Incidence and management of secondary deformities after megaendoprosthetic proximal femur replacement in skeletally immature bone sarcoma patients.

INTRODUCTION: Megaendoprosthetic reconstruction of bone defects in skeletally immature patients has led to the development of unique complications and secondary deformities not observed in adult patient cohorts. With an increasing number of megaendoprosthetic replacements performed, orthopedic oncologists still gain experience in the incidence and type of secondary deformities caused. In this study, we report the incidence, probable cause and management outcome of two secondary deformities after megaendoprosthetic reconstruction of the proximal femur: hip dysplasia and genu valgum. MATERIALS AND METHODS: Retrospective analysis of 14 patients who underwent primary and/or repeat reconstruction/surgery with a megaendoprosthetic proximal femur replacement between 2018 and 2022. RESULTS: Mean patient age was 9.1 years (range 4-17 years). Stress shielding was observed in 71.4%. Hip dislocation was the most frequent complication (50%). While four dislocations occurred without an underlying deformity, secondary hip dysplasia was identified in 58.3% (n = 7/12) of intraarticular resections and reconstructions, leading to dislocation in 71.4% (n = 5/7). A genu valgum deformity was observed in 41.6% (n = 5/12). The incidence of secondary hip dysplasia and concomitant genu valgum was 42.9% (n = 3/7). Triple pelvic osteotomy led to rebound hip dysplasia in two cases (patients aged < 10 years), whereas acetabular socket replacement led to stable hip joints over the course of follow-up. Temporary hemiepiphyseodesis was applied to address secondary genu valgum. CONCLUSIONS: Patients aged < 10 years were prone to develop secondary hip dysplasia and genu valgum following proximal femur replacement in this study. Management of secondary deformities should depend on remaining skeletal growth. Stress shielding was observed in almost all skeletally immature patients.

Reconstruction survival of segmental megaendoprostheses: a retrospective analysis of 28 patients treated for intercalary bone defects after musculoskeletal tumor resections.

INTRODUCTION: Intercalary endoprosthetic reconstructions have been reserved for patients with a limited life expectancy due to reports of high rates of early mechanical and reconstruction failure. MATERIALS AND METHODS: In this study, we retrospectively analyzed 28 patients who underwent intercalary endoprosthetic reconstruction of the femur (n = 17) or tibia (n = 11) regarding reconstruction survival and causes of complications and reconstruction failure. RESULTS: A total of 56 stems were implanted in this collective, 67.9% of which were implanted using cementation. Eight different stem designs were implanted. The mean patient age at the time of operation was 42.3 years. The mean bone defect needing reconstruction measured 18.5 cm. Resection margins were clear in 96.4% of patients. Of twenty-six complications, five were not implant-associated. We observed infection in 10.7% (n = 3) and traumatic periprosthetic fracture in 3.6% (n = 1) of cases. The most frequent complication was aseptic stem loosening (ASL) (53.8%; n = 14) occurring in eight patients (28.6%). The metaphyseal and meta-diaphyseal regions of femur and tibia were most susceptible to ASL with a rate of 39.1% and 31.3% respectively. No ASLs occurred in epiphyseal or diaphyseal location. Overall reconstruction survival was 43.9% and 64.3% including patients who died of disease with their implant intact. Overall limb survival was 72.7%. CONCLUSIONS: Proper planning of segmental reconstructions including stem design with regard to unique anatomical and biomechanical properties is mandatory to address the high rates of ASL in metaphyseal and metadiaphyseal stem sites. With continued efforts of improving stem design in these implantation sites and decreasing rates of mechanical failure, indications for segmental megaendoprostheses may also extend to younger patients with the localized disease for their advantages of early weight bearing and a lack of donor-site morbidity.

Analysis of surgical and oncological outcome in internal and external hemipelvectomy in 34 patients above the age of 65 years at a mean follow-up of 56 months.

BACKGROUND: With an increasing life expectancy and improved treatment regimens for primary or secondary malignant diseases of soft tissue or bone, hemipelvectomy will have to be considered more often in elderly patients in the future. Scientific reviews concerned with the surgical and oncological outcome of elderly patients undergoing hemipelvectomy are scarce. Therefore, it is the purpose of this study to review the outcome of patients treated with that procedure at our hospital and investigate the feasibility of such extensive procedures at an increased age. METHODS: A retrospective analysis of thirty-four patients who underwent hemipelvectomy at an age of 65 years or older was performed to determine their surgical and oncological outcome. The Kaplan-Meier method was used to calculate the cumulative probability of survival using the day of tumor resection as a starting point. Univariate analysis was carried out to investigate the influence of a particular single parameter. RESULTS: The mean age at operation was 70.2 years. Thirty patients were treated for intermediate- to high-grade sarcoma and 81.8% of tumors were larger than or equal to 10 cm in the longest diameter. Thirteen patients underwent internal hemipelvectomy and nine patients external hemipelvectomy as a primary procedure. Twelve patients were treated with external hemipelvectomy after failed local tumor control at primary operation. Wound infection occurred in 61.7% of cases. Three patients underwent amputation for non-manageable infection after internal hemipelvectomy. Hospital mortality was 8.8%. Clear resection margins were obtained in 88% of patients; in another 6% of patients planned intralesional resections were performed. Local recurrence occurred in 8.8% of patients at a mean time of 26 months after operation. Eleven patients are alive with no evidence of disease and 23 patients died of disease or other causes. Patients with pulmonary metastases had a mean survival period after operation to DOD of 22 months compared to 37 months in the curative group. CONCLUSION: Despite an elevated rate in hospital mortality and wound infection, this study suggests that hemipelvectomy is feasible in elderly patients, although requiring long hospitalization periods and causing a limited functional outcome.

Evaluation of the Effect of Photodynamic Therapy on CAM-Grown Sarcomas.

Resection margin adequacy plays a critical role in the local control of sarcomas. Fluorescence-guided surgery has increased complete resection rates and local recurrence-free survival in several oncological disciplines. The purpose of this study was to determine whether sarcomas exhibit sufficient tumor fluorescence (photodynamic diagnosis (PDD)) after administration of 5-aminolevulinic acid (5-ALA) and whether photodynamic therapy (PDT) has an impact on tumor vitality in vivo. Sixteen primary cell cultures were derived from patient samples of 12 different sarcoma subtypes and transplanted onto the chorio-allantoic membrane (CAM) of chick embryos to generate 3-dimensional cell-derived xenografts (CDXs). After treatment with 5-ALA, the CDXs were incubated for another 4 h. Subsequently accumulated protoporphyrin IX (PPIX) was excited by blue light and the intensity of tumor fluorescence was analyzed. A subset of CDXs was exposed to red light and morphological changes of both CAMs and tumors were documented. Twenty-four hours after PDT, the tumors were excised and examined histologically. High rates of cell-derived engraftments on the CAM were achieved in all sarcoma subtypes and an intense PPIX fluorescence was observed. PDT of CDXs resulted in a disruption of tumor-feeding vessels and 52.4% of CDXs presented as regressive after PDT treatment, whereas control CDXs remained vital in all cases. Therefore, 5-ALA mediated PDD and PDT appear to be promising tools in defining sarcoma resection margins (PDD) and adjuvant treatment of the tumor bed (PDT).

Effects of an Exercise Intervention on Gait Function in Young Survivors of Osteosarcoma with Megaendoprosthesis of the Lower Extremity-Results from the Pilot Randomized Controlled Trial proGAIT.

Limb preservation with megaendoprosthesis in adolescents and young adults (AYA) with bone tumors is associated with functional limitations and gait abnormalities. The proGAIT trial evaluated the effectiveness of an exercise program on gait function and quality of life, functional scales (MSTS, TESS), functional mobility, and fatigue as secondary outcomes. Eleven AYA survivors of malignant osteosarcoma with a tumor endoprosthesis around the knee (mean age: 26.6 (±8.4) years) were randomized into an intervention group receiving an 8-week exercise program or into a control group. Gait function was assessed via 3D motion capture and analyzed using the Gait Profile Score (GPS) and the Gait Deviation Index (GDI). GDI and GPS scores of participants suggest deviations from a healthy reference group. The exercise intervention had small-to-medium positive effects on gait score GDI |d| = 0.50 (unaffected leg), |d| = 0.24 (affected leg), subjective functional scores TESS |d| = 0.74 and MSTS |d| = 0.49, and functional tests TUG and TUDS |d| = 0.61 and |d| = 0.52. None of these changes showed statistical significance. Promising intervention effects suggest that regular exercise could improve lower limb function and follow-up care for survivors; however, a powered RCT as a follow-up project needs to confirm the pilot findings.

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.

Transcriptome-Wide Gene Expression Profiles from FFPE Materials Based on a Nuclease Protection Assay Reveals Significantly Different Patterns between Synovial Sarcomas and Morphologic Mimickers.

BACKGROUND: Transcriptome profiling provides large data on tumor biology, which is particularly valuable in translational research and is becoming more and more important for clinical decision-making as well. RNA sequencing is considered to be the gold standard for this. However, FFPE material, as the most available material in routine pathology, has been an undefeatable obstacle for RNAseq. Extraction-free nuclease protection assays have the potential to be a reliable alternative method for large-scale expression profiling. The aim of this study was to validate and test the basic feasibility, technical applicability robustness, and reliability of the HTG transcriptome profiling (HTP) assay on clinical tumor samples. METHODS: FFPE samples from 44 synovial sarcomas (SyS) and 20 spindle cell sarcomas (SpcS) were used. The HTP assay was performed on 10 µm thin FFPE slides. After nuclease protection in the HTG Edge Seq System, libraries were generated for sequencing on an Illumina NextSeq 500 platform. Fastq data were parsed and then analyzed by using the HTG analysis platform EdgeSeq REVEAL. Immunohistochemistry was performed to validate the expression of TLE1. RESULTS: The technical application of the HTP Panel revealed robust and reliable results with 62 samples, and only 2 samples failed due to an incomplete digestion of gDNA. The analysis, performed at the analysis platform REVEAL, showed 5964 genes being significantly differentially expressed between SpcS and SyS. In particular, overexpression of the known marker TLE1 in synovial sarcoma could be recovered, which underlines the reliability of this system. DISCUSSION: Transcriptome profiling gets more and more important for tumor research and diagnostics. Among other established technologies, the HTP Panel has shown to be a feasible method to get robust and reliable results. Thereby, this method needs very few sample-input by getting a success-rate of 96.88%, which indicates the upper average range, compared to other technologies working with FFPE tissue. CONCLUSION: The nuclease protection assay-based HTP Panel is a feasible method for adequate transcriptome profiling with low sample input and therefore is suitable for further research of biomarkers.

Highly Cancellous Titanium Alloy (TiAl6V4) Surfaces on Three-Dimensionally Printed, Custom-Made Intercalary Tibia Prostheses: Promising Short- to Intermediate-Term Results.

Custom-made, three-dimensionally-printed (3D) bone prostheses gain increasing importance in the reconstruction of bone defects after musculoskeletal tumor resections. They may allow preservation of little remaining bone stock and ensure joint or limb salvage. However, we believe that by constructing anatomy-imitating implants with highly cancellous titanium alloy (TiAl6V4) surfaces using 3D printing technology, further benefits such as functional enhancement and reduction of complications may be achieved. We present a case series of four patients reconstructed using custom-made, 3D-printed intercalary monobloc tibia prostheses treated between 2016 and 2020. The mean patient age at operation was 30 years. Tumor resections were performed for Ewing sarcoma (n = 2), high-grade undifferentiated pleomorphic bone sarcoma (n = 1) and adamantinoma (n = 1). Mean resection length was 17.5 cm and mean operation time 147 min. All patients achieved full weight-bearing and limb salvage at a mean follow-up of 21.25 months. One patient developed a non-union at the proximal bone-implant interface. Alteration of implant design prevented non-union in later patients. Mean MSTS and TESS scores were 23.5 and 88. 3D-printed, custom-made intercalary tibia prostheses achieved joint and limb salvage in this case series despite high, published complication rates for biological and endoprosthetic reconstructions of the diaphyseal and distal tibia. Ingrowth of soft tissues into the highly cancellous implant surface structure reduces dead space, enhances function, and appears promising in reducing complication rates.

Pelvic Ewing sarcoma: a retrospective outcome analysis of 104 patients who underwent pelvic tumor resection at a single supra-regional center.

BACKGROUND: Local treatment in pelvic Ewing sarcoma (ES) consists of operation, radiation therapy, or a combination of both. Reported outcomes vary depending on the treatment modality performed. It is the objective of this study to analyze surgical outcome and complications as well as oncological outcome and complications of chemo- and radiation therapy in this patient cohort and evaluate prognostic factors. METHODS: Retrospective review of 104 patients who underwent tumor resection for pelvic ES from 1988 to 2014. RESULTS: All patients underwent pelvic resection and radiation therapy was administered in 77.9%. Margins were clear in 94.2%. The response to chemotherapy was good in 78.8%. Local recurrence occurred in 7.7%. The presence of distant metastases at the time of operation was the most important negative predictor for overall survival (p = 0.003). The cumulative 5- and 10-year survival rates were 82.7% and 80.1% for non-metastasized and 61.4% and 41.6% for metastasized pelvic ES at operation. In the presence of a single-distant metastatic site at operation compared to multiple metastatic sites, the cumulative survival rates were 64.3% versus 50% at five and 50.7% versus 16.7% at 10 years. CONCLUSIONS: A combined treatment approach of tumor resection and radiation therapy leads to a local control and overall survival rates comparable with those of extremity locations in this study's patient cohort with localized pelvic ES. Therefore, surgical tumor resection (combined with (neo-)adjuvant radiation therapy) in non-metastatic pelvic ES seems feasible. In metastatic patients, however, the significance of tumor resection as a part of local treatment remains less certain and improved outcomes of combined local treatment approaches need to be weighed against these patients' prognosis and quality of life.

Analysis of drug sensitivity of human high-grade osteosarcoma in a chick chorioallantoic membrane (CAM) model: a proof of principle study.

OBJECTIVE: Multi-agent chemotherapy is an important pillar in treatment of high-grade osteosarcoma. In an effort to improve patient survival, it is imperative to determine the effectiveness of new substances. The objective of this study was to investigate whether the chick chorioallantoic membrane (CAM) model can be used to analyze drug sensitivity in high-grade osteosarcoma. RESULTS: Spare biopsy tissue from five patients diagnosed with high-grade osteosarcoma was transferred into non-immortalized primary cell culture. After a pre-incubation period of 10 days, fertilized chick eggs were inoculated with primary tumor cells suspended in extracellular matrix gel. On day 16, treatment with 20 µmol/l doxorubicin (n = 4) or 25 µl of culture medium (n = 6) was performed for 24 h. CAM membranes were documented macroscopically, harvested and examined histologically. Transfer of biopsy specimens into primary cell culture was successful in all cases. 50% (n = 10) of eggs died after inoculation with tumor cells and before application of doxorubicin. No deaths occurred after application of doxorubicin. Histological examination found a response to doxorubicin in all four specimens. Based upon these results, the CAM model represents a promising preclinical alternative to animal experiments to determine drug sensitivity of osteosarcoma cells. Further research with regard to other substances and dosages appear justified.

Small sharp exostosis tip in solitary osteochondroma causing intermittent knee pain due to pseudoaneurysm.

BACKGROUND: Complications of solitary or multiple osteochondromas are rare but have been reported in recent literature. Most reported complications arose in patients with multiple and/or sizable osteochondromas. CASE PRESENTATION: A 22-year-old, female, Caucasian patient with obesity presented with intermittent knee pain and hematoma of the right calf. The MRI depicted a small, sharp exostosis tip of the dorsal distal femur with a surrounding soft-tissue mass. After profuse bleeding occurred during biopsy of the soft tissue mass, angiography revealed a pseudoaneurysm of the right popliteal artery. In a second-stage surgery the exostosis tip and pseudoaneurysm were resected. CONCLUSION: Complications can also arise in small, seemingly harmless osteochondromas. Surgical resection should be considered as a preventive measure when exostoses form sharp tips close to neurovascular structures regardless of total osteochondroma size.