Brian E. Brigman

PDGF-BB, IGF-I and mechanical load stimulate DNA synthesis in avian tendon fibroblasts in vitro

Resident cells in the surface epitenon and internal compartment of flexor tendons are subjected to cyclic mechanical load as muscle contracts to move limbs or digits. Tendons are largely tensile load bearing tissues and are highly matrix intensive with nondividing cells providing maintenance functions. However, when an injury occurs, tendon cells are stimulated to divide by activated endogenous growth factors and those from platelets and plasma. We hypothesize that tendon cells detect mechanical load signals but do not interpret such signals as mitogenic unless an active growth factor is present. We have used an in vitro mechanical load model, application of cyclic strain to cells cultured on flexible bottomed culture plates, to test the hypothesis that tendon cells require platelet-derived growth factor (PDGF-BB) and insulin-like growth factor-I (IGF-I) in addition to mechanical load to stimulate DNA synthesis. In addition, we demonstrate that in avian tendon cells, load and growth factors stimulate phosphorylation of tyrosine residues in multiple proteins, including pp60src, a protein kinase that phosphorylates receptor protein tyrosine kinases. A lack of mitogenic responsiveness to mechanical load alone by tendon cells may be a characteristic of a regulatory pathway that modulates cell division.

Allografts about the Knee in Young Patients with High-Grade Sarcoma.

Reconstruction after resections for high-grade sarcomas about the knee in children and adolescents is a challenging problem because of the large soft tissue and skeletal defects, the effects of adjuvant therapy, and the potential for long-term use of the limb. One hundred sixteen patients, all 18 years or younger, with osteosarcoma or Ewing’s sarcoma located between the middle femur and middle tibia, were treated with chemotherapy, resection, and allograft reconstruction. One hundred three patients with osteosarcoma and 13 patients with Ewing’s sarcoma had 105 Stage II and 11 Stage III tumors. There were 72 osteoarticular grafts (39 femur, 33 tibia), 28 intercalary grafts (19 femur), seven allograft-prosthetic composites (all femur,) and nine allograft-arthrodeses (seven femur, two tibia). At latest followup, 49% of all of the allograft reconstructions were rated good or excellent, 14% were rated as fair, and 37% were failures. Sixteen percent had an infection develop. Twenty-seven percent of patients had a fracture, 34% had a nonunion, and 14 patients eventually required amputation. Reconstruction of large bone defects about the knee in young patients who are being treated with chemotherapy is difficult. Although complications significantly affect outcome, allografts are a viable option for reconstruction in children with high-grade sarcomas about the knee.

The Clinical Management of Chondrosarcoma

Opinion statementChondrosarcomas (CHS) represent a heterogeneous group of disorders ranging from indolent, low-grade tumors to aggressive, high-grade forms. Surgical resection represents the primary and preferred treatment modality for individuals with localized disease. Radiation therapy is appropriate for the treatment of positive surgical margins or palliation of disease-related symptoms. The treatment of advanced, metastatic disease is particularly challenging given the recognition that conventional chemotherapy has proven to be largely ineffective. Systemic chemotherapy may be considered in variant forms such as mesenchymal or dedifferentiated chondrosarcomas but high-quality data supporting its use is limited. There is universal agreement, however, that novel treatment strategies are desperately needed. This review will highlight the need for a coordinated multidisciplinary approach to optimize the management and care of patients.

A mouse-human phase 1 co-clinical trial of a protease-activated fluorescent probe for imaging cancer

A first-in-human phase 1 clinical trial of the PEGylated protease-activated fluorescent probe, LUM015, enables tumor imaging at a safe and tolerable dose in humans. Protease probe tested in humans Cancer cells secrete more of the protease cathepsin than healthy cells, partly as a way to enzymatically remodel their surroundings for tumor growth and metastasis. Whitley et al. developed an imaging probe that could be activated in the presence of these cathepsins, thus allowing surgeons to distinguish tumor margins intraoperatively. Their probe, called LUM015, was able to signal the presence of cancer in vivo in a mouse sarcoma model, and in a so-called “co-clinical trial” in 15 patients, it was safe and cleaved as expected in different types of tumor tissues. With favorable biodistribution and pharmacokinetics also demonstrated, protease-activated probes are now poised for further adaptation to tumor resections, signaling the presence of residual cancer. Local recurrence is a common cause of treatment failure for patients with solid tumors. Intraoperative detection of microscopic residual cancer in the tumor bed could be used to decrease the risk of a positive surgical margin, reduce rates of reexcision, and tailor adjuvant therapy. We used a protease-activated fluorescent imaging probe, LUM015, to detect cancer in vivo in a mouse model of soft tissue sarcoma (STS) and ex vivo in a first-in-human phase 1 clinical trial. In mice, intravenous injection of LUM015 labeled tumor cells, and residual fluorescence within the tumor bed predicted local recurrence. In 15 patients with STS or breast cancer, intravenous injection of LUM015 before surgery was well tolerated. Imaging of resected human tissues showed that fluorescence from tumor was significantly higher than fluorescence from normal tissues. LUM015 biodistribution, pharmacokinetic profiles, and metabolism were similar in mouse and human subjects. Tissue concentrations of LUM015 and its metabolites, including fluorescently labeled lysine, demonstrated that LUM015 is selectively distributed to tumors where it is activated by proteases. Experiments in mice with a constitutively active PEGylated fluorescent imaging probe support a model where tumor-selective probe distribution is a determinant of increased fluorescence in cancer. These co-clinical studies suggest that the tumor specificity of protease-activated imaging probes, such as LUM015, is dependent on both biodistribution and enzyme activity. Our first-in-human data support future clinical trials of LUM015 and other protease-sensitive probes.

Cross Species Genomic Analysis Identifies a Mouse Model as Undifferentiated Pleomorphic Sarcoma/Malignant Fibrous Histiocytoma

Undifferentiated pleomorphic sarcoma/Malignant Fibrous Histiocytoma (MFH) is one of the most common subtypes of human soft tissue sarcoma. Using cross species genomic analysis, we define a geneset from the LSL-KrasG12D; Trp53Flox/Flox mouse model of soft tissue sarcoma that is highly enriched in human MFH. With this mouse geneset as a filter, we identify expression of the RAS target FOXM1 in human MFH. Expression of Foxm1 is elevated in mouse sarcomas that metastasize to the lung and tissue microarray analysis of human MFH correlates overexpression of FOXM1 with metastasis. These results suggest that genomic alterations present in human MFH are conserved in the LSL-KrasG12D; p53Flox/Flox mouse model of soft tissue sarcoma and demonstrate the utility of this pre-clinical model.

Successful Translation of Fluorescence Navigation During Oncologic Surgery: A Consensus Report

Navigation with fluorescence guidance has emerged in the last decade as a promising strategy to improve the efficacy of oncologic surgery. To achieve routine clinical use, the onus is on the surgical community to objectively assess the value of this technique. This assessment may facilitate both Food and Drug Administration approval of new optical imaging agents and reimbursement for the imaging procedures. It is critical to characterize fluorescence-guided procedural benefits over existing practices and to elucidate both the costs and the safety risks. This report is the result of a meeting of the International Society of Image Guided Surgery (www.isigs.org) on February 6, 2015, in Miami, Florida, and reflects a consensus of the participants’ opinions. Our objective was to critically evaluate the imaging platform technology and optical imaging agents and to make recommendations for successful clinical trial development of this highly promising approach in oncologic surgery.

Malignant giant cell tumor of soft parts

Giant cell tumor of soft parts (GCTSP) is an extremely rare lesion with an unpredictable behavior. Some patients are cured with a simple surgical excision whereas others will develop metastatic disease within a relatively short interval. To date, there are no consistently reliable criteria, either clinical or histologic, to separate the benign from more aggressive lesions. We describe the clinical, histologic and radiologic features of a case with malignant behavior. The patient presented with a fungating skin and soft tissue mass and concurrent pulmonary nodules. The lesion recurred rapidly despite wide resection with negative surgical margins. Biopsy of the pulmonary lesions demonstrated metastatic disease.

Intraoperative detection and removal of microscopic residual sarcoma using wide-field imaging

The goal of limb‐sparing surgery for a soft tissue sarcoma of the extremity is to remove all malignant cells while preserving limb function. After initial surgery, microscopic residual disease in the tumor bed will cause a local recurrence in approximately 33% of patients with sarcoma. To help identify these patients, the authors developed an in vivo imaging system to investigate the suitability of molecular imaging for intraoperative visualization.

Oncogene-dependent control of miRNA biogenesis and metastatic progression in a model of undifferentiated pleomorphic sarcoma

Undifferentiated pleomorphic sarcoma (UPS) is one of the most common soft tissue malignancies. Patients with large, high‐grade sarcomas often develop fatal lung metastases. Understanding the mechanisms underlying sarcoma metastasis is needed to improve treatment of these patients. Micro‐RNAs (miRNAs) are a class of small RNAs that post‐transcriptionally regulate gene expression. Global alterations in miRNAs are frequently observed in a number of disease states including cancer. The signalling pathways that regulate miRNA biogenesis are beginning to emerge. To test the relevance of specific oncogenic mutations in miRNA biogenesis in sarcoma, we used primary soft tissue sarcomas expressing either BrafV600E or KrasG12D. We found that BrafV600E mutant tumours, which have increased MAPK signalling, have higher levels of mature miRNAs and enhanced miRNA processing. To investigate the relevance of oncogene‐dependent alterations in miRNA biogenesis, we introduced conditional mutations in Dicer and showed that Dicer haploinsufficiency promotes the development of distant metastases in an oncogene‐dependent manner. These results demonstrate that a specific oncogenic mutation can cooperate with mutation in Dicer to promote tumour progression in vivo.Copyright

Jaffe-Campanacci syndrome. A case report and review of the literature.

In 1942, Jaffe and Lichtenstein1 first described nonosteogenic fibroma (now known as nonossifying fibroma) of bone as a frequently encountered benign fibrous lesion of the long bones. In 1958, Jaffe2 subsequently described a rarely seen clinical entity in which multiple nonossifying fibromas occurred in association with cafe-au-lait spots and axillary freckling, but without accompanying neurofibromas. Jaffe suggested that the disorder was an unusual form of neurofibromatosis. In a subsequent report of the same findings-that is, multiple nonossifying fibromas and cafe-au-lait spots-Holt3 suggested that they were incidental and unrelated. Schwartz and Ramos4 attributed the two sets of findings to a syndrome called diffuse mesodermal dysplasia, but the name was never adopted. Several isolated cases of this unusual clinical presentation were reported by Mandell et al.5 and Pitcock6. In 1983, Campanacci et al.7 reported on ten patients with nonossifying fibromas associated with some features of neurofibromatosis and expressed the opinion that these cases represented a new syndrome. Mirra et al.8 reported on a patient with similar symptoms in 1982 and, on the basis of their knowledge of the large series reported on later by Campanacci et al., designated the syndrome as Jaffe-Campanacci syndrome. Since then, the syndrome has been widely accepted as a unique clinical entity, but very few cases have been reported in the English-language literature7,9-13. A fifteen-year-old boy was referred to the Massachusetts General Hospital Orthopaedic Oncology Service with a pathologic fracture of the distal part of the left femur. He had been diagnosed previously as having neurofibromatosis on the basis of a number of skin findings. The patient had had two previous surgical procedures consisting of curettage and bone graft packing for lesions in the distal parts …