Pediatric hand ultrasound: common indications, injury, inflammation and masses.

Ultrasound is a uniquely valuable tool for evaluating musculoskeletal problems in the pediatric hand. Acute and chronic injuries involving tendons and ligaments of the hand can be quickly assessed and can guide surgical decision-making. Using ultrasound, palpable lesions and masses can be evaluated for cystic and solid components aiding in differential diagnosis. Additionally, ultrasound provides evaluation of acute versus chronic changes of inflammatory arthritis, assessing disease severity and subclinical synovitis and serving as an adjunct to medical management. This review will cover common indications and ultrasound findings of the pediatric hand, focusing on common injuries, inflammatory arthritis and masses. Important anatomical features of the hand will be discussed as well as imaging technique and evaluation in the pediatric patient.

Direct Repair of the Lower Trunk to Residual Nerve Roots for Restoration of Finger Flexion After Total Brachial Plexus Injury.

PURPOSE: Residual nerve root stumps have been used to neurotize the median nerve in an attempt to restore finger flexion function in patients suffering from total brachial plexus injury. However, the results have been unsatisfactory mainly because of the need to use a long nerve graft. The authors have tried to improve the quality of restored finger flexion by direct approximation of available (ruptured) ipsilateral root stumps to the lower trunk (LT). We sought to validate these results using objective outcome measures. METHODS: This is a study of 27 cases of total posttraumatic brachial plexus palsies. In each case, the neck was explored and ruptured root stumps identified. The LT was mobilized by separating it from the posterior division and the medial cutaneous nerve of the forearm distally. The mobilized LT was then approximated directly to an ipsilateral root stump. The arm was immobilized against the trunk for 2 months. The patients were observed for return of function in the paralyzed upper limb. The presence and strength of finger flexion was measured using the British Medical Council grading. RESULTS: The follow-up period was 36 to 74 months (average, 56.9 ± 13.7 months). Recovery of active finger flexion was M4 in 10 patients, M3 in 8 patients, and M2 to M0 in 9 patients. Meaningful recovery (M3 or greater) of finger flexion was achieved in 18 of 27 patients. CONCLUSIONS: The results of active finger flexion can be improved by direct approximation of the LT to an ipsilateral root stump. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

Management of osteoarthrosis of the thumb joints.

We present current concepts and evidence to optimize diagnosis and management of osteoarthritis in the thumb joints. Numerous options and controversies exist for surgical treatment of carpometacarpal joint arthritis. Fewer options exist for metacarpophalangeal joint arthritis. Surgical treatment for interphalangeal arthritis is mainly arthrodesis.

Correlation of clinical disease severity to radiographic thumb osteoarthritis index.

PURPOSE: To determine if a slight modification of the 1987 Eaton-Glickel staging and interpreting 4 standardized radiographs for trapeziometacarpal (TMC) osteoarthritis (OA) improved analysis, to determine if a quantifiable index measurement from a single Robert (pronated anteroposterior) view enhanced reproducibility, and to examine whether improved radiographic staging correlated to clinically relevant disease and thus support validity. METHODS: We analyzed 4 thumb radiographs (posteroanterior, lateral, Robert, and stress views) in 60 consecutive subjects representing an adult population spectrum of asymptomatic to advanced disease. Two experienced hand surgeons (A.L.L. and A.P.C.W.), 1 chief resident (A.J.B.), and 1 medical student (J.M.M.) performed the analysis on each subject's radiographs. We analyzed all 4 radiographs for Eaton and modified Eaton staging and then later analyzed only the Robert view for the thumb osteoarthritis (ThOA) index measurement. The radiographs were randomized and reread a week later for each classification at separate times. Surgically excised trapeziums from 20/60 subjects were inspected for first metacarpal surface disease and correlated to the 3 classifications. RESULTS: All 3 staging classifications demonstrated high reproducibility, with the intraclass correlation coefficient averaging 0.73 for the Eaton, 0.83 for the modified Eaton, and 0.95 for the ThOA index. Articular wear and metacarpal surface eburnation correlated highest to the ThOA index, with advanced disease 1.55 or greater correlating to Eaton III/IV and modified Eaton stage 3/4 in a linear relationship. CONCLUSIONS: The ThOA index based on a Robert view provided a measurable alternative to Eaton staging and correlated to severity of surgically relevant thumb TMC OA. CLINICAL RELEVANCE: A simple reproducible radiographic measurement may enhance TMC OA classification and provide a reliable means to predict clinical disease. TYPE OF STUDY/LEVEL OF EVIDENCE: Diagnostic II.

Intra- and interobserver reliability of the Eaton classification for trapeziometacarpal arthritis: a systematic review.

BACKGROUND: Trapeziometacarpal, or thumb carpometacarpal (CMC), arthritis is a common problem with a variety of treatment options. Although widely used, the Eaton radiographic staging system for CMC arthritis is of questionable clinical utility, as disease severity does not predictably correlate with symptoms or treatment recommendations. A possible reason for this is that the classification itself may not be reliable, but the literature on this has not, to our knowledge, been systematically reviewed. QUESTIONS/PURPOSES: We therefore performed a systematic review to determine the intra- and interobserver reliability of the Eaton staging system. METHODS: We systematically reviewed English-language studies published between 1973 and 2013 to assess the degree of intra- and interobserver reliability of the Eaton classification for determining the stage of trapeziometacarpal joint arthritis and pantrapezial arthritis based on plain radiographic imaging. Search engines included: PubMed, Scopus(®), and CINAHL. Four studies, which included a total of 163 patients, met our inclusion criteria and were evaluated. The level of evidence of the studies included in this analysis was determined using the Oxford Centre for Evidence Based Medicine Levels of Evidence Classification by two independent observers. RESULTS: A limited number of studies have been performed to assess intra- and interobserver reliability of the Eaton classification system. The four studies included were determined to be Level 3b. These studies collectively indicate that the Eaton classification demonstrates poor to fair interobserver reliability (kappa values: 0.11-0.56) and fair to moderate intraobserver reliability (kappa values: 0.54-0.657). CONCLUSIONS: Review of the literature demonstrates that radiographs assist in the assessment of CMC joint disease, but there is not a reliable system for classification of disease severity. Currently, diagnosis and treatment of thumb CMC arthritis are based on the surgeon's qualitative assessment combining history, physical examination, and radiographic evaluation. Inconsistent agreement using the current common radiographic classification system suggests a need for better radiographic tools to quantify disease severity.

Long-Term Hand and Shoulder Function in Children following Early Surgical Intervention for a Birth-Related Upper Brachial Plexus Injury.

Purpose To better understand the long-term hand and shoulder outcomes of upper brachial plexus birth injuries. Methods We evaluated shoulder and hand function in 32 patients (13 males; 19 females) with a C5/C6 birth injury history). All patients had undergone primary nerve surgery as infants, and 12 underwent a simultaneous shoulder procedure as they presented with a fixed internal rotation contracture of the shoulder. On average, all patients were evaluated and examined 15 years postoperatively. The shoulder function was evaluated using the Miami Shoulder Scale. Hand function was measured by the 9-hole peg test (9-HPT) and statistical analysis included comparison of 9-HPT time against normative data using the Student's t -test. Results The cohort includes 22 right-hand-dominant and 10 left-hand-dominant patients. Mean age at surgery was 10 months; mean age at follow-up was 15 years ± 2 years 2 months. Cumulative shoulder function was "good" or "excellent" (Miami score) in 23 patients. For 9-HPT, 23 out of 32 patients seen had an involved hand with a significant alteration in function. Conclusion Early nerve surgery in cases of upper brachial plexus birth injuries result in the desired outcome. To ensure timely and targeted therapy for any residual deficits, it is imperative that limitations in hand function among children with an Erb's palsy.

Development of an affordable system for personalized video-documented surgical skill analysis for surgical residency training.

Surgical competency requires the development of decision-making and technical skills. Despite lectures, literature, and written and oral examinations, both skill sets are difficult to systematically teach and analyze. With the advent of head-mounted video cameras, we seek to incorporate a surgical video database into our surgical training curriculum. We hope to not only change the way and rate at which surgical trainees develop their surgical skills but to also introduce a novel tool for surgical skill assessment.

Histologic analysis of fetal bovine derived acellular dermal matrix in tissue expander breast reconstruction.

BACKGROUND: This study seeks to determine human host response to fetal bovine acellular dermal matrix (ADM) in staged implant-based breast reconstruction. METHODS: A prospective study was performed for patients undergoing immediate breast reconstruction with tissue expander placement and SurgiMend acellular fetal bovine dermis. At the time of exchange for permanent implant, we obtained tissue specimens of SurgiMend and native capsule. Histological and immunohistochemical assays were performed to characterize the extent of ADM incorporation/degradation, host cell infiltration, neovascularization, inflammation, and host replacement of acellular fetal bovine collagen. RESULTS: Seventeen capsules from 12 patients were included in our study. The average "implantation" time of SurgiMend was 7.8 months (range, 2-23 months). Histological analysis of the biopsy of tissue revealed rare infiltration of host inflammatory cells, even at 23 months. One patient had an infection requiring removal of the tissue expander at 2 months. Contracture, inflammatory changes, edema, and polymorphonuclear leukocyte infiltration were rare in the ADM. An acellular capsule was seen in many cases, at the interface of SurgiMend with the tissue expander. CONCLUSIONS: SurgiMend demonstrated a very infrequent inflammatory response. An antibody specific to bovine collagen allowed for direct identification of bovine collagen separate from human collagen. Cellular infiltration and neovascularization of SurgiMend correlated with the quality of the mastectomy skin flap rather than the duration of implantation. Future studies are needed to further characterize the molecular mechanisms underlying tissue incorporation of this product.

Detailed Management of Brachial Plexus Birth Injuries: The Miami Protocol at Nicklaus Children's Hospital.

The management of children with brachial plexus birth injuries is complex and requires a multidisciplinary approach. In the following article, we describe our approach to evaluation and management at Nicklaus Children's Hospital. It is our aim is to elucidate nuances in management.

Malignant ameloblastoma: concurrent presentation of primary and distant disease and review of the literature.

Malignant ameloblastoma is a rare tumor of odontogenic origin with a metastatic focus. Distant metastatic disease is found most commonly in the lungs. A review of the literature shows that most cases of malignant ameloblastoma involve a disease-free period from primary tumor extirpation to the discovery of metastasis. This report describes the case of a 56-year-old man presenting with ameloblastoma of the maxilla and a solitary pulmonary metastasis concurrently. This represents a rare case in which there is a simultaneous diagnosis of primary ameloblastoma and a metastatic lesion. Appropriate workup for ameloblastoma includes surveillance for metastatic disease. Surgical resection of primary and distant disease is recommended. Chemotherapy and radiation may play a role in palliation when resection of metastatic disease is not feasible.

Activated Wnt/beta-catenin signaling in melanoma is associated with decreased proliferation in patient tumors and a murine melanoma model.

This study demonstrates that in malignant melanoma, elevated levels of nuclear beta-catenin in both primary tumors and metastases correlate with reduced expression of a marker of proliferation and with improved survival, in contrast to colorectal cancer. The reduction in proliferation observed in vivo is recapitulated in B16 murine melanoma cells and in human melanoma cell lines cultured in vitro with either WNT3A or small-molecule activators of beta-catenin signaling. Consistent with these results, B16 melanoma cells expressing WNT3A also exhibit decreased tumor size and decreased metastasis when implanted into mice. Genome-wide transcriptional profiling reveals that WNT3A up-regulates genes implicated in melanocyte differentiation, several of which are down-regulated with melanoma progression. These findings suggest that WNT3A can mediate transcriptional changes in melanoma cells in a manner reminiscent of the known role of Wnt/beta-catenin signaling in normal melanocyte development, thereby altering melanoma cell fate to one that may be less proliferative and potentially less aggressive. Our results may explain the observed loss of nuclear beta-catenin with melanoma progression in human tumors, which could reflect a dysregulation of cellular differentiation through a loss of homeostatic Wnt/beta-catenin signaling.

Integrative genomic analyses identify MITF as a lineage survival oncogene amplified in malignant melanoma.

Systematic analyses of cancer genomes promise to unveil patterns of genetic alterations linked to the genesis and spread of human cancers. High-density single-nucleotide polymorphism (SNP) arrays enable detailed and genome-wide identification of both loss-of-heterozygosity events and copy-number alterations in cancer. Here, by integrating SNP array-based genetic maps with gene expression signatures derived from NCI60 cell lines, we identified the melanocyte master regulator MITF (microphthalmia-associated transcription factor) as the target of a novel melanoma amplification. We found that MITF amplification was more prevalent in metastatic disease and correlated with decreased overall patient survival. BRAF mutation and p16 inactivation accompanied MITF amplification in melanoma cell lines. Ectopic MITF expression in conjunction with the BRAF(V600E) mutant transformed primary human melanocytes, and thus MITF can function as a melanoma oncogene. Reduction of MITF activity sensitizes melanoma cells to chemotherapeutic agents. Targeting MITF in combination with BRAF or cyclin-dependent kinase inhibitors may offer a rational therapeutic avenue into melanoma, a highly chemotherapy-resistant neoplasm. Together, these data suggest that MITF represents a distinct class of 'lineage survival' or 'lineage addiction' oncogenes required for both tissue-specific cancer development and tumour progression.

Lack of extracellular signal-regulated kinase mitogen-activated protein kinase signaling shows a new type of melanoma.

The majority of human melanomas harbor activating mutations of either N-RAS or its downstream effector B-RAF, which cause activation of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase and the ERK MAPK cascade. The melanoma-relevant effectors of ERK activation, however, are largely unknown. In this work, we show that increased ERK activation correlates strongly with mutational status of N-RAS or B-RAF in 21 melanoma cell lines. Melanoma lines that were wild-type for RAS/RAF showed low levels of ERK activation comparable with primary human melanocytes. Through supervised analysis of RNA expression profiles, we identified 82 genes, including TWIST1, HIF1alpha, and IL-8, which correlated with ERK activation across the panel of cell lines and which decreased with pharmacologic inhibition of ERK activity, suggesting that they are ERK transcriptional targets in melanoma. Additionally, lines lacking mutations of N-RAS and B-RAF were molecularly distinct and characterized by p53 inactivation, reduced ERK activity, and increased expression of epithelial markers. Analysis of primary human melanomas by tissue microarray confirmed a high correlation among expression of these epithelial markers in a heterogeneous sample of 570 primary human tumors, suggesting that a significant frequency of primary melanomas is of this "epithelial-like" subtype. These results show a molecularly distinct melanoma subtype that does not require ERK activation or epithelial-mesenchymal transformation for progression.

Prognostic significance of cadherin-based adhesion molecules in cutaneous malignant melanoma.

BACKGROUND: The need for novel molecular prognostic markers that can supplement validated clinicopathologic correlates for cutaneous malignant melanoma is well recognized. Proteins that mediate the epithelial-mesenchymal transition, the process by which a cancer cell disengages from its parent tumor, are important candidates. METHODS: The prognostic relevance of E-cadherin, N-cadherin, and P-cadherin, calcium-dependent transmembrane glycoproteins that regulate cell-cell adhesion, and their adaptors, alpha-catenin, beta-catenin, and p120-catenin, was evaluated on a cohort of 201 primary and 274 metastatic melanoma tumors using fluorescence-based immunohistochemical methods and Automated Quantitative Analysis of protein expression on digitally captured photomicrographs. RESULTS: Increasing levels of N-cadherin expression improved overall survival (log-rank = 7.31; P = 0.03) but did not retain significance following adjustment for established clinicopathologic correlates (P = 0.50). Higher levels of E-cadherin approached significance for favorable prognosis on both univariate (P = 0.13) and multivariable (P = 0.10) analyses. Hierarchical clustering of the composite profiles for all six markers identified four unique clusters that yielded differential overall survival (log-rank = 10.54; P = 0.01). Cluster 4, expressing high E-cadherin and N-cadherin levels, possessed the most favorable outcome and cluster 2, featuring low E-cadherin and alpha-catenin but modest N-cadherin, showed least favorable outcomes. Cluster 2 remained significant on multivariable analysis (hazard ratio, 3.29; 95% confidence interval, 1.50-7.19; P = 0.003). CONCLUSIONS: Although none of the cadherin-based adhesion molecules were independently prognostic, multimarker profiles were significant. Similar to epithelial-derived tumors, loss of E-cadherin correlates with poor outcome. In contrast, for neural crest-derived cutaneous malignant melanoma, N-cadherin overexpression can be associated with either a successful epithelial-mesenchymal transition or a favorably differentiated tumor. Additional cadherin profiles are needed to discriminate these distinctive phenotypes.

Expression of tumor necrosis factor--related apoptosis-inducing ligand receptors 1 and 2 in melanoma.

PURPOSE: The proapoptotic receptors tumor necrosis factor--related apoptosis-inducing ligand receptor 1 (TRAIL-R1) and TRAIL-R2 are targets of drugs in clinical development, and receptor expression levels may be important determinants of sensitivity to receptor agonists. We assessed TRAIL-R1 and TRAIL-R2 expression patterns in a large cohort of melanomas and benign nevi. EXPERIMENTAL DESIGN: We analyzed tissue microarrays containing 546 melanomas and 540 nevi using our automated quantitative method to measure protein levels in situ (AQUA). The system uses S100 to define pixels as melanoma (tumor mask) within the array spot and measures intensity of TRAIL-receptor expression using Cy5-conjugated antibodies within the mask. AQUA scores were correlated with clinical and pathologic variables. RESULTS: TRAIL-R1 and TRAIL-R2 expression was higher in melanomas than in nevi (P < 0.0001), and higher in primary than in metastatic specimens (P = 0.0031 and P < 0.0001, respectively). TRAIL-R1 and TRAIL-R2 expression exceeding the 95th percentile for nevi was found in 19% and 74% of melanoma specimens, respectively. Although on univariate analysis, high TRAIL-R2 expression correlated with increased survival (P = 0.0439), it was not associated with survival within the primary or metastatic subcohorts. TRAIL-R1 expression was not associated with survival. CONCLUSIONS: TRAIL-R1 and TRAIL-R2 expression is higher in malignant melanocytes than in their benign counterparts, suggesting that these receptors might be effective therapeutic targets in melanoma. Expression is higher in early-stage disease than in metastatic specimens, and expression exceeding that found in nevi is found in a substantially larger fraction of melanomas for TRAIL-R2 compared with TRAIL-R1. Assessment of baseline tumor TRAIL receptor expression may be important in analysis of clinical trials involving TRAIL receptor agonists.

Automated quantitative analysis of activator protein-2alpha subcellular expression in melanoma tissue microarrays correlates with survival prediction.

The activator protein-2alpha (AP-2) transcription factor plays a key role in regulating expression of genes involved in tumor growth and metastasis of human melanoma. We sought to assess the prognostic significance of AP-2 expression and its role in the transition of nevi to metastatic melanoma. Two cohorts were analyzed. One was a "progression" microarray containing melanoma specimens from M.D. Anderson Cancer Center representing 84 cases and the other was a retrospective cohort from Yale University representing 214 primary melanomas and 293 metastases. Analysis of total AP-2 expression using two quantitative systems [automated quantitative analysis (AQUA) and laser scanning cytometry (LSC)] revealed no correlation with diagnosis group. LSC analysis of the M.D. Anderson Cancer Center array showed that the number of cells expressing nuclear AP-2 was highest in the benign nevi group (11.85%) and significantly decreased in each phase of melanoma progression to 0.39% in the metastatic group. Both LSC and AQUA showed decreased nuclear AP-2 levels and increased cytoplasmic AP-2 that is directly proportional to progression. Neither nuclear nor cytoplasmic expression levels correlated with outcome. Intriguingly, the ratio of cytoplasmic to nuclear AP-2 predicted outcome in the entire population and in the primary tumors alone, demonstrating the power of the ratio to normalize for variations. Furthermore, the AP-2 ratio directly correlated with other clinicopathologic factors, including Breslow depth (R = 0.334, P < 0.001). We show that a high level of AP-2 expression in the cytoplasm relative to the nucleus correlates with poor prognosis and the loss of nuclear AP-2 expression is associated with malignant transformation and progression of melanoma.

Automated quantitative analysis of E-cadherin expression in lymph node metastases is predictive of survival in invasive ductal breast cancer.

PURPOSE: The tumor suppressor adhesion molecule E-cadherin is believed to have an anti-invasive role in breast cancer. Lymph node involvement is the best prognostic marker known, yet there is variability in outcome among node-positive patients. We investigated the relationship between E-cadherin expression in primary invasive ductal tumors and corresponding nodal metastases, and determined the prognostic value of E-cadherin expression in node-positive breast cancer. EXPERIMENTAL DESIGN: Membrane E-cadherin expression was studied by immunohistochemical staining of tissue microarrays with fluorescent-labeled antibodies. An objective method of automated quantitative analysis (AQUA) was used. AQUA uses cytokeratin to define pixels as breast cancer (tumor mask) within the array spot, and measures E-cadherin expression using a Cy5-conjugated antibody within the mask. RESULTS: We employed a tissue microarray containing 207 primary and matched nodal metastases suitable for AQUA analysis. There was no significant difference in mean staining intensity between the primary and nodal specimens (P = 0.8). A scattergram was generated which identified a subset of patients (25%) with high E-cadherin expression in nodal metastases, and this top quartile had improved survival (P = 0.028). On univariate analysis, increased E-cadherin expression in nodal metastases was strongly associated with improved survival (P = 0.007), whereas expression in primary tumors was not (P = 0.13). On multivariate analysis, nodal E-cadherin expression retained its independent association with survival, as did tumor size and HER2/neu status. CONCLUSIONS: Strong E-cadherin expression in lymph node metastases was highly predictive of improved survival. This suggests that expression of adhesion molecules at metastatic sites portends less aggressive tumor behavior.

Automated quantitative analysis of HDM2 expression in malignant melanoma shows association with early-stage disease and improved outcome.

The incidence of cutaneous malignant melanoma continues to increase every year, and this disease remains the leading cause of skin cancer death in industrialized countries. Despite the aggressive nature of advanced melanoma, there are no standard biological assays in clinical usage that can predict metastasis. This may be due, in part, to the inadequacy of reproducible assessment of protein expression using traditional immunohistochemistry. We have previously described a novel method of quantitative assessment of protein expression (AQUA) with the continuity and accuracy of an ELISA assay but with maintenance of critical spatial information. Here, we modify this technology for the evaluation of protein expression in melanoma. Using a tissue microarray cohort of 405 melanoma lesions and 17 normal skin samples, we analyzed expression of HDM2, the human homologue of murine double minute 2 with automated quantitative analysis. We show that expression levels in the nucleus are significantly higher in primary melanomas than in metastatic lesions. Furthermore, high levels of expression are predictive of better outcome. This study demonstrates that quantitative assessment of protein expression is useful in melanoma to validate potential tissue biomarkers and suggests that human homologue of murine double minute 2 may be a valuable prognostic tool for management of malignant melanoma.