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Antiangiogenic Therapy for the Management of Aggressive Giant Cell Lesions of the Jaws
Oral Abstract Session 2 Statement of the Problem: The need for cost-effective bone substitutes to repair large and load-bearing defects is apparent to patients who suffer extensive bone trauma from injury or disease and their surgeons. The ageing population, the number of non-lethal injuries in the Middle East conflicts, and the rising cost of health care all contribute significantly to the demand. Presently, the use of autogolous bone is the standard for defect repair but the associated procedures make this option unattractive, particularly for large defects and elderly patients. Allograft also has serious risks including disease transmission or even death. Hydroxyapatite (HA) is an osteoconductive ceramic that has the same composition as the mineral phase of bone, making it an ideal candidate for the study. We will present preliminary data that demonstrate the potential for the use of HA scaffolds with tailored porosity and structure for large and loadbearing bone defects. Materials and Methods: The two types of HA scaffolds studied, those containing only microporosity (MP) and those containing both macro- and microporosity (MMP), were fabricated using a directed deposition technique. Scaffolds were doped with BMP-2 by incorporating the growth factor into gelatin microspheres and into the scaffolds. Scaffolds of each type were implanted into the dorsal muscle of Yorkshire pigs for 8 weeks (nMP ⫽ 16, nMMP ⫽ 16). Following sacrifice, samples were examined using histology and microcomputed tomography (micro-ct). Compression tests were also conducted on a sub-set of samples (nMP ⫽ 6, nMMP ⫽ 6) within 24 hours of sacrifice. Some samples were examined using a combination of mechanical testing, histology, and micro-ct. Method of Data Analysis: See results. Results: Implanted scaffolds exhibited a change in mechanical behavior from brittle to bone-like as compared to their as-fabricated counterparts. Those containing multi-scale porosity (MP) were more osteoconductive in vivo than those with a single pore size (MMP). In fact, bone only formed in MP samples. Vasculature, loose connective tissue, adipocytes, osteoclasts, and osteoblasts were also observed in all MP samples examined histologically (nMP ⫽ 6). In MMP scaffolds (nMMP ⫽ 9), vasculature was also present but the connective tissue was more dense and fibrous. Preliminary micro-ct imaging and histology of deformed MP samples showed that the natural bone arrested crack propagation in the ceramic, thereby toughening the composite. We postulate that this small quantity of bone and connective tissue likely contributes to the transition from brittle to bonelike behavior. Conclusion: The work presented will lead to a more complete understanding of the role of multi-scale porosity in bone growth and will allow the mechanical behavior of complex, porous, and potentially loadbearing, bone scaffolds to be better understood folAAOMS • 2006
lowing implantation. The results obtained will also provide a framework for assessing the quality and function of an implant in vivo, which in turn will guide clinicians in prescribing rehabilitation strategies for recovering patients with a range of load bearing bone defects. References CDC. Update: Unexplained deaths following knee surgery. MMWR 50(48):1080, 2001 Dellinger JG: Development of model hydroxyapatite bone scaffolds with multi-scale porosity for load bearing applications. Urbana: University of Illinois at Urbana-Champaign, 2005
Antiangiogenic Therapy for the Management of Aggressive Giant Cell Lesions of the Jaws Leonard B. Kaban, DMD, MD, MGH Dept OMF, Warren 1201, 55 Fruit St, Boston, MA 02114 (Dodson T; Wilkinson M; Troulis M; Ebb D; August M) Statement of the Problem: Aggressive giant cell lesions are invasive, locally destructive vascular tumors with a high recurrence rate. The purpose of this study is to report the results of a novel treatment protocol for these tumors consisting of enucleation with adjuvant therapy using interferon alpha. Materials and Methods: The case series is composed of subjects with aggressive giant cell lesions treated at Massachusetts General Hospital from April 1995 through January 2006. Giant cell lesions were classified as aggressive if they met the following criteria: 1) size ⬎5cm or 2) a combination of root resorption, tooth displacement, cortical bone perforation or thinning or 3) recurrence. The protocol has been previously reported. Subjects disease free two years after completing interferon were classified as cured of disease. Subjects who completed interferon therapy and are free of disease, but are within the two-year time frame were classified as being in remission. Method of Data Analysis: Data were collected from clinic and hospital records and included demographic information, operation, pathology, interferon dose, interferon side effects and complications, radiographic and clinical follow-up. Results: Twenty-five subjects (F:M ⫽ 17:8) met the criteria of having aggressive giant cell lesions and were entered into the protocol. The mean age of the sample was 18.5 years (range ⫽ 3.5-54 yrs) and ten patients were under age 12. There were 18 mandibular and 7 maxillary tumors. The mean size of the lesions was 45 mm (range ⫽ 15-100 mm). Sixteen patients presented with recurrent lesions and 9 were included on the basis of size or a combination of root resorption, tooth displacement, cortical bone thinning or perforation. 41
Oral Abstract Session 2 There were no pathologic fractures and no postoperative infections. To date, sixteen subjects completed the protocol; 13 are considered cured of disease and 3 are in remission (3-21 months post interferon treatment). Four subjects failed to complete the treatment protocol due to significant side effects from the interferon therapy. The side-effects limiting interferon treatment were the development of anti-thyroid antibodies (n ⫽ 1), brachial nerve palsy (n ⫽ 1), psychiatric problems (n ⫽ 1), fatigue (n ⫽ 1). Three of these subjects received alternative therapy: zoledronate (n ⫽ 2) and en bloc resection (n ⫽ 1). Two of these three are now considered cured and one is in remission. The lesion resolved in the fourth subject without further therapy and the patient is now considered cured. Five patients are currently in active treatment. Conclusion: The data from this study indicate that enucleation of aggressive giant cell lesions with preservation of vital structures and adjuvant interferon alpha therapy is an excellent strategy for managing these tumors. Although interferon side effects are common (20% of patients), they can usually be managed by altering the dosage schedule. References Kaban LB, Mulliken JB, Ezekowitz RE, Ebb D, Smith PS, Folkman J: Anti-angiogenic therapy of a recurrent giant cell tumor of the mandible with interferon alpha-2A. Pediatrics 103(6):1145, 1999 Kaban LB, Troulis MJ, Ebb D, August MA, Hornicek F, Dodson TB: Antiangiogenic therapy with interferon-alpha for giant cell lesions of the jaws. J Oral Maxillofac Surg 60:1103, 2002
Gelatin Interacts With rhTGF-beta1 for Improved Controlled Release Abby Morgan, BS, 1304 West Green Street, 314b MSEB, MC-246, Urbana, IL 61801 (Sendemir-Urkmez A; Chan L; Cunningham B; Ehrhart N; Jamison R) Statement of the Problem: Preoperative radiation therapy is often used in the treatment of cancers to decrease tumor size and sterilize the tumor edge for surgical removal. However, when used in the case of musculoskeletal sarcomas the risk of bone fracture and nonunion is increased. Recombinant human transforming growth factor (rhTGF)-beta1 has been used to encourage bone formation and has been shown to ionically complex with gelatin. This work investigated the effect of rhTGF-beta1 released from gelatin sheets on the healing of an irradiated critical-sized rabbit ulna defect and quantified the binding strength of rhTGF-beta1 to gelatin using the Biomolecular Interaction Detection (BIND) system. Materials and Methods: Acidic gelatin sheets containing 0 microg or 5 microg rhTGF-beta1 were implanted into New Zealand white rabbits. The animals were divided into four groups: 1) radiation therapy with 5 microg rhTGF-beta1; 2) radiation therapy with 0 microg 42
rhTGF-beta1; 3) non-irradiated with 5 microg rhTGFbeta1; and 4) non-irradiated with 0 microg rhTGF-beta1. A critical sized defect of 1.5 cm was created in the right ulna of twenty-four skeletally mature rabbits. All of the animals were sacrificed eight weeks after surgery. Histological specimens of the undecalcified bone segments were stained with toluidine blue and the area of total new bone formation was quantified with histomorphometry. Method of Data Analysis: See below. Results: The relative binding affinity of rhTGF-beta1 to gelatin and heparin was quantified using BIND. The BIND system detects biomolecular binding at the surface of a sub-wavelength grating which reflects only a narrow band of wavelengths when illuminated with white light. As molecules are bound to the surface, the shift in the peak reflected wavelength corresponds to the mass on the surface. A thin layer of gelatin was added to the grating surface and rhTGFbeta1 allowed to bind. Shifts in the peak wavelength were measured and the relative binding strength calculated. Conclusion: Histological slices collected from the midgap region of the defect revealed significant new bone formation within all defects treated with rhTGF-beta. No difference was observed between the irradiated group with rhTGF-beta1 and the non-irradiated group with rhTGF-beta1. When no rhTGF-beta1 was introduced, minimal new bone formation was observed in the defect. BIND measurements revealed larger shifts in peak wavelengths when rhTGF-beta1 was bound to gelatin, indicating rhTGF-beta1 has a higher affinity for gelatin than heparin. We conclude that rhTGF-beta1 released from gelatin hydrogels is capable of overcoming the negative effects of radiation therapy and that the strong interaction between rhTGF-beta1 and gelatin leads to controlled release. References Arnold M, et al: Radiother Oncol 48:259, 1998 Ikada Y, Tabata Y: Adv Drug Deliv Rev 31:287, 1998 Cunningham BT, et al: J Biomol Screen 9:481, 2004
Tissue Engineered Bone for Mandibular Reconstruction Aylin Sendemir-Urkmez, BS, MS, PhD, 1304 West Green Street, 314b MSEB, MC-246, Urbana, IL 61801 (Clark S; Goldwasser M; Wheeler M; Jamison R) Statement of the Problem: For the restoration of maxillofacial bone tissue loss, tissue engineering tools have been investigated in order to replace autogenous cancellous bone grafts with synthetic materials. A porous, three dimensional osteoconductive scaffold is required for the engineering of bone tissue to provide a frameAAOMS • 2006
lowing implantation. The results obtained will also provide a framework for assessing the quality and function of an implant in vivo, which in turn will guide clinicians in prescribing rehabilitation strategies for recovering patients with a range of load bearing bone defects. References CDC. Update: Unexplained deaths following knee surgery. MMWR 50(48):1080, 2001 Dellinger JG: Development of model hydroxyapatite bone scaffolds with multi-scale porosity for load bearing applications. Urbana: University of Illinois at Urbana-Champaign, 2005
Antiangiogenic Therapy for the Management of Aggressive Giant Cell Lesions of the Jaws Leonard B. Kaban, DMD, MD, MGH Dept OMF, Warren 1201, 55 Fruit St, Boston, MA 02114 (Dodson T; Wilkinson M; Troulis M; Ebb D; August M) Statement of the Problem: Aggressive giant cell lesions are invasive, locally destructive vascular tumors with a high recurrence rate. The purpose of this study is to report the results of a novel treatment protocol for these tumors consisting of enucleation with adjuvant therapy using interferon alpha. Materials and Methods: The case series is composed of subjects with aggressive giant cell lesions treated at Massachusetts General Hospital from April 1995 through January 2006. Giant cell lesions were classified as aggressive if they met the following criteria: 1) size ⬎5cm or 2) a combination of root resorption, tooth displacement, cortical bone perforation or thinning or 3) recurrence. The protocol has been previously reported. Subjects disease free two years after completing interferon were classified as cured of disease. Subjects who completed interferon therapy and are free of disease, but are within the two-year time frame were classified as being in remission. Method of Data Analysis: Data were collected from clinic and hospital records and included demographic information, operation, pathology, interferon dose, interferon side effects and complications, radiographic and clinical follow-up. Results: Twenty-five subjects (F:M ⫽ 17:8) met the criteria of having aggressive giant cell lesions and were entered into the protocol. The mean age of the sample was 18.5 years (range ⫽ 3.5-54 yrs) and ten patients were under age 12. There were 18 mandibular and 7 maxillary tumors. The mean size of the lesions was 45 mm (range ⫽ 15-100 mm). Sixteen patients presented with recurrent lesions and 9 were included on the basis of size or a combination of root resorption, tooth displacement, cortical bone thinning or perforation. 41
Oral Abstract Session 2 There were no pathologic fractures and no postoperative infections. To date, sixteen subjects completed the protocol; 13 are considered cured of disease and 3 are in remission (3-21 months post interferon treatment). Four subjects failed to complete the treatment protocol due to significant side effects from the interferon therapy. The side-effects limiting interferon treatment were the development of anti-thyroid antibodies (n ⫽ 1), brachial nerve palsy (n ⫽ 1), psychiatric problems (n ⫽ 1), fatigue (n ⫽ 1). Three of these subjects received alternative therapy: zoledronate (n ⫽ 2) and en bloc resection (n ⫽ 1). Two of these three are now considered cured and one is in remission. The lesion resolved in the fourth subject without further therapy and the patient is now considered cured. Five patients are currently in active treatment. Conclusion: The data from this study indicate that enucleation of aggressive giant cell lesions with preservation of vital structures and adjuvant interferon alpha therapy is an excellent strategy for managing these tumors. Although interferon side effects are common (20% of patients), they can usually be managed by altering the dosage schedule. References Kaban LB, Mulliken JB, Ezekowitz RE, Ebb D, Smith PS, Folkman J: Anti-angiogenic therapy of a recurrent giant cell tumor of the mandible with interferon alpha-2A. Pediatrics 103(6):1145, 1999 Kaban LB, Troulis MJ, Ebb D, August MA, Hornicek F, Dodson TB: Antiangiogenic therapy with interferon-alpha for giant cell lesions of the jaws. J Oral Maxillofac Surg 60:1103, 2002
Gelatin Interacts With rhTGF-beta1 for Improved Controlled Release Abby Morgan, BS, 1304 West Green Street, 314b MSEB, MC-246, Urbana, IL 61801 (Sendemir-Urkmez A; Chan L; Cunningham B; Ehrhart N; Jamison R) Statement of the Problem: Preoperative radiation therapy is often used in the treatment of cancers to decrease tumor size and sterilize the tumor edge for surgical removal. However, when used in the case of musculoskeletal sarcomas the risk of bone fracture and nonunion is increased. Recombinant human transforming growth factor (rhTGF)-beta1 has been used to encourage bone formation and has been shown to ionically complex with gelatin. This work investigated the effect of rhTGF-beta1 released from gelatin sheets on the healing of an irradiated critical-sized rabbit ulna defect and quantified the binding strength of rhTGF-beta1 to gelatin using the Biomolecular Interaction Detection (BIND) system. Materials and Methods: Acidic gelatin sheets containing 0 microg or 5 microg rhTGF-beta1 were implanted into New Zealand white rabbits. The animals were divided into four groups: 1) radiation therapy with 5 microg rhTGF-beta1; 2) radiation therapy with 0 microg 42
rhTGF-beta1; 3) non-irradiated with 5 microg rhTGFbeta1; and 4) non-irradiated with 0 microg rhTGF-beta1. A critical sized defect of 1.5 cm was created in the right ulna of twenty-four skeletally mature rabbits. All of the animals were sacrificed eight weeks after surgery. Histological specimens of the undecalcified bone segments were stained with toluidine blue and the area of total new bone formation was quantified with histomorphometry. Method of Data Analysis: See below. Results: The relative binding affinity of rhTGF-beta1 to gelatin and heparin was quantified using BIND. The BIND system detects biomolecular binding at the surface of a sub-wavelength grating which reflects only a narrow band of wavelengths when illuminated with white light. As molecules are bound to the surface, the shift in the peak reflected wavelength corresponds to the mass on the surface. A thin layer of gelatin was added to the grating surface and rhTGFbeta1 allowed to bind. Shifts in the peak wavelength were measured and the relative binding strength calculated. Conclusion: Histological slices collected from the midgap region of the defect revealed significant new bone formation within all defects treated with rhTGF-beta. No difference was observed between the irradiated group with rhTGF-beta1 and the non-irradiated group with rhTGF-beta1. When no rhTGF-beta1 was introduced, minimal new bone formation was observed in the defect. BIND measurements revealed larger shifts in peak wavelengths when rhTGF-beta1 was bound to gelatin, indicating rhTGF-beta1 has a higher affinity for gelatin than heparin. We conclude that rhTGF-beta1 released from gelatin hydrogels is capable of overcoming the negative effects of radiation therapy and that the strong interaction between rhTGF-beta1 and gelatin leads to controlled release. References Arnold M, et al: Radiother Oncol 48:259, 1998 Ikada Y, Tabata Y: Adv Drug Deliv Rev 31:287, 1998 Cunningham BT, et al: J Biomol Screen 9:481, 2004
Tissue Engineered Bone for Mandibular Reconstruction Aylin Sendemir-Urkmez, BS, MS, PhD, 1304 West Green Street, 314b MSEB, MC-246, Urbana, IL 61801 (Clark S; Goldwasser M; Wheeler M; Jamison R) Statement of the Problem: For the restoration of maxillofacial bone tissue loss, tissue engineering tools have been investigated in order to replace autogenous cancellous bone grafts with synthetic materials. A porous, three dimensional osteoconductive scaffold is required for the engineering of bone tissue to provide a frameAAOMS • 2006