研究者詳細 - 藤原　智洋

論文 - 藤原　智洋

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The role of radiotherapy in the treatment of superficial soft-tissue sarcomas. 国際誌

Tomohiro Fujiwara, Yusuke Tsuda, Louis-Romée Le Nail, Scott Evans, Jonathan Gregory, Roger Tillman, Adesegun Abudu

The bone & joint journal 102-B ( 8 ) 1088 - 1094 2020年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

AIMS: The existing clinical guidelines do not describe a clear indication for adjuvant radiotherapy (RT) in the treatment of superficial soft tissue sarcomas (STSs). We aimed to determine the efficacy of adjuvant RT for superficial STSs. METHODS: We retrospectively studied 304 patients with superficial STS of the limbs and trunk who underwent surgical resection at a tertiary sarcoma centre. The efficacy of RT was investigated according to the tumour size and grade: group 1, ≤ 5 cm, low grade; group 2, ≤ 5cm, high grade; group 3, > 5 cm, low grade; group 4, > 5 cm, high grade. RESULTS: The five- and ten-year local recurrence-free survival (LRFS) for all patients was 88% and 81%, respectively. While the efficacy of adjuvant RT was not proven in local control of all patients (five-year LRFS; RT+, 90% versus RT-, 83%; p = 0.074), the LRFS was significantly improved by adjuvant RT in group 2 (five-year LRFS; RT+, 96% versus RT-, 82%; p = 0.019), and group 4 (five-year LRFS; RT+, 87% versus RT-, 73%; p = 0.027). In groups 2 and 4, adjuvant RT significantly reduced the LR risk if the resection margin was clear but less than 5 mm; the LR rate was 7% with adjuvant RT compared with 26% with surgery alone (p = 0.003). There was no statistical relationship with the use of adjuvant RT and survival in every group. CONCLUSION: Adjuvant RT reduces the risk of local recurrence in patients with superficial high-grade STS regardless of tumour size, especially when resection margin is less than 5 mm. Cite this article: Bone Joint J 2020;102-B(8):1088-1094.

DOI： 10.1302/0301-620X.102B8.BJJ-2020-0043.R1

Clinical relevance and functional significance of cell-free microRNA-1260b expression profiles in infiltrative myxofibrosarcoma. 国際誌

Takuya Morita, Tomohiro Fujiwara, Aki Yoshida, Koji Uotani, Masahiro Kiyono, Suguru Yokoo, Joe Hasei, Toshiyuki Kunisada, Toshifumi Ozaki

Scientific reports 10 ( 1 ) 9414 - 9414 2020年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

Infiltrative tumor growth into adjacent soft tissues is a major cause of the frequent recurrence and tumor-related death of myxofibrosarcoma (MFS), but no useful biomarkers reflecting tumor burden and infiltrative growth are available. While emerging evidence suggests a diagnostic and functional role of extracellular/circulating microRNA (miRNA) in various malignant diseases, their significance in MFS patients remains unknown. Global miRNA profiling identified four upregulated miRNAs in MFS patient sera and culture media of MFS cells. Among these, serum miR-1260b level was significantly upregulated in patient serum discriminating from healthy individuals and closely correlated with clinical status and tumor dynamics in MFS-bearing mice. In addition, high miR-1260b expression in serum was correlated with radiological tail-like patterns, characteristic of the infiltrative MFS. The extracellular miR-1260b was embedded in tumor-derived extracellular vesicles (EVs) and promoted cellular invasion of MFS through the downregulation of PCDH9 in the adjacent normal fibroblasts. Collectively, circulating miR-1260b expression may represent a novel diagnostic target for tumor monitoring of this highly aggressive sarcoma. Moreover, EV-miR-1260b could act as a transfer messenger to adjacent cells and mediate the infiltrative growth of MFS, providing new insights into the mechanism of infiltrative nature via crosstalk between tumor cells and their microenvironment.

DOI： 10.1038/s41598-020-66120-8

Impact of chemotherapy-induced necrosis on event-free and overall survival after preoperative MAP chemotherapy in patients with primary high-grade localized osteosarcoma. 国際誌

Yusuke Tsuda, Kim Tsoi, Michael C Parry, Jonathan D Stevenson, Tomohiro Fujiwara, Vaiyapuri Sumathi, Lee M Jeys

The bone & joint journal 102-B ( 6 ) 795 - 803 2020年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

AIMS: To assess the correlation between the histological response to preoperative chemotherapy and event-free survival (EFS) or overall survival (OS) in patients with high-grade localized osteosarcoma. METHODS: Out of 625 patients aged ≤ 40 years treated for primary high-grade osteosarcoma between 1997 and 2016, 232 patients without clinically detectable metastases at the time of diagnosis and treated with preoperative high-dose methotrexate, adriamycin and cisplatin (MAP) chemotherapy and surgery were included. Associations of chemotherapy-induced necrosis in the resected specimen and EFS or OS were assessed using Cox model and the Pearson's correlation coefficients (r). Time-dependent receiver operating characteristic analysis was applied to determine the optimal cut-off value of chemotherapy-induced necrosis for EFS and OS. RESULTS: OS was 74% (95% confidence interval (CI) 67 to 79) at five years. Median chemotherapy-induced necrosis was 85% (interquartile range (IQR) 50% to 97%). In multivariate Cox model, chemotherapy-induced necrosis was significantly associated with EFS and OS (hazard ratio (HR) = 0.99 (95% CI 0.98 to 0.99); p < 0.001 and HR = 0.98 (95% CI 0.97 to 0.99); p < 0.001, respectively). Positive correlation was observed between chemotherapy-induced necrosis and five-year EFS and five-year OS (r = 0.91; p < 0.001, and r = 0.85; p < 0.001, respectively). The optimal cut-off value of chemotherapy-induced necrosis for five-year EFS and five-year OS was 85% and 72%, respectively. CONCLUSION: Chemotherapy-induced necrosis in the resected specimen showed positive correlation with EFS and OS in patients with high-grade localized osteosarcoma after MAP chemotherapy. In our analysis, optimal cut-off values of MAP chemotherapy-induced necrosis in EFS and OS were lower than the commonly used 90%, suggesting the need for re-evaluation of the optimal cut-off value through larger, international collaborative research. Cite this article: Bone Joint J 2020;102-B(6):795-803.

DOI： 10.1302/0301-620X.102B6.BJJ-2019-1307.R1

Is Microscopic Vascular Invasion in Tumor Specimens Associated with Worse Prognosis in Patients with High-grade Localized Osteosarcoma? 国際誌

Yusuke Tsuda, Kim Tsoi, Jonathan D Stevenson, Michael C Parry, Tomohiro Fujiwara, Vaiyapuri Sumathi, Lee M Jeys

Clinical orthopaedics and related research 478 ( 6 ) 1190 - 1198 2020年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Other than metastases at diagnosis and histological response to preoperative chemotherapy, there are few reliable predictors of survival in patients with osteosarcoma. Microscopic vascular invasion (MVI) has been identified in the resection specimens of patients with osteosarcoma. However, it is unknown whether the MVI in resected specimens is associated with worse overall survival and higher cumulative incidence of local recurrence or metastasis in a large cohort of patients younger than 40 years with high-grade localized osteosarcoma. QUESTIONS/PURPOSES: (1) Is MVI associated with worse overall survival and higher cumulative incidence of events (local recurrence or metastasis) in patients younger than 40 years with high-grade localized osteosarcoma? (2) What clinical characteristics are associated with MVI in patients with high-grade localized osteosarcoma? METHODS: A total of 625 patients younger than 40 years with primary high-grade osteosarcoma between 1997 and 2016 were identified in our oncology database. We included patients younger than 40 years with primary high-grade osteosarcoma who underwent definitive surgery and preoperative and postoperative chemotherapy. The minimum follow-up period was 2 years after treatment. Patients with the following were excluded: metastasis at initial presentation (21%, n = 133), progression with preoperative chemotherapy precluding definitive surgery (6%, n = 38), surgery at another unit (2%, n = 13), lost to follow-up before 2 years but not known to have died (3%, n = 18), and death related to complications of preoperative chemotherapy (1%, n = 4). A retrospective pathologic and record review was conducted in the remaining 419 patients. The median follow-up period was 5 years (interquartile range [IQR] 3 to 9 years). The overall survival of the entire group (n = 419) was 67% [95% CI 63 to 72] at 5 years. Of the 419 patients, 10% (41) had MVI in their resection specimens. The Kaplan-Meier method was used to estimate overall survival. The cumulative incidence of events captured the first event of either metastasis or local recurrence. This analysis was completed with a competing risk framework: deaths without evidence of local recurrence or metastasis were regarded as a competing event. Clinical and histological variables (sex, age, tumor site, tumor largest dimension, surgical margin, chemotherapy-induced necrosis, type of surgery, histologic type of tumor, type of chemotherapy regimen, pathologic fracture, and MVI) were evaluated using the log-rank test or Gray test in the univariate analyses and Cox proportional hazard model or Fine and Gray model in the multivariate analyses. RESULTS: After adjusting for other factors, multivariate analyses showed that the presence of MVI in resection specimens was associated with worse overall survival and higher cumulative incidence of event (hazard ratio 1.88 [95% CI 1.22 to 2.89]; p = 0.004 and HR 2.33 [95% CI 1.56 to 3.49]; p < 0.001, respectively). A subgroup analysis demonstrated that the relationship between MVI and survival applied only to patients with a poor response to chemotherapy (less than 90% necrosis; overall survival at 5 years, MVI [+] = 24% [95% CI 11 to 39] versus MVI [-] = 60% [95% CI 52 to 66]; p < 0.001 and cumulative incidence of events at 5 years, MVI [+] = 86% [95% CI 68 to 94] versus MVI [-] = 54% [95% CI 46 to 61]; p < 0.001). The MVI (+) group had a higher proportion of patients with a poor response to chemotherapy (85% [35 of 41] versus 53% [201 of 378]; p < 0.001), involved margins (15% [6 of 41] versus 5% [18 of 378]; p = 0.021), and limb-ablative surgery (37% [15 of 41] versus 21% [79 of 378]; p = 0.022) than the MVI (-) group did. CONCLUSIONS: MVI is associated with lower overall survival and higher cumulative incidence of local recurrence or metastasis, especially in patients with a poor histologic response to preoperative chemotherapy. Future studies in patients treated for osteosarcoma should consider this observation when planning new trials. LEVEL OF EVIDENCE: Level III, therapeutic study.

DOI： 10.1097/CORR.0000000000001079

Acetabular reconstruction with an ice-cream cone prosthesis following resection of pelvic tumors: Does computer navigation improve surgical outcome? 国際誌

Tomohiro Fujiwara, Deepak V Sree, Jonathan Stevenson, Yoichi Kaneuchi, Michael Parry, Yusuke Tsuda, Louis-Romée Le Nail, Ricardo M Medellin, Robert Grimer, Lee Jeys

Journal of surgical oncology 121 ( 7 ) 1104 - 1114 2020年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND AND OBJECTIVES: Acetabular reconstruction with a coned-stem prosthesis has been one of the reliable procedures following pelvic tumor resections but is associated with a risk of complications and postoperative morbidity. We investigated whether navigated reconstruction could decrease the complication rate and optimize outcomes. METHODS: A retrospective study was conducted on 33 patients who underwent acetabular resection and reconstruction with ice-cream cone prostheses; outcomes were compared between the navigated and nonnavigated groups. RESULTS: A clear margin was obtained in 91% and 82% of the navigated and nonnavigated groups, respectively. The local recurrence (LR) rate was 12%, and all LRs occurred in the nonnavigated group. The rate of major complications requiring surgical intervention was significantly lower in the navigated group (9%) than in the nonnavigated group (50%; P = .024). Two implant failures occurred in the nonnavigated group. Functional outcomes were significantly correlated with the occurrence of major complications (P = .010) and the use of navigation (P = .043); superior functional scores were observed in the navigated group (Musculoskeletal Tumor Society, 73% vs 55%; Toronto Extremity Salvage Score, 73% vs 56%). CONCLUSION: Ice-cream cone prosthesis is an acceptable reconstruction modality following periacetabular tumor resections, and computer navigation are useful to facilitate proper resection margins and implant position.

DOI： 10.1002/jso.25882

Denosumab in giant cell tumour of bone in the pelvis and sacrum: Long-term therapy or bone resection?

Andrea Sambri, Manuel R Medellin, Costantino Errani, Laura Campanacci, Tomohiro Fujiwara, Davide Donati, Michael Parry, Robert Grimer

Journal of orthopaedic science : official journal of the Japanese Orthopaedic Association 25 ( 3 ) 513 - 519 2020年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

INTRODUCTION: Surgery of GCTB in sacrum and pelvis is challenging, with high rates of complications and local recurrence. Denosumab can consolidate the peripheral rim of the tumour, thus reducing the rate of morbidities of surgery. The aim of this paper is to evaluate the use of denosumab in pelvic/sacrum giant cell tumours of bone (GCTB). PATIENTS AND METHODS: We retrospectively reviewed a cohort of 26 patients with aggressive GCTB in sacrum or pelvis treated with denosumab at two referral centres. Clinical response and local recurrence were recorded and the radiologic responses were evaluated with the MDA criteria. RESULTS: 69% of the pelvic GCTB treated with denosumab presented partial or good radiologic responses (type 2A or 2B) after 49 weeks of treatment. Denosumab was administered as adjuvant therapy prior and after surgery in 11 patients (group A), and as the only treatment in 15 patients (group B). In group A, 62% of local recurrence was observed in patients treated with intralesional curettage. No recurrences were identified after en bloc resection. In group B, 9 patients were on continuous bimonthly long term denosumab administration with type 2A and 2B responses. Six patients stopped denosumab and 66% remained stable after 10 months of follow-up. CONCLUSIONS: Long-term denosumab therapy can be considered with curative intent for pelvic and sacrum GCTB. If surgical intervention is required wide resection may be advisable to reduce the risk of recurrence.

DOI： 10.1016/j.jos.2019.05.003

Extra-articular resection of shoulder joint for bone sarcomas: Oncologic and limb-salvage outcomes of 32 cases compared with shoulder disarticulation and forequarter amputation. 国際誌

Yusuke Tsuda, Tomohiro Fujiwara, Scott Evans, Yoichi Kaneuchi, Adesegun Abudu

Journal of surgical oncology 121 ( 4 ) 612 - 619 2020年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND AND OBJECTIVES: We aimed to identify the overall survival (OS), surgical complications, survival of reconstruction, and functional outcome of patients who underwent extra-articular resection of the shoulder joint for primary bone sarcomas. The OS and local recurrence rates in patients who underwent an amputation were also evaluated for comparison. METHODS: Thirty-two patients treated between 1988 and 2017 were studied. The tumours were located in the humerus in 22 (69%) and scapula in 10 patients (31%). The resection types were Malawer type IV in 6 (19%), type V in 21 (66%), and type VI in 5 patients (15%). Reconstruction was performed with endoprosthesis in 23 patients (72%) while excision arthroplasty with the suspension of the humerus to the clavicle was performed in 9 patients (28%). Surgical margins were wide in 16, marginal in 8, intralesional in 3, and not available in 5 patients. During the study period, 40 patients underwent a forequarter amputation and 11 patients underwent a shoulder disarticulation. RESULTS: The 5-year OS for patients who underwent extra-articular resection of the shoulder joint was 42% which was not statistically different compared with that of patients who underwent amputation (5-year OS = 30%; P = .091). The 5-year survival of the reconstruction was 94%, similar for endoprosthesis and excision arthroplasty. Local recurrence and complications developed in 6 (19%) and 10 patients (31%), respectively. Failures of the reconstruction requiring revision surgery occurred in two patients (6%). Limb salvage was achieved in 30 patients (94%). The median Musculoskeletal Tumour Society functional score was 61% (interquartile range, 57%-70%) and was similar in the endoprosthesis and excision arthroplasty group. CONCLUSIONS: Extra-articular resection of the shoulder joint for bone sarcomas is an effective limb-salvage method. However, local recurrence remains a principal concern.

DOI： 10.1002/jso.25838

Sacral chordoma: do the width of surgical margin and the use of photon/proton radiotherapy affect local disease control? 国際誌

Tomohiro Fujiwara, Yusuke Tsuda, Jonathan Stevenson, Michael Parry, Lee Jeys

International orthopaedics 44 ( 2 ) 381 - 389 2020年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

PURPOSE: Chordoma is a rare but highly aggressive primary bone sarcoma that arises commonly from the sacrum. While en bloc resection has been the mainstay of the treatment, the role of resection margin in millimetres with/without adjuvant radiotherapy (RT) has been unknown. We investigated the prognostic impact of surgical margin width, adjuvant RT, and their combined factor for sacral chordoma. METHODS: Forty-eight patients who underwent surgical treatment between 1996 and 2016 were studied. Of these, 11 patients (23%) received adjuvant RT; photon RT in 7 (15%) and proton RT in 4 (8%). Margins were microscopically measured in millimetres from the resection surface to the closest tumour on histologic slides. RESULTS: The five year and ten year disease-specific survival was 88% and 58%, respectively, and the local recurrence (LR) rate was 48%. The LR rate with 0-mm, < 1.5-mm, and ≥ 1.5-mm margin was 50% (group 1), 50% (group 2: RT-, 61%; group 3: RT+, 14%), and 0% (group 4), respectively. We observed a significantly lower LR rate in patients with adjuvant photon/proton RT (18%) than without it (57%; p = 0.026), and no LR was observed after post-operative proton RT. The combined factor of margin with RT clearly stratified the LR risk: patients of group 1 (positive margin) and 2 (< 1.5-mm margin, RT-) had approximately 7.5× LR risk (p = 0.049) compared with those of group 3 (< 1.5-mm margin, RT+) and 4 (≥ 1.5-mm margin). CONCLUSION: This study identified the lowest risk of local failure in tumour resection with ≥ 1.5-mm margin or negative but < 1.5-mm margin with the use of adjuvant photon/proton radiotherapy for sacral chordoma. Early results of adjuvant proton RT demonstrated excellent local control.

DOI： 10.1007/s00264-019-04460-5

Surgical outcomes and prognostic factors of non-metastatic radiation-induced sarcoma of bone. 国際誌

Yusuke Tsuda, Martin Lowe, Scott Evans, Michael C Parry, Jonathan D Stevenson, Tomohiro Fujiwara, Yoichi Kaneuchi, Louis-Romee Le Nail, Lee M Jeys

European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology 46 ( 2 ) 293 - 298 2020年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: The survival and prognostic factors in non-metastatic, radiation-induced bone sarcomas of bone have not been described. Moreover, the quantitative data about surgical outcomes and complications after limb-salvage surgery versus amputation are quite limited. METHODS: Twenty-five patients with non-metastatic, radiation-induced sarcoma of bone who underwent definitive surgery were analysed. Histological diagnosis was osteosarcoma in 19 and undifferentiated pleomorphic sarcoma in six. The definitive surgery was limb-salvage surgery in 15 patients and an amputation in 10. RESULTS: The 5-year overall survival rate (OS) and the 5-year event-free survival rate (EFS) were 53% (95% CI 31%-70%) and 40% (21%-59%), respectively. Patients with wide or radical surgical margins (n = 13) showed significantly better OS compared with those with marginal (n = 8) or intralesional (n = 2) margins (5-year OS, radical or wide = 74%, marginal = 17%, intralesional = 0%, p = 0.044). The risk of local recurrence was significantly higher in the limb-salvage group compared to the amputation group (49% vs 0%, p = 0.011). OS and EFS were not significantly different between limb-salvage group and an amputation group (p = 0.188 and 0.912, respectively). CONCLUSIONS: We believe non-metastatic, radiation-induced sarcoma of bone should be resected with the aim of achieving wide or radical margins. Although limb-salvage surgery was related to higher rates of local recurrence compared with those of the amputation group, OS and EFS were not different among two groups. Surgeons need to discuss the higher risk of local recurrence in limb-salvage surgery.

DOI： 10.1016/j.ejso.2019.10.036

What is an adequate margin for infiltrative soft-tissue sarcomas? 国際誌

Tomohiro Fujiwara, Jonathan Stevenson, Michael Parry, Yusuke Tsuda, Kim Tsoi, Lee Jeys

European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology 46 ( 2 ) 277 - 281 2020年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

OBJECTIVES: What constitutes an adequate margin of resection for infiltrative subtypes of soft-tissue sarcomas remains unclear. We aimed to determine the prognostic significance of the margin in millimetres for myxofibrosarcoma (MFS) and undifferentiated pleomorphic sarcoma (UPS). METHODS: 305 patients diagnosed with either a high-grade, localised MFS (n = 98) or UPS (n = 207) were included. The relationship of closest margin in millimetres to viable tumour and oncological outcomes was analysed. RESULTS: The overall local recurrence (LR) rate for all patients were 12%: 19% with positive margin and 10% with negative margin (p = 0.051). The LR rate was similar in patients with negative but <10 mm margin; 13%, 6%, 15%, 17% with 0.1-0.9 mm, 1.0-1.9 mm, 2.0-4.9 mm, and 5.0-9.9 mm margin, respectively. However, the LR rate decreased to 3% if the margin was ≥10 mm. By the R- or R+1-classification, the 10-year cumulative probability of LR was 9%, 15%, 48% for R0, R1, R2 resections, respectively, which was not sensitive enough to stratify the LR risk in patients with negative margins. However, the cumulative probability of LR was significantly stratified by metric distance; the 10-year cumulative LR probability was 3%, 14%, 25% with ≥10.0 mm, 0.1-9.9 mm, and 0 mm, respectively (p = 0.026). A trend towards improved local control by adjuvant radiotherapy was seen in patients with 0-9.9 mm margin (p = 0.078). CONCLUSION: The resection margin, when measured as a metric distance, correlates with a reduction in LR, and appears to be more significant on local control than radiotherapy. To minimise the risk of LR, a margin distance of at least 10 mm is advocated for MFS and UPS.

DOI： 10.1016/j.ejso.2019.10.005

Extendable Endoprostheses in Skeletally Immature Patients: A Study of 124 Children Surviving More Than 10 Years After Resection of Bone Sarcomas. 国際誌

Yusuke Tsuda, Kim Tsoi, Jonathan D Stevenson, Tomohiro Fujiwara, Roger Tillman, Adesegun Abudu

The Journal of bone and joint surgery. American volume 102 ( 2 ) 151 - 162 2020年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Extendable endoprostheses are used to reconstruct segmental defects following resection of bone sarcomas in skeletally immature patients. However, there remains a paucity of studies with regard to long-term outcomes. METHODS: We retrospectively reviewed 124 skeletally immature children who underwent an extendable endoprosthetic replacement and survived more than 10 years after the surgical procedures. Anatomical sites included the distal part of the femur (n = 66), the proximal part of the femur (n = 13), the proximal part of the tibia (n = 29), and the proximal part of the humerus (n = 16). Complications and implant survival were classified according to the modified Henderson criteria. RESULTS: The mean follow-up was 24 years (range, 10 to 36 years). The mean age at the time of the extendable endoprosthetic replacement was 9 years (range, 2 to 16 years). All patients had reached skeletal maturity at the last follow-up. The 10-year endoprosthetic failure-free survival rate was 28%. A total of 243 complications occurred in 90% of patients; these complications were most frequently related to soft-tissue problems (27% of complications). The incidence of and cumulative survival with respect to each failure mode varied between anatomical sites. Soft-tissue failures occurred most frequently in the proximal part of the femur (77%; p = 0.003), and the distal part of the femur was the most frequent site of aseptic loosening (52%; p = 0.014) and structural failure (55%; p = 0.001). Excluding lengthening procedures, 105 patients (85%) underwent an additional surgical procedure, with a mean of 2.7 surgical procedures per patient (range, 0 to 7 surgical procedures per patient). The mean limb-length discrepancy at the final follow-up was 1 cm (range, 0 to 9 cm). Limb salvage was achieved in 113 patients (91%). The mean Musculoskeletal Tumor Society functional score (the percentage of a total score of 30 points) was 82% (range, 40% to 100%) in 115 patients with available data at the last follow-up. CONCLUSIONS: Extendable endoprostheses are associated with a high complication rate and a need for additional surgical procedures over time. Despite this, successful limb salvage with reasonable function and small limb-length discrepancy is achievable in the long term. Our study provides benchmark data for individual anatomical sites for further improvements of outcomes. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

DOI： 10.2106/JBJS.19.00621

The long-term results of extendable endoprostheses of the humerus in children after the resection of a bone sarcoma. 国際誌

Yusuke Tsuda, Tomohiro Fujiwara, Jonathan D Stevenson, Michael C Parry, Roger Tillman, Adesegun Abudu

The bone & joint journal 102-B ( 1 ) 64 - 71 2020年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

AIMS: The purpose of this study was to report the long-term results of extendable endoprostheses of the humerus in children after the resection of a bone sarcoma. METHODS: A total of 35 consecutive patients treated with extendable endoprosthetic replacement of the humerus in children were included. There were 17 boys and 18 girls in the series with a median age at the time of initial surgery of nine years (interquartile range (IQR) 7 to 11). RESULTS: The median follow-up time was 10.6 years (IQR 3.9 to 20.4). The overall implant survival at ten years was 75%. Complications occurred in 13 patients (37%). Subluxation at the proximal humerus occurred in 19 patients (54%) but only six (17%) were symptomatic. Subluxation was seen more commonly in children under the age of nine years (86%) than in those aged nine years or more (33%) (p = 0.002). Implant failure occurred in nine patients (26%): the most common cause was aseptic loosening (four patients, 11%). Lengthening of the implant was carried out in 23 patients (66%). At final follow up, three patients had a limb that was shortened by 5 cm or more. The mean Musculoskeletal Tumor Society (MSTS) functional score was 79% (73% to 90%). CONCLUSION: Extendable endoprosthetic replacement is a reliable method of reconstructing humerus after excision of a bone sarcoma. Children who are less than nine years old have a high risk of subluxation. Cite this article: Bone Joint J 2020;102-B(1):64-71.

DOI： 10.1302/0301-620X.102B12.BJJ-2020-0124.R1

The long-term outcomes of modified Harrington procedure using antegrade pins for periacetabular metastasis and haematological diseases. 国際誌

Roger Tillman, Yusuke Tsuda, Manoj Puthiya Veettil, Peter S Young, Deepak Sree, Tomohiro Fujiwara, Adesegun Abudu

The bone & joint journal 101-B ( 12 ) 1557 - 1562 2019年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

AIMS: The aim of this study was to present the long-term surgical outcomes, complications, implant survival, and causes of implant failure in patients treated with the modified Harrington procedure using antegrade large diameter pins. PATIENTS AND METHODS: A cohort of 50 consecutive patients who underwent the modified Harrington procedure for periacetabular metastasis or haematological malignancy between January 1996 and April 2018 were studied. The median follow-up time for all survivors was 3.2 years (interquartile range 0.9 to 7.6 years). RESULTS: The five-year overall survival rate was 33% for all the patients. However, implant survival rates were 100% and 46% at five and ten years, respectively. Eight patients survived beyond five years. There was no immediate perioperative mortality or complications. A total of 15 late complications occurred in 11 patients (22%). Five patients (10%) required further surgery to treat complications. The most frequent complication was pin breakage without evidence of acetabular loosening (6%). Two patients (4%) underwent revision for aseptic loosening at 6.5 and 8.9 years after surgery. Ambulatory status and pain level were improved in 83% and 89%, respectively. CONCLUSION: The modified Harrington procedure for acetabular destruction has low complication rates, good functional outcome, and improved pain relief in selected patients Cite this article: Bone Joint J 2019;101-B:1557-1562.

DOI： 10.1302/0301-620X.101B12.BJJ-2019-0265.R1

Extra-articular resection for bone sarcomas involving the hip joint. 国際誌

Tomohiro Fujiwara, Yusuke Tsuda, Scott Evans, Jonathan Stevenson, Michael Parry, Lee Jeys, Adesegun Abudu

Journal of surgical oncology 2019年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

AIM: The aim of this study was to determine the oncologic, functional, and clinical outcomes after the extra-articular resection and limb-salvage reconstruction of the hip joint. METHODS: A retrospective study of 34 patients who underwent extra-articular resection of the hip joint for bone sarcomas between 1996 and 2016 was conducted. The primary tumor site was pelvis in 26 patients (76%) and femur in eight (24%). RESULTS: The surgical margins achieved were clear in 31 (91%) patients, and seven (21%) patients developed local recurrence; mostly occurring in pelvic tumors (n = 6). The 3-year overall survival was 63% with a median follow-up of 38 months (range, 5-219), which showed no statistical difference in tumor location. The most common complication was deep infection (n = 7) and dislocation (n = 7), mostly seen in pelvic tumors. Implant failure was seen in two patients with pelvic tumors, while no failure was noted in patients with femoral tumors. The median Musculoskeletal Tumour Society score was 69%; 67% for pelvic tumors and 73% for femoral tumors (P = .535). CONCLUSION: Despite complex surgery, extra-articular resection of the hip joint can achieve oncologically and functionally acceptable outcomes. While tumors of the pelvis are associated with a higher incidence of infection and local recurrence after resection, resection of tumors involving the femur are well tolerated.

DOI： 10.1002/jso.25769

Surgical treatment for pelvic Ewing sarcoma: What is a safe and functional acetabular reconstruction when combined with modern multidisciplinary treatments? 国際誌

Tomohiro Fujiwara, Johnathan R Lex, Jonathan D Stevenson, Yusuke Tsuda, Rhys Clark, Michael C Parry, Robert J Grimer, Lee M Jeys

Journal of surgical oncology 120 ( 6 ) 985 - 993 2019年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

PURPOSE: The purpose of this study was to clarify which local treatment is oncologically and functionally effective in pelvic Ewing sarcoma (ES). METHODS: A consecutive series of patients who underwent pelvic resections and acetabular reconstructions after chemotherapy between 1986 and 2016 at a supra-regional center were evaluated. RESULTS: The cohort consisted of 35 patients. The 5-year overall survival (OS) and local recurrence-free survival (LRFS) was 61% and 72%, respectively. Preoperative radiotherapy (RT) and surgery provided an excellent/good histological response in 92% and achieved significantly better OS (5 years, 64%) and LRFS (5 years, 100%) than surgery alone or surgery with postoperative RT. The Musculoskeletal Tumor Society functional scores were significantly better in patients with hip transposition than those with structural reconstructions (74% vs 57%; P = .031) using custom-made prostheses, irradiated autografts, and ice-cream cone prostheses. These scores were significantly lower if patients had deep infection (P = .035), which was the most common complication (28%) in structural reconstructions but did not occur in hip transposition even when performed after preoperative RT. CONCLUSION: Acetabular reconstruction with hip transposition resulted in no deep infection and superior function in patients with pelvic ES even when combined with preoperative RT, which improved tumor necrosis and rate of local control and survival.

DOI： 10.1002/jso.25660

Is the Width of a Surgical Margin Associated with the Outcome of Disease in Patients with Peripheral Chondrosarcoma of the Pelvis? A Multicenter Study. 国際誌

Yusuke Tsuda, Scott Evans, Jonathan D Stevenson, Michael Parry, Tomohiro Fujiwara, Minna Laitinen, Hidetatsu Outani, Lee Jeys

Clinical orthopaedics and related research 477 ( 11 ) 2432 - 2440 2019年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: We attempted to resect peripheral chondrosarcoma of the pelvis with clear margins. Because of the proximity of vessels or organs, there is still concern that narrow surgical margins may have an adverse effect on disease outcomes. Although current guidelines recommend resection of histologic Grade II or Grade III chondrosarcomas with a "wide" margin, there are no specific recommendations for the adequate width of a surgical margin. QUESTIONS/PURPOSES: (1) What is the disease-specific and local recurrence-free survival of patients with peripheral chondrosarcoma of the pelvis treated with resection or amputation? (2) Is the width of a surgical margin associated with the outcome of disease in patients with peripheral chondrosarcoma of the pelvis? (3) Does the histologic grade as determined with a preoperative biopsy correlate with the final grade after resection? (4) What are surgical complications in these patients? METHODS: We retrospectively reviewed records from three international collaborating hospitals. Between 1983 and 2017, we resected 262 pelvic chondrosarcomas of all types. After reviewing the pathologic reports of these patients, we included 52 patients with peripheral chondrosarcomas of the pelvis who had an osteochondroma-like lesion at the base of the tumor and a cartilage cap with malignant cells in resected specimens. To be eligible for this study, a patient had to have a minimum of 1 year of follow-up. Two patients were excluded because they had less than 1 year of follow-up, leaving 50 patients for inclusion in this study. The median follow-up duration was 7.0 years (interquartile range 2.1-10 years). The median age was 37 years (IQR 29-54 years). The ilium was the most frequently affected bone (in 36 of 50 patients; 72%). The histologic status of the surgical margin was defined as microscopically positive (0 mm), negative < 1 mm, or negative ≥ 1 mm. Thirteen of the 50 patients (26%) had local recurrence. Seven of 34 patients had Grade I tumors, five of 13 had Grade II tumors, and one of three had a Grade III tumor. Nine of 16 patients had multiple local recurrences. Two patients with Grade I tumors and two with Grade II tumors died because of pressure effects caused by local recurrence. RESULTS: The 10-year disease-specific and local recurrence-free survival rates were 90% (95% confidence interval, 70-97) and 69% (95% CI, 52-81), respectively. A surgical margin ≥ 1 mm (n = 16) was associated with a better local recurrence-free survival rate than a surgical margin < 1 mm (n = 17) or 0 mm (n = 11) (10-year local recurrence-free survival: resection margin ≥ 1 mm = 100% versus < 1 mm = 52% [95% CI, 31 to 70]; p = 0.008). No patients with a surgical margin ≥ 1 mm had local recurrence, metastasis, or disease-related death, irrespective of tumor grade. Patients with local recurrence (n = 13) showed worse disease-specific survival than those without local recurrence (n = 37) (10-year disease-specific survival: local recurrence [+] = 59% [95% CI, 16 to 86] versus local recurrence [-] = 100%; p=0.001]). The preoperative biopsy results correctly determined the tumor grade in 15 of 41 patients (37%). The most frequent complication after surgery was local recurrence (13 of 50 patients, 26%). Deep infection was the most frequent nononcologic complication (four patients). CONCLUSIONS: We found a high local recurrence rate after surgical treatment of a peripheral pelvic chondrosarcoma, which was related to the width of the surgical margin. These local recurrences led to inoperable recurrent tumors and death. The tumor grade as determined by preoperative biopsy was inaccurate in 2/3 of patients compared with the final histologic assessment. Therefore, we believe every attempt should be made to achieve a negative margin during the initial resection to lessen the likelihood of local recurrence of peripheral chondrosarcoma of the pelvis of all grades. A margin of 1 mm or more appeared to be sufficient in these patients. LEVEL OF EVIDENCE: Level III, therapeutic study.

DOI： 10.1097/CORR.0000000000000926

The Clinical Outcomes of Hemicortical Extracorporeal Irradiated Autologous Bone Graft After Tumor Resection of Bone and Soft Tissue Sarcoma. 国際誌

Tomoki Nakamura, Tomohiro Fujiwara, Yusuke Tsuda, Adesegun Abudu, Yoshihito Nomoto, Akinori Takada, Yutaka Toyomasu, Tomohito Hagi, Kunihiro Asanuma, Akihiro Sudo

Anticancer research 39 ( 10 ) 5605 - 5610 2019年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND/AIM: We analyzed the process of healing at osteotomy sites and timing of achievement of full weight-bearing in sarcoma patients who underwent hemicortical or intercalary reconstruction using the extracorporeal irradiated autologous bone graft technique. PATIENTS AND METHODS: We studied 10 patients who had undergone tumor resection and reconstruction with hemicortical extracorporeal irradiated autologous bone graft at mid-shaft femur or tibia. The control group consisted of 30 patients who received the reconstruction using intercalary bone graft. RESULTS: Full weight-bearing was achieved in all 10 patients at a median time of 4.8 months. Function was excellent in all patients. When comparing the clinical outcome among the patients who received intercalary and hemicortical grafts, the duration to full weight-bearing achievement in patients who received hemicortical graft was shorter than that in those with intercalary graft. CONCLUSION: Early full weight-bearing may be achieved in patients undergoing hemicortical resection and reconstruction using extracorporeal irradiated autologous bone graft.

DOI： 10.21873/anticanres.13755

Secondary chondrosarcoma arising from osteochondroma: outcomes and prognostic factors. 国際誌

Yusuke Tsuda, Jonathan J Gregory, Tomohiro Fujiwara, Seggy Abudu

The bone & joint journal 101-B ( 10 ) 1313 - 1320 2019年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

AIMS: The aim of this study was to report the outcomes of patients who underwent definitive surgery for secondary chondrosarcomas arising from osteochondromas. PATIENTS AND METHODS: A total of 51 patients with secondary chondrosarcomas occurring from osteochondromas were reviewed. Median age was 36 years (interquartile range (IQR) 15 to 82). Median follow-up was 6.9 years (IQR 2.8 to 10.6). The pelvis was the most commonly affected site (59%). Histological grades were grade I in 35 (69%), grade II in 13 (25%), and grade III in three patients (6%). RESULTS: Preoperative biopsy histology correctly predicted the final histological grade in 27% of patients. The ten-year disease-specific survival (DSS) for all patients was 89.4%. Local recurrence occurred in 15 patients (29%), more commonly in pelvic tumours (37%) compared with limb tumours (19%). Four patients with pelvic tumours died from progression of local recurrence. No patient with limb tumours died of disease. Wide/radical margin was associated with improved local recurrence-free survival (p = 0.032) and local recurrence was associated with worse DSS (p = 0.005). CONCLUSION: We recommend that a secondary chondrosarcoma arising from osteochondroma of the pelvis is resected with wide/radical resection margins. The balance between the morbidity of surgery and risk of local recurrence needs to be considered in patients with limb secondary chondrosarcomas. Cite this article: Bone Joint J 2019;101-B:1313-1320.

DOI： 10.1302/0301-620X.101B9.BJJ-2019-0190.R1

Temporary External Fixation Can Stabilize Hip Transposition Arthroplasty After Resection of Malignant Periacetabular Bone Tumors. 国際誌

Toshiyuki Kunisada, Tomohiro Fujiwara, Joe Hasei, Eiji Nakata, Masuo Senda, Toshifumi Ozaki

Clinical orthopaedics and related research 477 ( 8 ) 1892 - 1901 2019年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: The choice of reconstructive procedure to restore limb function is challenging after internal hemipelvectomy. Hip transposition arthroplasty, also known as resection arthroplasty, removes a malignant or aggressive tumor of the pelvis and acetabulum after which the remaining femoral head is moved proximally to the lateral surface side of the sacrum or the underside of the resected ilium after internal hemipelvectomy. It may provide reasonable functional results and have some advantages such as lowering the risk of an infected implant compared with other reconstructions because no foreign implants are used. Hip transposition is generally managed with prolonged bed rest or immobilization postoperatively to stabilize the soft tissue surrounding the remaining femur. Because enabling patients to be mobile while the soft tissues heal might be advantageous, we reviewed our experience with an external fixation for this procedure. QUESTIONS/PURPOSES: (1) Does temporary external fixation facilitate postoperative physiotherapy in patients who undergo hip transposition arthroplasty? (2) What functional Musculoskeletal Tumor Society (MSTS) scores were achieved at short term in a small series of patients treated with hip transposition and temporary external fixation? (3) What were the complications of using external fixation in a small series of patients who received it for malignant tumors? METHODS: Between 2008 and 2012, we treated seven patients (three men and four women; median age, 37 years; age range, 18-53 years) with acetabular resection for malignant bone tumors; all were managed with a hip transposition, initially stabilized using external fixation. No other types of procedures were used for this indication in this period. Minimum followup in this retrospective study was 45 months, except for one patient who died at 18 months (range of followup duration, 18-90 months; median followup, 57 months), and no patients were lost to followup. The pins for external fixation were inserted into the affected side of the femur and the healthy contralateral ilium. External fixation was removed 6 weeks postoperatively and weightbearing was started at that time. Preoperative chemotherapy was administrated in four patients, but postoperative chemotherapy was delayed since it was given after external fixation removal in three patients. The postoperative rehabilitation course and functional results were assessed by chart review, functional results were determined using MSTS scores, tallied by physiotherapists who were not part of the surgical team, and complications were ascertained through chart review. Major complications were defined as complications that were treated with additional operations, such as deep infection, or ones that could cause severe postoperative dysfunction, such as nerve injury. RESULTS: With temporary external fixation, standing next to a bed was achieved in median 7 days (range, 6-9 days) postoperatively, transferring to a wheel chair in median 8 days (range, 6-28 days), and gait training using parallel bars in median 15 days (range, 7-48 days). At most recent followup, three patients could walk without a crutch or cane, three could walk with a cane, and one could walk with a crutch. The median MSTS score at most recent followup (median, 57 months) was 63%. Two patients had complications that resulted in reoperations; one had a wound dehiscence, and one had an abdominal herniation that gradually developed, and which was reconstructed using polypropylene mesh 2 years after pelvic resection. Two patients had nerve palsies that recovered by the end of the first year. All patients had pin tract infections that resolved with nonsurgical approaches. CONCLUSIONS: Hip transposition with temporary external fixation can stabilize the bone soft tissue after pelvic resection. Although we did not have a comparison group of patients, we believe that external fixation facilitates early postoperative physiotherapy and rehabilitation and provides good functional results without major surgical complications. Because it delays the resumption of chemotherapy, more patients with longer followup are needed to determine whether this will be associated with poorer oncologic results. LEVEL OF EVIDENCE: Level IV, therapeutic study.

DOI： 10.1097/CORR.0000000000000764

Metformin induces CD11b+-cell-mediated growth inhibition of an osteosarcoma: implications for metabolic reprogramming of myeloid cells and anti-tumor effects. 国際誌

Takenori Uehara, Shingo Eikawa, Mikako Nishida, Yuki Kunisada, Aki Yoshida, Tomohiro Fujiwara, Toshiyuki Kunisada, Toshifumi Ozaki, Heiichiro Udono

International immunology 31 ( 4 ) 187 - 198 2019年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

CD11b+ myeloid subpopulations, including myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs), play crucial roles in the suppression of T-cell-mediated anti-tumor immunity. Regulation of these cell types is a primary goal for achieving efficient cancer immunotherapy. We found that metformin (Met) induces CD11b+-cell-mediated growth inhibition of a K7M2neo osteosarcoma independent of T cells, as growth inhibition of K7M2neo was still observed in wild-type (WT) mice depleted of T cells by antibodies and in SCID; this contrasted with the effect of Met on Meth A fibrosarcoma, which was entirely T-cell-dependent. Moreover, the inhibitory effect seen in SCID was abrogated by anti-CD11b antibody injection. PMN-MDSCs were significantly reduced in both spleens and tumors following Met treatment. In TAMs, production of IL-12 and TNF-α, but not IL-10, became apparent, and elevation of MHC class II with reduction of CD206 was observed, indicating a shift from an M2- to M1-like phenotype via Met administration. Metabolically, Met treatment decreased basal respiration and the oxygen consumption rate (OCR)/extracellular acidification rate (ECAR) ratio of CD11b+ cells in tumors, but not in the spleen. In addition, decreased reactive oxygen species (ROS) production and proton leakage in MDSCs and TAMs were consistently observed in tumors. Uptake of both 2-deoxy-2-d-glucose (2-NBDG) and BODIPY® decreased in MDSCs, but only BODIPY® incorporation was decreased in TAMs. Overall, our results suggest that Met redirects the metabolism of CD11b+ cells to lower oxidative phosphorylation (OXPHOS) while elevating glycolysis, thereby pushing the microenvironment to a state that inhibits the growth of certain tumors.

DOI： 10.1093/intimm/dxy079

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