The effectiveness of the controlled release of gentamicin from polyelectrolyte multilayers in the treatment of Staphylococcus aureus infection in a rabbit bone model

While the infection rate of orthopedic implants is low, the required treatment, which can involve six weeks of antibiotic therapy and two additional surgical operations, is life threatening and expensive, and thus motivates the development of a one-stage re-implantation procedure. Polyelectrolyte multilayers incorporating gentamicin were fabricated using the layer-by-layer deposition process for use as a device coating to address an existing bone infection in a direct implant exchange operation. The films eluted about 70% of their payload in vitro during the first three days and subsequently continued to release drug for more than four additional weeks, reaching a total average release of over 550 μg/cm[superscript 2]. The coatings were demonstrated to be bactericidal against Staphylococcus aureus, and degradation products were generally nontoxic towards MC3T3-E1 murine preosteoblasts. Film-coated titanium implants were compared to uncoated implants in an in vivo S. aureus bone infection model. After a direct exchange procedure, the antimicrobial-coated devices yielded bone homogenates with a significantly lower degree of infection than uncoated devices at both day four (p < 0.004) and day seven (p < 0.03). This study has demonstrated that a self-assembled ultrathin film coating is capable of effectively treating an experimental bone infection in vivo and lays the foundation for development of a multi-therapeutic film for optimized, synergistic treatment of pain, infection, and osteomyelitis.National Institutes of Health (U.S.) (National Institute on Aging Grant 5R01AG029601-03

Atomic Resonance and Scattering

Contains research objectives and summary of research on eight research projects.National Science Foundation (Grant PHY75-15421-A01)U. S. Air Force - Office of Scientific Research (Grant AFOSR 76-2972)Joint Services Electronics Program (Contract DAAB07-76-C-1400)U. S. Air Force - Office of Scientific Research (Contract F44620-72-C-0057

Atomic Resonance and Scattering

Contains reports on nine research projects.U.S. Energy Research and Development Administration (Contract EG-77-S-02-4370)U. S. Air Force - Office of Scientific Research (Contract F44620-72-C-0057)Joint Services Electronics Program (Contract DAAB07-76-C-1400)National Science Foundation (Grant PHY75-15421-AO1)National Science Foundation (Grant PHY77-09155)National Science Foundation (Grant CHE76-81750)U. S. Air Force - Office of Scientific Research (Grant AFOSR-76-2972A

Atomic Resonance and Scattering

Contains reports on eight research projects.National Science Foundation (Grant PHY77-09155)Joint Services Electronics Program (Contract DAAG29-78-C-0020)U. S. Department of Energy (Grant EG-77-S-02-4370)National Science Foundation (Grant DMR 77-10084)National Aeronautics and Space Administration (Grant NSG-1551)U. S. Air Force - Office of Scientific Research (Grant AFOSR-76-2972)National Science Foundation (Grant CHE76-81750

Surface-Mediated Bone Tissue Morphogenesis from Tunable Nanolayered Implant Coatings

The functional success of a biomedical implant critically depends on its stable bonding with the host tissue. Aseptic implant loosening accounts for more than half of all joint replacement failures. Various materials, including metals and plastic, confer mechanical integrity to the device, but often these materials are not suitable for direct integration with the host tissue, which leads to implant loosening and patient morbidity. We describe a self-assembled, osteogenic, polymer-based conformal coating that promotes stable mechanical fixation of an implant in a surrogate rodent model. A single modular, polymer-based multilayered coating was deposited using a water-based layer-by-layer approach, by which each element was introduced on the surface in nanoscale layers. Osteoconductive hydroxyapatite (HAP) and osteoinductive bone morphogenetic protein–2 (BMP-2) contained within the nanostructured coating acted synergistically to induce osteoblastic differentiation of endogenous progenitor cells within the bone marrow, without indications of a foreign body response. The tuned release of BMP-2, controlled by a hydrolytically degradable poly(β-amino ester), was essential for tissue regeneration, and in the presence of HAP, the modular coating encouraged the direct deposition of highly cohesive trabecular bone on the implant surface. In vivo, the bone-implant interfacial tensile strength was significantly higher than standard bioactive bone cement, did not fracture at the interface, and had long-term stability. Collectively, these results suggest that the multilayered coating system promotes biological fixation of orthopedic and dental implants to improve surgical outcomes by preventing loosening and premature failure.David H. Koch Institute for Integrative Cancer Research at MIT (Koch Institute Swanson Biotechnology Center)National Institutes of Health (U.S.) (NIH R01 AG029601)United States. Army Research Office. Institute for Soldier Nanotechnologies (contract no.W911NF-07-D-0004)David H. Koch Institute for Integrative Cancer Research at MIT (NCI grant P30 CA014051)Natural Sciences and Engineering Research Council of Canada (Fellowship)National Science Foundation (U.S.) (Fellowship)David H. Koch Institute for Integrative Cancer Research at MIT (David H. Koch (1962) Chair Professorship in Engineering

The Significance of Brain Temperature in Focal Cerebral Ischemia: Histopathological Consequences of Middle Cerebral Artery Occlusion in the Rat

The purpose of this study was to determine the effect of selective modulation of brain temperature in the experimental settings of permanent and reversible middle cerebral artery (MCA) occlusion in Sprague–Dawley rats. Three models of proximal MCA occlusion were used, in which the effect of brain-temperature modulations could be studied. These included (a) permanent MCA occlusion with an initial 30-min period of hypotension (30 or 36°C × 4 h), (b) permanent MCA occlusion alone (30, 36, or 39°C × 2 h), and (c) 2 h of reversible MCA occlusion (30, 36, or 39°C × 2 h). In the transient MCA occlusion series, intra- and postischemic cortical blood flow was assessed using a laser–Doppler flowmeter placed over the dorsolateral cortex. After a 3-day survival, all rats were perfusion fixed for histopathological analysis and the determination of infarct volume. In animals with permanent MCA occlusion plus hypotension, no significant difference in infarct volume was demonstrated between the 30 and 36°C groups. In rats with permanent MCA occlusion without hypotension, significant differences in infarct volume were again not demonstrable, but an interaction between infarct area and temperature class was shown by repeated-measures analysis, indicating that hypothermia altered the topographic pattern of the cortical infarct. With 2 h of reversible MCA occlusion, there was a statistically significant reduction in infarct volume in the 30°C group compared to 39°C rats. Although intra- and postischemic CBF were not significantly different among the three temperature groups, the cortical infarct volume was positively correlated with postischemic CBF. The postischemic CBF, in turn, was positively correlated to the intraischemic brain temperature and was negatively correlated to CBF during the ischemic period. These findings demonstrate that moderate manipulations of brain temperature have a greater influence on the resulting cortical infarction in the setting of transient focal ischemia than in the context of permanent vascular occlusion

A Phase II Study of Ofatumumab in Combination with ICE or DHAP Chemotherapy in Relapsed or Refractory Aggressive B-Cell Lymphoma Prior to Autologous Stem Cell Transplantation (ASCT)

Abstract Abstract 957 Background: For patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), standard-of-care second-line therapy in patients eligible for consolidative high-dose therapy with autologous stem cell rescue (HDT/ASCR) is rituximab (R) combined with a platinum-containing regimen such as ifosfamide, carboplatin, and etoposide (ICE) or dexamethasone, cytarabine, and cisplatin (DHAP). In patients with early relapse or refractory disease following first-line treatment, the efficacy of second-line rituximab combined with salvage chemotherapy is lower in patients previously treated with rituximab combined with chemotherapy compared to patients treated with chemotherapy alone (Gisselbrecht et al. J Clin Oncol 2010). Ofatumumab (OFA), a fully human monoclonal antibody against CD20, uses an alternate binding site from that of rituximab, and demonstrates more potent complement-dependent cytotoxicity in vitro than does rituximab (Teeling et al. J Immunol 2006). We hypothesize that the inclusion of ofatumumab in second-line therapy could improve response rates for aggressive B-cell non-Hodgkin's lymphoma (NHL) relapsing after, or refractory to, rituximab-containing initial therapy. Methods: Between May 2009 and April 2011, 61 patients (pts) were enrolled with relapsed or refractory CD20 positive aggressive B-cell NHL (DLBCL, transformed low grade lymphoma or grade 3B follicular lymphoma). Pts were transplant eligible with either pathologically confirmed relapse after first-line therapy or primary refractory disease. Initial therapy must have included rituximab combined with anthracycline/anthracenedione chemotherapy. Sites elected to treat all of their pts with either ICE or DHAP. Chemotherapy was dosed every 21 days for 3 cycles. OFA was dosed on D1 and D8 of cycle 1, then D1 of cycles 2 and 3. Initially, the first dose of OFA was 300mg, but the study was amended to increase the first dose to 1000mg. All other doses of OFA were 1000mg. Response was assessed after cycles 2 (CT) and 3 (CT + PET). The primary endpoint was overall response rate (ORR) using modified RRCML criteria (Cheson et al. J Clin Oncol 2007). Results: 61 pts were enrolled; 35 pts were treated with ICE and 26 pts with DHAP. 21 pts received an initial OFA dose of 300mg and 40 pts received 1000mg. High risk disease was well represented, with 80% having disease that was either primary refractory (47%), relapsed within 12 months of diagnosis (30%), or progressed from unknown response within 12 months of diagnosis (3%); 48% of pts had a second-line age-adjusted IPI (sAAIPI) of 2 (41%) or 3 (7%) risk factors. 9 (15%) pts were prematurely withdrawn from treatment due to investigator decision (n=5, usually due to stable disease deemed an inadequate response), AEs (n=3) or pt decision (n=1). 2 pts were CD20 negative and excluded from the efficacy analysis. The ORR in the 59 evaluable pts was 61% (95% CI: 47%–74%), with CR in 37% (95% CI: 25%–51%). For OFA+DHAP, the ORR was 69% (95% CI: 48%–86%), with CR in 42% (95% CI: 23%–63%), and for OFA+ICE, was 55% (95% CI: 36%–72%), with CR in 33% (95% CI: 18%–52%). For patients with sAAIPI of 2 or 3 (29 pts), the ORR was 59% (95% CI: 39%–77%), with CR in 31% (95% CI: 15%–51%). For pts with primary refractory or early relapsing disease, the ORR was 55% (95% CI: 40%–70%), with CR in 30% (95% CI: 17%–45%). 45 pts underwent peripheral blood stem cell mobilization, and 43 (96%) mobilized ≥2×106 CD34+ cells/kg (median, 5.8×106 CD34+ cells/kg). Grade ≥3 AEs occurred in 47 pts (77%); the most common were thrombocytopenia (59% pts), anemia (36%), neutropenia (26%), lymphopenia (23%), leukopenia (18%), febrile neutropenia (13%), and hypokalemia (13%). 3 pts (12%) treated with OFA+DHAP had grade ≥3 nephrotoxicity. 3 pts discontinued treatment due to chemotherapy related AEs: mental status change (2 pts), respiratory distress (1 pt), and elevated creatinine (1 pt). No treatment related deaths were reported. Conclusions: OFA combined with salvage ICE or DHAP showed promising activity with an ORR of 61%. Treatment was adequately tolerated, with no unexpected toxicity, and stem cell mobilization was not adversely affected. Furthermore, the results are particularly promising in patients with primary refractory or early-relapsing disease, a group that has been reported to have extremely adverse outcomes. In order to compare rituximab to OFA in the salvage setting, a phase III randomized trial of OFA+DHAP and R+DHAP is ongoing. Disclosures: Matasar: GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Ofatumumab is an anti-CD20 monoclonal antibody approved for the treatment of fludarabine- and alemtuzumab-refractory chronic lymphocytic leukemia, and is currently under development for the treatment of B-cell malignancies (chronic lymphocytic leukemia, diffuse large B-cell lymphoma, Waldenstroms macroglobulinemia and follicular lymphoma), as well as autoimmune diseases (rheumatoid arthritis and multiple sclerosis). Czuczman:Ortho Biotech: Research Funding; Centocor: Research Funding; Novartis: Research Funding; GlaxoSmithKline: Consultancy, Research Funding; Abbott: Research Funding; Sanofi-Aventis: Consultancy; Genentech: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Cephalon: Consultancy, Research Funding. Rodriguez:Genentech: Research Funding; Pfizer Pharmaceuticals: Research Funding; Ortho Biotech: Research Funding. Fennessy:Glaxo Smith-Kline: Employment, Equity Ownership. Shea:Otsuka: Research Funding; Millenium: Research Funding; Genzyme: Research Funding; Novartis: Research Funding; GlaxoSmithKline: Research Funding; Bristol-Myers Squibb: Research Funding. Spitzer:Amgen: Equity Ownership; Celgene: Speakers Bureau; Millenium: Honoraria, Speakers Bureau; Cephalon: Honoraria, Speakers Bureau; Merck: Honoraria, Speakers Bureau; GSK: Honoraria, Speakers Bureau. Fayad:GSK: Research Funding. Liao:GlaxoSmithKline: Employment. Edvardsen:GlaxoSmithKline: Employment. Lisby:Genmab: Employment