Clinical Orthopaedics and Related Research ®

A Publication of The Association of Bone and Joint Surgeons ®

Published in
Clinical Orthopaedics and Related Research®
Volume 466 | Issue 9 | Sep, 2008

The Classic: Integration of Deoxyribonucleic Acid Specific for Rous Sarcoma Virus after Infection of Permissive and Nonpermissive Hosts

Harold E. Varmus, Peter K. Vogt, J. Michael Bishop A relatively simple but stringent technique was developed to detect the integration of virus-specific DNA into the genomes of higher organisms. In both permissive (duck) and nonpermissive (mammalian) cells which normally contain no nucleotide sequences specific for Rous sarcoma virus, transformation by the virus results in the appearance of DNA specific for Rous sarcoma virus covalently integrated into strands of host-cell DNA containing reiterated sequences. Early after infection of mouse or duck cells by Rous sarcoma virus, unintegrated DNA specific for the virus can be demonstrated.

Dominant Negative LRP5 Decreases Tumorigenicity and Metastasis of Osteosarcoma in an Animal Model

Yi Guo MD, PhD, Elyssa M. Rubin MD, Jun Xie BA, Xiaolin Zi MD, PhD, Bang H. Hoang MD Osteosarcoma (OS) is a primary malignant bone tumor with a high propensity for local recurrence and distant metastasis. We previously showed a secreted, dominant-negative LRP5 receptor (DNLRP5) suppressed in vitro migration and invasion of the OS cell line SaOS-2. Therefore, we hypothesized DNLRP5 also has in vivo antitumor activity against OS. We used the 143B cell line as a model to study the effect of DNLRP5 by stable transfection. Inhibition of Wnt signaling by DNLRP5 was verified by a reduction in TOPFLASH luciferase activity. In soft agar, DNLRP5-transfected 143B cells formed fewer and smaller colonies than control transfected cells. DNLRP5 transfection reduced in vivo tumor growth of 143B cells in nude mice. DNLRP5 also decreased in vitro cellular motility in a scratch wound assay. In a spontaneous pulmonary metastasis model, DNLRP5 reduced both the size and number of lung metastatic nodules. The reduction in cellular invasiveness by DNLRP5 was associated with decreased expression of matrix metalloproteinase-2, N-cadherin, and Snail. Our data suggest canonical Wnt/LRP5 signaling reflects an important underlying mechanism of OS progression. Therefore, strategies to suppress LRP5-mediated signaling in OS cells may lead to a reduction in local or systemic disease burden.

Polymorphisms and Methylation of the Reduced Folate Carrier in Osteosarcoma

Rui Yang MD, Jing Qin PhD, Bang H. Hoang MD, John H. Healey MD, Richard Gorlick MD High-dose methotrexate is a standard component in the treatment of osteogenic sarcoma. Impaired methotrexate uptake associated with decreased reduced folate carrier expression is a common mechanism of methotrexate resistance in osteogenic sarcoma samples. We investigated whether promoter methylation and polymorphisms in the 3′ untranslated region are involved in regulating reduced folate carrier expression. In a cohort of 66 osteogenic sarcoma specimens, quantitative methylation-specific polymerase chain reaction and single-strand conformation polymorphism were performed. We found detectable levels of promoter methylation in 84.3% of samples. When related to the reduced folate carrier mRNA levels, a trend was observed that reduced folate carrier expression is lower in samples (median, 0.7) with greater than 10% DNA methylation as compared with those (median, 2.3) with less than 10% DNA methylation. The heterozygous polymorphisms of 2582 T/G and 2617C/T in the 3′ untranslated region showed reduced folate carrier expression (median, 0.9) as compared with the wild-type 2582T and 2617C (median, 4.2). The data suggest promoter methylation and polymorphisms in the 3′ untranslated region of the reduced folate carrier may be involved in its transcriptional regulation in osteogenic sarcoma. Further study is required to confirm this finding.

Hypoxia Markers in Human Osteosarcoma: An Exploratory Study

Hiroo Mizobuchi MD, José Manuel García-Castellano MD, PhD, Shaji Philip BA, John H. Healey MD, Richard Gorlick MD Neoplastic cells growing under hypoxic conditions exhibit a more aggressive phenotype by activating a cascade of molecular events partly mediated by hypoxia-inducible transcription factor (HIF-1α) and vascular endothelial growth factor (VEGF). The roles of these markers have been studied previously in several cancer lines. We ascertained the frequency of HIF-1α expression, VEGF expression, the degree of neovascularization, and cell proliferation in osteosarcoma samples. Samples from osteosarcoma patients were assessed for HIF-1α and VEGF protein expression using immunohistochemistry, neovascularization using antibodies for Factor VIII, and cell proliferation using the Ki-67 labeling index. Associations between these parameters and clinical features were examined. HIF-1α staining was positive in 35% of patients and metastases were present in 61% of these HIF-1α-positive patients. VEGF protein expression was detected in 69% of patients, 92% of whom were female. We observed an insignificant trend for a higher frequency of VEGF expression in the high-grade as compared to low-grade osteosarcoma. We observed no association between vascular density and proliferation index and any clinical parameters. We found an association between HIF-1α expression and metastatic disease and between VEGF expression and female gender.

S100A6 Expression and Function in Human Osteosarcoma

Xiaoji Luo MD, PhD, Katie A. Sharff BA, Jin Chen MD, Tong-Chuan He MD, PhD, Hue H. Luu MD There is a critical need to identify markers that can accurately identify existing or predict future metastatic disease in patients with osteosarcoma since the majority of patients present with undetectable micrometastatic disease. We previously reported S100A6 is overexpressed in human osteosarcoma and increased expression of S100A6 by immunohistochemistry correlated with decreased clinical metastasis. We have established 11 primary cultures from biopsies of patients with osteosarcoma and ten of the 11 primary cultures have increased expression of S100A6 relative to normal human osteoblasts. To further explore possible mechanisms for metastasis suppression previously reported, we used in this report siRNA-mediated knockdown of S100A6 in four commonly used human osteosarcoma lines, then examined their cell adhesion, migration, and invasion properties. Knockdown of S100A6 expression inhibited cell adhesion and promoted cell migration and invasion in these lines. Conversely, S100A6 overexpression enhanced cell adhesion and inhibited cell invasion. Our data demonstrate S100A6 is commonly overexpressed in human osteosarcoma. S100A6 may inhibit osteosarcoma metastasis by promoting cell adhesion and inhibiting cell motility and invasion. Thus, S100A6 may be considered a potential marker for human osteosarcoma with prognostic value for identifying patients without metastases.

Metastatic Osteosarcoma Gene Expression Differs In Vitro and In Vivo

Jennifer W. Lisle MD, Joseph Y. Choi MD, PhD, Jason A. Horton BS, Matthew J. Allen VetMB, PhD, Timothy A. Damron MD An understanding of differential gene expression in highly metastatic osteosarcoma could provide gene targets for treatment of metastases. We compared gene expression profiles of high- (LM7) and low- (LM2) metastatic SaOS2-derived cell lines in an in vitro tissue culture model and examined several differentially regulated genes in vivo in a murine orthotopic xenograft model. We hypothesized an orthotopic inoculation of LM2 and LM7 cells would establish a primary lesion and the gene expression profile of cells grafted in this fashion would resemble the gene expression profile observed in an in vitro model. Thirty-five days after inoculation, animals were euthanized and both tibiae were harvested and rapidly frozen in liquid nitrogen. Human-specific GAPDH mRNA was present in two of four tibias inoculated with LM2 cells and three of four tibias inoculated with LM7 cells. Tibiae displaying the presence of human cells were assayed by semiquantitative reverse transcriptase polymerase chain reaction. We observed poor correspondence of in vitro to in vivo gene expression for either cell line. Accordingly, in vitro osteosarcoma gene expression data must be interpreted with caution until confirmed in vivo. Our orthotopic injection model allowed in vivo study of differential gene expression between these two cell lines but did not show radiographic evidence of an established primary lesion.

Histogenetic Characterization of Giant Cell Tumor of Bone

Manuela Salerno MSc, Sofia Avnet PhD, Marco Alberghini MD, Armando Giunti MD, Nicola Baldini MD [object Object]

Fas Death Pathway in Sarcomas Correlates with Epidermal Growth Factor Transcription

David E. Joyner PhD, Albert J. Aboulafia MD, Timothy A. Damron MD, R. Lor Randall MD, FACS Modulation of apoptosis may influence sarcoma pathogenesis and/or aggressiveness. The Fas death pathway, mediated by FasL or TGFβ, is one of two apoptotic pathways. Recent studies report that EGF can modulate TGFβ and/or FasL expression/activity; thus, EGF has the potential to influence activation of the Fas pathway. EGF is not always detectable in mesenchymal tumors; therefore, we hypothesized EGF would define which Fas ligand predominates. We assayed 57 surgically removed human sarcomas for 10 genes involved in the Fas pathway. Skeletal muscle biopsies from eight patients served as controls. Sample transcripts were detected by real-time RT-PCR. We attempted to identify relevant predictor variables. The 57 sarcomas were segregated into two categories defined by EGF mRNA content: (1) 23 tumors with EGF concentrations that approximated muscle EGF transcript levels (high-EGF tumors); and (2) 34 tumors that either lacked EGF mRNA, or whose mRNA levels were very low and frequently undetected by PCR (low-EGF tumors). TGFβ1 expression best predicted Fas transcript concentrations in the 34 low-EGF sarcomas, while FasL predicted Fas mRNA levels in the remaining 23 high-EGF sarcomas. The results suggest ligand activity in the Fas death pathway correlates with EGF transcription in sarcomas.

Global Protein-expression Analysis of Bone and Soft Tissue Sarcomas

Akira Kawai MD, PhD, Tadashi Kondo MD, PhD, Yoshiyuki Suehara MD, PhD, Kazutaka Kikuta MD, Setsuo Hirohashi MD, PhD Analysis of global protein expression, an approach known as expression proteomics, can offer important clues for understanding tumor biology that cannot be obtained by other approaches (e.g., genome or transcriptome analysis). Using two-dimensional difference gel electrophoresis (2D-DIGE) and mass spectrometry, we performed global protein expression studies of bone and soft tissue sarcomas to develop novel diagnostic and therapeutic biomarkers and allow molecular classification of the tumors. Among 1500 protein variants identified in the two-dimensional gel, 67 proteins correctly distinguished the eight subtypes of 99 histologically classified soft tissue sarcomas. Hierarchical clustering demonstrated leiomyosarcoma and MFH shared a similar protein expression profile, and clear cell sarcoma, synovial sarcoma, and MPNST could be grouped according to their protein expression patterns. Pleomorphic leiomyosarcoma and MFH showed similar tropomyosin isoform expression patterns. Patients with gastrointestinal stromal tumors expressing pfetin protein had better survival than those whose tumors lacked it. We identified 10 protein spots associated with the chemosensitivity of osteosarcoma to preoperative chemotherapy. These 10 spots could be new diagnostic and prognostic markers for osteosarcoma and new therapeutic targets for the disease. Proteomic analysis using 2D-DIGE provides novel information on the biology of bone and soft tissue sarcomas that could be used to diagnosis and treat these tumors.,[object Object]

Expression of Macrophage Migration Inhibitory Factor Relates to Survival in High-grade Osteosarcoma

Ilkyu Han MD, PhD, Mi Ra Lee BS, Kwang Woo Nam MD, Joo Han Oh MD, PhD, Kyung Chul Moon MD, PhD, Han-Soo Kim MD, PhD Macrophage migration inhibitory factor (MIF), a proinflammatory cytokine, is implicated in many aspects of tumor progression, including cell proliferation, invasion, and angiogenesis. We asked if MIF expression predicts survival and if it is associated with angiogenesis and cell invasion in osteosarcoma. We performed immunohistochemistry for MIF expression in prechemotherapy biopsy specimens of 58 patients with osteosarcoma. To investigate the role of MIF in angiogenesis, microvessel density was measured and compared with MIF expression. We also treated osteosarcoma cell lines (U2-OS and MG63) with MIF and measured vascular endothelial growth factor, a potent proangiogenic factor, by enzyme-linked immunosorbent assay. To study the role of MIF in cell invasion, Boyden chamber assay was performed after knockdown of MIF by short interfering RNA. MIF independently predicted overall survival and metastasis-free survival. MIF expression correlated with microvessel density and induced a dose-dependent increase in vascular endothelial growth factor. Knockdown of MIF by short interfering RNA resulted in decreased cell invasion. These results suggest MIF could serve as a prognostic marker and a potential therapeutic target for osteosarcoma.,[object Object]

Osteosarcoma Development and Stem Cell Differentiation

Ni Tang MD, PhD, Wen-Xin Song MD, Jinyong Luo MD, Rex C. Haydon MD, PhD, Tong-Chuan He MD, PhD Osteosarcoma is the most common nonhematologic malignancy of bone in children and adults. The peak incidence occurs in the second decade of life, with a smaller peak after age 50. Osteosarcoma typically arises around the growth plate of long bones. Most osteosarcoma tumors are of high grade and tend to develop pulmonary metastases. Despite clinical improvements, patients with metastatic or recurrent diseases have a poor prognosis. Here, we reviewed the current understanding of human osteosarcoma, with an emphasis on potential links between defective osteogenic differentiation and bone tumorigenesis. Existing data indicate osteosarcoma tumors display a broad range of genetic and molecular alterations, including the gains, losses, or arrangements of chromosomal regions, inactivation of tumor suppressor genes, and the deregulation of major signaling pathways. However, except for p53 and/or RB mutations, most alterations are not constantly detected in the majority of osteosarcoma tumors. With a rapid expansion of our knowledge about stem cell biology, emerging evidence suggests osteosarcoma should be regarded as a differentiation disease caused by genetic and epigenetic changes that interrupt osteoblast differentiation from mesenchymal stem cells. Understanding the molecular pathogenesis of human osteosarcoma could ultimately lead to the development of diagnostic and prognostic markers, as well as targeted therapeutics for osteosarcoma patients.

Gene Translocations in Musculoskeletal Neoplasms

Balaji Krishnan MS, Gaurav Khanna MD, Denis Clohisy MD Establishing the best diagnosis for musculoskeletal neoplasms requires a multidisciplinary approach using clinical, radiographic, and histologic analyses. Despite this rigorous approach, establishing accurate diagnoses and prognoses remains challenging. Improved diagnostic methods are expected as unique molecular signals for specific bone and soft tissue cancers are identified. We performed a systematic review of the best available evidence to explore three major applications of molecular genetics that will best benefit clinical management of musculoskeletal neoplasms: diagnostic, prognostic, and therapeutic applications. The specific questions addressed in this systematic review are: (1) What sets of histopathologic sarcoma subtypes will benefit from molecular evaluation and diagnosis? (2) What molecular methods are best applied to histopathologic sarcomas to distinguish between major subtypes? (3) How do the molecular patterns discovered on genetic diagnosis affect prognosis of certain sarcomas? (4) Which sarcoma translocations can benefit from an improved response and outcome using existing and forthcoming pharmacogenetic approaches targeting molecular events? This review summarizes recent advances in molecular genetics that are available and will soon be available to clinicians to better predict outcomes and subsequently help make future treatment decisions.,[object Object]

Neuronal Differentiation of Synovial Sarcoma and Its Therapeutic Application

Tatsuya Ishibe MD, PhD, Tomitaka Nakayama MD, PhD, Tomoki Aoyama MD, PhD, Takashi Nakamura MD, PhD, Junya Toguchida MD, PhD Synovial sarcoma is a rare sarcoma of unknown histologic origin. We previously reported the gene expression profile of synovial sarcoma was closely related to that of malignant peripheral nerve sheath tumors, and the fibroblast growth factor (FGF) signal was one of the main growth signals in synovial sarcoma. Here we further demonstrate the neural origin of synovial sarcoma using primary tumors and cell lines. The expression of neural tissue-related genes was confirmed in synovial sarcoma tumor tissues, but the expression of some genes was absent in synovial sarcoma cell lines. Treatment of synovial sarcoma cell lines with BMP4 or FGF2 enhanced or restored the expression of neural tissue-related genes and induced a neuron-like morphology with positive Tuj-1 expression. Treatment with all-trans-retinoic acid also induced the expression of neural tissue-related genes in association with growth inhibition, which was not observed in other cell lines except a malignant peripheral nerve sheath tumor cell line. A growth-inhibitory effect of all-trans-retinoic acid was also observed for xenografted tumors in athymic mice. The simultaneous treatment with FGF signal inhibitors enhanced the growth-inhibitory effect of all-trans-retinoic acid, suggesting the combination of growth signaling inhibition and differentiation induction could be a potential molecular target for treating synovial sarcoma.

Synovial Sarcoma: From Genetics to Genetic-based Animal Modeling

Malay Haldar PhD, R. Lor Randall MD, Mario R. Capecchi PhD Synovial sarcomas are highly aggressive mesenchymal cancers that show modest response to conventional cytotoxic chemotherapy, suggesting a definite need for improved biotargeted agents. Progress has been hampered by the lack of insight into pathogenesis of this deadly disease. The presence of a specific diagnostic t(X;18) translocation leading to expression of the unique SYT-SSX fusion protein in effectively all cases of synovial sarcoma suggests a role in the etiology. Other nonspecific anomalies such as overexpression of Bcl-2, HER-2/neu, and EGFR have been reported, but their role in the pathogenesis remains unclear. Using gene targeting, we recently generated mice conditionally expressing the human SYT-SSX2 fusion gene from mouse endogenous ROSA26 promoter in chosen tissue types in the presence of Cre recombinase. These mice develop synovial sarcoma when SYT-SSX2 is expressed within myoblasts, thereby identifying a source of this enigmatic tumor and establishing a mouse model of this disease that recapitulates the clinical, histologic, immunohistochemical, and transcriptional profile of human synovial sarcomas. We review the genetics of synovial sarcoma and discuss the usefulness of genetics-based mouse models as a valuable research tool in the hunt for key molecular determinants of this lethal disease as well as a preclinical platform for designing and evaluating novel treatment strategies.

Specific Tyrosine Kinase Inhibitors Regulate Human Osteosarcoma Cells In vitro

Patrick J. Messerschmitt MD, Ashley N. Rettew BS, Robert E. Brookover BS, Ryan M. Garcia MD, Patrick J. Getty MD, Edward M. Greenfield PhD [object Object]

Dendritic Cell-Ewing’s Sarcoma Cell Hybrids Enhance Antitumor Immunity

Wei Guo MD, PhD, Yi Guo MD, Shun Tang MD, Huayi Qu MD, Hui Zhao MD Given the effective immunotherapy of DC-based vaccine in other cancers, we hypothesized DC-based vaccines would induce effective immune responses against Ewing’s sarcoma. To verify this hypothesis and develop the most effective dendritic cell vaccine against Ewing’s sarcoma, we evaluated the antitumor efficacy of dendritic cell-Ewing’s sarcoma hybrids and dendritic cells pulsed with other antigen-loading methods, including cell lysates and the characteristic EWS-FLI1 gene of Ewing’s sarcoma, using an A673 cell line as a model. The hybrids were generated by electrofusion with fusion efficiency and viability determined by flow cytometry and fluorescent microscopy analyses. By interferon-γ secretion assay, the capacity of hybrids to stimulate cytotoxic T-lymphocytes (CTLs) is higher than that of other antigen-loading methods showing stronger tumor antigen-specific CTL cytotoxicity to A673. By in vivo experiment in SCID mice, all dendritic cell-based strategies induced specific immune responses to Ewing’s sarcoma after mice-human immune system reconstitution by inoculating human peripheral blood mononuclear cells into the peritoneal cavity of SCID mice. However, the hybrids most inhibited the subcutaneous tumor growth in SCID mice compared with dendritic cells pulsed with other loading methods. The data suggest A673 cells respond to dendritic cell-based immunotherapy.

PATCHED-ONE or SMOOTHENED Gene Mutations Are Infrequent in Chondrosarcoma

Taiqiang Yan MD, Mark Angelini MD, FRCSC, Benjamin A. Alman MD, FRCSC, Irene L. Andrulis PhD, Jay S. Wunder MD, MSc, FRCS(C)

Increased Carrying Angle is a Risk Factor for Nontraumatic Ulnar Neuropathy at the Elbow

Chein-Wei Chang MD, Yi-Chian Wang MD, Chang-Hung Chu MD The literature suggests a possible relationship between carrying angle and nontrauma-related ulnar neuropathy. To confirm that relationship, we asked whether carrying angle is a risk factor in patients with nontrauma-related ulnar neuropathy. We measured the carrying angles of the elbow in 36 patients with a clinically and electrophysiologically confirmed diagnosis of nontraumatic ulnar neuropathy at the elbow and in 50 healthy control subjects. Correlation analysis was performed between carrying angles and parameters of nerve conduction studies, including nerve conduction velocities and amplitudes of muscle and nerve action potentials. The mean carrying angle was greater in the patients than in the control subjects. Females had a greater carrying angle than males. We observed an inverse relationship between carrying angles and motor nerve conduction velocities at cross-elbow segments of the ulnar nerves and with sensory nerve conduction velocities of the distal ulnar nerves. An increased carrying angle of the elbow appears to be an independent risk factor of nontrauma-related ulnar neuropathy.,[object Object]

Anatomy of the Greater Trochanteric ‘Bald Spot’: A Potential Portal for Abductor Sparing Femoral Nailing?

Michael J. Gardner MD, William J. Robertson MD, Sreevathsa Boraiah MD, Joseph U. Barker MD, Dean G. Lorich MD Soft tissue injury occurs when using a piriformis portal for femoral nailing. Standard trochanteric portals also can injure the gluteus medius and external rotator tendons, which may be a source of hip pain after nailing. On the lateral facet of the greater trochanter, a “bald spot” may exist that is devoid of tendon insertion. This may be a potential portal for intramedullary nail insertion. We defined the dimensions and location of this region. Cadaveric specimens were dissected to expose the tendon insertions on the greater trochanter. A computer navigation system was used with a stylus and bone morphing to determine the tendon insertions and bald spot anatomy. The greater trochanteric bald spot is covered by the subgluteus medius bursa and has no tendon insertions. Its center lies 11 mm distal to the tip of the greater trochanter and 5 mm anterior to the midline. The shape is ellipsoid with a diameter of 21 mm. This region is large enough to accommodate the size of most nailing system reamers without tendon footprint infringement. Use of this modified entry site may reduce soft tissue injury with nailing procedures and minimize subsequent hip pain.

Small Increase of Actual Physical Activity 6 Months After Total Hip or Knee Arthroplasty

Ingrid B. Groot MSc, Hans J. Bussmann PhD, Henk J. Stam MD, PhD, Jan A. Verhaar MD, PhD Limitation in daily physical activity is one of the reasons for total hip arthroplasty (THA) or total knee arthroplasty (TKA). However, studies of the effects of THA or TKA generally do not determine actual daily activity as part of physical functioning. We determined the effect of THA or TKA on patients’ actual physical activity and body function (pain, stiffness), capacity to perform tasks, and self-reported physical functioning. We also assessed whether there are differences in the effect of the surgery between patients undergoing THA or TKA and whether the improvements vary between these different outcome measures. We recruited patients with long-standing end-stage osteoarthritis of the hip or knee awaiting THA or TKA. Measurements were performed before surgery and 3 and 6 months after surgery. Actual physical activity improved by 0.7%. Patients’ body function, capacity, and self-reported physical functioning also improved. The effects of the surgery on these aspects of physical functioning were similar for THA and TKA. The effect on actual physical activity (8%) was smaller than on body function (80%–167%), capacity (19%–36%), and self-reported physical functioning (87%–112%). Therefore, in contrast to the large effect on pain and stiffness, patients’ capacity, and their self-reported physical functioning, the improvement in actual physical activity of our patients was less than expected 6 months after surgery.,[object Object]

Radiographic Joint Space Width in Patients with Crowe Type-I Dysplastic Hips

Kunihiko Okano MD, PhD, Natsumi Kawahara MD, Ko Chiba MD, Hiroyuki Shindo MD, PhD Radiographic evaluation of preoperative joint space width is believed important to predict the long-term results of osteotomy. We asked whether joint space width differs in the supine and standing positions in patients with Crowe Type-1 osteoarthritis (OA) secondary to developmental dysplasia of the hip (DDH). Joint space width was measured in the supine and standing positions in 146 women and 16 men (231 hips) with OA. Subjects had a mean age of 46.7 years (range, 22–59 years). Differences were seen on radiographs in joint space width between supine (2.35 ± 1.65 mm; range, 0.1–6.2 mm) and standing (2.04 ± 1.78 mm; range, 0.0–5.9 mm). In 27 of 172 hips with greater than 1 mm joint space in the supine position, joint space width was decreased by greater than 1 mm in the standing position. To evaluate preoperative joint space width in patients scheduled for osteotomy, radiographs should be obtained with the patient in the standing position.,[object Object]

Sacral Chordoma: Can Local Recurrence After Sacrectomy Be Predicted?

S. A. Hanna MRCS, W. J. S. Aston FRCS (Orth), T. W. R. Briggs MCh (Orth), FRCS, S. R. Cannon MCh (Orth), FRCS, A. Saifuddin MRCP, FRCR Surgical resection margins are reportedly the most important predictor of survival and local recurrence with sacral chordomas. We examined the relevance of invasion of the surrounding posterior pelvic musculature (piriformis and gluteus maximus) at initial diagnosis to local recurrence after sacrectomy. We retrospectively reviewed 18 patients with histologically verified sacral chordoma seen at our institution between 1998 and 2005. There were 14 men and four women with a mean age of 65.1 years (range, 31–78 years). The average overall followup was 4.4 years (range, 0.5–10 years), 5.4 years for the living patients (range, 3–10 years), and 2.8 years for the deceased (range, 0.5–5.4 years). Local recurrence occurred in 12 patients (66%) 29 months postoperatively (range, 2–84 months). Six of these patients had wide excisions at initial surgery, five had marginal excisions, and one had an intralesional excision. Ten patients had wide surgical margins, six of whom (60%) had local recurrences. Tumor invasion of adjacent muscles at presentation was present in 14 patients, 12 of whom (85%) had local recurrences. Sacroiliac joint involvement was seen in 10 patients, nine of whom (90%) had local recurrences. The findings suggest obtaining wide surgical margins posteriorly, by excising parts of the piriformis, gluteus maximus, and sacroiliac joints, may result in better local disease control in patients with sacral chordoma.,[object Object]

Patients with Isolated Musculoskeletal Trauma Have Lower Mental Status Scores

Koray Unay MD, Omer Karatoprak MD, Nadir Sener MD, Melih Guven MD, Abdullah Bilge MD The subjective concerns and needs of patients who have experienced trauma are important to recovery. However, the mental status of patients with isolated musculoskeletal trauma is not known. Is the mental status of such patients different and does the severity, site, and type of trauma affect this difference? We evaluated the mental status of 195 patients hospitalized for isolated musculoskeletal trauma and determined the characteristics of the factors that affect mental status; 197 patients hospitalized for elective surgery and not exposed to acute trauma constituted the control group. We administered the Mini-Mental State Examination to study and control groups within the first 24 hours of hospitalization. Age, gender, and educational status in the study and control groups were recorded. In addition, the severity, site, and type of trauma in the study group were recorded. Mini-Mental State Examination scores of the trauma group were lower than those of the control group. Mini-Mental State Examination scores decreased with increasing trauma severity. The mental status of the patients sustaining isolated musculoskeletal trauma was affected by the severity, site, and type of trauma.,[object Object]

The Achilles Tendon Insertion is Crescent-shaped: An In Vitro Anatomic Investigation

Heinz Lohrer MD, Sabine Arentz MD, Tanja Nauck MA, Nadja V. Dorn-Lange MD, Moritz A. Konerding MD Anatomic and operative textbooks and current literature do not clearly describe the Achilles tendon interface to the calcaneal tuberosity. We dissected 51 specimens to identify the detailed anatomy of the Achilles tendon insertion. Achilles tendon fascicles expanded from the anterior aspect of the distal Achilles tendon over the retrocalcaneal bursa to the anterior part of the Haglund’s tuberosity in nearly half of the specimens. The insertion of the transverse section of the Achilles tendon regularly had a crescent-shape corresponding to the posterior calcaneal prominence. In transverse sections, all specimens had a curved appearance with a radius of curvature ranging from 13.8 mm to 43.6 mm (mean, 20.4 mm) and Achilles tendon extensions to the lateral and medial calcaneal surfaces reached 1.0 mm (mean) and 3.5 mm (mean) anterior in relation to the most posterior point of the calcaneal tuberosity. Knowledge of the arcuate configuration and of the medial and lateral extensions of the plantaris and the Achilles tendon insertion with respect to the transverse plane is important to avoid iatrogenic complications during resection of Haglund’s tuberosity.

Prospective Comparison of Auto and Allograft Hamstring Tendon Constructs for ACL Reconstruction

Cory M. Edgar MD, PhD, Scott Zimmer BS, Sanjeev Kakar MD, MRCS, Hugh Jones MD, Anthony A. Schepsis MD Although allograft use for primary anterior cruciate ligament reconstruction has continued to increase during the last 10 years, concerns remain regarding the long-term function of allografts (primarily that they may stretch with time) and clinical efficacy compared with autograft tendons. We attempted to address these issues by prospectively comparing identical quadrupled hamstring autografts with allograft constructs for primary anterior cruciate ligament reconstruction in patients with a minimum followup of 3 years. Eighty-four patients (37 with autografts and 47 with allografts) were enrolled; the mean followup was 52 ± 11 months for the autograft group and 48 ± 8 months for the allograft group. Outcome measurements included objective and subjective International Knee Documentation Committee scores, Lysholm scores, Tegner activity scales, and KT-1000 arthrometer measurements. The two cohorts were similar in average age, acute or chronic nature of the anterior cruciate ligament rupture, and incidence of concomitant meniscal surgeries. At final followup, we found no difference in terms of Tegner, Lysholm, KT-1000, or International Knee Documentation Committee scores. Five anterior cruciate ligament reconstructions failed: three in the autograft group and two in the allograft group. Our data suggest laxity is not increased in allograft tendons compared with autografts and clinical outcome scores 3 to 6 years after surgery are similar.,[object Object]

Double-bundle PCL and Posterolateral Corner Reconstruction Components are Codominant

Craig S. Mauro MD, Jon K. Sekiya MD, Kathryne J. Stabile MD, Marcus J. Haemmerle MD, Christopher D. Harner MD A more complete biomechanical understanding of a combined posterior cruciate ligament and posterolateral corner knee reconstruction may help surgeons develop uniformly accepted clinical surgical techniques that restore normal anatomy and protect the knee from premature arthritic changes. We identified the in situ force patterns of the individual components of a combined double-bundle posterior cruciate ligament and posterolateral corner knee reconstruction. We tested 10 human cadaveric knees using a robotic testing system by sequentially cutting and reconstructing the posterior cruciate ligament and posterolateral corner. The knees were subjected to a 134-N posterior tibial load and 5-Nm external tibial torque. The posterior cruciate ligament was reconstructed with a double-bundle technique. The posterolateral corner reconstruction included reattaching the popliteus tendon to its femoral origin and reconstructing the popliteofibular ligament. The in situ forces in the anterolateral bundle were greater in the posterolateral corner-deficient state than in the posterolateral corner-reconstructed state at 30° under the posterior tibial load and at 90° under the external tibial torque. We observed no differences in the in situ forces between the anterolateral and posteromedial bundles under any loading condition. The popliteus tendon and popliteofibular ligament had similar in situ forces at all flexion angles. The data suggest the two bundles protect each other by functioning in a load-sharing, codominant fashion, with no component dominating at any flexion angle. We believe the findings support reconstructing both posterior cruciate ligament bundles and both posterolateral corner components.

The Biceps Crease Interval for Diagnosing Complete Distal Biceps Tendon Ruptures

Amr ElMaraghy MD, FRCSC, Moira Devereaux MScPT, K. Tsoi BSc Complete distal biceps tendon ruptures require prompt surgical management for optimal functional and aesthetic outcome. The need exists for a valid and reliable diagnostic tool to expedite surgical referral. We hypothesized complete distal biceps tendon ruptures result in an objectively measurable anatomic landmark (the distance between the antecubital crease of the elbow and the cusp of distal descent of the biceps muscle, or the biceps crease interval), as a result of proximal retraction of the musculotendinous complex. We established normal biceps crease interval values and biceps crease ratios between dominant and nondominant arms in 80 men with no history of biceps injury (average age, 43 years). The mean (± standard deviation) biceps crease interval for dominant and nondominant arms was 4.8 ± 0.6 cm. The mean biceps crease ratio was 1.0 ± 0.1. We measured the biceps crease interval and biceps crease ratio on 29 consecutive patients presenting with a possible complete distal biceps tendon rupture. Using a diagnostic threshold of a biceps crease interval greater than 6.0 cm or biceps crease ratio greater than 1.2, the biceps crease interval test had a sensitivity of 96% and a diagnostic accuracy of 93% for identifying complete distal biceps tendon ruptures, making it a valid and reliable tool for clinicians to identify cases requiring urgent surgical referral.,[object Object]

Lewis A. Sayre: The First Professor of Orthopaedic Surgery in America

Jay M. Zampini MD, Henry H. Sherk MD Lewis Albert Sayre (1820–1900) is considered to be among the founding fathers of orthopaedic surgery in the United States. He studied medicine at the College of Physicians and Surgeons (now of Columbia University). Sayre later helped establish the first academic department of orthopaedics at the Bellevue Medical College where he served as their first Professor of Orthopaedics. Lewis Sayre treated a considerable diversity of musculoskeletal conditions and meticulously documented them with written notes, sketches, and photographs. As a public figure, his methods were controversial, attracting praise by some and inviting criticism by other prominent members of the international community. He made great strides for physicians, helping to charter the American Medical Association and to establish the weekly publication of the Journal of the American Medical Association.

Case Report: Meralgia Paresthetica in a Baseball Pitcher

Kenichi Otoshi MD, Yoshiyasu Itoh MD, PhD, Akihito Tsujino MD, PhD, Shinichi Kikuchi MD, PhD We report a case of meralgia paresthetica occurring in an amateur baseball pitcher who experienced inguinal pain and dysesthesia in the anterolateral thigh during pitching practice. The lateral femoral cutaneous nerve was pushed up by the iliac muscle to the inguinal ligament at the sharp ridge of its fascia and ensheathed in the tendinous origin of the sartorius muscle. Neurolysis of the lateral femoral cutaneous nerve and partial dissection of the inguinal ligament and sartorius muscle promptly relieved the symptoms and the patient resumed pitching 1 month later. These anatomic variations of the lateral femoral cutaneous nerve in the inguinal region might render the nerve susceptible to compression and irritation, and repetitive contraction of inguinal muscles during throwing motion might induce and exacerbate the neuropathy of the lateral femoral cutaneous nerve.

Case Reports: Splenic Rupture after Anterior Thoracolumbar Spinal Fusion Through a Thoracoabdominal Approach

Benton E. Heyworth MD, Joseph H. Schwab MD, Oheneba B. Boachie-Adjei MD The anterior approach in spinal deformity surgery has increased in popularity in recent years. The thoracoabdominal approach to the thoracolumbar spine is associated with numerous possible complications, including injury to vital intraabdominal structures in close proximity to the area of exposure, such as the spleen. We describe the case of a 44-year-old woman who underwent an emergent exploratory laparotomy for progressive abdominal pain and hemodynamic instability that revealed splenic rupture two days after single-stage anterior spinal fusion with instrumentation for thoracolumbar kyphoscoliosis. Because the suspected etiology of the splenic hemorrhage was related to retraction, surgeons using the anterior approach should consider intermittent release of retractors and inspection of intraabdominal structures. Splenic rupture should be considered as part of the differential diagnosis for patients with hemodynamic instability after anterior approaches to the thoracolumbar spine.

Suture Bridge Fixation of a Femoral Condyle Traumatic Osteochondral Defect

Andrea L. Bowers MD, G. Russell Huffman MD, MPH Internal fixation of a traumatic osteochondral defect presents a challenge in terms of obtaining anatomic reduction, fixation, and adequate compression for healing. Fixation with countersunk intraarticular screws, Herbert screws, bioabsorbable screws and pins, mini-cancellous screws, and glue tissue adhesive have been reported with varying results. We present an alternative fixation method used in two patients for femoral condylar defects that achieved anatomic reduction with compression via a cruciate-shaped suture bridge construct tied down over a bony bridge. This fixation method allowed early passive range of motion and permitted high-quality MRI for followup of fracture healing and articular cartilage integrity. Arthroscopic examination of one of two patients at 6 months followup showed the gross appearance of a healed, anatomically reduced fracture. With 1 year followup for one patient and 2 years for the other, the patients have resumed activity as tolerated with full, painless range of motion at the knee. Longer-term outcomes are unknown. However, the suture bridge is an alternative means of fixation with encouraging early results for treatment of traumatic osteochondral fragments in the knee.,[object Object]

Statistics in Brief: The Importance of Sample Size in the Planning and Interpretation of Medical Research

David Jean Biau MD, Solen Kernéis MD, Raphaël Porcher PhD The increasing volume of research by the medical community often leads to increasing numbers of contradictory findings and conclusions. Although the differences observed may represent true differences, the results also may differ because of sampling variability as all studies are performed on a limited number of specimens or patients. When planning a study reporting differences among groups of patients or describing some variable in a single group, sample size should be considered because it allows the researcher to control for the risk of reporting a false-negative finding (Type II error) or to estimate the precision his or her experiment will yield. Equally important, readers of medical journals should understand sample size because such understanding is essential to interpret the relevance of a finding with regard to their own patients. At the time of planning, the investigator must establish (1) a justifiable level of statistical significance, (2) the chances of detecting a difference of given magnitude between the groups compared, ie, the power, (3) this targeted difference (ie, effect size), and (4) the variability of the data (for quantitative data). We believe correct planning of experiments is an ethical issue of concern to the entire community.

Thigh Pain of 5 Years’ Duration in a 48-year-old Man

Shafic A. Sraj MD, Nabil J. Khoury MD, Nadim E. Afeiche MD, John Abdelnoor MD, FRCS
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