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Aims This study aimed to analyze the accuracy and errors associated with 3D-printed, patient-specific resection guides (3DP-PSRGs) used for bone tumour resection. Methods We retrospectively reviewed 29 bone tumour resections that used 3DP-PSRGs based on 3D CT and 3D MRI. We evaluated the resection amount errors and resection margin errors relative to the preoperative plans. Guide-fitting errors and guide distortion were evaluated intraoperatively and one month postoperatively, respectively. We categorized each of these error types into three grades (grade 1, < 1 mm; grade 2, 1 to 3 mm; and grade 3, > 3 mm) to evaluate the overall accuracy. Results The maximum resection amount error was 2 mm. Out of 29 resection amount errors, 15 (51.7%) were grade 1 errors and 14 (38.3%) were grade 2 errors. Complex resections were associated with higher-grade resection amount errors (p < 0.001). The actual resection margins correlated significantly with the planned margins; however, there were some discrepancies. The maximum guide-fitting error was 3 mm. There were 22 (75.9%), five (17.2%), and two (6.9%) grade 1, 2, and 3 guide-fitting errors, respectively. There was no significant association between complex resection and fitting error grades. The guide distortion after one month in all patients was rated as grade 1. Conclusion In terms of the accurate resection amount according to the preoperative planning, 3DP-PSRGs can be a viable option for bone tumour resection. However, 3DP-PSRG use may be associated with resection margin length discrepancies relative to the planned margins. Such discrepancies should be considered when determining surgical margins. Therefore, a thorough evaluation of the preoperative imaging and surgical planning is still required, even if 3DP-PSRGs are to be used. Cite this article: Bone Joint J 2023;105-B(2):190–197.

Hyehyun Jeong,1,&ast; Hyeon-Su Im,1,2,&ast; Wanlim Kim,3 Jong-Seok Lee,3 Si Yeol Song,4 Joon Seon Song,5 Kyung-Ja Cho,5 Hye Won Chung,6 Min Hee Lee,6 Jeong Eun Kim,1,&ast; Jin-Hee Ahn1,&ast; 1Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; 2Division of Hematology and Oncology, Ulsan University Hospital, Ulsan, Republic of Korea; 3Department of Orthopedic Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; 4Department of Radiation Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; 5Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; 6Department of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea&ast;These authors contributed equally to this workCorrespondence: Jeong Eun Kim; Jin-Hee AhnDepartment of Oncology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, Republic of KoreaTel +82-2-3010-3945; +82-2-3010-3222Fax +82-2-3010-6961Email jeongeunkim@amc.seoul.kr; drjiny@amc.seoul.krPurpose: Because of the heterogeneity of sarcomas, establishing a well-collected, sarcoma-specific database is important for sarcoma research. We analyzed the first histology-based, sarcoma-specific institutional registry in Korea, which collected 28 years of patient data according to a predefined data format.Patients and Methods: Adult bone and soft tissue sarcoma patients who were treated from June 1989 to January 2017 were identified and analyzed, based on the ICD-O-3 codes.Results: Among the 3420 patients included, soft tissue and bone sarcomas comprised 77.8% (n = 2661) and 22.2% (n = 759), respectively. Median age at diagnosis was 50 (range, 16– 98) in soft tissue sarcomas and 37 (range, 16– 85) in bone sarcomas. Males and females comprised 45.5% and 54.5% of soft tissue sarcomas and 52.7% and 47.3% of bone sarcomas, respectively. Among the 3407 patients with treatment data available, 90.5% of the patients with soft tissue sarcomas and 80.8% of the patients with bone sarcomas received surgery first, of which 57.8% and 71.7% did not receive any subsequent treatment, respectively. Overall, the proportion of patients who received surgery alone decreased from 85.7% to 60.5% from the pre-2000 period to the 2010– 2017 period. However, the use of adjuvant chemotherapy increased in patients with soft tissue sarcomas (from 8.0% to 17.2% in the same period), and the use of perioperative radiotherapy also increased in both groups (from 1.4% to 22.7% in soft tissue sarcomas, and 0% to 14.5% in bone sarcomas in the same period). In both soft tissue and bone sarcomas, old age (≥ 65 years) and diagnosis in the early study period were associated with poorer survival.Conclusion: We presented a comprehensive summary of our sarcoma registry, including the demographics, changes in treatment patterns, and survival outcomes. This study will provide a framework for future studies.Keywords: bone sarcoma, soft tissue sarcoma, sarcoma-specific registry, real-world evidence

The advent of receptor tyrosine kinase inhibitors (RTKi) are important contributions to treat NSCLC patients harboring genetic aberration effectively. Nevertheless, the emergence of acquired or intrinsic RTKi resistance by other RTK activation bypass finally limits their efficacy. First of all, in this study, we identified MED12 mutation in TKI-resistant NSCLC cells based-on NGS analysis. Although MED12 was known to controls the response to multiple cancer drugs through regulation of TGF-beta receptor signaling reportedly, we additionally found that MED12 mutation activates not only TGF-beta receptor not also other ones, such as EGFR, meaning that blocking TGF-beta receptor or EGFR alone may not effective to overcome MED12 mutation-induced RTKi resistance. To overcome the RTKi resistance in NSCLC harboring MED12 mutation, we elaborated the two downstream signaling of RTK in MED12 knock-out NSCLC cells and observed that PI3K/AKT signaling is downregulated but MEK/ERK signaling is upregulated. We observed that only MEK inhibitor (MEKi), not PI3K/mTOR inhibitor, shows effective anti-cancer effect. Therefore, we explored why MEKi alone is effective in RTKi resistant NSCLC cells harboring MED12 mutation and presented that MED12 mutation directly suppressed activation of YAP via blocking a large mediator complex of MED12, MED13, CDK8 and CCNC, thereby increasing PTEN expression by inhibition of miR-29 expression. Increased PTEN inhibits reactivation of PI3K/AKT pathway. In conclusion, we first identified that MED12 mutation induces RTKi resistance though activating other RTKs, such as TGF-beta receptor or EGFR, and blocks PI3K/AKT pathway via dysregulation of YAP/PTEN/AKT interaction. Therefore, among two downstream signaling of RTK, activated MEK/ERK pathway can be a definitive target enough to overcome RTKi resistant NSCLC patients harboring MED12 mutation and MEKi could be a primary treatment option for resistant patients harboring MED12 mutation among NSCLC patients with repetitive recurrence of RTKi resistance by another RTK activation bypass. Citation Format: Hyun-Min Ryu, Deokhoon Kim, Shinkyo Yoon, Ho-Su Lee, Eunjin Lee, Chang Hoon Lee, Wanlim Kim, Seyoung Seo, Kyung Hae Jung, Sook Ryun Park, Sang-We Kim, Kang-Seo Park, Dae Ho Lee. RTK inhibitor resistance in NSCLC harboring MED12 mutation is overcome by only blocking MEK signaling, not AKT due to mutated MED12-induced YAP-PTEN dysregulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 424.

Background/Aim: To compare absolute volume (AV) assessment according to Response Evaluation Criteria in Solid Tumors (RECIST) for the response evaluation of desmoid tumors (DTs) treated with radiotherapy. Patients and Methods: Eighteen patients with DTs ≥3 cm in size were included. Results: The median follow-up duration was 78.0 months. Five patients achieved a complete response according to RECIST, seven reached a partial response (PR), and one eventually exhibited progression. The overall response rate was 61%, the median time to PR was 8.0 months. Six patients achieved stable disease, although three developed progressions. Of the six patients with a PR, the median change in maximum diameter was −46%, and the median change in maximum volume was −84%. Three patients could have been diagnosed with progression at least 6 months earlier if the AV increment was considered. Conclusion: An AV assessment is essential for an accurate response assessment of DTs and radiotherapy seems feasible as a first-line treatment for DTs.

Pathological femoral fracture (PFF) after radiation therapy (RT) for soft tissue tumor is a debilitating complication with a high rate of nonunion that requires multiple subsequent procedures and hindrance of functional activity. We aimed to evaluate healing rate after repeated internal fixation in a case series of PFF after RT. We retrospectively reviewed the records of patients who had PFF after RT and were treated at our center between 2007 and 2018. We analyzed our surgical protocols and fracture healing rate. We identified and analyzed a total of seven patients (six females and one male) whose mean age at fracture was 58 years. Primary tumors consisted of soft tissue sarcoma (n = 5), melanoma (n = 1), and desmoid tumor (n = 1). All primary tumors were treated with surgical excision and adjuvant RT. The mean follow-up duration after fracture was 33 months (range, 16–58). At the last follow-up, five out of seven fractures had completely healed, and two lesions showed delayed union at 15 and 16 months, respectively. Among the five complete unions, one fracture was healed after the first fixation. The remaining four lesions were treated with second internal fixation due to nonunion/metal failure or delayed union. The mean time to radiologic healing after the last fixation was 6.8 months (range, 5–8). Our results suggest that bones within the RT field retain healing capacities, and that repeated internal fixation may be a viable option for the treatment of PFF after RT.

Background and objectives The propeller flap is a reliable option for reconstruction after soft tissue sarcoma resection. However, some parts of the resection margin may move away from its original position during flap rotation and thus can be excluded from the clinical target volume of adjuvant radiotherapy. This study aimed to evaluate local recurrence after soft tissue sarcoma resection with propeller flap or free flap reconstruction. Methods Patients who underwent resection of soft tissue sarcoma followed by a free flap or propeller flap reconstruction and adjuvant radiotherapy at a single institution were retrospectively reviewed. Results The 1- and 3-year local control rates were 94.6% and 88.6% in the free flap group vs 90.6% and 87.5% in the propeller flap group, without statistical significance. There were no statistically significant differences in 5-year local recurrence-free survival (88.6% vs 87.5%) and disease-free survival (82.5% vs 74.8%) between the groups. Conclusions Although there was no significant difference in local control and disease-free survival rates between propeller flap and free flap reconstruction after soft tissue sarcoma resection, a multidisciplinary approach is needed to obtain surgical information for determining the accurate clinical target volume of adjuvant radiotherapy and the area for meticulous follow-up postoperatively.

Introduction: Myxoid liposarcoma (MLS) is a common lipogenic sarcoma, which is difficult to diagnose in small specimens. New York oesophageal squamous cell carcinoma 1 (NY-ESO-1) is a cancer-testis antigen expressed in neoplastic tissue. In this study, NY-ESO-1 expression was assessed in various soft tissue tumors (STTs), and we also evaluated its diagnostic utility. Methods: We included 434 cases of STTs for collection of clinicopathological data. Tissue microarrays were designed, and immunostaining for NY-ESO-1 was examined. We investigated the correlation between NY-ESO-1 expression and various clinicopathological parameters. We also evaluated the role of NY-ESO-1 as a diagnostic marker for MLS and its possible use in prognostication. Results: Sixty-four of the 434 STTs (14.75%) were immunoreactive for NY-ESO-1, and the most frequent type of tumor in the NY-ESO-1 positive group was MLS (70.3%, 45/64), followed by synovial sarcoma (17.2%, 11/64). MLS showed 72.6% (45/62) immunopositivity for NY-ESO-1. The sensitivity and specificity of NY-ESO-1 expression for the diagnosis of MLS were 84.4% and 100%, respectively, compared to DDIT3 fluorescence in situ hybridization. When restricting analysis to the MLS (n=62), the NY-ESO-1 positive group had a poor overall survival (OS) rate (P=0.039). Conclusion: NY-ESO-1 was substantially and widely expressed in the majority of MLS cases. NY-ESO-1 positivity by IHC staining was also a predictor of a poor OS in patients with MLS. It is possible to use NY-ESO-1 for diagnosis and for predicting a prognosis in patients with MLS, and it may be used as a therapeutic target.

Oxalosis is a metabolic disorder characterized by the accumulation of calcium oxalate deposits in various organ systems. Bone oxalosis is a systemic manifestation of oxalosis, in which calcium oxalate deposits accumulate in the skeletal system. This report describes a 69-year-old female patient who presented with right hip pain and was later found to have an osseous mass-like lesion in the right proximal femur, with radiographic findings resembling those of a benign bone tumor. CT-guided biopsy and surgical biopsy showed that the mass had pathologic findings typical of bone oxalosis. Because the patient had no predisposing factors for systemic oxalosis and had no hyperoxalemia or hyperoxaluria, she could be diagnosed with localized bone oxalate deposition disease or bone oxaloma rather than bone oxalosis. This is the first report of this clinical entity to present as a benign-appearing bone mass and without any predisposing systemic causes.

The relationship between arthritis or repetitive stress injuries (RSIs) in thumbs and rapidly increasing hours of smartphone usage is not fully elucidated. We evaluated axial joint reaction forces (AJRFs) and thumb torques in 19 healthy subjects performing typical smartphone tasks, which included tapping, tap game, and swiping. We measured force and torque when a subject tapped or swiped the panel of the smartphone and analyzed the motions of each joint using surface markers and motion capture systems. We calculated AJRFs and torques on each thumb joint using inverse dynamics. The results were then compared with representative activities such as computer keyboard typing and handwriting. The mean AJRFs/torques at the thumb carpometacarpal joint (CMCJ) while tapping the smartphone and tap gaming were 12.5 N/95.5 N mm and 21.1 N/187.21 N mm, respectively. AJRFs and torques were significantly higher during tap gaming activities than during simple tapping subtasks (p = 0.003 and p < 0.001, respectively). Compared with those during computer keyboard typing, the mean AJRFs and torques at the CMCJ during smartphone tapping was 3 (p = 0.075) and 1.4 times (p = 0.680) larger, respectively. Considering the rapidly increasing dependency on smartphones in our daily lives, long-term exposure of the thumb to repetitive AJRFs and torques may lead to an acceleration of arthritis or aggravation of RSIs in thumbs. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:2437-2444, 2019.

Background Systemic inflammation plays a critical role in cancer progression and oncologic outcomes in cancer patients. We investigated whether preoperative inflammatory biomarkers, including C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and neutrophil to lymphocyte ratio (NLR), could be surrogate biomarkers for predicting overall survival (OS) in soft tissue sarcoma (STS) patients treated with surgery and postoperative radiotherapy. Methods A series of 99 patients who presented with localized extremity STS were retrospectively reviewed. The preoperative CRP levels, ESR, and NLR were evaluated for associations with OS, disease-free survival (DFS), local recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS). Cutoff values for CRP, ESR, and NLR were derived from receiver-operating characteristic curve analysis. Results Elevated CRP (> 0.14 mg/dL), ESR (> 15 mm/h), and NLR (> 1.95) levels were seen in 33, 44, and 45 patients, respectively. Of these three inflammatory biomarkers, elevated CRP and ESR were associated with a poorer OS (CRP: P = 0.050; ESR: P = 0.001), DFS (CRP: P = 0.023; ESR: P = 0.003), and DMFS (CRP: P = 0.015; ESR: P = 0.001). By multivariate analysis, an elevated ESR was found to be an independent prognostic factor for OS (HR 3.580, P = 0.025) and DMFS (HR 3.850, P = 0.036) after adjustment for other established prognostic factors. Conclusions The preoperative ESR level is a simple and useful surrogate biomarker for predicting survival outcomes in STS patients and might improve the identification of high-risk patients of tumor relapse in clinical practice.

Purpose For liposarcoma (LPS), clinical course and proper treatment strategies have not been well-established. Recently, immune-checkpoint inhibitors have shown potential efficacy in LPS. We aimed to describe the clinical course of LPS and evaluate the clinical impact of programmed death-ligand 1 (PD-L1).Materials and Methods We reviewed all consecutive patients (n=332) who underwent curative-intent surgery for localized LPS at Asan Medical Center between 1989 and 2017. PD-L1 testing was performed in well-differentiated and dedifferentiated LPS.Results The median age was 56 years with males comprising 60.8%. Abdomen-pelvis (47.6%) and well-differentiated (37.7%) were the most frequent primary site and histologic subtype, respectively. During a median follow-up of 81.2 months, recurrence was observed in 135 (40.7%), and 86.7% (117/135) were loco-regional. Well-differentiated subtype (hazard ratio [HR], 0.38), abdomen-pelvis origin (HR, 2.43), tumor size larger than 5 cm (HR, 1.83), positive resection margin (HR, 2.58), and postoperative radiotherapy (HR, 0.36) were significantly related with recurrence-free survival as well as visceral involvement (HR, 1.84) and multifocality (HR, 3.79) in abdomen-pelvis LPS. PD-L1 was positive in 31.5% (23/73) and 51.3% (39/76) of well-differentiated and dedifferentiated LPS, respectively, but had no impact on survival outcomes.Conclusion Clinical course of LPS was heterogeneous according to histology and anatomic location. Clear resection margin was important to lower recurrence and postoperative radiotherapy might have additional benefit. A decent portion of well-differentiated and dedifferentiated LPS were positive for PD-L1, but its prognostic role was unclear. Further research is needed to determine clinical implications of PD-L1, especially for advanced-stage LPS with unmet needs for effective systemic treatment.

Purpose To evaluate the osseous anatomy of the proximal femur extracted from a 3D-MRI volumetric interpolated breath-hold (VIBE) sequence using either a Dixon or water excitation (WE) fat suppression method, and to measure the overall difference using CT as a reference standard. Material and methods This retrospective study reviewed imaging of adult patients with hip pain who underwent 3D hip MRI and CT. A semi-automatically segmented CT model served as the reference standard, and MRI segmentation was performed manually for each unilateral hip joint. The differences between Dixon-VIBE-3D-MRI vs. CT, and WE-VIBE-3D-MRI vs. CT, were measured. Equivalence tests between Dixon-VIBE and WE-VIBE models were performed with a threshold of 0.1 mm. Bland–Altman plots and Lin’s concordance-correlation coefficient were used to analyze the agreement between WE and Dixon sequences. Subgroup analyses were performed for the femoral head/neck, intertrochanteric, and femoral shaft areas. Results The mean and maximum differences between Dixon-VIBE-3D-MRI vs. CT were 0.2917 and 3.4908 mm, respectively, whereas for WE-VIBE-3D-MRI vs. CT they were 0.3162 and 3.1599 mm. The mean differences of the WE and Dixon methods were equivalent (P = 0.0292). However, the maximum difference was not equivalent between the two methods and it was higher in WE method. Lin’s concordance-correlation coefficient showed poor agreement between Dixon and WE methods. The mean differences between the CT and 3D-MRI models were significantly higher in the femoral shaft area (P = 0.0004 for WE and P = 0.0015 for Dixon) than in the other areas. The maximum difference was greatest in the intertrochanteric area for both techniques. Conclusion The difference between 3D-MR and CT models were acceptable with a maximal difference below 3.5mm. WE and Dixon fat suppression methods were equivalent. The mean difference was highest at the femoral shaft area, which was off-center from the magnetization field.

Tumor-induced osteomalacia (TIO) is an uncommon paraneoplastic syndrome presenting with sustained hypophosphatemia. Treatment of choice is removal of the tumor causing the TIO, but identification of the culprit tumor by routine imaging is challenging. This study aimed to assess the usefulness of somatostatin receptor imaging, called 68Ga-DOTATOC PET/CT, in the management of patients with TIO. Twelve patients who were suspected of having TIO underwent 68Ga-DOTATOC PET/CT. Lesion detectability and maximum standardized uptake value (SUVmax) were determined and retrospectively compared with the clinical/imaging surveillance and histopathologic diagnosis. The median duration of suspected TIO with hypophosphatemia was 7.8 years (range 2.1–21.0). Conventional radiologic and/or nuclear medicine images failed to identify the culprit tumors. However, 68Ga-DOTATOC PET/CT scans showed that 8 of the 12 patients had positive lesions, suggesting the presence of focal culprit tumors. The SUVmax of positive tumors was 1.9–45.7 (median: 11.5). Six skeletal lesions and two extra-skeletal lesions were identified. Seven of the lesions were pathologically confirmed as potential culprits of TIO. Hypophosphatemia was resolved in five patients who underwent lesion excision. The 68Ga-DOTATOC PET/CT is a useful whole-body imaging modality for the detection of causative tumors in patients with suspected TIO.

PurposeHeat shock protein-90 (HSP90) remains an important cancer target because of its involvement in multiple oncogenic protein pathways and biologic processes. Although many HSP90 inhibitors have been tested in the treatment of KRAS-mutant non–small cell lung cancer (NSCLC), most, including AUY922, have failed due to toxic effects and resistance generation, even though a modest efficacy has been observed for these drugs in clinical trials. In our present study, we investigated the novel mechanism of resistance to AUY922 to explore possible avenues of overcoming and want to provide some insights that may assist with the future development of successful next-generation HSP90 inhibitors.Materials and MethodsWe established two AUY922-resistant KRAS-mutated NSCLC cells and conducted RNA sequencing to identify novel resistance biomarker.ResultsWe identified novel two resistance biomarkers. We observed that both integrin Av (ITGAv) and β3 (ITGB3) induce AUY922-resistance via focal adhesion kinase (FAK) activation, as well as an epithelial-mesenchymal transition, in both in vitro and in vivo xenograft model. mRNAs of both ITGAv and ITGB3 were also found to be elevated in a patient who had shown acquired resistance in a clinical trial of AUY922. ITGAv was induced by miR-142 downregulation, and ITGB3 was increased by miR-150 downregulation during the development of AUY922-resistance. Therefore, miR-150 and miR-142 overexpression effectively inhibited ITGAvB3-dependent FAK activation, restoring sensitivity to AUY922.ConclusionThe synergistic co-targeting of FAK and HSP90 attenuated the growth of ITGAvB3-induced AUY922-resistant KRAS-mutated NSCLC cells in vitro and in vivo, suggesting that this combination may overcome acquired AUY922-resistance in KRAS-mutant NSCLC.

CIC-DUX4 fusion gene associated sarcoma is a new emerging subgroup of round cell sarcoma with Ewing sarcoma-like morphology. Distinguishing these tumors from Ewing sarcoma family tumors (ESFT) is critical because of the clinical impact but is still challenging due to the overlapped histological and immunohistochemical phenotypes of each subtype. The present study investigated small round cell sarcoma to identify CIC-DUX4 fusion positive sarcoma, examined clinical, histopathologic and immunohistochemical characteristics of CIC-DUX4 sarcoma, and evaluated parameters to differentiate Ewing sarcoma family tumors. Seventy patients with undifferentiated round cell sarcoma or Ewing-like sarcoma were retrieved. Molecular tests including EWSR1, CIC break apart FISH, and RT-PCR for CIC-DUX4 gene fusion were performed and immunohistochemistry was performed. Six cases (8.6%) of CIC-DUX4 sarcomas were detected. Histologically, CIC-DUX4 sarcomas composed of heterogeneous round, plasmacytoid, and spindle cells and more commonly showed cytologic pleomorphism with bizarre nuclei and multinucleated cells and myxoid stoma unlike ESFT. CIC-DUX4 sarcomas didn't show overall survival differences (p = 0.325) compared to ESFT but they demonstrated short disease-free survival (p = 0.034) and poor response to treatment (p = 0.007). Therefore, molecular analysis to detect the distinctive genetic alteration is mandatory in tumors with atypical histologic, immunohistochemical and/or clinical presentation for accurate diagnosis and treatment.

Anti-PD-1/PD-L1 immunotherapy, as a treatment for many tumors, has shown good efficacy. However, responses to immunotherapy did not always occur or last long., i.e. primary or acquired resistance, even tumors were PD-L1 positive. Several oncogenic pathways, including PI3K/AKT activation by PTEN loss and NF-κB activation, induce PD-L1 expression and PD-L1 inhibitor-resistance. They also induce expression of CCL2, an inhibitory chemokine that blocks T cell tracking into the tumor by binding to CCR2 on the T cell surface. In this study, we showed that transglutaminase 2 (TG2), a post-translational modification enzyme, induced ubiquitin-proteasome dependent degradation of tumor suppressors including PTEN and IκBα by peptide cross-linking, inducing CCL2 as well as PD-L1 expression via PI3K/AKT and NF-κB activation. It also induced PD-L1 inhibitor-resistance because CCL2 was expressed despite increased PD-L1, which was blocked by PD-L1 inhibitor. We also revealed that inhibition of TG2, instead of PD-L1, restored T cell-dependent killing effect by blocking expression of both PD-L1 and CCL2 in PD-L1(+) triple negative breast cancer (TNBC) cells. In addition, the TG2-expressing TNBC patient group showed higher PD-L1 expression incidence than did the TG2-negative TNBC patient group. In conclusion, TG2 induces primary PD-1/PD-L1 inhibitor-resistance by inducing CCL2 expression. TG2 blockade can be utilized as an excellent therapeutic strategy to overcome PD-L1 inhibitor-resistance in PD-L1(+) TNBC patients. Our study suggested that PD-L1 expression alone might not always be a predictive biomarker for PD-L1(+) TNBC, but TG2 could be a useful predictive marker to select PD-L1 inhibitor-resistant TNBC patients.

Chondroblastomas of the talus can lead to joint collapse and are often treated using curettage and bone grafting. In the present report, we describe the case of a 19-year-old female with a large chondroblastoma of the talus associated with a secondary aneurysmal cyst. We treated the large cartilage lesion, which involved most of the talus, with an iliac bone graft combined with bone cement to fill the large bone defect and preserve the subchondral bone of the articular surface of the dome of the talus.

Introduction Little is known about undifferentiated pleomorphic sarcoma (UPS) because of the low incidence and heterogeneous diagnosis of sarcoma. We investigated the oncologic outcomes of patients with UPS in a real-practice setting in association with adjuvant treatments and assessment of PD-L1 expression. Materials and methods We retrospectively reviewed consecutive patients who were diagnosed with UPS in Asan Medical Center between January 1995 and December 2016. PD-L1 staining was performed using formalin-fixed paraffin-embedded tumour tissue by immunohistochemistry, and positive PD-L1 expression was defined as staining in ≥1% of tumour cells. The PD-L1 H-score, which was calculated for statistical analysis as intensity (0–3) multiplied by proportion (0–100), ranged from 0 to 300. Results Of 205 patients included in our analysis, 176 underwent a curative-intent operation for localised disease. The five-year disease-free survival (DFS) rate of resected UPS patients was 54.3%. Administration of adjuvant therapy did not overcome the poor prognostic factors such as primary tumour size (>5 cm) and locations, especially the abdomen and pelvis. The PD-L1 analysis was available for 114 patients, and 83 (72.8%) showed immunoreactivity for PD-L1 with weak (44/83), intermediate (29/83), and strong (10/83) staining intensities. The positive PD-L1 expression seemed to be associated with prolonged DFS, though no statistical significance was observed. Conclusion Complete surgical resection was the most important UPS treatment strategy, and adjuvant radio- or chemotherapy was insufficient to improve survival. Our results raise the possibility that immunotherapy could be a breakthrough in the treatment of UPS patients.

The high failure rate of cemented femoral components in the 1970s facilitated the improvement of the cementing technique and surface finishes such as polymethylmethacrylate (PMMA)-precoated stems, reporting a survival rate of >95% at 10 years from some studies. However, controversy persists regarding whether precoated femoral stems are associated with a longer revision-free prosthesis survival. The purpose of this study was to evaluate the clinical and radiological outcomes of PMMA-precoated femoral stems, and analyze factors associated with implant survival. We retrospectively reviewed 73 primary hybrid total hip arthroplasties performed using PMMA-precoated femoral stems. The mean age of the patients was 61 years. During the mean follow-up period of 13 years, 18 hips (24.7%) underwent aseptic loosening, and all of the loosened stems were subjected to revision surgery 8.8 years (range 4.6-15.5 years) from the index surgery. Younger age and poor cementing were significantly associated with aseptic loosening (P = 0.013 and P

RESEARCH OBJECTIVE: Global surgery is becoming an increasingly important global health agenda. Cardiovascular disease is the major cause of mortality around the world, and congenital heart disease is the leading cause of morbidity in children. This study aimed to investigate and illustrate the caregivers’ experiences of accessing the health care system and undergoing pediatric cardiac surgery for children with congenital heart disease (CHD). STUDY DESIGN: A qualitative study was conducted. Interviews were conducted in December 2019 in Amharic, then translated into English using trained local interpreters. Data were transcribed verbatim and analyzed according to the principles of interpretive thematic analysis, informed by the candidacy framework, using NVivo. The candidacy framework explores the access to health care utilization by seven elements: candidacy, navigation, the permeability of services, appearances at health services, adjudications, offers and resistance, and operating conditions and the local production of candidacy. POPULATION STUDIED: Interviews were conducted with 13 caregivers of 10 patients with congenital heart disease that received cardiac surgery during the week of the interview. PRINCIPAL FINDINGS: The following three themes emerged from the interviews: (a) Recognition of CHD mostly took place at birth, but for those born at home, they found out much later (max 14 years); (b) CHD was misdiagnosed multiple times prior to seeking care at a large hospital; and (c) patients were waiting for the surgery for more than a year, (d) being scheduled for surgery induced both anxiety and hopefulness. In the discussion, caregivers had financial difficulties and struggled in a fragmented delivery system and experienced poor service quality such as the inaccuracy of diagnosis while navigating the Ethiopian health care system. CONCLUSIONS: Major care‐seeking delays were related to the inefficient and complex health care system, largely due to lack of early CHD recognition and financial hardships. Financial protection is low despite the availability of fee waivers for medications. Low education attainment and distance to hospitals are contributing to this challenge. IMPLICATIONS FOR POLICY OR PRACTICE: Overall, Ethiopia needs to prioritize policies that protect the financial status of low‐income households that need health care services. Along with increasing health care workforce capacity for pediatric cardiac surgeries in Ethiopia, there is a need to strengthen the district‐level screening capacity to facilitate earlier diagnosis at easily accessible health care settings. PRIMARY FUNDING SOURCE: Search Results Web results Korea International Cooperation Agency.

This study was conducted to evaluate the added value of diffusion-weighted imaging (DWI) to conventional magnetic resonance imaging (MRI) for predicting fascial involvement of soft tissue sarcomas located in close proximity to fascial boundaries. This retrospective study included 29 patients with surgically resected soft tissue sarcomas located in proximity to deep fascia and with a curvilinear tail-like hyperintensity in the adjacent fascia on T2-weighted images. All patients underwent conventional MRI and DWI at 3.0 T and had detailed histologic reports on involvement of fascia. Two musculoskeletal radiologists with 21 and 1 year of experience independently reviewed conventional MRI and conventional imaging with added DWI. Readers scored their confidence for tumor involvement of fascia using a three-point scale. Diagnostic performance (area under the curve [Az]) of the two MRI sets was assessed with receiver-operating characteristic curve analysis. Fascial involvement was present in 22/29 patients (75.9%). Both readers showed improvement in diagnostic performance with the addition of DWI (Az, from 0.545 to 0.792 and from 0.646 to 0.792 for reader 1 and reader 2, respectively). Adding DWI did not improve sensitivity or specificity for either reader (p > 0.05). Interobserver agreement for the confidence scores improved from fair to moderate with the addition of DWI (κ, from 0.390 to 0.560). Adding DWI to conventional MRI improved diagnostic performance on prediction of fascial involvement of soft tissue sarcomas located in proximity to fascia, without significant improvement in sensitivity or specificity. • Adding DWI to conventional MRI improved readers’ confidence level for the prediction of fascial involvement of soft tissue sarcomas that are close to the deep fascia. • Addition of DWI also improved interobserver agreement. • Conversely, compared with conventional MRI, adding DWI did not significantly improve the sensitivity or specificity for the detection of fascial involvement.

Background Low-grade chondrosarcoma of long bones can be treated successfully with extended intralesional curettage using adjuvants. However, there is no study reporting the use of anhydrous alcohol as an adjuvant in the treatment of low-grade chondrosarcoma. We asked (1) whether intralesional curettage and anhydrous alcohol adjuvant for low-grade chondrosarcoma is associated with good oncologic outcomes; and we report (2) the complications of the procedure. Methods Thirty-six patients (13 men, 23 women) with a mean age of 46 years (range, 18–67 years) were treated for low-grade chondrosarcoma and followed up for a median of 62 months (range, 24–169 months). After intralesional curettage, and additional burring, anhydrous alcohol was used as an adjuvant therapy. Results At the time of last follow-up, there were no local recurrences or distant metastases. Six patients developed complications: 4 postoperative fractures (11%), 1 intra-articular loose body (3%) and 1 postoperative joint stiffness (3%). Conclusion Anhydrous alcohol is a reasonable adjuvant for the curettage of low-grade chondrosarcoma of long bones. A long-term follow-up study is necessary, considering the slow biological progression of low-grade chondrosarcoma.

BACKGROUND AND OBJECTIVES Prognostic factors predictive of postmetastasis survival (PMS) in metastatic osteosarcoma are poorly understood. Our aims were to evaluate PMS in patients with high-grade osteosarcoma in extremities, and to identify prognostic factors related to PMS. METHODS A retrospective review of data for 126 patients with metastatic osteosarcoma was conducted. The study population consisted of 70 men and 56 women, with a mean age of 21 years (range: 4-75 years). The mean postmetastasis follow-up period was 37 months (range: 1-245 months). RESULTS The 5-year PMS rate was 31% and median PMS duration was 22 months. In the multivariate analyses, no metastasectomy (P

Aim In the present study we assessed if postoperative radiotherapy (PORT) using conventional fractionation confers a benefit in cutaneous melanoma patients with lymph node (LN) metastasis. Patients and methods Sixty-two patients with axillary or inguinal LN metastasis were retrospectively reviewed. Twenty-eight patients received PORT. The median RT dose was 50 Gy in 25 fractions. The high-risk group was defined by the presence of any of the following: ≥3 LNs, size ≥3 cm, extranodal extension. Results The median follow-up time was 34 months. PORT showed a significant benefit on 5-year axilla-inguinal recurrence-free survival (RFS) in high-risk patients (RT 100% vs. No-RT 37%, p=0.001). There was also a benefit of RT on 5-year out-field RFS in the high-risk population (RT 93% vs. No-RT 29%, p=0.002). There were no ≥grade 2 lymphedemas after RT. Conclusion PORT using conventional fractionation for high-risk LN metastasis from cutaneous melanoma is feasible with comparable regional control and minimal toxicity.

Recursive partitioning analysis (RPA) enables grouping of patients into homogeneous prognostic groups in a visually intuitive form and has the capacity to account for complex interactions among prognostic variables. In this study, we employed RPA to generate a prognostic model for extremity soft tissue sarcoma (STS) patients with metastatic disease.A retrospective review was conducted on 135 patients with metastatic STS who had undergone surgical removal of their primary tumours. Patient and tumour variables along with the performance of metastasectomy were analysed for possible prognostic effect on post-metastatic survival. Significant prognostic factors on multivariate analysis were incorporated into RPA to build regression trees for the prediction of post-metastatic survival.RPA identified six terminal nodes based on histological grade, performance of metastasectomy and disease-free interval (DFI). Based on the median survival time of the terminal nodes, four prognostic groups with significantly different post-metastatic survival were generated: (1) group A: low grade/metastasectomy; (2) group B: low grade/no metastasectomy/DFI ⩾ 12 months or high grade/metastasectomy; (3) group C: low grade/no metastasectomy/DFI12 months or high grade/no metastasectomy/DFI ⩾ 12 months; and (4) group D: high grade/no metastasectomy/DFI12 months. The 3-year survival rates for each group were: group A, 76.1 ± 9.6%; group B, 42.3 ± 10.3%; group C, 18.8 ± 8.0%; and group D, 0.0 ± 0.0%.Our prognostic model using RPA successfully divides STS patients with metastasis into groups that can be easily implemented using standard clinical parameters.

Non-spine bone metastasis accounts for approximately 20% of all skeletal metastases, but little data have been published that focused on bone metastasis to the pelvis and extremities as an initial manifestation of cancer. We determined 1) clinicopathologic characteristics of patients who presented with non-spine bone metastasis of unknown primary malignancy, and 2) process by which the diagnosis of primary cancer was made. We retrospectively reviewed 84 patients with bone metastasis of unknown primary cancer site at the time of presentation. The study population consisted of 56 men and 28 women, with a mean age of 59.1 yr (17.5-85.6 yr). The average follow-up period was 20.8 months (1-120 mo). Primary cancer site was identified in 79 patients (94.0%), and was determined to be the lung (46.4%), kidney (13.1%), liver (9.5%), thyroid (8.3%), and prostate (4.8%). Five-year overall survival rate was 28.0%. Multiple bone metastases, distant organ metastasis, and multiple bone with organ metastases were the significant prognostic factors in univariate analysis. Multiple bone metastases remained significant after multivariate analysis (P = 0.008). Lung cancer is the most common site of primary cancer, and patients with multiple bone metastases have a poor prognosis, possibly due to disseminated cancer and a greater tumor burden. Graphical Abstract

Cortical atrophy is commonly observed after prosthetic reconstruction for bone sarcomas. However, relevant literature regarding this phenomenon in skeletally immature patients is limited. Therefore, in this study, we evaluated the incidence and patterns of cortical atrophy. We then assessed its predisposing factors. Finally, we analyzed whether cortical atrophy was associated with poor prosthesis survival. We retrospectively reviewed 31 stems in 19 skeletally immature osteosarcoma patients who were treated with resection and tumor prosthesis surgery. We measured the cortical thickness using plain radiographs annually. The mean patient age was 11 years (range, 6 to 14 y) and the mean follow-up period was 10 years (range, 2 to 14 y). Cortical atrophy developed in 13 stems, all within 3 years. There were 3 gross types of cortical atrophy: hourglass in 5, sharpening in 4, and shortening atrophy in 4. On multivariate analysis, stem-cortex diameter ratio of ≥0.5 and age of less than 10 years were significantly associated with cortical atrophy (P=0.002 and P=0.019, respectively). Cortical atrophy was significantly associated with eventual prosthesis failure (9/13 in the cortical atrophy group vs. 4/18 in the nonatrophy group, P=0.035). Cortical atrophy is common in the skeletally immature patients with tumor prosthesis and is associated with prosthesis failure. Patients with cortical atrophy should be closely monitored for prosthesis failure and appropriately managed to prevent failures. Level IV—therapeutic study.

The high failure rate of cemented femoral components in the 1970s facilitated the improvement of the cementing technique and surface finishes such as polymethylmethacrylate (PMMA)-precoated stems, reporting a survival rate of95% at 10 years from some studies. However, controversy persists regarding whether precoated femoral stems are associated with a longer revision-free prosthesis survival. The purpose of this study was to evaluate the clinical and radiological outcomes of PMMA-precoated femoral stems, and analyze factors associated with implant survival. We retrospectively reviewed 73 primary hybrid total hip arthroplasties performed using PMMA-precoated femoral stems. The mean age of the patients was 61 years. During the mean follow-up period of 13 years, 18 hips (24.7%) underwent aseptic loosening, and all of the loosened stems were subjected to revision surgery 8.8 years (range 4.6-15.5 years) from the index surgery. Younger age and poor cementing were significantly associated with aseptic loosening (P = 0.013 and P 0.001, respectively). However, the aseptic loosening rate was also high at 13.1% even with a good cementing technique. In conclusion, the PMMA-precoated stem failed to show expected advantages and needs to be replaced with other surface finish stem designs. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 1300-1306, 2017.

Cancellous allograft bone chips are commonly used in the reconstruction of defects in bone after removal of benign tumours. We investigated the MRI features of grafted bone chips and their change over time, and compared them with those with recurrent tumour. We retrospectively reviewed 66 post-operative MRIs from 34 patients who had undergone curettage and grafting with cancellous bone chips to fill the defect after excision of a tumour. All grafts showed consistent features at least six months after grafting: homogeneous intermediate or low signal intensities with or without scattered hyperintense foci (speckled hyperintensities) on T1 images; high signal intensities with scattered hypointense foci (speckled hypointensities) on T2 images, and peripheral rim enhancement with or without central heterogeneous enhancements on enhanced images. Incorporation of the graft occurred from the periphery to the centre, and was completed within three years. Recurrent lesions consistently showed the same signal intensities as those of pre-operative MRIs of the primary lesions. There were four misdiagnoses, three of which were chondroid tumours.We identified typical MRI features and clarified the incorporation process of grafted cancellous allograft bone chips. The most important characteristics of recurrent tumours were that they showed the same signal intensities as the primary tumours. It might sometimes be difficult to differentiate grafted cancellous allograft bone chips from a recurrent chondroid tumour.Cite this article: Bone Joint J 2015;97-B:121–8.

Purpose Although tension band wiring (TBW) is generally accepted as standard treatment for olecranon fractures, it has several shortcomings such as loss of reduction, skin irritation, and migration of the K-wires. To overcome these problems and increase fixation stability, we used a rigid fixation technique with double tension band wiring (DTBW). Here, we describe the technique and outcomes of the treatment. Methods We retrospectively reviewed 21patients with olecranon fractures who were treated by DTBW. We evaluated clinical and radiological outcomes by checking the range of motion, loss of reduction, functional scoring, skin complications, and pin migration. There were 15 cases of Mayo type IIA fractures (71%) and 6 of type IIB fractures (29%). The mean follow-up period was 37 months (range, 12−58 mo). We also compared the mechanical stability of DTBW and TBW in a sawbone model using a single cycle load to failure protocol. Results All fractures united without displacement, and no migration of the K-wires was observed during the period of follow-up. Mean loss of elbow extension was 2° (range, 0°–15°) and mean elbow flexion was 134° (range, 125°–140°). The mean Mayo Elbow Performance Score was 94 (range, 70–100). Biomechanical testing revealed greater mechanical strength in the DTBW technique than in the TBW when measured by mean maximum failure load and mean bending moment at failure. Conclusions DTBW produced good clinical and radiological outcomes and could be an effective option for the treatment of olecranon fractures by providing additional stability through a second TBW. Biomechanical comparison with a control group (TBW) supported the mechanical benefits of DTBW. Type of study/level of evidence Therapeutic IV.

Preoperative transcatheter arterial embolization for hypervascular bone tumors is now widely accepted as a safe and effective procedure for reducing intraoperative blood loss and surgical morbidity. However, few studies have reported the use of preoperative transcatheter arterial embolization for nonspine bone metastases from hepatocellular carcinoma. The goal of this study was to assess the effect of preoperative embolization on blood loss and clinical outcomes in surgery for nonspine bone metastasis from hepatocellular carcinoma. Seventy-five patients with metastases from hepatocellular carcinoma to the pelvis and extremities were reviewed retrospectively. The study population consisted of 62 men and 13 women, with a mean age of 64.6 years (range, 40.0–80.1). The average follow-up period was 8.2 months (range, 0.3–66.1). Twenty-two patients underwent transcatheter arterial embolization for preoperative devascularization (group A), and 53 patients underwent operative treatment only (group B). The proportion of pelvis metastases was significantly higher ( P P =.006) in group A than in group B. However, a significantly smaller decrease in hemoglobin level before and after surgery was seen in group A ( P =.017). No significant differences were seen in intraoperative estimated blood loss, perioperative hemoglobin level, number of allogeneic transfusions, or length of hospitalization between the 2 groups. Preoperative transcatheter arterial embolization is an effective means to reduce bleeding during surgery for nonspine metastases from hepatocellular carcinoma. In general, surgical procedures that included transcatheter arterial embolization took longer and were more extensive. [ Orthopedics. 2015; 38(2):e99–e105.]

The presence of early postoperative fever after megaprosthesis replacement surgery is a concern for orthopedic oncologists due to the possibility of infection. The aims of the current study were to determine the incidences and patterns of fever and factors associated with its development and to determine the clinical significance of fever after megaprosthesis replacement surgery. Seventy-one patients who had undergone megaprosthesis reconstruction for previously unoperated localized lower-extremity osteosarcoma were reviewed. No patient had evidence of infection preoperatively. Mean patient age was 23.72±16.84 years (range, 6.7–74 years), and average follow-up was 59.5 months (range, 4–240 months). Five postoperative surgical wound infections (4 deep, 1 superficial) occurred on postoperative days 5, 13, 14, 20, and 21. Fevers (body temperature of 38°C or higher) were present in 62 patients (87.3%) at some point during the first 2 postoperative weeks. Peak body temperature was observed on postoperative day 1 in 62% of the febrile patients. Of the 62 febrile patients, 94% were relieved of fever by postoperative day 5. No significant association was observed between the presence of fever and surgical wound infection. Body temperature curves in patients with infection showed that several atypical patterns, such as multiple fever peaks and persistent fever, were accompanied by physical findings within the normalization period. Fever during the first 5 postoperative days is common after megaprosthesis replacement for bone sarcomas and seems to be a normal physiologic response to surgery. However, atypical fever patterns or additional physical findings require investigation.

3-5) many healthy older patients with STS seem to have a greater ability to endure treatments and to experience more favorable outcomes than unhealthy young patients. Comorbidity, defined as coexisting diseases or conditions, has not been regarded as an independent prognostic factor in cancer patients because the impact of comorBackground: Comorbidity has not been examined as an independent prognostic factor in soft tissue sarcoma (STS). We examined the prognostic impact of comorbidity on oncologic outcome in STS with an adjustment for possible confounding factors. Methods: A retrospective review was performed on 349 patients who had undergone surgery for high-grade localized STS of extremity at our institute. Conditions known to alter the risk of mortality, as defined in the Charlson comorbidity index, were classi fied as comorbidities and 43 patients (12%) had at least one comorbidity at the time of surgery. The association of comorbidity and oncologic outcomes of local recurrence-free survival (LRFS) and disease-specific survival (DSS) were tested with adjustment for confounding factors. Results: Comorbidity was associated with old age, high tumor grade, and large tumor size. The presence of comorbidity was independently associated with poor LRFS and DSS, even after adjusting for confounding factors including age and treatment variables. Conclusions: Our data suggest that the presence of comorbidity is an independent prognostic factor for extremity STS.