Risk factors of local recurrence after surgery in extraabdominal desmoid-type fibromatosis: A multicenter study in Japan.

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.

Definitive radiation therapy in patients with unresectable desmoid tumors: a systematic review.

BACKGROUND: Desmoid tumors are rare soft tissue tumors. Wide local excision has been the standard surgical treatment for desmoid tumors. However, this procedure results in high local recurrence rates, so non-surgical treatments should be considered. The aim of this systematic review was to evaluate the effect of radiation therapy on patients with desmoid tumors, especially those with unresectable disease. METHODS: We evaluated studies published between 1 January 1990 and 31 August 2017 and cited in PubMed and Ichushi (in Japanese). All studies evaluating the effect of radiation therapy on desmoid tumors were included. Data regarding radiation dose, recurrence and adverse events were recorded. RESULTS: Among 218 identified studies, only 6 were finally included in this review. Local control was achieved in 253 of 317 patients with unresectable or unresected tumors who underwent definitive radiation therapy (the crude rate of local control was 79.8%). Toxicity was evaluated in patients who underwent definitive radiation therapy or surgery plus radiation therapy. One of the most common acute complications was skin toxicity. Frequent late complications of radiation therapy included fibrosis/contracture/joint stiffness, skin disorders, lymphedema and pain. Six patients developed secondary malignancies in the radiation field. CONCLUSIONS: In patients treated unsuccessfully with surgery, watchful waiting and pharmacotherapy, radiation therapy may be an option as salvage therapy because of the high rate of local control. Because desmoid tumors frequently develop in young individuals, children and young patients who receive radiation therapy for the treatment of desmoid tumors should be followed up on a long-term basis with periodic monitoring for late radiation toxicities.

Analysis of a limb-specific regulatory element in the promoter of the link protein gene.

Link protein is encoded by the Hapln1 gene and is a prototypical protein found in the cartilage matrix. It acts as an important component of the endochondral skeleton during early development. To study its transcriptional regulation, promoter fragments derived from the link protein gene were coupled to the ß-galactosidase reporter and used to study in vivo transgene expression in mice. In day 15.5 mouse embryos, a link promoter fragment spanning -1020 to +40 nucleotides demonstrated highly specific ß-galactosidase staining of skeletal structures, including the appendicular and axial cartilaginous tissues. Two shorter promoter fragments, spanning -690 to +40 and -315 to +40 nucleotides, demonstrated limb- and genitalia-specific expression resembling that of homeodomain-regulated tissues. Bioinformatic analysis revealed a highly conserved, Hox-like binding site (HLBS) at approximately -220 bp of the promoter, shared by both constructs, which contained the Hox-core consensus sequence TAATTA. Electromobility shift assays demonstrated binding of Hox-B4 recombinant protein to the HLBS, which was eliminated with nucleotide substitutions within the core-binding element. Co-transfection analysis of the HLBS demonstrated a 22-fold transcriptional activation by HoxA9 expression, which was ablated with a substitution within the core HLBS element. Together these findings establish promoter regions within the link protein gene that are important for in vivo expression and identify the potential role of homeodomain-containing proteins in controlling cartilage and limb gene expression.

Clinical features and treatment outcome of desmoid-type fibromatosis: based on a bone and soft tissue tumor registry in Japan.

BACKGROUND: Treatment modality of desmoid-type fibromatosis (DF) has changed from surgery with a wide surgical margin to conservative treatment. In this study, tumor characteristics of DF, transition of the treatment modality, and clinical outcome of surgical treatment were analyzed based on data obtained from the bone and soft tissue tumor registry established in Japan. METHODS: Data were collected as registration data and follow-up data. Five hundred and thirty registered cases of DF were identified, including 223 cases with follow-up data with or without surgical treatment. RESULTS: The number of registered patients increased gradually. The frequency of surgical treatment was gradually reduced year by year. The 3-year local recurrence free survival (LRFS) was 77.7%, with tumor location and size tending to correlate with LRFS. Interestingly, there was no significant difference in LRFS between wide and marginal margin (P = 0.34). CONCLUSIONS: The treatment modality has shifted from surgical to conservative treatment, with risk factors for surgical treatment similar to those noted in previous studies. The National registry system is crucial for a rare disease such as DF, and in the future, a population based registry system should be established to better comprehend the actual status of DF.

Tumor-induced osteomalacia caused by a massive phosphaturic mesenchymal tumor of the acetabulum: A case report.

We report a case of tumor-induced osteomalacia (TIO) caused by a massive phosphaturic mesenchymal tumor (PMT) of the acetabulum. A 68-year-old woman presented with progressive bone pain of the rib cage, and polyarthralgia and back pain for 3 years. She was diagnosed with hypophosphatemic osteomalacia because laboratory testing was remarkable for low serum phosphorus and a low level of 1,25(OH)2 vitamin D. Three years later, her hip radiograph revealed an osteolytic lesion of the acetabulum. Magnetic resonance imaging of the acetabulum showed a massive lesion. Laboratory data showed hypophosphatemia and an elevated serum level of fibroblast growth factor 23 (FGF-23). Samples obtained with open biopsy showed a low-grade spindle cell neoplasm with FGF-23 positivity, identified by using immunohistochemical staining, confirming the diagnosis of a PMT mixed connective tissue variant. Curettage of the tumor was performed, and the defects were filled with bone allografts. The hip joint was reconstructed with total hip arthroplasty using a Muller support ring. To our knowledge, this report represents the first documented case of massive PMT of the acetabulum causing TIO.

Factors associated with the decision of operative procedure for proximal femoral bone metastasis: Questionnaire survey to institutions participating the Bone and Soft Tissue Tumor Study Group of the Japan Clinical Oncology Group.

BACKGROUND: Pathological fracture of the proximal femur is a main cause of cancer patients losing their ability to walk. Although both osteosynthetic devices (predominantly intramedullary nails) and prosthetic replacement have been widely performed for treatment, controversies exist regarding which procedure should be used for the various conditions. In order to decide the eligibility criteria of a planned randomized prospective study about the treatment of pathological fractures of the proximal femur, we assessed the factors affecting the selection of operative procedures using questionnaires sent to the members of the Bone and Soft Tissue Tumor Study Group (BSTTSG) of the Japan Clinical Oncology Group (JCOG). METHODS: Questionnaire surveys to evaluate (1) the priority levels of the factors, (2) the equipoise range of each factor in situations where either procedure could be applied, (3) risk and benefit of each procedure, and (4) the degree of bone destruction affecting the selection of operative procedures, were sent to 26 institutions. RESULTS: Over 80% of the institutions answered. Orthopaedic surgeons of BSTTSG decided on the procedure according to the following factors in descending order: life expectancy, performance status before fracture, the degree of bone destruction, walking ability before fracture, general complications, the number of bone metastases in other sites, and the visceral metastasis status. With regard to bone destruction, (1) the involvement of the head, neck, calcar, and intertrochanteric region, (2) transverse destruction >1/2, and (3) soft-tissue tumor extension, were the factors that led to the choice of prosthesis treatment. CONCLUSIONS: Using these identified factors, the inclusion criteria for the prospective randomized study of the surgical treatment of metastatic bone tumors of the proximal femur were optimized. The evaluation system about the bone destruction of metastases needs to be refined through the following prospective randomized study.

Expression of Forkhead box M1 in soft tissue leiomyosarcoma: Clinicopathologic and in vitro study using a newly established cell line.

Leiomyosarcoma (LMS) of soft tissue is a sarcoma with smooth-muscle differentiation, and conventional chemotherapy does not improve its outcome. The application of novel antitumor agents and precise prognostication has been demanded. The expression of the protein Forkhead box M1 (FOXM1), a member of the FOX family, is considered an independent predictor of poor survival in many cancers and sarcomas. However, the expression status of FOXM1 in LMS is poorly understood. The purposes of this study were to examine the correlation between the expression of FOXM1 and clinicopathologic or prognostic factors and to clarify the efficacy of FOXM1 target therapy in LMS. We evaluated the immunohistochemical expressions of FOXM1 using 123 LMS tumor specimens. Univariate and multivariate survival analyses revealed that FOXM1 expression was associated with poor prognosis in LMS. An in vitro study was then carried out to examine the antitumor effect of a FOXM1 inhibitor (thiostrepton) and siRNA on a novel LMS cell line, TC616. We also assessed the efficacy of the combined use of doxorubicin and thiostrepton. Thiostrepton showed dose-dependent antitumor activity and TC616 cells treated with the combination of thiostrepton and doxorubicin showed lower proliferation compared to those treated with either drug individually. FOXM1 interruption by siRNA decreased cell proliferation and increased chemosensitivity. In conclusion, FOXM1 has potential to be a therapeutic target for LMS.

A randomized phase II/III trial of perioperative chemotherapy with adriamycin plus ifosfamide versus gemcitabine plus docetaxel for high-grade soft tissue sarcoma: Japan Clinical Oncology Group Study JCOG1306.

A randomized Phase II/III trial was planned to commence in March 2014. Perioperative chemotherapy with adriamycin plus ifosfamide is the current standard treatment for T2bN0M0 high-grade non-round cell soft tissue sarcoma. The purpose of this study is to confirm the non-inferiority of perioperative chemotherapy with gemcitabine and docetaxel to adriamycin plus ifosfamide for patients with T2bN0M0 or any TN1M0 non-round cell soft tissue sarcoma in the extremities and body wall. A total of 140 patients will be accrued from 28 Japanese institutions over 6 years. The primary endpoint in the Phase II part is the proportion of completion of pre-operative chemotherapy without progressive disease and overall survival in the Phase III part. The secondary endpoints are progression-free survival, response rate of pre-operative chemotherapy, pathological response rate, proportion of preservation of diseased limbs, disease control rate and proportion of adverse events. This trial has been registered in the UMIN Clinical Trials Registry as UMIN000013175 [http://www.umin.ac.jp/ctr/index.htm].

Intraosseous hemangioma arising in the clavicle.

Intraosseous hemangioma (IH) is commonly seen in the vertebral column and skull: however, IH occurring in the appendicular skeleton, including the clavicle, is uncommon. We herein report the case of a 69-year-old female presenting with IH of the left clavicle. The findings of preoperative imaging studies, including radiographs, computed tomography (CT), magnetic resonance imaging, fluorine-18-fludeoxyglucose ((18)F-FDG) positron emission tomography (PET)/CT and ultrasonography, are described. In particular, (18)F-FDG PET/CT showed an ill-defined osteolytic lesion with abnormally high FDG uptake. Surgical en bloc resection with preoperative embolization was carried out and a histopathological examination confirmed the presence of an intraosseous cavernous hemangioma in the clavicle.

DDIT3-amplified or low-polysomic pleomorphic sarcomas without MDM2 amplification: Clinicopathological review and immunohistochemical profile of nine cases.

Several high-grade pleomorphic sarcoma cases that cannot be classified into any existing established categories have been reported. These cases were provisionally classified into undifferentiated pleomorphic sarcoma (UPS). Some dedifferentiated liposarcoma (DDLS) cases may also have been classified into the UPS category due to the absence of MDM2 amplification or an atypical lipomatous tumor/well-differentiated liposarcoma component. We retrieved and reviewed 77 high-grade pleomorphic sarcoma cases, initially diagnosed as UPS in 66 cases and DDLS in 11 cases. Fluorescence in situ hybridization (FISH) analyses of DDIT3 and MDM2 were performed for available cases. Of the cases successfully subjected to DDIT3 FISH (n = 56), nine (7 UPS and 2 DDLS) showed DDIT3 amplification but no MDM2 amplification. Two UPS cases showed both telomeric (5') and centromeric (3') amplification of DDIT3 or low polysomy of chromosome 12, whereas 5 UPS and 2 DDLS cases showed 5'-predominant DDIT3 amplification. Histopathologically, all cases showed UPS-like proliferation of atypical pleomorphic tumor cells. Immunohistochemically, only one case showed focal nuclear positivity for DDIT3, supporting the previous finding that DDIT3 expression was not correlated with DDIT3 amplification. All three cases with focal MDM2 expression involved 5'-predominant amplification, two of which showed DDLS-like histological features. The majority of cases (7/9) showed decreased expression in p53 staining, suggesting that DDIT3 amplification regulates the expression of TP53 like MDM2. From a clinicopathological perspective, we hypothesize that DDIT3-amplified sarcoma, especially with 5'-predominant amplification, can be reclassified out of the UPS category.

Dedifferentiated chondrosarcoma of the cervical spine: a case report.

Dedifferentiated chondrosarcoma (DDCS) is a rare and aggressive bone tumor with poor prognosis. Primary DDCS of the mobile spine is extremely rare, particularly in the cervical spine. We herein describe a first case of cervical DDCS in an 81-year-old male presenting with a slowly growing mass. Radiographs showed an expansion of the cortical contour of the C2 lamina and a soft tissue mass with punctate calcification. Magnetic resonance imaging demonstrated a lobulated lesion expanding over the entire lamina and pedicles of C2 with the tumor protuberant to the adjacent soft tissue. A complete tumor resection was performed. Histologically, the majority of the tumor was a low-grade chondrosarcoma component. However, atypical spindle cells that had proliferated in a fascicular pattern with a collagenous stroma, mimicking fibrosarcoma, were focally observed without a transitional zone, and these features confirmed that the tumor was DDCS.

Myxoid liposarcoma in an 11-year-old patient.

Myxoid liposarcoma is a mesenchymal malignancy that most commonly presents in young adults, with peak incidence between the ages of 30-50 years. The clinical behavior of myxoid liposarcoma has been well characterized in adults. However, little is known about the clinical features and treatment outcomes of myxoid liposarcoma in child, owing to its rarity. This case report describes an 11-year-old previously healthy female who presented with a painless mass in her right thigh. Ultrasonography, computed tomography, and magnetic resonance imaging demonstrated a soft tissue mass with clear margins in the subfascial plane superficial to the gracilis and sartorius muscles. She was diagnosed with myxoid liposarcoma based on histological and molecular cytogenetic examinations of the core-needle biopsy specimen. The patient subsequently underwent wide resection without any adjuvant treatment. The patient has not experienced any symptoms of local recurrence and metastases as of 2.5 years after surgery.

Successful Management of Radiation-Associated Insufficiency Fracture of the Tibial Plateau with Low-Intensity Pulsed Ultrasound.

BACKGROUND Clinical management of radiation-associated pathological fracture is challenging because of a high nonunion rate and potential for morbidity. We report a case of radiation-associated insufficiency fracture of the tibial plateau after surgery, perioperative chemotherapy, and adjuvant radiation therapy for synovial sarcoma of the proximal calf that was successfully treated with low-intensity pulsed ultrasound (LIPUS). CASE REPORT A healthy 52-year-old Japanese woman presented with a slowly growing, painful soft tissue mass over her proximal calf. Histological examination of core needle biopsy specimens led to a pathological diagnosis of synovial sarcoma. After perioperative ifosfamide and doxorubicin chemotherapy and surgical resection, adjuvant radiation therapy was administered, with a total of 60 Gy in 30 fractions. At 5 months after surgery and 2 months after the completion of radiation therapy, she developed an insufficiency pathological fracture of the proximal tibia without any apparent trauma. The patient was treated with LIPUS for 1 year. There was no collapse or deformity of the knee joint. The patient remained free of symptoms and had no recurrences for 2 years after surgery. CONCLUSIONS This is the first report of radiation-associated pathological fracture that was successfully treated with LIPUS. LIPUS could be a safe and effective treatment option in the management of radiation-associated pathological fractures.

Clinical, Radiological, and Histopathological Characteristics of Periosteal Chondrosarcoma with a Focus on the Frequency of Medullary Invasion.

Periosteal chondrosarcoma is an extremely rare malignant cartilage-forming tumour that originates from the periosteum and occurs on the surface of bone. Often, it is difficult to distinguish periosteal chondrosarcoma from other tumours, and reports in the literature are scarce. This study aims to investigate the characteristics of periosteal chondrosarcoma, focusing particularly on medullary invasion. Among 33 periosteal cartilaginous tumours, seven patients with pathologically proven periosteal chondrosarcoma were identified retrospectively. The average tumour size was 5.4 cm in the long axis; two tumours were smaller than 3.0 cm. Six tumours were resected with a wide margin, and the remaining tumour had a marginal margin. Histology revealed that six tumours (85.7%) had invaded the medullary cavity; three of these did not show invasion into the medullary cavity on MRI evaluation. Neither local recurrence nor metastasis was observed among these patients. The frequency of invasion of the medullary cavity was higher than that reported previously. The recommended treatment for periosteal chondrosarcoma is resection with an adequate margin. Therefore, surgeons should consider the possibility of medullary invasion when attempting to achieve a histologically negative margin, even if the tumour does not show invasion into the medullary cavity on MRI.

Nuclear ß-catenin translocation plays a key role in osteoblast differentiation of giant cell tumor of bone.

Denosumab is a game-changing drug for giant cell tumor of bone (GCTB); however, its clinical biomarker regarding tumor ossification of GCTB has not been elucidated. In this study, we investigated the relationship between Wnt/ß-catenin signaling and the ossification of GCTB and evaluated whether endogenous nuclear ß-catenin expression predicted denosumab-induced bone formation in GCTB. Genuine patient-derived primary GCTB tumor stromal cells exhibited osteoblastic characteristics. Identified osteoblastic markers and nuclear ß-catenin translocation were significantly upregulated via differentiation induction and were inhibited by treating with Wnt signaling inhibitor, GGTI-286, or selective Rac1-LEF inhibitor, NSC23766. Furthermore, we reviewed the endogenous ossification and nuclear ß-catenin translocation of 86 GCTB clinical samples and elucidated that intra-tumoral ossification was significantly associated with the nuclear translocation. Three-dimensional quantitative analyses (n = 13) of tumoral CT images have revealed that the nuclear ß-catenin translocation of naïve GCTB samples was significantly involved with the denosumab-induced tumor ossification. Our findings suggest a close relationship between the nuclear ß-catenin translocation and the osteoblastic differentiation of GCTB. Investigations of the nuclear ß-catenin in naïve GCTB samples may provide a promising biomarker for predicting the ossification of GCTB following denosumab treatment.

Malignant Transformation of Giant Cell Tumor of Bone 7 years After Initial Surgery: A Case Report and Literature Review.

CASE: A 64-year-old man with a history of giant cell tumor of bone (GCTB) in the fibula 7 years earlier developed a recurrence with histologic features of osteosarcoma. Both the primary GCTB and the secondary osteosarcoma were found to have the H3F3A gene mutation. Despite immediate above-the-knee amputation, the patient died of respiratory failure because of lung metastases 3 months later. CONCLUSION: This is the first report of proven H3F3A mutation in both the primary GCTB and the secondary osteosarcoma in the same case. Clinicians should consider secondary malignancy in patients presenting with a lesion at the site of a previously treated GCTB after a long interval.

Giant Cell Tumor of Bone of the First Rib Successfully Treated with Combined Preoperative Denosumab Therapy and Surgery via a Transmanubrial Approach.

BACKGROUND Giant cell tumor of bone (GCTB) is a locally aggressive, intermediate tumor that rarely metastasizes. GCTB typically affects the ends of long bones and rarely involves the ribs. Curettage is typically the treatment of choice for GCTB in long bones. However, the optimal treatment of GCTB in ribs remains unclear. We report the case of a patient with asymptomatic GCTB of the first rib that was successfully treated with combined preoperative denosumab therapy and surgery via a transmanubrial approach without resection of the clavicle. CASE REPORT A healthy 27-year-old woman presented with a bone tumor involving the left first rib that was incidentally discovered on routine chest X-ray. Histological examination of core-needle biopsy specimens of the lesion led to a pathological diagnosis of GCTB. After preoperative denosumab treatment for 6 months, en bloc resection via a transmanubrial approach was performed. There were no serious postoperative complications. The patient remained free of symptoms and had no recurrence 4.5 years after surgery. CONCLUSIONS Compared with other ribs, masses located in the first rib can be challenging to treat surgically because of the clavicle and neighboring neurovascular structures. This report is the first to describe GCTB located on the anterior aspect of the first rib that was successfully treated with combined preoperative denosumab therapy and surgery via a transmanubrial approach, with no recurrence or functional impairment of the shoulder girdle.

Cardiac Tamponade as an Unusual Initial Clinical Manifestation of CIC-DUX4 Sarcoma.

BACKGROUND CIC-rearranged sarcoma (CRS) is a recently described subset of undifferentiated small-round-cell sarcomas of bone and soft tissue. DUX4 is the most common gene involved in CRS. CRS usually presents in the soft tissue of the trunk and extremities, and is recognized as being clinically aggressive, with poor prognosis. Our case highlights an unusual presentation of CRS with cardiac tamponade. CASE REPORT A 48-year-old man presented with hypotension caused by hemorrhagic cardiac tamponade. ¹8F-fluorodeoxyglucose-positron emission tomography showed increased uptake in multiple lesions, including lesions in the left proximal humerus and several lymph nodes. Biopsy specimens of the humerus revealed proliferation of round-shaped cells. In addition, CIC-DUX4 gene rearrangement was detected by polymerase chain reaction and direct sequencing, leading to a diagnosis of cardiac tamponade caused by CRS. Although the patient received systemic chemotherapy as well as radiotherapy to the mediastinal lesion and left humerus, he died of progressive disease 12 months after diagnosis. CONCLUSIONS Because CRS is a recently proposed entity that is distinct from Ewing sarcoma, the clinical presentation and outcome of CRS has not been well documented in the literature. This is the first case report of CRS presenting as cardiac tamponade. Although cardiac tamponade due to metastatic sarcoma is extremely rare, CRS can be included in the differential diagnosis.

Tumor microenvironment in giant cell tumor of bone: evaluation of PD-L1 expression and SIRPα infiltration after denosumab treatment.

Giant cell tumor of bone (GCTB) is an intermediate malignant bone tumor that is locally aggressive and rarely metastasizes. Denosumab, which is a receptor activator of nuclear factor kappa B ligand (RANKL) inhibitor, can be used to treat GCTB. We focused on potential immunotherapy for GCTB and investigated the tumor microenvironment of GCTB. Programmed death-ligand 1 (PD-L1) and indoleamine 2,3-dioxygenase 1 (IDO1) expression and signal-regulatory protein alpha (SIRPα), forkhead box P3 (FOXP3), and cluster of differentiation 8 (CD8) infiltration were assessed by immunohistochemical studies of 137 tumor tissues from 96 patients. Of the naive primary specimens, 28% exhibited PD-L1 expression and 39% exhibited IDO1 expression. There was significantly more SIRPα+, FOXP3+, and CD8+ cell infiltration in PD-L1- and IDO1-positive tumors than in PD-L1- and IDO1-negative tumors. The frequency of PD-L1 expression and SIRPα+ cell infiltration in recurrent lesions treated with denosumab was significantly higher than in primary lesions and recurrent lesions not treated with denosumab. PD-L1 expression and higher SIRPα+ cell infiltration were significantly correlated with shorter recurrence-free survival. PD-L1 and SIRPα immune checkpoint inhibitors may provide clinical benefit in GCTB patients with recurrent lesions after denosumab therapy.