Sachio Maehara

Tokyo Medical University, Edo, Tokyo, Japan

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Publications (27)77.79 Total impact

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    ABSTRACT: We reviewed the medical record of a series of patients with synchronous multiple lung cancers (SMLC), in an attempt to identify the optimal treatment strategy for multiple ground-glass opacities (GGOs). From 2004 to 2010, 1223 patients underwent complete resection of non-small cell lung cancer. Among these, there were 67 patients (5.5%) with SMLC with at least 1 of the nodules showing GGO appearance. SMLC was divided into the main cancer (MC) which was a main target based on its tumor size or radiological invasiveness and sub-nodules. According to consolidation/tumor ratio (CTR) on thin-section computed tomography, 67 cases were classified into GG-group (MC showing GGO-dominant lesion; CTR≤0.5) and GS-group (MC showing solid-dominant lesion; CTR>0.5). There were 24 patients in the GG-group (36%) and 43 patients in the GS-group (64%). Surgical resections included 11 sublobar resections (SLs), 32 lobectomies, 19 lobectomy+SLs, and 4 bilobectomies. There were 39 patients with a total of 118 unresected GGOs after the initial surgery. Among them, the frequency of growth was 8% on a per-nodule basis with the median tumor doubling time of 1373 days, and new GGOs emerged in 15 patients (23%). Multivariate analysis demonstrated that larger size of MC and the GS-group was associated with poor prognosis, whereas growth of the residual GGOs, the development of new GGOs, or whether or not all GGOs were treated did not affect survival. The 5-year OS proportions were 95.8% for the GG-group and 68.0% for the GS-group (p=0.009), and 92.4% for a MC of ≤25mm and 53.6% for a MC of >25mm (p=0.008). Survival of patients with multifocal GGOs is strongly affected by radiological findings of the MC. Strict surgical control for MC could be most important. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    No preview · Article · Mar 2015 · Lung cancer (Amsterdam, Netherlands)
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    ABSTRACT: To identify a possible new treatment modality for malignant pleural mesothelioma (MPM), we examined whether combination treatment consisting of pemetrexed chemotherapy and photodynamic therapy (PDT) using the photosensitizer NPe6, enhanced the antitumor effect in both in vitro and in vivo models. We also investigated preclinical treatment schedules. Four human malignant mesothelioma cell lines (MSTO‑211H, H2052, H2452 and H28) were assayed using the WST assay after treatment with pemetrexed and NPe6‑PDT. The treatment schedule for the combination treatment was examined using nude mice. Pemetrexed pre‑treatment enhanced the lethal effect of NPe6‑PDT in the four malignant mesothelioma cell lines, but NPe6‑PDT followed by pemetrexed treatment did not enhance cell lethality in the in vitro assay. Pemetrexed pre‑treatment did not enhance the intracellular accumulation of NPe6, which is one of the determinants of the antitumor effect of PDT. In nude mice injected with MSTO‑211H cells and then treated using a combination of pemetrexed and NPe6‑PDT (10 mg/kg NPe6, 10 J/cm2 laser irradiation), the tumor volume decreased by 50% but subsequently increased, reaching the pre‑treatment value after 14 days. Pemetrexed treatment followed by NPe6‑PDT resulted in an 80% reduction in the tumor size and inhibited re‑growth. NPe6‑PDT followed by pemetrexed treatment resulted in a 60% reduction in tumor size but did not inhibit re‑growth. NPe6‑PDT induced the expression of thymidylate synthase (TS), which confers resistance to pemetrexed, and NPe6‑PDT followed by pemetrexed treatment did not enhance the treatment outcome in vivo. In conclusion, combination treatment, consisting of pemetrexed followed by NPe6‑PDT, should be further investigated as a new treatment modality for MPM. In the future, this combination treatment may contribute to a reduction in local recurrence and a prolonged survival period in patients with MPM.
    No preview · Article · Nov 2014 · International Journal of Oncology

  • No preview · Article · Oct 2014 · Cancer Research

  • No preview · Article · Jan 2014 · Nihon Kikan Shokudoka Gakkai Kaiho
  • Sachio Maehara · Keisi Ohtani · Hidemitu Tsutsui · Norihiko Ikeda

    No preview · Article · Jan 2013 · Nihon Kikan Shokudoka Gakkai Kaiho
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    ABSTRACT: PDT induces apoptosis, inflammatory reactions, immune reactions, and damage to the microvasculature around the tumors. The mechanisms responsible for the anticancer effects of Photofrin-PDT and NPe6-PDT differ somewhat. To select a photosensitizer for lung cancer treatment and to improve the efficacy of PDT, the mechanisms of action for PDT using Photofrin or NPe6 must be elucidated and the phenomena validated by analyzing molecular determinants from clinical samples. We examined the role of immunological reactions in the anti-tumor effects of PDT using cytokine-overexpressing cells and investigated whether the anti-apoptotic protein Bcl-2 may be a molecular target. Moreover, we investigated the association between ATP-binding cassette transporter proteins such as breast cancer-resistant protein (BCRP), which can pump out some types of photosensitizer, and the efficacy of PDT using clinical samples from 81 early lung cancer lesions treated with PDT between 1998 and 2006 at the Tokyo Medical University Hospital. Photofrin-PDT damaged Bcl-2 and rapidly induced apoptosis, but NPe6-PDT did not damage Bc-2 nor did it induce morphologically typical apoptosis. However, NPe6-PDT exerted a strong anti-tumor effect, regardless of the overexpression of Bcl-2. By analyzing the BCRP-overexpressing cells, Photofrin, but not NPe6, was found to be a substrate of BCRP. All 81 lung cancer lesions were BCRP-positive; as Photofrin was found to be a substrate of BCRP, the expression of BCRP significantly affected the efficacy of Photofrin-PDT. However, NPe6-PDT exerted a strong antitumor effect regardless of BCRP expression, and the complete response rate after NPe6-PDT was much higher than that after Photofrin-PDT. Our translational research suggests that NPe6-PDT may be superior to Photofrin-PDT for the treatment of lung caner, and individualized approaches to PDT based on the expression status of Bcl-2 and/or BCRP may improve the efficacy of PDT in patients with lung cancers.
    No preview · Article · Sep 2011 · Lasers in Surgery and Medicine
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    ABSTRACT: Most centrally located early lung cancers (CLELC) <1.0 cm in diameter do not invade beyond the bronchial cartilage, and photodynamic therapy (PDT) with Photofrin is currently recommended as a treatment option for such lesions. NPe6 is a second-generation photosensitizer, and because it has a longer absorption band (664 nm) than Photofrin (630 nm), we hypothesized that NPe6-PDT would exert a strong antitumor effect against cancer lesions >1.0 cm in diameter, which are assumed to involve extracartilaginous invasion and to be unsuitable for treatment with Photofrin-PDT. Between June 2004 and December 2008, 75 patients (91 lesions) with CLELC underwent NPe6-PDT after the extent of their tumors had been assessed by fluorescence bronchoscopy for photodynamic diagnosis and tumor depth had been assessed by optical coherence tomography. Seventy cancer lesions < or =1.0 cm in diameter and 21 lesions >1.0 cm in diameter were identified, and the complete response rate was 94.0% (66 of 70) and 90.4% (19 of 21), respectively. After the mass of large tumors and deeply invasive tumors had been reduced by electrocautery, NPe6-PDT was capable of destroying the residual cancer lesions. NPe6-PDT has a strong antitumor effect against CLELCs >1.0 cm in diameter that have invaded beyond the bronchial cartilage, thereby enabling the destruction of residual cancer lesions after mass reduction of large nodular- or polypoid-type lung cancers by electrocautery. The PDT guidelines for lung cancers should therefore be revised because use of NPe6-PDT will enable expansion of the clinical indications for PDT.
    No preview · Article · Mar 2010 · Clinical Cancer Research
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    ABSTRACT: Patients with centrally located early lung cancer (CLELC) are often heavy smokers with a considerably high risk of multiple primary lung cancer (MPLC) lesions; treatment strategies for such patients must preserve the cardiopulmonary function. Between July 2004 and July 2008, patients with CLELC underwent photodynamic therapy (PDT) using NPe6, second-generation photosensitizer at Tokyo Medical University Hospital. Among these patients, we retrospectively analyzed MPLC, which was treated by surgery plus PDT or PDT alone and examined the effectiveness of PDT, and we propose a treatment strategy for patients with MPLC. A total of 64 patients with CLECL received NPe6-PDT, and MPLCs were found in 22 patients (34.4%) using sputum cytology and a bronchoscopical examination using autofluorescence bronchoscopy. Among these 22 patients, 10 patients underwent surgery for primary lung cancer and underwent NPe6-PDT for the treatment of secondary primary CLELC, one patient underwent PDT for CLELC as a primary lesion followed by an operation for peripheral-type lung cancer as a secondary primary lesion, and 11 patients underwent PDT alone for MPLC lesions (28 lesions) that were roentgenographically occult lung cancers. Among these 22 patients with MPLC including peripheral-type lung cancers, which were resected by surgery, all 39 CLELC lesions exhibited a complete response after PDT, and all patients were alive. For patients with lung cancer with a long-term history of smoking, careful follow-up examinations after surgical resection are needed considering the incidence of metachronous primary lung cancers. PDT can play an important role for the treatment strategy for MPLC.
    No preview · Article · Nov 2009 · Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer
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    ABSTRACT: The ATP-binding cassette (ABC) transporter protein, BCRP (breast cancer resistance protein)/ABCG2 pumps out some types of photosensitizers used in photodynamic therapy (PDT) and causes resistance to the antitumor effect of PDT. The purpose of this study was to investigate the association between the expression of BCRP and the efficacy of PDT using Photofrin, or the second-generation photosensitizer, NPe6, for centrally located early lung cancers. Using human epidermoid carcinoma cells, A431 cells and the BCRP-overexpressing A431/BCRP cells, we examined the effects of BCRP expression on the effect of PDT by cell viability assay in vitro, and investigated the expression of BCRP by immunohistochemical analysis in 81 tumor samples obtained from patients with centrally located early lung cancers. The A431/BCRP cells were more resistant to Photofrin-PDT than A431 cells in vitro, and Fumitremorgin C, a specific inhibitor of BCRP, reversed the resistance. However, there was no significant difference in the antitumor effect of NPe6-PDT between these cells. All of the 81 centrally located early lung cancer lesions were BCRP-positive (2+, 45 lesions; 1+, 30 lesions) and all the patients were male and heavy smokers (>30 pack-years). The expression of BCRP significantly affected the efficacy of Photofrin-PDT in cancer lesions > or =10mm in diameter (P=0.04). On the other hand, NPe6-PDT exhibited a strong antitumor effect, regardless of the expression status of BCRP. Photofrin may be a substrate of BCRP and be pumped out from the cells, therefore, BCRP may be a molecular determinant of the outcome of Photofrin-PDT.
    No preview · Article · May 2009 · Lung cancer (Amsterdam, Netherlands)
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    ABSTRACT: It is very important to elucidate the mechanism of action and identify the molecular determinant of photodynamic medicine, in order to increase the number of clinical applications of photodynamic therapy (PDT) and perform personalized medicine. We have previously reported that PDT using some photosensitizers, such as phthalocyanine 4 (Pc 4) damages the anti-apoptotic protein Bcl-2, and that Bcl-2 is a molecular PDT target using a mitochondrion-targeting photosensitizer. In this study, we examined the molecular targets of Photofrin-PDT and NPe6-PDT, which are approved for early stage lung cancers by the Japanese Ministry of Health Labor and Welfare, by evaluating the photodamage to Bcl-2 using Western blot analysis. Our results showed that Photofrin-PDT damaged Bcl-2, induced morphologically typical apoptosis, and demonstrated equal sensitivity between MCF-7c3 cells (human breast cancer cells expressing stably transfected procaspase-3) and Bcl-2 overexpressing cells, MCF-7c3-GFP-Bcl-2 cells, with a clonogenic assay. However, NPe6-PDT did not damage Bcl-2 and took longer to induce typical apoptosis compared with Photofrin-PDT. MCF-7c3-GFP-Bcl-2 cells were considerably more resistant to the lethal effects of NPe6-PDT than parental MCF-7c3 cells. In conclusion, Photofrin-PDT damages different molecular targets, and our data indicate that the extent of Bcl-2 photodamage can determine the sensitivity of cancer cells to apoptosis and to overall cell killing caused by PDT using Photofrin, but not the lysosomal targeting NPe6. The application of these findings to clinical PDT may depend on the levels of the Bcl-2 proteins in the tumor being treated, and the tailor-made medicine based on the Bcl-2 photodamage may overcome any resistance afforded by elevated amounts of Bcl-2.
    No preview · Article · Nov 2008 · International Journal of Oncology
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    ABSTRACT: We report a case of left main bronchial glomus tumor in a 39-year-old man who presented with a cough he had had for 1 month. A computed tomography (CT) scan revealed a polypoid tumor in the membranous portion of the left main bronchus. The tumor showed marked enhancement on the early phase of dynamic contrast-enhanced CT, and it was thought to be a hypervascular tumor. The tumor was carefully resected by a rigid bronchoscope, and the pathological and immunohistochemical findings yielded a diagnosis of glomus tumor. Marked enhancement of early phase dynamic contrast-enhanced CT may be useful for a diagnosis of bronchial glomus tumor.
    No preview · Article · May 2008 · Lung Cancer
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    ABSTRACT: Photodynamic therapy (PDT) using Photofrin induces cell death, inflammatory reactions, immunological responses and damage to the microvasculature. In this study, we evaluated the apoptotic response caused by PDT and examined the biological features of centrally located early lung cancers, which were treated by Photofrin®-PDT. We showed by DNA miroarray analysis in vitro that CHOP/GADD153 (growth arrest and DNA damage inducible gene 153) mRNA expressions were induced 4 h after Photofrin®-PDT applied at a dose killing 50% of the cells (LD50) using MCF-7c3 cells (stable trasfection with a pro-caspase-3 gene). In order to elucidate the effects of expression of CHOP/GADD 153 in MCF-7c3 cells after Photofrin®-PDT, we examined the effects of CHOP/GADD153 down regulation by small interfering RNA (siRNA) on the apoptotic response to PDT. We observed typically morphological apoptotic body by Hoechst staining using fluorescence microscopy. Two and 4 h after the transfection of CHOP/GADD153 siRNA, the apoptotic response caused by Photofrin-PDT was inhibited. These results suggested that the induction of CHOP/GADD153 expression may play a important role in a apoptotic response after PDT. We examined the expression of CHOP/GADD153 in centrally located early lung cancers, which were treated by PDT, by immunohistochemical analysis. Twenty-six of 53 lesions positively stained before PDT and there was no significant difference between the expression of CHOP/GADD153 and complete response (CR) rate after PDT. However, a high level of expression of CHOP/GADD153 protein was associated with the recurrence rate after CR. These results suggest that expression of CHOP/GADD153 may interfere with some protein before PDT. In conclusion, the induction of CHOP/GADD153 expression may play an important role in a apoptotic response after Photofrin®-PDT.
    No preview · Article · Apr 2008
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    ABSTRACT: NPe6 is a novel second-generation photosensitizer used for photodynamic therapy (PDT). PDT using NPe6 and diode laser (664 nm) induces cell death, inflammatory reactions, immunological responses and damage to the microvasculature. In this study, we evaluated the influence of the immunological responses and of enhanced angiogenesis on the anti-tumor effect of NPe6-PDT using cytokine-overexpressing Lewis lung carcinoma (LLC), LLC-IL-2 cells both in vitro and in vivo. We showed by DNA microarray analysis in vitro that IL-2 and GADD-45alpha (growth arrest and DNA damage 45 alpha) mRNA expressions were induced by 3 h after NPe6-PDT applied at a dose killing 90% of the cells (LD90). IL-2-overexpressing cells (LLC/IL-2 cells) were resistant to the loss of clonogenicity as compared to the parental LLC cells in vitro. Furthermore, in female C57BL/6 mice, NPe6-PDT produced a cure rate of 66.7% in LLC tumors, whereas the cure rate was only 16.6% in LLC/IL-2 tumors, and overexpression of IL-2 caused failure of NPe6-PDT, with tumor recurrence, in vivo. These results suggest that IL-2 expression may play an unfavorable role in attenuation of the antitumor effect of NPe6-PDT. It has been reported that the expression of vascular endothelial growth factor (VEGF), in particular, may cause tumor recurrence after PDT and exert unfavorable effect in relation to attenuate the anti-tumor activity of PDT. Results of immunohistochemical analysis of LLC/IL-2 tumors have revealed that the expressions of GADD-45alpha and VEGF are induced in these tumors after PDT, and in particular, 12 h after PDT, the expression levels were much higher as compared with those in the LLC tumors. The results of our studies using in vitro and in vivo models suggest that the cell death caused by PDT was inhibited by induction of GADD-45alpha expression and that tumor recurrence was promoted by the enhancement of VEGF expression mediated by IL-2 upregulation. Therefore, it is speculated that the use of an IL-2 inhibitor may improve the efficacy of NPe6-PDT.
    No preview · Article · Mar 2008 · International Journal of Oncology

  • No preview · Article · Feb 2008 · International Journal of Oncology

  • No preview · Article · Jan 2008 · Nihon Kikan Shokudoka Gakkai Kaiho
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    ABSTRACT: We had previously developed the possibility of use of a photodynamic diagnosis (PDD) system using a tumor-selective photosensitizer and laser irradiation for the early detection and photodynamic therapy (PDT) for centrally located early lung cancers. Recently, we established the autofluorescence diagnosis system integrated into a videoendoscope (SAFE-3000) as a very useful technique for the early diagnosis of lung cancer. Twenty-nine patients (38 lesions) with centrally located early lung cancer received PDD and PDT using the second-generation photosensitizer, talaporfin sodium (NPe6). Just before the PDT, we defined the tumor margin accurately using the novel PDD system SAFE-3000 with NPe6 and a diode laser (408nm). Red fluorescence emitted from the tumor by excitation of the photosensitizer by the diode laser (408nm) from SAFE-3000 allowed accurate determination of the tumor margin just before the PDT. The complete remission (CR) rate following NPe6-PDT in the cases with early lung cancer was 92.1% (35/38 lesions). We also confirmed the loss of red fluorescence from the tumors immediately after the PDT using SAFE-3000. We confirmed that all the NPe6 in the tumor had been excited and photobleached by the laser irradiation (664nm) and that no additional laser irradiation was needed for curative treatment. This novel PDD system using SAFE-3000 and NPe6 improved the quality and efficacy of PDT and avoided misjudgement of the dose of the photosensitizer or laser irradiation in PDT. PDT using NPe6 will become a standard option of treatments for centrally located early lung cancer.
    No preview · Article · Jan 2008 · Lung Cancer
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    ABSTRACT: Development of acquired resistance to gefitinib after an initial good response is common. Recently, it was reported that this acquired resistance is related to a secondary mutation associated with a substitution of threonine by methionine at codon 790 (T790M) of the epidermal growth factor receptor (EGFR) gene. In this report, we present a "never smoking" woman with advanced lung cancer who showed acquired resistance to gefitinib, and analysis of autopsy samples revealed no evidence of EGFR mutations in either exons 18-21 or codon 790, and positive immunostaining for breast cancer resistance protein (BCRP). We describe, for the first time, a case in which expression of BCRP was associated with acquired resistance to gefitinib, independent of EGFR mutations.
    No preview · Article · Dec 2007 · Lung Cancer
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    ABSTRACT: ATX-s10-Na(II) is a novel second-generation photo-sensitizer for photodynamic therapy (PDT). PDT using ATX-s10 and diode laser (670 nm) induces an apoptotic response, inflammatory reaction, immune reaction and damage to the microvasculature. In particular, the vascular shut-down effect plays an important role in the anti-tumor activity of ATX-s10-PDT. It has been reported that PDT induces hypoxia and expression of the vascular endothelial growth factor (VEGF) via the hypoxia-inducible factor 1 (HIF1)-alpha pathway. We hypothesized that the expression of VEGF may cause tumor recurrence after PDT and exert unfavorable effect against the anti-tumor activity of ATX-s10-PDT. In this study, we showed by DNA microarray analysis in vitro that VEGF mRNA expression was induced 3 h after laser irradiation in ATX-s10-PDT. We compared the anti-tumor activity of ATX-s10-PDT against lung cancer cell lines SBC-3 and SBC-3/VEGF, the latter overexpressing VEGF; there was no significant difference in the sensitivity to the PDT between the two cell lines as assessed by clonogenic assay. Furthermore, no statistically significant difference in the anti-tumor effect of PDT, as measured by tumor cures, was found between SBC-3 and SBC-3/VEGF tumors in female Balb/c-nu/nu nude mice in vivo. In conclusion, ATX-s10-PDT may prevent tumor recurrence despite induction of VEGF and promotion of tumor angiogenesis, which are known to enhance tumor proliferation and survival.
    No preview · Article · Oct 2007 · Oncology Reports
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    ABSTRACT: Because malignant mesothelioma is commonly seen as a diffuse neoplasm, a localized tumor is an extremely rare form of presentation. Only 45 cases have been reported, and little is known about their behavior. We report a new case of localized malignant mesothelioma with the microscopic appearance of diffuse malignant mesothelioma, but without any evidence of diffuse spread. A 54-year-old man, a former smoker, with a brief history of asbestos exposure for 3 months, presented with a severe right chest pain and a swelling in the same area. Chest-computed tomography (CT) showed a 4.5 cm extra pleural tumor with a smooth surface, located in the right anterior chest wall, and destruction of the 5th rib. A CT-guided needle biopsy revealed malignant mesothelioma. Detailed examinations revealed a resectable solitary localized mass with no distant metastasis. The patient underwent operation, a tumorectomy, plus a combined resection of the chest wall and part of the right middle lobe. A complete en bloc resection was achieved. Pathology revealed localized malignant mesothelioma, biphasic type. Immunohistochemical findings confirmed the mesothelial feature. Localized malignant mesothelioma should be distinguished from diffuse malignant mesothelioma because of its different biological behavior, and in the former complete resection it is associated with a good prognosis.
    Full-text · Article · Sep 2007 · Annals of thoracic and cardiovascular surgery: official journal of the Association of Thoracic and Cardiovascular Surgeons of Asia

  • No preview · Article · Aug 2007 · Journal of Thoracic Oncology

Publication Stats

281 Citations
77.79 Total Impact Points


  • 2006-2015
    • Tokyo Medical University
      • • Department of Surgery V
      • • Department of Thoracic Surgery
      Edo, Tokyo, Japan
  • 2008
    • Tokyo Medical and Dental University
      • Department of Surgery
      Edo, Tōkyō, Japan