5-ALA-mediated fluorescence of musculoskeletal tumors in a chick chorio-allantoic membrane model: preclinical in vivo qualification analysis as a fluorescence-guided surgery agent in Orthopedic Oncology

Background Fluorescence-guided surgery (FGS) with 5-aminolevulinic acid (5-ALA) and other contrast agents has shown its efficacy in improving resection margins, local recurrence and survival rates in several medical disciplines. It is the objective of this study to analyze the engraftment rate of musculoskeletal tumor specimens on the chick chorio-allantoic membrane (CAM), the rate of tumor fluorescence (PDD), and the effects of photodynamic therapy (PDT) after exposure of tumors to 5-ALA in an in vivo environment. Methods A total of 486 CAMs were inoculated with macroscopic tumor grafts (n = 26; n = 478 eggs) and primary cell culture suspensions (n = 2; n = 8 eggs) from 26 patients on day 10 of egg development. On day 16, 2 mg/200 µl 5-ALA were topically applied per egg. After 4 h of incubation, Protoporphyrin IX was excited using blue light (420 ± 10 nm). Tumor fluorescence (PDD) was photo-documented. A subgroup of specimens was additionally exposed to red light (635 nm ± 10 nm; PDT). After the termination of the experiment, CAM-grown tumors were histopathologically analyzed. Results Benign and borderline tumors (chondroblastoma, giant cell tumor of bone and atypical chondrogenic tumor) presented with high rates of detectable fluorescence. Comparable results were found for chondrosarcoma, osteosarcoma and Ewing’s sarcoma among bone and dedifferentiated liposarcoma, myxofibrosarcoma and undifferentiated pleomorphic sarcoma among soft tissue sarcomas. Overall, tumor fluorescence was negative for 20.2%, single-positive (+) for 46.9% and double-positive (++) for 32.9% of macroscopic xenografts, and negative in 20% and (+) in 80% of primary cell culture tumors. Macroscopic tumor xenografts (n = 478) were identified as viable in 14.8%, partially viable in 2.9% and partially to completely regressive in 45.2%. All (n = 8) tumors grown from primary cell culture were viable. After PDT, tumor samples were found viable in 5.5%, partially viable in 5.5% and partially to completely regressive in 68%. Egg survival increased with decreasing PDT doses. Conclusions The CAM model proves to be a suitable in vivo model for the investigation of short-term observation questions in musculoskeletal tumors. The findings of this study warrant further investigation of PDT effects on musculoskeletal tumors and a possible incorporation of 5-ALA FGS in clinical Orthopedic Oncology care.

Implant Survival, Clinical Outcome and Complications of Megaprosthetic Reconstructions Following Sarcoma Resection

Megaprosthetic reconstruction of segmental bone defects following sarcoma resection is a frequently chosen surgical approach in orthopedic oncology. While the use of megaprostheses has gained popularity over the last decades and such implants are increasingly used for metastatic reconstructions and in non-tumor cases, there still is a high risk of long-term complications leading to revision surgery. This article investigates current implant survivorship, frequency and types of complications as well as functional outcomes of upper and lower limb megaprosthetic reconstructions.

Incidence and risk factors of preoperative venous thromboembolism in patients with malignant musculoskeletal tumors: an analysis based on D-dimer screening and imaging

Background: Venous thromboembolism (VTE) is a major complication in patients with malignant tumors and orthopedic disorders. Although it is known that patients undergoing surgery for orthopedic oncology are at an increased risk of thromboembolic events, only few studies have investigated this risk in detail. Therefore, the aim of this study was to determine the incidence and risk factors for preoperative VTE in orthopedic oncology patients.Methods: We retrospectively reviewed the medical records of 270 patients who underwent surgical procedures, including biopsy for orthopedic oncology, have undergone measurements of preoperative D-dimer levels, and were subsequently screened for VTE by lower extremity venous ultrasonography and/or contrast-enhanced computed tomography scans. Statistical analyses were performed to examine the incidence and risk factors for VTE. Receiver operating characteristic (ROC) analysis was performed to verify the D-dimer cutoff value for the diagnosis of VTE.Results: Overall, 199 patients (103 with primary soft tissue sarcomas, 38 with primary bone sarcomas, 46 with metastatic tumors, and 12 with hematologic malignancies) were included. D-dimer levels were high in 79 patients; VTE was detected in 19 patients (9.5%). Multivariate analysis indicated that age ≥60 years (P = 0.021) and tumor location in the lower limbs (P = 0.048) were independent risk factors for VTE. ROC analysis showed that the D-dimer cutoff value for the diagnosis of VTE was 1.53 µg/mL; the sensitivity and specificity were 89.5% and 79.4%, respectively.Conclusions: Our study indicated that age and tumor location in the lower limbs were independent risk factors for preoperative VTE in orthopedic oncology patients. D-dimer levels were not associated with VTE in the multivariate analysis, likely because they are affected by a wide variety of conditions, such as malignancy and aging. Patients with high D-dimer levels and the identified risk factors are at an increased risk of preoperative VTE, and additional ultrasonography should be considered.Trial registration: Our study was approved by the institutional review board. The registration number is B200600056. The registration date was July 13, 2020.

Preoperative Venous Thromboembolism in Orthopedic Oncology Patients: Incidence, Risk Factors, and D-Dimer Cutoff Value

Background: Venous thromboembolism (VTE) is known as one of the major complications in patients with malignant tumors and orthopedic disorders. Patients undergoing surgery for orthopedic oncology are at an increased risk for thromboembolic events. However, there are limited studies regarding the incidence and risk factors for preoperative VTE in orthopedic oncology patients.Methods: The aim is to determine the incidence and risk factors of preoperative VTE by screening with D-dimer. We retrospectively reviewed the medical records of 270 patients who underwent surgical procedures, including biopsy for orthopedic oncology, had preoperative D-dimer levels measured and were subsequently screened for VTE by lower extremity venous ultrasonography and contrast-enhanced computed tomography (CT) scans if necessary. Statistical analyses were performed to examine the incidence and risk factors for VTE. Receiver operating characteristic (ROC) analysis was performed to verify the cutoff value of D-dimer for the diagnosis of VTE.Results: A total of 199 patients (103 with primary soft tissue sarcomas, 38 with primary bone sarcomas, 46 with metastatic tumors and 12 with hematologic malignancies) were included. The value of D-dimer was high in 79 patients. VTE was detected in 19 patients (9.5%). Multivariate analysis indicated that, age ≥60 years (P = 0.021), and tumor location in the lower limbs (P = 0.048) were independent risk factors for VTE. ROC analysis showed that the cutoff value of D-dimer for the diagnosis of VTE was 1.53 µg/mL (sensitivity of 89.5% and specificity of 79.4%).Conclusions: Our study indicated that age and tumor location in the lower limbs were independent risk factors for preoperative VTE in orthopedic oncology patients. D-dimer was not significantly different in the multivariate analysis because D-dimer is affected by a wide variety of conditions, such as malignancy and aging. Patients with high D-dimer levels and the abovementioned risk factors are at increased risk of preoperative VTE, and additional ultrasonography should be considered.Trial registration: Our study was approved by the institutional review board. The registration number is B200600056. The registration date was July 13, 2020.

Is three-dimensional–printed custom-made ultra-short stem with a porous structure an acceptable reconstructive alternative in peri-knee metaphysis for the tumorous bone defect?

Background Long-lasting reconstruction after extensive resection involving peri-knee metaphysis is a challenging problem in orthopedic oncology. Various reconstruction methods have been proposed, but they are characterized by a high complication rate. The purposes of this study were to (1) assess osseointegration at the bone implant interface and correlated incidence of aseptic loosening; (2) identify complications including infection, endoprosthesis fracture, periprosthetic fracture, leg length discrepancy, and wound healing problem in this case series; and (3) evaluate the short-term function of the patient who received this personalized reconstruction system. Methods Between September 2016 and June 2018, our center treated 15 patients with malignancies arising in the femur or tibia shaft using endoprosthesis with a 3D-printed custom-made stem. Osseointegration and aseptic loosening were assessed with digital tomosynthesis. Complications were recorded by reviewing the patients’ records. The function was evaluated with the 1993 version of the Musculoskeletal Tumor Society (MSTS-93) score at a median of 42 (range, 34 to 54) months after reconstruction. Results One patient who experienced early aseptic loosening was managed with immobilization and bisphosphonates infusion. All implants were well osseointegrated at the final follow-up examination. There are two periprosthetic fractures intraoperatively. The wire was applied to assist fixation, and the fracture healed at the latest follow-up. Two patients experienced significant leg length discrepancies. The median MSTS-93 score was 26 (range, 23 to 30). Conclusions A 3D-printed custom-made ultra-short stem with a porous structure provides acceptable early outcomes in patients who received peri-knee metaphyseal reconstruction. With detailed preoperative design and precise intraoperative techniques, the reasonable initial stability benefits osseointegration to osteoconductive porous titanium, and therefore ensures short- and possibly long-term durability. Personalized adaptive endoprosthesis, careful intraoperative operation, and strict follow-up management enable effective prevention and treatment of complications. The functional results in our series were acceptable thanks to reliable fixation in the bone-endoprosthesis interface and an individualized rehabilitation program. These positive results indicate this device series can be a feasible alternative for critical bone defect reconstruction. Nevertheless, longer follow-up is required to determine whether this technique is superior to other forms of fixation.

A radiological diagnostic approach to tumours and tumour-like lesions of the calcaneus

Objective: The calcaneus is a rare location for the development of primary bone tumours. The purpose of the study is to review the imaging findings in a cohort of patients presenting with tumours and tumour-like lesions of the calcaneus and to develop a more structured approach to the diagnosis of calcaneal lesions. Methods: A retrospective study with a collection of 167 cases of calcaneal tumours and tumour like lesions from our tertiary orthopedic oncology institution over a period of 13 years. Cases were reviewed by two consultant musculoskeletal radiologist and the location of the lesion within the calcaneus and demographics of the patient were noted for each case. A diagnostic algorithm which is based on patient age and tumour location was then extrapolated. Results: Out of the 167 cases we identified 24 different calcaneal pathologies which included both tumours and tumour-like lesions. The most common being simple bone cysts (18.3% of cases) and intra osseous lipoma (15% of cases) sited in the diaphyseal equivalent of the calcaneus. A diagnostic algorithm was formulated which describes the most common location of the different pathologies including both benign and malignant pathologies, subdivided by age. Conclusion: Our algorithm should help the radiologist narrow down the differential diagnosis when evaluating calcaneal lesions. Advances in knowledge: This article provides a radiological approach to calcaneal lesions.

Non-destructive Chemical Imaging of Bone Tissue for Intraoperative and Diagnostic Applications

Bone is difficult to image using traditional histopathological methods, leading to challenges in intraoperative consultations needed in orthopedic oncology. However, intraoperative pathological evaluation is critical in guiding surgical treatment. In this study, we demonstrate that a multimodal imaging approach that combines stimulated Raman scattering (SRS) microscopy, two-photon fluorescence (TPF) microscopy, and second harmonic generation (SHG) microscopy can provide useful diagnostic information regarding intact bone tissue fragments from surgical excision or biopsy specimens. We imaged bone samples from 14 patient cases and performed comprehensive chemical and morphological analyses of both mineral and organic components of bone. Our main findings show that carbonate content combined with morphometric analysis of bone organic matrix can separate several major classes of bone cancer associated diagnostic categories with an average accuracy of 92%. This proof-of-principle study demonstrate that multimodal imaging and machine learning-based analysis of bony tissue can provide crucial diagnostic information for guiding clinical decisions in orthopedic oncology.