Glycogen synthase kinase 3β as a potential therapeutic target in synovial sarcoma and fibrosarcoma.

13301甲第5142号博士（医学）金沢大学博士論文本文Full 以下に掲載：Cancer Science 111(2) pp.429-444 2020. WILEY. 共著者：Kensaku Abe, Norio Yamamoto, Takahiro Domoto, Dilireba Bolidong, Katsuhiro Hayashi, Akihiko Takeuchi, Shinji Miwa, Kentaro Igarashi, Hiroyuki Inatani, Yu Aoki, Takashi Higuchi, Yuta Taniguchi, Hirotaka Yonezawa, Yoshihiro Araki, Hisaki Aiba, Toshinari Minamoto, Hiroyuki Tsuchiy

Glycogen synthase kinase 3β as a potential therapeutic target in synovial sarcoma and fibrosarcoma.

13301甲第5142号博士（医学）金沢大学博士論文要旨Abstract 以下に掲載：Cancer Science 111(2) pp.429-444 2020. WILEY. 共著者：Kensaku Abe, Norio Yamamoto, Takahiro Domoto, Dilireba Bolidong, Katsuhiro Hayashi, Akihiko Takeuchi, Shinji Miwa, Kentaro Igarashi, Hiroyuki Inatani, Yu Aoki, Takashi Higuchi, Yuta Taniguchi, Hirotaka Yonezawa, Yoshihiro Araki, Hisaki Aiba, Toshinari Minamoto, Hiroyuki Tsuchiy

Symptomatic small schwannoma is a risk factor for surgical complications and correlates with difficulty of enucleation

Postoperative neurological deficits of schwannomas are the complications that we want to avoid most. Predicting postoperative neurological deficits is crucial; however, the correlation between preoperative symptoms and neurological findings with postoperative neurological complications has not yet been completely clarified. Here we analyzed the risk factors for postoperative neurological complications. The study included 131 tumors from 107 patients histologically confirmed as schwannomas, which developed in the extremities and trunk without spinal cord involvement. The correlation between clinical findings and postoperative complications were statistically analyzed. One-hundred three tumors (78.6 %) had the preoperative neurological symptoms; these symptoms were detected in 93.3 % of small tumors (<4 cm3). We defined it as follows about the anatomical location of schwannomas. One is “central type” that normal nerve bundles widely splayed over the tumor’s capsule (tumor located in the central region of the nerve). Another is “peripheral type” that easy to enucleate without neurolysis (tumor located in the peripheral region of the nerve). Static analysis showed a significant difference in the Tinel sign, numbness, and postoperative neurological deficits (p = 0.04, 0.006, p < 0.001, respectively). Twenty-one cases (16.0 %) showed new postoperative neurological symptoms, including numbness in 12 cases, dysesthesia in three cases, pain in three cases, and slight motor palsy in two cases. In statistical analysis, small tumors (<4 cm3) significantly correlated with Tinel sign (p < 0.001), and was marginally significant with postoperative neurological deficits (p = 0.05). Moreover, small tumors (<4 cm3) accompanying numbness preoperatively significantly correlated with postoperative neurological deficits (p = 0.04). Small (<4 cm3) tumors significantly correlated with the preoperative neurological symptoms. Those tumors accompanying numbness also significantly correlated with the difficulty of the enucleation and postoperative neurological deficits. These findings will help to predict the neurological complication. © 2015, Abe et al

Factors Associated With Discharge Destination in Advanced Cancer Patients With Bone Metastasis in a Japanese Hospital

Objective To analyze patient characteristics of cancer rehabilitation and outcomes at our hospital. Methods This retrospective study analyzed 580 patients, who underwent cancer rehabilitation at our hospital and rehabilitation outcome after therapy were investigated. The relationship between the initial Barthel index and discharge outcomes was investigated, with a special focus on cancer patients with bone metastasis. The Barthel index and performance status (Eastern Cooperative Oncology Group) before and after rehabilitation were analyzed, and threshold value of home discharge was calculated from a receiver operating characteristic curve (ROC). General criteria for home discharge from our hospital included independence in performing basic activities of daily living such as bathing, feeding, and toileting or availability of home support from a family member/caregiver. Results The outcomes after rehabilitation among all the patients were as follows: discharge home 59%, death 13%, and others 27%. Statistical differences were observed between the initial and final values of the Barthel index in patients with bone metastasis, who could be discharged home (p=0.012). ROC analysis of the initial Barthel index for predicting home discharge revealed a threshold value of 60, sensitivity of 0.76, and specificity of 0.72. Conclusion The patients with bone metastasis had a lower rate of home discharge and a higher rate of mortality than all the study patients who underwent cancer rehabilitation at our hospital. It is proposed that at the time of initiation of rehabilitation for patients with bone metastasis, an initial Barthel index lower than 60 might predict a worse outcome than home discharge

Surgical management of proximal fibular tumors: A report of 12 cases

Background/aim Aggressive benign or malignant tumors in the proximal fibula may require en bloc resection of the fibular head, including the peroneal nerve and lateral collateral ligament. Here, we report the treatment outcomes of 12 patients with aggressive benign or malignant proximal fibula tumors. Patients and methods Four patients with osteosarcoma and 1 patient with Ewing\u27s sarcoma were treated with intentional marginal resections after effective chemotherapy, and 4 patients underwent fibular head resections without ligamentous reconstruction. Clinical outcomes were investigated. Results The mean Musculoskeletal Tumor Society scores were 96% and 65% in patients without peroneal nerve resection and those with nerve resection, respectively. No patients complained of knee instability. Conclusion Functional outcomes after resection of the fibular head were primarily influenced by peroneal nerve preservation. If patients are good responders to preoperative chemotherapy, malignant tumors may be treated with marginal excision, resulting in peroneal nerve preservation and good function. © 2016 The AuthorsEmbargo Period 12 month

Knee joint preservation surgery in osteosarcoma using tumour-bearing bone treated with liquid nitrogen

Purpose: To preserve the joint structure in order to maintain good limb function in patients with osteosarcoma, we perform epiphyseal or metaphyseal osteotomy and reconstruction using frozen autografts that contain a tumour treated with liquid nitrogen. There are two methods of using liquid nitrogen-treated autografts: the free-freezing method and the pedicle-freezing method. The purpose of this study was to evaluate the results of intentional joint-preserving reconstruction using the free-freezing method and the pedicle-freezing method in patients with osteosarcoma. Methods: Between 2006 and 2014, we performed joint-preserving surgery (12 with the free-freezing method and six with the pedicle freezing method) to treat 18 cases of osteosarcoma (12 distal femurs and six proximal tibias) in patients who had achieved a good response to neoadjuvant chemotherapy. Results: Among the 18 patients (nine boys and nine girls) who had a mean age of 11.6 years, 13 remained continuously disease-free, three showed no evidence of disease, one was alive with the disease, and one died from the disease. Functional outcomes were assessed as excellent in 15 patients and poor in three, with a mean follow-up period of 46.1 months. The mean Musculoskeletal Tumour Society (MSTS) score was 90.2%. Except for one patient who underwent amputation, all patients could bend their knee through >90° flexion, and nine achieved full ROM. All but two patients could walk without aid, and 11 were able to run normally throughout the follow-up period. No intraoperative complications were observed, such as surrounding soft-tissue damage, neurovascular injury, or recurrence from frozen bone. Conclusions: Joint-preserving reconstruction using frozen autografts yielded excellent function in patients with osteosarcoma. © 2017 The Author(s)in Press / Embargo Period 12 month

Risk factors for postoperative deep infection in bone tumors

金沢大学医薬保健研究域医学系Background: Postoperative deep infection after bone tumor surgery remains a serious complication. Although there are numerous reports about risk factors for postoperative deep infection in general surgery, there is only a small number of reports about those for bone tumor surgery. This retrospective study aimed to identify risk factors for postoperative deep infection after bone tumor resection. Methods: We reviewed data of 681 patients (844 bone tumors) who underwent surgery. Associations between variables, including age, recurrent tumor, pathological fracture, surgical site (pelvis/other), chemotherapy, biological reconstruction, augmentation of artificial bone or bone cement, the use of an implant, intraoperative blood loss, operative time, additional surgery for complications, and postoperative deep infection were evaluated. Results: The rate of postoperative deep infection was 3.2% (27/844 tumors). A pelvic tumor (odds ratio [OR]: 3.4, 95% confidence interval [CI]: 1.0–11.3) and use of an implant (OR: 9.3, 95% CI: 1.9–45.5) were associated with an increased risk of deep infection. Conclusions: This retrospective study showed that pelvic tumor and use of an implant were independent risk factors for deep infection. This information will help surgeons prepare an adequate surgical plan for patients with bone tumors. © 2017 Miwa et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Anti-tumor effects of a nonsteroidal anti-inflammatory drug zaltoprofen on chondrosarcoma via activating peroxisome proliferator-activated receptor gamma and suppressing matrix metalloproteinase-2 expression.

金沢大学医薬保健研究域医学系Surgical resection is the only treatment for chondrosarcomas, because of their resistance to chemotherapy and radiotherapy; therefore, additional strategies are crucial to treat chondrosarcomas. Peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-activated transcription factor, which has been reported as a possible therapeutic target in certain malignancies including chondrosarcomas. In this study, we demonstrated that a nonsteroidal anti-inflammatory drug, zaltoprofen, could induce PPARγ activation and elicit anti-tumor effects in chondrosarcoma cells. Zaltoprofen was found to induce expressions of PPARγ mRNA and protein in human chondrosarcoma SW1353 and OUMS27 cells, and induce PPARγ-responsible promoter reporter activities. Inhibitory effects of zaltoprofen were observed on cell viability, proliferation, migration, and invasion, and the activity of matrix metalloproteinase-2 (MMP2); these effects were dependent on PPARγ activation and evidenced by silencing PPARγ. Moreover, we showed a case of a patient with cervical chondrosarcoma (grade 2), who was treated with zaltoprofen and has been free from disease progression for more than 2 years. Histopathological findings revealed enhanced expression of PPARγ and reduced expression of MMP2 after administration of zaltoprofen. These findings demonstrate that zaltoprofen could be a promising drug against the malignant phenotypes in chondrosarcomas via activation of PPARγ and inhibition of MMP2 activity. © 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.2957320

軟部肉腫のGSK3βを標的とする新規治療法の開発と分子メカニズムの解明

金沢大学附属病院すべての肉腫細胞の活性型GSK3βの発現は線維芽細胞より高く, その活性阻害により生存と増殖が抑制され，ミトコンドリア膜電位が低下，消失した. RNA干渉により同様の結果が得られた．これに伴ってmatrix metalloproteinase (MMP)-2の発現が低下し, コラーゲンゲル内での細胞浸潤能が抑制された. マウス移植腫瘍の治療実験では, 対照群（阻害剤の溶媒dimethyl sulfoxide (DMSO) 投与）に比べて，GSK3 β阻害剤投与により腫瘍容積と重量は有意に減少した．また摘出腫瘍では，GSK3 β阻害剤投与群では腫瘍細胞の壊死像を認めた．Expression of the active form of GSK3β was higher in sarcoma cells than in fibroblasts. Inhibition of GSK3β activity by pharmacological inhibitors or of its expression by RNA interference suppressed the proliferation of sarcoma cells and induced apoptosis. GSK3β inhibition suppressed the expression of cyclin D1, CDK4 and matrix metalloproteinase (MMP)-2 as well as sarcoma cell invasion of collagen gel. Treatment by intraperitoneal injection of either of the GSK3β inhibitors attenuated the proliferation of sarcoma xenografts in mice in comparison to the mice treated with dimethyl sulfoxide (diluent of GSK3β inhibitor). Pathology examination revealed marked necrosis in the tumors of mice treated with the inhibitor. No obvious side effects or adverse events were observed in the treated mice.研究課題/領域番号:16K20040, 研究期間(年度):2016-04-01 – 2018-03-3