Pericytes in Sarcomas and Other Mesenchymal Tumors.

Tumors of mesenchymal origin are a diverse group, with >130 distinct entities currently recognized by the World Health Organization. A subset of mesenchymal tumors grow or invade in a perivascular fashion, and their potential relationship to pericytes is a matter of ongoing interest. In fact, multiple intersections exist between pericytes and tumors of mesenchymal origin. First, pericytes are the likely cell of origin for a group of mesenchymal tumors with a common perivascular growth pattern. These primarily benign tumors grow in a perivascular fashion and diffusely express canonical pericyte markers such as CD146, smooth muscle actin (SMA), platelet-derived growth factor receptor beta (PDGFR-ß), and RGS5. These benign tumors include glomus tumor, myopericytoma, angioleiomyoma, and myofibroma. Second and as suggested by animal models, pericytes may give rise to malignant sarcomas. This is not a suggestion that all sarcomas within a certain subtype arise from pericytes, but that genetic modifications within a pericyte cell type may give rise to sarcomas. Third, mesenchymal tumors that are likely not a pericyte derivative co-opt pericyte markers in certain contexts. These include the PEComa family of tumors and liposarcoma. Fourth and finally, as "guardians" that enwrap the microvasculature, nonneoplastic pericytes may be important in sarcoma disease progression.

Cleft and Craniofacial Team Orthodontic Care in the United States: A Survey of the ACPA.

OBJECTIVE: To better understand the capacity for orthodontic care, service features, and finances among members of the American Cleft Palate-Craniofacial Association (ACPA). DESIGN: Cross-sectional survey. SETTING: ACPA-approved multidisciplinary cleft teams. PARTICIPANTS: Cleft team coordinators. INTERVENTIONS: Coordinators were asked to complete the survey working together with their orthodontists. MAIN OUTCOME MEASURE: Model for orthodontic care. RESULTS: Coordinators from 82 out of 167 teams certified by ACPA completed the survey (response rate = 49.1%). Most orthodontists were private practice volunteers (48%) followed by university/hospital employed (22.8%). Care was often delivered in community private practice facilities (44.2%) or combination of university and private practice facilities (39.0%). Half of teams reported offering presurgical infant orthopedics (PSIO), with nasoalveolar molding being the most common. Cleft/craniofacial patients typically comprise 25% or less of the orthodontists' practices. The presence of a university/hospital-based orthodontist was associated with higher rates of offering PSIO (P < .001) and an increased percentage dedication of their practice to cleft/craniofacial care (P < .001). CONCLUSION: Orthodontic models across ACPA-certified teams are highly varied. The employment of full-time craniofacial orthodontists is less common but is highly correlated with a practice with a high percentage of cleft care and the offering of advanced services such as PSIO. Future work should focus on how to effectively promote such roles for orthodontists to ensure high-level care for cleft/craniofacial patients requiring treatment from infancy through skeletal maturity.

Ang-1 and Ang-2 expression in angiomyolipoma and PEComa family tumors.

OBJECTIVE: Perivascular epithelioid cell tumors (PEComa) are an uncommon family of soft tissue tumors. Previously, we described that the presence of pericyte antigens among PEComa family tumors differs extensively by histologic appearance. METHODS: Here, we extend our findings using the pericyte antigens Angiopoietin-1 (Ang-1) and Angiopoietin-2 (Ang-2), using immunohistochemical detection in human tumor samples. RESULTS: While Ang-1 showed no expression across any PEComa family tumor, Ang-2 showed expression that like other pericyte markers was largely determined by cytologic appearance. CONCLUSION/IMPLICATIONS: Pericytic marker expression in PEComa may represent a true pericytic cell of origin, or alternatively aberrant pericyte marker adoption.

Ang-2 but not Ang-1 expression in perivascular soft tissue tumors.

Perivascular soft tissue tumors are relatively uncommon neoplasms of unclear line of differentiation, although most are presumed to originate from pericytes. Previously, we reported a shared immunophenotype across these related tumor types. Here, we extend these findings to examine the expression of the pericyte markers angiopoietin-1 and -2 (Ang-1 and -2) among perivascular soft tissue tumors. Results showed consistent Ang-2 but not Ang-1 expression across tumor types. In summary, the absence of Ang-1 expression distinguishes perivascular from vascular soft tissue tumors. Ang-2 expression is present across perivascular soft tissue tumors, with some variation between histologic subtypes.

Presurgical Dentofacial Orthopedic Management of the Cleft Patient.

Over the last decade, presurgical orthopedic molding for the patient with cleft lip and palate has become much more common; it is even reasonable to assume it may be the standard of care for those wide unilateral and bilateral clefts with substantial dentofacial deformities. In 2013, there was a comparative study of nasoalveolar molding methods, comparing the Grayson-NAM device and DynaCleft. The results showed the 2 to be equivocal with both methods significantly reducing the cleft width and improving the nasal asymmetry.

Pericytic mimicry in well-differentiated liposarcoma/atypical lipomatous tumor.

Pericytes are modified smooth muscle cells that closely enwrap small blood vessels, regulating and supporting the microvasculature through direct endothelial contact. Pericytes demonstrate a distinct immunohistochemical profile, including expression of smooth muscle actin, CD146, platelet-derived growth factor receptor ß, and regulator of G-protein signaling 5. Previously, pericyte-related antigens have been observed to be present among a group of soft tissue tumors with a perivascular growth pattern, including glomus tumor, myopericytoma, and angioleiomyoma. Similarly, malignant tumor cells have been shown to have a pericyte-like immunoprofile when present in a perivascular location, seen in malignant melanoma, glioblastoma, and adenocarcinoma. Here, we examine well-differentiated liposarcoma specimens, which showed some element of perivascular areas with the appearance of smooth muscle (n = 7 tumors). Immunohistochemical staining was performed for pericyte antigens, including smooth muscle actin, CD146, platelet-derived growth factor receptor ß, and regulator of G-protein signaling 5. Results showed consistent pericytic marker expression among liposarcoma tumor cells within a perivascular distribution. MDM2 immunohistochemistry and fluorescence in situ hybridization for MDM2 revealed that these perivascular cells were of tumor origin (7/7 tumors), whereas double immunohistochemical detection for CD31/CD146 ruled out an endothelial cell contribution. These findings further support the concept of pericytic mimicry, already established in diverse malignancies, and its presence in well-differentiated liposarcoma. The extent to which pericytic mimicry has prognostic significance in liposarcoma is as yet unknown.

The pericyte antigen RGS5 in perivascular soft tissue tumors.

Perivascular soft tissue tumors are relatively uncommon neoplasms of unclear lineage of differentiation, although most are presumed to originate from or differentiate to pericytes or a modified perivascular cell. Among these, glomus tumor, myopericytoma, and angioleiomyoma share a spectrum of histologic findings and a perivascular growth pattern. In contrast, solitary fibrous tumor was once hypothesized to have pericytic differentiation--although little bona fide evidence of pericytic differentiation exists. Likewise the perivascular epithelioid cell tumor (PEComa) family shares a perivascular growth pattern, but with distinctive dual myoid-melanocytic differentiation. RGS5, regulator of G-protein signaling 5, is a novel pericyte antigen with increasing use in animal models. Here, we describe the immunohistochemical expression patterns of RGS5 across perivascular soft tissue tumors, including glomus tumor (n = 6), malignant glomus tumor (n = 4), myopericytoma (n = 3), angioleiomyoma (n = 9), myofibroma (n = 4), solitary fibrous tumor (n = 10), and PEComa (n = 19). Immunohistochemical staining and semi-quantification was performed, and compared to αSMA (smooth muscle actin) expression. Results showed that glomus tumor (including malignant glomus tumor), myopericytoma, and angioleiomyoma shared a similar diffuse immunoreactivity for RGS5 and αSMA across all tumors examined. In contrast, myofibroma, solitary fibrous tumor and PEComa showed predominantly focal to absent RGS5 immunoreactivity. These findings further support a common pericytic lineage of differentiation in glomus tumors, myopericytoma and angioleiomyoma. The pericyte marker RGS5 may be of future clinical utility for the evaluation of pericytic differentiation in soft tissue tumors.

Pericyte antigens in angiomyolipoma and PEComa family tumors.

Perivascular epithelioid cell tumors (PEComas) are an uncommon family of soft tissue tumors with dual myoid-melanocytic differentiation. Although PEComa family tumors commonly demonstrate a perivascular growth pattern, pericyte antigen expression has not yet been examined among this unique tumor group. Previously, we demonstrated that a subset of perivascular soft tissue tumors exhibit a striking pericytic immunophenotype, with diffuse expression of αSMA, CD146, and PDGFRß. Here, we describe the presence of pericyte antigens across a diverse group of PEComa family tumors (n = 19 specimens). Results showed that pericyte antigens differed extensively by histological appearance. Typical angiomyolipoma (AML) specimens showed variable expression of pericyte antigens among both perivascular and myoid-appearing cells. In contrast, AML specimens with a predominant spindled morphology showed diffuse expression of pericyte markers, including αSMA, CD146, and PDGFRß. AML samples with predominant epithelioid morphology showed a marked reduction in or the absence of immunoreactivity for pericyte markers. Lymphangiomyoma samples showed more variable and partial pericyte marker expression. In summary, pericyte antigen expression is variable among PEComa family tumors and largely varies by tumor morphology. Pericytic marker expression in PEComa may represent a true pericytic cell of origin, or alternatively aberrant pericyte marker adoption. Markers of pericytic differentiation may be of future diagnostic utility for the evaluation of mesenchymal tumors, or identify actionable signaling pathways for future therapeutic intervention.

Pericytes in sarcomas of bone.

Pericytes are mesenchymal cells that closely enwrap small blood vessels, lying in intimate association with the endothelium. Pericytes have recently gained attention as an important mediator of vascular biology and angiogenesis in cancer. Although better studied in carcinoma, pericytes have known interaction with sarcomas of bone, including Ewing's sarcoma, osteosarcoma, and chondrosarcoma. Best studied is Ewing's sarcoma (ES), which displays a prominent perivascular growth pattern. Signaling pathways of known importance in intratumoral pericytes in ES include Notch, PDGF/PDGFR-ß, and VEGF signaling. In summary, pericytes serve important functions in the tumor microenvironment. Improved understanding of pericyte biology may hold significant implications for the development of new therapies in sarcoma.

Review of microRNA in osteosarcoma and chondrosarcoma.

MicroRNAs (miRNAs) are small noncoding RNAs, which play a complex role in posttranscriptional gene expression and can theoretically be used as a diagnostic or prognostic tool, or therapeutic target for neoplasia. Despite advances in the diagnosis and treatment of skeletal sarcomas, including osteosarcoma and chondrosarcoma, much remains unknown regarding their underpinning molecular mechanisms. Given the recent increasing knowledge base of miRNA roles in neoplasia, both as oncogenes and tumor suppressor genes, this review will focus on the available literature regarding the expression profiles and potential roles of miRNA in skeletal sarcomas. Although this is an emerging field, miRNA profiling may be of use in clarifying competing diagnoses of skeletal sarcomas and possibly indicate patient risk of resistance to traditional chemotherapeutic agents. While detecting and targeting miRNAs is currently limited to experimental investigations, miRNA may be utilized for future clinical management of skeletal sarcomas.

Current Status of Surgical Planning for Orthognathic Surgery: Traditional Methods versus 3D Surgical Planning.

BACKGROUND: Orthognathic surgery has traditionally been performed using stone model surgery. This involves translating desired clinical movements of the maxilla and mandible into stone models that are then cut and repositioned into class I occlusion from which a splint is generated. Model surgery is an accurate and reproducible method of surgical correction of the dentofacial skeleton in cleft and noncleft patients, albeit considerably time-consuming. With the advent of computed tomography scanning, 3D imaging and virtual surgical planning (VSP) have gained a foothold in orthognathic surgery with VSP rapidly replacing traditional model surgery in many parts of the country and the world. What has yet to be determined is whether the application and feasibility of virtual model surgery is at a point where it will eliminate the need for traditional model surgery in both the private and academic setting. METHODS: Traditional model surgery was compared with VSP splint fabrication to determine the feasibility of use and accuracy of application in orthognathic surgery within our institution. RESULTS: VSP was found to generate acrylic splints of equal quality to model surgery splints in a fraction of the time. Drawbacks of VSP splint fabrication are the increased cost of production and certain limitations as it relates to complex craniofacial patients. CONCLUSIONS: It is our opinion that virtual model surgery will displace and replace traditional model surgery as it will become cost and time effective in both the private and academic setting for practitioners providing orthognathic surgical care in cleft and noncleft patients.

Clinical and histopathological diagnosis of glomus tumor: an institutional experience of 138 cases.

BACKGROUND: Glomus tumors are relatively uncommon subcentimeteric benign perivascular neoplasms usually located on the fingers. With their blue-red color and common subungual location, they are commonly confused for vascular or melanocytic lesions. To date there is no comprehensive review of an institutional experience with glomus tumors. METHODS: A 14-year retrospective review of all cases within University of California, Los Angeles, with either a clinical or pathological diagnosis of glomus tumor was performed. Data obtained included demographic information, tumor description, pathological diagnoses, immunohistochemical studies, radiographic and treatment information, and clinical course. Rates of concordance between clinical and pathological diagnoses and an evaluation of overlap with other entities were assessed. RESULTS: Clinical diagnosis of glomus tumor showed concordance with a histopathological diagnosis (45.4% of cases). The most common alternate clinical diagnoses included lipoma, cyst, or angioma. A pathological diagnosis of glomus tumor was most common in the fourth to seventh decades of life. The most common presentation was a subcentimeter lesion on the digit. Deep-seated tumors had a strikingly increased risk for malignancy (33%). Radiological studies were not relied on frequently (18.2% of cases). Immunohistochemical analysis showed diffuse αSMA and MSA expression in nearly all cases (99% and 95%, respectively), with focal to diffuse CD34 immunostaining in 32% of cases. DISCUSSION: Our study illustrates trends in the clinical versus pathologic diagnoses of glomus tumor, common competing diagnoses, a difference in demographics than is commonly reported (older age groups most commonly affected), and important differences in the use adjunctive diagnostic tools including radiology and immunohistochemistry.

Roles of bone morphogenetic protein signaling in osteosarcoma.

PURPOSE: Since the original extraction of bone morphogenetic proteins (BMPs) from bovine bone, research interest and clinical use has increased exponentially. With this, a concomitant analysis of BMP expression in bone tumours has been performed. BMP ligands, receptors, and signaling activity have been observed in diverse benign and malignant bone tumours. However, the reported expression, function, and importance of BMPs in bone tumours, and specifically osteosarcomas, have been far from uniform. This review highlights recent advances in understanding the role of BMP signaling in osteosarcoma biology, focusing on the sometimes divergent findings by various researchers and the challenges inherent in the study of osteosarcoma. METHODS: We performed a literature review of all studies examining BMP signaling in osteosarcoma. RESULTS: Overall, multiple BMP ligands and receptors are expressed in most osteosarcoma cell lines and subtypes, although BMP signaling may be reduced in comparison with benign bone-forming tumours. Studies suggest that osteosarcomas with different lineages of differentiation may have differential expression of BMP ligands. Although significant disagreement in the literature exists, the presence of BMP signaling in osteosarcoma may impart a worse prognosis. On the cellular level, BMP signaling appears to mediate promigratory effects in osteosarcoma and chondrosarcoma cell types, possibly via interaction and activation of Integrin ß1. CONCLUSIONS: BMP signaling has clear biologic importance in osteosarcoma, although it is not yet fully understood. Future questions for study include assessing the utility of BMP signaling in prognostication of osteosarcoma and the potential modulation of BMP signaling for inhibition of osteosarcomagenesis, growth and invasion.

Brief review of models of ectopic bone formation.

Ectopic bone formation is a unique biologic entity--distinct from other areas of skeletal biology. Animal research models of ectopic bone formation most often employ rodent models and have unique advantages over orthotopic (bone) environments, including a relative lack of bone cytokine stimulation and cell-to-cell interaction with endogenous (host) bone-forming cells. This allows for relatively controlled in vivo experimental bone formation. A wide variety of ectopic locations have been used for experimentation, including subcutaneous, intramuscular, and kidney capsule transplantation. The method, benefits and detractions of each method are summarized in the following review. Briefly, subcutaneous implantation is the simplest method. However, the most pertinent concern is the relative paucity of bone formation in comparison to other models. Intramuscular implantation is also widely used and relatively simple, however intramuscular implants are exposed to skeletal muscle satellite progenitor cells. Thus, distinguishing host from donor osteogenesis becomes challenging without cell-tracking studies. The kidney capsule (perirenal or renal capsule) method is less widely used and more technically challenging. It allows for supraphysiologic blood and nutrient resource, promoting robust bone growth. In summary, ectopic bone models are extremely useful in the evaluation of bone-forming stem cells, new osteoinductive biomaterials, and growth factors; an appropriate choice of model, however, will greatly increase experimental success.

Current methods of adipogenic differentiation of mesenchymal stem cells.

There has been a recent increase in our understanding in the isolation, culture, and differentiation of mesenchymal stem cells (MSCs). Concomitantly, the availability of MSCs has increased, with cells now commercially available, including human MSCs from adipose tissue and bone marrow. Despite an increased understanding of MSC biology and an increase in their availability, standardization of techniques for adipogenic differentiation of MSCs is lacking. The following review will explore the variability in adipogenic differentiation in vitro, specifically in 3T3-L1 and primary MSCs derived from both adipose tissue and bone marrow. A review of alternative methods of adipogenic induction is also presented, including the use of specific peroxisome proliferator-activated receptor-gamma agonists as well as bone morphogenetic proteins. Finally, we define a standard, commonly used adipogenic differentiation medium in the hopes that this will be adopted for the future standardization of laboratory techniques--however, we also highlight the essentially arbitrary nature of this decision. With the current, rapid pace of electronic publications, it becomes imperative for standardization of such basic techniques so that interlaboratory results may be easily compared and interpreted.

School-based screening to identify at-risk students not already known to school professionals: the Columbia suicide screen.

OBJECTIVES: We sought to determine the degree of overlap between students identified through school-based suicide screening and those thought to be at risk by school administrative and clinical professionals. METHODS: Students from 7 high schools in the New York metropolitan area completed the Columbia Suicide Screen; 489 of the 1729 students screened had positive results. The clinical status of 641 students (73% of those who had screened positive and 23% of those who had screened negative) was assessed with modules from the Diagnostic Interview Schedule for Children. School professionals nominated by their principal and unaware of students' screening and diagnostic status were asked to indicate whether they were concerned about the emotional well-being of each participating student. RESULTS: Approximately 34% of students with significant mental health problems were identified only through screening, 13.0% were identified only by school professionals, 34.9% were identified both through screening and by school professionals, and 18.3% were identified neither through screening nor by school professionals. The corresponding percentages among students without mental health problems were 9.1%, 24.0%, 5.5%, and 61.3%. CONCLUSIONS: School-based screening can identify suicidal and emotionally troubled students not recognized by school professionals.

Effects of capitated mental health services on youth contact with the juvenile justice system.

OBJECTIVE: To evaluate the association between Medicaid mental health capitation and youth's involvement with the juvenile justice system. METHOD: A longitudinal, quasi-experimental pre/post design was used. Using administrative databases, juvenile justice contact, defined as any detention or commitment, was assessed for 13,365 Medicaid-eligible youths, aged 10-17 years, who received public mental health services over a 3-year period (1994-1997) in the state of Colorado. RESULTS: There was no significant effect of financing when secular time was controlled for (interaction financing x time: hazard rate = 0.92, p =.62). The main effects model demonstrates a significant secular trend with juvenile justice contacts decreasing over time for both types of financing (hazard rate = 0.80, p =.002) and a significant effect of financing with eventually capitated sites having higher rates of juvenile justice contact compared with sites that remained fee-for-service (hazard rate = 1.24, p =. 009). Multivariate analyses controlled for demographics, mental health and substance use diagnoses, and other risk factors for juvenile justice contact. CONCLUSIONS: After adjustment for secular trends, capitation was not associated with a reduction in juvenile justice contact. Nonetheless, these findings provide evidence that capitation did not increase the risk of juvenile justice contact.

Alcohol and juvenile justice contacts: a comparison of fee-for-service and capitated medicaid mental health services.

OBJECTIVE: This study examines whether youth with alcohol problems are especially vulnerable to juvenile justice contact when receiving public mental health services in fee-for-service versus capitated managed-care agencies. Capitation is a payment method often accompanying managed care; a fixed fee is paid per person enrolled, for a specific time period and range of services. METHOD: Youth services were studied in a statewide, quasi-experimental design from July 1994 to June 1997; subjects were 13,365 Medicaid-eligible youth (52% female) aged 10-17. Alcohol problems were measured using a clinician-generated psychiatric diagnosis and a subjective indicator of alcohol symptoms obtained from a psychometrically tested mental health treatment intake form. Analysis methods were hazard/survival rates, log-rank tests and Cox proportional hazards models. RESULTS: As measured by the presence of symptoms, alcohol-involved youth in capitated managed care were significantly less likely to have contact with the juvenile justice system, in uncontrolled analysis. In controlled analysis, they were also less likely; however, only at the level of a trend. CONCLUSIONS: Concerns regarding capitated managed mental health care (e.g., substitution of care or "cost-shifting") found no support. There was no evidence of a shifting of alcohol-involved youth receiving mental health services under capitated managed care to the juvenile justice system. If anything, such youth saw their likelihood of juvenile justice involvement decrease.