Percutaneous Cementoplasty for the Pelvis in Bone Metastasis: 12-Year Experience.

BACKGROUND: In advanced cancer patients, pelvic bone metastasis often causes pain and gait disturbance. The use of percutaneous bone cement [polymethylmethacrylate (PMMA)] injection for pain management and strengthening in pelvic bone metastasis has rarely been reported. To evaluate this method, we aimed to determine surgical outcomes and complications over a long-term follow-up period using a large patient group. PATIENTS AND METHODS: We retrospectively collected data from 178 patients who underwent percutaneous cementoplasty for pelvic metastatic lesions, 201 in total. Surgical outcomes evaluated included pain reduction and improvement of ambulation. Mortality within 1 month after procedure and pulmonary embolism caused by thrombus, fat, tumor emboli, or bone cement were investigated as surgical complications. For long-term survivors, pain relapse and mechanical failure were analyzed. The mean follow-up period was 12.6 months, and there were 159 fatalities at last follow-up. RESULTS: The mean regional pain numerical rating scale scores decreased from 6.1 preoperatively to 2.4 1 month after procedure (p < 0.01). Gait function was maintained, worsened, and uncheckable in 68%, 24%, and 8% of patients, respectively, 1 month after procedure. Of long-term survivors followed up for > 12 months (n = 53), there were no significant changes in serial plain radiographs, and regional pain aggravation was observed in 9%. Pulmonary cement embolism and bone cement implantation syndrome was observed in 11% and 10%, respectively. However, all patients with these complications were asymptomatic. CONCLUSIONS: Percutaneous cement injection into the pelvis is a feasible and safe palliative surgical option for patients with advanced malignancy in terms of pain reduction and maintenance of ambulatory function under regional anesthesia.

The application of 3D-printing technology in pelvic bone tumor surgery.

BACKGROUND: Three-dimensional (3D)-printing technology provides an advanced approach to pelvic bone tumor resection and reconstruction. However, only a few cases of pelvic bone tumor surgery using 3D-printing have been reported due to limited time since the introduction of the new implant. This study introduces pelvic bone tumor surgeries using 3D-printed bone-cutting guides and implants. METHODS: This single-center retrospective review included 12 patients who underwent malignant pelvic bone tumor surgeries using a 3D-printed bone-cutting guide and/or implant. Clinical information was collected regarding patient demographics, tumor characteristics, pathologic diagnosis, surgery details, and functional recovery. RESULTS: Type I internal hemipelvectomy was performed using 3D-printed bone-cutting guides for 4 patients that underwent cavitary bone tumor resection of the ilium. For 3 of these 4 patients, cavitary bone defects were filled with structural allobone graft precisely trimmed by the 3D-printed allograft-shaping guide (n = 1) and 3D-printed mesh-style titanium spacer (n = 2). For type II and III areas, one and two patients, respectively, underwent 3D-printing-assisted surgery. Five patients underwent type I, II, and III pelvic resection using 3D-printed cutting guides and reconstruction with 3D-printed implants. In all patients, independent gait was recovered except for a patient who underwent hindquarter amputation 4 months postoperatively because of local recurrence. CONCLUSIONS: This study provides preliminary, short-term data on the efficacy and safety of pelvic bone tumor surgery using 3D-printing.

Histologic Response and Toxicity following Interval-Compressed Four-Drug Therapy Given Preoperatively in Children and Young Adults with Osteosarcoma: A Retrospective Study.

OBJECTIVES: The histologic response to chemotherapy is an important prognostic factor in osteosarcoma. Thus, we attempted to develop an effective neoadjuvant regimen to achieve an improvement in histologic response. METHODS: Twenty-nine patients with a high-grade osteosarcoma received 2 courses of neoadjuvant chemotherapy non-randomly with either the MAP regimen (methotrexate 12 g/m2, cisplatin 120 mg/m2, and doxorubicin 75 mg/m2) or MAPI regimen (MAP plus ifosfamide 9 g/m2). We applied interval compression to MAPI by shortening the preoperative period to be aligned with that of MAP. Adjuvant chemotherapy was tailored according to the necrosis rate of resected tumor specimens. Necrosis rate, toxicity, and survival outcome were compared retrospectively between the 2 groups. RESULTS: The median interval between the beginning of neoadjuvant chemotherapy and surgery was 97.0 days in the MAPI group (17 patients) and 90.5 days in the MAP group (12 patients; p = 0.19). The good histologic response (>90% of necrosis) was observed in 71% of MAPI and in 42% of MAP (p = 0.12). Major toxicities of grade 3 or worse were not different between the 2 groups. The probability of 5-year progression-free survival and overall survival of the MAPI group were 74 and 83%, and those in the MAP group were 50 and 75%, showing no difference. CONCLUSIONS: Interval-compressed MAPI therapy given in a similar duration of the preoperative phase to that of conventional MAP therapy showed a marginal trend toward a better histologic response without a significant increase in major toxicities. Regarding the proportion of good histologic response, 71% is one of the highest values ever reported in the literature. The results warrant further testing in a prospective way in a larger cohort.

Preliminary results: use of multi-hole injection nails for intramedullary nailing with simultaneous bone cement injection in long-bone metastasis.

OBJECTIVE: For symptomatic metastasis of the long bones, intramedullary nailing has been the most accepted fixation method. Intramedullary nailing has effective control of pain, perioperative bleeding, and local tumor progression by augmentation with bone cement around the nail. Here, we report the preliminary results of a new surgical implant that allows for simultaneous injection of bone cement while inserting a percutaneous, flexible intramedullary nail. MATERIALS AND METHODS: We performed palliative surgeries for long-bone metastasis using a multi-hole injection nail (MIN) with multiple side holes in the distal one third. When the nail tip entered the metastatic cancer lesion, the bone cement injection was started, and continued until the nail was completely seated. Ten patients with advanced cancer underwent palliative surgery using the new implant with simultaneous bone cement injection for humeral (n = 4), femoral (n = 4), and tibial (n = 2) metastases. RESULTS: The mean operative time was 42 min (range, 36-52 min). The mean length of the injection nail was 23.0 cm (range, 18.0-33.0 cm), and the mean volume of cement was 28.0 ml (range, 14.0-40.0 ml). Marked pain palliation (p < 0.001) and functional recovery (p = 0.01) were verified. The mean Musculoskeletal Tumor Society (MSTS) functional score improved significantly from 12.5 at 6 weeks preoperatively, to 24.9 postoperatively. No acute postoperative complications, including cement embolism, occurred. CONCLUSION: This minimally invasive surgical method with MIN could be useful for stabilization of long-bone metastases in patients with advanced cancer.

Histological findings of regeneration in retrieved pasteurized bone grafts.

BACKGROUND: Despite a number of radiologic evaluations of the incorporation of pasteurized bone (PB) in human and histologic evaluations in animal models, there has been a scarce documentation regarding the histologic evaluation of PB from human. Herein, we present histologic findings of regeneration in retrieved PB graft from pediatric and adult patients. METHODS: PB was retrieved for various reasons in 7 patients (10-52 years old). Two bone pathologists independently counted the number of empty lacunae and lacunae with living cells in up to 10 randomly selected fields on medium-power (H&E, ×200) for each patient. Regeneration of PB was assessed as the ratio of the number of lacunae with nucleated cells to that of whole lacunae, which was defined as the "repair rate (RR)". RESULTS: The mean interval between initial reconstruction and retrieval (graft removal time; GRT) was 47.4 months (range, 11-144 months). The length of original PBs ranged from 5.8 to 20.6 cm. Microscopic examination of PBs showed areas with empty lacunae indicating necrosis and other areas contained lacunae with nucleated osteocytes, indicative of regeneration. Some Haversian canals of the PBs were filled with fibrovascular tissue and surrounded by lamellar bones including living osteocytes. RR varied widely from 21.7 to 62.4% with a mean of 36.8%. It was much higher in adult patients (46.6-62.4%, mean = 55.3%) than in pediatric patients (21.7-28.6%, mean = 25.3%), which was correlated with GRT (pediatric patients; mean of 14 months, adult patients; mean of 72.3 months). In adult patients, RR was higher in a patient with prosthesis composite in the proximal humerus (Case No. 3; 62.4%). CONCLUSIONS: RR was higher in whom GRT was longer, being correlated with GRT in retrieved PBs. In terms of our histological observation, PB is thought to be an acceptable temporary biologic spacer in limb-sparing surgery for malignant bone or soft tissue tumors.

Integrated molecular characterization of adult soft tissue sarcoma for therapeutic targets.

BACKGROUND: Several studies have investigated the molecular drivers and therapeutic targets in adult soft tissue sarcomas. However, such studies are limited by the genomic heterogeneity and rarity of sarcomas, particularly in those with complex and unbalanced karyotypes. Additional biomarkers are needed across sarcoma types to improve therapeutic strategies. To investigate the molecular characteristics of complex karyotype sarcomas (CKSs) for therapeutic targets, we performed genomic profiling. RESULTS: The mutational landscape showed that TP53, ATRX, and PTEN genes were highly mutated. CKS samples were categorized into three groups based on copy number variations that were associated with CDK4 and RB1 signatures. Integrated analysis of genomic and transcriptomic data revealed several pathways related to PDGFR, which could be a strategic target for anti-sarcoma therapy. CONCLUSIONS: This study provides a detailed molecular classification of CKSs and proposes several therapeutic targets. Targeted or combinational therapies for treating CKS should be considered before chemotherapy.

Bone tumor resection guide using three-dimensional printing for limb salvage surgery.

BACKGROUND AND OBJECTIVES: The three-dimensional (3D)-printed bone tumor resection guide can be personalized for a specific patient and utilized for bone tumor surgery. It is noninvasive, eidetic, and easy to use. We aimed to categorize the use of the 3D-printed guide and establish in vivo accuracy data. METHODS: We retrospectively reviewed 12 patients, who underwent limb salvage surgery using the 3D-printed guide at a single institution. To confirm the achievement of a safe bone margin, we compared the actual and planned distances between the cutting surface and tumor, which were reported in the final pathological report and measured from the same virtual cutting plane using graphical data of the cutting guide design, respectively. RESULTS: The use of the 3D-printed guide was categorized as follows: (a) wide excision only, (b) wide excision and biological reconstruction with a structural bone allograft shaped in accordance with the 3D-printed guide, and (c) wide excision and reconstruction with a 3D-printed personalized implant. The maximal cutting error was 3 mm. CONCLUSIONS: The 3D-printed resection guide is easy to use and shows promise in the field of orthopedic oncology, with its application in bone tumor resection and reconstruction with a structural bone allograft or 3D-printed implant.

Joint-preserving palliative surgery using self-locking screws of intramedullary nail and percutaneous cementoplasty for proximal humeral metastasis in the advanced cancer patients.

BACKGROUND: We introduced a palliative joint-preserving surgery using proximal self-locking screws of intramedullary (IM) nail and percutaneous cementoplasty (PC) in patients with proximal humeral metastases, including the head and neck, and evaluated the outcome of the surgical method. METHODS: Twenty-three patients (mean age = 63.0 ± 11.8 years, M:F = 14:9) had IM nailing with a self-locking screw system and PC for the treatment of humeral head and neck metastases. Usually, three proximal locking screws were inserted after IM nailing, and 20.9 ± 8.0 ml of polymethylmethacrylate (PMMA) bone cement was injected in the perimetal osteolytic area. RESULTS: Regional anesthesia with interscalene block was performed in 87.0% (20/23), and the duration of surgery (from anesthesia to awakening) was approximately 40-55 min. Red blood cell was not transfused intra- and/or postoperatively in 65.2% (15/23). The localized preoperative pain (visual analog scale (VAS), 8.2 ± 3.1) was gradually decreased at postoperative 1 week (VAS, 4.9 ± 2.1) and at 6 weeks (VAS, 2.9 ± 2.1) (P < 0.001). Among nine patients who underwent F-18-FDG PET/CT, the proximal humeral metastasis around PC showed improved, stable, and aggravated states in five (55.6%), three (33.3%), and one patient (11.1%), respectively. Meanwhile, 88.8% (8/9) of patients showed aggravation at the naive bone metastasis area. CONCLUSION: The selection of the self-locking screw type of the IM nail and PC was helpful in preventing fixation failure for joint-preserving palliative surgery in the proximal humeral metastasis.

Percutaneous Cementoplasty For Acetabulum In Patients With Bone Metastasis.

The purpose of this study is to demonstrate the surgical technique and to show the results of percutaneous cementoplasty (PC) for acetabular metastases using lateral approach under regional anesthesia. Forty-two cases underwent PC for acetabular metastases. The PC was performed using spinal anesthesia, lateral approach and fluoroscopic guidance. We assessed visual analogue scale (VAS) and revised musculoskeletal tumor society (MSTS) rating system and maximum standardized uptake value (SUVmax) of the acetabular lesion using F-18-FDG PET/CT before and after the PC. The mean injected volume of polymethylmethacrylamide to the pelvis was 21±11.8 ml. The mean of regional VAS (6.2±1.1 vs. 3.1±2.7, p<0.001), MSTS (10.3±3.9 vs. 18.3±3.2, p<0.001) and local SUVmax (8.6±5.2 vs. 5.7±3.6 , p = 0.012) on PET/CT showed significant reductions after surgery. Twenty-three patients (55%) died of disease at mean 11.8±4.8 months after surgery. PC using lateral approach and regional anesthesia could be a simple and safe surgical method for relieving pain and maintaining skeletal stability against acetabular metastasis.

Development of biopsy gun for aspiration and drug injection.

Tumor samples are required for pathological examinations, and different instruments are generally used to obtain samples of different types of tumors. Among the many methods available for obtaining tumor tissues, gun biopsy is widely used because it is much simpler than incisional biopsy and can collect many more samples than aspiration biopsy. However, conventional biopsy guns cannot simultaneously perform biopsy aspiration, bleeding prevention, and marker injection. In this study, we developed a biopsy gun that can simultaneously perform biopsy aspiration and sample collection, in addition to injecting a styptic agent and marker to prevent bleeding and contamination in the biopsy track. We then used a prototype to evaluate the feasibility of the developed device. The collectable sample size was also assessed. Performance of the biopsy aspiration feature was also evaluated, including the maximum aspiration viscosity. Finally, we tested the maximum amount of drug that can be injected. We found that the biopsy gun developed here is an alternative tool for biopsy collection with improved procedure safety and diagnostic accuracy.

Percutaneous navigation surgery of osteoid osteoma of the femur neck.

Surgery on benign bone tumors such as osteoid osteoma does not necessarily require bone exposure through a surgical incision. In most reported cases of the osteoid osteoma resection through computer-assisted surgery, registration and surgery were performed by exposing the bone. We have succeeded in performing percutaneous registration and navigated burr excision of the osteoid osteoma using computer-assisted navigation.

Hunting for the vulnerability in chondrosarcoma by tracing metabolic and genetic links.

In this Backstory, we narrate our journey in establishing a multidisciplinary team for sarcoma research and uncovering vulnerabilities in chondrosarcoma cells associated with their NAD+ dependencies for survival.1 Our findings hold promise for exploitation, yielding a synergistic cytotoxic effect when combined with systemic therapy.

Decoupling NAD+ metabolic dependency in chondrosarcoma by targeting the SIRT1-HIF-2α axis.

Chondrosarcomas represent the second most common primary bone malignancy. Despite the vulnerability of chondrosarcoma cells to nicotinamide adenine dinucleotide (NAD+) depletion, targeting the NAD+ synthesis pathway remains challenging due to broad implications in biological processes. Here, we establish SIRT1 as a central mediator reinforcing the dependency of chondrosarcoma cells on NAD+ metabolism via HIF-2α-mediated transcriptional reprogramming. SIRT1 knockdown abolishes aggressive phenotypes of chondrosarcomas in orthotopically transplanted tumors in mice. Chondrosarcoma cells thrive under glucose starvation by accumulating NAD+ and subsequently activating the SIRT1-HIF-2α axis. Decoupling this link via SIRT1 inhibition unleashes apoptosis and suppresses tumor progression in conjunction with chemotherapy. Unsupervised clustering analysis identifies a high-risk chondrosarcoma patient subgroup characterized by the upregulation of NAD+ biosynthesis genes. Finally, SIRT1 inhibition abolishes HIF-2α transcriptional activity and sensitizes chondrosarcoma cells to doxorubicin-induced cytotoxicity, irrespective of underlying pathways to accumulate intracellular NAD+. We provide system-level guidelines to develop therapeutic strategies for chondrosarcomas.

Hybrid solid mesh structure for electron beam melting customized implant to treat bone cancer.

15Bone replacement implants manufactured by electron beam melting have been widely studied for use in bone tumor treatment. In this application, a hybrid structure implant with a combination of solid and lattice structures guarantees strong adhesion between bone and soft tissues. This hybrid implant must exhibit adequate mechanical performance so as to satisfy the safety criteria considering repeated weight loading during the patient's lifetime. With a low volume of a clinical case, various shape and volume combinations, including both solid and lattice structures, should be evaluated to provide guidelines for implant design. This study examined the mechanical performance of the hybrid lattice by investigating two shapes of the hybrid implant and volume fractions of the solid and lattice structures, along with microstructural, mechanical, and computational analyses. These results demonstrate how hybrid implants may be designed to improve clinical outcomes by using patient-specific orthopedic implants with optimized volume fraction of the lattice structure, allowing for effective enhancement of mechanical performance as well as optimized design for bone cell ingrowth.

Whole Blood Titanium Concentration after Limb Salvage Surgery with Three-Dimensional-Printed Ti6Al4V Implants.

Background: Three-dimensional (3D)-printed customized implants can be fabricated and utilized for all bones with massive bone defects. The main safety issues with 3D-printed implants made of Ti6Al4V alloy are related to the release of metal debris and residual powder. In this study, we investigated the perioperative titanium concentrations in whole blood and peri-implant fluid samples of patients who underwent limb salvage surgery with a 3D-printed Ti6Al4V implant. Methods: Nineteen patients who underwent limb salvage surgery with 3D-printed Ti6Al4V implants were divided into two groups: the serial samples group and the follow-up group. To observe metal distribution and clearance in the body, serial samples of blood and peri-implant fluid from the surgical drain were prospectively collected for five patients in the serial samples group. For the remaining 14 patients who were followed up for more than a year, blood samples were collected only once. Results: In the serial samples group, the mean baseline titanium concentration was 0.78 µg/L (range, 0.1-2.2 µg/L): 3 patients showed peak concentration before the third postoperative month, while 2 patients still showed an increasing pattern at this point. Total titanium mass in the surgical drain showed a wash-out phenomenon in a week, with a significant uniform decrease (p = 0.04). In 14 patients in the follow-up group, the mean titanium concentration in the whole blood was 10.8 µg/L (range, 0.3-36.6 µg/L). For the 14 patients with a long-term follow-up, the aluminum and vanadium concentrations were all negligible. Conclusions: Whole blood titanium concentrations were higher after surgery using 3D-printed implants than after that using conventional orthopedic implants, but markedly lower than in patients with implant failure. None of the patients developed serious clinical adverse effects during follow-up.

Clinical characteristics and long-term outcomes of rhabdomyosarcoma in Korean children, adolescents and young adults: a single-center experience.

PURPOSE: This study aimed to analyze characteristics, treatment, long-term outcomes, and prognostic factors for children, adolescents and young adults with rhabdomysosarcoma (RMS). METHODS: This retrospective historical study included 75 patients with RMS treated between 2002 and 2019. Clinical data and follow-up results were collected including all diagnosis, treatment and prognosis information. RESULTS: Patients median-age-at-diagnosis was 6 years. Embryonal and alveolar histology occurred in 51 (68.0%) and 21 (28.0%) patients, respectively. The tumors most frequently originated from parameningeal site (28.0%). Of 74 evaluable patients for treatment outcome, 60 (81.1%) achieved complete response for first-line treatment, of whom, 34 (56.6%) maintained complete response, 26 (43.3%; 23/26, local relapse) showed relapse. Of 40 patients with treatment failure, 16 and 6 occurred in parameningeal area and retroperitoneum/perineum, respectively. The 5-year progression-free survival (PFS) and overall survival (OS) were 45.0% and 64.5%, respectively. In multivariate analyses, parameningeal site (p = 0.027), no gross total resection (p = 0.047), and no radiation therapy (RT) (p < 0.001) for PFS; and parameningeal site (p < 0.001) and no RT (p = 0.010) for worse OS, were significant. The median PFS and OS from treatment failure date in 40 patients with primary treatment failure were 1.3 and 4.1 years, respectively. Of 26 patients with relapse, interval to relapse < 7 months, retroperitoneum/perineum site, TNM stages III/IIV, and no salvage RT were independently associated with OS. CONCLUSION: The importance of adequate local therapy was highlighted in RMS treatment. Treatment failure was largely a local failure. Whether as a component of initial or salvage treatment, RT could improve patients' survival.

Sarcoma Immunotherapy: Confronting Present Hurdles and Unveiling Upcoming Opportunities.

Sarcomas are rare and heterogeneous mesenchymal neoplasms originating from the bone or soft tissues, which pose significant treatment challenges. The current standard treatment for sarcomas consists of surgical resection, often combined with chemo- and radiotherapy; however, local recurrence and metastasis remain significant concerns. Although immunotherapy has demonstrated promise in improving long-term survival rates for certain cancers, sarcomas are generally considered to be relatively less immunogenic than other tumors, presenting substantial challenges for effective immunotherapy. In this review, we examine the possible opportunities for sarcoma immunotherapy, noting cancer testis antigens expressed in sarcomas. We then cover the current status of immunotherapies in sarcomas, including progress in cancer vaccines, immune checkpoint inhibitors, and adoptive cellular therapy and their potential in combating these tumors. Furthermore, we discuss the limitations of immunotherapies in sarcomas, including a low tumor mutation burden and immunosuppressive tumor microenvironment, and explore potential strategies to tackle the immunosuppressive barriers in therapeutic interventions, shedding light on the development of effective and personalized treatments for sarcomas. Overall, this review provides a comprehensive overview of the current status and potential of immunotherapies in sarcoma treatment, highlighting the challenges and opportunities for developing effective therapies to improve the outcomes of patients with these rare malignancies.

New established cell lines from undifferentiated pleomorphic sarcoma for in vivo study.

As a high-grade soft-tissue sarcoma (STS), undifferentiated pleomorphic sarcoma (UPS) is highly recurrent and malignant. UPS is categorized as a tumor of uncertain differentiation and has few options for treatment due to its lack of targetable genetic alterations. There are also few cell lines that provide a representative model for UPS, leading to a dearth of experimental research. Here, we established and characterized new cell lines derived from two recurrent UPS tissues. Cells were obtained from UPS tissues by mincing, followed by extraction or dissociation using enzymes and culture in a standard culture environment. Cells were maintained for several months without artificial treatment, and some cell clones were found to be tumorigenic in an immunodeficient mouse model. Interestingly, some cells formed tumors in vivo when injected after aggregation in a non-adherent culture system for 24 h. The tissues from in vivo study and tissues from patients shared common histological characteristics. Pathways related to the cell cycle, such as DNA replication, were enriched in both cell clones. Pathways related to cell-cell adhesion and cell-cell signaling were also enriched, suggesting a role of the mesenchymal-to-epithelial transition for tumorigenicity in vivo. These new UPS cell lines may facilitate research to identify therapeutic strategies for UPS. [BMB Reports 2023; 56(4): 258-264].