pen solvent systems on the mass spectra obtained.
      • Fig. S7. MasSpec Pen detection of protein ions.
      • Fig. S8. PCA of the data obtained for the human tissue sections including normal and tumor thyroid and breast tissue sections.
      • Fig. S9. Comparison between the MasSpec Pen mass spectra obtained from the tissue section and fresh tissue piece.
      • Fig. S10. MasSpec Pen analysis of an HGSC tissue sample with mixed histologic composition.
      • Fig. S11. Intraoperative analysis of tumor and normal tissues in a murine model.
      • Fig. S12. MasSpec Pen analysis of the same tissue sample in vivo and ex vivo.
      • Table S1. Data obtained for the identification of selected negative ion mode molecular ions from mouse brain tissue.
      • Table S2. Data obtained for the identification of selected negative ion mode molecular ions from human thyroid tissue.
      • Table S3. Data obtained for the identification of selected negative ion mode molecular ions from human ovarian tissue.
      • Table S4. Data obtained for the identification of selected negative ion mode molecular ions from human lung tissue.
      • Table S5. Data obtained for the identification of selected negative ion mode molecular ions from human breast tissue.
      • Table S6. Patient demographics of the 253 human tissue samples used in this study.
      • Legend for movie S1

      [Download PDF]

      Other Supplementary Material for this manuscript includes the following:

      • Movie S1 (.mov format). Simulation demonstrating the use of the MasSpec Pen for routine intraoperative diagnosis.

      [Download Movie S1]

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