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Kosuke Fujino



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    MA12 - Mesothelioma Surgery and Novel Targets for Prognosis and Therapy (ID 913)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Mesothelioma
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 10:30 - 12:00, Room 202 BD
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      MA12.09 - Preclinical Investigations of Folate Receptor Targeted Nanoparticles for Photodynamic Therapy of Malignant Pleural Mesothelioma (ID 11277)

      11:30 - 11:35  |  Author(s): Kosuke Fujino

      • Abstract
      • Presentation
      • Slides

      Background

      Photodynamic therapy (PDT) following lung-sparing extended pleurectomy (EPD) for malignant pleural mesothelioma (MPM) has been investigated as a potential means to kill residual microscopic cells. High expression of folate receptor 1 (FOLR1) has been reported in MPM, and targeting the FOLR1 has been considered as a new potential strategy. We have developed FOLR1-targeting porphyrin-lipid nanoparticles (folate-porphysomes; FP) for PDT. The inhibition of survival pathways of activated epidermal growth factor (EGFR) also enhance the PDT efficacy. Here, we have combined these approaches by using FP based PDT together with an EGFR-tyrosine kinase inhibitor (EGFR-TKI).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      The frequency of FOLR1 and EGFR expression in MPM was analyzed using tissue microarrays. Confocal microscopy and a cell viability assay were performed to confirm the specificity of FOLR1-targeting cellular uptake and photocytotoxicity in vitro. In vivo fluorescence activation and the therapeutic efficacy were then examined. The effect of EGFR-TKI was assessed in vitro. The in vivo combined anti-tumor effect of EGFR-TKI and FP-PDT was then evaluated.

      4c3880bb027f159e801041b1021e88e8 Result

      FOLR1 and EGFR were expressed in 79 % and 89 % of the MPM samples, respectively. The intracellular uptake of FP corresponded well with FOLR1 expression. When MPM cells were incubated in FP and then irradiated at 671 nm, there was significant in vitro cell kill, which was inhibited in the presence of free folic acid, suggesting the specificity of FPs. FOLR1 targeting resulted in disassembly of the porphysomes and subsequent fluorescence activation in intrathoracic disseminated MPM tumors, as demonstrated by ex vivo tissue imaging. FP-PDT resulted in significant cellular damage and apoptosis in vivo. Furthermore, the combination of pre-treatment with EGFR-TKI plus FP-PDT showed further marked improvement of treatment responses.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Folate-porphysome based PDT shows selective destruction of MPM cells based on FOLR1 targeting, and pre-treatment with EGFR-TKI further enhances the therapeutic response.

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    MA23 - Early Stage Lung Cancer: Present and Future (ID 926)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Treatment of Early Stage/Localized Disease
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/26/2018, 10:30 - 12:00, Room 105
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      MA23.10 - Cone-Beam Computed Tomography-Guided Microcoil Localization of Pulmonary Nodules During Video-Assisted Thoracic Surgery (ID 13345)

      11:35 - 11:40  |  Author(s): Kosuke Fujino

      • Abstract
      • Presentation
      • Slides

      Background

      The standard procedure at our institution for intraoperative localization of non-palpable small lung nodules is computed tomography (CT)-guided microcoil placement prior to video-assisted thoracic surgery (VATS). Typically, microcoil placement is performed in the radiology suite followed by transfer to the operation room (OR). Our institution has built the Guided Therapeutics (GTx) OR, which includes a robotic cone-beam CT (CBCT). The GTx OR allows imaging and therapy to occur in one location. This can improve workflow and reduce patient transportation, which may increase the risk for microcoil dislodgement or the development of pneumothorax/hemothorax. Our objective was to determine the safety and efficacy of CBCT-guided microcoil placement for nodule localization during VATS.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      This is a single center phase I clinical trial (NCT02496624). Patients with small lung nodules who were candidates for standard CT-guided microcoil localization were enrolled. CBCT was used to generate a 3D reconstruction. The lesion was then segmented using Syngo iGuide software. This reconstruction was next integrated into the digital workspace and automatically registered onto the fluoroscopic images, creating ‘augmented fluoroscopy’. The microcoil was placed percutaneously using ‘augmented’ guidance, proximal to the lesion, using local anesthetic. Patients were subsequently induced into general anesthesia, intubated, and positioned for VATS. Minimally invasive resection of the nodule together with the microcoil was performed under standard fluoroscopic guidance.

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 11 patients were enrolled (mean age 70 ± 11SD). The average tumor size on CT was 1.3 cm (range 0.9-1.7). The average deepest depth from the pleural surface was 2.3 cm (1.3-3.8). The average CBCT-guided intervention time was 39 minutes (25-54), and VATS procedural time was 54 minutes (14-78). We were able to detect and successfully resect all nodules. Average total radiation dose was in an acceptable low range (8307 μGy*m2, range, 2402–18,371). There were no intraoperative complications. Average post-operative length of stay was 1.8 days. A pathological diagnosis was made for all patients: 8 primary lung cancers and 3 lung metastases. All surgical margins were negative on final pathology.

      8eea62084ca7e541d918e823422bd82e Conclusion

      CBCT-guided microcoil insertion followed by VATS was safe, with short operative times, short length of stay and 100% diagnostic yield. With the GTx OR’s real-time guidance capabilities, surgeons can operate with increased confidence of finding and removing the target lesion. This technique will become increasingly important in the future with growing numbers of small nodules being detected on CT by lung cancer screening programs.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P3.09 - Pathology (Not CME Accredited Session) (ID 975)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/26/2018, 12:00 - 13:30, Exhibit Hall
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      P3.09-14 - Pathobiology of Notch2 in Lung Cancer (ID 13789)

      12:00 - 13:30  |  Author(s): Kosuke Fujino

      • Abstract
      • Slides

      Background

      Notch signaling is known to be involved in the initiation, progression, and suppression of various types of cancers. The pathological significance of Notch1 has been well studied in lung cancer, but that of Notch2 is still unclear.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Immunohistochemical study was performed to measure the expression of NOTCH2 in non-neoplastic lung tissues and lung cancers in comparison with the Clara (Club) cell 10 kD protein (CC10), and Western blotting analysis was performed to detect NOTCH2 in human cancer cell lines. Notch2 gene knockdown experiment and transient transfection of the intracellular domain of the Notch2 (N2ICD) gene were conducted to reveal the function of Notch2. In addition, we studied the relationships between the expressions of Notch1, 2, and 3.

      4c3880bb027f159e801041b1021e88e8 Result

      Immunohistochemical study of lung tissues revealed that NOTCH2 was detected in bronchiolar epithelial cells and was often colocalized with CC10, and that adenocarcinoma tissues were more positively stained than those of squamous cell carcinoma and small cell carcinoma tissues. In human lung cancer cell lines the expression of NOTCH2 was similar to that of NOTCH1 and preferentially detected in non-small cell lung carcinoma (NSCLC) cell lines. Knockdown experiments of the Notch2 gene in NSCLC cell lines showed no significant changes in the expression of molecules associated with cell differentiation, proliferation, apoptosis, and motility. The effects of Notch2 gene knockdown could have be masked by concomitant Notch1 activation, as indicated by an increase in the intracellular domain of NOTCH1. Additionally, the transient transfection of the N2ICD gene induced CC10 expression in an adenocarcinoma cell line.

      8eea62084ca7e541d918e823422bd82e Conclusion

      notch2 iaslc-1.tif
      The present study revealed that Notch2 is important in Club cell differentiation in normal lungs and in adenocarcinoma. We also determined that Notch1 and Notch2 are covariant, and the balance of the expression of Notch receptors could determine the biological behaviors of lung cancer cells.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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