Creating an Intraoperative MRI Suite for the Musculoskeletal Tumor Center.

BACKGROUND: Altered anatomy in a previously irradiated surgical bed can make accurate localization of anatomic landmarks and local recurrence nearly impossible. The use of intraoperative MRI (iMRI) has been described in neurosurgical settings, but to our knowledge, no such description has been made regarding its utility for local recurrence localization in sarcoma surgery. CASE DESCRIPTION: A 58-year-old female presented after previously undergoing two previous resection and reresection procedures of a myxoid liposarcoma located adjacent to her proximal femoral vasculature. After postoperative radiation therapy, she was referred to our institution where she underwent two additional reexcisions of local recurrences during a 3-year span, eventually undergoing a regional rotational muscle flap for coverage. Two years after her third reexcision procedure, she presented with two additional, nonpalpable surgical-bed local recurrences. After converting an MRI bed and scanner to allow for proximal thigh imaging in an iMRI surgical suite, the patient underwent a successful resection that achieved negative margins. To date, she remains without evidence of disease at 37 months. LITERATURE REVIEW: Real-time iMRI in neurosurgical studies has shown a high rate of residual disease leading to immediate subsequent reexcision, thus lending to improved rates of negative margin resection. To our knowledge, this is the first example using iMRI technology to remove a recurrent soft tissue sarcoma that otherwise was clinically nonlocalizable. CLINICAL RELEVANCE: The use of an iMRI surgical suite can aid with identification of soft tissue nodules in conditions such as an altered tumor bed from prior resection and radiotherapy, which otherwise make recurrences difficult to localize. A team approach between administration, surgeons, and engineers is required to design and pragmatically implement the use of an MRI-compatible table extension to enhance existing iMRI surgical suite technology for extremity sarcoma resection procedures.

Consolidative Proton Radiotherapy for Pediatric Extramedullary Ocular Acute Myeloid Leukemia.

Purpose: Pediatric acute myeloid leukemia (AML) often involves extramedullary sites, which can be resistant to standard induction chemotherapy. Consolidative radiation therapy can be used in select cases to improve local control rates and help bridge patients to curative stem cell transplants. However, there is no previously published data to support the use of proton radiotherapy (PT) in this setting. We present radiographic findings and pathologic outcomes of the first reported patient with extramedullary ocular AML to be treated with PT. Patients and Methods: Details regarding diagnostic evaluation and treatment were obtained from the electronic medical records at the University of Florida Proton Therapy Institute, Nemours Children's Health, and St. Joseph's Children's Hospital. Results: This 7-month-old patient presented with biopsy-proven relapsed AML in the bilateral anterior chambers of the eyes, which did not resolve with induction chemotherapy. The patient then received PT to a dose of 24 cobalt gray equivalent to both eyes and was found to have no evidence of disease following treatment. Conclusion: This case provides further evidence that consolidative radiotherapy may be considered for select patients with extramedullary AML who have limited response to induction chemotherapy. Given the increased prevalence of extramedullary AML in pediatric patients, it is worth considering the utilization of PT to mitigate damage to nearby organs and the risk of secondary malignancies.

Chemotherapy for initial induction failures in childhood acute lymphoblastic leukemia: a Children's Oncology Group Study (POG 8764).

Children with acute lymphocytic leukemia who fail to enter remission have a poor prognosis. In a previous study, 9 of 14 children with induction failure entered remission after teniposide (VM26) plus cytosine arabinoside (Ara-C). We attempted to confirm these results. Twenty children received teniposide (200 mg/m/day IV) for 3 days and cytosine arabinoside (100 mg/m/day continuous IV infusion) for 7 days. There were 3 complete and 3 partial responses. Two additional patients achieved a complete response after a second, shorter course of the same agents. Although VM26 plus Ara-C is an active combination for treatment of acute lymphocytic leukemia induction failure, it does not appear as effective as in the initial report. Better treatments for this problem are needed.

Efficacy of a Standardized Premedication and Therapeutic Drug Monitoring Protocol for Pegaspargase to Prevent Hypersensitivity Reactions.

OBJECTIVE: The purpose of this study was to evaluate the efficacy of a standardized premedication and therapeutic drug monitoring (TDM) protocol to prevent hypersensitivity reactions from pegaspargase infusions. Pegaspargase is an essential therapeutic agent used for the treatment of acute lymphoblastic leukemia (ALL) in pediatric patients. METHODS: This study was a retrospective cohort study conducted at Wolfson Children's Hospital, Jacksonville, Florida, and included pediatric ALL patients 0 to 21 years old. Patients were excluded if they had not received the appropriate premedication after protocol implementation or had received premedication before protocol implementation. Patients were separated into 2 groups: those who received premedication before pegaspargase infusion and those who did not. The primary endpoint was the incidence of documented hypersensitivity reactions. Observational data endpoints included incidence of silent inactivation and cost savings from reducing complicated drug substitutions. RESULTS: A total of 38 patients (50 doses in no premedication group; 80 doses in premedication group) were evaluated. There was not a significant reduction in the incidence of hypersensitivity reactions for patients receiving premedication and TDM (5.3% vs 6.4%, p = 1.0). A trend towards patients reacting earlier with more severe reactions in the post-implementation group was observed. There were no incidences of silent inactivation. Observational cost analysis predicts potential drug cost savings of $106,550.45. CONCLUSIONS: A standardized premedication protocol did not reduce the incidence of hypersensitivity reactions. Premedication to prevent hypersensitivity reactions may provide a potential drug cost savings. Further investigation is warranted to assess the efficacy of a standardized premedication and TDM protocol to prevent hypersensitivity reactions.

Prognosticators in thigh soft tissue sarcomas.

BACKGROUND: In sarcoma patients the roles of smoking history, family cancer history, and leukoreduced blood transfusions have not been studied and the effect of preoperative radiation on blood loss has not been examined. METHODS: Seventy-seven patients with non-metastatic and non-recurrent thigh sarcomas surgically treated at the Cleveland Clinic were identified. Among patient variables studied were: close family history of cancer, perioperative transfusion history, smoking history, and radiation history. Median follow-up for the survivors was 3.2 years. RESULTS: We found that tumor grade, transfusion >3 U (P = 0.022), and pre- or post-operative radiation therapy (P = 0.041) were risk factors for distant metastasis. Tumor grade (P = 0.008), positive smoking history (P = 0.039), and >3 U of non-leukoreduced blood transfused (P = 0.037) were risk factors for death of any-cause. Close family history of cancer correlated with having a grade 3 sarcoma (P = 0.044). Neoadjuvant radiotherapy correlated with >3 U of blood transfused (P = 0.001) and biopsy performed at the treating institution led to a significant decrease in rate of recurrence (P = 0.016). CONCLUSIONS: We present novel findings in terms of transfusions, family history of cancer and site of initial biopsy in sarcoma patients.

Can MDM2 analytical tests performed on core needle biopsy be relied upon to diagnose well-differentiated liposarcoma?

Well-differentiated liposarcoma/atypical lipomatous tumor can be difficult to differentiate from benign lipomatous tumors, especially on limited biopsy material. Adjunctive tests for MDM2 (murine double minute 2) have proven useful in whole-tissue sections; however, their utility has not been determined within the increasingly popular core needle biopsy. Herein, we compare the ability of MDM2 immunohistochemistry and MDM2 fluorescence in situ hybridization (FISH) to discriminate benign lipomatous tumors from well-differentiated liposarcoma on core needle biopsies. Well-differentiated liposarcoma (n=17) and an assortment of benign lipomatous tumors (n=37), which had concurrent or previous core needle biopsies, and resection specimens were subjected to both MDM2 immunohistochemistry and MDM2 FISH on both whole-tissue sections and corresponding core needle biopsy sections. Percentage tumor cells positive for MDM2 by immunohistochemistry and an MDM2:CEP12 FISH ratio was calculated in each biopsy and resection specimen pair and the results were compared. MDM2 FISH had a higher sensitivity (100%) and specificity (100%) compared with MDM2 immunohistochemistry (65 and 89%) in core needle biopsies, respectively. In addition, MDM2 immunohistochemistry had a false-positive rate of 11%, compared to 0% with FISH. The average MDM2:CEP12 ratio was similar in the biopsy material compared with the whole-tissue sections in both well-differentiated liposarcoma and the benign lipomatous tumor group of neoplasms. Detection of MDM2 amplification by FISH is a more sensitive and specific adjunctive test than MDM2 immunohistochemistry to differentiate well-differentiated liposarcoma from various benign lipomatous tumors, especially on limited tissue samples.

Imaging findings, prevalence and outcome of de novo and secondary malignant fibrous histiocytoma of bone.

OBJECTIVE: To evaluate the radiographic and magnetic resonance (MR) imaging features of primary and secondary malignant fibrous histiocytoma in bone and determine the demographics, prevalence and outcome of patients with this tumor. MATERIALS AND METHODS: A retrospective search of files from two institutions identified 28 patients with malignant fibrous histiocytoma (MFH) of bone. Microscope slides were reviewed to confirm diagnosis and identify any pre-existing lesions. Medical records were reviewed with respect to patients' demographic characteristics and outcomes. RESULTS: Radiographic features demonstrated an aggressive osteolytic lesion with a permeative pattern of bone destruction. Periosteal reaction was seen in three of 13 lesions. T1-weighted images (T1WIs) demonstrated signal intensity iso- to slightly hyperintense to muscle. T2-weighted images (T2WIs) demonstrated mildly higher signal intensity than that of muscle. The 5-year survival rate was 53%. The tumor arose secondarily in pre-existing lesions in 43% of patients. Metastases occurred in 46% of patients during the course of the disease, with pulmonary and osseous metastases being the most common. CONCLUSION: Secondary MFH of bone was slightly less common than primary MFH and had a prognosis similar to that of primary MFH of bone. MR imaging showed variable and somewhat unusual low to intermediate T2 signal characteristics for a radiographically malignant osteolytic lesion.

Irradiating Residual Disease to 30 Gy with Proton Therapy in Pediatric Mediastinal Hodgkin Lymphoma.

BACKGROUND: Local relapse is a predominant form of recurrence among pediatric patients with Hodgkin lymphoma (PHL). Although PHL radiotherapy doses have been approximately 20 Gy, adults with Hodgkin lymphoma receiving 30 to 36 Gy experience fewer in-field relapses. We investigated the dosimetric effect of such a dose escalation to the organs at risk (OARs). MATERIALS AND METHODS: Ten patients with PHL treated with proton therapy to 21 Gy involved-site radiation therapy (ISRT21Gy) were replanned to deliver 30 Gy by treating the ISRT to 30 Gy (ISRT30Gy), delivering 21 Gy to the ISRT plus a 9-Gy boost to postchemotherapy residual volume (rISRTboost), and delivering 30 Gy to the residual ISRT target only (rISRT30Gy). Radiation doses to the OARs were compared. RESULTS: The ISRT30Gy escalated the dose to the target by 42% but also to the OARs. The rISRTboost escalated the residual target dose by 42%, and the OAR dose by only 17% to 26%. The rISRT30Gy escalated the residual target dose by 42% but reduced the OAR dose by 25% to 46%. CONCLUSION: Boosting the postchemotherapy residual target dose to 30Gy can allow for dose escalation with a slight OAR dose increase. Treating the residual disease for the full 30Gy, however, would reduce the OAR dose significantly compared with ISRT21Gy. Studies should evaluate these strategies to improve outcomes and minimize the late effects.

Cortical scalloping and cortical penetration by small eccentric chondroid lesions in the long tubular bones: not a sign of malignancy?

OBJECTIVES: The objective of this study was to evaluate by cross-sectional imaging the prevalence and degree of cortical scalloping by small eccentric chondromas correlated with histologic diagnosis and patient history. MATERIALS AND METHODS: From 122 patients with histologically proven enchondromas and two patients without histology but with radiologic and clinical follow-up, 11 patients with small, eccentrically located chondromas in the long bones had cross-sectional imaging available. The lesions were evaluated for location, size, presence, and degree of cortical scalloping. The patient's medical charts and microscope slides were reviewed for relevant clinical history, clinical management, and histology. RESULTS: The chondromas ranged in size from 1.6 to 3.8 cm (mean 2.3 cm). Two lesions were located in the proximal femoral diaphysis, two in the distal femoral diaphysis, six in the distal femoral metaphysis, and one in the proximal tibial epimetaphysis. The lesions were curetted due to diagnostic uncertainty, continued pain, marked radiologic cortical penetration, or due to patient insistence on biopsy. All 11 lesions were benign, nine histologically, and two by stability over 4 and 7 years. The prevalence of cortical scalloping among eccentric chondromas was 100%. Cortical scalloping or occupancy ranged from 50 to 100% (mean 75%). CONCLUSIONS: All small eccentric chondromas in this study were associated with an appearance of cortical scalloping of varying degree. All curetted lesions were histologically bland without nuclear atypia. Based on the benign histology of nine lesions and lack of growth of two lesions over several years, the degree of cortical scalloping is felt to be a result of lesion location within the endosteum rather than biological activity or malignancy.

Musculoskeletal allograft risks and recalls in the United States.

There have been several improvements to the US tissue banking industry over the past decade. Tissue banks had limited active government regulation until 1993, at which time the US Food and Drug Administration began regulatory oversight because of reports of disease transmission from allograft tissues. Reports in recent years of disease transmission associated with the use of allografts have further raised concerns about the safety of such implants. A retrospective review of allograft recall data was performed to analyze allograft recall by tissue type, reason, and year during the period from January 1994 to June 30, 2007. During the study period, more than 96.5% of all allograft tissues recalled were musculoskeletal. The reasons underlying recent musculoskeletal tissue recalls include insufficient or improper donor evaluation, contamination, recipient infection, and positive serologic tests. Infectious disease transmission following allograft implantation may occur if potential donors are not adequately evaluated or screened serologically during the prerecovery phase and if the implant is not sterilized before implantation.

Variation in Spot and Stripe Patterns in Original and Regenerated Zebrafish Caudal Fins.

Tissue regeneration requires not only the replacement of lost cells and tissues, but also the recreation of morphologies and patterns. Skin pigment pattern is a relatively simple system that can allow researchers to uncover the underlying mechanisms of pattern formation. To gain insight into how pigment patterns form, undergraduate students in the senior level course Developmental Biology designed an experiment that assayed pigment patterns in original and regenerated caudal fins of wild-type, striped, and mutant, spotted zebrafish. A majority of the WT fins regenerated with a similar striped pattern. In contrast, the pattern of spots even in the original fins of the mutants varied among individual fish. Similarly, the majority of the spots in the mutants did not regenerate with the same morphology, size, or spacing as the original fins. This was true even when only a small amount of fin was removed, leaving most of the fin to potentially reseed the pattern in the regenerating tissue. This suggests that the mechanism that creates the wild-type, striped pattern persists to recreate the pattern during regeneration. The mechanism that creates the spots in the mutants, however, must include an unknown element that introduces variability.

Primary embryonal carcinoma of the orbit in a 10-month-old female: a seven-year follow-up.

PURPOSE: Extra-gonadal germ cell tumors (GCTs) are rare and can be highly aggressive. If correctly identified and treated with multimodality chemotherapy, their prognosis can be significantly improved. We examined a 10 month-old female with primary embryonal carcinoma of the orbit. DESIGN: Case report and literature review. METHODS: Case study with 7-year follow-up and literature review of intracranial and intraorbital GCT cases. RESULTS: The patient presented with progressive proptosis and ophthalmoplegia. CT scan revealed an orbital apex mass and biopsy demonstrated a nongerminomatous GCT--an embryonal carcinoma. The patient is tumor-free 7 years after multimodality chemotherapy. She has mild amblyopia and a right micro esotropia. CONCLUSIONS: Nongonadal GCTs of the orbit can occur and should be considered in the differential diagnosis of a young child with proptosis and ophthalmoplegia. Five-year survival rates improve significantly with accurate identification and treatment.

Stump Neuroma.

A 24-year-old man presented for follow-up magnetic resonance imaging to rule out tumor recurrence 1 year after he underwent an above-knee amputation for synovial cell sarcoma.

Current concepts in total femoral replacement.

Total femoral replacement (TFR) is a salvage arthroplasty procedure used as an alternative to lower limb amputation. Since its initial description in the mid-20(th) century, this procedure has been used in a variety of oncologic and non-oncologic indications. The most compelling advantage of TFR is the achievement of immediate fixation which permits early mobilization. It is anticipated that TFR will be increasingly performed as the rate of revision arthroplasty rises worldwide. The existing literature is mainly composed of a rather heterogeneous mix of retrospective case series and a wide assortment of case reports. Numerous TFR prostheses are currently available and the surgeon must understand the unique implications of each implant design. Long-term functional outcomes are dependent on adherence to proper technique and an appropriate physical therapy program for postoperative rehabilitation. Revision TFR is mainly performed for periprosthetic infection and the severe femoral bone loss associated with aseptic revisions. Depending on the likelihood of attaining infection clearance, it may sometimes be advisable to proceed directly to hip disarticulation without attempting salvage of the TFR. Other reported complications of TFR include hip joint instability, limb length discrepancy, device failure, component loosening, patellar maltracking and delayed wound healing. Further research is needed to better characterize the long-term functional outcomes and complications associated with this complex procedure.

Adamantinoma.

A 73-year-old woman with no significant past medical history presents with a palpable lump in the midshaft of the left tibia and intermittent mild discomfort for the past 8 months.

Bone sarcomas: Overview of management, with a focus on surgical treatment considerations.

Outcomes for patients with bone sarcomas have improved dramatically over the past 40 years, and most bone sarcomas today are treated with surgery and chemotherapy. The most common clinical findings in patients with bone sarcomas are pain and an enlarging bone mass, although pain is not generally a good indicator of malignancy. In general, any patient with a bone mass with indeterminate imaging findings should be referred to an orthopedic oncologist. Bone sarcomas are diagnosed after a biopsy, which is best performed by the surgeon who will be doing the curative resection. Postresection reconstruction of the affected limb is generally done with an allograft-prosthetic composite or a modular metallic prosthetic joint replacement device. Post-therapy follow-up at frequent and regular intervals is critical to assess for recurrence and lung metastasis.

The F-BAR domain of SRGP-1 facilitates cell-cell adhesion during C. elegans morphogenesis.

Robust cell-cell adhesion is critical for tissue integrity and morphogenesis, yet little is known about the molecular mechanisms controlling cell-cell junction architecture and strength. We discovered that SRGP-1 is a novel component of cell-cell junctions in Caenorhabditis elegans, localizing via its F-BAR (Bin1, Amphiphysin, and RVS167) domain and a flanking 200-amino acid sequence. SRGP-1 activity promotes an increase in membrane dynamics at nascent cell-cell contacts and the rapid formation of new junctions; in addition, srgp-1 loss of function is lethal in embryos with compromised cadherin-catenin complexes. Conversely, excess SRGP-1 activity leads to outward bending and projections of junctions. The C-terminal half of SRGP-1 interacts with the N-terminal F-BAR domain and negatively regulates its activity. Significantly, in vivo structure-function analysis establishes a role for the F-BAR domain in promoting rapid and robust cell adhesion during embryonic closure events, independent of the Rho guanosine triphosphatase-activating protein domain. These studies establish a new role for this conserved protein family in modulating cell-cell adhesion.