Rehabilitation Treatment of a Patient With Total Humeral Endoprosthetic Replacement.

Total humeral endoprosthetic replacement (THR) is a rare surgery for malignant humeral bone tumors. Studies focusing on its surgical methods and functional status are limited. Furthermore, rehabilitation treatment after THR has not been reported. Therefore, this case report aimed to investigate its postoperative rehabilitation treatment and reinstatement. A 69-year-old woman was diagnosed with chondrosarcoma of her left humerus. THR was performed the day following patient admission. The wide resection caused the loss of her left shoulder motor function. She had a left ulnar nerve disorder and carpal tunnel syndrome. Rehabilitation treatments such as joint range of motion training were initiated on postoperative day (POD) 1. We designed a shoulder abductor brace to maintain her left shoulder in an abducted and flexed position so she could use her left hand effectively. The manual muscle testing scores for elbow joint movements gradually improved. On POD47, she was transferred to a convalescent rehabilitation hospital to receive training in activities of daily living and barber work. The patient was discharged on POD107. The Disabilities of the Arm, Shoulder, and Hand score improved from 86.2 (POD7) to 17.2 (POD107). She continued outpatient rehabilitation and reinstated work on POD143. The use of a brace and seamless rehabilitation from the acute phase to convalescence and community-based rehabilitation enabled the patient with THR to return to work. This study suggests that precise assessment of the disorders and consecutive rehabilitation treatment with a brace should be considered after THR.

Bacillus Calmette-Guérin osteomyelitis of the fifth metatarsal bone in a Japanese infant: a case report.

Bacillus Calmette-Guérin osteomyelitis is a rare complication following Bacillus Calmette-Guérin vaccination. Here, we describe a rare case of Bacillus Calmette-Guérin osteomyelitis of the fifth metatarsal in a 21-month-old Japanese infant. A 21-month-old Japanese female infant presented with a swollen mass on the dorsolateral aspect of the left foot. Based on physical examination, radiological and histopathologic findings and laboratory results, a diagnosis of Bacillus Calmette-Guérin osteomyelitis of the fifth metatarsal bone was made, and an oral anti-tuberculosis treatment was initiated. However, the mass recurred 10 months after the start of the anti-tuberculosis treatment, so additional surgical debridement was performed. Six months after surgery, clinical findings and plain radiograph images revealed complete improvement of the affected area, and anti-tuberculosis treatment was stopped. Bacillus Calmette-Guérin osteomyelitis of the fifth metatarsal in a 21-month-old Japanese infant was successfully treated with oral anti-tuberculosis therapy and surgical debridement.

Treatment Strategy of Fractured Osteochondroma in the Young Athlete's Knee.

Purpose: The main purpose of this study was to compare the clinical outcome of surgery versus observation in young athletes with fractured osteochondromas in the knee. The secondary aim was to evaluate displacement versus non-displacement fractures with regards to functional recovery. Methods: A retrospective analysis was performed in young athletes with fractures of osteochondromas in the knee. In the surgery group, resection of the osteochondromas was performed due to pain persisting at 4 weeks after injury. In contrast, patients with pain diminishing within 4 weeks after injury were observed without surgery. Displacement was defined as a gap widening of ≥1 mm between fragments, or translation of >50% of the distal fragment in relation to the proximal fragment. The time to return to the original sport was compared between groups. Results: The study sample was composed of 21 patients with a mean age of 12 years (range 9-16 years). There were 14 patients in the surgery group and 7 patients in the observation group. There were 10 patients (71%) with displacement and 4 patients (29%) with non-displacement fractures in the surgery group. Surgery was required more frequently in displacement than in non-displacement fracture patients (p = 0.01). The mean time to return to the original sport was 2.1 ± 1.1 and 7.2 ± 4.1 weeks in the surgery and observation groups, respectively (p < 0.01). Conclusions: Surgical excision is preferable in a young athlete's knee presenting with displacement of fractured osteochondromas due to disabling symptoms and in order to allow them to return faster to original sports activities.

Clinical Utility of Bland Embolization Using Microspheres for Painful Malignant Musculoskeletal Tumors.

BACKGROUND/AIM: To evaluate retrospectively whether bland embolization using microspheres is safe and useful for relieving pain in patients with painful malignant musculoskeletal (MSK) tumors. PATIENTS AND METHODS: Bland embolization using microspheres was performed for 20 patients (11 women/9 men) with a median age of 69 years (range=40-89 years) who had 22 painful malignant MSK tumors. The maximum tumor diameters were 2.4-13.8 cm (median, 7.5 cm). Pain was evaluated using the visual analog scale. A decrease of this score by 2 or more after embolization was defined as clinically effective pain relief. Adverse events (AEs) were evaluated using CTCAE v5.0. Objective response, disease control rates, and overall survival were also evaluated. RESULTS: Effective pain relief was achieved in 18 patients (90.0%, 18/20). Grade-3 AEs developed in four patients (20.0%, 4/20): skin ulcer (n=2), skin ulcer and pain (n=1), and muscle weakness with dysesthesia (n=1). No grade-4 or grade-5 AEs developed. Objective response and disease control rates were 26.7% (4/15) and 86.7% (13/15), respectively. The 1-year survival rate was 43.8%, with median survival of 9.2 months (range=0.5-41.0 months). CONCLUSION: Although the survival benefit is equivocal, bland embolization is acceptably safe and useful for relieving pain by controlling tumor growth in patients with painful malignant MSK tumors.

Sodium Valproate Enhances Semaphorin 3A-mediated Anti-angiogenesis and Tumor Growth Inhibition in Human Osteosarcoma Cells.

BACKGROUND/AIM: Class 3 semaphorins, including semaphorin 3A (SEMA3A), are known endogenous angiogenesis inhibitors associated with endothelial cell migration and proliferation, and have been identified in many cancer cells. SEMA3A suppresses tumor angiogenesis by competing with VEGF, but tumors are known to have active angiogenesis, suggesting that expression of SEMA3A and its receptors is epigenetically restrained. To overcome this condition, we aimed to use histone deacetylase (HDAC) inhibitors to enhance the SEMA3A expression in osteosarcoma (OS) cells, thereby suppressing angiogenesis and inhibiting their proliferation and metastasis. MATERIALS AND METHODS: OS cell lines and human microvascular endothelial (HMVE) cells were treated with HDAC inhibitors such as sodium valproate (VPA) and Trichostatin A (TSA). Changes in the SEMA3A expression and its related receptors at the mRNA and protein levels, as well as the inhibitory effects on tumor angiogenesis, were investigated. RESULTS: VPA and TSA increased the expression of SEMA3A and its receptor NRP1, without inducing PLXNA1 in OS cells. Similarly, SEMA3A and NRP1 expression was increased in HMVE cells, but no growth inhibition was observed. Furthermore, SEMA3A induced by VPA in OS cell culture medium inhibited vascular tube formation of HMVE cells, and overexpression of SEMA3A enhanced OS cell growth inhibition. This growth-inhibitory effect of SEMA3A induced G1/S cell cycle arrest in OS cells. CONCLUSION: HDAC inhibitors have anti-angiogenic and anti-tumor activities that may be, in part, mediated via the SEMA3A/NRP1/PLXNA1 autocrine and paracrine pathways.

Osteoscopic versus open surgery for the treatment of enchondroma in the foot.

INTRODUCTION: The conventional treatment of enchondromas is the open surgery with curettage of lesions. Osteoscopic surgery is a minimally invasive endoscopic approach for lesions inside bone. The aim of this study was to evaluate the feasibility of the osteoscopic surgery in comparison with the conventional open surgery for patients with foot enchondromas. MATERIALS AND METHODS: A retrospective cohort study comparing patients with foot enchondromas treated with osteoscopic or open surgery from 2000 to 2019. Functional evaluations were based on both the AOFAS score and the Musculoskeletal Tumor Society (MSTS) functional rate. Complication and local recurrence were evaluated. RESULTS: Seventeen patients underwent endoscopic surgery, and eight patients underwent open surgery. The AOFAS score was higher in the osteoscopic group than the open group at 1 and 2 weeks after surgery (mean, 89.18 vs 67.25 [p = 0.001], 93.88 vs 79.38 [p = 0.004]). The MSTS functional rate was also higher in the osteoscopic group than the open group at 1 and 2 weeks after surgery (mean, 81.96 vs 59.58% [p = 0.00], 90.98 vs 75.00% [p = 0.02]). No statistical differences were found after 1-month of surgery. The osteoscopic group had lower complication rate than the open group (12 vs 50%; p = 0.04). No local recurrence was found in any groups. CONCLUSION: The osteoscopic surgery is feasible to provide earlier functional recovery and fewer complications than the open surgery.

Extraskeletal Myxoid Chondrosarcoma of the Vulva: A Case Report.

Extraskeletal myxoid chondrosarcoma (EMC) of the vulva is extremely rare. We report our experience with a case of disease control by radiation therapy to a localized lesion of EMC. A 41-year-old woman presented to our clinic with a vulvar mass. Magnetic resonance imaging showed a 15 cm mass between the perineum and the medial thigh muscle. It was the "adductor magnus muscle." After the needle biopsy, a histopathological diagnosis of EMC was made. Tissue genomic analysis detected the EWSR1-NR4A3 fusion gene. A joint operation by the Department of Orthopedics, Gynecology, and Plastic Surgery was performed, which included a wide excision of the perineum, partial excision of the medial thigh muscle, and rectus abdominis valvuloplasty. Intraoperatively, pubic infiltration was detected. Postoperative pelvic radiotherapy was administered as adjuvant therapy. Recurrent common iliac lymph node metastases outside the irradiation field and multiple lung metastases were observed. Pazopanib was administered as adjuvant therapy. Pulmonary metastases were controlled, but the pelvic tumor had spread, so the patient underwent radiation therapy. After second-line chemotherapy with doxorubicin, left pleural effusion and mediastinal lymph node metastasis appeared, and third-line chemotherapy with eribulin mesylate was administered. The pleural effusion improved, but the patient developed cough again, and trabectedin was administered as the fourth chemotherapy. In this case, there was no local recurrence for three years after radiotherapy, suggesting the effectiveness of radiotherapy in local control.

Long-term survival following radiofrequency ablation of lung metastases in an elderly patient with calcaneal osteosarcoma: A case report and review of the literature.

RATIONALE: Recently, the number of osteosarcomas has been increasing in elderly patients due to human longevity. Lung metastases are the primary cause of death from osteosarcomas. Complete resection of lung metastases can prolong the survival. However, complete resection in elderly patients is often difficult due to high risk of operative complications. Computed tomography (CT) guided radiofrequency ablation (RFA) is a minimally invasive technique to destroy tumor nodules using heat. In this report, we present the first case older than 65 years applying RFA for lung metastases due to osteosarcoma. PATIENT CONCERNS: A 74-year-old male presented with 1-year history of heel pain. A conventional high-grade osteosarcoma in his calcaneus was diagnosed. Below-knee amputation was performed. However, lung metastases were found in both lungs 1 year after amputation. CT-guided lung RFA was chosen since surgical intervention for lung metastases was abandoned because of tumor multiplicity and medical comorbidities. A total of 18 lung metastases were treated by CT-guided RFA. The most frequent complication was pneumothoraxes in 4 of 8 (50%) procedures and chest tube drainage was required in 2 of these (2 of 8 (25%) procedures). DIAGNOSES: Six lung metastases of osteosaroma were found in both lungs at 1 year after surgery. INTERVENTIONS: CT-guided lung RFA was performed. A total of 18 lung metastases were treated in 8 lung RF procedures. OUTCOMES: The patient has been alive with disease for 5.5 years after the initial surgery. LESSONS: CT-guided lung RFA is effective for elderly patients with osteosarcoma lung metastases in spite of discouragement of lung metastasectomy due to multiplicity of metastases and medical-comorbidities.

Quantitative bone SPECT/CT applications for primary bone neoplasms.

OBJECTIVE: To evaluate the clinical utility of quantitative values obtained with bone single photon emission computed tomography/computed tomography (SPECT/CT) for primary bone neoplasms. SUBJECTS AND METHODS: Bone SPECT/CT scans of 23 patients with 19 benign bone neoplasms (5 osteoid osteomas, 4 bone giant cell tumor, 4 osteofibrous dysplasia, 3 intraosseous ganglion, 2 aneurysmal bone cyst, 1 intraosseous hemangioma) and 5 malignant bone neoplasms (2 osteosarcoma, 1 periosteal osteosarcoma, 1 malignancy in bone giant cell tumor, 1 Ewing sarcoma) were retrospectively analyzed with maximum standardized uptake value (SUVmax), peak SUV (SUVpeak), mean SUV (SUVmean), metabolic bone volume (MBV), and total bone uptake (TBU) of primary lesions. RESULTS: Mean SUVmax of 19 benign and 5 malignant primary bone neoplasms were 6.89±3.26 (range 3.9-15.13) and 10.31±3.19 (5.0-13.45) respectively, with statistically significant difference (P=0.048). Mean SUVpeak of those were 5.87±2.83 (range 3.5-13.63) and 9.18±3.05 (4.09-12.03) respectively, with statistically significant difference (P=0.032). Mean SUVmean of those were 4.43±2.11 (range 2.59-9.37) and 7.13±2.90 (3.3-10.42) respectively, with statistically significant difference (P=0.027). Mean MBV of those were 22.0±30.0 (range 2.47-110.61) and 27.8±39.94 (8.59-99.24) respectively, with no statistically significant difference (P=0.72). Mean TBU of those were 80.64±94.57 (range 10.50-373.57) and 166.60±203.97 (28.68-528.13) respectively, with no statistically significant difference (P=0.17). CONCLUSION: Quantitative values obtained with bone SPECT/CT may serve as osteoblastic biomarkers for primary bone neoplasm.

Programmed cell death 1 positive lymphocytes at palate tonsils in the elder patients with chronic tonsillitis.

Circulating lymphocytes infiltrate into local foci at the inflammatory phase of acute wound healing for activation of the immune system and express an immune checkpoint protein programmed cell death 1 (PD-1) at the resolution phase for inactivation of the immune system. Conversely, the PD-1 expression was still found even on circulating lymphocytes of the elder patients with chronic tonsillitis at the palliative stage. Recently, an adhesion G protein coupled receptor 56 (GPR56) was reported to at least work as a proliferation factor for infiltrated lymphocytes into local foci at the resolution phase of acute wound healing. To preliminary examine a similar role of PD-1 and GPR56 at local foci at chronic inflammation, palate tonsils were prepared from small amounts of patients with chronic tonsillitis and tonsillar hypertrophy. A positive relationship of RNA expression might be observed between PD-1 and GPR56 in the elder patients with chronic tonsillitis. In regard to immunohistopathological findings, there were huge and small amounts of PD-1 and GPR56 expression at the marginal zone of lymphoid follicles of palate tonsils with chronic tonsillitis. Moreover, the positive relationship of RNA expression between PD-1 and GPR56 confirmed in large numbers of the elder patients with chronic tonsillitis. Probably, GPR56 participates in a supplement of PD-1+ lymphocytes to circulating bloods of the elder patients with chronic tonsillitis through a lymphocyte cell maintenance system at the marginal zone of the lymphoid follicles of palate tonsils.

Quantitative Bone Single Photon Emission Computed Tomography/Computed Tomography for Evaluating Response to Bisphosphonate Treatment in Patients with Paget's Disease of Bone.

We here report on 2 cases of monostotic Paget's disease of bone, one in the ilium and the other in the skull, including quantitative values obtained with bone single photon emission computed tomography/computed tomography (SPECT/CT), which were useful to evaluate the response to bisphosphonate treatment. The quantitative parameters determined with those findings were decreased, with the maximum standardized uptake value (SUV), peak SUV, mean SUV, metabolic bone volume, and total bone uptake in case 1 and case 2 reduced by 48.8 and 60.3%, 46.6 and 58.8%, 24.3 and 60.5%, 87.0 and 11.8%, and 90.2 and 55.8%, respectively, while TRACP-5B and alkaline phosphatase (ALP) were also reduced by 39.5 and 88.6% and by 53.7 and 78.1%, respectively. Quantitative SPECT/CT parameter decreases were correlated with TRACP-5B and ALP, indicating the usefulness of this modality to examine treatment response.

Quantitative bone SPECT/CT applications for cartilaginous bone neoplasms.

OBJECTIVE: To evaluate the ability of quantitative values obtained with bone single photon emission computed tomography/computed tomography (SPECT/CT) to differentiate benign from malignant cartilaginous bone neoplasms. SUBJECTS AND METHODS: Bone SPECT/CT scans of 10 patients with 8 benign cartilaginous bone neoplasms (4 enchondromas, 1 periosteal chondroma, 1 osteochondroma, 1 bizarre parosteal osteochondromatous proliferation, 1 chondroblastoma) and 2 malignant cartilaginous bone neoplasms (1 periosteal chondrosarcoma, 1 chondrosarcoma) were retrospectively analyzed with maximum standardized uptake value (SUVmax), mean SUV (SUVmean), metabolic bone volume (MBV), and total bone uptake (TBU) of primary lesions. RESULTS: Mean SUVmax of 8 benign and 2 malignant cartilaginous bone neoplasms were 1.93±1.02 (range 0.59-3.41) and 6.07±0.86 (5.46-6.67), respectively with no overlap (P=0.028). Mean SUVmean of those were 1.24±0.71 (range 0.36-2.36) and 4.05±0.30 (3.84-4.26), respectively with no overlap (P=0.00036). Mean MBV of those were 7.17±4.19 (range 3.17-13.77) and 10.29±10.05 (3.19-17.4), respectively with no significant difference (P=0.74). Mean TBU of those were 9.22±8.31 (range 1.15-23.61) and 43.19±43.7 (12.26-74.13), respectively with no significant difference (P=0.47). CONCLUSION: Standardized uptake value obtained with bone SPECT/CT may be useful to differentiate benign from malignant cartilaginous bone neoplasms, thus helping the orthopedic surgeon towards the most appropriate treatment procedure.

What Factors Are Associated with Treatment Outcomes of Japanese Patients with Clear Cell Chondrosarcoma?

BACKGROUND: Clear cell chondrosarcoma is an extremely rare chondrosarcoma subtype; thus, its treatment outcomes and associated factors have not been widely studied. Knowing more about it is potentially important because clear cell chondrosarcomas are often misdiagnosed as other benign lesions and subsequently treated and followed inappropriately. QUESTIONS/PURPOSES: (1) What are the patient- and tumor-related characteristics of clear cell chondrosarcoma? (2) What proportion of patients with clear cell chondrosarcoma initially had a misdiagnosis or a misleading initial biopsy result? (3) What is the survivorship of patients with clear cell chondrosarcoma free from death, local recurrence, and distant metastasis, and what factors are associated with greater survivorship or a reduced risk of local recurrence? METHODS: Between 1985 and 2018, 12 Japanese Musculoskeletal Oncology Group (JMOG) hospitals treated 42 patients with a diagnosis of clear cell chondrosarcoma. All 42 patients had complete medical records at a minimum of 1 year or death, and were included in this multicenter, retrospective, observational study. No patients were lost to follow-up within 5 years of treatment but four were lost to follow-up greater than 5 years after treatment because their physicians thought their follow-up was sufficient. Clinical data were collected by chart review. The median (range) follow-up period was 69 months (2 to 392). In general, when a possibly malignant bone tumor was found on imaging studies, the histological diagnosis was made by biopsy before initiating treatment. Once the diagnosis had been made, the patients were treated by surgery only, complete resection if technically possible, because chondrosarcomas are known to be resistant to chemotherapy and radiotherapy. Unresectable tumors were treated with particle-beam radiation therapy. When patients with chondrosarcoma were referred after unplanned surgical procedures with inadequate surgical margins, immediate additional wide resection was considered before local recurrence developed. This diagnostic and treatment strategy is common to all JMOG hospitals and did not change during the study period. Primary wide resection was performed in 79% (33 of 42) patients, additional wide resection after initial inadequate surgery in 12% (five of 42), curettage and bone grafting in 5% (two of 42) patients, and radiotherapy was administered to 5% (two of 42). Surgical margins among the 40 patients who underwent surgery at JMOG hospitals were no residual tumor in 93% (37 of 42) of patients, microscopic residual tumor in 2% (one of 42), and macroscopic residual tumor or state after curettage or intralesional excision in 5% (two of 42). The oncological endpoints of interest were 5- and 10- year overall survival, disease-free survival, survival free of local recurrence, and survival free of distant metastases; these were calculated using the Kaplan-Meier method and compared using the log-rank test. Risk ratios with their respective 95% confidence intervals (CIs) were estimated in a Cox regression model. The Bonferroni adjustment was used for multiple testing correction. RESULTS: The sex distribution was 74% men and 26% women (31 and 11 of 42, respectively), with a mean age of 47 ± 17 years. Eighty one percent (34 of 42) of tumors occurred at the ends of long bones, and the proximal femur was the most common site accounting for 60% (25 of 42). The mean size of the primary tumors was 6.3 ± 2.7 cm. Definite pathologic fractures were present in 26% (10 of 42) and another 26% (10 of 42) had extraskeletal involvement. None had metastases at presentation. Twenty four percent (six of 25) tumors in the proximal femur were misdiagnosed as benign lesions and treated inadequately without biopsy. Twenty nine percent (10 of 35) patients had initial misdiagnoses by biopsy and core needle biopsies had a greater risk of resulting in inaccurate histological diagnoses. The study patients' 5- and 10-year overall survival rates were 89% (95% CI 74 to 96) and 89% (95% CI 74 to 96), respectively; 5- and 10- year disease-free survival rates 77% (95% CI 58 to 89) and 57% (95% CI 36 to 75), respectively; 5- and 10-year local recurrence-free survival rates 86% (95% CI 68 to 95) and 71% (95% CI 49 to 86), respectively; and 5- and 10-year distant metastasis-free survival rates 84% (95% CI 67 to 93) and 74% (95% CI 53 to 88), respectively. Notably, bone metastases (17%, seven of 42) were as common as pulmonary metastases (14%, six of 42); four patients developed both bone and pulmonary metastases. The difference between 10-year overall survival rates and 10-year disease-free survival indicated very late recurrence more than 5 years after the initial treatment. After controlling for multiple comparisons, the only factor we found that was associated with local recurrence-free survival was initial treatment (positive margin versus primary wide resection) (risk ratio 8.83 [95% CI 1.47 to 53.1]; p = 0.022 after the Bonferroni adjustment). Additional wide resection reduced the risk of local recurrence. CONCLUSIONS: The femoral head was the most common location of clear cell chondrosarcoma and had a high risk of misdiagnosis as common benign lesions that resulted in initial inadequate surgery and a consequent high risk of local recurrence. Immediate additional wide resection should be considered in patients who had initial inadequate surgery to reduce the risk of local recurrence. Because clear cell chondrosarcoma can recur locally or distantly in the bones and lungs in the long term, patients should be informed of the risk of very late recurrence and the necessity of decades-long with surveillance for local recurrence and lung and bone metastases. LEVEL OF EVIDENCE: Level IV, therapeutic study.

Laparoscopic resection of a dumbbell-shaped lipoma extending through the obturator foramen: A case report.

Lipomas are often lightweight and small in size with few subjective symptoms. Giant lipomas are uncommon. We herein report a case involving a giant, deep-seated dumbbell-shaped intermuscular lipoma in the right thigh that extended into the pelvic region through the obturator foramen and caused obturator neuropathy. A 64-year-old man with numbness while walking was diagnosed with a 17 × 16-cm lipomatous tumor. He underwent radical surgery performed by a multidisciplinary team consisting of orthopedic and colorectal surgeons. High-definition magnified laparoscopic images of the deep pelvis confirmed that tumor had infiltrated the obturator nerve. The tumor was completely resected with the obturator nerve. Six months after surgical resection, the patient had no gait disturbance or evidence of recurrence. The laparoscopic approach for this kind of complicated deep pelvic surgery was safe and feasible when performed by colorectal surgeon with ample knowledge of the pelvic anatomy.

Epigenetic modulators hydralazine and sodium valproate act synergistically in VEGI-mediated anti-angiogenesis and VEGF interference in human osteosarcoma and vascular endothelial cells.

Vascular endothelial growth inhibitor (VEGI; also referred to as TNFSF15 or TL1A) is involved in the modulation of vascular homeostasis. VEGI is known to operate via two receptors: Death receptor­3 (DR3) and decoy receptor­3 (DcR3). DR3, which is thus far the only known functional receptor for VEGI, contains a death domain and induces cell apoptosis. DcR3 is secreted as a soluble protein and antagonizes VEGI/DR3 interaction. Overexpression of DcR3 and downregulation of VEGI have been detected in a number of cancers. The aim of the present study was to investigate the effects of sodium valproate (VPA), a histone deacetylase inhibitor, in combination with hydralazine hydrochloride (Hy), a DNA methylation inhibitor, on the expression of VEGI and its related receptors in human osteosarcoma (OS) cell lines and human microvascular endothelial (HMVE) cells. Combination treatment with Hy and VPA synergistically induced the expression of VEGI and DR3 in both OS and HMVE cells, without inducing DcR3 secretion. In addition, it was observed that the combination of VPA and Hy significantly enhanced the inhibitory effect on vascular tube formation by VEGI/DR3 autocrine and paracrine pathways. Furthermore, the VEGI/VEGF­A immune complex was pulled down by immunoprecipitation. Taken together, these findings suggest that DNA methyltransferase and histone deacetylase inhibitors not only have the potential to induce the re­expression of tumor suppressor genes in cancer cells, but also exert anti­angiogenic effects, via enhancement of the VEGI/DR3 pathway and VEGI/VEGF­A interference.

Expression of p16 in nodular fasciitis: an implication for self-limited and inflammatory nature of the lesion.

Nodular fasciitis (NF) is a self-limited tumorous lesion occurring in the upper as well as lower extremities. NF is composed of a proliferation of "primary culture"-like myofibroblastic cells with nuclear atypia and large nucleoli, thus mimicking sarcoma. NF harbors a promoter-swapping fusion gene containing the entire coding region of USP6 gene. Therefore, NF is a tumor with a fusion oncogene but self-limited. In order to explore why NF is self-limited, we examined whether myofibroblastic cells in NF express p16 protein, a gene product of CDKN2A gene and an inhibitor of cyclin-dependent kinase 4 (CDK4) as well as one of the hallmarks of cellular senescence. We immunohistochemically demonstrated strong and diffuse expression of p16 in myofibroblastic cells in 11 out of 15 cases of NF, and strong but partial expression in the remaining 4 of the cases. We also showed that 15 out of 15 cases of NF were immunohistochemically negative or only showed focal and faint immunopositivity for CDK4, murine double minute 2 (MDM2), and TP53 proteins. Furthermore, there were no significant changes in the copy number of CDKN2A, CDK4 and MDM2 genes, and no significant mutations in TP53, RB1, and CDKN2A genes in 1 case of NF selected. These data suggest a possible involvement in cell cycle arrest and presumed cellular senescence by p16 in myofibroblastic cells in NF. This may explain the self-limited as well as inflammatory nature of NF as a senescence-associated secretory phenotype.

An extremely rare case of primary malignancy in giant cell tumor of bone, arising in the right femur and harboring H3F3A mutation.

We experienced a case of primary malignancy in giant cell tumor of bone (GCTB), arising in the right femur and harboring H3F3A mutation. A 27-year-old Japanese male without any prior disease history complained of pain in his right hip joint and right lower limb. Radiological images revealed an osteolytic and multicystic lesion existing mainly at the proximal epiphysis of the right femur. Preoperative clinical diagnosis was GCTB, although irregular marginal sclerosis was an atypical radiographic finding for conventional GCTBs. Biopsy sample from the lesion revealed the coexistence of typical GCTB and undifferentiated high-grade round cell sarcoma. Despite of the wide local resection of the tumor with preoperative and postoperative chemotherapy, the patient died of multiple distant metastases of the tumor 9 months after the surgery. Since heterozygous H3F3A c. 103G>T (p. Gly34Trp) mutation was detected not only in the biopsy sample from the primary site with typical GCTB and high-grade sarcoma components but also in the resected material from the metastatic site with only pure high-grade sarcoma component, the tumor was considered originally derived from conventional GCTB and acquire malignant transformation to high-grade sarcoma. Thus, this is an extremely rare case of primary malignancy in GCTB and the first case report of primary malignancy in GCTB proved the presence of H3F3A mutation even in the sarcoma component.

Osteoscopic Surgery of Giant Cell Tumor of Bone for Preservation of Proximal Fibula.

BACKGROUND: Osteoscopy is a minimally-invasive endoscopic technique for inspecting lesions inside bone marrow cavities. We describe the feasibility of osteoscopic surgery of giant cell tumor of bone (GCTB) in order to preserve the proximal fibula, and thereby achieve immediate recovery and avoid complications. PATIENTS AND METHODS: Five patients with GCTB in the proximal fibula were treated using osteoscopic curettage with adjuvants (argon plasma coagulation and cementation). Functional outcome was evaluated by knee stability, Musculoskeletal Tumor Society (MSTS) rating, and Tegner score. Oncological outcome was evaluated for local recurrence and pulmonary metastasis. RESULTS: Regarding functional outcome, knee instability was negative in all cases. Mean MSTS rating was 100%. Tegner scores were the same as those prior to surgery. Neither local recurrence nor pulmonary metastasis were found. CONCLUSION: Osteoscopic surgery is feasible for immediate and complete recovery, and can improve quality of life for patients with GCTB of the proximal fibula with satisfactory oncological outcome.

Usefulness of Quantitative Bone Single Photon Emission Computed Tomography/Computed Tomography for Evaluating Response to Neoadjuvant Chemotherapy in a Patient with Periosteal Osteosarcoma.

We report here a case of periosteal sarcoma in a 10-year-old female, along with quantitative values obtained with bone single photon emission computed tomography/computed tomography (SPECT/CT), which were useful to evaluate treatment response to preoperative chemotherapy. Pretreatment radiograph images of the lower leg showed cortical thickening eroded by a broad-based soft-tissue mass without the involvement of the underlying cortex, while computed tomography (CT) revealed a small juxtacortical mass with thick calcification and periosteal reaction. In magnetic resonance imaging (MRI), the mass showed hypointensity in the inner part and isointensity in the outer part in T1-weighted images, while the inner part showed hypointensity and the outer part hyperintensity in T2-weighted images. Bone SPECT/CT results indicated the focal and intense uptake of the mass. Following neoadjuvant chemotherapy (NAC), radiograph and MRI results revealed a slight increase in size, with growing calcification. Although visual inspection of the bone SPECT/CT findings showed nearly the same amount of focal uptake, quantitative parameters determined with those findings were decreased, with maximum standardized uptake value (SUV), peak SUV, mean SUV, metabolic bone volume (MBV), and total bone uptake (TBU) reduced by -20.7%, -22.0%, -12.6%, -33.5%, and -41.9%, respectively. The excision biopsy at the surgery showed a pathological grade 1 (non-complete response) after NAC, including a more than 20% of cell necrosis part. The quantitative bone SPECT/CT was considered to reflect treatment response in this case.

Primary undifferentiated small round cell sarcoma of the deep abdominal wall with a novel variant of t(10;19) CIC-DUX4 gene fusion.

We experienced a 38-year-old Japanese male with t(10;19) CIC-DUX4 -positive undifferentiated small round cell sarcoma in the deep abdominal wall. Three months before his first visit to our hospital, he noticed a mass in his right abdominal wall. Computed tomography on admission revealed a solid abdominal tumor 70×53mm in size and multiple small tumors in both lungs. The biopsy of the abdominal tumor revealed undifferentiated small round cell sarcoma, suggestive of Ewing sarcoma. Under the clinical diagnosis of Ewing-like sarcoma of the abdominal wall with multiple lung metastases, several cycles of ICE (ifosfamide, carboplatin and etoposide) therapy were performed. After the chemotherapy, the lung metastases disappeared, while the primary lesion rapidly grew. Additional VDC (vincristine, doxorubicin and cyclophosphamide) therapy was carried out without apparent effect. Although the surgical removal of the primary lesion was done, peritoneal dissemination and a huge metastatic liver tumor appeared thereafter. The patient died of disease progression two months after the surgery. The total clinical course was approximately one year, showing that the tumor was extremely aggressive. The tumor cells of the surgical specimen were positive for CD99, WT1, calretinin, INI1, ERG and Fli1 by immunohistochemistry. Fusion gene analyses using the frozen surgical material revealed negativity for EWSR1-Fli1, EWSR1-ERG and t(4;19) CIC-DUX4 fusions, but positivity for t(10;19) CIC-DUX4 fusion. Thus, we made a final pathological diagnosis of t(10;19) CIC-DUX4-positive undifferentiated small round cell sarcoma. To our knowledge, this is the 13th case of t(10;19) CIC-DUX4 undifferentiated small round cell sarcoma with precise clinicopathological information. Especially in our case, two types of t(10;19) CIC-DUX4 fusion transcripts were observed, both of which are in-frame and novel.