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Kristy L Weber

Publications and source records attributed to Kristy L Weber.

17 recordsLinked to original sources
PubMed2007

TGF-beta promotes the establishment of renal cell carcinoma bone metastasis.

UNLABELLED: Bone metastases develop in approximately 30% of patients with RCC, and the mechanisms responsible for this phenomenon are unknown. We found that TGF-beta1 stimulation of RCC bone metastasis cells promotes tumor growth and bone destruction possibly by stimulating paracrine interactions between tumor cells and the bone. INTRODUCTION: Bone metastasis is a frequent complication and causes marked morbidity in patients with renal cell carcinoma (RCC). Surprisingly, the specific mechanisms of RCC interaction with bone have been scarcely studied despite the inability to prevent or effectively treat bone metastasis. Bone is a reservoir for various growth factors including the pleiotropic cytokine TGF-beta1. TGF-beta1 has been shown to have tumor-supportive effects on advanced cancers and evidence suggests its involvement in promoting the development of breast cancer bone metastasis. Here, we studied the potential role of TGF-beta1 in the growth of RCC bone metastasis (RBM). MATERIALS AND METHODS: To inhibit TGF-beta1 signaling, RBM cells stably expressing a dominant-negative (DN) TGF-betaRII cDNA were generated. The in vivo effect of TGF-beta1 on RBM tumor growth and osteolysis was determined by histological and radiographic analysis, respectively, of athymic nude mice after intratibial injection of parental, empty vector, or DN RBM cells. The in vitro effect of TGF-beta1 on RBM cell growth was determined after TGF-beta1 treatment by MTT assay. RESULTS: TGF-beta1 and the TGF-beta receptors I and II (TGF-betaRI/II) were consistently expressed in both RBM tissues and cell lines. Inhibition of TGF-beta1 signaling in RBM cells significantly reduced tumor establishment and osteolysis observed in vivo after injection into the murine tibia, although no effect on tumor establishment was observed after injection of RBM cells subcutaneously or into the renal subcapsule. Treatment of five RBM cell lines with TGF-beta1 in vitro either had no effect (2/5) or resulted in a significant inhibition (3/5) of cell growth, suggesting that TGF-beta1 may promote RBM tumor growth indirectly in vivo. CONCLUSIONS: TGF-beta1 stimulation of RBM cells plays a role in promoting tumor growth and subsequent osteolysis in vivo, likely through the initiation of tumor-promoting paracrine interactions between tumor cells and the bone microenvironment. These data suggest that inhibition of TGF-beta1 signaling may be useful in the treatment of RBM.

Animals↗
PubMed2005

Use of a vascularized fibula bone flap and intercalary allograft for diaphyseal reconstruction after resection of primary extremity bone sarcomas.

BACKGROUND: The standard treatment for primary bone sarcomas of the extremities has become chemotherapy and limb salvage surgery. However, the difficulties in achieving reliable long-term healing with allograft reconstruction have led us to use vascularized fibula transfer to enhance healing. METHODS: From 1992 to 2003, 14 vascularized fibula transfers were performed at our institution for bone reconstruction in 12 patients with bone sarcoma. Free vascularized fibula transfers were performed in 13 cases, and a pedicled vascularized fibula transfer in one case. The mean age was 25 years (range, 6 to 71 years). Locations included the femur (n = 10), humerus (n = 1), and tibia (n = 3). The mean length of the vascularized fibula transfer was 17.4 cm (range, 10 to 24 cm). Indications for use of a vascularized fibula transfer included allograft nonunion (n = 8), and primary diaphyseal bone defect reconstruction combined with an intercalary allograft (n = 6). For all allograft nonunions, a vascularized fibula transfer was used with an onlay technique. For segmental bone defects, an intramedullary technique was used in three cases and an onlay technique in two cases. RESULTS: The overall mean time for bone union after a vascularized fibula transfer was 8.6 months (range, 3 to 24 months): 10 months (range, 5 to 24 months) for patients with allograft nonunions, and 6 months (range, 3 to 8 months) for patients who underwent immediate segmental bone reconstruction. All but one patient had successful bone union. One patient with persistent nonunion required a second vascularized fibula transfer. The mean time from initial limb salvage surgery to full use of the reconstructed limb without restrictions was 28 months (range, 13 to 45 months) for patients treated with a delayed vascularized fibula transfer for an allograft nonunion and 6 months (range, 3 to 8 months) for patients who underwent immediate reconstruction with a vascularized fibula transfer combined with an allograft. CONCLUSIONS: The use of a vascularized fibula transfer combined with an intercalary allograft to reconstruct bone defects after tumor resection can prevent allograft nonunion and result in decreased time to bone healing, leading to earlier patient recovery and return of function.

Adolescent↗
PubMed2004

Segmental femur reconstruction using an intercalary allograft with an intramedullary vascularized fibula bone flap.

The use of intercalary allografts has been an important innovation for use in limb-salvage surgery. However, the principal disadvantage of intercalary allografts is a high incidence of nonunion, fracture, and infection. With a recent trend toward higher doses of chemotherapy, an increased incidence of nonunion and healing problems can be anticipated with the use of allografts. In this article, the authors report two cases in which a vascularized fibula bone flap was used with an intercalary allograft, utilising an intramedullary approach, for immediate femur reconstruction following sarcoma resection. The rationale for this approach is to combine the mechanical strength of an allograft with the biologic activity of a vascularized bone flap. The allograft provides bone stock and early stability, while the addition of the vascularized bone flap substantially facilitates the host-allograft union.

Adolescent↗
PubMed2004

An approach to the management of the patient with metastatic bone disease.

Patients with primary sarcomas of bone and soft tissue are generally treated on protocol by a multidisciplinary team at tertiary referral centers. Conversely, patients with metastatic disease to the skeleton are often evaluated by general orthopaedic surgeons in the community. Skeletal metastases affect a growing percentage of the elderly population and can contribute to a marked decrease in their quality of life. Treatment includes stabilization with the latest prosthetic implants and new devices. Advances in the field of radiation oncology and bisphosphonate use in patients with bone metastasis are other management approaches.

Arm↗
PubMed2003

Blockade of epidermal growth factor receptor signaling leads to inhibition of renal cell carcinoma growth in the bone of nude mice.

Renal cell carcinoma (RCC) frequently produces metastases to the musculoskeletal system that are a major source of morbidity in the form of pain, immobilization, fractures, neurological compromise, and a decreased ability to perform activities of daily living. Patients with metastatic RCC therefore have a dismal prognosis because there is no effective adjuvant treatment for this disease. Because the epidermal growth factor receptor (EGF-R) signaling cascade is important in the growth and metastasis of RCC, its blockade has been hypothesized to inhibit tumor growth and hence prevent resultant bone destruction. We determined whether blockade of EGF-R by the tyrosine kinase inhibitor PKI 166 inhibited the growth of RCC in bone. We use a novel cell line, RBM1-IT4, established from a human RCC bone metastasis. Protein and mRNA expression of the ligands and receptors was assessed by Western and Northern blots. The stimulation of RBM1-IT4 cells with epidermal growth factor or transforming growth factor alpha resulted in increased cellular proliferation and tyrosine kinase autophosphorylation. PKI 166 prevented these effects. First, RBM1-IT4 cells were implanted into the tibia of nude mice, where they established lytic, progressively growing lesions, after which the mice were treated with PKI 166 alone or in combination with paclitaxel (Taxol). Immunohistochemical analysis revealed that tumor cells and tumor-associated endothelial cells in control mice expressed activated EGF-R. Treatment of mice with PKI 166 alone or in combination with Taxol produced a significant decrease in the incidence and size of bone lesions as compared with the results in control or Taxol-treated mice (P < 0.001). Treatment with PKI 166 also decreased the expression of phosphorylated EGF-R by tumor cells and tumor-associated endothelial cells, and this was even more pronounced with PKI 166 plus Taxol treatment. The PKI 166 plus Taxol combination produced apoptosis of tumor cells and tumor-associated endothelial cells. Tumor cell proliferation, shown by proliferating cell nuclear antigen positivity, was decreased in all treatment groups. In addition, the integrity of the bone was maintained in mice treated with PKI 166 or PKI 166 plus Taxol, whereas massive bone destruction was seen in control and Taxol-treated mice. These results suggest that blockade of EGF-R signaling inhibits growth of RCC in the bone by its effect on tumor cells and tumor-associated endothelial cells.

Animals↗
PubMed2003

Renal cell carcinoma bone metastasis: epidermal growth factor receptor targeting.

Renal cell carcinoma frequently metastasizes to the skeleton in the later stages of the disease. Patients with bone metastasis from renal cell carcinoma experience severe pain, neurologic compromise, and frequent pathologic fractures. These tumors are relatively resistant to chemotherapy and radiation, and the 5-year survival of patients is less than 10%. The epidermal growth factor receptor is overexpressed in human renal cell carcinoma and hypothesized to be a potential target in the treatment of bone metastasis. Using in vitro studies, it was shown that blockade of the epidermal growth factor receptor was effective in decreasing proliferation and receptor autophosphorylation of a human bone-derived renal cell carcinoma cell line. In an experimental nude mouse model, treatment with Taxol and protein tyrosine kinase inhibitor 166, a small molecule receptor tyrosine kinase inhibitor, blocked the growth of renal cell carcinoma in the tibia and resulted in decreased bone destruction. The use of protein tyrosine kinase inhibitor 166 and Taxol was cytostatic and nontoxic in long-term animal experiments. Epidermal growth factor receptor blockade is an exciting potential therapy for renal cell carcinoma bone metastasis in humans, but because it is cytostatic rather than cytotoxic, its optimal role may be as a supplement to cytotoxic chemotherapy. It ultimate role and its relationship to other therapeutic interventions remains to be elucidated and validated.

Animals↗
PubMed2003

Complex segmental elbow reconstruction after tumor resection.

Twenty-three patients were reviewed retrospectively to determine their oncologic and functional outcomes after resection of 15 primary or eight metastatic tumors about the elbow between 1985 and 2000. The indications for resection were dictated by the histologic features of the tumor, location of the lesion, and extent of bone destruction. A total humeral reconstruction was done in 12 patients. Of this group, an endoprosthesis was used in seven patients and a total humeral allograft with a proximal humeral prosthesis and osteoarticular elbow reconstruction (allograft-prosthetic composite) was used in five patients. Eleven additional patients had a segmental total elbow replacement after resection of the distal humerus or proximal ulna. Local disease control was achieved in 17 patients (74%). Fourteen patients presented with (48%) or had (13%) distant metastasis develop, but only eight (35%) died of their disease. Periprosthetic lysis or allograft resorption was present in five patients (22%), and two (18%) humeral components of total elbow prostheses required revision for loosening. The mean Musculoskeletal Tumor Society functional score was 23 of 30 points (77%) in the 12 living patients followed up for a mean of 46 months (range, 24-124 months). It was 83% in patients with a segmental total elbow reconstruction and 71% in patients with a total humeral reconstruction. Aggressive limb salvage of the humerus or elbow or both provides a satisfactory functional outcome without jeopardizing overall survival.

Activities of Daily Living↗
PubMed2002

Treatment and outcome of recurrent pelvic chondrosarcoma.

Little has been published about the outcome of patients with recurrent chondrosarcoma of the pelvis. The current study is a review of patients with surgically treated locally recurrent pelvic chondrosarcoma at one institution. Twenty-one patients had surgical resection of recurrent pelvic chondrosarcoma between July 1974 and July 1996. There were nine women and 12 men with a mean age of 46 years (range, 24-67 years) at first recurrence. Patients were followed up for a minimum of 3.3 years and median of 12 years from first (index) recurrence or until death. The mean time to index recurrence was 27 months (range, 5-87 months). In three cases (14%), the tumor at index recurrence was a higher grade than the initial lesion. There were six additional tumors that became a higher grade during subsequent recurrences. Fifteen of the 21 patients (71%) had a second local recurrence. Five patients (24%) had distant metastasis. At death or final followup, 11 patients (52%) had no evidence of disease, two patients (10%) are alive with disease, and eight patients (38%) died of their disease. The three patients with high-grade tumors at index recurrence all died of disease. The treatment of recurrent pelvic chondrosarcoma is a challenging problem. Tumor-free margins may require radical surgery, and the best chance of cure is at the time of initial resection. With aggressive surgical intervention, approximately 50% of patients with recurrent pelvic chondrosarcoma can achieve long-term survival.

Adult↗
PubMed2002

Current concepts in the treatment of Ewing's sarcoma.

Current concepts in the treatment of patients with Ewing's sarcoma are presented focusing on the role of chemotherapy, radiation therapy and surgical resection. Particular attention is given to current methods of limb salvage. Problem areas, including the pelvis, proximal femur and spine, are discussed.

Bone Neoplasms↗
PubMed2002

Characterization of a renal cell carcinoma cell line derived from a human bone metastasis and establishment of an experimental nude mouse model.

PURPOSE: We provide the necessary tools to study the biology of bone metastasis using renal cell carcinoma as a model. A relevant renal cell carcinoma cell line developed from a human bone metastasis is described and an experimental model in the nude mouse was established. MATERIALS AND METHODS: The novel cell line RBM1 was developed from bone metastasis from a patient with renal cell carcinoma. In vitro methods used to study the cell line included karyotype analysis, reverse-transcriptase polymerase chain reaction, ribonuclease protection assay and Western blot analysis. An intratibial injection model in the nude mouse resulted in bone lesions similar to those in human patients. RESULTS: Chromosomal analysis of this cell line revealed characteristic cytogenetic abnormalities common in renal cell carcinoma. RBM1 cells expressed parathyroid hormone parathyroid hormone related peptide, interleukin-6 and macrophage colony-stimulating factor, which are cytokines involved in osteoclast activation and subsequent bone resorption. Western blot analysis revealed the presence of high levels of epidermal growth factor receptor and c-MET. Reproducible osteolytic lesions developed in the nude mouse after injecting 1 x 106 cells into the tibia. CONCLUSIONS: This cell line and animal model may allow further study of the biology and mechanism of renal cell carcinoma bone metastasis.

Animals↗
PubMedDate not supplied

Coccidioidomycosis osteomyelitis masquerading as a bone tumor. A report of 2 cases.

BACKGROUND: Coccidioidomycosis involving the lung is common in endemic areas. However, it is unusual for it to present as a solitary bone lesion. CASES: Two cases of Coccidioides immitis osteomyelitis clinically and radiographically mimicked a primary bone tumor. Fine needle aspiration (FNA) biopsy of these lytic bone lesions yielded diagnostic material. Aspirated material in 1 case showed a suppurative, granulomatous inflammation and scattered spherules with refractile walls, some containing endospores consistent with coccidioidomycosis. Smears in the other case showed acute inflammation and necrosis, and rare spherules were identified with the Gomori-mathenamine-silver stain. C immitis infection was confirmed by culture in both cases. CONCLUSION: Although rare, coccidioidomycosis can involve the bone and mimic a primary bone tumor. FNA biopsy is helpful in differentiating between inflammatory and neoplastic processes involving bone by acquiring material for cytologic studies and cultures.

Adult↗