The History of Academic Leadership Education in Orthopaedic Surgery.

Background: The growth of the American academic orthopaedic community over the last 53 years has been accompanied by an expanding need for academic leadership education. Methods: The transition of the Association of Orthopaedic Chairmen, to the Academic Orthopaedic Society, to the American Orthopaedic Association through its Academic Leadership Committee and American Orthopaedic Association Council of Residency Directors is reviewed. Results: Academic orthopaedic community members recognized that the evolving leadership needs of the academic community could be better addressed by transitioning to a new organization, the Academic Orthopaedic Society and eventually by creating a new structure within a well aligned and well-resourced existing organization, the American Orthopaedic Association. Conclusion: Organizational and leadership flexibility has been vital to serving the evolving need of the American academic orthopaedic community for leadership education.

A rare case of cavitary lung lesions in an adolescent: Granulomatosis with polyangiitis.

Granulomatosis with Polyangiitis (GPA) is a life threatening disease if left untreated which predominantly affects the adult population. As clinical presentation is often non-specific there is a heavy reliance on radiologic, laboratory and biopsy findings in diagnosis. We present a case of a 17-year-old male who presented with a history of tea colored urine and recurrent epistaxis who now complained of cough and congestion. The patient failed multiple courses of outpatient antibiotics and a CT of the chest while in the ED demonstrated multiple cavitary lesions. Subsequent workup and biopsy confirmed the diagnosis of GPA. It is important for the Radiologist and other clinicians to keep GPA in their differential when presented with a cavitary lung lesion as prompt treatment is required for good outcomes.

Effectiveness of Clinical Decision Tools in Predicting Pulmonary Embolism.

OBJECTIVE: The Wells criteria and revised Geneva score are two commonly used clinical decision tools (CDTs) developed to assist physicians in determining when computed tomographic angiograms (CTAs) should be performed to evaluate the high index of suspicion for pulmonary embolism (PE). Studies have shown varied accuracy in these CDTs in identifying PE, and we sought to determine their accuracy within our patient population. METHODS: Patients admitted to the Emergency Department (ED) who received a CTA for suspected PE from 2019 Jun 1 to 2019 Aug 31 were identified. Two CDTSs, the Wells criteria and revised Geneva score, were calculated based on data available prior to CTA and using the common D-Dimer cutoff of >500 µg/L. We determined the association between confirmed PE and CDT values and determined the association between the D-Dimer result and PE. RESULTS: 392 CTAs were identified with 48 (12.1%) positive PE cases. The Wells criteria and revised Geneva score were significantly associated with PE but failed to identify 12.5% and 70.4% of positive PE cases, respectively. Within our cohort, a D-Dimer cutoff of >300 µg/L was significantly associated with PE and captured 95.2% of PE cases. CONCLUSIONS: Both CDTs were significantly associated with PE but failed to identify PE in a significant number of cases, particularly the revised Geneva score. Alternative D-Dimer cutoffs may provide better accuracy in identifying PE cases.

Kikuchi Disease with enlargement of intramammary lymph node.

We describe a rare case of intramammary lymphadenopathy due to Kikuchi-Fujimoto disease. A 15-year old female presented to the Breast Clinic with complaints of a tender, palpable right breast lump. An ultrasound of the area of concern demonstrated an enlarged 2.9 cm intramammary lymph node with preservation of the fatty hilum. An ultrasound guided core biopsy of the lymph node confirmed the diagnosis of Kikuchi-Fujimoto disease.

Motor patterns associated with crawling in a soft-bodied arthropod.

Soft-bodied animals lack distinct joints and levers, and so their locomotion is expected to be controlled differently from that of animals with stiff skeletons. Some invertebrates, such as the annelids, use functionally antagonistic muscles (circumferential and longitudinal) acting on constant-volume hydrostatics to produce extension and contraction. These processes form the basis for most theoretical considerations of hydrostatic locomotion in organisms including larval insects. However, caterpillars do not move in this way, and their powerful appendages provide grip independent of their dimensional changes. Here, we show that the anterograde wave of movement seen in the crawling tobacco hornworm, Manduca sexta, is mediated by co-activation of dorsal and ventral muscles within a body segment, rather than by antiphasic activation, as previously believed. Furthermore, two or three abdominal segments are in swing phase simultaneously, and the activities of motor neurons controlling major longitudinal muscles overlap in more than four segments. Recordings of muscle activity during natural crawling show that some are activated during both their shortening and elongation. These results do not support the typical peristaltic model of crawling, but they do support a tension-based model of crawling, in which the substrate is utilized as an anchor to generate propulsion.

Incidental vesicourachal diverticulum in a young female.

A vesicourachal remnant is the rarest presentation of the congenital urachal remnant anomalies, occurring approximately in 3% of those who have them. We discuss a case where a vesicourachal anomaly is discovered incidentally in a pediatric patient by ultrasound and subsequently confirmed by MRI. The urachus connects the dome of the bladder to the umbilical cord in fetal life. After birth, this structure is obliterated and becomes the median umbilical ligament. When complete obliteration does not occur, a urachal remnant is created.

Rare Presentation of Burned-Out Testicular Seminoma.

A 28 year old male who complained of abdominal pain over the past several months was found on CT to have lymphadenopathy along the right aspect of the inferior vena cava. The patient was subsequently seen by an oncologist where further work up of the lymphadenopathy was performed. A MR of the abdomen demonstrated right aortocaval and para-caval lymph nodes measuring to 3.7cm. A testicular ultrasound was then performed, which demonstrated an apparent peripheral focal hypoechoic region with no associated internal vascularity within the right testes. Biopsy of the retroperitoneal lymph nodes pathologically confirmed the diagnosis of seminoma. Keywords: Seminoma, Testicular Cancer, Retroperitoneal Adenopathy, Oncology, Burned-Out Tumor.

An orthotopic model of human osteosarcoma growth and spontaneous pulmonary metastasis.

Osteosarcoma is the most common primary malignancy of bone and patients often develop pulmonary metastases. In order to investigate the pathogenesis of human osteosarcoma, there is a great need to develop a clinically relevant animal model. Here we report the development of an osteosarcoma animal model using three related human osteosarcoma lines, the parental TE-85 and two derivative lines MNNG/HOS and 143B. In vitro characterization demonstrated that the 143B line had the greatest cell migration and the least cell adhesion activities among the three lines. The 143B line also exhibited the greatest ability for anchorage independent growth. When GFP-tagged osteosarcoma cells were injected into the proximal tibia of athymic mice, we found that 143B cells were highly tumorigenic and metastatic, and MNNG/HOS cells were tumorigenic but significantly less metastatic. TE85 cells were neither tumorigenic nor metastatic. The number of pulmonary metastases was found 50-fold higher in 143B injected animals than that in MNNG/HOS injected mice. No pulmonary metastases were detected in TE85 injected animals for up to 8 weeks. Primary tumors formed by MNNG/HOS and 143B cells could be visualized by whole body fluorescence imaging, while the pulmonary metastases were visualized on the necropsied samples. The GFP tagged 143B cells (and to a lesser extent, MNNG/HOS cells) were readily recovered from lung metastases. This clinically relevant model of human osteosarcoma provides varying degrees of tumor growth at the primary site and metastatic potential. Thus, this orthotopic model should be a valuable tool to investigate factors that promote or inhibit osteosarcoma growth and/or metastasis.

Increased expression of S100A6 is associated with decreased metastasis and inhibition of cell migration and anchorage independent growth in human osteosarcoma.

While most osteosarcoma patients have metastatic or micrometastatic lesions, less than 15% of them have clinically detectable metastatic diseases at presentation. To identify potential markers that may predict osteosarcoma metastasis, we analyzed the expression of S100A6 in 50 osteosarcoma cases and found that 84% of the analyzed specimens stained positive for S100A6. There is a trend towards decreased clinically evident metastasis with increased S100A6 staining. Overexpression of S100A6 in osteosarcoma cells decreases cell motility and anchorage independent growth on collagen gels. Our findings provide evidence that, while S100A6 is commonly overexpressed in human osteosarcoma, loss of its expression correlates with a metastatic phenotype.

Nuclear receptor agonists as potential differentiation therapy agents for human osteosarcoma.

PURPOSE: This study was designed to investigate whether nuclear receptor agonists can be used as potential differentiation therapy agents for human osteosarcoma. EXPERIMENTAL DESIGN: Four osteosarcoma cell lines (143B, MNNG/HOS, MG-63, and TE-85) were treated with proliferator-activated receptor (PPAR)gamma agonists, troglitazone and ciglitazone, and a retinoid X receptor (RXR) ligand, 9-cis retinoic acid. The proliferation and induction of apoptosis in the treated cells were assessed, as was the induction of alkaline phosphatase, a differentiation marker of osteoblasts. RESULTS: The expression of PPARgamma was readily detected in all tested osteosarcoma lines. On treatment with the PPARgamma and RXR ligands, all four osteosarcoma lines exhibited a significantly reduced proliferation rate and cell viability. Among the four lines, 143B and MNNG/HOS were shown to be more sensitive to ligand-induced apoptosis, as demonstrated by the Crystal Violet and Hoechst staining assays. Of the three tested ligands, troglitazone was shown to be the most effective in inducing cell death, followed by 9-cis retinoic acid. Moreover, a strong synergistic effect on the induction of cell death was observed when both troglitazone and 9-cis retinoic acid or ciglitazone and 9-cis retinoic acid were administered to osteosarcoma cells. Troglitazone was shown to effectively induce alkaline phosphatase activity, a well-characterized hallmark for osteoblastic differentiation. CONCLUSIONS: Our findings suggest that PPARgamma and/or RXR ligands may be used as efficacious adjuvant therapeutic agents for primary osteosarcoma, as well as potential chemopreventive agents for preventing the recurrence and metastasis of osteosarcoma after the surgical removal of the primary tumors.

Current bladder cancer tests: unnecessary or beneficial?

Bladder cancer is currently diagnosed using cystoscopy and cytology in patients with suspicious signs and symptoms. These same tests are used to monitor patients with a history of bladder cancer for recurrence. The recurrence rate for bladder cancer is high, thus necessitating long-term follow-up. Urine cytology requires an experienced cytopathologist and is costly. It has high specificity, but low sensitivity for low-grade bladder tumors. Recently many non-invasive bladder cancer tests, utilizing markers found in the urine, have been developed. The FDA has approved several of these for the use is bladder cancer diagnosis, and many others are undergoing development and investigation. An ideal bladder cancer test would be non-invasive, highly sensitive and specific, inexpensive, easy to perform, and yield highly reproducible results. Many of the tests reviewed meet some, but not all, of these criteria.

Benign fibrous histiocytoma: a rare finding on bone scan staging for prostate adenocarcinoma.

Benign fibrous histiocytoma is a rare bone tumor that usually presents with localized pain and/or a pathological fracture. We report on a patient with adenocarcinoma of the prostate who had a radionuclide bone scan for staging, which was suspicious for metastatic disease. Histologic examination of left eleventh rib revealed a Benign Fibrous Histiocytoma (BFH). To our knowledge, this is the first BFH found solely on bone scan.

A genome-wide screen identifies conserved protein hubs required for cadherin-mediated cell-cell adhesion.

Cadherins and associated catenins provide an important structural interface between neighboring cells, the actin cytoskeleton, and intracellular signaling pathways in a variety of cell types throughout the Metazoa. However, the full inventory of the proteins and pathways required for cadherin-mediated adhesion has not been established. To this end, we completed a genome-wide (~14,000 genes) ribonucleic acid interference (RNAi) screen that targeted Ca(2+)-dependent adhesion in DE-cadherin-expressing Drosophila melanogaster S2 cells in suspension culture. This novel screen eliminated Ca(2+)-independent cell-cell adhesion, integrin-based adhesion, cell spreading, and cell migration. We identified 17 interconnected regulatory hubs, based on protein functions and protein-protein interactions that regulate the levels of the core cadherin-catenin complex and coordinate cadherin-mediated cell-cell adhesion. Representative proteins from these hubs were analyzed further in Drosophila oogenesis, using targeted germline RNAi, and adhesion was analyzed in Madin-Darby canine kidney mammalian epithelial cell-cell adhesion. These experiments reveal roles for a diversity of cellular pathways that are required for cadherin function in Metazoa, including cytoskeleton organization, cell-substrate interactions, and nuclear and cytoplasmic signaling.

The Drosophila Cadherin Fat regulates tissue size and planar cell polarity through different domains.

The Drosophila Cadherin Fat (Ft) has been identified as a crucial regulator of tissue size and Planar Cell Polarity (PCP). However, the precise mechanism by which Ft regulates these processes remains unclear. In order to advance our understanding of the action of Ft, we have sought to identify the crucial Ft effector domains. Here we report that a small region of the Ft cytoplasmic domain (H2 region) is both necessary and sufficient, when membrane localized, to support viability and prevent tissue overgrowth. Interestingly, the H2 region is dispensable for regulating PCP signaling, whereas the mutant Ft lacking the H2 region is fully capable of directing PCP. This result suggests that Ft's roles in PCP signaling and tissue size control are separable, and each can be carried out independently. Surprisingly, the crucial regions of Ft identified in our structure-function study do not overlap with the previously reported interaction regions with Atrophin, Dco, or Lowfat.

Modulation of fat:dachsous binding by the cadherin domain kinase four-jointed.

In addition to quantitative differences in morphogen signaling specifying cell fates, the vector and slope of morphogen gradients influence planar cell polarity (PCP) and growth. The cadherin Fat plays a central role in this process. Fat regulates PCP and growth through distinct downstream pathways, each involving the establishment of molecular polarity within cells. Fat is regulated by the cadherin Dachsous (Ds) and the protein kinase Four-jointed (Fj), which are expressed in gradients in many tissues. Previous studies have implied that Fat is regulated by the vector and slope of these expression gradients. Here, we characterize how cells interpret the Fj gradient. We demonstrate that Fj both promotes the ability of Fat to bind to its ligand Ds and inhibits the ability of Ds to bind Fat. Consequently, the juxtaposition of cells with differing Fj expression results in asymmetric Fat:Ds binding. We also show that the influence of Fj on Fat is a direct consequence of Fat phosphorylation and identify a phosphorylation site important for the stimulation of Fat:Ds binding by Fj. Our results define a molecular mechanism by which a morphogen gradient can drive the polarization of Fat activity to influence PCP and growth.

Visceral-locomotory pistoning in crawling caterpillars.

Animals with an open coelom do not fully constrain internal tissues, and changes in tissue or organ position during body movements cannot be readily discerned from outside of the body. This complicates modeling of soft-bodied locomotion, because it obscures potentially important changes in the center of mass as a result of internal tissue movements. We used phase-contrast synchrotron X-ray imaging and transmission light microscopy to directly visualize internal soft-tissue movements in freely crawling caterpillars. Here we report a novel visceral-locomotory piston in crawling Manduca sexta larvae, in which the gut slides forward in advance of surrounding tissues. The initiation of gut sliding is synchronous with the start of the terminal prolegs' swing phase, suggesting that the animal's center of mass advances forward during the midabdominal prolegs' stance phase and is therefore decoupled from visible translations of the body. Based on synchrotron X-ray data and transmission light microscopy results, we present evidence for a two-body mechanical system with a nonlinear elastic gut that changes size and translates between the anterior and posterior of the animal. The proposed two-body system--the container and the contained--is unlike any form of legged locomotion previously reported and represents a new feature in our emerging understanding of crawling.

Primary tumor necrosis predicts distant control in locally advanced soft-tissue sarcomas after preoperative concurrent chemoradiotherapy.

PURPOSE: Various neoadjuvant approaches have been evaluated for the treatment of locally advanced soft-tissue sarcomas. This retrospective study describes a uniquely modified version of the Eilber regimen developed at the University of Chicago. METHODS AND MATERIALS: We treated 34 patients (28 Stage III and 6 Stage IV) with locally advanced soft-tissue sarcomas of an extremity between 1995 and 2008. All patients received preoperative therapy including ifosfamide (2.5 g/m2 per day for 5 days) with concurrent radiation (28 Gy in 3.5-Gy daily fractions), sandwiched between various chemotherapy regimens. Postoperatively, 47% received further adjuvant chemotherapy. RESULTS: Most tumors (94%) were Grade 3, and all were T2b, with a median size of 10.3 cm. Wide excision was performed in 29 patients (85%), and 5 required amputation. Of the resected tumor specimens, 50% exhibited high (> or =90%) treatment-induced necrosis and 11.8% had a complete pathologic response. Surgical margins were negative in all patients. The 5-year survival rate was 42.3% for all patients and 45.2% for Stage III patients. For limb-preservation patients, the 5-year local control rate was 89.0% and reoperation was required for wound complications in 17.2%. The 5-year freedom-from-distant metastasis rate was 53.4% (Stage IV patients excluded), and freedom from distant metastasis was superior if treatment-induced tumor necrosis was 90% or greater (84.6% vs. 19.9%, p = 0.02). CONCLUSIONS: This well-tolerated concurrent chemoradiotherapy approach yields excellent rates of limb preservation and local control. The resulting treatment-induced necrosis rates are predictive of subsequent metastatic risk, and this information may provide an opportunity to guide postoperative systemic therapies.