Language：English   Publishing type：Research paper (scientific journal)  

This study aimed to clarify the effects of ipriflavone, which effectively reduces KIAA1199 activity, on osteoarthritis (OA) development and progression in an in vivo OA mouse model. The OA model mice were divided into the ipriflavone (200 mg/kg/day) group and the control group. OA onset and progression were evaluated with the Mankin score, and KIAA1199 expression and hyaluronan (HA) accumulation were analyzed by immunostaining. The molecular weight of HA in the cartilage tissue and serum HA concentration were analyzed by chromatography and competitive HA enzyme-linked immunoassay. The effects of ipriflavone on the bovine cartilage explant culture under the influence of IL-1β were also investigated. In the ipriflavone group, Safranin-O stainability was well-preserved, resulting in significant reduction of the Mankin score (p = 0.027). KIAA1199 staining positivity decreased and HA stainability was preserved in the ipriflavone group. The serum HA concentration decreased, and the molecular weight of HA in the cartilage tissue increased in the ipriflavone group. The results of the cartilage explant culture indicated that ipriflavone could reduce GAG losses and increase the molecular weight of HA. Thus, ipriflavone may have an inhibitory effect on OA development/progression. Ipriflavone could be a therapeutic drug for OA by targeting KIAA1199 activity.

DOI： 10.3390/ijms241512422

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Publisher：三輪書店  

DOI： 10.11477/mf.5002202087

CiNii Research

Language：English   Publishing type：Research paper (scientific journal)  

Osteosarcoma, the most common primary malignant bone tumor, is defined by the formation of neoplastic osteoid and/or bone. This sarcoma is a highly heterogeneous disease with a wide range of patient outcomes. CD109 is a glycosylphosphatidylinositol-anchored glycoprotein that is highly expressed in various types of malignant tumors. We previously reported that CD109 is expressed in osteoblasts and osteoclasts in normal human tissues and plays a role in bone metabolism in vivo. While CD109 has been shown to promote various carcinomas through the downregulation of TGF-β signaling, the role and mechanism of CD109 in sarcomas remain largely unknown. In this study, we investigated the molecular function of CD109 in sarcomas using osteosarcoma cell lines and tissue. Semi-quantitative immunohistochemical analysis using human osteosarcoma tissue revealed a significantly worse prognosis in the CD109-high group compared with the CD109-low group. We found no association between CD109 expression and TGF-β signaling in osteosarcoma cells. However, enhancement of SMAD1/5/9 phosphorylation was observed in CD109 knockdown cells under bone morphogenetic protein-2 (BMP-2) stimulation. We also performed immunohistochemical analysis for phospho-SMAD1/5/9 using human osteosarcoma tissue and found a negative correlation between CD109 expression and SMAD1/5/9 phosphorylation. In vitro wound healing assay showed that osteosarcoma cell migration was significantly attenuated in CD109-knockdown cells compared with control cells in the presence of BMP. These results suggest that CD109 is a poor prognostic factor in osteosarcoma and affects tumor cell migration via BMP signaling.

DOI： 10.1016/j.prp.2023.154443

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Hyaluronan (HA) plays crucial roles in the maintenance of high-quality cartilage extracellular matrix. Several studies have reported the HA in synovial fluid in patients with osteoarthritis (OA), but few have described the changes of HA in articular cartilage of OA or idiopathic osteonecrosis of the femoral head (ONFH). KIAA1199 was recently reported to have strong hyaluronidase activity. The aim of this study was to clarify the HA metabolism in OA and ONFH, particularly the involvement of KIAA1199. Immunohistochemical analysis of KIAA1199 and HA deposition was performed for human OA (n = 10), ONFH (n = 10), and control cartilage (n = 7). The concentration and molecular weight (MW) of HA were determined by competitive HA ELISA and Chromatography, respectively. Regarding HA metabolism-related molecules, HAS1, HAS2, HAS3, HYAL1, HYAL2, and KIAA1199 gene expression was assessed by reverse transcriptase polymerase chain reaction. Histological analysis showed the overexpression of KIAA1199 in OA cartilage, which was accompanied by decreased hyaluronic acid binding protein (HABP) staining compared with ONFH and control. Little KIAA1199 expression was observed in cartilage at the collapsed area of ONFH, which was accompanied by a slight decrease in HABP staining. The messenger RNA (​​​​​mRNA) expression of HAS2 and KIAA1199 was upregulated in OA cartilage, while the mRNA expression of genes related to HA catabolism in ONFH cartilage showed mostly a downward trend. The MW of HA in OA cartilage increased while that in ONFH cartilage decreased. HA metabolism in ONFH is suggested to be generally indolent, and is activated in OA including high expression of KIAA1199. Interestingly, MW of HA in OA cartilage was not reduced.

DOI： 10.1002/jor.25364

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Phosphaturic mesenchymal tumor (PMT) is a rare tumor that secretes fibroblast growth factor 23 (FGF23) and causes hypophosphatemia and tumor-induced osteomalacia (TIO). Fusion genes FN1-FGFR1 and FN1-FGF1 have been detected in some PMTs, but the pathogenesis of PMTs without these fusion genes remains unclear. Here, we report a 12-year-old boy with persistent muscle weakness and gait disturbance. Roentgenographic examination revealed a radiolucent lesion with endosteal scalloping in the left fibula, while his serum level of FGF23 was markedly increased. Combined with simple X-ray findings of other body parts, we suspected that TIO was caused by PMT, and resected the tumor. After resection, the serum level of FGF23 started to decrease immediately and normalized within 3 hours after resection, with this being earlier than normalization of the serum phosphorus level. In RNA sequencing, FN1-FGFR1 and FN1-FGF1 were not detected, but a novel NIPBL-BEND2 fusion gene was identified. When we forcedly expressed this fusion gene in HEK293T cells and MG63 cells, cell proliferation was enhanced in both cell lines. Furthermore, Gene set enrichment analysis of HEK293T cells showed significant upregulation of MYC-target genes. Our results suggest that this novel NIPBL-BEND2 fusion gene promotes cell proliferation possibly via the MYC pathway and might be one of the etiologies of PMTs other than FN1-FGFR1 or FN1-FGF1.

DOI： 10.3389/fonc.2022.956472

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CiNii Research

Language：English   Publisher：Cancer Medicine  

Background: The treatment of choice for desmoid-type fibromatosis (DF) has been changed to active surveillance (AS). However, few studies have reported clinical outcomes of AS modality in Asian countries. This study aimed to clarify the significance of AS as a DF treatment modality. Methods: A total of 168 lesions from 162 patients with extra-abdominal DF were included. The mean age at diagnosis was 39 years (1–88 years), and the median maximum tumor diameter at the first visit was 64.1 mm (13.2–255.8 mm). The clinical outcomes of AS and the risk factors requiring active treatment (AT) (defined as an event) from AS modality were investigated. Results: Of the 168 lesions, 94 (56%) were able to continue AS, with a 5-year event-free survival of 54.8%. Of the 68 lesions with PD, 21 (30.9%) lesions were able to continue AS. Neck location (p = 0.043) and CTNNB1 S45F mutation (p = 0.003) were significantly associated with the transition to AT, and S45F mutation was a significant factor associated with the transition to AT by multivariate analysis (hazard ratio: 1.96, p = 0.048). AT outcomes after AS were evaluable in 65 lesions, and 49 (75%) lesions did not require a transition to a second AT. Conclusions: AS was revealed as an effective treatment modality. The transition to AT needs to be considered for neck location and CTNNB1 S45F mutation DF. Good results can be obtained by selecting a treatment method that considers the tumor location even in cases that require intervention.

DOI： 10.1002/cam4.5329

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BACKGROUND: Nodular plexiform neurofibromas in individuals with neurofibromatosis type 1 often cause significant symptoms and are treated with surgical excision despite the potential risk of complications. This study aimed to clarify the surgical outcomes of deep-seated nodular plexiform neurofibromas and identify the factors associated with postoperative complications. METHODS: We retrospectively reviewed patients with neurofibromatosis type 1 who underwent surgical excision for deep-seated nodular plexiform neurofibromas in our hospital from 2015 to 2021. Enucleation while preserving the nerve fascicles was attempted first, and en bloc resection, ligating the nerve origin in cases in which the parent nerve was entrapped by the tumor, making the tumor difficult to dissect, was performed. RESULTS: In 15 patients, 24 nodular plexiform neurofibromas received surgical excision. Sixteen tumors were enucleated, and eight were en bloc resected. The symptoms of all 10 patients with preoperative symptoms resolved after surgery. Four patients developed new neurological deficits immediately after surgery, two of whom had retained neurological symptoms at the last visit, but these symptoms were mild. CONCLUSIONS: The present study demonstrates that surgical treatment of nodular plexiform neurofibromas, even deep-seated neurofibromas, is safe with a low risk of severe complications and improvement in preoperative symptoms.

DOI： 10.3390/jcm11195695

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Anticancer drugs and molecular targeted therapies are used for refractory desmoid-type fibromatosis (DF), but occasionally cause severe side effects. The purpose of this study was to identify an effective drug with fewer side effects against DF by drug repositioning, and evaluate its efficacy. FDA-approved drugs that inhibit the proliferation of DF cells harboring S45F mutations of CTNNB1 were screened. An identified drug was subjected to the investigation of apoptotic effects on DF cells with analysis of Caspase 3/7 activity. Expression of β-catenin was evaluated with western blot analysis, and immunofluorescence staining. Effects of the identified drug on in vivo DF were analyzed using Apc1638N mice. Auranofin was identified as a drug that effectively inhibits the proliferation of DF cells. Auranofin did not affect Caspase 3/7 activity compared to control. The expression level of β-catenin protein was not changed regardless of auranofin concentration. Auranofin effectively inhibited the development of tumorous tissues by both oral and intraperitoneal administration, particularly in male mice. Auranofin, an anti-rheumatic drug, was identified to have repositioning effects on DF. Since auranofin has been used for many years as an FDA-approved drug, it could be a promising drug with fewer side effects for DF.

DOI： 10.1038/s41598-022-15756-9

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OBJECTIVE: In patients with neurofibromatosis type 1 (NF1), it is important to accurately determine when plexiform neurofibroma (pNF) transforms to a malignant peripheral nerve sheath tumor (MPNST). The purpose of this study is to investigate the usefulness of diffusion-weighted imaging (DWI) in differentiating pNF and MPNST in NF1 patients. METHODS: Among the NF1 patients who were referred to our hospital between 1985 and 2015, 10 cases of MPNST and 19 cases of pNF were included. We evaluated features of standard magnetic resonance imaging according to the differentiation criteria of malignancy from benignancy as previously reported, apparent diffusion coefficient (ADC) value based on the DWI and the correlation between ADC value and benignancy/malignancy. ROC analysis was performed to determine the appropriate cutoff value of ADC. RESULTS: There were significant differences between MPNST and pNF in the size of the tumor (P = 0.009), peripheral enhancement pattern (P = 0.002), perilesional edema-like zone (P = 0.0008), and intratumoral cystic change (P = 0.02). The mean and minimum values of ADC were significantly lower in MPNST than those in pNF (P = 0.03 and P = 0.003, respectively). When we set a cutoff value of mean ADC as 1.85 × 10-3 mm2/s, the sensitivity and specificity were 80% and 74%, respectively. The area under the curve value improved by adding the Wasa score to the mean ADC evaluation. CONCLUSIONS: ADC values determined by DWI are useful in differentiating MPNST from pNF and adding ADC evaluation to standard MRI evaluation improved the diagnostic accuracy.

DOI： 10.1016/j.wneu.2021.09.130

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CiNii Research

Language：English   Publishing type：Research paper (scientific journal)  

RATIONALE: Fibrous dysplasia is a rare disorder that results in fractures, pain, and disability and can affect any bone in the body. The treatment of symptomatic fibrous dysplasia is determined based on the affected bones. Although some lesions are often too extensive for surgical procedures, there are currently no effective or recommended medical treatments available for them. PATIENT CONCERNS: A 27-year-old woman developed right buttock pain and was diagnosed with a bone tumor in the right ilium. Clinical images revealed an expansive osteolytic lesion with thinning of the cortex and cystic change from the acetabulum to the sacroiliac joint. DIAGNOSIS: An incisional biopsy was performed, and the lesion was diagnosed as cystic fibrous dysplasia. Occasional osteoclast-like giant cells and woven bone were observed. The patient had no evidence of polyostotic lesions or findings of McCune-Albright syndrome. Biochemical blood test results showed no obvious abnormal values, except for an increase in serum tartrate-resistant acid phosphatase 5b to 459 mU/dL. INTERVENTIONS: Since surgical treatment appeared to be challenging, she was treated with denosumab with decreased dose-intensity schedules. OUTCOMES: The administration of denosumab caused osteosclerosis within the lesion, resulting in the elimination of bone pain. The patient received denosumab treatment for 18 months. Pain relief and lesion radiodensity were maintained for 9 months after denosumab discontinuation. The serum level of tartrate-resistant acid phosphatase 5b was measured to monitor the response to denosumab, which was suppressed during denosumab treatment. LESSONS: We described successful denosumab treatment in a patient with cystic fibrous dysplasia (FD) who maintained efficacy for 9 months after treatment. Although the use of denosumab in fibrous dysplasia is currently off-label, our experience with this patient supports the potential of denosumab therapy for patients for whom surgical treatment is challenging.

DOI： 10.1097/MD.0000000000028138

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BACKGROUND: The optimal procedure for functional reconstruction of the extensor mechanism after proximal tibia mega-prosthetic replacement remains unclear. METHODS: Since 2006, 14 consecutive patients with aggressive bone tumors in the proximal tibia who underwent mega-prosthetic replacement were prospectively treated with reconstruction of the extensor mechanism using an ipsilateral iliotibial band. The surgical procedure consisted of wrapping the reversed iliotibial band around the tibia component, firmly suturing it to the remaining patellar tendon and tibialis anterior fascia, and covering it with a muscle flap. At the last follow up, the function was assessed based on extensor lag, active flexion of the knee, and Musculoskeletal Tumor Society score. Patellar height was measured with the Insall-Salvati ratio (ISR) preoperatively, postoperatively, and at the last follow up. RESULTS: At the last follow up, the extensor lag and active flexion in 14 patients averaged 2.5° and 86°, respectively. Musculoskeletal Tumor Society score could be obtained in nine surviving patients at the last follow up and was a mean of 20.7 points. The mean ISR preoperatively, postoperatively, and at the last follow up was 1.04, 0.75, and 0.89, respectively. The extensor lag was not associated with the ISR value at any points, while reduced active flexion significantly correlated with a low ISR at the last follow up (P = 0.015). Four patients underwent additional surgeries due to postoperative infection, but none required eventual revision or amputation. CONCLUSION: The extensor mechanism reconstruction with the reverse transferred iliotibial band for mega-prosthetic replacement after proximal tibia resection yielded reliable outcomes with functional benefit to stabilize active knee extension.

DOI： 10.1016/j.knee.2021.09.006

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OBJECTIVE: The mainstay of treatment modality for extra-abdominal desmoid-type fibromatosis (DF) has shifted from surgery, which often impairs ADL/QOL, to conservative treatment including active surveillance. In the present study, we conducted a longitudinal survey on the diagnosis and treatment of DF at facilities belonging to the Japanese Musculoskeletal Oncology Group, which is a research group of facilities specializing in the treatment of bone and soft tissue tumors in Japan to clarify the transition of medical care for extra-abdominal DF. METHODS: The same questionnaire was administered in 2015 and 2018, and responses were obtained from 46 (69%) of 67 facilities and 42 (53%) of 80 facilities in 2015 and 2018, respectively. RESULTS: Although immunostaining for β-catenin was often used for the pathological diagnosis in both 2015 and 2018, CTNNB1 mutation analysis was not performed either in 2015 or in 2018. As for the treatment strategy for resectable cases, surgical treatment including wide resection was selected at 11 facilities (24% of respondents) in 2015, and further decreased to 5 facilities (12%) in 2018. Conservative treatment with active surveillance or medical treatment was the most common treatment for both resectable and difficult-to-resect cases. COX-2 inhibitors and tranilast were often used in the drug treatment of both resectable and difficult-to-resect cases. Few facilities provided radiotherapy, methotrexate and vinblastine, or DOX-based chemotherapy for refractory cases in both 2015 and 2018. CONCLUSIONS: A good trend was found in the questionnaire survey. It will be further necessary to disseminate clinical practice guidelines to physicians more widely, and to have them understand and implement the most up-to-date medical practice strategies for this rare disease.

DOI： 10.1093/jjco.hyab146

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Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

The mainstay of treatment for desmoid has been shifted to active surveillance (AS). However, surgery is still being performed on abdominal wall desmoid with a wide surgical margin. The purposes of this study are to clarify the treatment results of less-invasive, fascia preserving surgery for patients with abdominal wall desmoid, and to propose a new treatment modality. Since 2009, 34 patients with abdominal desmoid have been treated in our institution. Among them, as a final treatment modality, 15 (44%) were successful with AS, 15 were subjected to less-invasive surgery, and 4 methotrexate and vinblastine treatment. The clinical results of less-invasive surgery were clarified. In the surgical group, although the surgical margin was all microscopic positive (R1), only one patient (6.7%), who has the S45F mutation type of CTNNB1, showed recurrence, at a mean follow-up of 45 months. There were no patients with familial adenomatous polyposis (FAP)-related desmoid in this cohort. Only two patients (13%) required fascia lata patch reconstruction after removal of the tumor. In patients with non FAP-related abdominal wall desmoid, less-invasive, fascia preserving surgery is recommended as a favorable option as active treatment. Based on the results of this study, multi-institutional further research is warranted with an increased number of patients.

DOI： 10.1038/s41598-021-98775-2

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Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

A 52-year-old man, with a history of diabetic nephropathy and renal cancer, had been treated with peritoneal dialysis for four months before consulting our hospital. At the time of imaging evaluation, three years after surgery for renal cancer, fluorodeoxyglucose accumulation was found at the distal metaphysis of the left radius. After the biopsy, he was diagnosed with giant cell tumor of bone (GCTB), and surgery was scheduled. However, osteogenesis was observed in the images retaken before surgery. It was found that his intact parathyroid hormone level had been abnormally high four months prior to his visit to us but had subsequently normalized. The tissue obtained by re-biopsy revealed osteogenesis with the disappearance of multinucleated giant cells, suggesting a brown tumor (BT). The tumor was thought to have been caused by secondary hyperparathyroidism (HPT) associated with peritoneal dialysis. When osteolytic lesions mimicking GCTB are found, the possibility of BT should be considered based on comorbidities and clinical information.

DOI： 10.7759/cureus.17078

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Language：English   Publishing type：Research paper (scientific journal)  

Several types of soft tissue sarcomas have peripheral infiltrative growth characteristics called tail-like lesions. The efficacy of neoadjuvant therapy for tumors with tail-like lesions has not been elucidated. From 2012 to 2019, we analyzed 36 patients with soft tissue sarcoma with tail-like lesions treated with neoadjuvant therapy, including chemotherapy, radiotherapy, or both. The effect of neoadjuvant therapy on the tail sign was investigated by analyzing the change in tail-like lesions during neoadjuvant therapy and histological responses. The median length of the tail-like lesion reduced from 29.5 mm at initiation to 19.5 mm after neoadjuvant therapy. The extent of shrinkage in tail-like lesions was related to the histopathological responses in the main part of the tumor. Complete disappearance of the tail-like lesion was observed in 12 patients; however, it was not related to achieving a microscopically negative margin. The oncologic outcomes did not significantly differ between cases with and without the complete disappearance of tail-like lesions. This study indicated that the shrinkage of tail-like lesions did not have a significant effect on complete resection or improvements of clinical outcomes. A more comprehensive evaluation is needed to elaborate on the surgical strategy.

DOI： 10.3390/cancers13153901

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Hyaluronan (HA) has been shown to play important roles in the growth, invasion, and metastasis of malignant tumors. KIAA1199, which has potent HA-degrading activity, has been reported to be expressed in various malignancies and associated with patient prognosis. However, there are no reports on the expression of KIAA1199 in osteosarcoma. The aim of this study was to investigate the impact of KIAA1199 and HA expression in osteosarcoma tissues on the prognosis and other clinical characteristics of osteosarcoma patients. METHODS: From 2003 to 2013, we included 49 patients with osteosarcoma at our institution, whose FFPE (formalin fixed paraffin embedded) tissue was available at the time of biopsy. The expressions of KIAA1199 and HA in each sample were assessed by immunohistochemistry using the primary antibody for KIAA1199 and HA-binding protein (HABP), respectively. For evaluation of the positivity of KIAA1199 staining, we divided the samples into two groups: High group with more than 75% positive staining and Low group with less than 75% positive staining. In the HABP staining, those with more than and less than 60% were assigned to a High group, and Low group respectively. Various clinical features were correlated with staining positivity. Prognostic factors including positivity of the staining were analyzed. Levels of mRNA expression for enzymes related to HA metabolism were assessed in two osteosarcoma cell lines using real-time RT-PCR. RESULTS: In KIAA1199 staining, high positivity was significantly correlated with occurrence of distant metastases (P = 0.002). The necrosis rate after preoperative chemotherapy was significantly lower in the High positivity group (59%), compared to that in the Low group (84.8%) (P = 0.003). HABP positivity was not correlated with any demographic variables, although the Low positivity group had a significantly better overall survival than the High group with KIAA1199 and HABP staining (P = 0.026 and P = 0.029, respectively). In multivariable analysis, KIAA1199 (P = 0.036) and HABP staining (P = 0.002), location (P = 0.001), and distant metastasis at initial diagnosis (P < 0.001) were identified as significant prognostic factors. KIAA1199 and hyaluronan synthase mRNA were expressed at different levels in the two osteosarcoma cell lines. CONCLUSIONS: Our results showed that high expression of KIAA1199 and HA are both poor prognostic factors in osteosarcoma. KIAA1199 may be a useful marker for distant metastasis and chemoresistance.

DOI： 10.1186/s13018-021-02590-4

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Authorship：Lead author   Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

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 × 106). 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.

DOI： 10.1016/j.ejca.2020.12.001

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DOI： 10.1111/cas.14802.

Language：English   Publishing type：Research paper (scientific journal)  

The purposes of this study were to re-confirm the usefulness of PET/CT in the differentiation of benignity/malignancy of neurogenic tumors in NF1 patients, and to analyze the natural course of plexiform neurofibroma (pNF) and clarify whether PET/CT is also useful for detecting tumors other than neurogenic tumors. PET/CT was prospectively imaged in 36 NF1 patients. There were 14 malignant peripheral nerve sheath tumors (MPNSTs) in 14 patients, and 54 pNFs in 30 patients. Nine patients had both MPNST and pNF. Maximal standardized uptake value (SUVmax) was significantly higher in MPNST (median 7.6: range 4.1-10.4) (P < .001) compared with that of pNF (median 3.7: range 1.6-9.3). The cut-off value of 5.8 resulted in a sensitivity of 78.6% and specificity of 88.9%. Median age was 29 y, and median maximum tumor diameter was 82 mm in 14 MPNST patients. The 5-y overall survival rate was 46.8%. Three patients with low-grade MPNST were alive without disease at the time of this report. In 9 patients in which pNF and MPNST co-existed, 2 showed a higher SUVmax of pNF than that of MPNST. Natural history analysis of pNF (n = 43) revealed that no factors significantly correlated with increased tumor size. Nine lesions other than neurogenic tumors were detected by PET/CT including 5 thyroid lesions and 3 malignant neoplasms. This study revealed the usefulness and limitation of PET/CT for NF1 patients. In the future, it will be necessary to study how to detect over time the malignant transformation of pNF to MPNST, via an intermediate tumor.

DOI： 10.1111/cas.14802

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Low-dose methotrexate (MTX) plus vinblastine (VBL) chemotherapy is an effective treatment for desmoid-type fibromatosis (DF). However, previous reports have described a weekly regimen, with no reports available on a biweekly one. The aim of this study was to determine the clinical outcomes of a biweekly regimen in a cohort prospectively treated in our single institution. Since 2010, we have prospectively treated refractory DF patients with biweekly MTX (30 mg/m2 ) + VBL (6 mg/m2 ). Efficacy, progression-free survival (PFS), and correlating factors were analyzed. Adverse events (AEs) were recorded. In total, 38 patients received low-dose MTX + VBL therapy, and its efficacy was assessed in 37 of them. Nineteen (51%) patients showed partial response (PR). Clinical benefit rate was 95%. PFS at 5 y was 80.8%. In PR cases, median time to response was 10 mo. Longer duration of therapy was significantly associated with the response of PR (P = .007) by univariate analysis. There was no clear association between various clinicopathological factors, including tumor size, location, catenin beta-1 (CTNNB1) mutation status with effect. Only 3 AEs of grade 3/4 were observed. Tumor regrowth after MTX + VBL discontinuation was observed in 5 (20%) of 25 patients. Biweekly administration of MTX + VBL chemotherapy was well tolerated compared with weekly administration, and its efficacy was anticipated in DF patents, although the time needed to achieve a response may be relatively long. The treatment interval should be determined taking into account both the condition of the tumor and the patient's preference.

DOI： 10.1111/cas.14626

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BACKGROUND: The mainstay of the treatment for desmoid-type fibromatoses has been shifting from surgery to drug treatment, making accurate prediction of the efficacy of drug treatment of extreme importance. On the other hand, desmoid-type fibromatoses arise everywhere in the body. The purpose of this systematic review was to address the clinical question of whether tumour location has an impact on the efficacy of drug treatment. METHODS: A literature search from January 1990 to August 2017 was conducted. Four reviewers independently assessed and screened the literature for eligibility and determined the final articles. They rated each report according to the Grading of Recommendations Development and Evaluation approach. Based on the quality of 'Body of Evidence', our clinical guideline committee developed a recommendation for the clinical question. RESULTS: In total, 128 articles were extracted. After the screenings, 5 were chosen for the final evaluation. The drugs used in these articles were one each of toremifene, sorafenib, and methotrexate and vinblastine and of meloxicam. There were no randomized controlled trials, and two prospective and three retrospective case series were included. Therapeutic effects were observed slightly more markedly in extremity using meloxicam or methotrexate and vinblastine. In contrast, the efficacy of toremifene was slightly higher in non-extremity. However, the evidence level of all of the reports was judged to be low. CONCLUSIONS: Considering the low evidence level, we concluded that the site-specific therapeutic effects of drugs could not be confirmed in desmoid-type fibromatoses.

DOI： 10.1093/jjco/hyaa078

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BACKGROUND: An accurate diagnosis is crucial to determine the treatment modality for desmoid-type fibromatosis, although the histopathological diagnosis is occasionally difficult to make. Many desmoid-type fibromatosis have been reported to have hotspot mutation of β-catenin gene (CTNNB1). In the present study, we performed a systematic review to verify the usefulness of CTNNB1 mutation analysis in the diagnosis of desmoid-type fibromatosis. METHODS: A literature search from January 1990 to August 2017 was conducted. Three reviewers independently assessed and screened the literature for eligibility and determined the final articles to be evaluated. Data regarding the sensitivity, specificity, accuracy and usefulness of CTNNB1 mutation analysis in the diagnosis of desmoid-type fibromatosis were recorded. We rated each report according to the Grading of Recommendations Development and Evaluation approach. RESULTS: The search yielded 90 studies, seven of which were included after the first and second screenings. The positive rate of CTNNB1 mutation in desmoid-type fibromatosis was 86.8%, but the cohort of six of the seven reports was already diagnosed histopathologically as desmoid-type fibromatosis. Therefore, the usefulness of CTNNB1 mutation analysis in a cohort that is difficult to diagnose histopathologically is not clear in this review. Nevertheless, CTNNB1 mutation showed very high specificity in desmoid-type fibromatosis, indicating the usefulness of CTNNB1 mutation analysis in its diagnosis in combination with histological examination. CONCLUSION: Because the lack of data precludes any useful comparison with histological diagnosis, the evidence level is low. However, considering its specificity, CTNNB1 mutation analysis may be useful in cases in which the histopathological diagnosis is difficult.

DOI： 10.1093/jjco/hyaa080

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PubMed

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Myxoid liposarcoma is well known to have an unusual proclivity for extrapulmonary metastasis. However, cardiac metastasis of myxoid liposarcoma is very rare, even in patients with advanced disease. CASE PRESENTATION: A 40-year-old man was diagnosed with myxoid liposarcoma of the right thigh and treated with wide resection. Two years after the surgery, a low-density area in the left ventricle was found on follow-up chest computed tomography, and was suspected of being metastatic disease. He underwent surgical treatment, and the lesion was pathologically confirmed as metastasis of myxoid liposarcoma. Fifteen months later, he complained of slight dyspnea and developed metastatic disease in the right atrium. He was treated with surgical excision, followed by radiotherapy. Although there was no recurrence in the heart since the second cardiac metastasectomy, multiple metastases occurred in the abdominal cavity, lungs, and muscles. He finally died of the disease 2 years after the second cardiac metastasectomy. CONCLUSION: We experienced a case of primary myxoid liposarcoma in the thigh, accompanied by ectopic and metachronous cardiac metastases. Although this condition is rare, we should follow-up patients with myxoid liposarcoma, considering the possibility of cardiac metastasis.

DOI： 10.1186/s12957-020-02009-0

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PubMed

Language：English   Publishing type：Research paper (scientific journal)  

This study was undertaken to clarify the risk factors, including the mutation status of CTNNB1, for the local recurrence after surgery of the rare disease desmoid-type fibromatosis. It was designed as a multiinstitutional joint research project with 7 major centers in Japan participating. The committee members of 7 major medical centers specializing in bone and soft tissue tumors formed this study group to develop clinical care guidelines. Of 196 cases with specimens and medical records collected from the 7 institutions, 88 surgically treated ones were analyzed regarding clinicopathologic prognostic factors including CTNNB1 mutation status. Excluding R2 cases (n = 3), 5-year local recurrence-free survival (LRFS) was 52.9%. No case had received pre- or postoperative radiotherapy. Univariate analysis revealed that extremity location (P < .001) and larger size (8 cm or more, P = .036) were significant adverse risk factors for LRFS. Multivariate analysis indicated that extremity location (P < .001) was a significantly adverse factor in addition to recurrent tumor (P = .041), S45F mutation (P = .028), and R1 surgical margin (P = .039). Preoperative drug treatment, including nonsteroidal antiinflammatory drugs, did not reduce the incidence of local recurrence (P = .199). This is the first study to analyze the factors correlating with outcomes of surgical treatment, including CTNNB1 mutation status, in a relatively large number of cases from an Asian country. Tumor location was found to be the most influential prognostic factor for local recurrence, similar to the results from Europe and North America. The development of more sensitive method(s) for determination of CTNNB1 mutation is a priority for future study.

DOI： 10.1111/cas.14528

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PubMed

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: The present study aimed to determine functional outcomes in patients undergoing deltoid muscle resection for soft tissue sarcoma. METHODS: Between 2002 and 2014, 18 patients with soft tissue sarcoma of the shoulder who underwent wide resection including the deltoid muscle, and were followed up for more than 12 months, were retrospectively included in the study. In all, 11 patients were male and 7 were female. The median age was 59 years, median follow-up duration was 37 months. The extent of resection of deltoid muscle, with or without rotator cuff damage, reconstruction methods, adjuvant therapy, oncological outcomes, and the International Society of Limb Salvage (ISOLS) score as functional outcomes were analyzed. RESULTS: Six patients underwent total resection, and twelve underwent partial resections of deltoid muscle. The rotator cuff was resected in four patients. Soft tissue reconstruction was performed in 17 patients using a pedicled latissimus dorsi muscle flap. Two local recurrences and three distant metastases occurred during follow-up. Median overall survival was 72 months. The mean ISOLS score was 25.0 points (±4.6points). Univariate analysis revealed that there was no significant difference in ISOLS score regarding the extent of deltoid muscle resection. Multivariate analysis identified only combined resection of the rotator cuff as a significant prognostic factor for poor functional outcomes (P < 0.001). CONCLUSIONS: The extent of resection of the deltoid muscle might not affect the functional outcomes determined by ISOLS score. If the rotator cuff is resected concurrently, satisfactory functional outcomes might not be obtained.

DOI： 10.1093/jjco/hyaa039

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PubMed

Publisher：株式会社医学書院  

DOI： 10.11477/mf.1408201651

CiNii Research

Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVE: The treatment modality for desmoid-type fibromatosis has shifted from surgery to conservative treatment. This systematic review aims to evaluate the efficacy of low-dose chemotherapy with methotrexate and vinblastine for patients with extra-abdominal desmoid-type fibromatosis. METHODS: We searched the pertinent literature from January 1990 to August 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: The search yielded 40 studies, 9 of which were included after the first and second screenings. There were three prospective case series but no randomized controlled trials among the nine studies. There was no case-control report (vs. no treatment). According to Response Evaluation Criteria in Solid Tumors criteria, the mean response rate (complete remission or partial response) was 36% (11-57%). Including stable disease, namely, clinical benefit was consistently as high as 85% (69-100%). Mean adverse event rate of G3 or G4 according to CTCAE was 31%. One study reported improvement of pain (87.5%) because of this chemotherapy. CONCLUSION: The efficacy of this chemotherapy was convincing. However, the overall evidence was weak, and this chemotherapy is not covered by insurance in Japan; we only weakly recommend low-dose chemotherapy with methotrexate and vinblastine in patients with extra-abdominal desmoid-type fibromatosis.

DOI： 10.1093/jjco/hyz204

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PubMed

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：English  

DOI： 10.3324/haematol.2019.218735

Open Access

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PubMed

Language：English   Publishing type：Research paper (scientific journal)  

Tenosynovial giant cell tumor (TSGCT) is a rare neoplasm. Although surgical resection is the widely accepted primary treatment for TSGCT, recurrences are frequent, and patients' joint function may be severely compromised. Previous studies reported that CSF1-COL6A3 fusion genes were identified in approximately 30% of TSGCTs. The aim of our study was to comprehensively clarify the genomic abnormalities in TSGCTs. We performed whole exome sequencing in combination with target sequence validation on 34 TSGCT samples. RNA sequencing was also performed on 18 samples. RNA sequencing revealed fusion transcripts involving CSF1, including novel CSF1-VCAM1, CSF1-FN1 and CSF1-CDH1 fusions, in 13/18 (72%) cases. These fusion genes were validated by chromogenic in situ hybridization. All CSF1 fusions resulted in the deletion of CSF1 exon 9, which was previously shown to be an important negative regulator of CSF1 expression. We also found that 12 (35%) of the 34 TSGCT samples harbored CBL missense mutations. All mutations were detected in exons 8 or 9, which encode the linker and RING finger domain. Among these mutations, C404Y, L380P and R420Q were recurrent. CBL-mutated cases showed higher JAK2 expression than wild-type CBL cases (p = 0.013). CSF1 fusion genes and CBL mutations were not mutually exclusive, and both alterations were detected in six of the 18 (33%) tumors. The frequent deletion of CSF1 exon 9 in the fusion transcripts suggested the importance of this event in the etiology of TSGCT. Our results may contribute to the development of new targeted therapies using JAK2 inhibitors for CBL-mutated TSGCT.

DOI： 10.1002/ijc.32421

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PubMed

Language：English   Publishing type：Research paper (scientific journal)  

INTRODUCTION: This study aimed to determine the clinical significance of MRI characteristics as a possible predictor of responsiveness to meloxicam treatment in patients with desmoid-type fibromatosis (DF). Additionally, it analysed the correlation between CTNNB1 mutation status and signal intensity of MRI. METHODS: Forty-six patients consecutively treated with meloxicam composed this study. The low-intensity area (LIA) on T2-weighted MRI was determined. We divided patients into two groups based on the efficacy of meloxicam: a clinical benefit group (CB group, including CR: complete response; PR: partial response; and SD: stable disease) and non-clinical benefit group (NB group, including PD: progressive disease). Correlations of the efficacy with LIA and CTNNB1 mutation status with LIA were investigated. RESULTS: In total, 11, 17 and 18 patients showed PR, SD and PD, respectively. The mean LIA ratio before treatment was significantly higher (P < 0.001) in the CB group than in the NB group. For predicting the efficacy, sensitivity was 68%, and specificity was 89% when setting the cut-off value as 20% for LIA. Mean changes in the LIA ratio before and after treatment were significantly higher (P = 0.01) in the CB group than in the NB group. Mean LIA ratio before treatment was significantly lower (P < 0.001) in the S45F mutation group than in the other mutation group. In multivariate analysis, the LIA ratio before treatment was a significant predictor of responsiveness (P = 0.02). CONCLUSIONS: MRI characteristics were a useful predictor of the efficacy of meloxicam in DF patients. It may be possible to predict the clinical outcome more accurately when combined with other factors, such as CTNNB1 mutantion status.

DOI： 10.1111/1754-9485.12940

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PubMed

Publisher：The Lancet Oncology  

DOI： 10.1016/S1470-2045(19)30543-1

Scopus

PubMed

Web of Science

Publisher：株式会社医学書院  

DOI： 10.11477/mf.1408201410

CiNii Research

Web of Science

Language：English   Publishing type：Research paper (scientific journal)  

Immunohistochemical staining with anti-β-catenin antibody has been applied as a diagnostic tool for desmoid-type fibromatoses (DFs). In recent years, specific gene mutation (CTNNB1) analysis has also been reported to be useful for diagnosis of DF; however, the association between CTNNB1 mutation status and immunohistochemical staining pattern of β-catenin is rarely reported. The purposes of this study are to clarify the relationship of the staining pattern of β-catenin with the CTNNB1 mutation status and various clinical variables, and to investigate the significance of immunohistochemical staining of β-catenin in cases diagnosed as DF. Between 1997 and 2017, 104 cases diagnosed as DF from 6 institutions in Japan were enrolled in this study: Nagoya University, National Cancer Center Hospital, Niigata University, Okayama University, Kyushu University, and Cancer Institute Hospital. For all cases, immunohistochemical staining of β-catenin and gene mutation analysis of CTNNB1 were performed. Of 104 cases, 87 (84%) showed nuclear staining of β-catenin, and 95 (91%) showed positive staining in the cytoplasm. The proportion of cases showing strong nuclear staining of β-catenin was significantly higher in the cases with S45F than in those with T41A or wild type. The proportion of cases stained strongly in the cytoplasm rather than in the nucleus was significantly higher in the group of T41A than that of S45F or wild type. Among 17 cases in which nuclear immunostaining was absent, CTNNB1 mutation was observed in 5 cases (29.4%). There were unignorable cases of DF with negative β-catenin immunostaining despite a definitive clinical and pathological diagnosis of DF and/or positive CTNNB1 mutation.

DOI： 10.1016/j.humpath.2018.09.018

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PubMed

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Immunohistochemical staining with conventional anti-β-catenin antibody has been applied as a diagnostic tool for desmoid-type fibromatosis (DF). This study aimed to evaluate the diagnostic and prognostic value of immunohistochemical staining with anti-non-phospho β-catenin antibody, which might more accurately reflect the aggressiveness of DF, in comparison to the conventional anti-β-catenin antibody. METHODS: Between 2003 and 2015, 40 patients with extra-peritoneal sporadic DF were prospectively treated with meloxicam or celecoxib, a COX-2 inhibitor, therapy. The efficacy of this treatment was evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST). Immunohistochemical staining was performed on formalin-fixed material to evaluate the expression of β-catenin and non-phospho β-catenin, and the positivity was grouped as negative, weak, moderate, and strong. DNA was isolated from frozen tissue or formalin-fixed materials, and the CTNNB1 mutation status was determined by direct sequencing. RESULTS: Of the 40 patients receiving COX-2 inhibitor treatment, there was one with complete remission, 12 with partial remission, 7 with stable disease, and 20 with progressive disease. The mutation sites in CTNNB1 were detected in 22 (55%) of the 40 cases: T41A (17 cases), S45F (3 cases), and T41I and S45P (1 each). The positive nuclear expression of non-phospho β-catenin showed a significant correlation with positive CTNNB1 mutation status detected by Sanger method (p = 0.025), and poor outcome in COX-2 inhibitor therapy (p = 0.022). In contrast, nuclear expression of β-catenin did not show a significant correlation with either CTNNB1 mutation status (p = 0.43) or outcome of COX-2 inhibitor therapy (p = 0.38). CONCLUSIONS: Nuclear expression of non-phospho β-catenin might more appropriately reflect the biological behavior of DF, and immunohistochemical staining with non-phospho β-catenin could serve as a more useful diagnostic and prognostic tool of COX-2 inhibitor therapy for patients with DF.

DOI： 10.1186/s13000-017-0654-z

Open Access

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Scopus

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

A recent study reported that heat stress stimulates osteogenesis in an in vivo rat model using alginate gel and magnetite cationic liposomes. However, for clinical use, the efficacy for promoting osteogenesis needs to be investigated using clinically approved materials, and preferably with animals larger than rats. The aim of this study was to evaluate multiple heat stimuli-triggered osteogenesis in rat tibial defect models using already clinically applicable materials (Resovist® and REGENOS®) and determine the efficacy also in the rabbit. Fifty-eight rats and 10 rabbits were divided into two groups, respectively, with or without hyperthermia treatment at 45°C for 15 min. (hyperthermia; 20 rats once a week, 8 rats three times a week, 5 rabbits once a week, control; 30 rats and 5 rabbits). Micro-CT assessment at 4 weeks revealed that a significantly stimulated osteogenesis was observed in the once a week group of both rats and rabbits as compared to the control group (p = 0.018 and 0.036, respectively). In contrast, the three times a week group did not show enhanced osteogenesis. Histological examination and image analysis showed consistent results in which the area of mineralized bone formation in the once a week hyperthermia group was significantly increased compared with that in the control group at four weeks (rat; p = 0.026, rabbit; p = 0.031). Newly formed bone was observed in the grafted materials from the periphery toward the center, and more osteoclasts were found in the once a week group. Heat stress also induced enhanced alkaline phosphatase expression in cultured osteoblastic cells, MC3T3, in vitro (p = 0.03). On the other hand, heat stress had no obvious effects on chondrogenic differentiation using ATDC5 cells. Our study demonstrates that heat-stimuli with clinically applicable novel heating materials can promote significant osteogenesis, and may thus be a promising treatment option for diseases associated with bone defects.

DOI： 10.1371/journal.pone.0181404

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PubMed

Event date： 2024.5

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：福岡   Country：Japan  

Event date： 2024.4

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：米子   Country：Japan  

Event date： 2024.2

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：名古屋   Country：Japan  

Event date： 2021.7

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：広島   Country：Japan  

Event date： 2021.5

Language：Japanese   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2021.5

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：オンライン   Country：Japan  

Event date： 2020.10

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：オンライン   Country：Japan  

Event date： 2020.9

Language：Japanese   Presentation type：Poster presentation  

Venue：オンライン   Country：Japan  

Event date： 2020.6 - 2020.8

Language：Japanese   Presentation type：Poster presentation  

Venue：オンライン   Country：Japan