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Metastatic bone disease is a common complication of malignant tumours. As cancer treatment improves the overall survival of patients, the number of patients with bone metastases is expected to increase. The treatments for bone metastases include surgery, radiotherapy, and bone-modifying agents, with patients with a short expected prognosis requiring less invasive treatment. Patients with metastatic bone disease show greatly varying primary tumour histology, metastases sites and numbers, and comorbidities. Therefore, randomised clinical trials are indispensable to compare treatments for these patients. This editorial reviews recent findings on the diagnosis and prognosis prediction and discusses the current treatment of patients with metastatic bone disease.

Background This systematic review assessed and compared the efficacy of marginal resection to wide resection in patients with atypical lipomatous tumours (ALT) by evaluating the local recurrence rates, overall survival and adverse event rates. Methods We evaluated studies published between 1 January 1990 and 31 January 2019. The risks of bias in the selected studies were analyzed using the Cochrane Collaboration Risk of Bias Tool. The quality of the evidence was evaluated using the Grading of Recommendations, Assessment, Development and Evaluation approach. Results Three case–control studies and three case series studies were identified. A meta-analysis was performed of six studies to evaluate the local recurrence rate after resection. Comparison of marginal and wide resections showed that the local recurrence rate was not significantly higher in the marginal resection group (14.2 and 1.4%, odds ratio: 2.88, 95% confidence interval 0.99–8.33, P = 0.05). We observed no difference in overall survival. In one study, the rates of adverse events were 14.7% in the marginal resection group and 45.4% in the wide treatment group (odds ratio, 0.32; 95% confidence interval 0.11–80.91, P Conclusions In our analyses, five of six studies reported no recurrence for wide resection, compared to three to seven recurrences in the marginal resection group. One study reported only one case of recurrence for wide resection. Because ALT has a relatively good prognosis, the use of marginal resection is acceptable to preserve musculoskeletal function.

In giant cell tumor of bone (GCTB), an intermediate malignant bone tumor, approximately 4% of all cases undergo malignant transformation. Accordingly, we analyzed risk factors for malignant transformation of GCTB treated without radiotherapy. We retrospectively reviewed medical records of 530 patients with GCTB of the extremities, admitted and treated at two institutions between January 1980 and December 2019. Overall, 4 patients with primary malignant GCTB, 4 patients with missing data, 3 patients with a history of radiotherapy, 22 patients with a follow-up of less than 6 months, and 36 patients who received denosumab were excluded. Accordingly, 461 patients were included for further analysis. Malignant transformation was observed in 15 of 461 patients (3.3%) at a median follow-up period of 192 months. The median follow-up duration was 89.4 months. Multivariate analysis revealed that local recurrence was an independent prognostic factor for unfavorable malignant transformation (Hazard ratio [HR], 11.33, 95% confidence interval [CI] 2.33–55.13, p = 0.003 for once versus none and HR, 11.24, 95% CI, 1.76–71.96, and p = 0.011 for twice or more versus none). The interval between the last surgery to local recurrence and malignant transformation was longer than that to local recurrence of benign GCTB, with a median of 15.2 years (interquartile range [IQR], 5.2–25.4) versus 1.3 months (IQR, 0.8–2.6), respectively (p &lt, 0.001). Late local recurrence of GCTB is associated with a higher risk of malignant transformation.

The squat excise is a fundamental movement in athletic training and rehabilitation. In this study, we measured muscle activities in a normal squat posture (NSP) and a squat posture with the center of foot pressure (COP) intentionally shifted forward as far as possible (FSP). Ten healthy men performed double-limb squats, adopting the NSP and FSP, with three knee flexion angles (30, 60, and 90 degrees). The muscle activities of the vastus medialis (VM), semitendinosus (ST), tibialis anterior (TA), and gastrocnemius muscle lateral head (GL) were measured using surface electromyography, and activity patterns were analyzed. Compared to that for the NSP, the COP was significantly shifted forward in the FSP by at least 30% of the foot length for all knee flexion angles (p < 0.05). At all knee flexion angles, VM muscle activity significantly decreased, while GL muscle activity increased, in the FSP compared to that for the NSP (p < 0.05). In addition, ST muscle activity increased significantly in the FSP compared to that for the NSP at knee flexion angles of 30 and 60 degrees (p < 0.05). TA muscle activity significantly decreased in the FSP compared to that for the NSP at only 90 degrees of knee flexion (p < 0.05). These results demonstrate that muscle activity patterns vary significantly according to squat posture. Thus, the active control of the COP position during the squat can be a new training approach in targeting specific muscle groups.

Few studies have examined the relationship between functional outcome and sociooccupational or psychological status in adolescent and young adults (AYA) generation and childhood sarcoma patients. We retrospectively analyzed clinical (prognostic and functional) and sociooccupational outcomes in 50 patients; 22 children aged under 14 years and 28 AYAs generation (15 to 29 y). There were 35 cases of bone sarcomas and 15 of soft tissue sarcomas. Limb-sparing surgery was performed in 30 of 37 extremity cases. The most prevalent problems among patients were as follows: limited activities; drop-out or delayed studies among high school and college students; limitation in job searching; and changes in social relationships. These problems were unaffected by limb-sparing. Regression analysis between functional and sociooccupational disability showed that the correlation coefficient was significant (P=0.005) in all limb-salvaged patients, but there was no significant correlation among osteosarcoma patients (P=0.07). These findings suggest that quality of life is a multidimensional measure: it depends on physical status, spiritual health, and social well-being of both patients and family members. To overcome the disadvantages of this type of disease, it is essential to provide comprehensive care at the earliest convenience using multidimensional approaches.

We reviewed the recent literature related to primary musculoskeletal tumors and metastatic bone tumors. With regard to primary bone tumors, computer navigation systems and three-dimensional-printed prostheses seem to be new treatment options, especially in challenging anatomical locations, such as the sacrum and pelvis. Regarding the treatment of giant cell tumor of bone, recent studies have suggested that denosumab administration is related to a higher local recurrence rate following curettage, but a lower local recurrence rate following en bloc resection. In addition, there was no difference in the local recurrence rate at five years after surgery between short-term and long-term denosumab therapy. With regard to soft tissue tumors, percutaneous cryoablation appears to be a new treatment option for extra-abdominal desmoid tumors, with encouraging results. Regarding soft tissue sarcomas, a negative surgical margin of

Introduction The options for the reconstruction of diaphyseal defects following the resection of bone tumors include biological or prosthetic implants. The purpose of our study was to evaluate different types of intercalary reconstruction techniques, including massive bone allograft, extracorporeal devitalized autograft, vascularized free fibula, and modular prosthesis. Methods We performed a systematic review of articles using the terms diaphyseal bone tumor and intercalary reconstruction. All the studies reporting the non-oncological complications such as infection, nonunion and fracture of the intercalary reconstructions were included. We excluded articles published before 2000 or did not involve humans in the study. Case reports, reviews, technique notes and opinion articles were also excluded based on the abstracts. Thirty-three articles included in this review were then studied to evaluate failure rates, complications and functional outcome of different surgical intercalary reconstruction techniques. Results Nonunion rates of allograft ranged 6%–43%, while aseptic loosening rates of modular prosthesis ranged 0%–33%. Nonunion rates of allograft alone and allograft with a vascularized fibula graft ranged 6%–43% and 0%–33%, respectively. Fracture rates of allograft alone and allograft with a vascularized fibula graft ranged 7%–45% and 0%–44%, respectively. Infection rates of allograft alone and allograft with a vascularized fibula graft ranged 0%–28% and 0%–17%, respectively. All of the allograft (range: 67%–92%), extracorporeal devitalized autograft including irradiation (87%), autoclaving (70%), pasteurization (88%), low-heat (90%) or freezing with liquid nitrogen (90%), and modular prosthesis (range: 77%–93%) had similar Musculoskeletal Tumor Society functional scores. Addition of a vascularized fibula graft to allograft did not affect functional outcome [allograft with a vascularized fibula graft (range: 86%–94%) vs. allograft alone (range: 67%–92%)]. Conclusion Aseptic loosening rates of modular prosthesis seem to be less than nonunion rates of allograft. Adding a vascularized fibula graft to allograft seems to increase bone union rate and reduce the risk of fractures and infections, though a vascularized fibula graft needs longer surgical time and has the disadvantage of donor site morbidity. These various intercalary reconstruction techniques with or without a vascularized fibula autograft had similar functional outcome.

BackgroundThis study compared the clinical and functional outcomes of patients initially treated with observation or medical treatment with those of patients treated with local treatment (surgery alone or surgery with adjuvant radiotherapy) to confirm whether observation or medical treatment is an appropriate first-line management approach for patients with desmoid tumors.MethodsWe retrospectively reviewed the medical records of 99 patients with histologically confirmed primary desmoid tumors treated between 1978 and 2018. The median follow-up period was 57 months. We evaluated event-free survival, defined as the time interval from the date of initial diagnosis to the date of specific change in treatment strategy or recurrence or the last follow-up.ResultsAn event (specific change in treatment strategy or recurrence) occurred in 28 patients (28.3%). No significant difference in event-free survival was found between the first-line observation/medical treatment and local treatment groups (p= 0.509). The median Musculoskeletal Tumor Society score of the patients treated with first-line local treatment was 29 (interquartile range [IQR], 23–30), whereas that of the patients managed with first-line observation or medical treatment was 21 (IQR, 19–29.5). First-line observation or medical treatment was more frequently chosen for larger tumors (p= 0.045). In the patients treated with local treatment, local recurrence was not related to the surgical margin (p= 0.976).ConclusionUpfront surgery is not advantageous compared to more conservative treatments such as observation or medical treatment for patients with desmoid tumors.

Pterostilbene (PTE) is a natural sterbenoid contained in blueberries that has an antioxidant effect. In contrast, PTE also generates oxidative stress in cancer cells and provides an antitumor effect. Here, we examined the potential mechanism of this contrasting effect of PTE using three gastrointestinal cancer cell lines, namely CT26, HT29, and MKN74. PTE showed a dose-dependent inhibition of cell proliferation, sphere-forming ability, and stem cell marker expression in all three cell lines. Furthermore, the cells treated with PTE showed an increase in mitochondrial membrane potential and an increase in mitochondrial oxidative stress and lipid peroxide. Upon concurrent treatment with vitamin E, N-acetyl-L-cysteine, and PTE, the PTE-induced mitochondrial oxidative stress and growth inhibition were suppressed. These findings indicate that PTE induces oxidative stress in cancer cells, suppresses stemness, and inhibits proliferation. These antitumor effects of PTE are considered to be useful in cancer treatment., 博士（医学）・甲第821号・令和4年3月15日, © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).

Patients with Werner syndrome present with diverse signs of aging that begin in adolescence. A Japanese nationwide survey was conducted to establish a registry that could clarify the disease profile of patients with Werner syndrome. The questionnaires were sent to 7888 doctors. The survey identified 116 patients diagnosed with Werner syndrome based on the diagnosis criteria. Forty patients were enrolled in the registry. Data on clinical symptoms, treatment information, and laboratory examination from patients who provided informed consent were collected. The data at enrollment were analyzed. The patients' average age at enrollment was 50.1±7.5 years. The mean onset age was 26.1±9.5 years, but the mean age at diagnosis was 42.5±8.6 years. Average height and weight of the study patients were lower than those of Japanese individuals. Almost all patients experienced hair change and cataracts. More than 60% of patients presented with glycolipid abnormalities. Overall, 15% of patients had a history of foot amputation. Approximately 30% of the patients' parents had a consanguineous marriage. The average grip strength, walking speed, and skeletal muscle mass index met the diagnostic criteria for sarcopenia. The registry revealed that there are opportunities for early diagnosis and intervention; therefore, sensitization about the disease is needed.

Approximately one-fourth of osteosarcoma patients have metastases at presentation. The best treatment options for these patients include chemotherapy, surgery, and radiotherapy; however, the optimal scheme has not yet been defined. Standard chemotherapy for osteosarcoma metastatic at presentation is based on high-dose methotrexate, doxorubicin, and cisplatin (the MAP regimen), with the possible addition of ifosfamide. Surgical treatment continues to be fundamental; complete surgical resection of all sites of disease (primary and metastatic) remains essential for survival. In patients whose tumors do not respond to neoadjuvant chemotherapy, early surgical resection of the primary tumor with limb-salvage surgery or amputation and multiple metastasectomies, if feasible, after the completion of adjuvant chemotherapy is a reasonable option, as the reduction of the tumor volume could probably increase the effect of chemotherapy. Advanced radiotherapy techniques, such as carbon ion radiotherapy and stereotactic radiosurgery, and molecular targeted chemo-therapy with drugs such as pazopanib or apatinib have improved the dismal prognosis, especially for patients who are medically inoperable or who refuse surgery. Given that the presence of metastatic disease at diagnosis of a patient with osteosarcoma is a poor prognostic factor, a multidisciplinary approach by surgeons, medical oncologists, and radiotherapists is important. [ Orthopedics . 2020;43(5):e345–e358.]

Background Neoplastic spinal cord compression is a cause of severe disability in cancer patients. To prevent irreversible paraplegia, a structured strategy is required to address the various impairments present in cancer patients. In this study, we aimed to identify the status where rehabilitation with minimally invasive spine stabilization (MISt) effectively improves ADL. Methods We retrospectively reviewed 27 consecutive patients with neoplastic spinal compression who were treated with MISt. We classified the impairments of patients through our multidisciplinary tumor board based on spine-specific factors, skeletal instability, and tumor growth. The neurological deficits, progress of pathological fracture, incidence of vertebral collapse, and postoperative implant failure were examined. Changes of the Barthel index (BI) scores before and after surgery were investigated throughout the clinical courses. Results The average duration to ambulation was 7.19 ± 11 days, and we observed no collapse or progression of paralysis except in four cases of complete motor paraplegia before the surgery. Neurological deficiency was improved to or maintained at Frankel’s grade E in 16 patients, remained unchanged in 6 patients (in grades B, C, D), and worsened in 5 patients. BI score comparisons before and after surgery in all patients showed statistically significant increments (p < 0.05). On further analysis, we noted good functional prognosis in patients capable of ambulation within 7 days (p < 0.05) and in patients who could survive longer than 3 months after the surgery (p < 0.05). Conclusions In various cancer patients with neoplastic spinal cord compression, skeletal instability as the primary impairment is a good indication for MISt, as the patients showed early ambulation with improved BI scores.

BackgroundThe outcomes of patients with lung metastases from giant cell tumor of bone (GCTB) vary from spontaneous regression to uncontrolled growth. To investigate whether observation is an appropriate first-line management approach for patients with lung metastases from GCTB, we evaluated the outcomes of patients who were initially managed by observation.MethodsWe retrospectively reviewed the data of 22 patients with lung metastases from histologically confirmed GCTB who received observation as a first-line treatment approach. The median follow-up period was 116 months.ResultsDisease progression occurred in 12 patients (54.5%). The median interval between the discovery of lung metastases and progression was 8 months. Eight patients underwent metastasectomy following initial observation. The median interval between the discovery of lung metastases and treatment by metastasectomy was 13.5 months. None of the patients experienced spontaneous regression. Of the 22 patients, 36.4% needed a metastasectomy, and 9.1% required denosumab treatment during the course of the follow-up period. Disease progression occurred in 45.5% of the 11 patients with lung nodules ≤ 5 mm, while all five of the patients with lung nodules > 5 mm experienced disease progression. Progression-free survival was significantly worse in the group with lung nodules > 5 mm compared to the group with lung nodules ≤ 5 mm (p= 0.022).ConclusionsObservation is a safe first-line method of managing patients with lung metastases from GCTB. According to radiological imaging, approximately half of the patients progressed, and approximately half required a metastasectomy or denosumab treatment. However, patients with lung nodules > 5 mm should receive careful observation because of the high rate of disease progression in this group.

Background: The outcome of lung metastases in patients with giant cell tumor of bone (GCTB) varies from spontaneous regression to uncontrolled growth. To investigate whether observation is an appropriate first-line management for patients with lung metastases from GCTB, we compared the outcomes of patients initially treated with observation with those treated with metastasectomy.Methods: We retrospectively reviewed the data of 29 patients with lung metastases from histologically confirmed GCTB. The median follow-up period was 114 months. We evaluated progression-free survival, which was defined as the time from the date of occurrence of lung metastases to the date of disease progression in the observation or incomplete metastasectomy group, disease recurrence in the complete metastasectomy group, or the last follow-up.Results: Disease progression or recurrence occurred in 14 patients (48.3%). Progression-free survival did not vary significantly between the observation and metastasectomy groups (p=0.373). The total number of metastasectomies was significantly higher in the initial metastasectomy group than in the observation group (p=0.017).Conclusions: The number of patients included in this study is small, however the data suggests that observation can be used safely as first-line management for patients with lung metastases from GCTB with an outcome similar to that of metastasectomy. It is necessary to confirm our result in multi-institutional study with sufficient number of patients.

Cancer rehabilitation addresses the functional needs of patients who have various impairments. Disease control is a critical oncological consideration, while physical intervention increased weights of importance in several situations. To identify the clinical status that necessitates active physical intervention in cancer patients with skeletal metastasis, we performed a content analysis in the multidisciplinary tumor board (MDTB) records. From January 2017 to September 2019, the MDTB discussed 168 consecutive patients with skeletal metastasis. We reviewed the MDTB records and asked responsible physicians to frame clinical questions. Based on these data, we identified the predictor valuables with the association to rehabilitation-related clinical questions using univariate and multivariate analyses. Moreover, we investigated a predictor of the change in Barthel index (BI) scores using univariate analyses. Rehabilitation-related questions arose more frequently in older patients (p = 0.011), in patients with slow-growth vs. rapid-growth tumor (p = 0.002), and in patients with skeletal-related events (p = 0.001) at MDTB. The tumor growth speed was associated with the change in BI scores, as slower-growth tumors had the benefit of BI gains (p = 0.017). Regarding rehabilitation in patients with skeletal metastasis, we should pay attention to three parameters: occurrence of skeletal events, patient age, and growth speed of tumors. Rehabilitation-related questions may reflect patients’ functional needs that occur more frequently in patients with pathological fractures or neurological symptoms, older patients, and patients with slow-growth tumors.

Background: Neoplastic spinal cord compression is a cause of severe disability in cancer patients. To prevent irreversible paraplegia, a structured strategy is required to address the various impairments present in cancer patients. Methods: We retrospectively reviewed 27 consecutive patients with neoplastic spinal compression who were treated with minimally invasive spine stabilization (MISt). We classified the impairments of patients through our multidisciplinary tumor board based on spine-specific factors, skeletal instability and tumor growth. The neurological deficits, ambulation status, progress of pathological fracture, incidence of vertebral collapse, postoperative implant failure were examined. Changes of the Barthel index (BI) scores before and after surgery were investigated throughout the clinical courses. Results: The average duration to ambulation was 7.19±11 days, and we observed no collapse or progression of paralysis except in four cases of complete motor paraplegia before the surgery. We noted good functional prognosis in patients capable of ambulation within seven days and in patients who could survive longer than three months after the surgery. Conclusions: In various cancer patients with neoplastic spinal cord compression, skeletal instability as the primary impairment is a good indication for MISt, as the patients showed early ambulation with improved BI scores.

Despite the evolution in imaging, especially the introduction of advanced imaging technologies, radiographs still are the key for the initial assessment of a bone tumor. Important aspects to be considered in radiographs are the location, shape and size or volume, margins, periosteal reaction, and internal mineralization of the tumor's matrix; careful evaluation of these may provide for accurate diagnosis in >80% of cases. Computed tomography and magnetic resonance imaging are often diagnostic for lesions with typical findings such as the nidus of osteoid osteoma and bone destruction such as in Ewing sarcoma and lymphoma that may be difficult to detect with radiographs; they may also be used for surgical planning. Magnetic resonance imaging accurately determines the intraosseous extent and articular and vascular involvement by the tumor. This article summarizes the diagnostic accuracy of imaging analyses in bone tumors and emphasizes the specific radiographic findings for optimal radiographic diagnosis of the patients with these tumors.

Differentiation of malignant from benign soft tissue tumors is challenging with imaging alone, including that by magnetic resonance imaging and computed tomography. However, the accuracy of this differentiation has increased owing to the development of novel imaging technology. Detailed patient history and physical examination remain essential for differentiation between benign and malignant soft tissue tumors. Moreover, measurement only of tumor size based on Response Evaluation Criteria In Solid Tumors criteria is insufficient for the evaluation of response to chemotherapy or radiotherapy. Change in metabolic activity measured by 18F-fluorodeoxyglucose positron emission tomography or dynamic contrast enhanced-derived quantitative endpoints can more accurately evaluate treatment response compared to change in tumor size. Magnetic resonance imaging can accurately evaluate essential factors in surgical planning such as vascular or bone invasion and “tail sign”. Thus, imaging plays a critical role in the diagnosis and treatment of soft tissue tumors.

There are conflicting reports regarding the outcome and effect of denosumab for distal radius giant cell tumor of bone (GCTB). The authors performed this study to evaluate the behavior of distal radius GCTB in relation to the type of treatment and the administration of denosumab. The files of 72 patients with distal radius GCTB treated from 1984 to 2018 were reviewed. Fourteen patients were administered denosumab. Surgical treatment consisted of curettage (25 patients) or resection (47 patients) and allograft or vascularized fibular head graft reconstruction. Median follow-up was 63.1 months (interquartile range [IQR], 35.5–107.1 months). The authors evaluated local recurrences, metastasis, function, and complications. The local recurrence rate was 30.6% at a median of 14.0 months (IQR, 10–19 months), with no difference between curettage and resection. The local recurrence rate was significantly higher in the patients who received denosumab. The metastasis rate was 9.7% at a median of 41.0 months (IQR, 15–114 months), with no difference regarding denosumab administration. Function was significantly better in patients after curettage. The complication rate was 25%; vascularized fibular graft reconstruction was associated with fewer complications. This study found that denosumab increases the risk of local recurrence after curettage, function is better after curettage, and vascularized fibular graft is the optimal reconstruction after resection of distal radius GCTB. [ Orthopedics . 2020;43(5):284–291.]

This study aimed to clarify the role of mesenchymal stem cells (MSCs) as a component of the cancer microenvironment. We investigated the homing-related chemokine expression levels of MSCs treated with a prostate cancer cell line (PC-3) -conditioned medium. Among several homing chemokines, an antibody array revealed that expression of eotaxin-3 (but not eotxin-1 and -2) was highly enhanced in MSCs treated with PC-3-conditioned medium. A gene expression array showed significantly increased expression of CCR3, a receptor of eotaxin-3, in PC-3. In a matrigel invasion assay, interferon-gamma, a specific inhibitor of eotaxin-related homing, significantly reduced the transmigration of PC-3 cells, under co-cultured condition with MSCs, in a dose-dependent manner (P 0.05). Consistent with these results, anti-CCR3 antibody successfully reduced PC-3 migration under the co-cultured condition. These findings suggest that MSCs to modulation of the invasive potential of prostate cancer cells via the eotaxin-3/CCR3 axis.

Purpose: There are conflicting reports on the effect of denosumab on lung metastases in patients with giant cell tumor (GCT) of bone. To address these reports, we performed this study to determine if denosumab prevents lung metastasis and to evaluate univariate and multivariate predictors for lung metastases in these patients. Materials and methods: We retrospectively studied 381 GCT patients with surgery alone and 30 GCT patients with surgery and denosumab administration. The median follow-up was 85.2months (IQR, 54.2–124.4months). We evaluated lung metastases and local recurrences, univariate and multivariate predictors for lung metastases, response, and adverse events of denosumab administration. Results: The occurrence of lung metastases was similar (surgery alone 4.7%, 18 patients; denosumab administration 3.3%, 1 patient); however, the occurrence of local recurrences was significantly higher in the patients with denosumab administration. Denosumab administration was not an important predictor for lung metastases; Campanacci stage and type of surgery were the only univariate predictors for lung metastases, and type of surgery and local recurrence were the only multivariate predictors for lung metastases. Histology showed viable tumour in all tumor specimens of the patients with denosumab administration. Conclusion: Denosumab does not decrease the risk of lung metastases in patients with bone GCT; the only important predictors for lung metastases in these patients are type of surgery and local recurrence. However, because the number of patients with lung metastases was small for a multivariate analysis, the possibility of denosumab’s effect could not be completely eliminated.

Background: Recent clinical studies have suggested that denosumab is associated with tumor response and reduced surgical morbidity in patients with giant-cell tumor of bone (GCTB). We therefore evaluated the recurrence-free survival rate of patients who had GCTB in an extremity and were treated with surgery and denosumab, to determine the influence of denosumab and clinical factors on the risk of local recurrence. Methods: We retrospectively reviewed the medical records of 408 patients treated for GCTB in an extremity in a single institution from 1990 through 2013. Two hundred and forty-seven patients underwent curettage (intralesional surgery) with a high-speed burr, and 161 underwent resection. Phenol adjuvant was used in 221 of the 247 patients who had curettage. We also reviewed the medical records of 30 patients treated surgically (25 with curettage and 5 with resection) and with denosumab from 2010 through 2013 and compared their clinical results with 378 historical control subjects. The overall minimum duration of follow-up was 24 months. Results: The local recurrence rates were 60% (15) of 25 patients treated with curettage and denosumab and 16% (36) of 222 patients treated with curettage alone. The joint preservation rates were 80% (20) of 25 patients treated with curettage and denosumab and 94% (209) of 222 patients treated with curettage alone. Univariate and multivariable analyses showed that denosumab was the only independent factor associated with a poor prognosis when recurrence-free survival and joint preservation were considered. The overall median duration of follow-up was 85.6 months (interquartile range, 54.3 to 125.1 months). Viable tumor was present in all 30 specimens from patients treated with denosumab. Conclusions: There was a higher rate of recurrence in the cohort exposed to denosumab. Because there were substantial differences in the cohorts and randomization was not applied, however, causation could not be evaluated. Level of Evidence: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Simple Summary The effect of adjuvant chemotherapy on localized malignant giant cell tumors of the bone (GCTB) is unclear. We compared the mortality associated with wide resection compared to wide resection plus adjuvant chemotherapy for localized primary and secondary localized malignant GCTB. Among 745 relevant studies, 9 were included, with 39 and 73 primary and secondary malignant patients. In primary localized malignant GCTB, the mortality rates were 40% (6/15 patients) and 33% (8/24 patients) in the surgery plus adjuvant chemotherapy and surgery-only groups, respectively. The overall pooled odds ratio was 1.07 (p = 0.92). In secondary localized malignant GCTB, the mortality rates were 30.6% (11/36 patients) and 62.2% (23/37 patients) in the surgery plus adjuvant chemotherapy and surgery-only groups, respectively. The overall pooled odds ratio was 0.31 (p = 0.04). The effect of adjuvant chemotherapy remains unclear for primary localized malignant GCTB, but adjuvant chemotherapy improved the survival of patients with secondary localized malignant GCTB. Abstract A malignant giant cell tumor of the bone (GCTB) is a rare primary malignant tumor classified as primary or secondary. Wide resection of the primary tumor is recommended for localized malignant GCTB, but the effect of adjuvant chemotherapy is unclear. A systematic review was performed to compare the mortality associated with wide resection with that of wide resection plus adjuvant chemotherapy for primary and secondary localized malignant GCTB. Among the 745 studies identified, 9 were included. A total of 112 cases of localized malignant GCTB were included, with 39 and 73 cases being primary and secondary malignant GCTB. In primary localized malignant GCTB, the mortality rates were 40% (6/15 patients) and 33% (8/24 patients) in the surgery plus adjuvant chemotherapy and surgery-only groups, respectively. Overall pooled odds ratio was 1.07 (95% confidence interval, 0.26–4.37; p = 0.92). In secondary localized malignant GCTB, the mortality rates were 30.6% (11/36 patients) and 62.2% (23/37 patients) in the surgery plus adjuvant chemotherapy and surgery-only groups, respectively. The overall pooled odds ratio was 0.31 (95% confidence interval, 0.10–0.95; p = 0.04). The effect of adjuvant chemotherapy remains unclear for primary localized malignant GCTB, but adjuvant chemotherapy improved the survival of patients with secondary localized malignant GCTB.

Isometric bodyweight squats are fundamental exercises in athletic training and rehabilitation. Previously, we measured muscle activity in a normal squat posture (NSP) and a squat posture with the center of foot pressure (COP) intentionally shifted forward as far as possible (forward-shifted posture: FSP), and the muscle activity patterns varied significantly according to the COP location. This study focused on stepwise loading as a training strategy. Ten healthy male participants performed isometric bodyweight squats in a previous study, adopting the NSP and FSP, with three knee flexion angles (30°, 60°, and 90°). The muscle activities of the vastus medialis (VM), semitendinosus, tibialis anterior (TA), and gastrocnemius muscle lateral head were measured using surface electromyogram. This study further explored the relationship between COP shifting and knee flexion angles on electromyogram changes using three-dimensional diagrams. In one-way repeated measures analysis of variance by ranks, knee flexion angles affected the muscle activities of the VM and TA in the NSP and muscle activities of the VM in the FSP. Combining these findings, stepwise loading tasks were created to train individual target muscles. The ten male participants examined all the tasks, and the feasibility was confirmed accordingly.

Simple Summary According to the 2020 World Health Organization classification, a giant cell tumor of bone is an intermediate malignant bone tumor. Denosumab treatment before curettage should be avoided due to the increased risk of local recurrence. Administration of denosumab before en bloc resection of the giant cell tumors of the pelvis and spine facilitates en bloc resection. Nerve-sparing surgery after embolization is a possible treatment for giant cell tumors of the sacrum. Denosumab therapy with or without embolization is indicated for inoperable giant cell tumors of the pelvis, spine, and sacrum. A wait-and-see approach is recommended for lung metastases at first, then denosumab should be administered to the growing lesions. Radiotherapy is not recommended owing to the risk of malignant transformation. Local recurrence after 2 years or more should be indicative of malignant transformation. This review summarizes the treatment approaches for non-malignant and malignant giant cell tumors of bone. Abstract The 2020 World Health Organization classification defined giant cell tumors of bone (GCTBs) as intermediate malignant tumors. Since the mutated H3F3A was found to be a specific marker for GCTB, it has become very useful in diagnosing GCTB. Curettage is the most common treatment for GCTBs. Preoperative administration of denosumab makes curettage difficult and increases the risk of local recurrence. Curettage is recommended to achieve good functional outcomes, even for local recurrence. For pathological fractures, joints should be preserved as much as possible and curettage should be attempted. Preoperative administration of denosumab for pelvic and spinal GCTBs reduces extraosseous lesions, hardens the tumor, and facilitates en bloc resection. Nerve-sparing surgery after embolization is a possible treatment for sacral GCTBS. Denosumab therapy with or without embolization is indicated for inoperable pelvic, spinal, and sacral GCTBs. It is recommended to first observe lung metastases, then administer denosumab for growing lesions. Radiotherapy is associated with a risk of malignant transformation and should be limited to cases where surgery is impossible and denosumab, zoledronic acid, or embolization is not available. Local recurrence after 2 years or more should be indicative of malignant transformation. This review summarizes the treatment approaches for non-malignant and malignant GCTBs.

Malignant transformation of giant cell tumor of bone (GCTB) without radiotherapy exposure is exceptionally rare, occurring in less than 1% of GCTBs. The safety and efficacy of denosumab in patients with GCTB was recently reported. We herein report a case of a benign recurrent GCTB with an H3F3A mutation that underwent secondary malignant transformation during treatment with denosumab. A 29-year-old woman underwent curettage of a GCTB of the left ischium in 2005. Ten years after the first surgery, the GCTB recurred locally. We started treatment with denosumab. During the first 5 months of treatment, we observed a demarcated area of osteosclerosis in the recurrent lesion, and the patient's clinical condition improved. At 6 months, however, the patient developed pain, and a rapidly growing mass was detected by computed tomography. An incisional biopsy was performed. Histologic analysis showed a high-grade osteosarcoma. The patient developed lung metastases and died soon after beginning chemotherapy. The mechanism of sarcomatous transformation of GCTB during denosumab therapy is unclear. These findings suggest that the scientific community should be aware of the possible malignant transformation of GCTB during denosumab treatment.

Background Endoscopic laryngopharyngeal surgery (ELPS) was developed for superficial pharyngeal cancers in Japan. In this study, we present our results of ELPS for superficial pharyngeal cancers. Methods From November 2009 to December 2015, 258 patients with superficial pharyngeal cancers underwent ELPS. Results, including survival rates, postoperative complications, and vocal function, are reviewed. Results The median follow-up period of 258 patients was 31 months. The overall and cause-specific survival rates over 3 years were 85.7% and 100%, respectively. Only 3 patients incurred local recurrences and were successfully salvaged by re-ELPS. Regarding postoperative complications, 4 patients required reoperation because of postoperative bleeding. As for the postoperative quality of life, no patients developed vocal fold paralysis. Every patient was able to consume meals at preoperative levels. Conclusion ELPS is a feasible and minimally invasive treatment for superficial pharyngeal cancers with impressive quality of life results.

Recent clinical studies have suggested that denosumab is associated with beneficial tumour response, surgical down-staging, and reduced surgical morbidity in patients with giant cell tumour of bone. However, these studies reported results of patients still on denosumab treatment, or patients after denosumab treatment but with a short follow-up. Other studies reported that the new osseous tumour matrix and thickened cortical bone that develop with denosumab treatment does not allow the surgeon to delineate the true extent of the tumour, and probably increases the risk for local recurrence. A study showed that cell proliferation is only diminished by denosumab; the cells continue to proliferate in vitro, albeit at a slower rate. More importantly, nine cases of malignant transformation of GCT during denosumab therapy without previous radiation exposure have been reported; inhibition of RANKL may increase the risk of new malignancies due to immunosuppression. With these concerns in mind, this article is an attempt to put essential information in one place, creating a comprehensive review that the curious reader would find interesting and informative.

Introduction: The purpose of our study is to verify possible clinical and radiological findings with regard to distinguishing enchondroma from atypical cartilaginous tumour (ACT). In addition, this study determined risk factors that are associated with local recurrence of enchondroma or ACT treated with curettage. Materials and methods: We retrospectively reviewed the records of 54 patients with enchondroma and 35 patients with ACT of the long bones treated by curettage between 1986 and 2015. The minimum follow-up was 18 months. The relationship between clinical and radiological factors and the tumour type or local recurrence was assessed using Chi-square test or Fischer exact test. Results: Endosteal scalloping (p = 0.004) and soft tissue extension (p = 0.017) were shown to statistically favour ACT over enchondroma; by contrast, pain (p = 0.034) was more frequent in enchondroma compared to ACT. All patients with enchondroma had no local recurrence; in contrast, local recurrence occurred in four patients with ACT (11%). Soft tissue extension (p = 0.049) and the diagnosis of ACT (p = 0.021) were associated with an increased risk of local recurrence. We had a disease progression in three of four patients with local recurrence, and these had higher histological grade than the original tumour. Discussion: Our data show that endosteal scalloping and soft tissue extension could be helpful in the differential diagnosis between enchondroma and ACT. We suggest following only those patients with ACT after surgery to identify any possible recurrence and, in case of recurrence, treat these patients with resection for the risk of disease progression.

Backgrounds: Recently, several studies have demonstrated the usefulness of cold polypectomy (CP), a safe and simple method for the removal of small polyps. We investigated the safety and efficacy o...

We reviewed the files of 203 patients with extremities GCTB treated with curettage as first surgery from 1990 to 2013. Median follow-up was 84.2 months. We evaluated whether the years of practice and training in orthopaedic oncology are associated with local recurrences, function and complications after curettage as first surgery for giant cell tumour of bone (GCTB). Local recurrences were not significantly different between orthopaedic oncology trained and non-trained orthopaedic surgeons and between orthopaedic surgeons with

Background There are conflicting reports for the outcome of the patients with giant cell tumor of bone (GCTB) and pathological fracture at presentation treated with curettage or resection. This study compared local recurrence, complications, and function after curettage versus resection for these patients. Materials and methods We retrospectively studied the files of 46 patients with histologically confirmed GCTB of the extremities admitted and treated from 1982 to 2015. The median follow-up was 79.5 months (57.0-125.5 months). We evaluated local recurrence and type of surgery-related complications with imaging and function with the Musculoskeletal Tumor Society (MSTS) score. Results Overall local recurrence was 6.5%. There were one patient with curettage and two patients with resection; local recurrence rate was similar between the two procedures but the time to local recurrence was shorter after curettage. MSTS score was significantly better after curettage. Complications occurred in two patients after curettage and in five patients after resection; because of the low number of patients with complications, a statistical comparison was not possible; however, by direct comparison of the numbers, complications were more common after resection compared with curettage. Conclusion Curettage is recommended for GCTB and pathological fracture at presentation because of similar local recurrence but better function compared with resection. The treating physicians should be aware and inform their patients for a shorter time to local recurrence after curettage and for more complications after resection.

Purpose: To compare and discuss the gender disparities in the Orthopaedic specialty.Methods: We reviewed the literature to find the rates of women applying for an orthopaedic residency, fellowship, and academic career program, to understand the causes of the disparities in women in orthopaedics, and how this relates to orthopaedic surgical practice.Results: The idea that men and women are different and have different working styles and skills and the belief that males are more dominant and more status-worthy than females leads to gender barriers and stereotypes that restrict women from entering male-dominated specialties. It is important to mention that equivalent barriers restrict men from pursuing female-dominated specialties such as Gynecology. Economic disparities and gender stereotypes that divide medical specialties into masculine and feminine, creating a gender gap in health care are major concerns. However, the number of women in the health sector is expected to increase due to the growing amount of female students that are expected to soon graduate. A leadership gender gap also exists; although women consist of 70% of the health care workforce they occupy only 25% of leadership positions.Conclusion: The existence of gender-based disparities in healthcare is multifactorial. The explanation behind the existence of a so-called gender gap lies in organizational and individual factors. Early development and family relations, the decision between work and life balance, personal choices and interests, as well as working conditions, absence of role models and mentorship and institutional policies make gender disparities even more evident.

Evidence is limited regarding the immunologic profile and immune microenvironment of soft tissue sarcoma subtypes. The aim of the present study was to describe the clinical significance and prognostic implications of PD-L1, PD-L2, and PD-1 in patients with retroperitoneal sarcoma (RSar). In this retrospective, multicenter, collaborative study, medical charts were reviewed and the immunohistochemical staining results of resected tissue specimens from 51 patients with RSar were examined. Immunohistochemical staining was performed with primary antibodies against PD-L1, PD-L2, PD-1, and Ki-67. The correlations between the baseline clinical parameters and expression levels of the four molecules in sarcoma cells were evaluated, and their prognostic values after tumor resection were assessed. Dedifferentiated liposarcoma (41%), leiomyosarcoma (20%), and undifferentiated pleomorphic sarcoma (16%) were the three major types identified. Dedifferentiated liposarcoma and leiomyosarcoma showed higher levels of PD-L1 expression than did other sarcomas. The Spearman correlation analysis revealed that baseline serum lactate dehydrogenase levels were moderately and positively correlated with PD-L1 (P=0.02, r=0.41) and PD-L2 (P=0.006, r=0.47) expression. The median recurrence-free and disease-specific survival was 58 and 16 months, respectively, during the 29-month median follow-up after surgery. On univariate analysis, a higher expression level of PD-1 was associated with a higher risk of recurrence, whereas multivariate analyses revealed that independent predictors of recurrence-free and disease-specific survival indicated a high expression of Ki-67 (P=0.03; hazard ratio, 2.29 vs. low expression) and prognostic stage IIIB (P=0.04; hazard ratio, 5.11 vs. stage I-II), respectively. Findings of the current study provide novel insights about the prognostic value of PD-L1, PD-L2, and PD-1 expression in RSar. Serum lactate dehydrogenase levels constitute a potential predictor of PD-L1 and PD-L2 expression levels in RSar. Further investigations are needed to determine the immunologic landscape of RSar and provide a foundation for therapeutic intervention using immune checkpoint inhibitors.

Extraskeletal osteosarcoma (ESOS) is a very rare form of primary osteosarcoma that is histologically characterized by tumorous osteoid production with no association with bone. ESOS accounts for less than 5% of all osteosarcoma and 1% of all soft-tissue tumor. The prevalence of ESOS in the upper limbs is approximately 20% and only five cases of ESOS of the hand have been reported. To achieve curative surgical margin for hand sarcomas, amputation is essential for certain cases, and ESOS is not exceptional. Although adjuvant chemotherapy and radiotherapy remain controversial in the treatment of ESOS, because of the hand’s functional importance, adjuvant therapies with surgery should be considered. We report a case of ESOS of the hand treated successfully with marginal resection and subsequent adjuvant chemotherapy and radiotherapy. The function of the affected hand was satisfactorily preserved and no evidence of relapse occurred for 46 months from the initial diagnosis. In this case report, we reviewed the previous reports of ESOS, namely, five cases of ESOS of the hand, and even though the role of adjuvant chemo- and/or radio-therapy remains controversial, we propose that marginal resection with adjuvant chemo- and radio-therapy are recommended for ESOS of the hand to achieve satisfactory oncological and functional outcome.

Last and second name of an author have been mixed up. It shows Piergiuseppe as the last name, but his second name is Tanzi and the first name is Piergiuseppe.

Giant cell tumor (GCT) of the soft tissue (GCT-ST) is a rare, unusual primary soft tissue tumor that is completely distinct from, and should not be confused with, any giant cell–rich tumor of bone or soft tissue. Currently, GCT-ST is included in the group of so-called fibrohistiocytic tumors of intermediate (borderline) malignancy. The most common symptom is a painless, slow-growing mass in a superficial location. Computed tomography and magnetic resonance imaging show a solid, nonhomogeneous, frequently hemorrhagic mass. Differential diagnosis is broad and should include benign and malignant entities. The treatment and excision margins of GCT-ST are controversial. Incomplete surgical excision is usually followed by local recurrence. Biological behavior is unpredictable. Giant cell tumor of the soft tissue has shown a lower mean local recurrence rate compared to GCT of bone but has a higher metastatic and death rate. Therefore, close clinical follow-up is recommended. [ Orthopedics . 2019; 42(4):e364–e369.]

Malignant granular cell tumors are an extremely rare, high-grade sarcoma with a schwannian phenotype and are composed of malignant granular cells with cytoplasmic lysosomal inclusion. To date, 157 cases of malignant granular cell tumors have been reported. We report the first case of a malignant granular cell tumor arising from the digital nerve to the median nerve in the palm, and we review the 157 previously reported cases and summarize the clinical profile, treatment, and outcome of this tumor. The median age, tumor size, and follow-up periods were 51 years, 6 cm, and 24 months respectively. With respect to the oncological result, 53 patients (33.8%) had no evidence for disease, 31 (19.7%) were alive with the disease, and 51 (32.5%) died because of the disease. Our case report indicates that rare malignant tumors can arise from the digital nerve to the median nerve in the palm, an anatomical site that is usually affected by benign lesions. Exhaustive discussions between surgeons and pathologists are necessary for the treatment of this rare malignant tumor.

Ubiquilin 2 (UBQLN2), a member of the ubiquitin-like protein family (ubiquilins), maintains protein homeostasis. Although UBQLN2 has been implicated in the pathogenesis of neurodegenerative diseases, it is also associated with malignant tumors. Therefore, we examined whether UBQLN2 plays a role in human osteosarcoma. The human osteosarcoma cell line MG63 was transfected with UBQLN2 siRNA and cultured under hypoxic conditions. The rat osteosarcoma cell line COS1NR was inoculated into Fischer 344 rats, followed by injection of UBQLN2 siRNA with atelocollagen. An immunohistochemical analysis of UBQLN2 was performed using 34 cases of human high-grade osteosarcomas, and metastasis-free survival was estimated by the Kaplan-Meier method. Silencing of UBQLN2 by siRNA transfection under hypoxia led to activation of JNK and p38, resulting in induction of apoptosis in the osteosarcoma cell line MG63. Injection of UBQLN2 siRNA suppressed tumor growth in the rat osteosarcoma model, followed by apoptosis induction. The immunohistochemical examination revealed that high UBQLN2 expression was significantly associated with the unfavorable metastasis-free survival of osteosarcoma patients. UBQLN2 plays an important role in resistance to hypoxic stress and enhances tumor progression in osteosarcoma. UBQLN2 may be a new molecular target for chemotherapeutics and a useful clinicopathological marker in human osteosarcoma.

The treatment of giant cell tumor (GCT) of bone remains controversial. Intralesional surgery (curettage) results in a higher rate of local recurrence, but better functional results compared to resection. The aim of this study was to assess whether the use of curettage was successful in the treatment of GCT of long bones. We evaluated the influence of adjuvant treatment, local tumor presentation, and demographic factors on the risk of recurrence. We retrospectively reviewed the records of patients treated for GCT of long bones between 1990 and 2013, using curettage. No patient had any treatment other than surgery. After detailed curettage, the bone cavity was filled with bone allografts and/or cement. Recurrence rates, risk factors for recurrence and the development of pulmonary metastases were determined. The minimum follow-up was 24 months. We enrolled 210 patients with GCT of long bones treated by curettage. The rate of local recurrence was 16.2% (34/210 patients). The median follow-up was 89.2 months. In the multivariate analysis, no significant statistical effect on the local recurrence rate could be identified for gender, patient’s age, Campanacci’s grading, or cement versus bone allografts. The only independent risk factor related to the local recurrence was the site, with a statistically significant higher risk for patients with GCT of the proximal femur. Our observation on the correlation of tumor location and risk of local recurrence is new. We suggest that patients with GCT of bone in the proximal femur should be followed closely soon after surgery to identify any possible recurrence.

Extraskeletal mesenchymal chondrosarcoma is rare and metastasis to the pancreas is extremely rare, with only four cases reported in the literature. The therapeutic effectiveness of chemotherapy remains uncertain. We report a 39-year-old man with extraskeletal mesenchymal chondrosarcoma of the buttock, who had metastases to the pancreas, bones, and lung. He underwent distal pancreatectomy, resection of the buttock tumor, and chemotherapy. He had a good response to chemotherapy and survived for about 3 years after surgery.

Extra-axial chordoma is a chordoma that occurs in non-axial locations. It is a very rare tumor, with 20 cases reported to date; 14 in bone and six in soft tissue. Of the 14 skeletal extra-axial chordomas, ten were intramedullary and four were intracortical. We report the first case of parosteal extra-axial chordoma arising in the second metacarpal bone, expressing brachyury on immunohistochemical analysis, and describe the pathologic and radiologic findings. We suggest that extra-axial chordoma can occur in parosteal bone lesions or the hand, without features of bone distribution or bone-specific sites.