The complex nature of bony orbital fractures and their impact upon orbital soft tissue structure and visual function presents a particular challenge to the orbital surgeon. The tenants of surgical management of symptomatic orbital fractures involve open reduction of the fracture, release of the entrapped tissues, repositioning of the herniated orbital soft tissue within the orbit, and repair of the post-traumatic defect with an orbital implant as needed. The orbital implant restores the structural integrity of the orbital wall by bridging the defect and preventing orbital contents from herniating into the adjacent periorbital sinuses. The implant should prevent extra-ocular motility limitations by minimizing scar tissue adhesion with orbital contents. These implants can also serve to augment the orbital volume by compressing the intraorbital contents to correct enophthalmos. Current implants include autogenous grafts, human donor grafts, xenografts and alloplastic implants. The ideal alloplastic implant has been described as readily sizeable, sterilizable, strong, inert, non-allergenic, durable, non-carcinogenic, easily manipulated and shaped, and suitable for single stage reconstruction. Implants should be accepted and well integrated into the surrounding tissues with minimal inflammatory response, foreign body reaction, or risk of infection. The implant should provide mechanical support strong enough to hold up the orbital contents, and have the ability to be easily anchored to the surrounding bone to prevent migration and extrusion. Finally, it should be readily available in larger quantities if necessary, at a reasonable cost.

The complex nature of bony orbital fractures and their impact upon orbital soft tissue structure and visual function presents a particular challenge to the orbital surgeon. The tenants of surgical manage- ment of symptomatic orbital fractures involve open reduction of the fracture, release of the entrapped tissues, repositioning of the herniated orbital soft tis- sue within the orbit, and repair of the post-traumat- ic defect with an orbital implant as needed. The orbital implant restores the structural integrity of the orbital wall by bridging the defect and preventing orbital contents from herniating into the adjacent periorbital sinuses. The implant should prevent extra-ocular motility limitations by minimizing scar tissue adhesion with orbital contents. These implants can also serve to augment the orbital volume by compressing the intraorbital contents to correct enophthalmos. 1 Current implants include autoge- nous grafts, human donor grafts, xenografts and alloplastic implants. The ideal alloplastic implant has been described as readily sizeable, sterilizable, strong, inert, non-allergenic, durable, non-carcino- genic, easily manipulated and shaped, and suitable for single stage reconstruction. 2 Implants should be accepted and well integrated into the surrounding tissues with minimal inflammatory response, foreign body reaction, or risk of infection. The implant should provide mechanical support strong enough to hold up the orbital contents, and have the ability to be easily anchored to the surrounding bone to prevent migration and extrusion. Finally, it should be readily available in larger quantities if necessary, at a reasonable cost.

This phase 1 clinical trial was conducted to evaluate the safety and to determine the maximum tolerated dose (MTD) of the immunocytokine EMD 273066 huKS-IL2 and, secondarily, to assess its pharmacokinetics, immunogenic potential, and immunologic activity in patients with androgen-independent prostate cancer (n = 22). EMD 273066 was administered in 3-day cycles (separated by 4 weeks) of once-daily, 4-hour intravenous infusions at a dose determined by an escalation protocol (0.4, 0.7, 1.4, 2.8, 4.3, 6.4, or 8.5 mg/m/d). Approximately 2/3 of patients received a second cycle of treatment. The results show that the MTD of EMD 273066 [ie, one dose level below that producing dose-limiting toxicity (DLT) in at least 33% of patients in a dosing group] was 6.4 mg/m/d. EMD 273066 was generally well tolerated up to a dose of 4.3 mg/m/d. No DLTs, defined as drug-related toxicities >OR= Grade 3 occurring during the first treatment cycle, were observed among patients in the 0.4-, 0.7-, 1.4-, or 4.3-mg/m/d dosing groups. Four patients treated with 2.8, 6.4, or 8.5 mg/m/d EMD 273066 experienced DLTs. Titers of both antiimmunocytokine and anti-FcIL-2 antibody responses were observed after the first dose cycle and either decreased or remained stable during a second course of treatment. No hypersensitivity reactions were observed. EMD 273066 exhibited immunologic activity as demonstrated by increases in lymphocyte counts, natural killer cell number and specific activity, and antibody-dependent cellular cytotoxicity activity. On average, Cmax, which was dose-dependent, was achieved within 1 hour after infusion. Mean t(1/2) which was independent of dose, ranged from 4.0 to 6.7 hours across doses. A zero-compartment body model with one-order kinetics best described the concentration-time profiles. These data demonstrate that the novel immunocytokine EMD 273066 is well tolerated at doses above a level of observed systemic biologic activity in patients with androgen-independent prostate cancer.

PURPOSEPrevious studies showed that reducing the interaction of antibody-interleukin 2 immunocytokines with Fc receptors improved their circulating half-life in mice and increased their antitumor activity. We sought to modify sequences that would increase half-life but retain the ability to activate Fc receptor-mediated effector functions.EXPERIMENTAL DESIGNModified immunocytokines were assessed in vitro for effector function and protease sensitivity and in vivo for pharmacokinetic and antitumor activities in an syngeneic tumor regression model.RESULTSSingle amino acid changes in the junction sequence between the antibody and interleukin-2 components had dramatic effects on circulating half-life and antitumor activity. This effect was independent of Fc receptor binding to either Fcgamma receptors or the Fc protection receptor, but was associated with changes in susceptibility to intracellular proteases.CONCLUSIONSWe have identified modifications that dramatically improve the circulating half-life of immunocytokines based on increased resistance to intracellular degradation and thus have demonstrated how these molecules can be recycled in and out of an intracellular compartment. Use of these improved immunocytokines with highly favorable pharmacokinetic properties and retained effector functions should lead to more effective treatment of epithelial cancers.

X-ray absorption microtomography, a high resolution variant of medical "CT", and synchrotron x-ray phase contrast imaging reveal the distribution of mineral within teeth of the sea urchin Lytechinus variegatus. Data from these imaging modalities on intact teeth are compared with histochemically stained thin sections observed with transmission optical microscopy. Because these teeth grow continuously, the complex variation of attenuation from aboral to incisal end shows how the sea urchin increases mineralization to produce a hard, self-sharpening cutting edge. The phase contrast radiographs appear to show the calcite crystal morphology with greater sensitivity, at least in some portions of the tooth.

ABSTRACT Information systems, i. e. MIS, and organisations are seen today as two separate parts. This causes obstacles in designing tomorrow's organisations and their information systems. J. P. van Gigch and J. L. Le Moigne (1990) proposes an OIS-paradigm in which