Publications by authors named "Akira Kawai"

325 Publications

Efficacy and safety of TAS-115, a novel oral multi-kinase inhibitor, in osteosarcoma: an expansion cohort of a phase I study.

Invest New Drugs 2021 Jun 12. Epub 2021 Jun 12.

Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan.

Background osteosarcoma is a rare, primary malignant bone tumour with limited available treatments for advanced or recurrent disease, resulting in a poor prognosis for patients. TAS-115 is a novel tyrosine kinase inhibitor under investigation in a phase I study in patients with solid tumours. We report data of osteosarcoma patients in the expansion cohort of this ongoing study. Patients and methods an analysis of this multicentre, open-label study was performed 6 months after the final patient was enrolled, and included patients aged ≥15 years, with unresectable or recurrent osteosarcoma, and who had refractory to standard therapy or for whom no standard therapy was available. TAS-115 650 mg/day was orally administered in a 5 days on/2 days off schedule. Results a total of 20 patients with osteosarcoma were enrolled. The most common adverse drug reactions (ADRs) were neutrophil count decreased (75%), aspartate aminotransferase increased (50%), and platelet count decreased (50%); 85% of patients had grade ≥ 3 ADRs. Long-term disease control (>1 year) with TAS-115 was achieved in three patients. The best overall response was stable disease (50%); no patient achieved a complete or partial response. Median progression-free survival was 3 months; 4-month and 12-month progression-free rates were 42% and 31%, respectively. Conclusion the safety and tolerability of TAS-115 and long-term disease stability for patients with unresectable or recurrent osteosarcoma were confirmed in this study, suggesting that TAS-115 is a promising novel therapy for advanced osteosarcoma patients. Trial registration number: JapicCTI-132333 (registered on November 8, 2013).
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http://dx.doi.org/10.1007/s10637-021-01107-4DOI Listing
June 2021

The 'other' bone sarcomas in Japan: a retrospective study of primary bone sarcomas other than osteosarcoma, Ewing sarcoma and chondrosarcoma, using data from the Bone Tumuor Registry in Japan.

Jpn J Clin Oncol 2021 Jun 9. Epub 2021 Jun 9.

The Department of Rare Cancer Center, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan.

Background: To date, no standard treatments for primary bone sarcomas other than those for osteosarcoma, Ewing sarcoma and chondrosarcoma have been developed.

Methods: The clinical characteristics and prognostic factors of 330 patients with primary bone sarcomas other than osteosarcoma, Ewing sarcoma and chondrosarcoma, listed in a nationwide tumour registry (Bone and Soft Tissue Tumor Registry in Japan) were investigated. The effects of adjuvant chemotherapy were determined by comparing the outcomes of patients with non-metastatic bone tumours who received surgery plus chemotherapy with those of patients who underwent surgery alone.

Results: The most common diagnosis was undifferentiated high-grade pleomorphic sarcoma. Axial site tumours (47.8%) and distant metastases at presentation (24.5%) were frequent. The 5-year overall and progression-free survival rates were 44.9 and 39.9%, respectively. Prognostic factor analysis identified surgery as an independent predictor of overall survival, and distant metastases at presentation was significant and independent predictor of both overall and progression-free survival. No significant difference in outcome was observed between patients treated with surgery alone and those treated with surgery plus chemotherapy (P = 0.71).

Conclusions: Patients with bone sarcomas other than osteosarcoma, Ewing sarcoma and chondrosarcoma without metastasis at presentation have a relatively good prognosis with definitive surgery; however, the benefit of adjuvant chemotherapy is unclear.
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http://dx.doi.org/10.1093/jjco/hyab090DOI Listing
June 2021

Establishment and characterization of NCC-MFS3-C1: a novel patient-derived cell line of myxofibrosarcoma.

Hum Cell 2021 Jul 15;34(4):1266-1273. Epub 2021 May 15.

Division of Rare Cancer Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.

Myxofibrosarcoma (MFS) is one of the most aggressive sarcomas with highly complex karyotypes and genomic profiles. Although a complete resection is required in the treatment of MFS, it is often not achieved due to its strong invasive nature. Additionally, MFS is refractory to conventional chemotherapy, leading to poor prognosis. Therefore, it is necessary to develop novel treatment modalities for MFS. Patient-derived cell lines are important tools in basic research and preclinical studies. However, only 10 MFS cell lines have been reported to date. Furthermore, among these cell lines, merely two MFS cell lines are publicly available. Hence, we established a novel MFS cell line named NCC-MFS3-C1, using a surgically resected tumor specimen from a patient with MFS. NCC-MFS3-C1 cells had copy number alterations corresponding to the original tumor. NCC-MFS3-C1 cells demonstrate constant proliferation, spheroid formation, and aggressive invasion. In drug screening tests, the proteasome inhibitor bortezomib and the histone deacetylase inhibitor romidepsin demonstrated significant antiproliferative effects on NCC-MFS3-C1 cells. Thus, the NCC-MFS3-C1 cell line is a useful tool in both basic and preclinical studies for MFS.
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http://dx.doi.org/10.1007/s13577-021-00548-6DOI Listing
July 2021

The current status of inpatient cancer rehabilitation provided by designated cancer hospitals in Japan.

Jpn J Clin Oncol 2021 May 15. Epub 2021 May 15.

Department of Musculoskeletal Oncology and Rehabilitation, National Cancer Center Hospital, Tokyo, Japan.

Objective: This survey was conducted to clarify the current status of inpatient cancer rehabilitation provided by designated cancer hospitals in Japan.

Methods: A survey questionnaire was sent to 427 designated cancer hospitals in Japan. Information was sought regarding whether inpatient cancer rehabilitation was provided by the center, and if so, whether respondents regarded such provision as satisfactory.

Results: Responses were obtained from 235/427 surveyed institutions (55.0%). Cancer rehabilitation was provided in inpatient settings by 97.4%. Two-thirds of respondents (67.7%) regarded inpatient cancer rehabilitation provision as still inadequate. The primary reasons claimed for this inadequacy were a lack of human resources, a lack of rehabilitation professionals with the requisite knowledge/skills and patients who would benefit from cancer rehabilitation present but not prescribed. The total number of rehabilitation staff was identified as associated factor of inadequate inpatient cancer rehabilitation in multivariate analysis (odds ratio = 0.979, 95% confidence interval = 0.96-1.00, P = 0.009).

Conclusions: In order to provide adequate cancer rehabilitation, a sufficient supply of rehabilitation staff, education and recognition of the need for cancer rehabilitation within oncology units are necessary.
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http://dx.doi.org/10.1093/jjco/hyab070DOI Listing
May 2021

Ultra-rare sarcomas: A consensus paper from the Connective Tissue Oncology Society community of experts on the incidence threshold and the list of entities.

Cancer 2021 Apr 28. Epub 2021 Apr 28.

Department of Epidemiology, Regional Health Council, Biomedical Research Institute of Murcia-Arrixaca, Murcia University, Murcia, Spain.

Background: Among sarcomas, which are rare cancers, many types are exceedingly rare; however, a definition of ultra-rare cancers has not been established. The problem of ultra-rare sarcomas is particularly relevant because they represent unique diseases, and their rarity poses major challenges for diagnosis, understanding disease biology, generating clinical evidence to support new drug development, and achieving formal authorization for novel therapies.

Methods: The Connective Tissue Oncology Society promoted a consensus effort in November 2019 to establish how to define ultra-rare sarcomas through expert consensus and epidemiologic data and to work out a comprehensive list of these diseases. The list of ultra-rare sarcomas was based on the 2020 World Health Organization classification, The incidence rates were estimated using the Information Network on Rare Cancers (RARECARENet) database and NETSARC (the French Sarcoma Network's clinical-pathologic registry). Incidence rates were further validated in collaboration with the Asian cancer registries of Japan, Korea, and Taiwan.

Results: It was agreed that the best criterion for a definition of ultra-rare sarcomas would be incidence. Ultra-rare sarcomas were defined as those with an incidence of approximately ≤1 per 1,000,000, to include those entities whose rarity renders them extremely difficult to conduct well powered, prospective clinical studies. On the basis of this threshold, a list of ultra-rare sarcomas was defined, which comprised 56 soft tissue sarcoma types and 21 bone sarcoma types.

Conclusions: Altogether, the incidence of ultra-rare sarcomas accounts for roughly 20% of all soft tissue and bone sarcomas. This confirms that the challenges inherent in ultra-rare sarcomas affect large numbers of patients.
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http://dx.doi.org/10.1002/cncr.33618DOI Listing
April 2021

Benefit of surgical resection of distant metastasis in soft tissue sarcoma: a systematic review.

Jpn J Clin Oncol 2021 Apr 6. Epub 2021 Apr 6.

Division of Musculoskeletal Oncology, National Cancer Center Hospital, Tokyo, Japan.

Objective: The aim of this systematic review was to evaluate the efficacy of metastasectomy for patients with advanced soft tissue sarcoma and to develop a recommendation outlining clinical guidelines for soft tissue sarcoma.

Methods: We searched the pertinent literature from January 1985 to December 2017. Two reviewers evaluated and screened the literature independently for eligibility and extracted data. We evaluated the quality of body of evidence and made a recommendation according to the Grading of Recommendations Development and Evaluation methodology.

Results: Among 244 identified studies, only 10 were finally included in this review and no randomized controlled trial reports were present. The median survival period after metastasectomy ranged from 9.6 to 39.6 months, and the 5-year survival rate ranged from 8 to 52%. The complication rate ranged from 7.3 to 25%, and the perioperative mortality rate was 0-1%. The guidelines committee proposed 'Metastasectomy can be offered for malignant soft tissue tumours with distant metastases'. This recommendation gained 100% consensus among the members of the guidelines group.

Conclusions: Although the level of evidence is very low, many retrospective studies support a clinical advantage for metastasectomy, and surgical indications should be carefully considered for patients with metastasis from soft tissue sarcoma. Metastasectomy is an option for patients with metastasis and should be done only if it can be performed safely and if potential advantages outweigh disadvantages.
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http://dx.doi.org/10.1093/jjco/hyab049DOI Listing
April 2021

Is perioperative chemotherapy recommended in childhood and adolescent patients with synovial sarcoma? A systematic review.

Jpn J Clin Oncol 2021 May;51(6):927-931

Department of Musculoskeletal Oncology, National Cancer Center Hospital Tokyo, Japan.

Objective: Synovial sarcoma is the most common soft tissue sarcomas among childhood and adolescents, accounting for 8-10% of all soft tissue sarcoma. Synovial sarcoma is considered a relatively chemosensitive tumor compared with other soft tissue sarcomas. However, the role of perioperative chemotherapy in synovial sarcoma remains controversial. The purpose of this systematic review is to evaluate the role of perioperative chemotherapy in childhood and adolescent patients with synovial sarcoma.

Methods: We evaluated studies published between 1 January 1990 and 31 December 2017. The following databases were searched: MEDLINE, Cochrane database (via PubMed) and Ichushi (in Japanese).

Results: The search yielded 216 articles in English and Japanese. After the initial screening, based on the title and abstract, 160 articles were excluded. As a second screening, we then assessed the full text of the remaining 56 articles for eligibility. Finally, 10 articles were included in the systematic review. Surgical resection with R0 margin alone was recommended because of the excellent results of two prospective studies. Meta-analysis was performed using data from two retrospective studies of 261 patients. Perioperative chemotherapy did not have a significant effect on survival and event-free survival.

Conclusions: We weakly do not recommend perioperative chemotherapy in patients with non-metastatic synovial sarcoma ≤ 5 cm when R0 resection is acquired. There was no consensus concerning the role of perioperative chemotherapy in patients with synovial sarcoma > 5 cm or those with ≤5 cm who undergo R1 or R2 resection.
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http://dx.doi.org/10.1093/jjco/hyab039DOI Listing
May 2021

Soft tissue sarcoma in adolescent and young adult patients: a retrospective study using a nationwide bone and soft tissue tumor registry in Japan.

Jpn J Clin Oncol 2021 Apr 1. Epub 2021 Apr 1.

Department of Musculoskeletal Oncology, National Cancer Center Hospital, Tokyo, Japan.

Objective: The relationship between the adolescent and young adult age groups and poor overall survival in soft tissue sarcoma and the risk factors for poor outcomes in adolescent and young adult patients with soft tissue sarcoma were analyzed.

Methods: The medical records of 7759 Japanese patients diagnosed with soft tissue sarcoma from 2006-13 were accessed from the Bone and Soft Tissue Tumor registry. The epidemiological features of adolescent and young adult patients were compared with those of other age groups. The cancer survival rates were calculated using the Kaplan-Meier method. The prognostic factors for cancer survival were analyzed with the Cox proportional hazards models. The primary endpoint for prognosis was tumor-related death.

Results: There were 210 children, 1467 adolescent and young adults, 2771 adults and 3311 elderly among the 7759 patients identified with soft tissue sarcoma. Compared with other age groups, the proportions of myxoid/round cell liposarcoma, synovial sarcoma, malignant peripheral nerve sheath tumor, primitive neuroectodermal tumor and rhabdomyosarcoma in adolescent and young adult patients were the highest, but none was significantly more prevalent in adolescent and young adult patients. On multivariate analysis, age was not a prognostic factor for poor cancer survival among adolescent and young adult patients with soft tissue sarcoma. The cancer survival rates of adolescent and young adult patients with malignant peripheral nerve sheath tumor were poorer than those of the other age groups; however, adolescent and young adult age was not a prognostic factor on multivariate analysis in malignant peripheral nerve sheath tumor patients.

Conclusions: Our study is the first to investigate soft tissue sarcoma in adolescent and young adult patients using the nationwide Bone and Soft Tissue Tumor registry. Adolescent and young adult age is not a prognostic factor for poor cancer survival among those with soft tissue sarcoma in Japan.
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http://dx.doi.org/10.1093/jjco/hyab044DOI Listing
April 2021

[Musculoskeletal Tumor Recent Chemotherapeutic Trials for Various Types of Musculoskeletal Tumors].

Authors:
Akira Kawai

Gan To Kagaku Ryoho 2021 Mar;48(3):341

Dept. of Musculoskeletal Oncology and Rehabilitation Medicine, National Cancer Center Hospital.

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March 2021

Prognostic factors and impact of surgery in patients with metastatic soft tissue sarcoma at diagnosis: A population-based cohort study.

Jpn J Clin Oncol 2021 May;51(6):918-926

Department of Orthopedic Surgery, The University of Tokyo, Tokyo, Japan.

Background: Approximately 10% of the patients with soft tissue sarcoma show metastasis at initial diagnosis, and hence, poorer prognosis. However, the prognostic factors and whether definitive surgery for the primary lesion improves overall survival, especially when complete resection of metastasis is difficult, remain unclear.

Methods: This retrospective analysis was based on the Bone and Soft Tissue Tumor Registry in Japan. Patients with soft tissue sarcoma having metastasis at diagnosis were enrolled, excluding those with Ewing's sarcoma, rhabdomyosarcoma and several other sarcomas with unique behavior and treatment strategies. Overall survival was estimated using the Kaplan-Meier method and compared among the common histologic subtypes. Multivariate analysis with the Cox regression model was used to identify the prognostic factors.

Results: In total, 1184 patients were included, with a median follow-up duration of 10 months (range: 1-83). The median overall survival was 21 months (95% confidence interval: 18.2-23.8). The multivariate analyses indicated that tumor size, grade and histologic subtypes significantly correlated with overall survival. Moreover, surgery for the primary lesion, in addition to surgery for metastases and chemotherapy, showed significant association with better survival.

Conclusions: The prognostic factors in patients with metastatic soft tissue sarcoma at diagnosis are generally similar to those in patients with localized disease. The overall survival in patients differed significantly according to histologic subtype. Surgical resection of primary lesions, especially those with a wide margin, may be an independent prognostic factor. Further studies are needed identify which subgroup of patients would benefit the most from primary lesion surgery.
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http://dx.doi.org/10.1093/jjco/hyab033DOI Listing
May 2021

Clinicopathologic Characterization of Epithelioid Hemangioendothelioma in a Series of 62 Cases: A Proposal of Risk Stratification and Identification of a Synaptophysin-positive Aggressive Subset.

Am J Surg Pathol 2021 05;45(5):616-626

Departments of Diagnostic Pathology.

Epithelioid hemangioendothelioma (EHE) is a rare vascular endothelial neoplasm with characteristic histology and distinctive fusion genes. Its clinical presentation and outcome are heterogeneous, and the determinants of survival are controversial. In this study, we aimed to identify clinicopathologic prognostic factors of EHE in a retrospective cohort of 62 cases with CAMTA1/TFE3/WWTR1 alterations. The tumors were of the CAMTA1 subtype for 59 cases, TFE3 subtype for 2 cases, and variant WWTR1 subtype (WWTR1-ACTL6A) for 1 case. Twenty-two tumors (35.5%) demonstrated atypical histology, defined by having at least 2 of the following 3 findings: high mitotic activity (>1/2 mm2), high nuclear grade, and coagulative necrosis. During a median follow-up of 34 months, 11 patients (18%) died, and the 5-year overall survival rate was 78.8%. Survival did not correlate with such clinical parameters as age, sex, tumor sites, multifocality, and multiorgan involvement. Conversely, based on both univariate and multivariate analyses, large tumor size (>30 mm) and histologic atypia were significantly associated with a shorter survival. A proposed 3-tiered risk assessment system using these 2 parameters significantly stratified the patients into low-risk, intermediate-risk, and high-risk groups with 5-year overall survival rates of 100%, 81.8%, and 16.9%, respectively (P<0.001). Four tumors (6.4%) expressed synaptophysin, which all belonged to the high-risk group and pursued an aggressive course. The present study demonstrated the independent prognostic significance of large tumor size and atypical histology in EHE, as well as the value of risk stratification using these 2 factors. Moreover, we revealed a small EHE subset with aberrant synaptophysin expression, which may have potential prognostic and diagnostic implications.
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http://dx.doi.org/10.1097/PAS.0000000000001660DOI Listing
May 2021

Systemic therapies in advanced epithelioid haemangioendothelioma: A retrospective international case series from the World Sarcoma Network and a review of literature.

Cancer Med 2021 04 13;10(8):2645-2659. Epub 2021 Mar 13.

Department of Medical Oncology, IRCCS Fondazione Istituto Nazionale Tumori, Milano, Italy.

Background: This observational, retrospective effort across Europe, US, Australia, and Asia aimed to assess the activity of systemic therapies in EHE, an ultra-rare sarcoma, marked by WWTR1-CAMTA1 or YAP1-TFE3 fusions.

Methods: Twenty sarcoma reference centres contributed data. Patients with advanced EHE diagnosed from 2000 onwards and treated with systemic therapies, were selected. Local pathologic review and molecular confirmation were required. Radiological response was retrospectively assessed by local investigators according to RECIST. Progression free survival (PFS) and overall survival (OS) were estimated by Kaplan-Meier method.

Results: Overall, 73 patients were included; 21 had more than one treatment. Thirty-three patients received anthracyclines regimens, achieving 1 (3%) partial response (PR), 25 (76%) stable disease (SD), 7 (21%) progressive disease (PD). The median (m-) PFS and m-OS were 5.5 and 14.3 months respectively. Eleven patients received paclitaxel, achieving 1 (9%) PR, 6 (55%) SD, 4 (36%) PD. The m-PFS and m-OS were 2.9 and 18.6 months, respectively. Twelve patients received pazopanib, achieving 3 (25%) SD, 9 (75%) PD. The m-PFS and m-OS were.2.9 and 8.5 months, respectively. Fifteen patients received INF-α 2b, achieving 1 (7%) PR, 11 (73%) SD, 3 (20%) PD. The m-PFS and m-OS were 8.9 months and 64.3, respectively. Among 27 patients treated with other regimens, 1 PR (ifosfamide) and 9 SD (5 gemcitabine +docetaxel, 2 oral cyclophosphamide, 2 others) were reported.

Conclusion: Systemic therapies available for advanced sarcomas have limited activity in EHE. The identification of new active compounds, especially for rapidly progressive cases, is acutely needed.
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http://dx.doi.org/10.1002/cam4.3807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026938PMC
April 2021

Establishment and characterization of NCC-DDLPS3-C1: a novel patient-derived cell line of dedifferentiated liposarcoma.

Hum Cell 2021 May 6;34(3):1008-1018. Epub 2021 Mar 6.

Division of Rare Cancer Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.

Dedifferentiated liposarcoma (DDLPS) is a highly malignant subtype of liposarcoma, with characteristic amplification of MDM2 and CDK4 (12q14-15). It is caused by the dedifferentiation of well-differentiated liposarcoma. DDLPS is refractory to conventional chemotherapy; thus, surgical resection is the primary treatment modality. However, complete resection of DDLPS is difficult because of its deep location, which results in poor prognosis. Therefore, novel systemic chemotherapy is required to improve the clinical outcome. Patient-derived cell lines are important tools in the development of novel chemotherapy. However, there are no DDLPS cell lines available from public cell banks. In this study, we established a novel DDLPS cell line, NCC-DDLPS3-C1, using a surgically resected specimen from a patient with DDLPS. NCC-DDLPS3-C1 cells retained the characteristic gene amplification of MDM2 and CDK4. In addition, other gene amplifications and losses related to the poor prognosis of DDLPS were also observed in concordance with the original tumor. The cells also exhibited rapid cell proliferation, aggressive invasion ability, spheroid formation ability, and tumorigenic ability in nude mice. Furthermore, a drug-screening test showed significant antiproliferative effects of proteasome inhibitors and HDAC inhibitors. Thus, the NCC-DDLPS3-C1 cell line should be a useful tool for the development of novel chemotherapy for DDLPS.
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http://dx.doi.org/10.1007/s13577-021-00515-1DOI Listing
May 2021

Prospective Evaluation of Doxorubicin Cardiotoxicity in Patients with Advanced Soft-tissue Sarcoma Treated in the ANNOUNCE Phase III Randomized Trial.

Clin Cancer Res 2021 Feb 25. Epub 2021 Feb 25.

Department of Medicine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, New York.

Purpose: Few prospective studies have assessed anthracycline-associated cardiotoxicity in patients with sarcoma. We evaluated cardiotoxicity in patients with soft-tissue sarcomas administered doxorubicin in the phase III ANNOUNCE trial (NCT02451943).

Patients And Methods: Patients were anthracycline-naïve adults with locally advanced or metastatic disease and left ventricular ejection fraction (LVEF) ≥50%. Patients could receive eight cycles of doxorubicin at 75 mg/m. The cardioprotectant, dexrazoxane, was allowed at investigator discretion. Symptomatic cardiac adverse events (AEs) were recorded using Medical Dictionary for Regulatory Activities and graded using Common Terminology Criteria for Adverse Events 4.0. LVEF deterioration was measured by echocardiogram or multigated acquisition scan, defined as a decrease to <50%, or decrease from baseline value >10%.

Results: A total of 504 patients received ≥1 cycles of doxorubicin [median cumulative dose, 450.3 mg/m (range, 72.3-634.0)]. Median follow-up of cardiac AEs was 28 weeks. Dexrazoxane was coadministered more frequently to patients receiving higher cumulative doxorubicin doses (38.6% receiving <450 mg/m, 88.5% receiving 450-<600 mg/m, and 90% receiving ≥600 mg/m) and did not affect treatment efficacy. LVEF deterioration was seen in 62 of 153 (40.5%) patients who received a cumulative dose <450 mg/m, 82 of 159 patients (51.6%) who received 450-<600 mg/m, and 50 of 89 patients (56.2%) who received ≥600 mg/m. Grade ≥3 cardiac dysfunction occurred in 2% of patients at <450 mg/m, 3% at 450-<600 mg/m, and 1.1% at ≥600 mg/m. Incidence of treatment-related cardiac AEs was low across all dose ranges.

Conclusions: Although follow-up was short, these results suggest doxorubicin can be administered at high cumulative doses (>450 mg/m), with a low rate of cardiotoxicities, in the context of dexrazoxane coadministration.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4592DOI Listing
February 2021

Establishment and characterization of NCC-SS4-C1: a novel patient-derived cell line of synovial sarcoma.

Hum Cell 2021 May 20;34(3):998-1007. Epub 2021 Feb 20.

Division of Rare Cancer Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.

Synovial sarcoma (SS) is defined as a monomorphic blue spindle cell sarcoma showing variable epithelial differentiation, and is characterized by a specific fusion gene, SS18-SSX. Although SS is rare, it accounts for approximately 8% of all soft tissue sarcomas, which occupies a significant proportion of soft tissue tumors. The prognosis of SS is unfavorable, with 5-year survival rate of 50-60%, and only a few anti-cancer agents are recommended for its treatment. Thus, we need to urgently establish novel treatment methods. Patient-derived cell lines are essential tools in basic research and pre-clinical studies. However, there are only 4 publicly available SS cell lines. Therefore, we established a novel SS cell line, NCC-SS4-C1, using surgically resected tumor tissues of a patient with SS. The cell line maintained the characteristic fusion gene, SS18-SSX1, and copy number alteration, in concordance with the original tumor. The cells also exhibited moderate cell proliferation, invasion ability, and spheroid formation ability. Moreover, a drug-screening test using 4 SS cell lines, including NCC-SS4-C1, demonstrated the significant anti-proliferative effects of ALK and HDAC inhibitors. Thus, we concluded that the NCC-SS4-C1 cell line is a useful tool for basic and pre-clinical studies of SS.
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http://dx.doi.org/10.1007/s13577-021-00509-zDOI Listing
May 2021

The incidence of unplanned excision in patients with soft tissue sarcoma: Reports from the Bone and Soft Tissue Tumor registry in Japan.

J Orthop Sci 2021 Feb 5. Epub 2021 Feb 5.

Department of Orthopedic Surgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu-city, Mie, 514-8507, Japan.

Background: Due to their rarity, soft tissue sarcomas (STS)s are often treated surgically as unplanned excisions (UE)s before referral to specialists. The Bone and Soft Tissue Tumor (BSTT) registry is a nationwide, organ-specific cancer registry for bone and soft-tissue tumors in Japan. The aim of this study was to elucidate the incidence and risk factors for UEs using data from the BSTT registry.

Methods: Our study comprised 8761 patients with STS including 4826 males and 3935 females, with a mean age of 59 years (range, 0-105 years). Patients were classified into primary STS and UE groups.

Results: Superficial and deep tumors were found in 2533 and 6120 patients, respectively. The mean STS size was 8.6 cm (range, 0.2-49 cm). We identified 6610 patients with high-grade, and 1758 patients with low-grade STS. Of the total 8761 patients, 7770 patients had primary STSs, whereas 991 patients were referred after undergoing UE. The UE mean incidence rate over 11 years was 11.3%. The UE incidence rates for leiomyosarcoma (LMS) (odds ratio [OR] = 1.75, p < 0.0001), fibrosarcoma (FS) (OR = 2.28, p < 0.0001), and epithelioid sarcoma (OR = 1.82, p = 0.01) were higher than the mean UE incidence rate (11.3%). Of 757 patients who underwent UE, 354 (47%) patients had superficial (≤5 cm) STSs, whereas 156 (20.6%) of patients had deep STSs (>5 cm) (p < 0.0001). Logistic regression analysis revealed that UE was frequently associated with males and small, superficial, and trunk STSs.

Conclusions: In the present study, the mean UE incidence rate (11.3%) was significantly different from the individual UE incidence rates of histological diagnoses suggesting that surgeons should consider STS, even with small tumors. Continuous education during training for medical students and surgeons is essential to ensure awareness and correct diagnostic procedures for STS.
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http://dx.doi.org/10.1016/j.jos.2020.12.025DOI Listing
February 2021

Is no additional excision after unplanned excision with positive margins justified in patients with small (≤5 cm) high-grade soft-tissue sarcoma?: Analysis from the Bone and Soft Tissue Tumor registry in Japan.

J Orthop Sci 2021 Feb 3. Epub 2021 Feb 3.

Department of Orthopedic Surgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu-city, Mie, 514-8507, Japan.

Background: This study aimed to elucidate the clinical outcomes of patients with small (≤5 cm) high-grade soft tissue sarcoma, who underwent unplanned excision with positive surgical margin, using data from the Bone and Soft Tissue Tumor registry in Japan.

Methods: We examined 174 patients (101 males and 73 females; mean age, 59 years) with primary non-metastatic soft tissue sarcoma. The tumor size was ≤5 cm, and tumor histological grade was high in all patients. The mean follow-up duration was 50 months.

Results: Unplanned excision with R1 and R2 margins was reported in 115 (66%) and 59 patients (34%), respectively. After unplanned excision, immediate additional excision was performed in 154 patients, whereas no additional excision was performed in the remaining 20. Of the 154 patients who underwent additional excision, wide surgical margin resection was achieved in 140 patients, while marginal and intralesional resections were achieved in 10 and 3 patients, respectively. Additionally, 93 patients (60%) underwent reconstruction after additional excision. During the last follow-up, 8 patients died of the disease, 22 developed distant metastasis, and 14 reported local recurrence. The 5-year disease-specific survival rate and 5-year metastasis-free survival rate was 93.5% and 85%, respectively. Tumor depth and additional excision after unplanned excision showed statistical significance in the multivariate analysis. The 5-year metastasis-free survival rate was 89.1% in patients with additional excision and 39.2% in those without. Univariate analysis showed an association between additional excision and local control. The 5-year local recurrence-free survival was significantly worse in patients without additional excision after unplanned excision (52.6%) than in those with additional excision (92.8%).

Conclusion: If unplanned excision is performed in patients with small high-grade soft tissue sarcoma, additional excision is recommended for preventing metastasis, along with necessary preparations for reconstruction.
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http://dx.doi.org/10.1016/j.jos.2020.12.022DOI Listing
February 2021

Image-guided core needle biopsy for musculoskeletal lesions.

J Orthop Sci 2021 Jan 30. Epub 2021 Jan 30.

Department of Musculoskeletal Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan; Rare Cancer Center, National Cancer Center Hospital, Tokyo, Japan.

Background: Image-guided percutaneous core needle biopsy (CNB) has been an important diagnostic procedure for musculoskeletal lesions. Here we surveyed the variety of diagnostic strategies available and assessed the clinical usefulness and limitations of image-guided CNB carried out by a multidisciplinary team comprising specialists in various fields.

Methods: We conducted a retrospective study of 284 image-guided CNBs among 1899 consecutive biopsy procedures carried out at our institution for musculoskeletal tumorous conditions, focusing on their effectiveness including diagnostic accuracy and utility for classification of specimens according to malignant potential and histological subtype as well as their correlation with biopsy routes.

Results: Among the 284 studied biopsies, 252 (88.7%) were considered clinically "effective". The sensitivity for detection of malignancy was 94.0% (110/117) and the specificity was 95.3% (41/43). The diagnostic accuracy for detection of malignancy was 94.4% (151/160) and that for histological subtype was 92.3% (48/52). The clinical effectiveness of the procedure was correlated with the complexity of the biopsy route (P = 0.015); the trans-pedicular, trans-retroperitoneal and trans-sciatic foramen approaches tended to yield ineffective results. Repeat biopsy did not have a significant impact on the effectiveness of image-guided CNB (P = 0.536).

Conclusions: The diagnostic accuracy rates of image-guided CNB performed at multidisciplinary sarcoma units were usable even for patients who have variety of diagnostic biopsy procedures. It is important to establish and implement diagnostic strategies based on an understanding that complicated routes, especially for spine and pelvic lesions, may be associated with ineffectiveness and/or complications.
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http://dx.doi.org/10.1016/j.jos.2020.12.017DOI Listing
January 2021

Immunological status of peripheral blood is associated with prognosis in patients with bone and soft-tissue sarcoma.

Oncol Lett 2021 Mar 18;21(3):212. Epub 2021 Jan 18.

Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center Hospital, Tokyo 104-0045, Japan.

Immune-checkpoint inhibitors have shown promising antitumor effects against certain types of cancer. However, specific immune-checkpoint inhibitors for patients with sarcoma have yet to be identified, whereas the immunological status of peripheral blood in patients with bone sarcoma and soft-tissue sarcoma (STS) remains unknown. In addition, it is unclear whether the immunological status from the peripheral blood could be used as a prognostic indicator. Therefore, the present study aimed to clarify the immunological status of peripheral blood samples derived from patients with bone sarcoma and STS. Immune monitoring was performed using the peripheral blood samples of 61 patients with no metastasis of high-grade sarcoma. A total of 25 patients with metastatic sarcoma were used for comparison. A total of 41 immune cell subsets were analyzed using multicolor-flow cytometry. The patients that did not have metastasis demonstrated higher quantities of monocytic myeloid-derived suppressor cells (M-MDSCs) and T cell immunoglobulin and mucin domain-3 (Tim-3) CD8 T cells, which were significantly associated with poor disease-free survival (DFS) time, while higher quantities of NKG2D CD8 T cells were significantly associated with improved DFS time. Multivariate Cox regression analysis demonstrated that the number of Tim-3 CD8 T cells was associated with lower DFS time. A significant association was also found between the number of M-MDSCs and progression-free survival (PFS) time in patients with metastasis. The results suggested the occurrence of immune surveillance, which indicated that the host immune reaction against cancer existed in patients with bone sarcoma and STS. Notably, a high number of M-MDSCs was associated with both DFS and PFS time, suggesting a strong prognostic value. The data suggested that the immune status of peripheral blood was associated with the prognosis in patients with sarcoma, as previously reported in patients with other cancer types. In summary, the results may assist with the development of novel strategies for sarcoma treatment, based on the use of biomarkers or immunotherapy.
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http://dx.doi.org/10.3892/ol.2021.12473DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836390PMC
March 2021

Clinical outcome of patients with recurrent or refractory localized Ewing's sarcoma family of tumors: A retrospective report from the Japan Ewing Sarcoma Study Group.

Cancer Rep (Hoboken) 2021 Jan 16:e1329. Epub 2021 Jan 16.

Department of Orthopedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.

Background: Patients with Ewing's sarcoma family of tumors (ESFT) who experience relapse or progression have a poor prognosis.

Aim: This study aimed to identify the prognostic and therapeutic factors affecting overall survival (OS) of patients with recurrent or refractory localized ESFT.

Methods And Results: Thirty-eight patients with localized ESFT who experienced first relapse or progression between 2000 and 2018 were retrospectively reviewed. The 5-year OS rate of the entire cohort was 48.3% (95% confidence interval, 29.9%-64.5%). Multivariate analysis of OS identified time to relapse or progression, but not stem cell transplantation (SCT), as the sole independent risk factor (hazard ratio, 35.8; P = .002). Among 31 patients who received salvage chemotherapy before local treatment, 21 received chemotherapy regimens that are not conventionally used for newly diagnosed ESFT. The objective response rate to first-line salvage chemotherapy was 55.2% in the 29 evaluable patients. Time to relapse or progression was significantly associated with response to first-line salvage chemotherapy (P = .006).

Conclusions: The present study fails to demonstrate significant clinical benefit of SCT for recurrent or refractory localized ESFT. Recently established chemotherapy regimens may increase the survival rate of patients with recurrent or refractory localized ESFT while attenuating the beneficial effect of SCT.
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http://dx.doi.org/10.1002/cnr2.1329DOI Listing
January 2021

Comprehensive molecular and clinicopathological profiling of desmoid tumours.

Eur J Cancer 2021 Mar 11;145:109-120. Epub 2021 Jan 11.

Division of Cellular Signaling, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan. Electronic address:

Previous studies have not clearly identified a prognostic factor for desmoid tumours (DT). Whole-exome sequencing (WES) and/or RNA sequencing (RNA-seq) were performed in 64 cases of DT to investigate the molecular profiles in combination with the clinicopathological characteristics. CTNNB1 mutations with specific hotspots were identified in 56 cases (87.5%). A copy number loss in chromosome 6 (chr6) was identified in 14 cases (21.9%). Clustering based on the mRNA expression profiles was predictive of the patients' prognoses. The risk score generated by the expression of a three-gene set (IFI6, LGMN, and CKLF) was a strong prognostic marker for recurrence-free survival (RFS) in our cohort. In risk groups stratified by the expression of IFI6, the hazard ratio for recurrence-free survival in the high-risk group relative to the low-risk group was 12.12 (95% confidence interval: 1.56-94.2; p = 8.0 × 10). In conclusion, CTNNB1 mutations and a chr6 copy number loss are likely the causative mutations underlying the tumorigenesis of DT while the gene expression profiles may help to differentiate patients who would be good candidates for wait-and-see management and those who might benefit from additional systemic or radiation therapies.
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http://dx.doi.org/10.1016/j.ejca.2020.12.001DOI Listing
March 2021

Clinical Outcome of Dermatofibrosarcoma Protuberance. Report From the Bone and Soft Tissue Tumor (BSTT) Registry in Japan.

In Vivo 2021 Jan-Feb;35(1):611-615

Department of Orthopaedic Surgery, Mie University Graduate School of Medicine, Tsu, Japan.

Background: Owing to its rarity, dermatofibrosarcoma protuberance (DFSP) is often inappropriately excised. After unplanned excision (UE), additional excision is commonly performed. We aimed to elucidate the effect of additional excision after UE.

Patients And Methods: We examined 306 patients with primary DFSP. We analyzed surgical outcomes in 291 patients who received planned excision (PE) or additional excision after UE.

Results: Of 306 patients, 194 received PE and the remaining 112 received UE. Of 112 patients, 97 received additional excision after UE. Additional surgery due to complications was more frequent in patients with UE than in those with PE. The 5-year local recurrence-free rate in patients without additional excision after UE was significantly worse than that in those with additional excision after UE.

Conclusion: If UE is performed, we recommend additional excision for preventing local recurrence; however, the surgical wound should be carefully observed.
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http://dx.doi.org/10.21873/invivo.12298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880785PMC
November 2020

Direct conversion of osteosarcoma to adipocytes by targeting TNIK.

JCI Insight 2021 02 8;6(3). Epub 2021 Feb 8.

Division of Cellular Signaling, National Cancer Center Research Institute, Tokyo, Japan.

Osteosarcoma (OS) is an aggressive mesenchymal tumor for which no molecularly targeted therapies are available. We have previously identified TRAF2- and NCK-interacting protein kinase (TNIK) as an essential factor for the transactivation of Wnt signal target genes and shown that its inhibition leads to eradication of colorectal cancer stem cells. The involvement of Wnt signaling in the pathogenesis of OS has been implicated. The aim of the present study was to examine the potential of TNIK as a therapeutic target in OS. RNA interference or pharmacological inhibition of TNIK suppressed the proliferation of OS cells. Transcriptome analysis suggested that a small-molecule inhibitor of TNIK upregulated the expression of genes involved in OS cell metabolism and downregulated transcription factors essential for maintaining the stem cell phenotype. Metabolome analysis revealed that this TNIK inhibitor redirected the metabolic network from carbon flux toward lipid accumulation in OS cells. Using in vitro and in vivo OS models, we confirmed that TNIK inhibition abrogated the OS stem cell phenotype, simultaneously driving conversion of OS cells to adipocyte-like cells through induction of PPARγ. In relation to potential therapeutic targeting in clinical practice, TNIK was confirmed to be in an active state in OS cell lines and clinical specimens. From these findings, we conclude that TNIK is applicable as a potential target for treatment of OS, affecting cell fate determination.
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http://dx.doi.org/10.1172/jci.insight.137245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934882PMC
February 2021

The treatment landscape of advanced angiosarcoma in Asia-A multi-national collaboration from the Asian Sarcoma Consortium.

Cancer Sci 2021 Mar 7;112(3):1095-1104. Epub 2021 Feb 7.

Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong, China.

Angiosarcoma (AS) is a rare disease with a dismal prognosis. The treatment landscape and prognostic factors for advanced AS, including locally advanced, unresectable, and metastatic disease remain elusive. The Asian Sarcoma Consortium is an international collaborative effort to understand the sarcoma treatment landscape in Asia. We undertook a retrospective chart review of AS patients seen in 8 sarcoma academic centers across Asia. Patients with complete clinical, treatment, and follow-up data were enrolled. Overall, 276 advanced AS patients were included into this study; 84 (30%) of the patients had metachronous metastatic AS. The median age was 67 y; primary sites of AS was cutaneous in 55% and visceral in 45% of patients. In total, 143 (52%) patients received at least 1 line of systemic chemotherapy. The most common first-line chemotherapy regimen used was paclitaxel (47.6%) followed by liposomal doxorubicin (19.6%). The median overall survival (OS) was 7.8 mo. Significant prognostic factors for OS included age > 65 (hazard ratio (HR) 1.54, P = .006), male gender (HR 1.39, P = .02), and a cutaneous primary AS site (HR 0.63, P = .004). The median progression-free survival (PFS) for first-line chemotherapy was 3.4 mo. PFS for single vs combination or paclitaxel vs liposomal doxorubicin chemotherapy regimens were comparable. This study provides an insight into the treatment patterns and prognostic factors of advanced AS patients in Asia. Prognosis of advanced AS remains poor. Data from this study serve as a benchmark for future clinical study design.
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http://dx.doi.org/10.1111/cas.14793DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935784PMC
March 2021

Usefulness of dual-axis rotational coronary angiography in primary percutaneous coronary intervention for patients with ST-elevation myocardial infarction.

Heart Vessels 2021 May 4;36(5):621-629. Epub 2020 Dec 4.

Department of Cardiovascular Medicine, Dokkyo Medical University, Mibu, Tochigi, Japan.

Several studies have shown that dual-axis rotational coronary angiography (DARCA) reduces contrast medium volume and radiation exposure compared to conventional coronary angiography (CCA). However, there are no studies comparing the safety and usefulness of DARCA in primary percutaneous coronary intervention (PCI) for patients with ST-elevation myocardial infarction (STEMI). The aim of this study was to investigate the effects of DARCA on contrast medium volume, radiation exposure, time course of treatment, and adverse events in primary PCI for patients with STEMI. A total of 82 patients undergoing primary PCI were included in this study. Subjects were propensity matched to 41 patients in the CCA group and 41 in the DARCA group. Data were retrospectively collected from in-patient medical records and the contrast medium volume and radiation exposure (dose-area product, DAP) during the PCI procedure was compared between the two groups. Contrast medium volume [100.0 (82.5-115.0) vs 110 (102.5-127.5) ml, p = 0.018, r = 0.26] and DAP [113.4 (74.3-141.1) vs 138.1 (100.5-194.7) Gy cm, p = 0.014, r = 0.27] were significantly lower in the DARCA group, compared with the CCA group. Door to device time (68.7 ± 26.1 vs 76.5 ± 44.2 min, p = 0.33) were comparable between the two groups. There were no adverse events requiring treatment reported in either groups. DARCA may reduce contrast medium volume and radiation exposure in primary PCI for patients with STEMI, and can be used safely, without delaying reperfusion of the infarct-related coronary artery.
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http://dx.doi.org/10.1007/s00380-020-01738-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8032619PMC
May 2021

Surgical resection of the primary lesion for osteosarcoma patients with metastasis at initial diagnosis.

Jpn J Clin Oncol 2021 Mar;51(3):416-423

Department of Orthopedic Surgery, The University of Tokyo, Tokyo, Japan.

Background: Approximately 10-20% of osteosarcoma patients present with metastasis on diagnosis. Completely resecting the lesion is associated with better prognosis. However, evidence regarding optimal surgical strategies for patients with unresectable metastasis is limited.

Methods: This retrospective analysis was based on the Japanese Nationwide Bone and Soft Tissue Tumor registry. In total, 335 patients diagnosed with osteosarcoma with metastasis were included. Factors affecting overall survival were identified using multivariate analysis. Kaplan-Meier method was used to compare the overall survival by the status of surgical intervention. Two hundred and four patients who did not undergo surgery for metastasis were divided into two groups, depending on whether they underwent surgery for the primary lesion. The background differences between these two groups were adjusted with propensity score matching, with 43 patients per group. The overall survival was calculated using the Kaplan-Meier method and compared with a log-rank test.

Results: Factors positively impacting overall survival were age <40, female sex, extremity origin, surgery for the primary lesions, surgery for metastasis and radiotherapy without surgery. For patients with unresectable metastasis, after propensity score matching, the survival rate was higher in the group that underwent primary lesion surgery than the group without surgery. Their median survival was 19 (95% confidence interval: 11.7-26.3) and 11 months (95% confidence interval: 4.5-17.5) (P = 0.02), respectively.

Conclusions: Surgical resection of the primary osteosarcoma lesion did not worsen prognosis, even in patients with unresectable metastasis. Further study is needed to identify which patient group will benefit from primary lesion resection.
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http://dx.doi.org/10.1093/jjco/hyaa204DOI Listing
March 2021

Symptomatic Venous Thromboembolism in Patients with Malignant Bone and Soft Tissue Tumors: A Prospective Multicenter Cohort Study.

Ann Surg Oncol 2021 Jul 9;28(7):3919-3927. Epub 2020 Nov 9.

Division of Orthopedic Surgery, Chiba Cancer Center, 666-2 Nitona-cho, Chuo-ku, Chiba, 260-8717, Japan.

Background: A prospective cohort study was conducted to determine the incidence and risk factors of symptomatic venous thromboembolism (sVTE) during the perioperative period in patients with malignant bone and soft tissue tumors.

Methods: Patients with newly diagnosed primary malignant bone and soft tissue tumors for whom definitive surgery was planned were consecutively registered among 27 tertiary hospitals specializing in musculoskeletal oncology. Clinicopathological information on each patient was collected prospectively, and careful follow-up was conducted for 6 months after surgery. The study endpoint was the occurrence of sVTE, including deep vein thrombosis (DVT) and pulmonary embolism (PE).

Results: Eleven of 929 patients developed sVTE, including 8 patients with DVT, 2 with PE, and 1 with both, making the incidence of sVTE 1.18%. The median time until the development of sVTE after tumor resection was 11 days, ranging from - 7 to 95 days. Multiple logistic regression analyses revealed that ischemic heart disease as a comorbidity, maximum tumor diameter exceeding 8 cm, and elevated preoperative platelet count were independent risk factors for sVTE.

Conclusions: The incidence of sVTE in this series of patients with bone and soft tissue sarcomas was 1.18%, which was relatively lower than in previous retrospective studies. We identified the risk factors for sVTE specific to patients with malignant bone and soft tissue tumors, and these included ischemic heart disease, tumor size, and elevation of the preoperative platelet count.
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http://dx.doi.org/10.1245/s10434-020-09308-6DOI Listing
July 2021

Establishment and characterization of NCC-DDLPS1-C1: a novel patient-derived cell line of dedifferentiated liposarcoma.

Hum Cell 2021 Jan 19;34(1):260-270. Epub 2020 Sep 19.

Division of Rare Cancer Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.

Dedifferentiated liposarcoma (DDLPS) is one of the four subtypes of liposarcomas; it is characterized by the amplification of the 12q13-15 region, which includes MDM2 and CDK4 genes. DDLPS has an extremely high local recurrence rate and is refractory to chemotherapy and radiation, which leads to poor prognosis. Therefore, a novel therapeutic strategy should be urgently established for improving the prognosis of DDLPS. Although patient-derived cell lines are important tools for basic research, there are no DDLPS cell lines available from public cell banks. Here, we report the establishment of a novel DDLPS cell line. Using the surgically resected tumor tissue from a patient with DDLPS, we established a cell line and named it NCC-DDLPS1-C1. The NCC-DDLPS1-C1 cells contained 12q13-15, 1p32, and 1q23 amplicons and highly expressed MDM2 and CDK4 proteins. NCC-DDLPS-C1 cells exhibited constant growth, spheroid formation, aggressive invasion, and tumorigenesis in mice. By screening a drug library, we identified that the proteasome inhibitor, bortezomib, had inhibitory effects on the proliferation of NCC-DDLPS1-C1 cells. We concluded that the NCC-DDLPS1-C1 cell line may serve as a useful tool for basic and pre-clinical studies of DDLPS.
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http://dx.doi.org/10.1007/s13577-020-00436-5DOI Listing
January 2021

Prognostic factors of metastatic myxoid liposarcoma.

BMC Cancer 2020 Sep 14;20(1):883. Epub 2020 Sep 14.

Department of Orthopaedic Surgery, Teikyo University School of Medicine, Tokyo, Japan.

Background: Myxoid liposarcoma (MLS) has the tendency to metastasize extrapulmonary. Although prognostic factors at the initial diagnosis of MLS have been reported, those at diagnosis of metastasis remain unclear. The purpose of this study was to investigate the prognostic factors for disease-specific survival at the initial diagnosis of metastasis.

Methods: This retrospective observational study was conducted at three cancer centers and two university hospitals in Japan. Of 274 MLS patients pathologically diagnosed between 2001 and 2015, 48 metastatic patients were examined.

Results: Lung metastases were detected in nine patients (18.8%) and extrapulmonary metastases in 45 (93.8%). Interval from primary diagnosis to the first metastasis was significantly shorter in patients with lung metastases than without (p = 0.007). Median disease-specific survival after diagnosis of metastases was 52.5 months in all patients. In multivariable analysis, liver metastasis (hazard ratio (HR), 2.71 [95% confidence interval (CI), 1.00-7.09]) and no evidence of disease (NED) achieved by radical treatment (resection with or without radiation therapy, or radiation therapy ≥60 Gy) or semi-radical (radiation therapy ≥40 Gy) treatment were significantly related to survival (HR, 0.36; 95%CI [0.13-0.95]). The number of metastases (odds ratio (OR), 0.44; 95%CI [0.25-0.78]) and abdominal/retroperitoneal metastases (OR, 0.09; 95%CI [0.008-0.95]) were the significant inhibitory factors of achieving NED.

Conclusions: This is the first study to statistically demonstrate the importance of achieving NED with surgical resection or radiation therapy for longer survival in metastatic MLS patients. As number of metastases was a significant factor for achieving NED, early detection of metastases might be important.
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http://dx.doi.org/10.1186/s12885-020-07384-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7491192PMC
September 2020

Yokukansan for Treatment of Preoperative Anxiety and Prevention of Postoperative Delirium in Cancer Patients Undergoing Highly Invasive Surgery. J-SUPPORT 1605 (ProD Study): A Randomized, Double-Blind, Placebo-Controlled Trial.

J Pain Symptom Manage 2021 01 12;61(1):71-80. Epub 2020 Aug 12.

Department of Psycho-Oncology, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan; Behavioral Sciences and Survivorship Research Group, Division of Health Care Research, Center for Public Health Sciences, National Cancer Center Japan, Chuo-ku, Tokyo, Japan; Innovation Center for Supportive, Palliative and Psychosocial Care, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan. Electronic address:

Context: No standard preventive or therapeutic methods have been established for preoperative anxiety and postoperative delirium in patients with cancer.

Objectives: To clarify the therapeutic effect of yokukansan for perioperative psychiatric symptoms in patients with cancer as well as to confirm its safety profile.

Methods: This is a randomized, double-blind, and placebo-controlled trial conducted at a single center in Tokyo, Japan. About 195 patients with cancer scheduled to undergo tumor resection took one packet of the study drug, which was administered orally. Coprimary outcomes were change in preoperative anxiety assessed with the Hospital Anxiety and Depression Scale-Anxiety and incidence of postoperative delirium assessed with the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Interim analysis was performed with one-third (n = 74) of the target number of registered patients.

Results: Because this trial was canceled based on the results of the interim analysis and the protocol treatment was discontinued in patients who were already registered, conclusions were based on the full analysis set of 160 participants. There were no significant differences between groups in the change of mean Hospital Anxiety and Depression Scale-Anxiety score (intervention group [SD] 0.4 [3.0] vs. placebo group 0.5 [3.0]; P = 0.796) or the incidence of postoperative delirium (32% vs. 30%; P = 0.798). There were no serious adverse events in either group.

Conclusion: In patients with cancer undergoing highly invasive surgeries, yokukansan demonstrated no significant efficacy for the treatment of preoperative anxiety or the prevention of postoperative delirium. Yokukansan is already used in daily practice in Japan, but we should be careful with its future use.
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http://dx.doi.org/10.1016/j.jpainsymman.2020.07.009DOI Listing
January 2021