Re: Calcium phosphate cement in musculoskeletal tumor surgery, by Matsumine A, Kusuzaki K, Matsubara T, et al.
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Bone Cements↗
Biomedical subjects
Timothy A Damron
Publications and source records attributed to Timothy A Damron.
Restoration of growth plate function following radiotherapy is driven by increased proliferative and synthetic activity of expansions of chondrocytic clones.
Radiation therapy encompassing an active epiphysis can negatively impact the potential for bone growth by disrupting cell-cycle progression and accelerating apoptosis and terminal differentiation in physeal chondrocytes. Despite functional derangement following radiation exposure, the irradiated growth plate retains a capacity for regeneration and recovery of growth. The purpose of this study was to characterize the initial sequence of events leading to functional growth recovery in irradiated weanling rat growth plates. We hypothesized that growth in an irradiated epiphysis would be partially restored due to the expansion of chondrocytic clones. Stereological histomorphometry was used to compare chondrocytic cell and matrix turnover between the first and second week following irradiation, and to determine the relative contribution of each of the cellular and extracellular matrix (ECM) compartments to growth. We found that restoration of growth in the irradiated limb was strongly associated with the proliferative activity and production of ECM by these chondrocytic clones, as they expand in average volume, but not in numerical density. We conclude that chondrocytes forming expansive clones and exhibiting increased mitotic and matrix synthesis activity initiate the early restoration of function in the irradiated growth plate, and would be a logical target for strategies to restore full growth potential.
Animals↗
Soft tissue osteochondroma: case report and immunohistochemistry for parathyroid hormone-related protein.
Surface lesions of bone usually present little diagnostic dilemma because the majority are conventional osteochondromas. Other surface bone lesions include periosteal chondroma, periosteal chondrosarcoma, and parosteal osteosarcoma. Mineralized soft tissue lesions such as myositis ossificans, synovial chondroma, and synovial sarcoma may present in a similar fashion when they occur in a juxtaarticular position. The soft tissue osteochondroma or paraarticular osteochondroma may simulate some of these more aggressive tumors, and its recognition is important to avoid overtreatment. A case of an 11-year-old male with a soft tissue osteochondroma is reported to illustrate the characteristic radiographic and histological features of this rare entity. No prior reports have examined soft tissue osteochondroma for expression of parathyroid hormone related protein, an established cartilage tumor proliferative mitogen.
Biomarkers, Tumor↗
Adjuvant high dose rate brachytherapy in the management of soft tissue sarcoma: a dose-toxicity analysis.
OBJECTIVES: Although brachytherapy has been used in the management of soft tissue sarcoma for decades, there is little published data regarding dose and toxicity. We performed an interim analysis of our high dose-rate experience to establish dosing guidelines. METHODS: We analyzed our first 12 soft tissue sarcoma patients treated with high dose-rate brachytherapy as tumor bed boost (in conjunction with beam therapy), seeking an association between treatment factors and wound-healing complications. In the process of our analysis, we devised a dosimetric method to retrospectively quantify delivered dose. Our findings were used to formulate dosing guidelines; the first 5 cases treated along these guidelines are also presented. RESULTS: Despite the small number of cases, we were able to demonstrate a correlation (P < 0.01) between wound healing and brachytherapy dose (fractional or total biologically equivalent dose). We found no relationship between wound healing and patient age, diabetes, width of excised skin, cross-sectional area of implant, sequencing of therapy, or surgery-to-brachytherapy interval. CONCLUSION: There appears to be a relationship between dose and disturbed wound healing that should be respected to avoid unnecessary toxicity. An objective technique for defining target volume and quantifying dose is proposed for meaningful analysis of dose/effect relationships.
Brachytherapy↗
Combination radioprotectors maintain proliferation better than single agents by decreasing early parathyroid hormone-related protein changes after growth plate irradiation.
Our hypothesis was that combinations of radioprotectors would be more effective than individual agents in minimizing the effects of radiation on the growth plate after single-fraction hind-limb irradiation of Sprague-Dawley rats. At 2 days postirradiation, the decrease in parathyroid hormone-related protein and parathyroid hormone receptor 1 expression in the irradiated growth plate transitional and hypertrophic zones was reversed in both of the combination groups but persisted in the groups treated with the individual drugs. By 2 weeks, positive findings unique to the combination-treatment animals included greater mean proliferation in the irradiated growth plate than on the contralateral side, smaller limb length discrepancies, reversal of the increased overall matrix area fraction, and reversal of the usual deficiency in Indian hedgehog staining in the irradiated hypertrophic zone. While all treatments had a positive effect in reversing the decrease in B-cell leukemia 2 protein and coincident increase in Bax previously observed 2 weeks postirradiation, the two combination groups had a more robust effect. Combinations of radioprotectors may achieve their beneficial additive effects in the growth plate by decreasing the usual early drop in parathyroid hormone-related protein and parathyroid hormone receptor 1 after irradiation, resulting in a cascade of parathyroid hormone-related protein-mediated events.
Animals↗
Temporal changes in bone mass and mechanical properties in a murine model of tumor osteolysis.
Pathological fracture is a devastating complication of osteolytic bone metastases. The progression of osteolysis and its effect on bone fracture risk are poorly understood. The goal of this study was to determine the temporal changes in bone strength following tumor inoculation in a preclinical model of tumor osteolysis. In addition, a predictive model was developed between non-invasive radiographic measures and bone strength. The right femora of female nude mice were injected with breast cancer cells; the left limb served as a sham-operated control. Radiographs and DEXA scans were obtained at the time of surgery and at 3, 6, and 9 weeks. Groups of mice were euthanized at each time point for mechanical assessment. Micro-CT analysis was performed on a sub-set of mice with advanced state disease to quantify bone loss. Radiographs documented an increase in tumor osteolysis over time, with 58% of the mice showing signs of osteolysis at 3 weeks, 75% at 6 weeks, and 81% at 9 weeks. BMD measurements revealed a 21.6% increase from baseline in the controls whereas tumor-injected femora failed to increase in BMD over the same time course. Tumor-bearing limbs exhibited statistically significant decreases in torque at failure (86%), energy to failure (88%), and initial stiffness (94%) compared to the controls. Both lysis scores and BMD measurements proved to be modest predictors of mechanical strength, accounting for approximately 73% and 41% of variation in torque at failure, respectively. Micro-CT analysis revealed decreases in both total bone volume in the distal femur (31%) and metaphyseal fractional trabecular bone (89%). We have shown that non-invasive radiographic techniques provide a useful tool for monitoring the progression of tumor osteolysis and for predicting the mechanical strength of tumor-bearing bones in this model. By integrating non-invasive measures of tumor osteolysis and fracture risk, we have validated a clinically relevant platform for evaluating new therapeutic approaches for preserving and/or restoring bone affected by metastatic disease.
Absorptiometry, Photon↗
Radioprotectant combinations spare radiation-induced damage to the physis more than fractionation alone.
PURPOSE: The aim of this study was to determine if fractionation and individual or combinations of radioprotectants could minimize damage to physeal longitudinal growth in an animal model to any greater extent than fractionation alone. MATERIALS AND METHODS: Sixty-three weanling male Sprague-Dawley rats were randomized into seven equal groups. Five groups received a total 25 Gy radiation exposure in three equal fractions to the right knee with the left as non-irradiated control. For each group, pentoxifylline, misoprostol, and amifostine were given individually and amifostine was also given in combination with each of the other drugs prior to the radiation fractions. One group each received 25 Gy in one or three fractions without radioprotection. At six weeks, limb lengths and histomorphometry were assessed. RESULTS: The single fraction of 25 Gy caused a mean tibial length discrepancy of 24.4%. Fractionation decreased this to 18.8% (p < 0.001). Beyond fractionation alone, the mean femoral length discrepancies were significantly decreased by each of the added individual and combination radioprotectant drugs (p < 0.0004). The smallest absolute femoral length discrepancy (11%) was achieved with fractionation and the combination of amifostine and misoprostol. CONCLUSIONS: Radioprotectants may be beneficial in growth plate radioprotection, alone or in combination.
Amifostine↗
Ultraporous beta-tricalcium phosphate is well incorporated in small cavitary defects.
Numerous bone graft substitutes are available as alternatives to autologous and allograft bone grafts. The use of ultraporous beta-tricalcium phosphate for cavitary bone defects in our institution was based on the hypothesis that it would have gradual but complete incorporation over several months, similar to the smooth transition seen in animal models. This retrospective, uncontrolled study reviews 24 patients who had bone grafting of a cavitary defect with ultraporous beta-tricalcium phosphate mixed with local blood. Radiographically, resorption and trabeculation increased steadily with time, with trabeculation lagging slightly behind resorption. Resorption and trabeculation were more advanced at times beyond 6 weeks in small defects (< 43 cm) compared with large defects (>/= 43 cm). The presence of peripheral radiolucency seen early around nearly all grafts disappeared in small lesions by 1 year, but still was visible in larger lesions at the latest followup. Bone renewal seems to correspond temporally with gradual replacement of graft material, but incorporation is not complete even at 1 year in large defects. Clinically, there is a low rate of complications associated with the use of ultraporous beta-tricalcium phosphate, and patients progressed to unrestricted activities of daily living and recreational activities within 3 months.
Adolescent↗
Transit tumor retrieval preserves RNA fidelity and obviates snap-freezing.
UNLABELLED: Genetic expression profiling is enabling investigators to discover new diagnostic and possibly therapeutic pathways in sarcoma biology. To draw substantial conclusions from these molecular analyses, adequate tissue samples must be accrued. Beyond cohort size, the most variable and limiting aspect of doing gene expression analyses on fresh human tissue is the preservation of labile ribonucleic acids extracted from clinical specimens. We have developed a novel retrieval protocol that is readily amenable to the clinical constraints placed on surgeons and pathologists that minimizes variables that can corrupt ribonucleic acid fidelity. We evaluate critically genomic message integrity of mesenchymal tumors derived from transcontinental inter-institutional collaboration. Intact total ribonucleic acid was isolated and assessed for quality and quantity. Ribosomal RNA integrity was quantified using a bioanalyzer. Ribonucleic acid from 42 mesenchymal tumors was isolated and quantified, with selected samples amplified. The mean ribosomal ratios for collaborative institutions ranged from 1.0 to 1.18. Samples remained at 4 degrees C before processing from 1 to 17 days. Tumors stabilized using this protocol retained total ribonucleic acid integrity suitable for amplification and genomic expression analysis regardless of the institutional source or preprocessing duration, enabling a potential consortium of investigators to collaborate in the expression profiling of sarcomas. LEVEL OF EVIDENCE: Diagnostic study, Level III-3 (no consistently applied gold standard). See the Guidelines for Authors for a complete description of levels of evidence.
Biopsy, Needle↗
Microarray analysis of proliferative and hypertrophic growth plate zones identifies differentiation markers and signal pathways.
Longitudinal bone growth results from coordination of proliferation and hypertrophy of chondrocytes, calcification of the matrix, vascular invasion, and completion of endochondral bone formation in the growth plate. Although proliferative and hypertrophic chondrocytes are well characterized histomorphologically, the understanding of factors governing this transition is not fully explained. Our hypothesis was that significant differential gene expression exists between proliferative and hypertrophic chondrocytes that may provide clues to the regulation of this transition at the transcriptional level. Normal Sprague-Dawley rat growth plate chondrocytes from the proliferative zone (PZ) and hypertrophic zone (HZ) were isolated by laser capture microdissection and then subjected to microarray analysis. Confirmation of the differential expression of selected genes was done by in situ hybridization and quantitative reverse transcription (RT) polymerase chain reaction (PCR). A total of 40 transcripts showed at least twofold greater expression in the PZ compared to HZ at both 6 and 7 weeks of age, while 52 transcripts showed twofold greater expression in the HZ compared to PZ at these time points. Many of the differentially expressed genes in each zone had very high levels of expression and thus were classified as "enriched transcripts" for that zone. The PZ-enriched transcripts included fibromodulin, proline arginine-rich end leucine-rich repeat protein, lactate dehydrogenase, and enolase 1 alpha. In contrast, HZ-enriched transcripts included collagen I, protein kinase (lysine deficient 4), proteasome (prosome, macropain) activator subunit 4, prostaglandin I2 synthase, and integrin-binding sialoprotein, matrix metalloproteinase 13 (MMP13), and collagen X. Other genes were highly expressed in cells from both zones, including collagen II, aggrecan, cartilage oligomeric protein, cartilage link protein, laminin receptor, and eukaryotic translocation elongation factor. Functional classification of the PZ-enriched transcripts showed an increased percentage of genes expressed in nuclear cell cycle and transcription functions. In contrast, the HZ-enriched transcripts were more involved in extracellular structure and membrane receptor and transporter functions. Pathway analysis indicated that transforming growth factor beta and parathyroid hormone-related protein (PTHrP) pathways were important in both zones, and bone morphogenic protein pathway played a role in the HZ. It is likely that these differentially expressed genes are involved in regulation of the transition from proliferation to differentiation functions in the growth plate.
Animals↗
Biomechanical study of pins in cementing of contained proximal tibia defect.
Defects from curettage for giant cell tumors of bone frequently have been reconstructed with bone cement with or without reinforcement pins. The biomechanical basis for the addition of reinforcement pins was examined using a model of a contained defect in the proximal tibia. Fifty-four cadaveric proximal tibia in matched pairs were divided into five test groups: intact tibia, medial metaphyseal contained defect, defect reconstructed with cement alone, defect reconstructed with cement and pins inserted within the medullary canal, and defect reconstructed with cement and pins inserted through the cortex. Specimens were tested to failure during one cycle of compressive loading. Defect specimens were significantly weaker and less stiff than intact specimens, establishing the validity of the model-contained defects. For the reconstructions, there was no statistically significant difference in load to failure, stiffness, energy to failure, or displacement for the polymethylmethacrylate treatment alone when compared with matched specimen receiving polymethylmethacrylate and pins treatment. Similarly, there was no statistical difference in biomechanical properties in comparing matched specimens treated with polymethylmethacrylate alone or polymethylmethacrylate/pins (cortex). For contained defects of the proximal tibia that are typical after curettage for giant cell tumor, there appears to be no biomechanical advantage to use of reinforcement pins in the cement.
Biomechanical Phenomena↗
Decreased proliferation precedes growth factor changes after physeal irradiation.
The effects of irradiation on growth plate chondrocytes and mediators of chondrocytic differentiation are poorly understood. In earlier work on rat growth plate changes 1/2 to 4 weeks after irradiation, a nadir was identified at 1 week in proliferation and growth factor expression coincident with maximal histomorphometric derangement. The purpose of this study was to determine the earlier sequential relationship of proliferative, growth factor, and histomorphometric changes after irradiation leading to the 1-week nadir. Twenty-four weanling 5-week-old male Sprague-Dawley rats had right knee irradiation with single fraction 17.5 Gy whereas the left leg served as an internal control. The earliest change identified was a significant decrease in BrdU evidence of proliferative activity between 6 and 12 hours after irradiation, which persisted through 48 hours. Twelve to 24 hours after irradiation, caspase-3 staining for apoptosis was higher than that in growth plates not having received radiotherapy. Histomorphometric changes after irradiation were observed as early as 24 hours. Growth factors and their downstream antiapoptotic and proapoptotic mediators did not differ significantly between limbs through 48 hours. The current study suggests that decreased proliferation and apoptosis precede any change in histomorphometric features of the growth plate after irradiation and that decreased growth factor expression occurs later.
Analysis of Variance↗
Combinations of radioprotectants spare radiation-induced damage to the physis.
Radiotherapy used in the treatment of bone and soft tissue sarcomas in pediatric patients often results in undesirable growth plate damage. Radioprotectants may hold promise in the selective protection of growth plate tissue in this setting. In an animal model, the hypothesis tested was that pentoxifylline, selenium, or misoprostol, used in combination with amifostine, would significantly reduce longitudinal growth loss during one radiation dose exposure to a greater extent than the protection provided by only amifostine without increased morbidity or mortality or adverse effects on bone mineral density. Amifostine alone and in combination with each of the other radioprotectants resulted in limb discrepancy reduction to levels significantly less than radiated controls. The tibial length discrepancy in the selenium and amifostine group was 12.1 +/- 0.8%, less than the 15.5 +/- 2.6% tibial length discrepancy in the animals treated with amifostine alone, and less than the mean 18.8% tibial length discrepancy in the radiated limbs without radioprotection. There were no adverse effects on bone density in any group, but the selenium and amifostine group showed some increased mortality. Combinations of amifostine with these radioprotectants show efficacy in growth plate radioprotection and therefore warrant additional study in a clinically relevant fractionated model.
Amifostine↗
Temporal changes in PTHrP, Bcl-2, Bax, caspase, TGF-beta, and FGF-2 expression following growth plate irradiation with or without radioprotectant.
This study examined temporal changes in growth plate apoptosis molecules and growth factors in an animal model of radiation injury with and without a radioprotectant. Thirty weanling 5-week Sprague-Dawley rats underwent right knee irradiation with single-fraction 17.5 Gy while the left served as internal control. Six animals each were sacrificed at 0.5, 1, 2, 3, or 4 weeks after irradiation. Half of the animals received pretreatment with amifostine (WR-2721) radioprotectant. Immunohistochemical staining for PTHrP, Bcl-2, Bax, caspase-3, FGF-2, and TGF-beta was performed. PTHrP decreased to a nadir at 1 week after irradiation but rebounded to above control levels at 2 weeks in the reserve and transitional zones. The radioprotectant amifostine blunted the decrease in PTHrP but kept PTHrP expression lower than controls during the rebound phase in untreated irradiated animals. Hypertrophic zone Bax expression was decreased by amifostine in both irradiated and non-irradiated limbs at 1 and 2 weeks. FGF, TGF-beta, Bcl-2, and caspase levels generally decreased at 1 week and returned thereafter toward control levels. These findings underscore the importance of PTHrP in response to growth plate irradiation and show the novel finding of a decrease in Bax expression with amifostine pretreatment.
Amifostine↗
Comparison of needle core biopsy and fine-needle aspiration for diagnostic accuracy in musculoskeletal lesions.
CONTEXT: Needle core biopsy has been reported to be the choice of biopsy for musculoskeletal tumors. Fine-needle aspiration, on the other hand, has been widely accepted for nonmusculoskeletal tumors, but is only used in selected medical centers for musculoskeletal tumors. While fine-needle aspiration appears to have advantages to needle core biopsy in the aspects of simplicity and cost, the diagnostic accuracy should be the most critical parameter in determining the choice of biopsy. However, few studies comparing the diagnostic accuracy of these 2 biopsy methods have been performed. OBJECTIVE: This study was designed to compare the diagnostic accuracy of fine-needle aspiration and needle core biopsy in musculoskeletal tumors. DESIGN: Prospective study was performed in patients aged 10 years or older. Diagnostic accuracy was compared in 50 consecutive concurrent needle core biopsies and fine-needle aspirations of musculoskeletal lesions. RESULTS: For primary musculoskeletal lesions, fine-needle aspiration achieved a diagnostic accuracy rate of 88% for nature of lesion, 64% for specific diagnosis, 78% for histologic grading, and 74% for histologic typing. Needle core biopsy achieved an accuracy rate of 93% for nature of lesions, 83% for specific diagnosis, 83% for histologic grading, and 90% for histologic typing. Both biopsy methods have a higher diagnostic accuracy rate for high-grade tumors than for low-grade or benign lesions in determining the nature, specific diagnosis, and histologic grading. CONCLUSIONS: The needle core biopsy has a higher diagnostic accuracy than fine-needle aspiration in all aspects, including determining the nature of the tumor, establishing the histologic type and grade, and achieving a specific diagnosis.
Adolescent↗
Contained femoral defects: biomechanical analysis of pin augmentation in cement.
Although in the proximal tibia the need for pin augmentation of cemented giant cell tumor defects depends on whether the defect is contained, there is controversy regarding the role for pins in the distal femur. The current study investigated whether Steinmann pin augmentation offers biomechanical advantages in cement reconstruction of contained defects of the lateral femoral condyle. Twelve pairs of human femurs were used. They were tested either with the bone intact, with a standardized contained defect in the lateral condyle, with a defect repaired with cement alone, and with a defect repaired with pins in the cement. Intact specimens had significantly higher load to failure than specimens with a defect. In the repaired specimens there were no significant differences in stiffness, peak load to failure, and energy to failure between the specimens repaired with just cement or augmented with pins. This study did not show any significant biomechanical advantage of this configuration of Steinmann pin reinforcement in cement for contained defects of the lateral femoral condyle.
Biomechanical Phenomena↗
Soft-tissue lumps and bumps.
Soft-tissue masses of the extremities and torso are a common problem encountered by the orthopaedic surgeon. Although these soft-tissue masses are often benign, the orthopaedic surgeon must be able to recognize the features key to differentiating benign and malignant masses. An understanding of the epidemiology and clinical presentation of soft-tissue masses is needed in order to outline a practical approach to evaluation and surgical management.
Biopsy↗
What to do with deep lipomatous tumors.
Although most deep soft-tissue sarcomas are fairly easily recognized as heterogenous masses that are bright on T2-weighted MRI and dark on T1-weighted MRI, liposarcomas are often difficult to distinguish from lipomas and other benign fatty tumors. Because clinical features overlap considerably between lipomas and liposarcomas, the radiographic features are of utmost importance in differentiating these entities. Key MRI features, such as homogeneity of fatty signal, absence of gadolinium enhancement, and low signal on short tau inversion recovery images, strongly support the diagnosis of benign lipoma, but the absence of these findings is not specific for liposarcoma. Unfortunately, biopsy frequently results in false negative findings; therefore, early referral to an orthopaedic oncologist is indicated when any radiographic features suggest that the mass could represent a liposarcoma.
Biopsy↗