A comparison of transforaminal lumbar interbody fusion (TLIF) cage material on fusion rates: A systematic review and network meta-analysis.

Background: A wide variety of materials are used for lumbar interbody fusion, but there is no unified consensus on the superiority of one material over another. The aim of this systematic review and network meta-analysis (NMA) is to compare and rank the various TLIF interbody materials based on fusion rates. Methods: We queried PubMed, EMBASE and Scopus from inception until August 2023, in which 2135 studies were identified. Inclusion criteria were applied based on the PRISMA guidelines. The fusion assessment employed the Bridwell's criteria with a length of follow-up of at least 12 months. The NMA was conducted to compare multiple approaches from multiple studies using the frequentist framework with STATA16. Results: In total, 13 TLIF studies involving 1919 patients with 1981 lumbar interbody levels fulfilled our eligibility criteria. Seven different cage materials were utilized: polyetheretherketone (PEEK, as the reference), allograft, autograft, PEEK with titanium coating (TiPEEK), titanium, carbon/carbon fiber reinforced polymer (CFRP) and 3D-printed titanium. The average patient age was 60.9 (SD = 7.5) years old. When compared to PEEK, the other six materials did not have a significantly different rate of lumbar fusion. However, the SUCRA number of the 3D-printed titanium, TiPEEK, Ti, allograft, autograft, CFRP, and PEEK were 0.8, 0.6, 0.5, 0.5, 0.4, 0.4, and 0.3 consecutively. Conclusions: Based on a network meta-analysis within the confines of our clinical study, 3D-printed titanium interbody cage may promote the highest success rate of fusion while PEEK may be the material with the least success rate of fusion in TLIF.

Prevalence of osteoporosis, sarcopenia, and high falls risk in healthy community-dwelling Thai older adults: a nationwide cross-sectional study.

Thailand has transitioned from an aging society to an aged society, which implies that the prevalence of age-related disorders will increase; however, epidemiological data specific to the prevalence of age-related degenerative musculoskeletal disorders among Thai older adults remain limited. Accordingly, the aim of this study was to investigate the prevalence of age-related musculoskeletal diseases, including osteoporosis, sarcopenia, and high falls risk among healthy community-dwelling Thai older adults. This cross-sectional nationwide study enrolled Thai adults aged ≥60 yr from 2 randomly selected provinces from each of the 6 regions of Thailand via stratified multistage sampling during March 2021 to August 2022. All enrolled participants were evaluated for BMD, skeletal muscle mass, grip strength, and gait speed. Osteoporosis was diagnosed according to the World Health Organization definition, and sarcopenia was diagnosed according to the Asian Working Group for Sarcopenia (AWGS) 2019 criteria. Falls risk was determined using the self-rated Fall Risk Questionnaire. A total of 2991 eligible participants were recruited. The mean age of participants was 69.2 ± 6.5 yr (range: 60-107), and 63.1% were female. The prevalence of osteoporosis, sarcopenia, and high falls risk was 29.7%, 18.1%, and 38.5%, respectively. Approximately one-fifth of subjects (19.1%) had at least 2 of 3 risk factors (ie, osteoporosis, sarcopenia, and high falls risk) for sustaining a fragility fracture, and 3.4% had all 3 risk factors. In conclusion, the results of this study revealed a high and increasing prevalence of osteoporosis, sarcopenia, and high falls risk in healthy community-dwelling Thai older adults. Since these conditions are all major risk factors for fragility fracture, modification of Thailand's national health care policy is urgently needed to address the increasing prevalence of these conditions among healthy community-dwelling older adults living in Thailand.

Establishing Normative Values for Performance-Based Tests in Older Thai Adults: A Nationwide Cross-Sectional Study.

OBJECTIVE: To determine normative values and identify contributing factors for physical performance tests in older, Thai, community-dwelling adults. DESIGN: Nationwide cross-sectional study. SETTING: Thai older community-dwelling adults. PARTICIPANTS: Thai older community-dwelling adults aged ≥60 years who had no major health problems (N=1430) between March 2021 and August 2022. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Normative values for the timed Up and Go (TUG) test, gait speed test, and 5-times sit-to-stand (5TSTS) test were determined for sex and age groups. Multivariable quantile regression analysis was employed to evaluate the participants, considering factors that may influence physical performance, such as height, and Charlson comorbidity index (CCI). RESULTS: The study included 1430 eligible participants. Their mean age was 68.4±5.8 years, and 58.5% were women. Men demonstrated superior physical performance in the medians (p50) of the TUG (10.0 s vs 11.0 s), gait speed (0.98 m/s vs 0.91 m/s), and 5TSTS (14.0 s vs 16.1 s) tests compared with women. These differences were consistently observed across age groups. Moreover, age, sex, and height were significantly associated with poor physical performance. CONCLUSION: This study observed variations in the normative values of TUG, gait speed, and 5TSTS tests among different age groups of older, Thai, community-dwelling adults. Additionally, our findings identified age, sex, and height as significant contributing factors to physical performance in this population.

Sarcopenia in Thai community-dwelling older adults: a national, cross-sectional, epidemiological study of prevalence and risk factors.

BACKGROUND: Sarcopenia is an age-related condition characterized by a progressive loss of skeletal muscle mass. It leads to declining physical performance, potentially culminating in a diminished quality of life or death. This study investigated the prevalence of sarcopenia and its associated risk factors among Thai community-dwelling individuals of advanced age. METHODS: Between March 2021 and August 2022, we conducted a nationwide community-based epidemiological survey across all six major regions of Thailand. Participants with sarcopenia were identified according to the 2019 criteria of the Asian Working Group for Sarcopenia (AWGS). The risk factors were examined using multivariable logistic regression. RESULTS: Of the 2456 participants, the overall prevalence of sarcopenia was 18.1%, with nearly two-thirds (66.9%) classified as having severe sarcopenia. Multivariate analysis identified six associated risk factors for sarcopenia. They are a lower body mass index (odds ratio [OR] = 11.7, 95% confidence interval [CI] = 7.8-17.4), suboptimal leg calf circumference (OR = 6.3, 95% CI = 4.3-9.5), male sex (OR = 2.8, 95% CI = 2.2-3.7), a history of chronic obstructive pulmonary disease (OR = 2.3, 95% CI = 2.3-5.0), advanced age (OR = 2.1, 95% CI = 1.3-3.3), and an increasing time in the timed up-and-go test (OR = 1.1, 95% CI = 1.0-1.1). CONCLUSIONS: This is the first large-scale national study to represent the prevalence and risk factors for sarcopenia in Thai community-dwelling individuals of advanced age using the AWGS 2019 criteria. Interventions such as lifestyle modifications and appropriate nutrition should be promoted throughout adulthood to maintain muscle strength and delay the onset of sarcopenia, particularly in males. TRIAL REGISTRATION: The Central Research Ethics Committee of the National Research Council of Thailand authorized the study protocol (approval number COA-CREC023/2021).

What Are the MSTS Scores and Complications Associated With the Use of Three-dimensional Printed, Custom-made Prostheses in Patients Who Had Resection of Tumors of the Hand and Foot?

BACKGROUND: There are a few good options for restoring bone defects in the hand and foot. 3D-printed implants have been used in the pelvis and elsewhere, but to our knowledge, they have not been evaluated in the hand and foot. The functional outcome, complications, and longevity of 3D-printed prostheses in small bones are not well known. QUESTIONS/PURPOSES: (1) What are the functional outcomes of patients with hand or foot tumors who were treated with tumor resection and reconstruction with a 3D-printed custom prosthesis? (2) What complications are associated with using these prostheses? (3) What is the 5-year Kaplan-Meier cumulative incidence of implant breakage and reoperation? METHODS: Between January 2017 and October 2020, we treated 276 patients who had tumors of the hands or feet. Of those, we considered as potentially eligible patients who might have extensive loss in their joint that could not be fixed with a bone graft, cement, or any prostheses available on the market. Based on this, 93 patients were eligible; a further 77 were excluded because they received nonoperative treatment such as chemoradiation, resection without reconstruction, reconstruction using other materials, or ray amputation; another three were lost before the minimum study follow-up of 2 years and two had incomplete datasets, leaving 11 for analysis in this retrospective study. There were seven women and four men. The median age was 29 years (range 11 to 71 years). There were five hand tumors and six tumors of the feet. Tumor types were giant cell tumor of bone (five), chondroblastoma (two), osteosarcoma (two), neuroendocrine tumor (one), and squamous cell carcinoma (one). Margin status after resection was ≥ 1 mm. All patients were followed for a minimum of 24 months. The median follow-up time was 47 months (range 25 to 67 months). Clinical data; function according to the Musculoskeletal Tumor Society, DASH, and American Orthopedic Foot and Ankle Society scores; complications; and survivorship of implants were recorded during follow-up in the clinic, or patients with complete charts and recorded data were interviewed on the telephone by our research associates, orthopaedic oncology fellows, or the surgeons who performed the surgery. The cumulative incidence of implant breakage and reoperation was assessed using a Kaplan-Meier analysis. RESULTS: The median Musculoskeletal Tumor Society score was 28 of 30 (range 21 to 30). Seven of 11 patients experienced postoperative complications, primarily including hyperextension deformity and joint stiffness (three patients), joint subluxation (two), aseptic loosening (one), broken stem (one), and broken plate (one), but no infection or local recurrence occurred. Subluxations of the metacarpophalangeal and proximal interphalangeal joints in two patients' hands were caused by the design of the prosthesis without a joint or stem. These prostheses were revised to a second-generation prosthesis with joint and stem, leading to improved dexterity. The cumulative incidence of implant breakage and reoperation in the Kaplan-Meier analysis was 35% (95% CI 6% to 69%) and 29% (95% CI 3% to 66%) at 5 years, respectively. CONCLUSION: These preliminary findings suggest that 3D implants may be an option for reconstruction after resections that leave large bone and joint defects in the hand and foot. Although the functional results generally appeared to be good to excellent, complications and reoperations were frequent; thus, we believe this approach could be considered when patients have few or no alternatives other than amputation. Future studies will need to compare this approach to bone grafting or bone cementation. LEVEL OF EVIDENCE: Level IV, therapeutic study.

Tumor-to-bone distance and radiomic features on MRI distinguish intramuscular lipomas from well-differentiated liposarcomas.

BACKGROUND: To develop a machine learning model based on tumor-to-bone distance and radiomic features derived from preoperative MRI images to distinguish intramuscular (IM) lipomas and atypical lipomatous tumors/well-differentiated liposarcomas (ALTs/WDLSs) and compared with radiologists. METHODS: The study included patients with IM lipomas and ALTs/WDLSs diagnosed between 2010 and 2022, and with MRI scans (sequence/field strength: T1-weighted (T1W) imaging at 1.5 or 3.0 Tesla MRI). Manual segmentation of tumors based on the three-dimensional T1W images was performed by two observers to appraise the intra- and interobserver variability. After radiomic features and tumor-to-bone distance were extracted, it was used to train a machine learning model to distinguish IM lipomas and ALTs/WDLSs. Both feature selection and classification steps were performed using Least Absolute Shrinkage and Selection Operator logistic regression. The performance of the classification model was assessed using a tenfold cross-validation strategy and subsequently evaluated using the receiver operating characteristic curve (ROC) analysis. The classification agreement of two experienced musculoskeletal (MSK) radiologists was assessed using the kappa statistics. The diagnosis accuracy of each radiologist was evaluated using the final pathological results as the gold standard. Additionally, we compared the performance of the model and two radiologists in terms of the area under the receiver operator characteristic curves (AUCs) using the Delong's test. RESULTS: There were 68 tumors (38 IM lipomas and 30 ALTs/WDLSs). The AUC of the machine learning model was 0.88 [95% CI 0.72-1] (sensitivity, 91.6%; specificity, 85.7%; and accuracy, 89.0%). For Radiologist 1, the AUC was 0.94 [95% CI 0.87-1] (sensitivity, 97.4%; specificity, 90.9%; and accuracy, 95.0%), and as to Radiologist 2, the AUC was 0.91 [95% CI 0.83-0.99] (sensitivity, 100%; specificity, 81.8%; and accuracy, 93.3%). The classification agreement of the radiologists was 0.89 of kappa value (95% CI 0.76-1). Although the AUC of the model was lower than of two experienced MSK radiologists, there was no statistically significant difference between the model and two radiologists (all P > 0.05). CONCLUSIONS: The novel machine learning model based on tumor-to-bone distance and radiomic features is a noninvasive procedure that has the potential for distinguishing IM lipomas from ALTs/WDLSs. The predictive features that suggested malignancy were size, shape, depth, texture, histogram, and tumor-to-bone distance.

Robustness of Radiomic Features: Two-Dimensional versus Three-Dimensional MRI-Based Feature Reproducibility in Lipomatous Soft-Tissue Tumors.

This retrospective study aimed to compare the intra- and inter-observer manual-segmentation variability in the feature reproducibility between two-dimensional (2D) and three-dimensional (3D) magnetic-resonance imaging (MRI)-based radiomic features. The study included patients with lipomatous soft-tissue tumors that were diagnosed with histopathology and underwent MRI scans. Tumor segmentation based on the 2D and 3D MRI images was performed by two observers to assess the intra- and inter-observer variability. In both the 2D and the 3D segmentations, the radiomic features were extracted from the normalized images. Regarding the stability of the features, the intraclass correlation coefficient (ICC) was used to evaluate the intra- and inter-observer segmentation variability. Features with ICC > 0.75 were considered reproducible. The degree of feature robustness was classified as low, moderate, or high. Additionally, we compared the efficacy of 2D and 3D contour-focused segmentation in terms of the effects of the stable feature rate, sensitivity, specificity, and diagnostic accuracy of machine learning on the reproducible features. In total, 93 and 107 features were extracted from the 2D and 3D images, respectively. Only 35 features from the 2D images and 63 features from the 3D images were reproducible. The stable feature rate for the 3D segmentation was more significant than for the 2D segmentation (58.9% vs. 37.6%, p = 0.002). The majority of the features for the 3D segmentation had moderate-to-high robustness, while 40.9% of the features for the 2D segmentation had low robustness. The diagnostic accuracy of the machine-learning model for the 2D segmentation was close to that for the 3D segmentation (88% vs. 90%). In both the 2D and the 3D segmentation, the specificity values were equal to 100%. However, the sensitivity for the 2D segmentation was lower than for the 3D segmentation (75% vs. 83%). For the 2D + 3D radiomic features, the model achieved a diagnostic accuracy of 87% (sensitivity, 100%, and specificity, 80%). Both 2D and 3D MRI-based radiomic features of lipomatous soft-tissue tumors are reproducible. With a higher stable feature rate, 3D contour-focused segmentation should be selected for the feature-extraction process.

Novel CSF1R-positive tenosynovial giant cell tumor cell lines and their pexidartinib (PLX3397) and sotuletinib (BLZ945)-induced apoptosis.

Tenosynovial giant cell tumor (TGCT) is a mesenchymal tumor derived from the synovium of the tendon sheath and joints, most frequently in the large joints. The standard of care for TGCTs is surgical resection. A new targeting approach for treating TGCTs has emerged from studies on the role of the CSF1/CSF1 receptor (CSF1R) in controlling cell survival and proliferation during the pathogenesis of TGCTs. We established four novel cell lines isolated from the primary tumor tissues of patients with TGCTs. The cell lines were designated Si-TGCT-1, Si-TGCT-2, Si-TGCT-3, and Si-TGCT-4, and the TGCT cells were characterized by CSF1R and CD68. These TGCT cells were then checked for cell proliferation using an MTT assay and three-dimensional spheroid. The responses to pexidartinib (PLX3397) and sotuletinib (BLZ945) were evaluated by two-dimensional MTT assays. All cells were positive for α­smooth muscle actin (α­SMA), fibroblast activation protein (FAP), CSF1R, and CD68. Except for Si-TGCT-4, all TGCT cells had high CSF1R expressions. The cells exhibited continuous growth as three-dimensional spheroids formed. Treatment with pexidartinib and sotuletinib inhibited TGCT cell growth and induced cell apoptosis correlated with the CSF1R level. Only Si-TGCT-4 cells demonstrated resistance to the drugs. In addition, the BAX/BCL-2 ratio increased in cells treated with pexidartinib and sotuletinib. With the four novel TGCT cell lines, we have an excellent model for further in vitro and in vivo studies.

Three-dimensional printed, proximal phalangeal prosthesis with metatarsophalangeal joint arthroplasty for the treatment of a giant cell tumor of the fifth toe: The first case report.

INTRODUCTION: The majority of patients with bone sarcoma or an aggressive benign tumor of the toe can be successfully treated by amputation. However, limb-salvage surgery for toe tumors remains challenging. PRESENTATION OF CASE: A 26-year-old female presented with an enlarging mass on her right 5th toe. Imaging studies revealed an expansile osteolytic, destructive lesion of the proximal phalanx of the 5th toe with metatarsophalangeal (MTP) joint invasion. A biopsy specimen confirmed a grade 1, giant cell tumor of the bone. An en bloc resection of the proximal phalanx was performed, and the defect was reconstructed with a patient-matched, three-dimensional, printed titanium proximal phalanx endoprosthesis with an MTP joint extension. The postoperative course was uneventful. The patient has walked with full weight-bearing since early postoperatively. No local recurrence or metastases were evident. However, scar formation occurred after two years, causing an overriding toe deformity. DISCUSSION: This case represents the first use of a toe prosthesis with MTP joint reconstruction. The complex MTP structure with a preserved metatarsal head facilitates the effort to mimic normal weight-bearing. CONCLUSION: A three-dimensional printed prosthesis of the 5th toe is a viable alternative to a bone graft or amputation. However, to avoid stiffness and complications, further study is needed to improve the prosthesis design.

Arthroscopic Treatment of a Large Mass of the Medial Side of the Leg Caused by Distal Extension of a Meniscal Cyst: A Case Report.

CASE: We report a 39-year-old man who presented with a painful mass that had been growing over the anteromedial aspect of his left leg for 2 years and was recurrent after an open excisional biopsy. Magnetic resonance imaging showed a lobulated cyst that extended from the medial meniscus. Arthroscopic cyst decompression, anterior cruciate ligament reconstruction, partial meniscectomy, and repair of the meniscotibial capsule were performed. There was no recurrence during the 1-year follow-up. CONCLUSIONS: Arthroscopic cyst decompression and repair of the posterior meniscotibial capsule is a good and safe alternative procedure for the treatment of large-sized meniscal cysts with distal extensions.

Long-term outcomes of cement in cement technique for revision endoprosthesis surgery.

BACKGROUND AND OBJECTIVE: Cemented endoprosthetic reconstruction after resection of primary bone sarcomas has been a standard-of-care option for decades. With increased patient survival, the incidence of failed endoprostheses requiring revision surgery has increased. Revision of cemented endoprotheses by cementing into the existing cement mantle (CiC) is technically demanding. METHODS: This is a retrospective review of our endoprosthesis database of 512 consecutive cemented endoprosthetic reconstructions performed for oncologic diagnoses between 1980 and 2014. A total of 54 implants (mean patient age 32 years, range 13-81) were revised with a CiC technique. Outcomes evaluated were prosthesis survival, revision surgery categorized according to the Henderson Failure Mode Classification, complications, and functional scores. RESULTS: Fifteen-year Kaplan-Meier survival rate was 34% for initial revision and 39% for subsequent revision implants. Mean revised Musculoskeletal Tumor Society (MSTS) Score was 27 at latest follow-up. Infection rate was 2%, 9%, and 13% for primary endoprostheses, initial revisions, and subsequent revisions, respectively. Limb salvage rate was 87%. CONCLUSIONS: At long-term follow up, endoprostheses revised with the CiC technique showed consistent 15-year survival from initial (34%) to subsequent (39%) revision. Despite a relatively high failure rate, these results are encouraging and demonstrate that this is a conservative, repeatable technique.

Genomic aberrations frequently alter chromatin regulatory genes in chordoma.

Chordoma is a rare primary bone neoplasm that is resistant to standard chemotherapies. Despite aggressive surgical management, local recurrence and metastasis is not uncommon. To identify the specific genetic aberrations that play key roles in chordoma pathogenesis, we utilized a genome-wide high-resolution SNP-array and next generation sequencing (NGS)-based molecular profiling platform to study 24 patient samples with typical histopathologic features of chordoma. Matching normal tissues were available for 16 samples. SNP-array analysis revealed nonrandom copy number losses across the genome, frequently involving 3, 9p, 1p, 14, 10, and 13. In contrast, copy number gain is uncommon in chordomas. Two minimum deleted regions were observed on 3p within a ∼8 Mb segment at 3p21.1-p21.31, which overlaps SETD2, BAP1 and PBRM1. The minimum deleted region on 9p was mapped to CDKN2A locus at 9p21.3, and homozygous deletion of CDKN2A was detected in 5/22 chordomas (∼23%). NGS-based molecular profiling demonstrated an extremely low level of mutation rate in chordomas, with an average of 0.5 mutations per sample for the 16 cases with matched normal. When the mutated genes were grouped based on molecular functions, many of the mutation events (∼40%) were found in chromatin regulatory genes. The combined copy number and mutation profiling revealed that SETD2 is the single gene affected most frequently in chordomas, either by deletion or by mutations. Our study demonstrated that chordoma belongs to the C-class (copy number changes) tumors whose oncogenic signature is non-random multiple copy number losses across the genome and genomic aberrations frequently alter chromatin regulatory genes. © 2016 Wiley Periodicals, Inc.

Conservative surgery in the treatment of giant cell tumor of the sacrum: 35 years' experience.

OBJECT There is no consensus regarding the appropriate treatment of sacral giant cell tumor (GCT). There are 3 main management problems: tumor control, neurological loss, and pelvic instability. The objective of this study was to examine oncological, neurological, and structural outcomes of sacral GCT after intralesional excision and local intraoperative adjunctive treatment. METHODS The authors retrospectively reviewed the records of 24 patients with sacral GCT who underwent conservative surgery (intralesional resection/curettage) at Memorial Sloan Kettering Cancer Center from 1973 through 2012. They analyzed patient demographic data, tumor characteristics, and operative techniques, and examined possible correlations with postoperative functional outcomes, complications, recurrence, and mortality. RESULTS There were 7 local recurrences (30%) and 3 distant recurrences (13%). Three of 24 patients (12.5%) had significant neurological loss after treatment-specifically, severe bowel and/or bladder dysfunction, but all regained function within 1-4 years. Larger tumor size (> 320 cm3) was associated with greater postoperative neurological loss. Radiation therapy and preoperative embolization were associated with prolonged disease-free survival. There were no local recurrences among the 11 patients who were treated with both modalities. Based on radiographic and clinical assessment, spinopelvic stability was present in 23 of 24 patients at final follow-up. CONCLUSIONS High local and distant recurrence rates associated with sacral GCT suggest the need for careful local and systemic follow-up in managing these patients. Intraoperative preservation of sacral roots was associated with better pain relief, improvement in ambulatory function, and retention of bowel/bladder function in most patients. Fusion and instrumentation of the sacroiliac joint successfully achieved spinopelvic stability in cases deemed clinically unstable. Despite improvement in the management of sacral GCT over 35 years, a need for novel therapies remains. The strategy of combining radiotherapy and embolization merits further study.

Optimal internal fixation of anatomically shaped synthetic bone grafts for massive segmental defects of long bones.

BACKGROUND: Large segmental bone defects following tumor resection, high-energy civilian trauma, and military blast injuries present significant clinical challenges. Tissue engineering strategies using scaffolds are being considered as a treatment, but there is little research into optimal fixation of such scaffolds. METHODS: Twelve fresh-frozen paired cadaveric legs were utilized to simulate a critical sized intercalary defect in the tibia. Poly-ε-caprolactone and hydroxyapatite composite scaffolds 5 cm in length with a geometry representative of the mid-diaphysis of an adult human tibia were fabricated, inserted into a tibial mid-diaphyseal intercalary defect, and fixed with a 14-hole large fragment plate. Optimal screw fixation comparing non-locking and locking screws was tested in axial compression, bending, and torsion in a non-destructive manner. A cyclic torsional test to failure under torque control was then performed. FINDINGS: Biomechanical testing showed no significant difference for bending or axial stiffness with non-locking vs. locking fixation. Torsional stiffness was significantly higher (P=0.002) with the scaffold present for both non-locking and locking compared to the scaffold absent. In testing to failure, angular rotation was greater for the non-locking compared to locking constructs at each torque level up to 40 N-m (P<0.05). The locking constructs survived a significantly higher number of loading cycles before reaching clinical failure at 30 degrees of angular rotation (P<0.02). INTERPRETATION: The presence of the scaffold increased the torsional stiffness of the construct. Locking fixation resulted in a stronger construct with increased cycles to failure compared to non-locking fixation.

CA-074Me compound inhibits osteoclastogenesis via suppression of the NFATc1 and c-FOS signaling pathways.

The osteoclast is an integral cell of bone resorption. Since osteolytic disorders hinge on the function and dysfunction of the osteoclast, understanding osteoclast biology is fundamental to designing new therapies that curb osteolytic disorders. The identification and study of lysosomal proteases, such as cathepsins, have shed light on mechanisms of bone resorption. For example, Cathepsin K has already been identified as a collagen degradation protease produced by mature osteoclasts with high activity in the acidic osteoclast resorption pits. Delving into the mechanisms of cathepsins and other osteoclast related compounds provides new targets to explore in osteoclast biology. Through our anti-osteoclastogenic compound screening experiments we encountered a modified version of the Cathepsin B inhibitor CA-074: the cell membrane-permeable CA-074Me (L-3-trans-(Propylcarbamoyl) oxirane-2-carbonyl]-L-isoleucyl-L-proline Methyl Ester). Here we confirm that CA-074Me inhibits osteoclastogenesis in vivo and in vitro in a dose-dependent manner. However, Cathepsin B knockout mice exhibited unaltered osteoclastogenesis, suggesting a more complicated mechanism of action than Cathepsin B inhibition. We found that CA-074Me exerts its osteoclastogenic effect within 24 h of osteoclastogenesis stimulation by suppression of c-FOS and NFATc1 pathways.

Non-contact small animal fluorescence imaging system for simultaneous multi-directional angular-dependent data acquisition.

We present a novel non-contact small animal fluorescent molecular tomography (FMT) imaging system. At the heart of the system is a new mirror-based imaging head that was designed to provide 360-degree measurement data from an entire animal surface in one step. This imaging head consists of two conical mirrors, which considerably reduce multiple back reflections between the animal and mirror surfaces. These back reflections are common in existing mirror-based imaging heads and tend to degrade the quality of raw measurement data. In addition, the introduction of a novel ray-transfer operator allows for the inclusion of the angular dependent data in the image reconstruction process, which results in higher image resolution. We describe in detail the system design and implementation of the hardware components as well as the transport-theory-based image reconstruction algorithm. Using numerical simulations, measurements on a well-defined phantom and a live animal, we evaluate the system performance and show the advantages of our approach.

Proteomic identification of 14-3-3ϵ as a linker protein between pERK1/2 inhibition and BIM upregulation in human osteosarcoma cells.

Despite advancements in multimodality chemotherapy, conventional cytotoxic treatments still remain ineffective for a subset of patients with aggressive metastatic or multifocal osteosarcoma. It has been shown that pERK1/2 inhibition enhances chemosensitivity to doxorubicin and promotes osteosarcoma cell death in vivo and in vitro. One of the pro-apoptotic mechanisms is upregulation of Bim by pERK1/2 inhibitors. To this end, we examined proteomic changes of 143B human osteosarcoma cells with and without treatment of PD98059, pERK1/2 inhibitor. Specifically, we identified 14-3-3ϵ protein as a potential mediator of Bim expression in response to inhibition of pERK1/2. We hypothesized that 14-3-3ϵ mediates upregulation of Bim expression after pERK1/2 inhibition. We examined the expression of Bim after silencing 14-3-3ϵ using siRNA. The 14-3-3ϵ gene silencing resulted in downregulation of Bim expression after PD98059 treatment. These data indicate that 14-3-3ϵ is required for Bim expression and that it has an anti-cancer effect under pERK1/2 inhibition in 143B cells. By playing an essential role upstream of Bim, 14-3-3ϵ may potentially be a coadjuvant factor synergizing the effect of pERK1/2 inhibitors in addition to conventional cytotoxic agents for more effective osteosarcoma treatments.

MAPK/ERK Signaling in Osteosarcomas, Ewing Sarcomas and Chondrosarcomas: Therapeutic Implications and Future Directions.

The introduction of cytotoxic chemotherapeutic drugs in the 1970's improved the survival rate of patients with bone sarcomas and allowed limb salvage surgeries. However, since the turn of the century, survival data has plateaued for a subset of metastatic, nonresponding osteo, and/or Ewing sarcomas. In addition, most high-grade chondrosarcoma does not respond to current chemotherapy. With an increased understanding of molecular pathways governing oncogenesis, modern targeted therapy regimens may enhance the efficacy of current therapeutic modalities. Mitogen-Activated Protein Kinases (MAPK)/Extracellular-Signal-Regulated Kinases (ERK) are key regulators of oncogenic phenotypes such as proliferation, invasion, angiogenesis, and inflammatory responses; which are the hallmarks of cancer. Consequently, MAPK/ERK inhibitors have emerged as promising therapeutic targets for certain types of cancers, but there have been sparse reports in bone sarcomas. Scattered papers suggest that MAPK targeting inhibits proliferation, local invasiveness, metastasis, and drug resistance in bone sarcomas. A recent clinical trial showed some clinical benefits in patients with unresectable or metastatic osteosarcomas following MAPK/ERK targeting therapy. Despite in vitro proof of therapeutic concept, there are no sufficient in vivo or clinical data available for Ewing sarcomas or chondrosarcomas. Further experimental and clinical trials are awaited in order to bring MAPK targeting into a clinical arena.

The management of sacral schwannoma: report of four cases and review of literature.

Sacral schwannoma is a rare retrorectal tumor in adults. Postoperative sacral neurological deficit is difficult to avoid. Currently, there is no established consensus regarding best treatment options. We present the management and outcomes of sacral schwannoma in 4 patients treated with intralesional curettage and postoperative radiation. There were 3 women and one man (average age: 45.5 years) with long duration of lumbosacral pain with or without radiculopathy. Intralesional curettage was performed by posterior approach and adjuvant radiation therapy with dosage of 5000-6600 cGy was given after surgery. The mean follow-up time was 18 months (range 4-23 months). Symptoms of radiculopathy had decreased in all patients. The recent radiographic findings show evidence of sclerosis at the sacrum one year postoperatively, but the size was unchanged. Intralesional curettage and adjuvant radiation therapy can be used in the treatment of sacral schwannoma to relieve symptoms and preserve neurological function.