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Pseudofungi are septate hyphae–like structures very similar morphologically to true fungal elements. Histologically their presence poses a diagnostic challenge as they mimic fungal infection. Accurate identification of pseudofungi is required to avoid unnecessary treatment, and this can be accomplished by careful morphologic analysis with the use of appropriate histochemical stains. We report a patient with pseudofungi within a paratracheal lymph node, describe the morphologic findings, and discuss the differential diagnosis.

Calcifying fibrous tumors (CFTs) are benign soft tissue masses that can occur at many sites. This case report outlines the diagnostic workup for this rare, fast-growing, solitary mass in an otherwise healthy 8 year old patient. We also describe the radiographic and pathological characteristics unique to this lesion.

To determine whether the clinical behavior of giant cell lesions (GCLs) or their anatomic location can be differentiated by histologic criteria alone.We performed a retrospective study of patients with GCLs treated at Massachusetts General Hospital between 1993 and 2008. Predictor variables were histologic parameters: number of giant cells (GCs) per high-power field, number of nuclei per GC, GC size, stromal cellularity, stromal type, presence of hemorrhage and reactive osteoid, and blinded pathologists' prediction of location and behavior. Outcome variables were clinical behavior (aggressive or nonaggressive) and GCL location, that is, maxillofacial (MF) or axial/appendicular (AA). Descriptive and bivariate statistics were computed with statistical significance set at P ≤ .05.The sample included 88 subjects: 41 MF GCLs (35 aggressive) and 47 AA GCLs (28 aggressive). Aggressive AA lesions had more GCs per high-power field, larger mean GC size, and increased stromal cellularity, and they more frequently had a mononuclear stroma when compared with aggressive MF lesions (P.05). There were no significant histologic differences between aggressive and nonaggressive MF lesions or between nonaggressive MF and nonaggressive AA lesions. Aggressive AA lesions had more nuclei/GC than nonaggressive AA lesions (P = .03). Using histologic criteria only, blinded pathologists predicted clinical behavior in only 45% of cases (κ = 0.19, P = .09). They predicted a lesion's location in 82% of cases with fair agreement (κ = 0.44, P.01).Results of this study indicate that histologic differences between aggressive and nonaggressive GCLs are insufficient for pathologists to differentiate them consistently regardless of location.

Desmoid tumors are rare and exhibit a highly unpredictable natural history. We sought to analyze prognostic factors associated with recurrence in a large single-institution study of patients with desmoid tumors.We performed a retrospective review of 177 patients with desmoid tumor who underwent macroscopically complete surgical resection, with or without the addition of radiotherapy (RT) or systemic therapy, from 1970 to 2009. We examined patterns of presentation, all known risk factors for recurrence, and their association with recurrence-free survival (RFS).Twenty-two patients (12 %) had intra-abdominal desmoid tumors, and 155 (88 %) had extra-abdominal tumors. Patterns of presentation included primary (n = 133, 75 %) and locally recurrent (n = 44, 25 %) disease. Treatment was surgery alone in 125 patients (71 %), surgery and RT in 36 (20 %), and surgery and systemic therapy with or without RT in 20 (11 %). Median follow-up was 40 months. Overall, the local relapse rate was 29 %, and 10-year RFS was 60 %. R0 resection status was the only predictor of freedom from local recurrence on multivariate analysis (odds ratio 0.32; 95 % confidence interval 0.15-0.66; P = 0.002). The selective use of adjuvant RT appeared to improve local control in patients with positive margins.For patients with desmoid tumors undergoing surgery, wide excision with negative margins should be the goal, but not at the expense of function, as fewer than half of patients with positive margins will experience recurrence.

Chordoma is a rare primary malignant bone tumor and there exist only a few established human chordoma cell lines. The scarcity of robust chordoma cell lines has limited the ability to study this tumor. In this report, we describe the establishment of a novel chordoma cell line and characterize its in vitro and in vivo behaviors. The tumor tissue was isolated from a patient with recurrent chordoma of the sacrum. After 6 months in culture, the chordoma cell line, referred here as CH22, was established. Microscopic analysis of two-dimensional culture confirmed that the CH22 cells exhibited a typical vacuolated cytoplasm similar to the well-established chordoma cell line U-CH1. Electron microscopy showed cohesive cells with numerous surface filopodia, pockets of glycogen and aggregates of intermediate tonofilaments in cytoplasm. Three-dimensional culture revealed that the CH22 cells could grow and form clusters by day 8. The MTT assays demonstrated that, compared with sensitive osteosarcoma cell lines, CH22 cells were relatively resistant to conventional chemotherapeutic drugs. Western blotting and immunofluorescence analysis confirmed that the CH22 cells expressed brachyury, vimentin, and cytokeratin. Finally, histological analysis of CH22 xenograft tumor tissues demonstrated the appearance of physaliphorous cells and positive staining of brachyury, cytokeratin, and S100. By CT and MRI, imaging xenografts showed the typical appearances seen in human chordomas. These findings suggest that the established novel human chordoma cell line CH22 and its tumorigenecity in SCID nude mice may serve as an important model for studying chordoma cell biology and the development of new therapeutic modalities.

Enchondromas are benign lesions that may present with nonspecific features on imaging in children. Correlation of histology with imaging findings is often required to make the final diagnosis of a benign lesion. The aim of this study was to review imaging and pathological findings of enchondromas in children.Imaging examinations of 12 enchondromas in 11 patients (median age 14 years) were retrospectively reviewed. Imaging evaluation included an assessment of lesion size, relationship to the growth plate, mineralization, matrix and periosteal reaction, intrinsic MR signal characteristics, and intraosseous and soft-tissue edema. Pathological findings were reviewed.Lesions were located in the phalanx in 33% (4 out of 12), metacarpal in 25% (3 out of 12), femur in 33% (4 out of 12) and tibia in 8% cases (1 out of 12). The mean size was 28 mm (range, 11-70 mm). Matrix mineralization in a typical "rings-and-arcs" pattern was observed in 20% of the lesions with available radiographs/CT (2 out of 10). Lesions were expansive with endosteal scalloping in 75% of cases (9 out 12) and contacted the growth plate in 50% of cases (6 out of 12). All enchondromas in which MR imaging was available (5 out of 5) demonstrated typical cartilaginous matrix of lobules of high T2 signal, low T1 signal, and peripheral enhancement.Enchondromas in children are relatively large lesions, with frequent endosteal scalloping and rare matrix mineralization.

A 3-year-old Filipino girl presented with progressive left-sided ptosis and proptosis after resection of a superomedial orbital tumor 2.5 years ago. She had been followed with serial MRI, which demonstrated interval growth of a recurrent lesion. Repeat resection was undertaken via an eyelid-splitting anterior orbitotomy. The patient's pediatric oncologist and sarcoma specialist did not recommend adjuvant chemotherapy, and the family declined proton radiotherapy. The patient will continue to be monitored with serial imaging. Histopathology, immunohistochemistry, and reverse transcriptase polymerase chain reaction were most consistent with a diagnosis of adult-type fibrosarcoma. This is the first reported case of adult-type fibrosarcoma presenting in the orbit of a child. Fibrosarcoma is a fibroblast-derived tumor that commonly presents in the extremities, usually in patients in their fourth to sixth decades. It is rarely seen in the orbit, with the largest case series to date only including 5 patients.

BACKGROUND: Patients with large, high-grade, extremity soft tissue sarcomas (STS) are at significant risk for distant recurrence and death. A regimen of preoperative chemotherapy consisting of mesna, Adriamycin (doxorubicin), ifosfamide, and dacarbazine (MAID), interdigitated with radiotherapy (RT) and followed by resection and postoperative chemotherapy with or without RT, has demonstrated high rates of local and distant control. We report the long-term follow-up data on 48 patients treated with this regimen compared to an historical matched-control patient population. METHODS: Adult patients with high-grade extremity STS ≥ 8 cm were treated with 3 cycles of preoperative chemotherapy combined with 44 Gy of RT followed by surgery. Three cycles of postoperative MAID were planned. For patients with positive surgical margins, 16 Gy of RT was delivered postoperatively. RESULTS: Patients received the MAID/RT regimen from 1989 through 1999. After a median follow-up of 9.3 years in surviving patients in the MAID group and 13.2 years in surviving patients in the control group, the 7-year disease-specific and overall survival rates were 81% and 50% (P = .004) and 79% and 45% (P = .003) for the MAID and control patients, respectively. Five of 11 patients in the MAID group and 7 of 25 control patients died of sarcoma ≥5 years after treatment. One patient in the MAID group developed a fatal myelodysplasia at 53 months. CONCLUSIONS: For patients with high-risk, extremity STS, the significant survival benefits conferred by an intense regimen of neoadjuvant chemoradiotherapy and surgery are sustained even with long-term follow-up. Cancer 2012. © 2011 American Cancer Society.

Numerous preclinical studies have demonstrated that angiogenesis inhibitors can increase the efficacy of radiotherapy (RT). We sought to examine the safety and efficacy of bevacizumab (BV) and RT in soft tissue sarcomas and explore biomarkers to help determine the treatment response.Patients with ≥5 cm, intermediate- or high-grade soft tissue sarcomas at significant risk of local recurrence received neoadjuvant BV alone followed by BV plus RT before surgical resection. Correlative science studies included analysis of the serial blood and tumor samples and serial perfusion computed tomography scans.The 20 patients had a median tumor size of 8.25 cm, with 13 extremity, 1 trunk, and 6 retroperitoneal/pelvis tumors. The neoadjuvant treatment was well tolerated, with only 4 patients having Grade 3 toxicities (hypertension, liver function test elevation). BV plus RT resulted in ≥80% pathologic necrosis in 9 (45%) of 20 tumors, more than double the historical rate seen with RT alone. Three patients had a complete pathologic response. The median microvessel density decreased 53% after BV alone (p.05). After combination therapy, the median tumor cell proliferation decreased by 73%, apoptosis increased 10.4-fold, and the blood flow, blood volume, and permeability surface area decreased by 62-72% (p.05). Analysis of gene expression microarrays of untreated tumors identified a 24-gene signature for treatment response. The microvessel density and circulating progenitor cells at baseline and the reduction in microvessel density and plasma soluble c-KIT with BV therapy also correlated with a good pathologic response (p.05). After a median follow-up of 20 months, only 1 patient had developed local recurrence.The results from the present exploratory study indicated that BV increases the efficacy of RT against soft tissue sarcomas and might reduce the incidence of local recurrence. Thus, this regimen warrants additional investigation. Gene expression profiles and other tissue and circulating biomarkers showed promising correlations with treatment response.

UNLABELLED Voiding cystourethrography (VCUG) is commonly performed to screen for vesicoureteric reflux or other urological anomalies but has a potential to provoke distress in infants and children. We performed a systematic review of randomized controlled trials of interventions to reduce distress, pain or anxiety during VCUG. Eight trials (591 participants) met the inclusion criteria. CONCLUSION Conscious sedation with midazolam effectively alleviates the distress of VCUG in children older than 1 year of age. Psychological preparation and warmed contrast medium may also be effective. Nitrous oxide 50% may be an alternative to midazolam, but further evidence is needed.

A 56-year-old man presented with recurrent bone pain, stress fractures, and hypophosphatemia. A tumor of the jaw had been resected in the past, with resolution of symptoms. Studies of the jaw revealed no recurrent tumor. Diagnostic tests were performed.

A variety of different diseases affect the synovium, including infection, noninfectious immunologic inflammatory conditions, degenerative arthroses, crystal deposits, trauma, and tumors. Tumors of the synovium are relatively uncommon. Any mesenchymal tumor may arise in the synovium, but most recapitulate its normal counterpart including synoviocytes, blood vessels, fat, and fibrous tissue. These tumors can arise in any synovial lined structures both within joints and in extraarticular locations. Most synovial tumors are benign. Malignant tumors are rare but important to recognize because many are aggressive and must be treated appropriately. Among common nonneoplastic conditions that affect the synovium and surrounding structures are crystal deposits such as monosodium urate crystals, calcium pyrophosphate dihydrate crystals, and hydroxyapatite crystals. These crystal deposits may be asymptomatic or cause severe pain or chronic joint destruction. Their accurate identification is important to guide appropriate therapy.

Joint arthroplasty is a commonly performed surgical procedure that provides significant benefit to the patient. The prosthetic devices are composed of combinations of polyethylene, ceramics, metal alloys, bone cement, and silicone and are associated with complications as well as eventual failure from wear and corrosion. The pathologic findings of these processes are complex and require accurate interpretation to help guide therapy and identify the underlying biological mechanisms.

Primary sarcomas of the uterus are uncommon, leiomyosarcoma being the most frequent. Most uterine sarcomas arise de novo, with malignant transformation of a benign mesenchymal tumor being a very rare event, and is reported only in leiomyomata.The clinicopathologic features of 3 uterine liposarcomas arising in association with a lipoleiomyoma were studied. Immunohistochemistry for desmin, h-caldesmon, S100, and MDM2, and fluorescence in situ hybridization for the t(12;16) (q13;p11) were performed in all cases.Patients ranged in age from 49 to 70 (mean, 59) years. The tumors were centered in the myometrium, ranged in size from 10 to 18.5 cm, and showed a gelatinous cut surface with foci of necrosis. On microscopic examination, the tumors had well-circumscribed pushing margins. One neoplasm was uniformly hypocellular with a prominent myxoid background, and a striking delicate vascular network. Another neoplasm showed alternating hypocellular (myxoid) and hypercellular areas, whereas the third tumor was uniformly hypercellular with a hyalinized background. In the myxoid areas, the cells were small and spindle with oval nuclei and inconspicuous nucleoli. In the hypercellular areas, the cells were pleomorphic with large, hyperchromatic nuclei. Mitotic activity ranged from3 to 7/10 high-power fields. Lipoblasts were present in all tumors but were more common in the hypercellular areas. Two tumors merged imperceptibly with a lipoleiomyoma (1 typical and 1 with bizarre nuclei), whereas the third tumor showed an infarcted area composed of ghost mature adipocytes admixed with hyalinized smooth muscle most consistent with an infarcted lipoleiomyoma. Tumors were classified as myxoid, mixed myxoid and pleomorphic, and pleomorphic liposarcoma, respectively. The benign and malignant adipose components were positive for S100, whereas the benign smooth muscle component stained for desmin and h-caldesmon. MDM2 immunostain was positive in the 2 cases with a pleomorphic liposarcoma component. Fluorescence in situ hybridization analysis was successfully completed in only 1 of 3 tumors (pure pleomorphic liposarcoma), which failed to show the t(12;16) and HMAG2 amplification. The patients are alive and well 1, 2, and 20 years after initial surgery with no adjuvant therapy.Primary liposarcomas of the uterus are extremely rare and are most likely to arise from malignant transformation of a lipoleiomyoma. These tumors should be added to the differential diagnosis of benign lipomatous tumors, myxoid mesenchymal tumors, and malignant mixed Müllerian tumors (if pleomorphic) of the uterus.

PURPOSE It is thought that the function of a damaged kidney will deteriorate further with time because of impaired maturation and compensatory hyperfiltration. The aim of this study was to determine changes in relative renal function (RRF) over time in children with vesicoureteric reflux (VUR) and/or urinary tract infection (UTI) where the unilaterally scarred kidney was found to contribute 30% or less to overall function. PATIENTS AND METHODS Children who met the inclusion criteria and had multiple radionuclide studies during a 12-year period were identified, and RRF was compared. RESULTS Twenty-seven boys and 3 girls with a median age of 0.8 years (0.08-13.05 years) were included. Eight patients had unilateral VUR, 21 patients had bilateral VUR, and 1 patient had UTIs without VUR. Twenty-one patients underwent reimplantation surgery, and 9 were managed conservatively.At a mean follow-up of 2.64 years (0.26-6.77 years), there was a nonsignificant mean decrease in RRF from 19% (11%-28%) to 18% (9%-29%). The mean change in renal function was not affected by the severity of the initial RRF. CONCLUSIONS In the medium term, there is no deterioration of RRF of unilaterally severely damaged kidneys associated with either VUR or UTI managed either surgically or conservatively. Boys are at a much greater risk of severe reflux nephropathy.

Well-differentiated osteosarcoma of the jaw bones is rare, and is often confused with a variety of benign fibroosseous lesions. To better understand its clinicopathologic features, we reviewed our experience with 15 cases. The patients included 7 males and 8 females (age range 14 to 66 y; mean 42.8 y). Six of the tumors arose in the mandible, and 9 in the maxilla. Microscopically, the tumors were infiltrative, relatively hypocellular, and consisted of monomorphic, minimally atypical spindle cells that were usually arranged in fascicles. The tumor cells were intimately related to the surfaces of elongated trabeculae of neoplastic woven bone that lacked osteoblastic rimming. Nine patients were treated with wide excision, 2 patients with marginal excision, and 2 patients with excision and radiation therapy. After definitive therapy, there were no reports of recurrence or metastasis over an average follow-up of 34 months (range 1 to 80 mo). Well-differentiated gnathic osteosarcoma is a low-grade malignancy that may be successfully treated with wide local excision. The prognosis in our series was excellent.

Chondromyxoid fibroma (CMF) is an uncommon benign cartilaginous tumor of bone usually occurring during the second decade of life. CMF is associated with recurrent rearrangements of chromosome bands 6p23-25, 6q12-15, and 6q23-27. To delineate further the role and frequency of the involvement of three candidate regions (6q13, 6q23.3 and 6q24) in the pathogenesis of CMF, we studied a group of 43 cases using a molecular cytogenetic approach. Fluorescence in situ hybridization with probe sets bracketing the putative breakpoint regions was performed in 30 cases. The expression level of nearby candidate genes was studied by immunohistochemistry and quantitative RT-PCR in 24 and 23 cases, respectively. Whole-genome copy number screening was performed by array comparative genomic hybridization in 16 cases. Balanced and unbalanced rearrangements of 6q13 and 6q23.3 occurred in six and five cases, respectively, and a hemizygous deletion in 6q24 was found in five cases. Two known tumor suppressor genes map to the latter region: PLAGL1 and UTRN. However, neither of these two genes nor BCLAF1 and COL12A1, respectively located in 6q23.3 and 6q13, showed altered expression. Therefore, although rearrangements of chromosomal regions 6q13, 6q23.3, and 6q24 are common in CMF, the complexity of the changes precludes the use of a single fluorescence in situ hybridization probe set as an adjunct diagnostic tool. These data indicate that the genetic alterations in CMF are heterogeneous and are likely a result of a cryptic rearrangement beyond the resolution level of combined binary ratio fluorescence in situ hybridization or a point mutation.

There is little information on the appropriate three-dimensional (3D) preoperative radiotherapy (XRT) volume for extremity soft-tissue sarcomas (STS). We retrospectively analyzed the pattern of local failure (LF) to help elucidate optimal field design.We analyzed the 56 patients who underwent computed tomography-planned XRT for Stage I to III extremity STS between June 2000 and December 2006. Clinical target volume (CTV) included the T1 post-gadolinium-defined gross tumor volume with 1- to 1.5-cm radial and 3.5-cm longitudinal margins. Planning target volume expansion was 5 to 7 mm, andor=95% of dose was delivered to the planning target volume. Preoperative XRT was 44 to 50.4 Gy (median, 50). Postoperative boost of 10 to 20 Gy was given to 12 patients (6 with positive and 6 with close margins).Follow-up ranged from 15 to 76 months (median, 41 months). The 5-year local control, freedom from distant metastasis, disease-free survival, and overall survival were 88.5%, 80.0%, 77.5% and 82.8%, respectively. Three patients (all with positive margin) experienced local failure (LF) as first relapse (2 isolated, 1 with distant failure), and 2 additional patients (all with margin1 mm) had late LF after distant metastasis. The LFs were within the CTV in 3 patients and within and also extending beyond the CTV in 2 patients.These target volume definitions appear to be appropriate for most patients. No local recurrences were observed with surgical marginsor=1 mm, and it appears that these may be adequate for patients with extremity STS treated with preoperative radiotherapy.

An experimental study to investigate the characterization of 3 chordoma cell lines.To characterize chordoma cell lines and generate hypothesis for further chordoma studies.Three cultured human chordoma cell lines have been successfully generated; however, their characterization is incomplete. Complete characterization of chordoma cell lines is necessary for these reagents to be a useful preclinical model.Three chordoma cell lines, CH 8, U-CH1, and GP 60, were cultured in different commercially available tissue culture media. They were also cultured in different environments, which included collagen substrate, various concentrations of glucose, and various levels of hypoxic conditions. The rate of cell proliferation was assessed by either MTT or numeration assay. A 3-dimensional (3D) cell culture model of these chordoma cell lines was also studied, and the expression of vimentin and cytokeratin was measured by immunofluorescence and Western blot. Additionally, the sensitivity of the 3 chordoma cell lines to 6 chemotherapeutic drugs was analyzed.CH 8, GP 60, and U-CH1 cells proliferate more actively in Iscove Modified Dulbecco Medium or Dulbecco modified Eagle Medium and less actively in RPMI medium. All 3 chordoma cell lines universally grow better in collagen substrate and survive in hypoxic conditions, whereas glucose concentration has no significant influence on their growth properties. Chordoma cell lines grew well in 3D culture systems and formed acini-like spheroids and retained the expression of vimentin and cytokeratin. MTT analysis indicates that all 3 chordoma cell lines are sensitive to doxorubicin, yondelis, zalypsis, and cisplatin.We characterized 3 chordoma cell lines for differential growth properties in a variety of media and response to chemotherapeutic agents.

Hypoxia is a common finding in the anesthetized patient. Although there are a variety of methods to address hypoxia, it is not well documented what strategies are used by anesthesiologists when faced with a hypoxic patient. Studies have identified that lung protective ventilation strategies have beneficial effects in both oxygenation and mortality in acute respiratory distress syndrome. We sought to describe the ventilation strategies in anesthetized patients with varying degrees of hypoxemia as defined by the Pao(2) to fraction of inspired oxygen (Fio(2)) (P/F) ratio.We conducted a review of all operations performed between January 1, 2005, and July 31, 2009, using a general anesthetic, excluding cardiac and thoracic procedures, to assess the ventilation settings that were used in patients with different P/F ratios. Patients older than 18 years who received a general anesthetic were included. Four cohorts of arterial blood gases (ABGs) were identified with P/F300, 300or = P/F200, 200or = P/F100, 100or = P/F. Using the standard predicted body weight (PBW) equation, we calculated the milliliters per kilogram (mL/kg PBW) with which the patient's lungs were being ventilated. Positive end-expiratory pressure (PEEP), peak inspiratory pressures (PIPs), Fio(2), oxygen saturation (Sao(2)), and tidal volume in mL/kg PBW were compared.A total of 28,706 ABGs from 11,445 operative cases met criteria for inclusion. There were 19,679 ABGs from the P/F300 group, 5364 ABGs from the 300or = P/F200 group, 3101 ABGs from the 200or = P/F100 group, and 562 ABGs from the 100or = P/F group identified. A comparison of ventilation strategies found statistical significance but clinically irrelevant differences. Tidal volumes ranged between 8.64 and 9.16 and the average PEEP varied from 2.5 to 5.5 cm H(2)O. There were substantial differences in the average Fio(2) and PIP among the groups, 59% to 91% and 22 to 29 cm H(2)O, respectively.Similar ventilation strategies in mL/kg PBW and PEEP were used among patients regardless of P/F ratio. The results of this study suggest that anesthesiologists, in general, are treating hypoxemia with higher Fio(2) and PIP. The average Fio(2) and PIP were significantly escalated depending on the P/F ratio.

11547Background: Inhibition of programmed-death 1 (PD1) by pembrolizumab (P) produced overall response rates (ORR) of 19% in advanced STS [SARC028]. Vascular endothelial growth factor (VEGF) suppre...

Monostotic fibrous dysplasia of the spine is rare, with the cases of fewer than thirty-five patients discussed in the literature. Dahlin and Unni reviewed the cases of 418 patients with monostotic fibrous dysplasia and noted six (1.4%) involving the spine1. In a series reported by Harris et al., one patient with spine involvement was noted in a total of thirteen patients with monostotic fibrous dysplasia2. Most reports have described the case of a single patient with minimal to no follow-up1-23. As a result, the natural history and ideal treatment for this condition remain poorly understood. For example, the prevalence of scoliosis in patients with polyostotic fibrous dysplasia has been found to be up to 40%24, whereas scoliosis in monostotic fibrous dysplasia appears to be quite rare25. The reported treatment of monostotic fibrous dysplasia in the spine also has varied widely, from surgical resection4,5,7,9-19 to biopsy and observation2,21. We present the cases of a series of seven patients who were diagnosed with monostotic fibrous dysplasia of the spine at our institution. The history, physical examination, and histologic characteristics are described along with the results of clinical follow-up evaluations. The Massachusetts General Hospital and Partners Healthcare institutional review board approved this study. We utilized our Bone Sarcoma Registry to identify all eleven patients diagnosed with fibrous dysplasia of the spine between 1980 and 2007. The histologic diagnosis of fibrous dysplasia was made on the basis of the appearance of curvilinear trabeculae of woven bone surrounded by a fibrous-appearing stroma composed of spindle cells (Fig. 1). Two patients were excluded because of the presence of polyostotic disease, one was excluded because of the lack of a tissue diagnosis, …

A majority of patients with acute and chronic pain experience breakthrough pain above their baseline, despite a fixed regimen. The characteristics of current short-acting oral medications are not optimal because they often peak too late and last beyond the duration of pain. Oral absorption limits the onset time, whereas the development of newer routes can shorten onset times. A number of medications, both opioid and nonopioid, are being developed for intranasal delivery with promising results. In addition to the intranasal administration route being efficacious, it also provides better patient satisfaction by allowing the patient to titrate their own pain medication. There are legitimate concerns for abuse and addiction with these medications, which will need to be minimized with proper dispensing modifications. A number of nonopioid agents are also entering the market that will allow for multimechanistic analgesic plans. Although ketamine is not a common component of current pain treatment plans, the development of an intranasal formulation may potentially produce wider acceptance. Many traditional medications, including ibuprofen and acetaminophen, have been developed for parenteral administration. Intravenous ibuprofen or diclofenac can be administered for a longer duration and have a lower bleeding risk then ketorolac. Intravenous acetaminophen can provide balanced analgesia when nonsteroidal anti-inflammatory drugs are contraindicated, as is common in the postoperative period. The role of individual agents in each specialty is not currently clear, but the future treatment of pain, both acute and chronic, is brighter with the addition of these formulations.

This study was conducted to determine the prevalence of infiltrative lymphocytic mural folliculitis (ILMF) in skin-biopsy specimens from 354 cats with various inflammatory dermatoses and from 33 cats with normal skin. Although ILMF was present in 33/47 dermatoses evaluated, the prevalence of ILMF in allergic dermatoses (116/172 cats; 67%) was significantly greater than that in non-allergic dermatoses (61/182 cats; 33%). Cats with allergic dermatoses had a 4.1 times greater odds of having ILMF than cats with non-allergic dermatoses. ILMF was not observed in any of the normal skin specimens.

Emerging evidence suggests that microRNA (miRNA) expression signatures in cancer may have important diagnostic, prognostic, and therapeutic value, but there is no data on miRNA expression in chordoma. The purpose of this study was to identify the role of miRNAs in human chordoma. We analyzed miRNA expression in chordoma-derived cell lines and chordoma tissue by using miRNA microarray technology with unsupervised hierarchical clustering analysis. The relative expression levels of these miRNAs were confirmed by real-time quantitative RT-PCR and Northern blot analysis. To characterize the potential role of miRNA-1, miRNA-1 was stably transfected into a chordoma cell line, UCH1. The expression of miRNA-1 targeted gene Met in chordoma tissues was also studied. We observe that human chordoma tissues and cell lines can be distinguished from normal muscle tissue by comparing miRNA expression profiles. Several miRNAs were differentially expressed in chordoma cell lines compared to controls, and similar expression patterns were found in primary chordoma tissues. Importantly, we were able to show for the first time, to our knowledge, that expression of miRNA-1 and miRNA-206, two miRNAs implicated in a number of other cancer types, were markedly decreased in both chordoma tissues and cell lines. When chordoma cell lines were transfected with miRNA-1, downregulation of known miRNA-1 targets was observed. These targets included Met and HDAC4-two genes that were observed to be overexpressed in chordoma. Our results demonstrate that some miRNAs are differentially expressed in chordoma and, in particular, miRNA-1 may have a functional effect on chordoma tumor pathogenesis.

Despite radiographic and histologic evidence of trabecular bone density changes within and adjacent to osseous metastases, there currently exist no data to demonstrate whether these changes are important in predicting the risk of fracture. To determine if these density changes result in significant reductions in mechanical properties, trabecular bone specimens were prepared from lower thoracic and lumbar vertebrae from two cadavers with radiographic, gross, and histologic evidence of lytic and/or blastic osseous metastases. Each specimen was classified as normal, lytic, or blastic based on appearance in fine-grain radiographs of 8-9 mm thick coronal plane sections. Specimens were tested to failure in uniaxial compression, and tissue and apparent densities were measured. Mean tissue densities were within normal ranges. The mean apparent density for all specimens combined was within the normal range for human vertebrae, and the mean apparent density for radiographically normal (0.131 g/ml) and lytic (0.111 g/ml) specimens was less than the mean apparent density of blastic (0.182 g/ml) specimens (p0.02). The moduli of lytic and blastic specimens were less than for normal specimens (p0.025). The strength of lytic specimens was less than normal (p = 0.057), but the strength of blastic specimens was not (p0.1). Apparent density explained significant fractions of the variations in both modulus (p0.001) and strength (p0.001). The data suggest that blastic changes associated with osseous metastases to trabecular bone disrupt the normal dependence of trabecular mechanical properties on apparent density, but lytic changes do not.(ABSTRACT TRUNCATED AT 250 WORDS)

The digestion of type I collagen is an essential step in bone resorption. It is well established that osteoclasts solubilize the mineral phase of bone during the resorptive process, but the mechanism by which they degrade type I collagen, the major proteinaceous component of bone, is controversial. Differential screening of a human osteoclastoma cDNA library was performed to characterize genes specifically expressed in osteoclasts. A large number of cDNA clones obtained by this procedure were found to represent 92 kD type IV collagenase (gelatinase B; MMP-9, EC 3.4.24.35), as well as tartrate-resistant acid phosphatase. In situ hybridization localized mRNA for gelatinase B to multinucleated giant cells in human osteoclastomas. Gelatinase B immunoreactivity was demonstrated in giant cells from eight of eight osteoclastomas, osteoclasts in normal bone, and osteoclasts of Paget's disease by use of a polyclonal antiserum raised against a synthetic gelatinase B peptide. In contrast, no immunoreactivity for 72 kD type IV collagenase (gelatinase A; MMP-2, EC 3.4.24.24), which is the product of a separate gene, was detected in osteoclastomas or normal osteoclasts. We propose that the 92 kD type IV collagenase/gelatinase B plays an important role in the resorption of collagen during bone remodeling.

Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disorder characterized by selective loss of motor neurons (MNs). Twenty percent of familial ALS cases are associated with mutations in Cu(2+)/Zn(2+) superoxide dismutase (SOD1). To specifically understand the cellular mechanisms underlying mutant SOD1 toxicity, we have established an in vitro model of ALS using rat primary MN cultures transfected with an adenoviral vector encoding a mutant SOD1, G93A-SOD1. Transfected cells undergo axonal degeneration and alterations in biochemical responses characteristic of cell death such as activation of caspase-3. Vascular endothelial growth factor (VEGF) is an angiogenic and neuroprotective growth factor that can increase axonal outgrowth, block neuronal apoptosis, and promote neurogenesis. Decreased VEGF gene expression in mice results in a phenotype similar to that seen in patients with ALS, thus linking loss of VEGF to the pathogenesis of MN degeneration. Decreased neurotrophic signals prior to and during disease progression may increase MN susceptibility to mutant SOD1-induced toxicity. In this study, we demonstrate a decrease in VEGF and VEGFR2 levels in the spinal cord of G93A-SOD1 ALS mice. Furthermore, in isolated MN cultures, VEGF alleviates the effects of G93A-SOD1 toxicity and neuroprotection involves phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling. Overall, these studies validate the usefulness of VEGF as a potential therapeutic factor for the treatment of ALS and give valuable insight into the responsible signaling pathways and mechanisms involved.

Radiotherapy (XRT) for spine sarcomas is constrained by spinal cord, nerve, and viscera tolerance. Negative surgical margins are uncommon; hence, doses ofor=66 Gy are recommended. A Phase II clinical trial evaluated high-dose photon/proton XRT for spine sarcomas.Eligible patients had nonmetastatic, thoracic, lumbar, and/or sacral spine/paraspinal sarcomas. Treatment included pre- and/or postoperative photon/proton XRT with or without radical resection; patients with osteosarcoma and Ewing's sarcoma received chemotherapy. Shrinking fields delivered 50.4 cobalt Gray equivalent (Gy RBE) to subclinical disease, 70.2 Gy RBE to microscopic disease in the tumor bed, and 77.4 Gy RBE to gross disease at 1.8 Gy RBE qd. Doses were reduced for radiosensitive histologies, concurrent chemoradiation, or when diabetes or autoimmune disease present. Spinal cord dose was limited to 63/54 Gy RBE to surface/center. Intraoperative boost doses of 7.5 to 10 Gy could be given by dural plaque.A total of 50 patients (29 chordoma, 14 chondrosarcoma, 7 other) underwent gross total (n = 25) or subtotal (n = 12) resection or biopsy (n = 13). With 48 month median follow-up, 5-year actuarial local control, recurrence-free survival, and overall survival are: 78%, 63%, and 87% respectively. Two of 36 (5.6%) patients treated for primary versus 7/14 (50%) for recurrent tumor developed local recurrence (p0.001). Five patients developed late radiation-associated complications; no myelopathy developed but three sacral neuropathies appeared after 77.12 to 77.4 Gy RBE.Local control with this treatment is high in patients radiated at the time of primary presentation. Spinal cord dose constraints appear to be safe. Sacral nerves receiving 77.12-77.4 Gy RBE are at risk for late toxicity.

Current concepts of the pathophysiology of necrotizing fasciitis (NF), a life-threatening infection of soft tissues associated with a toxic shock syndrome, emphasizes the role of bacterial superantigens as mediators of cytokine release by immune lymphocytes. In order to assess the cellular basis of immune activation, immunohistochemistry was applied to the analysis of inflammatory cell subsets in situ in 13 patients with NF. The percentage of inflammatory cells in skin and soft tissue was scored from 0 to 3+ (>50%). Substantial numbers of CD15+ polymorphonuclear leukocytes were present in 12 of 13 patients. CD3+ T-lymphocytes accounted for >10%, CD68+ macrophages for >50%, and Factor XIIIa+ mononuclear cells for >10% of the mononuclear cell infiltrates, respectively, in 10 of 13 patients, whereas CD1a+ cells were present in only 3 of 13 cases and accounted for

Purpose: Chordomas are rare, malignant bone neoplasms in which the pathogenic mechanisms remain unknown. Interestingly, tuberous sclerosis complex (TSC) is the only syndrome in which the incidence of chordomas has been described. We previously reported the pathogenic role of the TSC genes in TSC-associated chordomas. In this study, we investigated whether aberrant TSC/mammalian target of rapamycin complex 1 (mTORC1) signaling pathway is associated with sporadic chordomas. Experimental Design: We assessed the status of mTORC1 signaling in primary tumors/cell lines of sacral chordomas and further examined upstream of mTORC1 signaling, including the PTEN (phosphatase and tensin homologue deleted on chromosome ten) tumor suppressor. We also tested the efficacy of the mTOR inhibitor rapamycin on signaling and growth of chordoma cell lines. Results: Sporadic sacral chordoma tumors and cell lines examined commonly displayed hyperactivated Akt and mTORC1 signaling. Strikingly, expression of PTEN, a negative regulator of mTORC1 signaling, was not detected or significantly reduced in chordoma-derived cell lines and primary tumors. Furthermore, rapamycin inhibited mTORC1 activation and suppressed proliferation of chordoma-derived cell line. Conclusions: Our results suggest that loss of PTEN as well as other genetic alterations that result in constitutive activation of Akt/mTORC1 signaling may contribute to the development of sporadic chordomas. More importantly, a combination of Akt and mTORC1 inhibition may provide clinical benefits to chordoma patients.

Soft tissue sarcomas generally have a ≤5% risk of lymph node metastasis, but synovial, epithelioid, and clear cell subtypes reportedly have a much higher risk. The utility of sentinel lymph node biopsy (SLNB) for patients with these sarcoma subtypes is unknown. 29 patients with nonmetastatic synovial, epithelioid, and clear cell sarcomas who underwent SLNB were examined. Median age was 35 years (range 11–73 years), and 69% were male. Tumors were located in the lower extremity in 17 patients and the upper extremity in 12. The histological subtypes were synovial sarcoma in 16 patients, epithelioid sarcoma in 10, and clear cell sarcoma in 3. All patients had a staging chest computed tomography (CT) scan, none of which were suspicious, and 20 patients had staging positron emission tomography (PET) scans (16 negative, 3 indeterminate, and 1 suspicious). All patients had resection of their primary tumor. At least one sentinel node was found in 28 patients (97%), and the median number of sentinel nodes identified was 2 (range 1–4). One patient had a positive sentinel node on routine hematoxylin and eosin (H&E) staining and developed lung metastases. Two patients had positive sentinel nodes following immunohistochemical staining, and both remain disease free despite not undergoing completion lymphadenectomy. One patient developed a lymph node metastasis after a negative SLNB. For patients with these sarcoma subtypes without radiological evidence of nodal or distant metastases, the incidence of occult lymph node metastasis is relatively low. Determining utility of SLNB may require a multicenter trial.

In addition to inhibiting the excitation conduction process in peripheral nerves, local anesthetics (LAs) cause toxic effects on the central nervous system, cardiovascular system, neuromuscular junction, and cell metabolism. Different postoperative neurological complications are ascribed to the cytotoxicity of LAs, but the underlying mechanisms remain unclear. Because the clinical concentrations of LAs far exceed their EC(50) for inhibiting ion channel activity, ion channel block alone might not be sufficient to explain LA-induced cell death. However, it may contribute to cell death in combination with other actions. In this study, we compared the cytotoxicity of six frequently used LAs and will discuss the possible mechanism(s) underlying their toxicity.In human SH-SY5Y neuroblastoma cells, viability upon exposure to six LAs (bupivacaine, ropivacaine, mepivacaine, lidocaine, procaine, and chloroprocaine) was quantitatively determined by the MTT-(3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetra-odium bromide) colorimetry assay and qualitatively confirmed by fluorescence imaging, using the LIVE/DEAD assay reagents (calcein/AM and ethidium homodimer-1). In addition, apoptotic activity was assessed by measuring the activation of caspase-3/-7 by imaging using a fluorescent caspase inhibitor (FLICA). Furthermore, LA effects on depolarization- and carbachol-stimulated intracellular Ca(2+)-responses were also evaluated.1) After a 10-min treatment, all six LAs decreased cell viability in a concentration-dependent fashion. Their killing potency was procaineor = mepivacainelidocainechloroprocaineropivacainebupivacaine (based on LD(50), the concentration at which 50% of cells were dead). Among these six LAs, only bupivacaine and lidocaine killed all cells with increasing concentration. 2) Both bupivacaine and lidocaine activated caspase-3/-7. Caspase activation required higher levels of lidocaine than bupivacaine. Moreover, the caspase activation by bupivacaine was slower than by lidocaine. Lidocaine at high concentrations caused an immediate caspase activation, but did not cause significant caspase activation at concentrations lower than 10 mM. 3) Procaine and chloroprocaine concentration-dependently inhibited the cytosolic Ca(2+)-response evoked by depolarization or receptor-activation in a similar manner as a previous observation made with bupivacaine, ropivacaine, mepivacaine, and lidocaine. None of the LAs caused a significant increase in the basal and Ca(2+)-evoked cytosolic Ca(2+)-level.LAs can cause rapid cell death, which is primarily due to necrosis. Lidocaine and bupivacaine can trigger apoptosis with either increased time of exposure or increased concentration. These effects might be related to postoperative neurologic injury. Lidocaine, linked to the highest incidence of transient neurological symptoms, was not the most toxic LA, whereas bupivacaine, a drug causing a very low incidence of transient neurological symptoms, was the most toxic LA in our cell model. This suggests that cytotoxicity-induced nerve injury might have different mechanisms for different LAs and different target(s) other than neurons.

Background The authors sought to identify the incidence, risk factors, and mortality impact of acute kidney injury (AKI) after general surgery using a large and representative national clinical data set. Methods The 2005-2006 American College of Surgeons-National Surgical Quality Improvement Program participant use data file is a compilation of outcome data from general surgery procedures performed in 121 US medical centers. The primary outcome was AKI within 30 days, defined as an increase in serum creatinine of at least 2 mg/dl or acute renal failure necessitating dialysis. A variety of patient comorbidities and operative characteristics were evaluated as possible predictors of AKI. A logistic regression full model fit was used to create an AKI model and risk index. Thirty-day mortality among patients with and without AKI was compared. Results Of 152,244 operations reviewed, 75,952 met the inclusion criteria, and 762 (1.0%) were complicated by AKI. The authors identified 11 independent preoperative predictors: age 56 yr or older, male sex, emergency surgery, intraperitoneal surgery, diabetes mellitus necessitating oral therapy, diabetes mellitus necessitating insulin therapy, active congestive heart failure, ascites, hypertension, mild preoperative renal insufficiency, and moderate preoperative renal insufficiency. The c statistic for a simplified risk index was 0.80 in the derivation and validation cohorts. Class V patients (six or more risk factors) had a 9% incidence of AKI. Overall, patients experiencing AKI had an eightfold increase in 30-day mortality. Conclusions Approximately 1% of general surgery cases are complicated by AKI. The authors have developed a robust risk index based on easily identified preoperative comorbidities and patient characteristics.

Objective: To evaluate the independent influence of fluid balance on outcomes for patients with acute lung injury. Design: Secondary analysis of a prospective cohort study conducted between March 1996 and March 1999. Setting: The study involved 10 academic clinical centers (with 24 hospitals and 75 Intensive Care Units). Patients: All patients for whom fluid balance data existed (844) from the 902 patients enrolled in the National Heart Lung Blood Institute's ARDS Network ventilator-tidal volume trial. Interventions: The study had no interventions. Measurements/Results: On the first day of study enrollment, 683 patients were, on average, more than 3.5 L in positive fluid balance compared to 161 patients in negative fluid balance (P < .001). Cumulative negative fluid balance on day 4 of the study was associated with an independently lower hospital mortality (OR, 0.50; 95% CI, 0.28-0.89; P < .001) more ventilator and intensive care unit—free days. Conclusions: Negative cumulative fluid balance at day 4 of acute lung injury is associated with significantly lower mortality, independent of other measures of severity of illness.

Background and Objectives Osteoblastoma is a rare, bone-forming neoplasm accounting for 1% of primary bone tumors. It arises in young patients and develops in long bones and posterior elements of the spine. Osteoblastoma is characterized by interconnecting trabeculae of woven bone and rimmed by prominent osteoblasts. In the current study we characterize osteoblastoma by its demographic and anatomic prevalence. We looked at rates of recurrence as related to treatment. Methods We performed a review of our institution's Orthopaedic Oncology tumor registry and identified 99 verified cases of osteoblastoma treated between 1974 and 2006. Data related to demographic, anatomic, surgical treatment and follow-up information were analyzed. Results The cohort included 69 males and 30 females with an average age of 24 ± 14 years. The most common sites of occurrence were the vertebral column (28 patients) and the humerus (21 patients). The tumors were treated with en bloc surgical resection or curettage with allograft or autograft. Local recurrence rate was 24% and most followed curettage and packing. No patient died of disease. Conclusions Osteoblastoma frequently affects the long bones and the spine. The recurrence rate following curettage is relatively high and can be minimized by resective surgery, in select cases. J. Surg. Oncol. 2008;98:179–183. © 2008 Wiley-Liss, Inc.

The notochord plays a critical role in organizing and directing vertebral development. In humans, most notochordal cells are eventually sequestered into the nucleus pulposus and disappear within the first decade of life. Although notochordal remnants and related lesions have been described in the axial skeleton of adults, their presence in intervertebral disks is rare. We describe herein 3 cases of incidental notochordal remnants identified in surgically removed adult intervertebral disks. Their histologic features were reminiscent of notochordal vestiges in the fetus. However, they raised the differential diagnosis of benign notochordal cell tumor and chordoma. Notochordal rests can be a source of diagnostic confusion and should be distinguished from notochordal neoplasms because they do not necessitate resection or other forms of therapy.

One of the most common and important pitfalls in soft tissue pathology are the so-called pseudosarcomas. These lesions are nonneoplastic; however, their rapid growth, hypercellularity, cytologic atypia, and mitotic activity makes them prone to be misinterpreted as sarcoma. The most common of these lesions are fibroblastic/myofibroblastic and matrix-forming proliferations, including nodular fasciitis, proliferative fasciitis and myositis, ischemic fasciitis, massive localized edema, myositis ossificans, and bizarre parosteal osteochondromatous proliferation and related entities. Most of these lesions rarely recur following simple excision; therefore, their accurate recognition helps prevent excessive therapy.

A 65-year-old woman was seen in the oral surgery clinic because of a nonhealing ulcer of the mandible at the site of a tooth that had been extracted 3 years earlier. The patient had multiple myeloma and had been treated with intravenous bisphosphonates for 6 years. Examination disclosed red, raised soft tissue in the right mandible, with mucosal ulceration and exposed bone. A diagnostic procedure was performed.

A renal length discrepancy (RLD) of more than 10 mm by ultrasound (US) is accepted as a potential indicator of an underlying renal pathology; however, there are few supporting data for this in children. Our objective was to determine a cutoff at which RLD on US is a reliable predictor of dimercaptosuccinate acid (DMSA) scan abnormality. We present data from 90 patients who had both renal US and a DMSA scan, as well as DMSA scan results compared with bipolar RLD by US. Positive (PPV) and negative (NPV) predictive values were calculated for renal RLD from 6 to10 mm. The left kidney was longer in 56%, whereas the right kidney was longer in 37%; their lengths were equal in 8%. For children at all ages, a left kidney longer than the right byor=10 mm or a right kidney longer than the left byor=7 mm gave a PPV for DMSA abnormality of 79% and 100%, respectively. In children older than 4 years, if the right kidney was longer byor=7 mm or if the left kidney was longer byor=10 mm, the PPVs for DMSA abnormality were 100% and 63%, respectively. In children younger than 4 years, when the right kidney was longer byor=6 mm or the left was kidney longer byor=10 mm, the PPV were 86% and 100%, respectively. Thus, children with a right kidney longer than the left by even10 mm is a reliable predictor of an abnormal DMSA scan.