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Osteosarcomas (OSs) are aggressive bone tumors with many divergent histologic patterns. During pathology review, OSs are subtyped based on the predominant histologic pattern; however, tumors often demonstrate multiple patterns. This high tumor heterogeneity coupled with scarcity of samples compared with other tumor types render histology-based prognosis of OSs challenging. To combat lower case numbers in humans, dogs with spontaneous OSs have been suggested as a model species. Herein, a convolutional neural network was adversarially trained to classify distinct histologic patterns of OS in humans using mostly canine OS data during training. Adversarial training improved domain adaption of a histologic subtype classifier from canines to humans, achieving an average multiclass F1 score of 0.77 (95% CI, 0.74-0.79) and 0.80 (95% CI, 0.78-0.81) when compared with the ground truth in canines and humans, respectively. Finally, this trained model, when used to characterize the histologic landscape of 306 canine OSs, uncovered distinct clusters with markedly different clinical responses to standard-of-care therapy.

With improved chemotherapeutic treatment, patients with primary or metastatic bone tumor have improved prognoses and longer life expectancies; therefore, durable limb-salvage constructs are critical. For tumors of the proximal femur, endoprosthetic replacement is an option for treatment in primary and metastatic disease, with the goals being tumor and pain control, earlier mobilization, shorter recovery period, and, in primary tumors, cure. This study provides a summary of current concepts in the treatment of oncologic lesions in the proximal femur with endoprostheses. Discussion of the inherent complications of these constructs is presented as well as the risks and treatment of reconstruction failure.

The proximal humerus is a common location for primary tumors, benign lesions, and metastatic disease. Advances in neoadjuvant and adjuvant therapy have allowed for limb-salvage surgery in most of the cases. There are numerous of options for surgical management of proximal humerus lesions and the decision to pursue one over another depends on factors such as age, comorbidities, pathology, location within the proximal humerus, planned resection margins/size of defect, and bone quality. Long-term outcomes for these techniques tend to be retrospective comparative studies, with recent studies highlighting the improved outcomes of reverse total shoulders.

Since ancient times, Artemisia annua (A. annua) has been used as a medicinal plant in Traditional Chinese Medicine. In addition, recent studies have investigated the cytotoxic effects of A. annua extracts towards cancer cells. The leading aim of the present research is to evaluate the cytotoxic effects of an hydroalcoholic extract of A. annua on two canine osteosarcoma (OSA) cell lines, OSCA-8 and OSCA-40, focusing on the possible involvement of ferroptosis. The quantitative determination of artemisinin concentration in the extract, culture medium and OSA cells was carried out through the use of an instrumental analytical method based on liquid chromatography coupled with spectrophotometric detection and tandem mass spectrometry (LC-DAD-MS/MS). OSCA-8 and OSCA-40 were exposed to different dilutions of the extract for the EC

Introduction: There are several studies in the literature about pathological fractures but almost no in-formation about patients whose pathological fracture caused by a malignant lesion misdiagnosed and treated as a simple fracture. The aim of this study was to investigate patient and fracture characteristics, and outcomes in cases where fractures occurred in the presence of a malign pathology but were treated as simple fractures. Patients andMethods: Cases of malign bone lesions between 20 0 0 and 2020 were retrospectively re-viewed. Patients with a final diagnosis of malign bone lesion but whose pathological fractures were treated ignoring the underlying malign bone disease were included. Demographic, clinical and outcome data were collected from patient\"s medical records and analyzed.Results: Six patients met the inclusion criteria. Three of the patients were female and the cohort mean age was 56.8 +/- 21.8 years at the time of admission. Patient diagnoses were: renal cell carcinoma metas-tasis ( n = 1); colon cancer metastasis ( n = 1); chondrosarcoma ( n = 2); osteosarcoma ( n = 1); and undif-ferentiated pleomorphic sarcoma of bone ( n = 1). In all cases surgical management differed from those that should have been applied if the pathological fracture had been identified. Furthermore, surgical man-agement after definitive histological diagnosis were more aggressive compared to if the malignancy had been identified at first admission. All patients died after a mean follow-up of 16.67 +/- 11.7 months and the complication rate was 100%.Conclusion: When a pathological fracture is misdiagnosed and managed as a simple bone fracture, out-comes are extremely poor. In these situations, remedial surgery is more extensive, with increased com-plication rates and there is poor life expectancy.(c) 2022 Elsevier Ltd. All rights reserved.

Osteosarcoma (OS) is a highly metastatic bone cancer that usually affects children. Rhizoma Paridis saponins (RPS) have been identified to show a broad-spectrum anti-tumor activity. Our previous study has identified vasculogenic mimicry (VM) as an indicator of poor prognosis for OS. Rhizoma Paridis ethanol extract exhibits potent anti-OS property. However, the anti-metastatic effect of RPS on OS and the detailed mechanisms remain unknown. RPS was characterized by liquid chromatography/quadrupole time-of-flight mass spectrometry (LC/Q-TOF/MS) analysis. The anti-OS, anti-metastasis and anti-VM activities of RPS were investigated using in vitro biological assays and a xenograft mouse model. Western blot, qRT-PCR, ELISA, Phalloidin staining and immunohistochemistry assays were conducted to investigate the molecular mechanism of RPS. A total of 34 phytochemicals from RPS were identified by LC/Q-TOF/MS. RPS dose-dependently suppressed the OS cell proliferation, metastasis and VM formation in vitro and in vivo. Mechanically, we found that RPS downregulated migration-inducing gene 7 (MIG-7) expression, resulting in inhibition of the PI3K/MMPs/Ln-5γ2 pathway and cell protrusion formation. Additionally, we confirmed that RPS downregulated MIG-7 by upregulating miR-520d-3p expression. Our results suggests that RPS inhibits the VM formation and metastasis of OS by modulating the miR-520d-3p/MIG-7 signaling axis.

Pelvic sarcomas are a rare and heterogenous group of tumors divided into two groups: soft tissue sarcomas and bone sarcomas. Soft tissue sarcomas of the pelvis include most commonly liposarcoma, leiomyosarcoma, gastrointestinal stromal tumors, malignant peripheral nerve sheath tumors, and solitary fibrous tumors. Bone sarcomas of the pelvis most commonly include osteosarcoma and chondrosarcoma. Multidisciplinary treatment at a center experienced in the treatment of sarcoma is essential. Management is dictated by histologic type and grade. Surgical resection with wide margins is the cornerstone of treatment for pelvic sarcomas, although this is often challenging due to anatomic constraints of the pelvis. Multimodal treatment is critical due to the high risk of local recurrence in the pelvis.

External beam radiation therapy (EBRT) to oligometastases may improve outcomes in patients with oligometastatic hormone-sensitive prostate cancer (oHSPC). Follow-up on this cohort has been limited to5 years and prospective data on de novo patients with oHSPC are lacking. We reviewed the long-term outcomes of patients with oHSPC treated with EBRT and androgen deprivation therapy on a prospective trial.From 2006 to 2011, patients with oHSPC with 1 to 5 metastases received 36 weeks of androgen deprivation therapy (luteinizing hormone-releasing hormone agonist + bicalutamide) and up to 53 Gy to all visible metastases. When indicated, the primary tumor or prostate bed was treated with EBRT up to 78 or 66 Gy, respectively.Twenty-nine patients were treated: 15 de novo, 14 oligorecurrent, and 21 patients (72.4%) had bone metastases. Median number of metastases per patient was 1 (range, 1-5). EBRT was administered to 52 lesions (38 bone, 12 pelvic lymph nodes [LNs], 2 nonpelvic LNs) up to 53 Gy (range, 47-66). Median follow-up was 9.9 years (years; range, 0.2-14.4). Median overall survival was 9.7 years (95% confidence interval [CI], 5.8-not reached). Median progression-free survival was 1.9 years (95% CI, 1.6-2.2). Patients who presented with prostate cancer-defined de novo metastases had significantly improved (P = .04) median progression-free survival (2.0 years; 95% CI, 1.3-6.0) compared with oligorecurrent patients (1.8 years; 95% CI, 1.0-2.0). Patients who presented with LN-only metastases had numerically improved (P = .13) median PFS (5.8 years; 95% CI, 1.2-not reached) compared with patients with bony metastases (1.8 years; 95% CI, 1.3-2.0). At last follow-up, 17 patients (58.6%) had local control of all EBRT-treated metastases. The metastases that locally progressed had previously been controlled for median 3.5 years (range, 1.7-10.5).Our results compare favorably with other reported studies of patients with oHSPC and provide new insights into their long-term outcomes.

Chemokines are well equipped with chemo-attractive signals that can regulate cancer cell trafficking to specific organ sites. Currently, updated concepts have revealed the diverse role of chemokines in the biology of cancer initiation and progression. Genomic instabilities and alterations drive tumor heterogeneity, providing more options for the selection and metastatic progression to cancer cells. Tumor heterogeneity and acquired drug resistance are the main obstacles in managing cancer therapy and the primary root cause of metastasis. Studies emphasize that multiple chemokine/receptor axis are involved in cancer cell-mediated organ-specific distant metastasis. One of the persuasive mechanisms for heterogeneity and subsequent events is sturdily interlinked with the crosstalk between chemokines and their receptors on cancer cells and tissue-specific microenvironment. Among different metastatic niches, skeletal metastasis is frequently observed in the late stages of prostate, breast, and lung cancer and significantly reduces the survival of cancer patients. Therefore, it is crucial to elucidate the role of chemokines and their receptors in metastasis and bone remodeling. Here, we review the potential chemokine/receptor axis in tumorigenesis, tumor heterogeneity, metastasis, and vicious cycle in bone microenvironment.

Graphene-based three-dimensional (3D) porous scaffolds have been extensively investigated in the photothermal treatment of tumor-induced bone defects due to their photothermal and osteogenic capacity. However, scaffold processing destroys conjugated graphene structure and reduces its photothermal conversion efficiency. In this study, a graphene-based 3D scaffold (GS) with intact conjugated structure was prepared by chemical vapor deposition (CVD). GS was rapidly mineralized biomimetically by a newly developed semi-dry electrochemical deposition method to form a hydroxyapatite (HA) incorporated graphene scaffold (HA-GS). The simulation of the charged particle dynamics provides a better understanding of the mechanism of semi-dry electrodeposition. This scaffold exhibits high photothermal sensitivity that generates sufficient thermal energy for photothermal therapy even under near-infrared irradiation (980 nm) with extremely low power density (0.2 W/cm

Plasma cell neoplasms are exceptionally rare in the pediatric population; the demographic characteristics and the clinical outcomes of plasma cell neoplasms in this population are currently poorly understood. The aim of this study was to provide a comprehensive analysis of pediatric plasma cell neoplasms, based on the United-States Surveillance, Epidemiology, and End Results (SEER) program registries.All pediatric patients (aged less than 20 years) diagnosed with a malignant plasma cell neoplasm were retrieved from the SEER Program database (18 registries), collecting patient records between 2000 and 2018. The plasma cell neoplasm type, sex, age at diagnosis, year of diagnosis, race and origin, primary disease site, follow-up duration, and vital status at the last known contact were retrieved and analyzed.The age-adjusted incidence rate of plasma cell neoplasms for 1,000,000 person-years was 0.06 for the pediatric population (compared with 90.6 for the adult population). The types of pediatric plasma cell neoplasms predominantly consisted of plasmacytomas, with 11 solitary extraosseous plasmacytoma (42.3%) and 7 solitary bone plasmacytoma (26.9%), while plasma cell myelomas represented only a minority of the neoplasms (8 patients; 30.8%). Most plasmacytomas were localized in the head and neck region. Hispanic patients represented 50% of the pediatric plasma cell neoplasm cases (but only 11.1% of adult cases, P.01). Female-to-Male ratio was 1.36. Five-year overall survival rates were 88.2% (95% confidence interval [95% CI]: 74.2%-100%) for pediatric plasmacytoma and 36.5% (95% CI: 12.4%-100%) for pediatric plasma cell myeloma (P = .013).This first population-based study of pediatric plasma cell neoplasms underlines the rarity of this entity and demonstrates its unique characteristics, including the significant predominance of plasmacytomas, of female patients, and of patients from hispanic origin, and the poor clinical outcomes of pediatric plasma cell myeloma patients.

Mutant isocitrate dehydrogenase (IDH) in chondrosarcoma produces the oncometabolite 2-hydroxyglutarate (2-HG) and contributes to malignant progression, and is therefore a potential therapeutic target for chondrosarcoma. Robust historical control data are important in clinical trials of rare cancers such as chondrosarcoma in order to show a clear benefit of new drugs. However, it remains controversial whether IDH mutation status is associated with the clinical outcome of chondrosarcoma, and this hinders the development of mutant IDH inhibitors in clinical trials.background METHODS: We investigated the relationship between IDH gene status and clinicopathological data in 38 chondrosarcoma patients from whom frozen tumor samples were obtained at the time of biopsy or surgery. Targeted next-generation sequencing was also performed to compare genetic alterations between patients with and without IDH mutations.The results revealed 15 cases (40%) of heterozygous IDH1 mutations and five cases (13%) of IDH2 mutations. IDH-mutant chondrosarcoma was associated with worse overall survival than IDH-wild-type chondrosarcoma (IDH1/2 Mut vs. IDH Wt, P = 0.006; IDH1 Mut vs. IDH Wt, P = 0.030; IDH2 Mut vs. IDH Wt, P 0.0001). IDH mutation was also a significant poor prognostic factor both in univariate (P = 0.026) and multivariate (P = 0.048) analyses. Targeted next-generation sequencing revealed that characteristic mutations in chondrosarcoma, including TP53 and COL2A1, were more common in the IDH-mutant group than in the IDH-wild-type group.results CONCLUSION: This study is the first to report in detail the characteristics and clinical courses of IDH-mutant chondrosarcoma patients in Japan. Our data suggested that IDH-mutant chondrosarcomas might have a worse prognosis than that of IDH-wild-type chondrosarcoma, possibly through the more aggressive characters after metastasis. This information will be useful for designing clinical trials of mutant IDH inhibitors for treatment of advanced chondrosarcoma.

Background Endoprosthetic replacement of the proximal femur plays a vital role in managing metastatic and primary bone tumours1. Length of stay (LOS) has important resource implications but is driven by patient and disease factors over and above the procedure itself. The aim of this project was to identify factors that drive LOS in patients undergoing proximal femoral replacement (PFR). Methods This was a retrospective analysis of clinical records from a single centre (RNOH). 144 cases were identified over a 4 year-period. These were divided into 3 diagnostic categories: primary bone tumour with chemotherapy, primary bone tumour without chemotherapy and metastatic bone disease. Several factors were considered that could influence the length of stay including age, ASA grade, gender, admission to the high dependency unit (HDU), diagnosis, saving the greater trochanter, pre-operative radiotherapy, admission with a fracture and return to theatre. Results The median LOS for PFR was 15 days, with 79% admitted to HDU. LOS was almost doubled for patients returning to theatre (P = 0.04). Patients with ASA grades of 3 and 4 had a 75% longer LOS compared to those with grade 1. Additionally, a 10-year increase in age was associated with a 6–8% increase in LOS. Incorporating these factors produced a model which explained 27% of the variability of LOS. Conclusion Majority of the variables which were tested were significantly associated with LOS. However, factors other than those in our model drive length of stay. This analysis can support conversations with patients and service planning around LOS.

Ewing sarcoma, a malignancy originating from the bone or soft tissues most commonly diagnosed in adolescents, requires multimodality therapy. Although both surgical resection and radiation therapy are effective local control modalities, there are limited data comparing outcomes in patients treated with surgery versus radiation. We sought to determine whether there were differences in 5-year local failure-free survival, event-free survival, and overall survival based on the modality used for local control.Patients treated for Ewing sarcoma at a single tertiary pediatric hospital between 2010 and 2020 were included for retrospective analysis. Patient and tumor demographics, treatment information, and patient response to therapies were collected from the medical record. Outcome measures were local failure-free survival, event-free survival, and overall survival at 5 years from diagnosis.Sixty-one patients met inclusion criteria. All patients received chemotherapy, and 68.9% of patients presented with localized disease. Of these, 23.8% were treated with radiation alone; the remaining 76.2% underwent resection ± radiation. A total of 52.4% of patients with localized disease achieved R0 resection. Only 3 patients experienced local progression; there was no difference between treatment groups. There was no significant association between local control modality and event-free survival or overall survival in patients with localized disease, regardless of margin status.There was no significant difference in 5-year local failure-free survival, event-free survival, or overall survival in Ewing sarcoma patients treated with radiation versus surgery ± radiation, regardless of whether or not R0 resection was achieved. Future directions include a multi-institutional study to allow for further subgroup analysis and increased sample size.

The FLASH effect is a potential breakthrough in radiotherapy because ultra-high dose-rate irradiation can substantially widen the therapeutic window. While the normal tissue sparing at high doses and short irradiation times has been demonstrated with electrons, photons, and protons, so far evidence with heavy ions is limited to in vitro cell experiments. Here we present the first in vivo results with high-energyLM8 osteosarcoma cells were subcutaneously injected in the posterior limb of female C3H/He mice 7 days before radiation exposure. Both hind limbs of the animals were irradiated with 240 MeV/nIrradiation with carbon ions was able to control the tumour both at conventional and ultra-high dose rate. FLASH decreases normal tissue toxicity as demonstrated by the reduced structural changes in muscle compared to conventional dose-rate irradiation. Carbon ion irradiation in FLASH conditions significantly reduced lung metastasis compared to conventional dose-rate irradiation and sham-irradiated animals.We demonstrated the FLASH effect in vivo with high-energy carbon ions. In addition to normal tissue sparing, we observed tumor control and a substantial reduction of lung metastasis in an osteosarcoma mouse model.

Giant-cell tumor (GCT) is often more aggressive when located in the distal radius, and wide resection is then the gold-standard. No single reconstruction protocol is recommended, and the technique depends upon the surgeon's preferences. The aim of the present review was to determine the recurrence rate of GTC of the distal radius after intralesional treatment, to assess the results, advantages and complications of the various surgical techniques, and to draw up a decision-tree for surgical indications. The review of literature was performed in the main healthcare databases, searching for studies that reported results of wide resection and reconstruction of distal radius GCT. Local recurrence rates, metastasis rates, reconstruction techniques and respective results and complications were evaluated and analyzed. Sixteen studies were selected, for a total population of 226 patients; 6.0% and 0.9% experienced local recurrence and lung metastasis, respectively. Arthroplasty with non-vascularized or vascularized ipsilateral fibula were the most common techniques and were associated with the highest satisfaction rates: 86.4% and 88.0%, respectively. Arthroplasty with allograft presented a MusculoSkeletal Tumor Society (MSTS) score of 79.2% and arthroplasty with custom-made prosthesis presented an MSTS score of 81.8%. Arthrodesis was performed in 46 cases, with an MSTS score of 82.7%. Arthroplasty techniques are the most common in literature; they are used in patients who wish to conserve joint motion. Reconstruction with non-vascularized fibula seems to provide the best results, with lower morbidity. Arthrodesis is usually reserved for heavy manual workers or in case of arthroplasty failure.

Radium-223 is an alpha-emitting, bone-targeting radiopharmaceutical that confers a survival benefit in patients with confirmed bone-metastatic, castration-resistant prostate cancer with no visceral metastases. We studied real-world use of radium-223 in eligible patients from a tertiary hospital.We retrospectively collected clinical data of patients treated with radium-223 in Tungs' Taichung MetroHarbor Hospital by chart review. Data included biochemical parameters, pain scores, other prostate cancer treatments received and adverse events (AEs).Of 36 patients included in the study, 12 patients received radium-223 as first-line therapy, 11 as second-line treatment and 13 as third-line treatment. Prostate-specific antigen significantly increased from baseline in patients who received radium-223 as third-line treatment and in patients who received radium-223 post-chemotherapy. Pain scores significantly decreased when radium-223 was given as second-line and as third-line treatment. In the patients who were naive to novel anti-hormone (NAH) therapy and chemotherapy, mean alkaline phosphatase level significantly decreased from baseline. The most common AE was anemia, found in 16.7% of patients.Radium-223 had early biochemical benefits, while in the later stages of the disease, it reduced bone pain in this real-world cohort of chemotherapy-naive, NAH-naive patients, and patients with prior therapy, from a tertiary institution in Taiwan.

Bone metastases are common in malignant tumors and the effect of conventional treatment is limited. How to effectively inhibit tumor bone metastasis and deliver the drug to the bone has become an urgent issue to be solved. While bone targeting drug delivery systems have obvious advantages in the treatment of bone tumors. The research on bone-targeted anti-tumor therapy has made significant progress in recent years. We introduced the related tumor pathways of bone metastases. The tumor microenvironment plays an important role in metastatic bone tumors. We introduce a drug-loading systems based on different environment-responsive nanocomposites for anti-tumor and anti-metastatic research. According to the process of bone metastases and the structure of bone tissue, we summarized the information on bone-targeting molecules. Bisphosphate has become the first choice of bone-targeted drug delivery carrier because of its affinity with hydroxyapatite in bone. Therefore, we sought to summarize the bone-targeting molecule of bisphosphate to identify the modification effect on bone-targeting. And this paper discusses the relationship between bisphosphate bone targeting molecular structure and drug delivery carriers, to provide some new ideas for the research and development of bone-targeting drug delivery carriers. Targeted therapy will make a more outstanding contribution to the treatment of tumors.

Bone metastases; Metastatic castration-resistant prostate cancer Metástasis óseas; Cáncer de próstata metastásico resistente a la castración Metàstasis òssies; Càncer de pròstata resistent a la castració metastàtic Purpose The paper aims to evaluate the efficacy and safety of 223Ra in patients who progressed after first-line androgen deprivation therapy. Patients and methods EXCAAPE (NCT03002220) was a multicentre, single-arm, open-label, non-controlled phase IIa trial in 52 patients with metastatic castration-resistant prostate cancer and asymptomatic bone metastases who have progressed on abiraterone acetate or enzalutamide, up to six doses of 223Ra (55 kBq/kg of body weight per month). The primary end-point was radiographic progression-free survival (rPFS). Secondary end-points included rPFS based on androgen receptor splice variant 7 (AR-V7) expression in circulating tumour cells (CTCs), overall survival, and safety. Results Median rPFS was 5.5 months (95% CI 5.3–5.5). Median rPFS of patients with AR-V7(−) CTCs was longer than that of patients with AR-V7(+) CTCs (5.5 versus 2.2 months, respectively; P = 0.056). Median overall survival was 14.8 months (95% CI 11.2–not reached) and was significantly greater for AR-V7(−) patients than for AR-V7(+) patients (14.8 months versus 3.5 months, respectively; P < 0.01). 223Ra was well tolerated; anaemia and thrombocytopenia were the most common grade 3/4 adverse events (5.8% and 11.5%, respectively). Conclusions 223Ra seems to be a reasonable treatment for patients with metastatic castration-resistant prostate cancer and asymptomatic bone metastases progressing on novel hormonal therapy and had an acceptable safety profile. The study was conceived and designed by Joan Carles in collaboration with Medica Scientia Innovation Research (MEDSIR). MEDSIR, as legal sponsor of the study, is responsible for compliance with all clinical and regulatory procedures and adherence to the study protocol. MEDSIR had a role in study design, collection, management, analysis, and interpretation of the data and writing of the report. Bayer Inc. funded the study and provided 223Ra. The funder of the study had no role in data collection, management, data analysis, data interpretation, writing of the report, or decision to submit the manuscript for publication. All authors had full access to the data used to prepare the manuscript and participated in writing, editing, and/or critically reviewing the manuscript. The manuscript was written with editorial support from a medical writer, funded by MEDSIR. The corresponding author had final responsibility for the decision to submit for publication.

Bone metastases are a common site of spread in advanced breast cancer and responsible for morbidity and high health care costs. Imaging contributes to staging and response assessment of the skeleton and has been instrumental in guiding patient management for several decades. Historically this has been with radiographs, computed tomography and bone scans. More recently, molecular and hybrid imaging methods have undergone significant development, including the addition of single photon emission computed tomography/computed tomography to the bone scan, positron emission tomography, with bone-specific and tumor-specific tracers, and magnetic resonance imaging with complementary functional diffusion-weighted imaging. These have allowed different aspects of the abnormal biology associated with bone metastases to be explored. There is ability to interrogate the bone microenvironment with bone-specific tracers and cancer cell characteristics with tumor-specific methods that complement morphological appearances on computed tomography or magnetic resonance imaging. Alongside the advent of novel, more effective and nuanced therapies for bone metastases in breast cancer, there is accumulating evidence that the developments in imaging allow more sensitive and specific detection of bone metastases as well as more accurate and earlier assessment of treatment response leading to improvements in patient management.

Novel effective therapies are urgently needed in recurrent osteosarcoma. GD2 is expressed in human osteosarcoma tumours and cell lines. This study evaluated the disease control rate (DCR) in patients with recurrent osteosarcoma treated with the anti-GD2 antibody dinutuximab plus cytokine therapy as compared to historical outcomes.AOST1421 was a single-arm Phase 2 study for patients with recurrent pulmonary osteosarcoma in complete surgical remission. Patients received up to five cycles of dinutuximab (70 mg/mThirty-nine eligible patients were included in the outcome analysis. Dinutuximab did not demonstrate evidence of efficacy as 11/39 patients remained event free for a DCR of 28.2% (95% CI 15-44.9%). One of 136 administered therapy cycles met criteria for unacceptable toxicity when a patient experienced sudden death of unknown cause. Other ≥ Grade 3 toxicities included pain, diarrhoea, hypoxia, and hypotension. Pharmacokinetic parameters were similar in the two schedules.The combination of dinutuximab with GM-CSF did not significantly improve DCR in recurrent osteosarcoma. Dinutuximab toxicity and pharmacokinetics in adolescent and young adult osteosarcoma patients were similar to younger patients. Other strategies for targeting GD2 in osteosarcoma are being developed.

The purpose of this study was to assess the long-term efficacy of CT-guided microwave ablation (MWA) in the treatment of osteoid osteoma. Secondary objectives were to assess early outcome and side-effects of MWA.Twenty-eight consecutive patients (18 men, 10 women) with a median age of 19.5 years (IQR: 16, 25.5) with a total of 28 non-spinal osteoid osteoma treated by CT-guided MWA were retrospectively included. The ablations were performed with a median power and duration of 60 Watt and 1 min 30 s, respectively. Pain referred to osteoid osteoma was assessed at predefined time points using a 0-10 numeric rating scale. At one month, contrast-enhanced follow-up MRI was performed to evaluate the nidus vascularization and the volume of necrosis induced by MWA. Clinical success was defined by the absence of osteoid osteoma-related pain, and technical success was defined by the presence of necrosis of the nidus on the one-month post-MWA MRI.Long term success rate was 93% (26/28) after a follow-up of 55.5 months (IQR: 25.75, 74.5) and technical success rate was 96 % (25/26). One late failure was observed after a patient had been declared cured at one month but the formal proof of a late recurrence of osteoid osteoma could not be brought. Three minor complications were reported including mild reversible superficial radial nerve injury with a skin burn (grade 2) in one patient and moderate skin burn only in two patients.Our results suggest that CT-guided MWA is an effective option for a minimally-invasive treatment of osteoid osteoma with a low rate of complication and no late recurrence.

Radiation utilization for breast cancer and metastatic bone disease varies in modality, fractionation, and cost, despite evidence demonstrating equal effectiveness and consensus recommendations such as Choosing Wisely that advocate for higher value care. We assessed whether the Oncology Care Model (OCM), an alternative payment model for practices providing chemotherapy to patients with cancer, affected the overall use and value of radiation therapy in terms of Choosing Wisely recommendations.We used Centers for MedicareMedicaid Services administrative data to identify beneficiaries enrolled in traditional fee-for-service Medicare who initiated chemotherapy episodes at OCM and propensity-matched comparison practices. Difference-in-difference (DID) analyses evaluated the effect of OCM on overall use of postoperative radiation for breast cancer, use of intensity modulated radiation therapy and hypofractionation for breast cancer, and fractionation patterns for treatment of metastatic bone disease from breast or prostate cancer. We performed additional analyses stratified by the presence or absence of a radiation oncologist in the practice.Among 27,859 postoperative breast cancer episodes, OCM had no effect on overall use of radiation therapy after breast surgery (DID percentage point difference = 0.4%; 90% confidence interval [CI], -1.7%, 2.4%) or on use of intensity modulated radiation therapy in this setting (DID = -0.6; 90% CI, -3.1, 2.0). Among 19,366 metastatic bone disease episodes, OCM had no effect on fractionation patterns for palliation of bone metastases (DID for ≤10 fractions = -1.1%; 90% CI, -2.6%, 0.4% and DID for single fraction = -0.2%; 90% CI, -1.9%, 1.6%). Results were similar for practices with and without a radiation oncologist. We did not evaluate the effect of OCM on hypofractionated radiation after breast-conserving surgery owing to evidence of differential baseline trends.OCM had no effect on use of radiation therapy after breast-conserving surgery for breast cancer or on fractionation patterns for metastatic bone disease. Future payment models directly focused on radiation oncology providers may be better poised to improve the value of radiation oncology care.

Sialic acid-bound immunoglobulin lectin 15 (Siglec-15) plays a crucial role in many kinds of tumors. The relationship between Siglec-15 and the prognosis of osteosarcoma patients and its role in the apoptosis and pyroptosis of osteosarcoma cells are not sufficiently understood. Our study aimed to investigate the function of Siglec-15 in osteosarcoma cells and its effect on tumor cell proliferation, apoptosis and pyroptosis.The Siglec-15 expression in pathological sections of osteosarcoma patients was analyzed and the overall survival time related to the expression of Siglec-15 was further analyzed. Next, we detected the expression of Siglec-15 in osteosarcoma cells and downregulated the expression of Siglec-15 by small interfering RNA (siRNA). The proliferation, apoptosis and pyroptosis of osteosarcoma cells were studied by proliferation and apoptosis kits and Western blotting. Furthermore, the Siglec-15 signaling pathway was examined, which may be involved in the observed cellular effects.We demonstrated the expression of Siglec-15 in osteosarcoma cells. SiRNA-mediated downregulation of Siglec-15 was successful. We found that knockdown of Siglec-15 in osteosarcoma cell lines significantly inhibited proliferation while promoting apoptosis. Further investigation showed that the expression of proliferation-related proteins was downregulated and that apoptosis- and pyroptosis-related proteins were upregulated. In addition, we found that Siglec-15 may inhibit proliferation while inducing apoptosis and pyroptosis via the (Signal Transducer and Activator of Transcription 3) STAT3/Bcl-2 pathway in osteosarcoma.In this study, we demonstrated that the ablation of Siglec-15 in osteosarcoma inhibited proliferation and promoted apoptosis and pyroptosis by targeting the Siglec-15/STAT3/Bcl-2 pathway.

To explore the role of imaging features in the diagnosis of endolymphatic sac tumour (ELST).Twenty-two patients with ELST confirmed at histopathology were included in this retrospective study. All patients underwent computed tomography (CT) and magnetic resonance imaging (MRI) examinations, including diffusion-weighted imaging (DWI; n=18) and dynamic contrast-enhanced (DCE) MRI (n=3). The imaging features of this series were analysed.All lesions appeared as irregular soft-tissue mass lesions located in the middle and posterior margin of the petrous bone. At CT, the normal vestibular aqueduct structure disappeared. Multiple osteoid tissues were present inside the tumour, and destructive bone changes had a "honeycomb" pattern. Twenty cases were accompanied by the incomplete thin bony peripheral rim along the medial margin. On both T1-weighted imaging (WI) and T2WI, all lesions showed hyperintense, hypointense, and isointense mixed signal intensity. Scattered peripheral hyperintensities were found in all cases on T1WI. The mean apparent diffusion coefficient (ADC) value of 18 lesions was (1.35 ± 0.13) × 10The imaging features of ELST, including its location, bone destruction form, MRI signal intensity, and enhancement pattern, are helpful to improve the diagnostic accuracy of this rare tumour.

Our study aims to highlight the role of Magnetic Resonance Imaging (MRI) in monitoring the therapeutic response after neoadjuvant chemotherapy in osteosarcoma of the long bones.In this retrospective study, data from the Orthopaedics and Internal Medicine Department of Istanbul University Cerrahpasa Hospital was used. We selected the study cohort from our departmental database of patients with biopsy-proven osteosarcoma initially treated with preoperative chemotherapy at Istanbul University Cerrahpasa Hospital from 2010 to 2017. MRI images of 21 patients (male/female ratio: 2.5 with a mean age of 22) were analysed before and after neoadjuvant chemotherapy. The histological response to chemotherapy was graded according to The Huvos classification. Computed volumetry was performed to determine the size of the intramedullary component, largest enhancing component, and tumour volume. P 0.05 was considered to denote a significant difference.The mean tumour volume before chemotherapy was 409 cmMRI can help predict histological necrosis after the administration of preoperative chemotherapy to osteosarcoma via measuring the largest enhancing component. Hence, it is a promising preoperative indicator of response to neoadjuvant chemotherapy. However, tumour volume and intramedullary component size measurement are not effective predictors of histological necrosis. The increased volume and intramedullary component of the tumour were attributed to the increased central necrotic component of the tumour after chemotherapy.In this study, we showed that MRI can help predict histological necrosis and thus, prognosis after the administration of preoperative chemotherapy to osteosarcoma via the measurement of the largest enhancing component of the tumour. This is significant because histological necrosis is currently the gold standard method for assessing the treatment response. However, this requires an invasive procedure, and a non-invasive method would be beneficial. Assessing the treatment response through imaging after the completion of the initial chemotherapy will also help determine the final surgical approach and thus predict survival.

Osteosarcoma is a bone tumor that often affects children, adolescents and young people. Non-coding RNA activated by DNA damage (NORAD) can promote the proliferation of cancer cells in multiple tumors. Thus, the current study set out to explore the role of NORAD derived from extracellular vesicles (EVs) of bone mesenchymal stem cells (BMSCs) in osteosarcoma. First, NORAD was highly expressed in osteosarcoma cells and tissues, which might be associated with the progression and metastasis of osteosarcoma. We isolated EVs from the characterized BMSCs, and found that NORAD was transferred from BMSCs to osteosarcoma cells via EVs in the co-culture system. Consequently, NORAD delivered by BMSC-derived EVs promoted the proliferation and invasion of osteosarcoma cells. Subsequently, bioinformatics analyses suggested potential binding relationship between NORAD and microRNA-30c-5p (miR-30c-5p) as well as between miR-30c-5p and Krueppel-like factor 10 (KLF10), and the results of which were further verified by dual luciferase reporter gene assay, RNA immunoprecipitation, and RNA pull-down assay. Mechanistically, NORAD acted as a sponge of miR-30c-5p and up-regulated the expression of KLF10 where miR-30-c-5p mimic declined the effect induced by NORAD on cancer cells. The osteosarcoma cells were injected into mice to develop tumor growth and metastasis models. In these two models, injection of BMSC-EVs elevated NORAD expression and KLF10 but reduced miR-30c-5p expression, whereby suppressing tumor growth and lung metastasis. To conclude, BMSC-EVs deliver NORAD to osteosarcoma cells to regulate the miR-30c-5p/KLF10 axis, thereby accelerating the progression and metastasis of osteosarcoma.

Skeletal reconstruction after tumour resection in paediatric patients is challenging. The resultant reconstruction needs to meet the demands of graft incorporation as well as the potential for growth. The vascularised fibular epiphyseal transfer (VFET) offers the potential for both. We retrospectively reviewed eight paediatric patients treated with VFET after bony tumour resection. All patients underwent a dual pedicle transfer with the peroneal artery for the diaphyseal blood supply and the recurrent branch of the anterior tibial artery for the physis. This is the largest series in literature for dual pedicle transfers for bony reconstruction. We present our surgical technique and outcomes in terms of functional limb salvage and growth.

Castration-sensitive metastatic prostate cancer is heterogeneous. Our objective is to identify metastatic prostate cancer phenotypes and their prognostic impact on survival.The National Cancer Database was queried. The Surveillance, Epidemiology, and End Results database was used for validation. Patterns were split into: nonregional lymph node, bone only, and visceral (any brain/liver/lung). Hazard ratios (HR) with 95% confidence intervals (CI) were calculated for the univariate and multivariate Cox proportional hazards regression models, odds ratios were calculated, Kaplan-Meier curves were generated, and a nomogram of the multivariate regression model was created.The training set included 13,818 men; bone only was most common (n = 11,632, 84.2%), then nonregional lymph node (n = 1388, 10.0%), and any visceral (brain/liver/lung; n = 798, 5.8%). Risk of death was increased by metastases to a visceral organ versus nonregional lymph node (HR = 2.26; 95% CI [2.00, 2.56]), bone only metastases versus nonregional lymph node (HR = 1.57; 95% CI [1.43, 1.72]), T-stage 4 versus 1 (HR = 1.27; 95% CI [1.17, 1.36]), Grade Group 5 versus 1 (HR = 1.93; 95% CI [1.61, 2.31]), PSA20 ng/mL versus10 ng/mL (HR = 1.32; 95% CI [1.23, 1.42]), and age ≥ 80 versus50 (HR = 1.96; 95% CI [1.69, 2.29]). On internal validation, the model had C-indices 20.5%, 22.7%, and 14.6% higher than the current staging system for overall survival, 1-year, and 5-year survival, respectively.We developed and validated prognostic metastatic prostate cancer phenotypes that can assist risk stratification to potentially personalize therapy. Our nomogram (https://tinyurl.com/prostate-met) may be used to predict survival.

To assess the predictive value of the tumor staging system in the AJCC Cancer Staging Manual, Eighth Edition, and histologic features for outcomes and metastasis patterns in conjunctival melanoma (CM).Retrospective, single-center cohort study.Eighty-three patients with CM were treated at Shanghai Ninth People's Hospital between 2000 and 2021.We reviewed the clinical and histologic parameters and used Kaplan-Meier survival curves and Cox proportional hazards regression models for risk factor analyses.Time to nodal/distant metastasis, disease-specific survival, metastatic pattern, and metastatic site.At presentation, 5 patients (6%) had clinical tumor (cT)1 disease, 34 patients (41%) had cT2 disease, and 44 patients (53%) had cT3 disease. Four patients (5%) had nodal metastasis (N1), and none had distant metastasis (M1). During follow-up, 12 patients (14%) developed nodal metastasis, 29 patients (35%) developed distant metastasis, and 26 patients (31%) died of disease. The brain, liver, and lung were common distant metastasis sites. Higher cT category was associated with increased risks of distant metastasis (P0.001) and disease-specific death (P = 0.002). The separate analysis of primary and recurrent tumors at presentation showed that the patients with cT3 tumors had a higher risk of distant metastasis than those with cT2 tumors. Greater tumor thickness, ulceration, and the presence of regression were correlated with distant metastasis. Previously unreported mutations were detected in the tumor suppressor genes FAT atypical cadherin 4 (FAT4) and spleen associated tyrosine kinase (SYK). Among the 29 patients who developed distant metastasis, we analyzed 2 patterns of metastasis: Eleven patients (38%) developed nodal metastasis before distant metastasis, and 18 patients (62%) developed distant metastasis without previously known nodal metastasis. The patients with cT3 tumors were more likely to follow the latter metastasis pattern (P = 0.02).Conjunctival melanoma presented with mostly advanced stages and high rates of distant metastasis in the current Chinese cohort. This study confirmed the prognostic value of the tumor staging system in the AJCC Cancer Staging Manual, Eighth Edition, for Chinese patients. Histologic features, such as tumor thickness and ulceration, should be emphasized when assessing prognosis and guiding the treatment of CM.

Cervical squamous cell carcinoma (CESC) is a cancer with high mortality caused by human papillomavirus. The aim of this study was to uncover potential CESC biomarkers to help early diagnosis and treatment.The mRNA transcriptome data and DNA methylation data were downloaded from database for the identification of differentially expressed mRNAs (DEmRNAs) and DNA methylation analysis. Functional analysis was used to reveal the molecular functions. Then, the association between differential methylation and DEmRNA was analyzed. Protein-protein interaction (PPI) network analysis was performed on the selected differentially methylated genes (DEGs). Subsequently, we analyzed the prognosis and constructed a prognostic risk model. We also performed diagnostic analyses of risk model genes. In addition, we verified the protein expression level of identified DEGs.1438 DEmRNAs, 1669 differentially methylated sites (DMSs), 46 differentially methylated CpG islands and 53 differential methylation genes (DMGs) were obtained. In PPI, the highest interaction scores were MX2 and IRF8, and their interaction score was 0.928. Interestingly, 5 DMGs were found to be associated with CESC prognosis. In addition, our results demonstrated that high risk score was associated with poor prognosis of CESC. Furthermore, it was found that ZIK1, ZNRF2, HHEX, VCAM1 could be diagnostic molecular markers for CESC.Analysis of methylated-differentially expressed genes may contribute to the identification of early diagnosis and therapeutic targets of CESC. In addition, a prognostic model based on 5 DMGs can be used to predict the prognosis of CESC.

Massive bone allograft with an intramedullary vascularized fibula (Capanna technique) represents one of the most widely used methods for the reconstruction of massive bone defect. However, the mechanisms, healing process, and underlying influential factors were poorly understood due to the lack of suitable experimental animal models.Critical-sized defects (CSD) in bone were constructed in the proximal tibia of 24 rabbits and randomly divided into two groups. Allogeneic bone segments of the same size as CSDs were obtained from another 12 rabbits and then inactivated. In group Ⅰ, an ipsilateral pedicled vascularized fibula was dissociated and transferred into the intramedullary cavity of allograft to assemble a composite for CSD reconstruction (Capanna technique), while group Ⅱ received a reconstruction with allogeneic bone alone. Radiographic evaluation was performed every week after the operation to assess union status. All animals were sacrificed at 16th week, and the specimens were histologically analyzed.All animals survived without severe intraoperative complications. There was one rabbit (8.33%) in group Ⅰ developed a postoperative infection and died, while three rabbits (25%) had postoperative complications in group Ⅱ (two died of infection and one died of internal fixation fracture). Radiographically, the mean time to union at the allograft-host junction in group Ⅰ was 12.8 ± 1.80 weeks, significantly shorter than in group II (15.18±1.12 weeks; p0.001). The grade of graft union of group Ⅰ was significantly higher than that of group Ⅱ both at 8th and 16th week (8th week: p = 0.035; 16th week: p = 0.033). Fully bone union at the junctions was histologically confirmed in all specimens in group Ⅰ and 66.67% (8/12) in group Ⅱ.Combined allograft and intramedullary vascularized fibula transfer in rabbit's tibia represent an ideal model that accurately simulates the Capanna technique for CSD reconstruction.

Prostate cancer is a significant cause of morbidity and mortality among men worldwide. Although most patients present with localized or regional disease and experience excellent outcomes with treatment, approximately 10% to 20% of patients develop castrate-resistant prostate cancer (CRPC) within 5 years of diagnosis. Bone metastases, which can cause pain and adversely affect quality of life, are common among this population. Radium-223 has a relatively short half-life and decays via α-decay. Its daughter products, α-particles, have a short path length in tissue and exhibit high linear energy transfer. Together, these properties allow radium-223 to achieve relatively high cell kill in its target tissue while sparing the surrounding normal tissues. Administered in the clinic as radium-223 dichloride (Xofigo), radium-223 acts as a calcium mimetic in the human body, forming complexes with hydroxyapatite. In areas of high bone turnover, such as the osteoblastic bone metastases that are common in patients with CRPC, radium-223 is preferentially incorporated into the bone matrix, where it can exert an antitumor effect. In May 2013, the U.S. Food and Drug Administration approved Xofigo for use in patients with CRPC who have symptomatic bone metastases and no visceral metastases. In this topic discussion, we review the mechanism of action and clinical efficacy of radium-223 in patients with metastatic CRPC. We also discuss its administration and handling, distribution and elimination, and associated toxicities.

The clinical development of immune checkpoint-targeted immunotherapies has been disappointing so far in paediatric solid tumours. However, as opposed to adults, very little is known about the immune contexture of paediatric malignancies.We investigated by gene expression and immunohistochemistry (IHC) the immune microenvironment of five major paediatric cancers: Ewing sarcoma (ES), osteosarcoma (OS), rhabdomyosarcoma (RMS), medulloblastoma (MB) and neuroblastoma (NB; 20 cases each; n = 100 samples total), and correlated them with overall survival.NB and RMS tumours had high immune cell gene expression values and high T-cell counts but were low for antigen processing cell (APC) genes. OS and ES tumours showed low levels of T-cells but the highest levels of APC genes. OS had the highest levels of macrophages (CSF1R, CD163 and CD68), whereas ES had the lowest. MB appeared as immune deserts. Tregs (FOXP3 staining) were higher in both RMS and OS. Most tumours scored negative for PD-L1 in tumour and immune cells, with only 11 of 100 samples positive for PD-L1 staining. PD-L1 and OX40 levels were generally low across all five indications. Interestingly, NB had comparable levels of CD8 by IHC and by gene expression to adult tumours. However, by gene expression, these tumours were low for T-cell cytotoxic molecules GZMB, GZMA and PRF1. Surprisingly, the lower the level of tumour infiltrative CD8 T-cells, the better the prognosis was in NB, RMS and ES. Gene expression analyses showed that MYCN-amplified NB have higher amounts of immune suppressive cells such as macrophages, myeloid-derived suppressor cells and Tregs, whereas the non-MYCN-amplified tumours were more infiltrated and had higher expression levels of Teff.Our results describe the quality and quantity of immune cells across five major paediatric cancers and provide some key features differentiating these tumours from adult tumour types. These findings explain why anti-PD(L)1 might not have had single agent success in paediatric cancers. These results provides the rationale for the development of biologically stratified and personalised immunotherapy strategies in children with relapsing/refractory cancers.

Osteosarcoma (OS) is one of the most common malignancies in children and adolescents. Multimodal chemotherapy and aggressive surgical resection have improved the prognosis of patients with osteosarcoma. However, the prognosis of OS patients with unresectable advanced tumors, distant metastasis or chemotherapy is still poor. Chimeric antigen receptor (CAR) T cells have achieved remarkable success in the treatment of hematologic malignancies, injecting new vitality into the field of adoptive cell therapy. However, the efficacy in solid tumors has been largely limited. The reason for the poor curative effect of solid tumors is mainly the heterogeneity of solid tumor antigen, immune escape, tumor microenvironment barrier, resistance of immunosuppressive cells and inhibitory factors, which lead to the obstruction of CAR T cell infiltration and the aggravation of failure. Potential antigenic targets for osteosarcoma CAR T cell therapy are under continuous exploration. Some of the antigenic targets, such as anti-HER2-CAR T cells, have achieved good results in preclinical studies, and some of them have entered clinical studies and achieved certain clinical effects. In this review, we discuss the research progress of potential antigen targets and osteosarcoma microenvironment of CAR T cells in the treatment of osteosarcoma.

This study aimed to explore the treatment modalities of relapsed osteosarcoma, treatment results, and prognostic factors.We conducted a retrospective study of patients treated for relapsed osteosarcoma between 2005 and 2019. Patient survival was compared according to age, performance status, time to relapse, and surgical treatment at the relapse. Values of p0.05 were considered to indicate statistical significance.We included 49 patients who were treated for osteosarcoma. During the 13-year study period, 16 patients had relapsed osteosarcoma (32.7%). Prognostic factors of relapse were age over 18 years (p = 0.03), axial tumors (p = 0.01), and positive surgical margins (p = 0.018). Nine patients had palliative chemotherapy at the time of relapse. After a median follow-up of 8 months (range: 4-65 months), the overall survival at 1 year, 2 years, and 5 years after diagnosis of the relapse was 46.7%, 31.1%, and 20.7%, respectively. Relapsed osteosarcoma patients who had good performance status, late relapse (after 12 months), as well as surgery of the relapsed disease had better overall survival (OS).Surgical treatment of relapsed osteosarcoma should be performed whenever possible since it improves significantly the survival of patients. Good performance status and late relapse were also associated with better survival.

In rare cases, giant cell tumor of bone (GCTB) can undergo primary or secondary malignant transformation to malignant giant cell tumor of bone (MGCTB), but the details of the molecular alterations are still unclear. The present study aimed to elucidate the clinicopathologic and molecular features of MGCTBs based on immunohistochemistry, fluorescence in situ hybridization (FISH) and next generation sequencing (NGS) of nine MGCTBs (five primary and four secondary). Seven (78%) of 9 MGCTBs were immunohistochemically positive for H3.3 G34W. In two (22%) patients, although GCTB components were focally or diffusely positive for H3.3 G34W, their malignant components were entirely negative for H3.3 G34W, which was associated with heterozygous loss of H3F3A by FISH. NGS on four MGCTBs revealed pathogenic mutations in TP53 (n = 3), EZH2 (n = 1) and several other genes. Immunohistochemical analysis of the nine MGCTBs confirmed the p53 nuclear accumulation (n = 5) and loss of H3K27me3 expression (n = 3) and showed that they were mutually exclusive. In addition, four (80%) of five cases of pleomorphic or epithelioid cell-predominant MGCTBs were positive for p53, while three (75%) of four cases of spindle cell-predominant MGCTBs were negative for trimethylation at lysine 27 of histone 3 (H3K27me3). The results suggested that p53 alteration and dysfunction of histone methylation as evidenced by H3K27me3 loss may play an important role in the malignant progression of GCTB, and might contribute to the phenotype-genotype correlation in MGCTB. The combined histologic, immunohistochemical and molecular information may be helpful in part for the diagnosis of challenging cases.

Due to the wide variations in location, size, local invasiveness, and treatment options, the complications associated with surgery for giant cell tumor of bone have been sporadically reported. For quality assessment, fundamental data based on large-scale surveys of complications under a universal evaluation system is needed. The Dindo-Clavien classification is an evaluation system for complications based on severity and required intervention type and is suitable for the evaluation of surgery in a heterogeneous cohort.A multi-institutional retrospective survey of 141 patients who underwent surgery for giant cell tumor of bone in the extremity was performed. The incidence and risk factors of complications, type of intervention for complication control, and impact of complications on functional and oncological outcomes were analyzed using the Dindo-Clavien classification.Forty-six cases (32.6%) had one or more complications. Of them, 18 (12.8%), 11 (7.8%), and 17 (12.1%) cases were classified as Dindo-Clavien classification grade I, II, and III complications, respectively. There were no cases with grade IV or V complications. Progression in Campanacci grading (p = 0.04), resection (over curettage, p 0.0001), reconstruction with prosthesis (p = 0.0007), and prolonged operative duration (p = 0.0002) were significant risk factors for complications. Complications had a significant impact on function (p 0.0001). Differences in the impact of complication types and tumor location on function were confirmed. Complications had no impact on local recurrence and metastasis development.The Dindo-Clavien classification could provide fundamental information, under a uniform definition and classification system, on postoperative complications in patients with giant cell tumor of bone in terms of incidence, type of intervention for complication control, risk factors, and impact on functional outcome. The data are useful not only for preoperative evaluation for the risk of complications under specific conditions but also for quality assessment of surgery for giant cell tumor of bone.

No curative therapy is currently available for metastatic prostate cancer (PCa). The diverse mechanisms of progression include fibroblast growth factor (FGF) axis activation.To investigate the molecular and clinical implications of fibroblast growth factor receptor 1 (FGFR1) and its isoforms (α/β) in the pathogenesis of PCa bone metastases.In silico, in vitro, and in vivo preclinical approaches were used. RNA-sequencing and immunohistochemical (IHC) studies in human samples were conducted.In mice, bone metastases (chi-square/Fisher's test) and survival (Mantel-Cox) were assessed. In human samples, FGFR1 and ladinin 1 (LAD1) analysis associated with PCa progression were evaluated (IHC studies, Fisher's test).FGFR1 isoform expression varied among PCa subtypes. Intracardiac injection of mice with FGFR1-expressing PC3 cells reduced mouse survival (α, p 0.0001; β, p = 0.032) and increased the incidence of bone metastases (α, p 0.0001; β, p = 0.02). Accordingly, IHC studies of human castration-resistant PCa (CRPC) bone metastases revealed significant enrichment of FGFR1 expression compared with treatment-naïve, nonmetastatic primary tumors (p = 0.0007). Expression of anchoring filament protein LAD1 increased in FGFR1-expressing PC3 cells and was enriched in human CRPC bone metastases (p = 0.005).FGFR1 expression induces bone metastases experimentally and is significantly enriched in human CRPC bone metastases, supporting its prometastatic effect in PCa. LAD1 expression, found in the prometastatic PCa cells expressing FGFR1, was also enriched in CRPC bone metastases. Our studies support and provide a roadmap for the development of FGFR blockade for advanced PCa.We studied the role of fibroblast growth factor receptor 1 (FGFR1) in prostate cancer (PCa) progression. We found that PCa cells with high FGFR1 expression increase metastases and that FGFR1 expression is increased in human PCa bone metastases, and identified genes that could participate in the metastases induced by FGFR1. These studies will help pinpoint PCa patients who use fibroblast growth factor to progress and will benefit by the inhibition of this pathway.

Parosteal osteosarcoma (PO) is a rare malignant tumor arising from the surface of the bone. Locations in the hand are even more exceptional. This low-grade osteosarcoma shows non-specific clinical and radiological presentation, making diagnosis challenging. Moreover, histologic examination is extremely difficult and can easily lead to misdiagnosis. We report the case of a 21-year-old woman who presented PO of the right thumb, initially diagnosed as a "benign exostosis" 9 years previously. En-bloc resection followed by reconstruction using a free corticocancellous iliac crest autograft provided good esthetic and functional outcome. No recurrence occurred at 2 years' follow-up. Our literature review confirmed the rarity of PO of the hand, with only 8 cases reported in the past 60 years. Amputation was the main treatment, but some authors reported limb-sparing surgery. The present result and those in the literature review support conservative surgery when feasible, with little recurrence and better functional and esthetic results. These rare tumors should not be misdiagnosed, and should be treated in specialized centers to optimize outcome.

This study aimed to assess the clinical characteristics affecting outcomes after immune checkpoint inhibitors (ICI) therapies in non-small cell lung cancer (NSCLC) patients, and the underlying mechanism in tumor immune micro-environment (TIME).A total of 144 patients treated with ICI-based strategies were retrospectively analyzed. Expression of 10 immune antibodies in tumor tissues from other 60 untreated NSCLC patients were sequentially tested using multiplexed immunofluorescence (mIF) staining method. Correlation of clinical characteristics with ICI treatment outcomes and TIME characteristics were analyzed.Multivariate logistic and cox regression indicated that BoM negatively affected disease control rate (OR = 0.32, 95%CI: 0.13-0.82, P = 0.018), progression free survival (HR = 3.44, 95% CI:1.97-6.00, P 0.001) and overall survival (HR = 3.24, 95% CI:1.62-6.50, P = 0.001), irrespective of programmed death-ligand 1 (PD-L1) expression. BoM patients were with significantly lower PD-L1, and this heterogeneity of TIME was then confirmed in the mIF staining, where 36 (61.0%) patients were clustered into immune-subtype A, with low expression of all the detected immune markers, similar to "cold" tumors, and 23 (39.0%) in cluster B with likely "hot" tumors. More patients in immune-subtype A were non-smokers (63.9% vs. 39.1% P = 0.063), with BoM (66.7% vs. 21.7%, P = 0.001), in stage IV(88.9% vs. 65.2%, P = 0.045), and with adenocarcinoma (91.7% vs. 69.6%, P = 0.037). Multivariate logistic regression indicated that BoM was independently associated with the "cold" immune characteristics (OR = 0.19, 95% CI:0.04-0.84, P = 0.028). Combination therapy with chemotherapy /antiangiogenesis or use of bisphosphonate during ICI treatment significantly improved clinical outcomes in BoM patients.BoM displays adverse impact on clinical outcomes after ICI treatments in NSCLC patients. The "cold" characteristics of TIME may be the underlying mechanism for the attenuated efficacy of ICIs in bone metastatic NSCLC patients.

Rothmund-Thomson syndrome (RTS) is an autosomal recessive cancer-predisposition disorder characterized by the presence of a wide range of clinical features including poikiloderma, sparse hair, growth deficiency, cataracts, and skeletal abnormalities. Importantly, two-thirds of individuals with RTS have a significant risk of developing osteosarcoma due to the presence of biallelic pathogenic variants in RECQL4, a critical gene involved in DNA repair and replication. It is unknown whether individuals who are heterozygous for a RECQL4 pathogenic variant also have an increased risk of cancer. To address this question, we examined the largest international RTS registry and analyzed 123 RECQL4 heterozygous family members of RTS probands. Overall, the prevalence of cancer among RECQL4 heterozygous family members was 2.4% (3/123). We found that compared to the age-adjusted population estimate of 5.6% from the Surveillance, Epidemiology, and End Results program, the prevalence of cancer was not significantly different in this cohort of RECQL4 heterozygotes (Fisher's exact test, P = 0.2). Given that the biological parents of individuals with RTS are obligate heterozygotes and that siblings have a fifty-percent chance of being asymptomatic heterozygotes, these findings provide valuable information to help guide clinicians in counseling RTS family members regarding the likelihood of developing cancer.

Exosomes as nanosized membrane vesicles, could targeted deliver therapeutic agents by modification with target ligands. Exosome-derived non-coding RNAs play a vital role in the development of tumors. Previous evidences reveal that long non-coding RNA maternally expressed gene 3 (lncRNA MEG3) has anti-tumor properties. Whereas, the inhibitory effects of exosome-derived lncRNA MEG3 in osteosarcoma (OS) remain largely unknown. In this study, we utilize the engineering technology to combine exosome and lncRNA for tumor-targeting therapy of OS. We elucidated the anti-OS effects of lncRNA MEG3, and then prepared the c(RGDyK)-modified and MEG3-loaded exosomes (cRGD-Exo-MEG3). The engineered exosomes cRGD-Exo-MEG3 could deliver more efficiently to OS cells both in vitro and in vivo. In this way, cRGD-Exo-MEG3 facilitate the anti-OS effects of MEG3 significantly, with the help of enhanced tumor-targeting therapy. This study elucidates that engineered exosomes as targeted lncRNA MEG3 delivery vehicles have potentially therapeutic effects for OS.

This article focuses on skeletal sarcomas, a group of rare, heterogenous malignant tumors. We present information on the multi-disciplinary approach to the diagnosis, staging, treatment, and surveillance of these complex tumors that are critical to enhancing function and improving survival.

Amongst cancer patients, bone pain due to skeletal metastases is a major cause of morbidity. A number of beta-emitting radiopharmaceuticals have been used to provide internal radiotherapy of bone metastases and provide palliative pain relief. In this article we describe the different physical characteristics of the various beta emitting radionuclides which have been used in this clinical setting and the potential impact of differences in dose-rate on radiobiological outcomes. A detailed review of the biodistribution of these treatments, based on both in-vivo clinical investigations and post mortem autoradiography assessments is provided. These treatments result in physiological delivery of radiation doses to the target disease as well as to critical healthy organs. Particular attention is paid to the radiation doses received by normal bone tissue, bone marrow as well as metastatic bone disease. The underlying models of radiation transport within bone and bone marrow are reviewed alongside the practical steps that must be taken to acquire and analyse the information require for clinical dosimetry assessments. The role of whole body measurements, blood and faecal assays as well as both planar and tomographic gamma camera imaging are considered. In addition we review the rationale for allocating measured bone uptake between trabecular and cortical bone tissue. The difference between bone volume and bone surface seeking radiopharmaceuticals are also discussed. This review also extends to the development of preclinical models of bone metastases which may inform future dosimetric calculations. Finally, we also present a comprehensive review of the dosimetry of the established treatments

Hydroxyapatite-binding albumin nanoclusters (NCs) were developed for improving the anticancer agent accumulation in bone tumors. Human serum albumin (HSA) was decorated with alendronate (AD), and doxorubicin (DOX)-loaded NCs (HSA-AD/DOX) were fabricated via the ball-milling technology, an innovative nano-fabrication method by which more than 90% of the secondary structures of albumin can be preserved. The targeting ability of NCs was confirmed using a novel in vitro bone cancer model, wherein hydroxyapatite and collagen, the major components of the bone matrix representing the highly mineralized bone tumor microenvironment, were co-cultured with HOS/MNNG, a human osteosarcoma cell line. The binding affinity of HSA-AD/DOX to hydroxyapatite was evaluated based on the DOX binding efficiency. HSA-AD/DOX showed a 5.04-fold higher affinity than HSA/DOX. The enhanced distribution of HSA-AD/DOX to bone tumors was verified using a newly developed mouse model bearing HOS/MNNG tumors with hydroxyapatite beads. HSA-AD/DOX led to a 52.0% increase in tumor accumulation compared to that of the unmodified HSA/DOX. This is mainly due to the hydroxyapatite-binding affinity of the AD moiety, which is supported by histological analyses performed on the dissected tumors. Furthermore, HSA-AD/DOX changed the protein expression patterns of the tumors, implying the enhanced apoptotic process. Overall, the targeting ability of HSA-AD/DOX are effectively translated into improved therapeutic efficacy in bone tumor-xenografted mice, suggesting that the developed NCs are a promising delivery system for bone tumor treatment.

Summary Background With the advent of new techniques, foot salvage is feasible following talus oncological resection. As the reconstruction aims to achieve a pain-free, stable ankle for ambulation, biological limb reconstruction is the best option. This case series will evaluate the primary indications, complications, and functional outcomes of the reconstructed talus and highlighting the technical aspects of the surgery with a novel technique of triangular double-barrel free fibula flap. Methods We performed a retrospective case note review of patients undergoing foot salvage surgeries and primary talus reconstruction with double-barrel free fibula flaps between 2009 and 2019. Patient demographics, aetiologies, operative details, complications, and outcomes were analysed. All patients underwent the same talar reconstruction technique whereby a wide-based triangular framework was created from two bony struts of the osteotomized fibula. The Musculoskeletal Tumour Society (MSTS) scoring system was used to analyse the short- to mid-term functional outcomes. Results Four consecutive patients with aggressive benign and malignant tumours were identified. They consist of three males and one female, with a median age of 32 (range 27–39). Patients were followed up for a median duration of 60 months (range 24–132). Two flaps were complicated with venous thromboses; however, all were salvageable following re-explorations. All patients achieved solid bony fusion with good functional and aesthetic outcomes. The median MSTS score was 74.5% (range 66–76). No donor site morbidity and local recurrence were reported. Conclusion The triangular double-barrel free fibular flap is a good option for limb salvage following total talus resection, with good short- to mid-term functional and aesthetic outcomes.

Most prostate cancer (PCa)-related deaths are caused by progression to bone metastasis. Recently, the importance of extracellular vesicles (EVs) in pre-metastatic niche formation has been reported. However, whether and how tumor-derived EVs interact with bone marrow macrophages (BMMs) to release EV-delivered microRNAs to promote osteolysis and induce pre-metastatic niche formation for PCa bone metastasis remain unclear. Our in vitro and in vivo functional and mechanistic assays revealed that EV-mediated release of miR-378a-3p from tumor cells was upregulated in bone-metastatic PCa, maintaining low intracellular miR-378a-3p concentration to promote proliferation and MAOA-mediated epithelial-to-mesenchymal transition. Moreover, miR-378a-3p enrichment in tumor-derived EVs was induced by hnRNPA2B1 (a transfer chaperone) overexpression. After tumor-derived EVs were taken in by BMMs, enriched miR-378a-3p promoted osteolytic progression by inhibiting Dyrk1a to improve Nfatc1 (an osteolysis-related transcription factor) nuclear translocation, to activate the expression of downstream target gene Angptl2. As a feedback, increased Angptl2 secretion into the tumor environment promoted PCa progression. In conclusion, tumor-derived miR-378a-3p-containing EVs play a significant role in PCa bone metastasis by activating the Dyrk1a/Nfatc1/Angptl2 axis in BMMs to induce osteolytic progression, making miR-378a-3p a potential predictor of metastatic PCa. Reducing the release of miR-378a-3p-containing EVs or inhibiting the recruitment of miR-378a-3p into EVs can be a therapeutic strategy against PCa metastasis.

This article reviews soft tissue tumors of the head and neck following the 2020 revision of WHO Classification of Soft Tissue and Bone Tumours. Common soft tissue tumors in the head and neck and tumors are discussed, along with newly added entities to the classification system. Salient clinical and imaging features that may allow for improved diagnostic accuracy or to narrow the imaging differential diagnosis are covered. Advanced imaging techniques are discussed, with a focus on diffusion-weighted and dynamic contrast imaging and their potential to help characterize soft tissue tumors and aid in distinguishing malignant from benign tumors.