Response rate specific to bone metastasis of various cancers for immune checkpoint inhibitors: a systematic review.

PURPOSE: Immune checkpoint inhibitors (ICIs) have improved the prognosis of patients with cancer, such as melanoma, renal cell carcinoma, head and neck cancer, non-small cell lung cancer (NSCLC), and urothelial carcinoma. The extension of life expectancy has led to an increased incidence of bone metastases (BM) among patients with cancer. BM result in skeletal-related events, including severe pain, pathological fractures, and nerve palsy. Surgery is typically required for the treatment of BM in patients with an impending fracture; however, it may be avoided in those who respond to ICIs. We systematically reviewed studies analyzing BM responses to treatment with ICIs. METHODS: This study was conducted in accordance with the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-analyses 2020 statement and registered in the UMIN Clinical Trials Registry (ID: UMIN000053707). Studies reporting response rates based on the Response Evaluation Criteria in Solid Tumors (RECIST) or the MD Anderson Cancer Center (MDA) criteria specific for BM in patients treated with ICIs were included; reports of fewer than five cases and review articles were excluded. Studies involving humans, published in English and Japanese, were searched. The PubMed, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) databases were searched. Ultimately, nine studies were analyzed. The Risk of Bias Assessment tool for Non-randomized Studies was used to assess the quality of studies. RESULTS: Based on the MDA criteria, complete response (CR) or partial response (PR) was observed in 44-78% and 62% patients treated with ICIs plus denosumab for NSCLC and melanoma, respectively. According to the RECIST, CR or PR was recorded in 5% and 7-28% of patients treated with ICIs for renal cell carcinoma and urothelial carcinoma, respectively. CONCLUSION: Although response rates to ICIs for BM are poor, patients treated with ICI plus denosumab for bone metastases with impending fractures from NSCLC and melanoma are likely to avoid surgery to prevent fractures.

A reduction in tumor volume exceeding 65% predicts a good histological response to neoadjuvant chemotherapy in patients with Ewing sarcoma.

OBJECTIVE: No consensus exists for tumor volume response criteria in patients with Ewing sarcoma. This study aimed to identify an optimal cutoff for predicting a good histological response by analyzing tumor volume changes and tumor necrosis after neoadjuvant chemotherapy. MATERIALS AND METHODS: We performed a retrospective analysis of 184 Ewing sarcoma patients, analyzing tumor volume changes before and after neoadjuvant chemotherapy. Patients were divided into two groups based on histological response: good (tumor necrosis ≥ 95%) and poor (tumor necrosis < 95%) responders. The receiver operating characteristic (ROC) area under the curve (AUC) method was used to determine the optimal thresholds for predicting the histological response. Additionally, the prognostic value of this cutoff for relapse-free survival was assessed. RESULTS: Out of 184 patients, 83 (45%) had tumor necrosis ≥ 95%, while 101 (55%) had tumor necrosis < 95%. ROC analysis identified the optimal cutoff for a good histological response as over 65% tumor volume reduction (AUC = 0.69; p < 0.001). Patients with volume reduction of ≥ 65% had a higher likelihood of a good histological response than those with lesser reductions (p = 0.004; odds ratio = 2.61). Multivariable analysis indicated a correlation between poor histological response and reduced relapse-free survival (hazard ratio = 2.17; p = 0.01), while tumor volume reduction itself did not impact survival. CONCLUSION: We reported that a tumor volume reduction of ≥ 65% was able to predict a good histological response in Ewing sarcoma patients. We recommend preoperative tumor volume assessment to identify patients at greater risk for poor histological response who could benefit from more intensive chemotherapy protocols or additional radiotherapy.

Malawer type I/V proximal humerus reconstruction after tumor resection: a systematic review.

BACKGROUND: Several reconstruction methods exist for Malawer type I/V proximal humerus reconstruction after bone tumor resection; however, no consensus has been reached regarding the preferred methods. METHODS: We conducted a literature search on various types of proximal humerus oncologic reconstruction methods. We collected data on postoperative functional outcomes assessed based on Musculoskeletal Tumor Society (MSTS) scores, 5-year reconstruction survival rates, and complications. We calculated each reconstruction's weighted mean based on the sample size and standard errors. Complications were categorized based on the Henderson classification. Based on these integrated data, our primary objective is to propose an optimal strategy for proximal humerus reconstruction after bone tumor resection. RESULTS: We examined various reconstruction techniques, including modular prosthesis (752 patients in 21 articles), osteoarticular allograft (142 patients in 6 articles), allograft prosthesis composites (APCs) (236 patients in 12 articles), reverse shoulder total arthroplasty (141 patients in 10 articles), composite reverse shoulder total arthroplasty (33 patients in 4 articles), claviculo-pro-humero (CPH) technique (51 patients in 6 articles), and cement spacer (207 patients in 4 articles). Weighted mean MSTS scores were: modular prosthesis (73.8%), osteoarticular allograft (74.4%), APCs (79.2%), reverse shoulder total arthroplasty (77.0%), composite reverse shoulder total arthroplasty (76.1%), CPH technique (75.1%), and cement spacer (69.1%). Weighted 5-year reconstruction survival rates were modular prosthesis (85.4%), osteoarticular allograft (67.6%), APCs (85.2%), reverse shoulder total arthroplasty (84.1%), and cement spacer (88.0%). Reconstruction survival data was unavailable for composite reverse shoulder total arthroplasty and CPH technique. Major complications included shoulder joint instability: modular prosthesis (26.2%), osteoarticular allograft (41.5%), APCs (33.9%), reverse shoulder total arthroplasty (17%), composite reverse shoulder total arthroplasty (6.1%), CPH technique (2.0%), and cement spacer (8.7%). Aseptic loosening of the prosthesis occurred: modular prosthesis (3.9%) and reverse shoulder total arthroplasty (5.7%). Allograft fracture was observed in 54.9% of patients with osteoarticular allograft. CONCLUSION: The complication profiles differed among reconstruction methods. Weighted mean MSTS scores exceeded 70% in all methods except cement spacer, and the 5-year reconstruction survival rate surpassed 80% for all methods except osteoarticular allograft. Proximal humerus reconstruction after bone tumor resection should consider potential complications and patients' individual factors.

Risk of complications and implant survival of surgical treatment of proximal femoral metastasis: a meta-analysis.

PURPOSE: The patients with femoral metastasis in the inter- or subtrochanteric area could be treated with intramedullary nailing or prosthetic reconstruction, however, it is controversial which surgical treatment could offer less complications and implant failure. Our purpose was to define the risk of complications and implant survival in patients treated with intramedullary nailing or prosthetic reconstruction. METHODS: We analyzed studies reporting the risk of complications, reoperations and removal of the implant in patients treated with intramedullary nailing, hemiarthroplasty, arthroplasty or megaprosthesis. RESULTS: We analyzed 27 studies (1346 patients) reporting patients treated with intramedullary nail (51%), hemiarthroplasty (15%), arthroplasty (2%), megaprosthesis with (25%) or without (7%) acetabular component. No difference was found in the overall risk of complications between patients treated with intramedullary nailing 6%, hemiarthroplasty or total hip arthroplasty 7% and megaprosthesis 11% (p = 0.23). However, patients treated with megaprosthesis had increased risk of reoperation due to infection (70%), compared to the patients treated with intramedullary nail (13%), and patients treated with hemiarthroplasty or total hip arthroplasty (23%) (p = 0.02). Revision due to disease progression was required in 61% of the patients treated with intramedullary nail, but not in patients treated with hemiarthroplasty, total arthroplasty, and megaprosthesis (p = 0.03). CONCLUSION: Patients treated with megaprosthesis had higher risk of reoperation due to infection, while patients treated with intramedullary nailing had higher risk of revision due to disease progression. Regarding patients treated with megaprosthesis, the risk of reoperation due to dislocation was higher in those treated with acetabular component.

Predicting Trabectedin Efficacy in Soft Tissue Sarcoma: Inflammatory Biomarker Analysis.

BACKGROUND/AIM: Trabectedin is used as a treatment for advanced-stage soft tissue sarcomas (STSs), particularly liposarcoma and leiomyosarcoma. Aside from its direct effect on tumor cells, trabectedin can affect the immune system in the tumor microenvironment. This study aimed to evaluate whether inflammatory biomarkers predict trabectedin efficacy in STSs. PATIENTS AND METHODS: We retrospectively reviewed the clinical features and outcomes of patients with STS treated with trabectedin at our institution between 2016 and 2020. The neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), platelet-to-lymphocyte ratio (PLR), and systemic inflammation response index (SIRI=neutrophil × monocyte/lymphocyte) were calculated based on the blood samples obtained prior to trabectedin treatment initiation. Analyses of overall survival (OS) and progression-free survival (PFS) were performed according to various factors. RESULTS: Of the 101 patients identified, 54 had L-sarcoma (leiomyosarcoma: 30; liposarcoma: 24), and 47 had other types of STSs. Elevated SIRI, NLR, PLR, LMR, and C-reactive protein (CRP) were associated with worse PFS (p<0.001, p=0.008, p=0.027, p=0.013, and p<0.001, respectively) according to the results of the univariate analysis. Multivariate analysis showed that elevated SIRI, other histology, and CRP were associated with poor PFS (p=0.007, p=0.008, and p=0.029, respectively). In addition, the multivariate analysis of OS showed that SIRI was an independent prognostic factor (hazard ratio=2.16, p=0.006). CONCLUSION: Pretreatment SIRI can be considered a biomarker for the prognostic prediction of patients with STS treated with trabectedin.

Histological and imaging features of myoepithelial carcinoma of the bone and soft tissue.

OBJECTIVE: To depict histological and imaging features of myoepithelial carcinoma of the bone and soft tissue. MATERIALS AND METHODS: We retrospectively examined histological features in 22 patients with myoepithelial carcinoma of the bone (4 patients) and soft tissue (18 patients) at a single institution. Imaging analysis of 15 patients (bone, 3 patients; soft tissue, 12 patients;) with preoperative images involved classifying lytic bone lesions via the modified Lodwick-Madewell classification; the growth patterns of soft tissue lesions were classified as well-defined, focally invasive, or diffusely invasive. RESULTS: Local recurrence occurred in eight out of 22 patients (36.3%). Four of 22 patients (18.2%) had metastasis at presentation, whereas 11 of 22 patients (50.0%) had distant metastasis during follow-up. Severe cytological pleomorphism was observed in 14 of 22 patients (63.6%), and 10 of 22 tumors (45.5%) showed ≥ 10 mitoses/10 high-power fields. Vascular invasion was observed in 10 of 22 patients (45.5%). Extracapsular/extraskeletal infiltration into the surrounding tissues was assessed in 20 patients, with 14 of them (70%) showing infiltration beyond the tumor border. Regarding imaging of bone lesions, two patients had Ludwick type IIIB, whereas one patient had type II. The growth pattern of soft tissue lesions was well-defined in two patients (16.7%), focally invasive in seven patients (58.3%), and diffusely invasive in three (25.0%) out of 12 patients. CONCLUSION: Myoepithelial carcinoma of the bone and soft tissue presents high risk of local recurrence and distant metastasis. Histological and imaging features might be important to understand the aggressive behavior of the tumor.

Incidence of skeletal-related events in patients with Ewing sarcoma: An observational retrospective study in Japan.

BACKGROUND: Skeletal-related events (SREs), including the pathological fracture, surgical treatment or radiation of bone lesions, malignant spinal cord compression, hypercalcemia, are important considerations when managing metastatic bone tumors; however, owing to their rarity, the incidence of SREs in patients with Ewing sarcoma remains unknown. METHODS: We retrospectively reviewed the clinical data from 146 patients with Ewing sarcoma treated at a single institution from 2005 to 2019. The median age at diagnosis was 22.7 years. Fifty patients (34.2%) had metastatic disease at diagnosis. The primary outcome was the SRE-free rate among patients with Ewing sarcoma. Moreover, we identified the risk factors for SREs using univariate or multivariate analyses. RESULTS: During the observational period (median, 2.6 years), SREs occurred in 23 patients. Radiation to the bone, malignant spinal cord compression, and hypercalcemia were documented as the initial SREs in 12 patients (52.2%), 10 patients (43.5%), and one patient (4.3%), respectively. The SRE-free rate was 94.2 ± 2.0, 87.3 ± 3.0, and 79.6 ± 3.8% at 1, 2, and 3 years after the initial visit, respectively. Multivariate analysis revealed bone metastasis at diagnosis (hazard ratio [HR] = 4.41, p = 0.007), bone marrow invasion (HR = 34.08, p < 0.001), and local progression or recurrence after definitive treatment (HR = 3.98, p = 0.012) as independent risk factors for SREs. CONCLUSIONS: SREs are non-rare events that can occur during the treatment course for Ewing sarcoma, with an especially high incidence of malignant spinal cord compression. Patients with metastatic disease at diagnosis, especially in the bone or bone marrow, or with local progression or recurrence after definitive treatment, should be carefully monitored for the occurrence of SREs. The most effective methods to monitor the occurrence of SREs and new preventative therapies for SREs should be investigated in the future.

Similar complications, implant survival, and function following modular prosthesis and allograft-prosthesis composite reconstructions of the proximal femur for primary bone tumors: a systematic review and meta-analysis.

PURPOSE: There is a lack of consensus regarding the best type of reconstruction of the proximal femur following bone tumor resection. The objective of this study was to analyze the complication risks, implant survival, and functional outcomes following modular prosthesis (MP) and allograft-prosthesis composite (APC) reconstruction of the proximal femur after primary bone tumor resections. METHODS: We performed a search in the PubMed and Scopus libraries, obtaining 1 843 studies. We included studies reporting functional outcomes, complications, and implant survival of proximal femur reconstruction with MP or APC following primary bone tumor resection with a 2-year minimum follow-up. We excluded studies analyzing metastatic patients or studies with pooled data in which it was impossible to separate the data of patients with primary bone tumors from those with bone metastases. RESULTS: We analyzed 18 studies (483 patients) reporting on 234 (48%) patients with MP reconstruction and 249 (52%) patients with APC reconstruction. The risk of complications was similar in patients with MP reconstruction (29%; 95% CI [0.11; 0.47]) and APC reconstruction (36%; 95% CI [0.24; 0.47]) (p = 0.48). Implant survival following MP reconstruction ranged from 81 to 86% at 5 years, 75 to 86% at 10 years, and 82% at 15 years. Implant survival following APC reconstruction ranged from 86 to 100% at 5 years and 86% at 10 years, and 86% at 15 years. Functional outcomes following MP reconstruction and APC reconstruction ranged from 24.0 to 28.3 and from 21.9 to 27.8, respectively. CONCLUSION: Patients with primary bone tumor of the proximal femur who underwent MP or APC reconstruction seem to have similar complication risks, implant survival, and functional outcomes.

What Is the Revision-free Survival of Resurfaced Allograft-prosthesis Composites for Proximal Humerus Reconstruction in Children With Bone Tumors?

BACKGROUND: Reconstruction of the proximal humerus in children who undergo bone tumor resection is challenging because of patients' small bone size and possible limb length discrepancy at the end of skeletal growth due to loss of the physis. There are several options for proximal humerus reconstruction in children, such as clavicula pro humero, free vascularized fibula grafting, massive bone osteoarticular allografting, endoprostheses, and allograft-prosthesis composites, but no consensus exists on the best method for reconstruction. Resurfaced allograft-prosthesis composites could be an alternative surgical option, but little is known about the results of this surgical technique. QUESTIONS/PURPOSES: (1) What are the complications and what is the survivorship free from reconstruction failure associated with resurfaced allograft-prosthesis composites in a small, single-center case series? (2) What Musculoskeletal Tumor Society scores do patients achieve after reconstructions with resurfaced allograft-prosthesis composites? METHODS: This study was a retrospective, single-arm case analysis in a single institution. We generally considered resurfaced allograft-prosthesis composites in children with malignant bone tumors involving the metaepiphysis of the proximal humerus in whom there was no evidence of joint contamination and in whom axillary nerve preservation was possible. Between 2003 and 2021, we treated 100 children (younger than 15 years) with bone tumors of the humerus. Thirty children (30%) with diaphyseal tumors (21 children) or distal tumors (9 children) were excluded. Among the potentially eligible children, 52 were not analyzed because they were treated with other procedures such as amputation, modular prostheses, cement spacers, free vascularized fibula grafting, and massive bone osteoarticular allografts. We included 18 children (26% of the potentially eligible children) who were treated with resurfaced allograft-prosthesis composites. There were 9 boys and 9 girls, with a median age of 10 years (range 4 to 15 years) at the time of diagnosis. A long stem (≥ 6 cm) in the resurfaced allograft-prosthesis composite was used in 9 children and a short stem (< 6 cm) was used in the remaining 9. One of the 18 children had a follow-up of less than 2 years. The median follow-up of the remaining 17 children was 4.7 years (range 2 to 19 years). The children' medical records were reviewed for clinical and functional outcomes. We performed a competing risk analysis to calculate the reconstruction failure-free survival of resurfaced allograft-prosthesis composites. Reconstruction failure was defined as removal of the implant or allograft because of implant loosening or breakage and allograft fracture or resorption. We analyzed the children's postoperative complications and functional outcomes at the end of the follow-up period using the Musculoskeletal Tumor Society functional scoring system. RESULTS: The competing risk analysis revealed that reconstruction failure was 25% (95% confidence interval 7% to 40%) at 3 years, reaching a plateau. Four of 18 children underwent surgical revision with a new reconstruction. The reasons for reconstruction revision were resorption of the allograft at the proximal part (2 children) and fracture of the allograft (2 children). Reconstruction revision was performed in 3 of 9 children who underwent reconstruction with a short stem and in 1 of 9 children who underwent reconstruction with a long stem. Several children had other complications that did not result in removal of the allograft. Allograft resorption was observed in 4 of 18 children, but no additional surgical treatment was performed. Shoulder instability or subluxation was observed in 4 of 18 children, but only 1 child underwent surgery with a reverse shoulder arthroplasty without removal of the resurfaced allograft-prosthesis composite. Limited elbow motion because of plate impingement was observed in 1 child who underwent surgical cutting of the protruding distal part of the plate. Incomplete radial nerve palsy after surgery occurred in 1 child, with spontaneous resolution after 2 months. Screw loosening occurred in 2 children who underwent surgery with removal of loose screws. Two children had a nonunion at the graft-host bone junction; 1 child underwent surgery with bone grafting and refixation of the graft-host bone junction, and the other child with both nonunion and plate breakage was treated with bone grafting and refixation of the graft-host bone junction with a new plate. Among 17 children who had a follow-up longer than 2 years, the median Musculoskeletal Tumor Society functional score at the last follow-up interval was 23 of 30 (range 20 to 26); 1 child was considered to have an excellent result (functional score ≥ 26), 15 children were considered to have a good result (functional score 21 to 25), and 1 child was considered to have a fair result (functional score ≤ 20). The Musculoskeletal Tumor Society functional score did not change after excluding 4 children who underwent replacement of resurfaced allograft-prosthesis composites (24 of 30 [range 20 to 26]). The median angle of flexion of the shoulder was 40° (range 20º to 90°), and the median angle of abduction was 30° (range 20º to 90°). CONCLUSION: Resurfaced allograft-prosthesis composites showed a high risk of complications, but not all complications resulted in removal of the reconstructed allograft. We used this technique mainly for very young children with small bones and for older children who underwent axillary nerve preservation. Although its success may be limited owing to a high risk of complications, a resurfaced allograft-prosthesis composite could be an alternative surgical option in order to preserve the bone stock and achieve good functional outcomes in very young children. We recommend using a long-stem resurfaced allograft-prosthesis composite, which may reduce the risk of complications. LEVEL OF EVIDENCE: Level IV, therapeutic study.

Reoperation after surgery for bone metastasis of renal cell carcinoma.

BACKGROUND AND OBJECTIVE: The prognosis of metastatic renal cell carcinoma (RCC) has markedly improved with the advent of molecular targeted therapies and immune checkpoint inhibitors. However, the therapeutic response in patients with bone metastasis remains low; therefore, surgery still plays a significant role in treatment of bone metastasis. It is important to maintain quality of life for patients with bone metastasis from RCC and avoid reoperation after surgery for bone metastasis. Therefore, we investigated the risk factors for reoperation after surgery in patients with bone metastasis from RCC. METHODS: We retrospectively studied 103 bones of 97 patients who underwent surgery for bone metastasis of RCC from 2001 to 2023 at our institutions. RESULTS: Reoperation was performed in 10 (9.7%) of 103 bones. There was no correlation between reoperation-free survival and any of the following variables: preoperative and postoperative radiotherapy, site of bone metastasis, indication for surgery (solitary bone metastasis or impending or pathologic fractures), surgical method (intramedullary nailing fixation, curettage, or en bloc resection), preoperative embolization, or survival. CONCLUSION: The risk of reoperation for bone metastasis of RCC does not appear to be based on the surgical method.

Diagnostic challenges in low-grade central osteosarcoma.

Aims: Low-grade central osteosarcoma (LGCOS), a rare type of osteosarcoma, often has misleading radiological and pathological features that overlap with those of other bone tumours, thereby complicating diagnosis and treatment. We aimed to analyze the clinical, radiological, and pathological features of patients with LGCOS, with a focus on diagnosis, treatment, and outcomes. Methods: We retrospectively analyzed the medical records of 49 patients with LGCOS (Broder's grade 1 to 2) treated between January 1985 and December 2017 in a single institute. We examined the presence of malignant features on imaging (periosteal reaction, cortical destruction, soft-tissue invasion), the diagnostic accuracy of biopsy, surgical treatment, and oncological outcome. Results: Based on imaging, 35 of 49 patients (71.4%) exhibited malignant features. Overall, 40 of 49 patients (81.6%) had undergone a biopsy before en-bloc resection: 27 of 40 patients (67.5%) were diagnosed on the first biopsy, which was more accurate when carried out by open rather than needle biopsy (91.3% vs 35.3% diagnostic accuracy, respectively; p < 0.001). Of the 40 patients treated by en-bloc resection, surgical margins were wide in 38 (95.0%) and marginal in two (5.0%). Furthermore, nine of 49 patients (18.4%) underwent curettage (intralesional margin) without previous biopsy. All patients with a positive margin developed local recurrence. Distant metastases occurred in five of 49 patients (10.2%). The mean five-year overall survival (OS) and distant relapse-free survival (D-RFS) were 89.3% (SD 5.1%) and 85.7% (SD 5.5%), respectively. Univariate analysis showed that the occurrence of distant metastasis was a poor prognostic factor for OS (hazard ratio 11.54, 95% confidence interval (CI) 1.92 to 69.17; p < 0.001). Local recurrence was a poor prognostic factor for D-RFS (HR 8.72, 95% CI 1.69 to 45.0; p = 0.002). Conclusion: The diagnosis of LGCOS can be challenging because it may present with non-malignant features and has a low diagnostic accuracy on biopsy. If precisely diagnosed, LGCOS can be successfully treated by surgical excision with wide margins.

Myoepithelial carcinoma of soft tissues and bone.

AIM: Myoepithelial carcinoma occurs mainly in salivary glands but rarely can also occur in soft tissues or bone. In this paper, we evaluated the role of surgical margins, radiotherapy, and chemotherapy in myoepithelial carcinoma of soft tissue and bone (MC-SB) treated at our Institute. METHODS: Medical records of 33 patients presenting with MC-SB between 1998 and 2015 at our institution were retrospectively analysed, and diagnosis and treatment were studied. RESULTS: The median follow-up was 58.5 months. Twenty patients had tumours originating in soft tissues and 13 in bone. Eight patients (24.2%) had metastases at diagnosis, the remaining 25 had localised disease. Thirty-two underwent resection of the primary lesion. In 29 surgical margins were evaluated: wide in 28 with 10/28 who recurred (35.7%) and marginal resection in 1 who also recurred. Six patients received adjuvant radiotherapy. Metastases developed in 15/25 patients (60%) with localised disease at onset. Chemotherapy was administered in patients with metastatic advanced disease. Cisplatin+doxorubicin was administered in six patients as first-line chemotherapy with an objective response in 5/6 patients with a median 4-month duration. Five-year overall survival rate was 62.6% in patients with localised tumours and 12.5% in those metastatic at diagnosis. CONCLUSIONS: MC-SB showed a high incidence of local recurrences and metastases. Despite different chemotherapy regimens, the outcome remains poor in patients with metastatic disease. Due to the absence of a standard protocol, we encourage treatment by multidisciplinary teams in referral centres with renowned expertise.

Multiple Bone Cysts Caused by Hyperparathyroidism: A Case Report and Review of the Literature.

Background: Brown tumor, a skeletal complication of severe hyperparathyroidism, comprises reparative granulation tissue and proliferating fibrous tissue with hemosiderin deposition. Multiple brown tumors are extremely rare complications of primary hyperparathyroidism. Case Report: A 41-year-old woman presented with pain in the left knee. Radiography showed multiple cystic lesions in both femurs and the left proximal tibia, and additional radiography showed multiple cystic lesions in the left humerus and ulna. Magnetic resonance imaging (MRI) revealed multiple cystic lesions in the bilateral femurs, left proximal tibia, and ilium. Laboratory tests revealed hypercalcemia (albumin-corrected calcium level, 13.9 mg/dl), hypophosphatemia (phosphate level, 1.6 mg/dl), elevated level of alkaline phosphatase level (614 U/l), and markedly elevated parathyroid hormone (PTH) level (1,070 pg/ml; normal range=10-65 ng/l). 99mTc-hexakis-2-methoxyisobutyl-isonitrile scintigraphy revealed tracer accumulation in the left upper parathyroid gland, which was consistent with parathyroid tumor. Although resection of the parathyroid tumor was planned, the patient developed parathyroid apoplexy before tumor excision. After the parathyroid apoplexy, serum calcium and PTH levels temporarily normalized. Resurgence of the PTH level was observed 2 years after the diagnosis, and the patient underwent left upper parathyroidectomy. One year after the tumor excision, the patient had no symptoms, and MRI showed shrinkage of the cystic bone lesions. Conclusion: This report emphasizes the importance of considering hyperparathy-roidism as a differential diagnosis for patients with multiple bone lesions.

Special Issue: "Pediatric Orthopedic Malignancy: Types, Symptoms, and Treatment".

Pediatric orthopedic malignancies are extremely rare and require appropriate diagnosis and treatment by a multidisciplinary team [...].

What Are the Complications, Function, and Survival of Tumor-devitalized Autografts Used in Patients With Limb-sparing Surgery for Bone and Soft Tissue Tumors? A Japanese Musculoskeletal Oncology Group Multi-institutional Study.

BACKGROUND: Tumor-devitalized autografts treated with deep freezing, pasteurization, and irradiation are biological reconstruction methods after tumor excision for aggressive or malignant bone or soft tissue tumors that involve a major long bone. Tumor-devitalized autografts do not require a bone bank, they carry no risk of viral or bacterial disease transmission, they are associated with a smaller immunologic response, and they have a better shape and size match to the site in which they are implanted. However, they are associated with disadvantages as well; it is not possible to assess margins and tumor necrosis, the devitalized bone is not normal and has limited healing potential, and the biomechanical strength is decreased owing to processing and tumor-related bone loss. Because this technique is not used in many countries, there are few reports on the results of this procedure such as complications, graft survival, and limb function. QUESTIONS/PURPOSES: (1) What was the rate of complications such as fracture, nonunion, infection, or recurrence in a tumor-devitalized autograft treated with deep freezing, pasteurization, and irradiation, and what factors were associated with the complication? (2) What were the 5-year and 10-year grafted bone survival (free from graft bone removal) of the three methods used to devitalize a tumor-containing autograft, and what factors were associated with grafted bone survival? (3) What was the proportion of patients with union of the tumor-devitalized autograft and what factors were associated with union of the graft-host bone junction? (4) What was the limb function after the tumor-devitalized autograft, and what factors were related to favorable limb function? METHODS: This was a retrospective, multicenter, observational study that included data from 26 tertiary sarcoma centers affiliated with the Japanese Musculoskeletal Oncology Group. From January 1993 to December 2018, 494 patients with benign or malignant tumors of the long bones were treated with tumor-devitalized autografts (using deep freezing, pasteurization, or irradiation techniques). Patients who were treated with intercalary or composite (an osteoarticular autograft with a total joint arthroplasty) tumor-devitalized autografts and followed for at least 2 years were considered eligible for inclusion. Accordingly, 7% (37 of 494) of the patients were excluded because they died within 2 years; in 19% (96), an osteoarticular graft was used, and another 10% (51) were lost to follow-up or had incomplete datasets. We did not collect information on those who died or were lost to follow-up. Considering this, 63% of the patients (310 of 494) were included in the analysis. The median follow-up was 92 months (range 24 to 348 months), the median age was 27 years (range 4 to 84), and 48% (148 of 310) were female; freezing was performed for 47% (147) of patients, pasteurization for 29% (89), and irradiation for 24% (74). The primary endpoints of this study were the cumulative incidence rate of complications and the cumulative survival of grafted bone, assessed by the Kaplan-Meier method. We used the classification of complications and graft failures proposed by the International Society of Limb Salvage. Factors relating to complications and grafted autograft removal were analyzed. The secondary endpoints were the proportion of bony union and better limb function, evaluated by the Musculoskeletal Tumor Society score. Factors relating to bony union and limb function were also analyzed. Data were investigated in each center by a record review and transferred to Kanazawa University. RESULTS: The cumulative incidence rate of any complication was 42% at 5 years and 51% at 10 years. The most frequent complications were nonunion in 36 patients and infection in 34 patients. Long resection (≥ 15 cm) was associated with an increased risk of any complication based on the multivariate analyses (RR 1.8 [95% CI 1.3 to 2.5]; p < 0.01). There was no difference in the rate of complications among the three devitalizing methods. The cumulative graft survival rates were 87% at 5 years and 81% at 10 years. After controlling for potential confounding variables including sex, resection length, reconstruction type, procedure type, and chemotherapy, we found that long resection (≥ 15 cm) and composite reconstruction were associated with an increased risk of grafted autograft removal (RR 2.5 [95% CI 1.4 to 4.5]; p < 0.01 and RR 2.3 [95% CI 1.3 to 4.1]; p < 0.01). The pedicle freezing procedure showed better graft survival than the extracorporeal devitalizing procedures (94% versus 85% in 5 years; RR 3.1 [95% CI 1.1 to 9.0]; p = 0.03). No difference was observed in graft survival among the three devitalizing methods. Further, 78% (156 of 200 patients) of patients in the intercalary group and 87% (39 of 45 patients) of those in the composite group achieved primary union within 2 years. Male sex and the use of nonvascularized grafts were associated with an increased risk of nonunion (RR 2.8 [95% CI 1.3 to 6.1]; p < 0.01 and 0.28 [95% CI 0.1 to 1.0]; p = 0.04, respectively) in the intercalary group after controlling for confounding variables, including sex, site, chemotherapy, resection length, graft type, operation time, and fixation type. The median Musculoskeletal Tumor Society score was 83% (range 12% to 100%). After controlling for confounding variables including age, site, resection length, event occurrence, and graft removal, age younger than 40 years (RR 2.0 [95% CI 1.1 to 3.7]; p = 0.03), tibia (RR 6.9 [95% CI 2.7 to 17.5]; p < 0.01), femur (RR 4.8 [95% CI 1.9 to 11.7]; p < 0.01), no event (RR 2.2 [95% CI 1.1 to 4.5]; p = 0.03), and no graft removal (RR 2.9 [95% CI 1.2 to 7.3]; p = 0.03) were associated with an increased limb function. The composite graft was associated with decreased limb function (RR 0.4 [95% CI 0.2 to 0.7]; p < 0.01). CONCLUSION: This multicenter study revealed that frozen, irradiated, and pasteurized tumor-bearing autografts had similar rates of complications and graft survival and all resulted in similar limb function. The recurrence rate was 10%; however, no tumor recurred with the devitalized autograft. The pedicle freezing procedure reduces the osteotomy site, which may contribute to better graft survival. Furthermore, tumor-devitalized autografts had reasonable survival and favorable limb function, which are comparable to findings reported for bone allografts. Overall, tumor-devitalized autografts are a useful option for biological reconstruction and are suitable for osteoblastic tumors or osteolytic tumors without severe loss of mechanical bone strength. Tumor-devitalized autografts could be considered when obtaining allografts is difficult and when a patient is unwilling to have a tumor prosthesis and allograft for various reasons such as cost or socioreligious reasons. LEVEL OF EVIDENCE: Level III, therapeutic study.

Outcomes of Window Therapy with Carboplatin and Ifosfamide for Pediatric Osteosarcoma: A Case Series.

For the treatment of osteosarcoma, cisplatin (CDDP) can be substituted by carboplatin (CBDCA) to reduce toxicity. We report a single institution experience of CBDCA-based regimen. Two to three cycles of CBDCA + ifosfamide (IFO) therapy (window therapy) were administered as neoadjuvant therapy for osteosarcoma. Depending on the response of window therapy, the subsequent protocols were determined; for good responders, surgery is performed, and postoperative therapies with CBDCA + IFO, adriamycin (ADM) and high-dose methotrexate (MTX) were administered; for stable disease, the postoperative regimens were advanced before surgery, and the remaining amount of postoperative chemotherapy is deduced; for progressive disease, CBDCA-based regimen is changed to CDDP-based regimen. From 2009 to 2019, seven patients were treated with this protocol. During the window therapy, two patients (28.6%) were assessed as good responders and completed the regimen as planned. Four patients (57.1%) had stable disease, and the chemotherapy schedules were modified. One patient (14.2%) with progressive disease was shifted to the CDDP-based regimen. At final follow-up, four patients showed no evidence of disease and three patients died of the disease. Since the efficacy during window therapy was limited, a CBDCA-based regimen in the neoadjuvant setting was considered insufficient for performing adequate surgery.

Current Concepts in the Resection of Bone Tumors Using a Patient-Specific Three-Dimensional Printed Cutting Guide.

Orthopedic oncology has begun to use three-dimensional-printing technology, which is expected to improve the accuracy of osteotomies, ensure a safe margin, and facilitate precise surgery. However, several difficulties should be considered. Cadaver and clinical studies have reported more accurate osteotomies for bone-tumor resection using patient-specific cutting guides, especially in challenging areas such as the sacrum and pelvis, compared to manual osteotomies. Patient-specific cutting guides can help surgeons achieve resection with negative margins and reduce blood loss and operating time. Furthermore, this patient-specific cutting guide could be combined with more precise reconstruction using patient-specific implants or massive bone allografts. This review provides an overview of the basic technologies used in the production of patient-specific cutting guides and discusses their current status, advantages, and limitations. Moreover, we summarize cadaveric and clinical studies on the use of these guides in orthopedic oncology.

Giant cell tumor of bone with secondary aneurysmal bone cyst does not have a higher risk of local recurrence.

BACKGROUND: Fluid-fluid levels (FFLs) is found in 10%-16% of giant cell tumor of bone (GCTB), and the presence of FFLs raises the suspicion of GCTB with secondary aneurysmal bone cyst (ABC), which can lead to increased intraoperative bleeding and, blurring the operative field, be associated with a risk of local recurrence. The first objective of this study is to determine whether secondary ABC is associated with a higher risk of local recurrence after curettage in patients with GCTB of the extremities. The second objective of this study is to investigate the sensitivity, specificity, positive predictive value, and negative predictive value of the presence of FFLs detected on magnetic resonance imaging (MRI) to diagnose secondary ABC associated with GCTB. METHODS: Two hundred and eighty patients with GCTB of the extremities who underwent curettage at the authors' institutions between 1980 and 2021 were included in this study. RESULTS: Secondary ABC was found in 36 of 280 patients (12.9%) and local recurrence occurred in 66 of 280 patients (23.6%). Multivariate analysis showed no significant correlation between secondary ABC and local recurrence (hazard ratio [HR]: 1.87 (95% confidence interval [CI]: 1.00-3.53]; p = 0.051). Preoperative MRI revealed FFLs in 13 of 82 patients (15.9%). Sensitivity, specificity, positive predictive value, and negative predictive value of FFLs detected on preoperative MRI to diagnose secondary ABC were 36.8%, 90.5%, 53.8%, and 82.6%, respectively. CONCLUSION: The results of this study showed that secondary ABC does not increase the risk of local recurrence after curettage in patients with GCTB of the extremities. Although rare, FFLs were present in patients with GCTB and half of those with FFLs detected on preoperative MRI had secondary ABC.

Clinical characteristics of primary cutaneous and subcutaneous Ewing sarcoma.

OBJECTIVE: Given the rarity of cutaneous/subcutaneous Ewing sarcoma, their clinical characteristics remain poorly understood. In this study, we aimed to analyse the clinical characteristics of patients with cutaneous/subcutaneous Ewing sarcoma and review the treatment strategy. METHODS: We reviewed the clinical data of 154 patients with Ewing sarcoma who were treated at our hospital between 2005 and 2019. Amongst these patients, 21 patients with cutaneous/subcutaneous Ewing sarcoma were analysed. As a basic strategy, patients with localized disease received intensive chemotherapy (vincristine-doxorubicin-cyclophosphamide/ifosfamide-etoposide), followed by definitive surgery with or without radiotherapy. In total, 15 patients underwent pre-diagnostic resection with macroscopic residue (seven patients) or non-macroscopic residue (eight patients) before intensive chemotherapy. RESULTS: The median tumour length of the measurable lesions was 3.2 cm, and the ratio of metastasis was significantly lower than the Ewing sarcoma of other anatomical sites (10% vs. 37%, P = 0.013). Despite the pre-diagnostic resection, local recurrence after additional resection and/or adjuvant radiotherapy did not occur in any of the patients with localized disease. Overall survival was significantly higher in patients with cutaneous/subcutaneous Ewing sarcoma than in patients with Ewing sarcoma of other anatomical sites (hazard ratio = 0.33, P = 0.013). The event-free survival rate of cutaneous/subcutaneous Ewing sarcoma was also superior to that of Ewing sarcoma of other anatomical sites (hazard ratio = 0.35, P = 0.01). CONCLUSIONS: Patients with cutaneous/subcutaneous Ewing sarcoma may have better prognosis than those with Ewing sarcoma at other anatomical sites. Although pre-diagnostic resection without appropriate investigations is not recommended, local control may be recovered by using a combination of additional resection, chemotherapy and radiotherapy.