Primary Osteoarthritis Early Joint Degeneration Induced by Endoplasmic Reticulum Stress Is Mitigated by Resveratrol.

Increasing numbers of people are living with osteoarthritis (OA) due to aging and obesity, creating an urgent need for effective treatment and preventions. Two top risk factors for OA, age and obesity, are associated with endoplasmic reticulum (ER) stress. The I-ERS mouse, an ER stress-driven model of primary OA, was developed to study the role of ER stress in primary OA susceptibility. The I-ERS mouse has the unique ability to induce ER stress in healthy adult articular chondrocytes and cartilage, driving joint degeneration that mimics early primary OA. In this study, ER stress-induced damage occurred gradually and stimulated joint degeneration with OA characteristics including increased matrix metalloproteinase activity, inflammation, senescence, chondrocyte death, decreased proteoglycans, autophagy block, and gait dysfunction. Consistent with human OA, intense exercise hastened and increased the level of ER stress-induced joint damage. Notably, loss of a critical ER stress response protein (CHOP) largely ameliorated ER stress-stimulated OA outcomes including preserving proteoglycan content, reducing inflammation, and relieving autophagy block. Resveratrol diminished ER stress-induced joint degeneration by decreasing CHOP, TNFα, IL-1ß, MMP-13, pS6, number of TUNEL-positive chondrocytes, and senescence marker p16 INK4a. The finding, that a dietary supplement can prevent ER stressed-induced joint degeneration in mice, provides a preclinical foundation to potentially develop a prevention strategy for those at high risk to develop OA.

Early Resveratrol Treatment Mitigates Joint Degeneration and Dampens Pain in a Mouse Model of Pseudoachondroplasia (PSACH).

Pseudoachondroplasia (PSACH), a severe dwarfing condition associated with early-onset joint degeneration and lifelong joint pain, is caused by mutations in cartilage oligomeric matrix protein (COMP). The mechanisms underlying the mutant-COMP pathology have been defined using the MT-COMP mouse model of PSACH that has the common D469del mutation. Mutant-COMP protein does not fold properly, and it is retained in the rough endoplasmic reticulum (rER) of chondrocytes rather than being exported to the extracellular matrix (ECM), driving ER stress that stimulates oxidative stress and inflammation, driving a self-perpetuating cycle. CHOP (ER stress signaling protein) and TNFα inflammation drive high levels of mTORC1 signaling, shutting down autophagy and blocking ER clearance, resulting in premature loss of chondrocytes that negatively impacts linear growth and causes early joint degeneration in MT-COMP mice and PSACH. Previously, we have shown that resveratrol treatment from birth to 20 weeks prevents joint degeneration and decreases the pathological processes in articular chondrocytes. Resveratrol's therapeutic mechanism of action in the mutant-COMP pathology was shown to act by primarily stimulating autophagy and reducing inflammation. Importantly, we demonstrated that MT-COMP mice experience pain consistent with PSACH joint pain. Here, we show, in the MT-COMP mouse, that resveratrol treatment must begin within 4 weeks to preserve joint health and reduce pain. Resveratrol treatment started at 6 or 8 weeks (to 20 weeks) was not effective in preventing joint degeneration. Collectively, our findings in MT-COMP mice show that there is a postnatal resveratrol treatment window wherein the inevitable mutant-COMP joint degeneration and pain can be prevented.

Prospective randomized phase II Trial of accelerated reepithelialization of superficial second-degree burn wounds using extracorporeal shock wave therapy.

BACKGROUND: As extracorporeal shock wave therapy (ESWT) can enhance healing of skin graft donor sites, this study focused on shock wave effects in burn wounds. METHODS: A predefined cohort of 50 patients (6 with incomplete data or lost to follow-up) with acute second-degree burns from a larger study of 100 patients were randomly assigned between December 2006 and December 2007 to receive standard therapy (burn wound debridement/topical antiseptic therapy) with (n = 22) or without (n = 22) defocused ESWT (100 impulses/cm at 0.1 mJ/mm) applied once to the study burn, after debridement. Randomization sequence was computer-generated, and patients were blinded to treatment allocation. The primary endpoint, time to complete burn wound epithelialization, was determined by independent, blinded-observer. A worst case scenario was applied to the missing cases to rule out the impact of withdrawal bias. RESULTS: Patient characteristics across the 2 study groups were balanced (P > 0.05) except for older age (53 ± 17 vs. 38 ± 13 years, P = 0.002) in the ESWT group. Mean time to complete (≥95%) epithelialization (CE) for patients that did and did not undergo ESWT was 9.6 ± 1.7 and 12.5 ± 2.2 days, respectively (P < 0.0005). When age (continuous variable) and treatment group (binary) were examined in a linear regression model to control the baseline age imbalance, time to CE, age was not significant (P = 0.33) and treatment group retained significance (P < 0.0005). Statistical significance (P = 0.001) was retained when ESWT cases with missing follow-up were assigned the longest time to CE and when controls with missing follow-up were assigned the shortest time to CE. CONCLUSIONS: In this randomized phase II study, application of a single defocused shock wave treatment to the superficial second-degree burn wound after debridement/topical antiseptic therapy significantly accelerated epithelialization. This finding warrants confirmation in a larger phase III trial (ClinicalTrials.gov identifier: NCT01242423).

miRNA-34c Suppresses Osteosarcoma Progression In Vivo by Targeting Notch and E2F.

The expression of microRNAs (miRNAs) is dysregulated in many types of cancers including osteosarcoma (OS) due to genetic and epigenetic alterations. Among these, miR-34c, an effector of tumor suppressor P53 and an upstream negative regulator of Notch signaling in osteoblast differentiation, is dysregulated in OS. Here, we demonstrated a tumor suppressive role of miR-34c in OS progression using in vitro assays and in vivo genetic mouse models. We found that miR-34c inhibits the proliferation and the invasion of metastatic OS cells, which resulted in reduction of the tumor burden and increased overall survival in an orthotopic xenograft model. Moreover, the osteoblast-specific overexpression of miR-34c increased survival in the osteoblast specific p53 mutant OS mouse model. We found that miR-34c regulates the transcription of several genes in Notch signaling (NOTCH1, JAG1, and HEY2) and in p53-mediated cell cycle and apoptosis (CCNE2, E2F5, E2F2, and HDAC1). More interestingly, we found that the metastatic-free survival probability was increased among a patient cohort from Therapeutically Applicable Research to Generate Effective Treatments (TARGET) OS, which has lower expression of direct targets of miR-34c that was identified in our transcriptome analysis, such as E2F5 and NOTCH1. In conclusion, we demonstrate that miR-34c is a tumor suppressive miRNA in OS progression in vivo. In addition, we highlight the therapeutic potential of targeting miR-34c in OS. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Targeting TGF-ß for treatment of osteogenesis imperfecta.

BACKGROUNDCurrently, there is no disease-specific therapy for osteogenesis imperfecta (OI). Preclinical studies demonstrate that excessive TGF-ß signaling is a pathogenic mechanism in OI. Here, we evaluated TGF-ß signaling in children with OI and conducted a phase I clinical trial of TGF-ß inhibition in adults with OI.METHODSHistology and RNA-Seq were performed on bones obtained from children. Gene Ontology (GO) enrichment assay, gene set enrichment analysis (GSEA), and Ingenuity Pathway Analysis (IPA) were used to identify dysregulated pathways. Reverse-phase protein array, Western blot, and IHC were performed to evaluate protein expression. A phase I study of fresolimumab, a TGF-ß neutralizing antibody, was conducted in 8 adults with OI. Safety and effects on bone remodeling markers and lumbar spine areal bone mineral density (LS aBMD) were assessed.RESULTSOI bone demonstrated woven structure, increased osteocytes, high turnover, and reduced maturation. SMAD phosphorylation was the most significantly upregulated GO molecular event. GSEA identified the TGF-ß pathway as the top activated signaling pathway, and IPA showed that TGF-ß1 was the most significant activated upstream regulator mediating the global changes identified in OI bone. Treatment with fresolimumab was well-tolerated and associated with increases in LS aBMD in participants with OI type IV, whereas participants with OI type III and VIII had unchanged or decreased LS aBMD.CONCLUSIONIncreased TGF-ß signaling is a driver pathogenic mechanism in OI. Anti-TGF-ß therapy could be a potential disease-specific therapy, with dose-dependent effects on bone mass and turnover.TRIAL REGISTRATIONClinicalTrials.gov NCT03064074.FUNDINGBrittle Bone Disorders Consortium (U54AR068069), Clinical Translational Core of Baylor College of Medicine Intellectual and Developmental Disabilities Research Center (P50HD103555) from National Institute of Child Health and Human Development, USDA/ARS (cooperative agreement 58-6250-6-001), and Sanofi Genzyme.

Sensory nerve induced inflammation contributes to heterotopic ossification.

Heterotopic ossification (HO), or bone formation in soft tissues, is often the result of traumatic injury. Much evidence has linked the release of BMPs (bone morphogenetic proteins) upon injury to this process. HO was once thought to be a rare occurrence, but recent statistics from the military suggest that as many as 60% of traumatic injuries, resulting from bomb blasts, have associated HO. In this study, we attempt to define the role of peripheral nerves in this process. Since BMP2 has been shown previously to induce release of the neuroinflammatory molecules, substance P (SP) and calcitonin gene related peptide (CGRP), from peripheral, sensory neurons, we examined this process in vivo. SP and CGRP are rapidly expressed upon delivery of BMP2 and remain elevated throughout bone formation. In animals lacking functional sensory neurons (TRPV1(-/-) ), BMP2-mediated increases in SP and CGRP were suppressed as compared to the normal animals, and HO was dramatically inhibited in these deficient mice, suggesting that neuroinflammation plays a functional role. Mast cells, known to be recruited by SP and CGRP, were elevated after BMP2 induction. These mast cells were localized to the nerve structures and underwent degranulation. When degranulation was inhibited using cromolyn, HO was again reduced significantly. Immunohistochemical analysis revealed nerves expressing the stem cell markers nanog and Klf4, as well as the osteoblast marker osterix, after BMP2 induction, in mice treated with cromolyn. The data collectively suggest that BMP2 can act directly on sensory neurons to induce neurogenic inflammation, resulting in nerve remodeling and the migration/release of osteogenic and other stem cells from the nerve. Further, blocking this process significantly reduces HO, suggesting that the stem cell population contributes to bone formation.

Efficient and rapid osteoinduction in an immune-competent host.

Osteoinductive systems to induce targeted rapid bone formation hold clinical promise, but development of technologies for clinical use that must be tested in animal models is often a difficult challenge. We previously demonstrated that implantation of human cells transduced with Ad5F35BMP2 to express high levels of bone morphogenetic protein-2 (BMP2) resulted in rapid bone formation at targeted sites. Inclusion of human cells in this model precluded us from testing this system in an immune-competent animal model, thus limiting information about the efficacy of this approach. Here, for the first time we demonstrate the similarity between BMP2-induced endochondral bone formation in a system using human cells in an immune-incompetent mouse and a murine cell-based BMP2 gene therapy system in immune-competent animals. In both cases the delivery cells are rapidly cleared, within 5 days, and in neither case do they appear to contribute to any of the structures forming in the tissues. Endochondral bone formation progressed through a highly ordered series of stages that were both morphologically and temporally indistinguishable between the two models. Even longterm analysis of the heterotopic bone demonstrated similar bone volumes and the eventual remodeling to form similar structures. The results suggest that the ability of BMP2 to rapidly induce bone formation overrides contributions from either immune status or the nature of delivery cells.

Adenovirus BMP2-induced osteogenesis in combination with collagen carriers.

Adenovirus BMP2 gene therapy has potential of a robust endogenous BMP2 production, while circumventing many of the problems currently associated with recombinant BMP2. The study objective was to determine and compare the ability of adenovirus BMP2 ex vivo gene therapy in combination with three types of collagen carriers to release BMP2 in vitro and to induce heterotopic bone formation in vivo. Human CD45-negative bone marrow cells were ex vivo transduced with a chimeric Ad5F35BMP2. The bioactivity of BMP2 produced by the transduced cells without a carrier, or in combination with three types of collagen carriers (injectable gel, microporous sponge, collagen-mineral composite) was measured and compared to rhBMP2. The heterotopic osteoinductivity assay was performed in immunocompromised NOD/SCID mice. A statistically significant decrease in the amount of rhBMP2 and adenoviral BMP2 released in vitro from the collagen-mineral composite carrier was noted (21% and 12%, respectively), whereas the amounts of rhBMP2 and adenoviral BMP2 released from the gel or sponge carriers were comparable. In vivo, 14 days post-implantation, no bone was formed consistently in groups with the empty Ad5F35HM4 control vector. New bone formation was evident radiographically and histologically in all groups with the Ad5F35BMP2-transduced cells irrespective of the presence or absence of a carrier. The presence of a carrier resulted in osteogenesis limited to the implantation site, and was most pronounced for solid (sponge, composite) carriers. The physical characteristics of the carrier determined the new bone spatial distribution at the site. Solid carriers reduced the clearance of AD5F35-transduced cells by the host immune cells. Adenoviral ex vivo BMP2 gene therapy in combination with collagen carriers with distinct physical characteristics offers the prospects of adjusting this approach to optimally match the specific therapeutic requirements.

Oxygen tension directs chondrogenic differentiation of myelo-monocytic progenitors during endochondral bone formation.

Synthesis of bone requires both essential progenitors to form the various structures and the correct microenvironment for their differentiation. To identify these factors, we have used a system that exploits bone morphogenetic protein's ability to induce endochondral bone formation rapidly. One of the earliest events observed was the influx and proliferation of fibroblastic cells that express both vascular smooth muscle cell markers, alpha smooth muscle actin (alpha SMA), smooth muscle myosin heavy chain, and the monocytic marker CD68. The expression of these factors was lost by days 4 to 5, coincident with the up-regulation of Sox9 and the appearance of chondrocytes. Studies with a cyclization recombination (Cre)/lox system, in which a myeloid-specific promoter driving Cre recombinase can irreversibly unblock expression of beta-galactosidase only in cells of myeloid origin, showed specific activity in the newly formed chondrocytes. These results suggest that early chondrocyte progenitors are of myeloid origin. Simultaneous with this recruitment, we determined that a numbers of these cells were in a hypoxic state, indicative of a low-oxygen environment. The cells in the hypoxic regions were undergoing chondrogenesis, whereas cells in adjacent normoxic regions appeared to be assembling into new vessels, suggesting that the oxygen microenvironment is critical for establishment of the cartilage.

The efficacy of cylindrical titanium mesh cage for the reconstruction of a critical-size canine segmental femoral diaphyseal defect.

The authors developed a novel technique for the reconstruction of large segmental long bone defects using a cylindrical titanium mesh cage (CTMC). Although the initial clinical reports have been favorable, the CTMC technique has yet to be validated in a clinically relevant large animal model, which is the purpose of this study. Under general anesthesia, a unilateral, 3-cm mid-diaphyseal segmental defect was created in the femur of an adult canine. The defect reconstruction technique consisted of a CTMC that was packed and surrounded with a standard volume of morselized canine cancellous allograft and canine demineralized bone matrix. The limb was stabilized with a reamed titanium intramedullary nail. Animals were distributed into four experimental groups: in Groups A, B, and C (six dogs each), defects were CTMC reconstructed, and the animals euthanized at 6, 12, and 18 weeks, respectively; in Group D (three dogs), the same defect reconstruction was performed but without a CTMC, and the animals were euthanized at 18 weeks. The femurs were harvested and analyzed by gross inspection, plain radiography, computed tomography (CT), and single photon emission computed tomography (SPECT). The femurs were mechanically tested in axial torsion to failure; two randomly selected defect femurs from each group were analyzed histologically. Groups A, B, and C specimens gross inspection, plain radiography, and CT, demonstrated bony restoration of the defect, and SPECT confirmed sustained biological activity throughout the CTMC. Compared to the contralateral femur, the 6-, 12-, and 18-week mean defect torsional stiffness was 44.4, 45.7, and 72.5%, respectively; the mean torsional strength was 51.0, 73.6, and 83.4%, respectively. Histology documented new bone formation spanning the defect. Conversely, Group D specimens (without CTMC) demonstrated no meaningful bone formation, biologic activity, or mechanical integrity at 18 weeks. The CTMC technique facilitated healing of a canine femur segmental defect model, while the same technique without a cage did not. The CTMC technique may be a viable alternative for the treatment of segmental long bone defects.

Bilateral adrenal histoplasmosis in an immunocompetent man from Texas.

Disseminated histoplasmosis affecting the adrenal gland(s) of immunocompetent adults is a very rare infection. Here, we present a case of bilateral adrenal histoplasmosis in an immunocompetent, 62-year-old gentleman from Texas along with a brief review of the published literature. Given the risk of patient decompensation secondary to adrenal insufficiency and the wide availability of effective treatments, adrenal histoplasmosis must be considered even in immunocompetent adults who acquire adrenal masses.

Novel compound enables high-level adenovirus transduction in the absence of an adenovirus-specific receptor.

Viral vectors are extensively used to deliver foreign DNA to cells for applications ranging from basic research to potential clinical therapies. A limiting step in this process is virus uptake and internalization into the target cells, which is mediated by membrane receptors. Although it is possible to modify viral capsid proteins to target the viruses, such procedures are complex and often unsuccessful. Here we present a rapid, inexpensive system for improving transduction of cells, including those that lack receptors for adenovirus fiber proteins. Addition of GeneJammer (Stratagene, La Jolla, CA) during the adenovirus transduction led to a significant increase in both the total number of transduced cells and the level of transgene expression per cell. Studies using cell lines deficient in adenovirus receptors demonstrated that addition of GeneJammer provided a novel cellular entry mechanism for the virus. These findings were tested in a cell-based gene therapy system for the induction of bone, which is contingent on high-level expression of the transgene. Inclusion of GeneJammer in either Ad5BMP2 or Ad5F35BMP2 transduction of a variety of cells demonstrated a correlating increase in bone formation. The results suggest a novel and versatile method for achieving high-level transduction using adenovirus.

Neonatal lethal osteochondrodysplasia with low serum levels of alkaline phosphatase and osteocalcin.

Neonatal lethal skeletal dysplasias are rare and typically involve thoracic malformations and severe limb shortening. We report on a newborn boy manifesting an osteochondrodysplasia associated with fatal respiratory insufficiency who had normal lung volumes and extremity lengths. His disorder featured aberrant skeletal patterning and defective ossification including a severely osteopenic skull, apparent absence of clavicles, and clefting of the mandible and vertebrae. Serum alkaline phosphatase and osteocalcin levels were markedly low. Biochemical studies suggested parathyroid insufficiency probably from critical illness. Histopathology at autopsy excluded impaired mineralization of skeletal matrix, but endochondral bone formation appeared disorganized with growth plate clustering of chondrocytes in hypertrophic zones and in zones of provisional calcification. Parathyroid glands were not found. Despite features of two distinctive heritable entities, hypophosphatasia and cleidocranial dysplasia, the cumulative findings did not match either condition, and no mutations were found in either the tissue nonspecific ALP isoenzyme or core-binding factor genes, respectively, or in the genes encoding osteocalcin or the osteoblast transcription factor osterix. This patient could represent the extreme of cleidocranial dysplasia (a disorder not always associated with structural mutation in core-binding factor A1), but more likely he defines a unique osteochondrodysplasia disrupting both intramembranous and endochondral bone formation.

Use of a chimeric adenovirus vector enhances BMP2 production and bone formation.

Recombinant adenoviral vectors have potential for the treatment of a variety of musculoskeletal defects and such gene therapy systems have been a recent research focus in orthopedic surgery. In studies reported here, two different adenovirus vectors have been compared for their ability to transduce human bone marrow mesenchymal stem cells (hBM-MSCs) and elicit bone formation in vivo. Vectors consisted either of standard adenovirus type 5 (Ad5) vector or a chimeric adenovirus type 5 vector that contains an adenovirus type 35 fiber (Ad5F35), which has been recently demonstrated to bestow a different cellular tropism, and a complete cDNA encoding human bone morphogenetic 2 (BMP2). Studies were also conducted to compare the transduction efficiency of these vectors using enhanced green fluorescent protein (GFP). hBM-MSCs transduced with Ad5F35 vectors had higher levels of transgene expression than those transduced with Ad5 vectors. The results also demonstrate that hBM-MSCs lack the coxsackie-adenovirus receptor (CAR), which is responsible for cellular adsorption of Ad5. Therefore, the data suggest that Ad5 virus adsorption to hBM-MSCs is inefficient. Ad5BMP2- or Ad5F35BMP2-transduced hBM-MSCs were also compared in an in vivo heterotopic bone formation assay. Mineralized bone was radiologically identified only in muscle that received the Ad5F35BMP2 transduced hBM-MSCs. In summary, Ad5F35BMP2 can efficiently transduce hBM-MSCs leading to enhanced bone formation in vivo.

Chondrosarcoma of the larynx: a clinicopathologic study of 111 cases with a review of the literature.

Chondrosarcomas of the larynx are rare tumors accounting for about 0.5% of all laryngeal primary tumors. A total of 111 laryngeal chondrosarcoma cases, diagnosed between 1970 and 1997, were retrieved from the Otorhinolaryngic-Head & Neck Tumor Registry of the Armed Forces Institute of Pathology. There was a 3.6:1 male/female ratio of patients 25-91 years of age (mean, 64.4 years). Patients presented most frequently with hoarseness (n = 72 patients) present for a mean of 28.2 months. The majority of tumors involved the cricoid cartilage (n = 77) with a mean size of 3.5 cm. All tumors were invasive and malignant by radiology and/or histology (into bone within the ossified laryngeal cartilages in 52 tumors). Most tumors were low-grade lesions: grade 1 (n = 51), grade 2 (n = 54); there were six grade 3 tumors. An associated benign chondroma with (n = 41 tumors) or without ischemia (n = 24 tumors) was noted. All patients had surgery and five had radiation therapy. Wide excision or voice-sparing surgery was used in 73 patients, whereas 37 patients had a laryngectomy. Recurrences occurred in 20 (18%) patients, 10 of whom underwent salvage laryngectomy. At the last follow-up, 102 patients had no evidence of disease (alive or dead, mean 11.2 years) and five patients had evidence of disease (alive, one patient, 6.5 years; dead, four patients, mean 6.4 years). The six patients with high-grade chondrosarcoma were all without disease at the last follow-up (mean, 15.1 years). There was no difference in clinical outcome based on grade (p = 0.210), location (p = 0.078), or treatment (p = 0.607) but was worse for patients with a myxoid-type chondrosarcoma (p = 0.044). Primary laryngeal chondrosarcomas are typically low- to moderate-grade lesions involving the cricoid cartilage, frequently associated with a chondroma. They usually portend an excellent overall long-term prognosis with initial conservative voice-sparing surgery.

From the archives of the AFIP: benign musculoskeletal lipomatous lesions.

Benign lipomatous lesions involving soft tissue are common musculoskeletal masses that are classified into nine distinct diagnoses: lipoma, lipomatosis, lipomatosis of nerve, lipoblastoma or lipoblastomatosis, angiolipoma, myolipoma of soft tissue, chondroid lipoma, spindle cell lipoma and pleomorphic lipoma, and hibernoma. Soft-tissue lipoma accounts for almost 50% of all soft-tissue tumors. Radiologic evaluation is diagnostic in up to 71% of cases. These lesions are identical to subcutaneous fat on computed tomographic (CT) and magnetic resonance (MR) images and may contain thin septa. Lipomatosis represents a diffuse overgrowth of mature fat affecting either subcutaneous tissue, muscle or nerve, and imaging is needed to evaluate lesion extent. Lipoblastoma is a tumor of immature fat occurring in young children, and imaging features may reveal a mixture of fat and nonadipose tissue. Angiolipoma, myolipoma, and chondroid lipoma are rare lipomatous lesions that are infrequently imaged. Spindle cell and pleomorphic lipoma appear as a subcutaneous lipomatous mass in the posterior neck or shoulder, with frequent nonadipose components. Hibernoma appears as a lipomatous mass with serpentine vascular elements. Benign lipomatous lesions affecting bone, joint, or tendon sheath include intraosseous lipoma, parosteal lipoma, liposclerosing myxofibrous tumor, discrete lipoma of joint or tendon sheath, and lipoma arborescens. Intraosseous and parosteal lipoma have a pathognomonic CT or MR appearance, with fat in the marrow space or on the bone surface, respectively. Liposclerosing myxofibrous tumor is a rare intermixed histologic lesion commonly located in the medullary canal of the intertrochanteric femur. Benign lipomatous lesions may occur focally in a joint or tendon sheath or with diffuse villonodular proliferation in the synovium (lipoma arborescens) and are diagnosed based on location and identification of fat. Understanding the spectrum of appearances of the various benign musculoskeletal lipomatous lesions improves radiologic assessment and is vital for optimal patient management.

From the archives of the AFIP: imaging of primary chondrosarcoma: radiologic-pathologic correlation.

Chondrosarcoma is a malignant tumor that produces cartilage matrix, and lesions that arise de novo are called primary. Primary chondrosarcoma is the third most common primary malignant tumor of bone, constituting 20%-27% of all primary malignant osseous neoplasms. There are numerous types of primary chondrosarcomas, including conventional intramedullary, clear cell, juxtacortical, myxoid, mesenchymal, extraskeletal, and dedifferentiated. The conventional intramedullary chondrosarcoma is the most frequent type, and it most commonly involves the long bones or pelvis in up to 65% of cases. Although the pathologic appearance varies with specific lesion type, chondrosarcomas grow with lobular type architecture, and these hyaline cartilage nodules demonstrate high water content and peripheral enchondral ossification. Imaging features directly reflect this pathologic appearance, and the various subtypes often show distinctive features. Radiographic findings often suggest the diagnosis of chondrosarcoma because of identification of typical "ring-and-arc" chondroid matrix mineralization (representing the enchondral ossification) and aggressive features of deep endosteal scalloping and soft-tissue extension. These latter features are usually best assessed, as is lesion staging, with computed tomography (CT) or magnetic resonance (MR) imaging. CT is optimal to detect the matrix mineralization, particularly when it is subtle or when the lesion is located in anatomically complex areas. Both CT and MR imaging depict the high water content of these lesions as low attenuation and very high signal intensity with T2-weighting, respectively. Understanding and recognizing the spectrum of appearances of the various types of primary chondrosarcoma allow improved patient assessment and are vital for optimal clinical management including diagnosis, biopsy, staging, treatment, and prognosis.

Mesenchymal chondrosarcoma of the sinonasal tract: a clinicopathological study of 13 cases with a review of the literature.

OBJECTIVES/HYPOTHESIS: Mesenchymal chondrosarcoma of the sinonasal tract is a rare, malignant tumor of extraskeletal origin. Isolated cases have been reported in the English literature, with no large series evaluating the clinicopathological aspects of these tumors. STUDY DESIGN: Retrospective review. METHODS: Thirteen patients with sinonasal mesenchymal chondrosarcoma were retrieved from the Otorhinolaryngologic-Head and Neck Registry of the Armed Forces Institute of Pathology. RESULTS: Nine women and 4 men (age range, 11 to 83 y; mean age, 38.8 y) presented with nasal obstruction (n = 8), epistaxis (n = 7), or mass effect (n = 4), or a combination of these. No patients reported prior head and neck irradiation. The maxillary sinus was the most common site of involvement (n = 9), followed by the ethmoid sinuses (n = 7) and the nasal cavity (n = 5). Tumors had an overall mean size of 5.1 cm. Microscopically, the tumors displayed a small, blue, round cell morphology appearance arranged in a hemangiopericytoma-like pattern with foci of cartilaginous matrix. All cases were managed by surgery with adjuvant radiation therapy (n = 4) and/or chemotherapy (n = 3). The overall mean survival was 12.1 years, although five of six patients who developed local recurrences died of disease (mean survival, 6.5 y). Six patients were alive and disease free (mean survival, 17.3 y), and two patients were lost to follow-up. CONCLUSIONS: Mesenchymal chondrosarcoma of the sinonasal tract is an aggressive tumor with a predilection for young women. The pattern of growth and scarcity of cartilaginous matrix result in frequent misdiagnosis. Recurrence develops in approximately one-third of patients and seems to predict a poor prognosis. Aggressive, exenterative surgery combined with adjuvant therapy appears to yield the best clinical outcome.

Dedifferentiated chondrosarcomas of the larynx: a report of two cases and review of the literature.

OBJECTIVE: To analyze the long-term clinical outcome of dedifferentiated chondrosarcoma or chondrosarcoma with additional malignant mesenchymal component (CAMMC) of the larynx and compare the results with those of axial chondrosarcomas. STUDY DESIGN/METHODS: Two patients with CAMMC of the larynx (0.03%) were retrospectively identified within the archives of the Armed Forces Institute of Pathology between 1970 and 2001. We compared the clinical and histologic features of these two cases with those reported in the English literature (Medline 1966-2001) (Table I). RESULTS: Patient no. 1 was a 67-year-old man who presented with a 12-month history of hoarseness and was found to have a 4-cm mass involving the cricoid cartilage. Enucleation was performed and histologically demonstrated a dedifferentiated chondrosarcoma. Without additional intervention, the patient died after 136 months without evidence of disease. Patient no. 2 was a 41-year-old man who also presented with a 12-month history of hoarseness and dysphagia and was found to have a 5-cm mass involving the cricoid cartilage. A total laryngectomy was performed for the dedifferentiated chondrosarcoma. He is alive without evidence of disease at last contact (91 mo). CONCLUSION: CAMMC of the larynx are rare tumors but have a better prognosis than their axial counterparts (mean, 6 mo). Initial voice-sparing surgery can be followed with more aggressive surgery if recurrences develop.

Craniosynostosis and altered patterns of fetal TGF-beta expression induced by intrauterine constraint.

Recent work has demonstrated that fusion of the calvarial sutures is mediated by locally elaborated soluble growth factors, including the transforming growth factor-betas (TGF-betas), leading some to speculate that external biomechanical forces play little role in suture development. Clinical evidence has long suggested, however, that fetal head constraint may play a critical role in the pathogenesis of many cases of nonsyndromic craniosynostosis. The purpose of these experiments was to test the hypothesis that intrauterine constraint leads to an alteration in normal patterns of TGF-beta expression and that these alterations are associated with craniosynostosis. Fetal constraint was induced by allowing C57Bl/6 murine fetuses to grow for 2.5 days beyond the normal 20-day gestation by performing uterine cerclage on the eighteenth day. Cranial suture morphology was examined in hematoxylin and eosin-stained sections and in cleared whole-mount specimens, double stained with alizarin red S and Alcian blue. Expression patterns of TGF-beta1 and TGF-beta3 were examined by immunohistochemical techniques. Gross and microscopic examination of the cranial sutures of 17 constrained fetuses revealed changes that ranged from narrowing to complete osseous obliteration of the coronal and squamosal sutures. All sutures of 14 nonconstrained control pups remained patent. Fetal head constraint was associated with increased TGF-beta1 immunoreactivity within the new bone and the underlying dura when compared with nonconstrained age-matched controls. TGF-beta3 immunoreactivity was associated with the dura underlying patent, nonconstrained sutures, whereas constraint-induced synostosis was characterized by down-regulation of dural TGF-beta3 expression. These experiments confirm the ability of intrauterine constraint to induce premature fusion of the cranial sutures and provide evidence that intrauterine head constraint induces the expression of osteogenic growth factors in fetal calvarial bone and the underlying dura.