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K. Hirohashi



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    MO01 - Lung Cancer Biology - Techniques and Platforms (ID 90)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Biology
    • Presentations: 1
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      MO01.09 - A novel murine xenograft model using samples obtained by EBUS-TBNA (ID 773)

      11:10 - 11:15  |  Author(s): K. Hirohashi

      • Abstract
      • Presentation
      • Slides

      Background
      Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a minimally invasive approach for lymph node staging in patients with lung cancer. Although EBUS-TBNA has been utilized for various molecular testing, intrinsic characteristics of different lesions produce variability in the amount of cellular material that can be obtained. In some samples, the quantity of tumor recovered may be limited for subsequent testing. To overcome this problem, we evaluated the feasibility of establishing a murine tumor xenograft model using EBUS-TBNA samples for advanced translational research.

      Methods
      After confirmation of adequate sampling for cytopathological diagnosis during EBUS-TBNA, one additional pass was performed for this study (NCT01487603). The aspirate was stored in cell preservative solution (RPMI1640 with 10% FBS) for inoculation of the tumor for the xenograft model. The sample was transported to the laboratory on ice, then mixed with Matrigel and centrifuged. The pellet which contained tumor fragments was implanted to the subcutaneous pocket on the right flank of a NSG (NOD scid gamma) mouse. Once we confirmed the engraftment of the tumor, we passed the tumor to another mouse until 3 passages were completed. The success rate of tumor xenograft establishment was examined along with histopathology and the cellularity and cytopathologial diagnosis of the primary EBUS-TBNA samples.

      Results
      From December 2011 to June 2012, 19 patients were enrolled in this study. The cytopathological diagnoses were as follows; 12 adenocarcinoma, 3 squamous cell carcinoma, 1 large cell carcinoma NOS, and 3 small cell carcinomas. 8 out of 19 cases (42.1%) showed tumor formation. The mean duration between inoculation and tumor formation was 62.38 days (13-144 days). All engrafted tumors could be passed to the second mouse. The histological types of the engrafted tumors were 3 adenocarcinoma (3/12: 25%), 2 squamous cell carcinoma (2/3: 67%), 1 large cell carcinoma (1/1: 100%), and 2 small cell carcinomas (2/3: 67%). The tumor cellularity of primary EBUS-TBNA samples was sufficient for diagnosis and there was no correlation between engraftment and the degree of blood/lymphocyte contamination or percentage of necrosis.

      Conclusion
      EBUS-TBNA samples can be used for establishment of tumor xenograft model in immunodeficient mice. EBUS-TBNA allows minimally invasive sampling of metastatic lymph nodes in patients with advanced lung cancer which opens up possibilities for translational research. We need to continuously seek better ways to improve and standardize procurement and processing of samples obtained by minimally invasive techniques in order to optimize diagnosis and molecular analysis for improved patient care. Figure 1

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    P1.07 - Poster Session 1 - Surgery (ID 184)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Surgery
    • Presentations: 1
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      P1.07-023 - Direct projection of three dimensional volume analyzed CT images to the surgical field by the portable digital light processing projector for assisting minimally invasive thoracic surgery (ID 1910)

      09:30 - 09:30  |  Author(s): K. Hirohashi

      • Abstract

      Background
      Video-assisted thoracoscopic surgery (VATS) has been applied widely to thoracic surgery such as VATS lobectomy, resection of chest wall/ mediastinal tumors. The appropriate placement of trocar is the keys for these procedures. Many surgeons places the first -port to look inside of the thoracic cavity by thoracoscope, and determine the position of the other ports. However, there are differences in deformation and the thickness of the thorax of individual patients. In this study, we analyzed the adequate surgical approach by analyzing the three dimensional Computed tomography (3D-CT), and develop the prototype system to project the 3D-CT image to the patient body directly to mark the points of surgical approach.

      Methods
      3D-CT based minimally invasive surgery was designed using 3D-CT volume analyzer Synapse Vincent (Fuji film, Japan). Skin window, skeletal structure, intra-thoracic anatomical images were reconstructed respectively. The designed points of trocar were marked in 3D-CT image of skin window and projected on the patinet’s body by a liquid projector. Positional / magnification power correction was made using the land marks such as sternal notch, bilateral nipples, costal arch, and acromion. The error of the system was evaluated using artificial thorax model. Two chest wall tumor patients and 2 mediastinal tumor patients were enrolled for the clinical study. Each surgical incision was planned based on the system. The system validity was evaluated by 3 surgeons.

      Results
      The error of liquid projector guided skin marking was within 9.3 ± 2.5mm in the distance of 15 cm the center of projection point using artificial thorax model. 3D-CT based surgical approach were prospectively planned and the position of skin incisions were marked on the patients’ body by the liquid projector which projecting the position of the trocars determined by 3D-CT simulations. In the clinical study, Each skin incision made on the point indicated by the liquid projector were placed in the adequate position.

      Conclusion
      Direct projection of three dimensional volume analyzed CT images to the surgical field by the portable liquid projector indicated the adequate approaching point on the surgical field for the minimally invasive surgery. This method may present the appropriate surgical approach to thoracic surgeons.

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    P2.05 - Poster Session 2 - Preclinical Models of Therapeutics/Imaging (ID 158)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P2.05-009 - Porphysome-enhanced bronchoscopic fluorescence detection and photothermal ablation of peripheral lung cancer: Preliminary in vivo studies (ID 1105)

      09:30 - 09:30  |  Author(s): K. Hirohashi

      • Abstract

      Background
      Bronchoscopic ablation of lung cancer has to date been limited to carcinoma in-situ located in the central airway or, using high-power lasers, to palliation in advanced obstructive disease . Bronchoscopic ablation of peripheral lung cancer is still under development. We are developing a new technology platform for localization (by fluorescence) and enhanced photothermal therapy (PTT) of peripheral lung lesions, based on porphysomes, which are novel, multi-functional, all-organic porphyrin-lipid nanoparticles. Even without active targeting, porphysomes accumulate within tumor through the enhanced permeability and retention (EPR) effect. In parallel, we have developed a prototype fluorescent endoscope system that allows visualization of peripheral lesions by the porphyrin fluorescence. Using this combination of novel instrumentation and nanoparticles, endoscopic PTT of lung cancer is demonstrated in preclinical lung cancer animal models in vivo.

      Methods
      The in vivo porphysome biodistribution was evaluated in both orthotopic lung tumors (A549, H460, H520) in mice and in VX2 tumors implanted directly in rabbit lung. Porphysomes were administered intravenously at a dose of 20 mg/kg, and the tumor fluorescence was imaged in vivo daily for 3 days (excised lung in the mouse model and endoscopically in the rabbit model). Ex vivo VX2 tissue was illuminated using a 670 nm diode laser to determine the optimized treatment parameters for PTT. Subsequently, in vivo bronchoscopic visualization of VX2 fluorescence and PTT was demonstrated in the rabbit model. The extent of ablation was histologically evaluated by NADH metabolic activity staining.

      Results
      The highest tumor-to-normal lung fluorescence ratio was achieved at 48 h post-injection of porphysomes(Rabbit VX2: n=4). The same trend was confirmed in the 3 kinds of orthotopic lung cancer mouse Xenografts (n=8). The ex vivo study revealed that 250 mW and 10 min of 670 nm laser irradiation raised the tumor tissue temperature by more than 20[o]C, so that this setting was used also in vivo and achieved thermal coagulation zones within the tumor of up to 13 mm diameter. In comparison, laser treatment alone without porphysomes caused minimal ablation zones of < 1.5 mm diameter.

      Conclusion
      Systemically administrated porphysomes accumulated in the lung cancer tissue with a high enough concentration to enable marked photothermal coagulation. The combination of systemically-administrated porphysomes with endoscopic near-infrared laser irradiation is a promising strategy for minimally-invasive bronchoscopic interventional therapy for peripherally-located lung cancer.