Timothy B. Rapp, M.D.

Sox2 maintains self renewal of tumor-initiating cells in osteosarcomas
Basu-Roy U; Seo E; Ramanathapuram L; Rapp TB; Perry JA; Orkin SH; Mansukhani A; Basilico C
2011 Sep 19;:?-?, Oncogene
Tumors are thought to be sustained by a reservoir of self-renewing cells, termed tumor-initiating cells or cancer stem cells. Osteosarcomas are high-grade sarcomas derived from osteoblast progenitor cells and are the most common pediatric bone malignancy. In this report we show that the stem cell transcription factor Sox2 is highly expressed in human and murine osteosarcoma (mOS) cell lines as well as in the tumor samples. Osteosarcoma cells have increased ability to grow in suspension as osteospheres, that are greatly enriched in expression of Sox2 and the stem cell marker, Sca-1. Depletion of Sox2 by short-hairpin RNAs in independent mOS-derived cells drastically reduces their transformed properties in vitro and their ability to form tumors. Sox2-depleted osteosarcoma cells can no longer form osteospheres and differentiate into mature osteoblasts. Concomitantly, they exhibit decreased Sca-1 expression and upregulation of the Wnt signaling pathway. Thus, despite other mutations, these cells maintain a requirement for Sox2 for tumorigenicity. Our data indicate that Sox2 is required for osteosarcoma cell self renewal, and that Sox2 antagonizes the pro-differentiation Wnt pathway that can in turn reduce Sox2 expression. These studies define Sox2 as a survival factor and a novel biomarker of self renewal in osteosarcomas, and support a tumor suppressive role for the Wnt pathway in tumors of mesenchymal origin. Our findings could provide the basis for novel therapeutic strategies based on inhibiting Sox2 or enhancing Wnt signaling for the treatment of osteosarcomas.Oncogene advance online publication, 19 September 2011; doi:10.1038/onc.2011.405
— id: 137542, year: 2011, vol: , page: ?, stat: Journal Article,

Metastatic lesions of the proximal femur
Doung, Yee-Cheen; Kenan, Samuel; Rapp, Timothy
2011 ;69(1):81-86, Bulletin of the NYU Hospital for Joint Diseases
Skeletal metastases are common in the adult population. The proximal femur is a frequently affected bone in the appendicular skeleton. The orthopaedic surgeon may be the first to find a pathologic lesion of the proximal femur and appropriate diagnosis and nonoperative management is essential prior to surgical treatment. Bisphosphonates and radiation therapy are used in conjunction with surgical management to minimize pain and prevent further destruction. Surgical management may consist of internal fixation, with or without polymethylmethacrylate, or endoprosthesic replacement. The goal of treatment is to relieve pain and allow for function while minimizing systemic complications
— id: 128799, year: 2011, vol: 69, page: 81, stat: Journal Article,

Hospitalist-orthopedic co-management of high-risk patients undergoing lower extremity reconstruction surgery
Pinzur, Michael S; Gurza, Edward; Kristopaitis, Theresa; Monson, Rebecca; Wall, Michael J; Porter, Anne; Davidson-Bell, Victoria; Rapp, Timothy
2009 Jul;32(7):495-495, Orthopedics (Thorofare NJ)
The introduction of the hospitalist co-management model represents an opportunity to improve care by changing the system as it applies to a small group of patients. Eighty-six consecutive patients with multiple comorbidities were selectively enrolled in an academic medical center hospitalist-orthopedic surgery co-management patient care program. Patients were stratified by all patient refined diagnosis-related groups, severity of illness, and risk of mortality. Hospital length of stay, cost of care, in-hospital mortality, complications, and intensive care unit admissions were compared with a retrospectively constructed control group of 54 patients undergoing similar surgery during the period immediately preceding initiation of the program. The University Health System Consortium observed-to-expected ratio for hospital length of stay was 0.693 compared to 0.862 for the control group. The severity of illness and risk of mortality scores represented a relatively higher risk stratification in the study group. While the overall observed-to-expected cost of care remained virtually unchanged, the positive impact of the study model revealed an increased positive effect on the more severely affected severity of illness and risk of mortality patients. The results of this study suggest that a proactive, cooperative, co-management model for the perioperative management of high-risk patients undergoing complex surgery can improve the quality and efficiency metrics associated with the delivery of service to patients
— id: 105324, year: 2009, vol: 32, page: 495, stat: Journal Article,

Radiologic case study: Ewing's Sarcoma
Wrigley, Kristen; Demos, Terrence C; Lomasney, Laurie M; Rapp, Timothy
2009 Feb;32(2):70-70, Orthopedics (Thorofare NJ)
Enhance your diagnostic skills with this 'test yourself' monthly column, which features a radiograph and challenges you to make a diagnosis
— id: 105325, year: 2009, vol: 32, page: 70, stat: Journal Article,

Megaprosthesis versus Condyle-sparing intercalary allograft: distal femoral sarcoma
Zimel, Melissa N; Cizik, Amy M; Rapp, Timothy B; Weisstein, Jason S; Conrad, Ernest U 3rd
2009 Nov;467(11):2813-2824, Clinical orthopaedics & related research
Although functionally appealing in preserving the native knee, the condyle-sparing intercalary allograft of the distal femur may be associated with a higher risk of tumor recurrence and endoprosthetic replacement for malignant distal femoral bone tumors. We therefore compared the risk of local tumor recurrence between patients in these two types of reconstruction groups. We retrospectively reviewed 85 patients (mean age, 22 years; range, 4-82 years), 38 (45%) of whom had a condyle-sparing allograft and 47 (55%) of whom had endoprostheses. The minimum followup for both groups was 2 years (mean, 7 years; range, 2-19 years). Local recurrences occurred in 11% (five of 47) of the patients having implants versus 18% (seven of 38) of the patients having allografts. Using time to local recurrence as an end point, the Kaplan-Meier survivorship of the implant group was similar to that of the condyle-sparing allograft group at 2, 5, and 10 years (93% versus 87% at 2 years, 87% versus 81% at 5 years, and 87% versus 81% at 10 years, respectively). The condyle-sparing allograft procedure offers the potential advantage of retaining the native knee in a young patient population while incurring no greater risk of local recurrence as those offered the endoprosthetic procedure. LEVEL OF EVIDENCE: Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence
— id: 104103, year: 2009, vol: 467, page: 2813, stat: Journal Article,

The case. Giant-cell tumor
Gruenwald, Nicholas; Demos, Terrence C; Lomasney, Laurie M; Rapp, Timothy
2006 Feb;29(2):94, 167-71, Orthopedics (Thorofare NJ)
Giant-cell tumor is a benign but locally aggressive primary bone tumor that requires surgical management. Most giant-cell tumors initially are demonstrated on radiographs as distal, subarticular, geographic osteolytic lesions. Abundant giant cells on histology are reactive secondary to a neoplastic fibroblast-like stromal cell. Giant cells are present in many neoplastic and non-neoplastic bone lesions; therefore the diagnosis of giant-cell tumors requires correlation of clinical, imaging, and pathologic data to exclude other lesions that demonstrate a similar histologic pattern. A small number of giant-cell tumors result in lung lesions, many of which have benign histology, can be treated by wedge resection, and do not affect long-term outcome. After adequate surgical curettage and the use of intraoperative surgical adjuvants, recurrence rates of approximately 10% are reported
— id: 105326, year: 2006, vol: 29, page: 94, 167, stat: Journal Article,

Your diagnosis? Aneurysmal bone cyst
Patel, Parag J; Demos, Terrence C; Lomasney, Laurie M; Rapp, Timothy
2005 May;28(5):428, 507-11, Orthopedics (Thorofare NJ)
The etiology of aneurysmal bone cysts is uncertain, but they may originate as a localized arteriovenous malformation. These benign lesions can be primary or occur secondary to an underlying lesion. The majority of patients who present with aneurysmal bone cysts are younger than age 20 years. One half of lesions occur within the long bones and one third involve the spine. Most flat bone lesions, approximately 10%, occur in the pelvis. Fluid-fluid levels are common on CT and MRI but are not pathognomonic. Although aneurysmal bone cyst is benign, there may be aggressive clinical and imaging features. Treatment for aneurysmal bone cyst is surgical curettage, intraoperative adjuvant therapy, and bone grafting of the lesion. The prognosis following treatment is very good, although 10% to 20% of cases are reported to recur
— id: 105327, year: 2005, vol: 28, page: 428, 507, stat: Journal Article,

RNA splicing mediated by YB-1 is inhibited by TLS/CHOP in human myxoid liposarcoma cells
Rapp, Timothy B; Yang, Liu; Conrad, Ernest U 3rd; Mandahl, Nils; Chansky, Howard A
2002 Jul;20(4):723-729, Journal of orthopaedic research
Human myxoid liposarcoma contains a characteristic t(12;16) chromosomal translocation that results in fusion of the N-terminal domain of the translocated in liposarcoma (TLS) protein to the C/EBP homologous protein (CHOP). TLS possesses structural motifs that suggest it may participate in RNA processing. We demonstrate that in human myxoid liposarcoma cells, wild-type TLS binds to RNA polymerase II (Pol II) via its N-terminal domain and to the transcription and translation factor Y-box binding protein-1 (YB-1) through its C-terminal domain. The liposarcoma fusion protein TLS/CHOP retains the ability to bind RNA Pol II but lacks the ability to recruit YB-1 due to replacement of the C-terminal domain of TLS by CHOP. In an in vivo splicing assay, YB-1 promotes splicing of adenovirus EIA pre-mRNA predominantly to the 13S isoform. The oncogenic TLS/CHOP fusion protein inhibits this splicing function of YB-1 in a dominant negative manner. When considered in conjunction with studies on other sarcoma fusion proteins, these data suggest that aberrant RNA splicing may be a common feature of human sarcomas
— id: 103884, year: 2002, vol: 20, page: 723, stat: Journal Article,

Nonoperative management of dens fracture nonunion in elderly patients without myelopathy
Hart, R; Saterbak, A; Rapp, T; Clark, C
2000 Jun 1;25(11):1339-1343, Spine
STUDY DESIGN: A retrospective review of elderly patients treated without surgery for chronic mobile nonunions of the odontoid process. Patients were observed on an annual basis with clinical examinations and flexion/extensions plain film radiographs. OBJECTIVES: To evaluate the clinical and radiographic results of elderly patients without myelopathy treated without surgery for dens fracture nonunion. SUMMARY OF BACKGROUND DATA: Because of the risk of progressive myelopathy or sudden neurologic injury, many surgeons recommend operative stabilization for patients with mobile dens nonunions who are able to withstand an operation. There is, however, a lack of information about the radiographic and neurologic progression of dens nonunions. Although a less aggressive surgical approach has been recommended by some authors for elderly or medically compromised patients with acute fractures, long-term follow-up evaluation of patients with resulting nonunions has not been reported. METHODS: A series of elderly patients with chronic, unstable, dens nonunions without myelopathy were treated with a nonoperative treatment protocol. Patients were informed of the nature of their lesion, including the risk of acute or chronic spinal cord injury and the options for operative treatment. Patients were evaluated yearly for clinical and radiographic progression. No intervention to slow progression of atlantoaxial instability was undertaken. RESULTS: None of the patients developed myelopathic symptoms during the follow-up period, and no patient experienced more than a 1 mm radiographic increase in atlantoaxial excursion. None of the reported patients had less than 14 mm available for the spinal cord in either flexion or extension at the start of clinical monitoring. CONCLUSIONS: Although further follow-up evaluation is needed, the authors believe on the basis of this review that this treatment protocol may be considered for patients who are poor candidates for surgical fusion
— id: 105328, year: 2000, vol: 25, page: 1339, stat: Journal Article,

CD44 in growing normal and neoplastic rat cartilage
Stevens, J W; Noonan, K J; Bosch, P P; Rapp, T B; Martin, J A; Kurriger, G L; Maynard, J A; Daniels, K J; Solursh, M; Tammi, R; Tammi, M; Midura, R J
1996 Jun 8;785:333-336, Annals of the New York Academy of Sciences
— id: 104181, year: 1996, vol: 785, page: 333, stat: Journal Article,