A new limb salvage surgery in cases of high‐grade soft tissue sarcoma using photodynamic surgery, followed by photo‐ and radiodynamic therapy with acridine orange

Nakamura, Tomoki; Kusuzaki, Katsuyuki; Matsubara, Takehiro; Matsumine, Akihiko; Murata, Hiroaki; Uchida, Atsushi

doi:10.1002/jso.21025

Cited by 33 publications

(38 citation statements)

References 14 publications

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“…Additionally, it has marked advantages such as preserving excellent limb function, reducing local recurrence rates, and adjuvant therapy for unresectable tumor in musculoskeletal systems [7], [8], [12]. Compared with surgery, radiotherapy, and chemotherapy, PDT is generally safe on the surrounding normal tissue because PS can selectively accumulate in tumor tissues, whereas accumulation in normal tissues is rarely observed [2].…”

Section: Discussionmentioning

confidence: 99%

Hematoporphyrin Monomethyl Ether-Mediated Photodynamic Therapy Selectively Kills Sarcomas by Inducing Apoptosis

et al. 2013

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We investigated the antitumor effect and mechanism of hematoporphyrin monomethyl ether-mediated photodynamic therapy (HMME-PDT) in sarcomas. Intracellular uptake of HMME by osteosarcoma cells (LM8 and K7) was time- and dose-dependent, while this was not observed for myoblast cells (C2C12) and fibroblast cells (NIH/3T3). HMME-PDT markedly inhibited the proliferation of sarcoma cell lines (LM8, MG63, Saos-2, SW1353, TC71, and RD) (P<0.05), and the killing effect was improved with increased HMME concentration and energy intensity. Flow cytometry analysis revealed that LM8, MG63, and Saos-2 cells underwent apoptosis after treatment with HMME-PDT. Additionally, apoptosis was induced after HMME-PDT in a three-dimensional culture of osteosarcoma cells. Hoechst 33342 staining confirmed apoptosis. Cell death caused by PDT was rescued by an irreversible inhibitor (Z-VAD-FMK) of caspase. However, cell viability was not markedly decreased compared with the HMME-PDT group. Expression levels of caspase-1, caspase-3, caspase-6, caspase-9, and poly (ADP-ribose) polymerase (PARP) proteins were markedly up-regulated in the treatment groups and increased with HMME concentration as determined by western blot analysis. In vivo, tumor volume markedly decreased at 7–16 days post-PDT. Hematoxylin and eosin staining revealed widespread necrotic and infiltrative inflammatory cells in the HMME-PDT group. Immunohistochemistry analysis also showed that caspase-1, caspase-3, caspase-6, caspase-9, and PARP proteins were significantly increased in the HMME-PDT group. These results indicate that HMME-PDT has a potent killing effect on osteosarcoma cells in vitro and significantly inhibits tumor growth in vivo, which is associated with the caspase-dependent pathway.

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Section: Discussionmentioning

confidence: 99%

Hematoporphyrin Monomethyl Ether-Mediated Photodynamic Therapy Selectively Kills Sarcomas by Inducing Apoptosis

et al. 2013

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“…Microscopic curettage was repeated until the green fluorescence (tumor cells) had disappeared. After AO-PDS, AO-PDT was performed [13][14][15][16][17][18]. AO-PDT was applied to the area of tumor curettage under illumination with >100,000 lx of unfiltered light (visible light) from a xenon lamp for 10 min, again using fluorescence surgical microscopy.…”

Section: Ao Therapymentioning

confidence: 99%

“…We have focused on photodynamic therapy (PDT) with photosensitizers as a neoadjuvant therapy. We employed acridine orange (AO) as a photosensitizer to establish AO photodynamic therapy [9][10][11][12][13][14][15][16][17]. With this technique, tumor cells labeled with AO are visualized under a fluorescence microscope to allow curettage to be easily performed with minimal damage to normal tissue [18][19][20][21].…”

Section: Introductionmentioning

confidence: 99%

A Minimally Invasive Surgery for Bone Metastases Using the Combination of Photodynamic Therapy and Hyperthermia Treatment

Matsubara¹,

Matsumine²,

Kusuzaki³

et al. 2013

IJCM

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Cancer patients with bone metastases in their extremities may require surgical intervention to prevent deterioration in their quality of life due to a pathological fracture or severe bone pain. However, curative surgical interventions sometimes have severe complications due to the status of the original cancers. To avoid the decreased quality of life caused by bone metastasis, minimally invasive surgery that avoids additional surgical morbidity is required. We have established two therapeutic treatments for bone metastasis, a photodynamic acridine orange treatment (AOT) and an electronic magnetic hyperthermia treatment (EMHT). The present study investigated the clinical outcomes of combination therapy with EMHT and AOT for patients with bone metastases in their extremities. Methods: The study included 6 patients with 7 bone cancer metastasis locations. For bone metastases, all patients received intraregional tumor excision supported by AOT, in which photodynamic and radiodynamic therapy kills tumor cells during surgery with minimal damage to normal tissues. After the curettage, bone reconstruction was performed by using magnetic materialswith calcium phosphate cement. EMHT was repeatedly performed after surgery. In EMHT, tumor cells are killed with an electric magnetic field generator, and bony union is promoted by electronic stimulation. Results: The mean duration of follow-up was 14 months. During the follow-up period, only one patient experienced a local recurrence, and this recurrence occurred 14 months after surgery. Bony union occurred in 4 of 5 cases (80%), and the pain score was significantly reduced after surgery. Conclusions: In the present study, AOT reduced the invasiveness of surgery. EMHT reduced the tumor growth without major complications and promoted bone formation after surgery. Our clinical results confirmed that EMHT and AOT combination therapy for bone metastasis can preserve limb function without local recurrence or bone absorption.

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“…This phototherapeutic modality consists of three main procedures: 1) intraoperative PDS (iPDS) immediately after intraoperative PDD (iPDD), 2) intraoperative PDT (iPDT) after intra-lesional or extra-capsular marginal tumor resection, and 3) RDT immediately following surgery (postoperative RDT). We have obtained good local control rates and markedly better limb functions with this approach as compared to the results of conventional wide resection surgery which commonly causes serious limb dysfunction [24][25][26][27][28][29][30][31].…”

Section: Introductionmentioning

confidence: 99%

Intraoperative Photodynamic Surgery (iPDS) with Acridine Orange for Musculoskeletal Sarcomas

Kusuzaki¹,

Matsubara²,

Satonaka³

et al. 2014

Cureus

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We recently established the new limb salvage modality of acridine orange (AO) therapy (AOT), in an attempt to develop minimally invasive limb salvage surgery with minimal damage of normal tissues and a low risk of local recurrence. The treatment modality consists of intraoperative photodynamic surgery (iPDS) and photodynamic therapy (iPDT), followed by postoperative radiodynamic therapy (RDT) using AO for patients with high-grade malignant musculoskeletal sarcomas. Clinical results have shown that the treatment is associated with a low risk of local recurrence, the risk being almost the same as that following conventional wide resection, and yields superior limb function as compared to that obtained after wide resection.In this review, we present the detailed mechanism of selective accumulation of AO in sarcomas, which is related to the acidic environment and lysosomal acidity of the tumor cells induced by cancer-specific glycolysis not involving the define tricarboxylic acid (TCA) cycle (Warburg's effect). We also describe the clinical uses of AOT and the procedure for intraoperative photodynamic surgery (iPDS) using local administration of AO.

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A new limb salvage surgery in cases of high‐grade soft tissue sarcoma using photodynamic surgery, followed by photo‐ and radiodynamic therapy with acridine orange

Abstract: Based on these results, we concluded that AO therapy is useful for local control after margin-positive tumor resection and for preserving excellent limb function in patients with high-grade soft tissue sarcomas.

Cited by 33 publications

References 14 publications

Hematoporphyrin Monomethyl Ether-Mediated Photodynamic Therapy Selectively Kills Sarcomas by Inducing Apoptosis

Hematoporphyrin Monomethyl Ether-Mediated Photodynamic Therapy Selectively Kills Sarcomas by Inducing Apoptosis

A Minimally Invasive Surgery for Bone Metastases Using the Combination of Photodynamic Therapy and Hyperthermia Treatment

Intraoperative Photodynamic Surgery (iPDS) with Acridine Orange for Musculoskeletal Sarcomas

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