Panobacumab adjunctive immuno-therapy for Pseudomonas aeruginosa hospital-acquired pneumonia versus a cohort group

Objectives: To assess the efficacy of Panobacumab, a fully human IgM monoclonal antibody against P. aeruginosa serotype O11, by comparing a phase IIa trial with a standard care cohort trial both in hospital acquired pneumonia (HAP) caused by P. aeruginosa O11. Methods: Demographics, outcome and survival of HAP including Ventilator Associated Pneumonia (VAP) in patients either treated with standard antimicrobial therapy in a retrospective cohort trial (CT) or with adjunctive Panobacumab therapy during an open phase IIa trial were compared. Both trials applied the same inclusion exclusion criteria and the same trial period of 30 days. Results: 17 patients with VAP/HAP (14 / 3) caused by P. aeruginosa O11 were enrolled in a phase IIa trial (ITT population) and treated with Panobacumab, 13 of them received the full treatment course of 3 infusions (PP population, 12 VAP, 1 HAP) and 4 patients received only one infusion. In the cohort trial 14 patients (VAP/HAP: 12 / 2) treated with standard antibiotic therapy were included. The mean age and weight were 65.8 y (years) (SD 17.2) and 78.0 kg (SD 22.1) in the PP, 67.8 y (SD 15.4) and 77.1 kg (SD 20.2) in the ITT population and 51.8 y (SD 22.3) and 67.1 kg (SD 13.0) in the CT. At the time of suspicion of pneumonia a mean APACHE II and CPIS of 19.4 (13 - 33) and 8.7 (7 - 11) in the PP, 18.9 (13-33) and 8.5 (7 -11) in the ITT and 14.5 (2 - 24) and 7.5 (3 -12) in the CT population were observed. Tracheostomy was present in 53.8% and 52.9% in the PP and ITT populations and 38.4% in the CT. The pneumonia was polymicrobial in 69.2%, 70.6% and 85.7% in the PP, ITT and CT respectively. Stay at ICU and hospital before diagnosis of pneumonia were similar in the 3 groups. All 13 patients that received 3 doses of Panobacumab achieved resolution of pneumonia with only two relapsing during the study. Hence 85% achieved resolution and 15% recurrence at day 30. In the ITT group 64.7% of the pneumonia resolved 11.8% recurred and 23.5% continued while in the CT 57% resolved, 7% recurred and 34% continued. Resolution of pneumonia occurred markedly earlier in the Panobacumab trial (8.9 days, SD: 3.3) than in the cohort trial (15.3 days, SD: 9.5). The expected mortality derived from APACHE II score was 31% and 32% in the PP and ITT population and 22% in the cohort group. All patients who received 3 doses of Panobacumab survived, 18% died in the ITT group while in the CT 21% mortality matched the predicted mortality. Conclusions: Treatment of VAP/HAP caused by P. aeruginosa O11 with 3 doses of Panobacumab resulted in 100% survival, with highest pneumonia resolution (85%), and in a shorter time when compared with patients under standard therapy. The results indicate that Panobacumab may be effective in such life-threatening indication and warrants larger controlled trials.

Evaluation of Rumble Stripes on Low-Volume Rural Roads in Iowa—Phase II Final Report, November 2011

Single-vehicle run-off-road crashes are the most common crash type on rural two-lane Iowa roads. Rumble strips have proven effective in mitigating these crashes, but the strips are commonly installed in paved shoulders on higher-volume roads that are owned by the State of Iowa. Lower-volume paved rural roads owned by local agencies do not commonly feature paved shoulders but frequently experience run-off-road crashes. This project involved installing rumble stripes, which are a combination of conventional rumble strips with a painted edge line placed on the surface of the milled area, along the edge of the travel lanes, but at a narrow width to avoid possible intrusion into the normal vehicle travel paths. The research described in this report was part of a project funded by the Federal Highway Administration, Iowa Highway Research Board, and Iowa Department of Transportation to evaluate the effectiveness of edge-line rumble strips in Iowa. The project evaluated the effectiveness of rumble stripes in reducing run-off-road crashes and in improving the longevity and wet-weather visibility of edge-line markings. This project consisted of two phases. The first phase was to select pilot study locations, select a set of test sites, install rumble stripes, summarize lessons learned during installation, and provide a preliminary assessment of the rumble stripes’ performance. The purpose of this report was to document results from Phase II. A before and after crash analysis was conducted to assess whether use of the treatment had resulted in fewer crashes. However, due to low sample size, results of the analysis were inconclusive. Lateral position was also evaluated before and after installation of the treatment to determine whether vehicles engaged in better lane keeping. Pavement marking wear was also assessed.

Cilengitide: an RGD pentapeptide ανβ3 and ανβ5 integrin inhibitor in development for glioblastoma and other malignancies.

Cilengitide, a cyclicized arginine-glycine-aspartic acid-containing pentapeptide, potently blocks ανβ3 and ανβ5 integrin activation. Integrins are upregulated in many malignancies and mediate a wide variety of tumor-stroma interactions. Cilengitide and other integrin-targeting therapeutics have preclinical activity against many cancer subtypes including glioblastoma (GBM), the most common and deadliest CNS tumor. Cilengitide is active against orthotopic GBM xenografts and can augment radiotherapy and chemotherapy in these models. In Phase I and II GBM trials, cilengitide and the combination of cilengitide with standard temozolomide and radiation demonstrate consistent antitumor activity and a favorable safety profile. Cilengitide is currently under evaluation in a pivotal, randomized Phase III study (Cilengitide in Combination With Temozolomide and Radiotherapy in Newly Diagnosed Glioblastoma Phase III Randomized Clinical Trial [CENTRIC]) for newly diagnosed GBM. In addition, randomized controlled Phase II studies with cilengitide are ongoing for non-small-cell lung cancer and squamous cell carcinoma of the head and neck. Cilengitide is the first integrin inhibitor in clinical Phase III development for oncology.

Antibody-mediated and cellular immune responses induced in naive volunteers by vaccination with long synthetic peptides derived from the Plasmodium vivax circumsporozoite protein.

Plasmodium vivax circumsporozoite (CS) protein is a leading malaria vaccine candidate. We describe the characterization of specific immune responses induced in 21 malaria-naive volunteers vaccinated with long synthetic peptides derived from the CS protein formulated in Montanide ISA 720. Both antibody- and cell-mediated immune responses were analyzed. Antibodies were predominantly of IgG1 and IgG3 isotypes, recognized parasite proteins on the immunofluorescent antibody test, and partially blocked sporozoite invasion of hepatoma cell lines in vitro. Peripheral blood mononuclear cells from most volunteers (94%) showed IFN-γ production in vitro upon stimulation with both long signal peptide and short peptides containing CD8+ T-cell epitopes. The relatively limited sample size did not allow conclusions about HLA associations with the immune responses observed. In summary, the inherent safety and tolerability together with strong antibody responses, invasion blocking activity, and the IFN-γ production induced by these vaccine candidates warrants further testing in a phase II clinical trial.

Embankment Quality, TR-401, Phase I, 1998

Phase I was initiated as a result of internal Iowa Department of Transportation (Iowa DOT) studies that raised concerns about the quality of embankments being constructed. Some large embankments have recently developed slope stability problems. In addition, pavement roughness has been noted shortly after roads were opened to traffic. This raised the question as to whether the current Iowa DOT embankment construction specifications are adequate. The primary objective of Phase I was to evaluate the quality of embankments being constructed under the current Iowa DOT specifications. The project was initiated in May 1997 with a tour of several embankment projects being constructed around the state. At each of these projects the resident construction engineer, field inspector, and contractor were interviewed with respect to their opinion of the current specifications. From construction observations and discussion during these visits it became obvious that there were problems with the current embankment construction specifications. Six embankment projects were selected for in-depth analysis and to represent the full range of soil types being used across the state. The results of Phase I field and laboratory construction testing and observations and post construction testing are presented in this report. Overall evaluation of the results of Phase I indicate that Iowa is not consistently obtaining a quality embankment constructed under the current Iowa DOT specifications. Based on these results, recommendations are made for Phase II to evaluate alternative specifications and develop rapid field methods for compaction control and soil identification.

Strengthening of Existing Single Span Steel Beam and Concrete Deck Bridges, HR-238, Part II, 1985

The unifying objective of Phases I and II of this study was to determine the feasibility of the post-tensioning strengthening method and to implement the technique on two composite bridges in Iowa. Following completion of these two phases, Phase III was undertaken and is documented in this report. The basic objectives of Phase III were further monitoring bridge behavior (both during and after post-tensioning) and developing a practical design methodology for designing the strengthening system under investigation. Specific objectives were: to develop strain and force transducers to facilitate the collection of field data; to investigate further the existence and effects of the end restraint on the post-tensioning process; to determine the amount of post-tensioning force loss that occurred during the time between the initial testing and the retesting of the existing bridges; to determine the significance of any temporary temperature-induced post-tensioning force change; and to develop a simplified design methodology that would incorporate various variables such as span length, angle-of-skew, beam spacing, and concrete strength. Experimental field results obtained during Phases II and III were compared to the theoretical results and to each other. Conclusions from this research are as follows: (1) Strengthening single-span composite bridges by post-tensioning is a viable, economical strengthening technique. (2) Behavior of both bridges was similar to the behavior observed from the bridges during field tests conducted under Phase II. (3) The strain transducers were very accurate at measuring mid-span strain. (4) The force transducers gave excellent results under laboratory conditions, but were found to be less effective when used in actual bridge tests. (5) Loss of post-tensioning force due to temperature effects in any particular steel beam post-tensioning tendon system were found to be small. (6) Loss of post-tensioning force over a two-year period was minimal. (7) Significant end restraint was measured in both bridges, caused primarily by reinforcing steel being continuous from the deck into the abutments. This end restraint reduced the effectiveness of the post-tensioning but also reduced midspan strains due to truck loadings. (8) The SAP IV finite element model is capable of accurately modeling the behavior of a post-tensioned bridge, if guardrails and end restraints are included in the model. (9) Post-tensioning distribution should be separated into distributions for the axial force and moment components of an eccentric post-tensioning force. (10) Skews of 45 deg or less have a minor influence on post-tensioning distribution. (11) For typical Iowa three-beam and four-beam composite bridges, simple regression-derived formulas for force and moment fractions can be used to estimate post-tensioning distribution at midspan. At other locations, a simple linear interpolation gives approximately correct results. (12) A simple analytical model can accurately estimate the flexural strength of an isolated post-tensioned composite beam.

Evaluation of Control Structures for Stabilizing Degrading Stream Channels in Western Iowa, Phases II and III, HR-208A, 1985

Since the turn of the century, tributaries to the Missouri River in western Iowa have entrenched their channels to as much as six times their original depth. This channel degradation is accompanied by widening as the channel side slopes become unstable and landslides occur. The deepening and widening of these streams have endangered about 25% of the highway bridges in 13 counties [Lohnes et al. 1980]. Grade stabilization structures have been recommended as the most effective remedial measure for stream degradation [Brice et al., 1978]. In western Iowa, within the last seven years, reinforced concrete grade stabilization structures have cost between $300,000 and $1,200,000. Recognizing that the high cost of these structures may be prohibitive in many situations, the Iowa Department of Transportation (Iowa DOT) sponsored a study at Iowa State University (ISU) to find low-cost alternative structures. This was Phase I of the stream degradation study. Analytical and laboratory work led to the conclusion that alternative construction materials such as gabions and soil-cement might result in more economical structures [Lohnes et al. 1980]. The ISU study also recommended that six experimental structures be built and their performance evaluated. Phase II involved the design of the demonstration structures, and Phase III included monitoring and evaluating their performance.

Concept Highway Maintenance Vehicle, Final Report, Phase Two, 1998

This report documents Phase II activities of a potentially four-phase project. The goal of the project is to study the feasibility of using advanced technologies from other industries to improve the efficiency and safety of winter highway maintenance vehicle operations. State departments of transportation from Iowa, Minnesota, and Michigan initially formed the study consortium, and several private vendors have become project partners. The Center for Transportation Research and Education (CTRE) at Iowa State University is managing project tasks

Molecular diagnostics of gliomas: the clinical perspective.

Significant progress has been made in the molecular diagnostic subtyping of brain tumors, in particular gliomas. In contrast to the classical molecular markers in this field, p53 and epidermal growth factor receptor (EGFR) status, the clinical significance of which has remained controversial, at least three important molecular markers with clinical implications have now been identified: 1p/19q codeletion, O⁶-methylguanine methyltransferase (MGMT) promoter methylation and isocitrate dehydrogenase-1 (IDH1) mutations. All three are favorable prognostic markers. 1p/19q codeletion and IDH1 mutations are also useful to support and extend the histological classification of gliomas since they are strongly linked to oligodendroglial morphology and grade II/III gliomas, as opposed to glioblastoma, respectively. MGMT promoter methylation is the only potentially predictive marker, at least for alkylating agent chemotherapy in glioblastoma. Beyond these classical markers, the increasing repertoire of anti-angiogenic agents that are currently explored within registration trials for gliomas urgently calls for efforts to identify molecular markers that predict the benefit derived from these novel treatments, too.

Bortezomib(Velcade®)-Thalidomide-Dexamethasone (VTD) Is Superior to Thalidomide-Dexamethasone (TD) In Patients with Multiple Myeloma (MM) Progressing or Relapsing After Autologous Transplantation

Introduction: The Thalidomide-Dexamethasone (TD) regimen has provided encouraging results in relapsed MM. To improve results, bortezomib (Velcade) has been added to the combination in previous phase II studies, the so called VTD regimen. In January 2006, the European Group for Blood and Marrow Transplantation (EBMT) and the Intergroupe Francophone du Myélome (IFM) initiated a prospective, randomized, parallel-group, open-label phase III, multicenter study, comparing VTD (arm A) with TD (arm B) for MM patients progressing or relapsing after autologous transplantation. Patients and Methods: Inclusion criteria: patients in first progression or relapse after at least one autologous transplantation, including those who had received bortezomib or thalidomide before transplant. Exclusion criteria: subjects with neuropathy above grade 1 or non secretory MM. Primary study end point was time to progression (TTP). Secondary end points included safety, response rate, progression-free survival (PFS) and overall survival (OS). Treatment was scheduled as follows: bortezomib 1.3 mg/m2 was given as an i.v bolus on Days 1, 4, 8 and 11 followed by a 10-Day rest period (days 12 to 21) for 8 cycles (6 months) and then on Days 1, 8, 15, 22 followed by a 20-Day rest period (days 23 to 42) for 4 cycles (6 months). In both arms, thalidomide was scheduled at 200 mg/Day orally for one year and dexamethasone 40 mg/Day orally four days every three weeks for one year. Patients reaching remission could proceed to a new stem cell harvest. However, transplantation, either autologous or allogeneic, could only be performed in patients who completed the planned one year treatment period. Response was assessed by EBMT criteria, with additional category of near complete remission (nCR). Adverse events were graded by the NCI-CTCAE, Version 3.0.The trial was based on a group sequential design, with 4 planned interim analyses and one final analysis that allowed stopping for efficacy as well as futility. The overall alpha and power were set equal to 0.025 and 0.90 respectively. The test for decision making was based on the comparison in terms of the ratio of the cause-specific hazards of relapse/progression, estimated in a Cox model stratified on the number of previous autologous transplantations. Relapse/progression cumulative incidence was estimated using the proper nonparametric estimator, the comparison was done by the Gray test. PFS and OS probabilities were estimated by the Kaplan-Meier curves, the comparison was performed by the Log-Rank test. An interim safety analysis was performed when the first hundred patients had been included. The safety committee recommended to continue the trial. Results: As of 1st July 2010, 269 patients had been enrolled in the study, 139 in France (IFM 2005-04 study), 21 in Italy, 38 in Germany, 19 in Switzerland (a SAKK study), 23 in Belgium, 8 in Austria, 8 in the Czech republic, 11 in Hungary, 1 in the UK and 1 in Israel. One hundred and sixty nine patients were males and 100 females; the median age was 61 yrs (range 29-76). One hundred and thirty six patients were randomized to receive VTD and 133 to receive TD. The current analysis is based on 246 patients (124 in arm A, 122 in arm B) included in the second interim analysis, carried out when 134 events were observed. Following this analysis, the trial was stopped because of significant superiority of VTD over TD. The remaining patients were too premature to contribute to the analysis. The number of previous autologous transplants was one in 63 vs 60 and two or more in 61 vs 62 patients in arm A vs B respectively. The median follow-up was 25 months. The median TTP was 20 months vs 15 months respectively in arm A and B, with cumulative incidence of relapse/progression at 2 years equal to 52% (95% CI: 42%-64%) vs 70% (95% CI: 61%-81%) (p=0.0004, Gray test). The same superiority of arm A was also observed when stratifying on the number of previous autologous transplantations. At 2 years, PFS was 39% (95% CI: 30%-51%) vs 23% (95% CI: 16%-34%) (A vs B, p=0.0006, Log-Rank test). OS in the first two years was comparable in the two groups. Conclusion: VTD resulted in significantly longer TTP and PFS in patients relapsing after ASCT. Analysis of response and safety data are on going and results will be presented at the meeting.

Adjuvant dibromodulcitol and BCNU chemotherapy in anaplastic astrocytoma: results of a randomised European Organisation for Research and Treatment of Cancer phase III study (EORTC study 26882).

BACKGROUND: In a previous randomised EORTC study on adjuvant dibromodulcitol (DBD) and bichloroethylnitrosourea (BCNU) in adults with glioblastoma multiforme (GBM) and anaplastic astrocytoma (AA), a clinically significant trend towards a longer overall survival (OS) and a progression-free survival (PFS) was observed in the subgroup of AA. The aim of the present study was to test this adjuvant regimen in a larger number of AA patients. METHODS: Continuation of the previous phase III trial for newly diagnosed AA according to the local pathologist. Patients were randomised to either radiotherapy only or to radiotherapy in combination with BCNU on day 2 and weekly DBD, followed by adjuvant DBD and BCNU in cycles of six weeks for a maximum total treatment duration of one year. OS was the primary end-point. RESULTS: Patients (193 ) with newly diagnosed AA according to local pathological assessment were randomised to radiotherapy (RT) alone (n=99), or to RT plus DBD/BCNU (n=94); 12 patients were considered not eligible. At central pathology review, over half (53%) of the locally diagnosed AA cases could not be confirmed. On intent-to-treat analysis, no statistically significant differences in OS (p=0.111) and PFS (p=0.087) were observed, median OS after RT was only 23.9 months 95% confidence interval (CI), [18.4-34.0] after RT plus DBD/BCNU 27.3 months 95% CI [21.4-46.8]. CONCLUSION: No statistically significant improvement in survival was observed after BCNU/DBD adjuvant chemotherapy in AA patients. The trend towards improved survival is consistent with previous reports. Central pathology review of grade 3 tumours remains crucial.

Intravitreal chemotherapy for vitreous seeding in retinoblastoma: Recent advances and perspectives.

For decades intravitreal chemotherapy (IViC) remained virtually banished from the therapeutic armamentarium against retinoblastoma, except as a heroic attempt of salvage before enucleation in only eyes with refractory vitreous seeding. Very recently, we have initiated a reappraisal of this route of administration by (1) profiling eligibility criteria, (2) describing a safety-enhanced injection procedure, (3) adjusting the tumoricidal dose of melphalan, and (4) reporting an unprecedented efficacy in terms of tumor control of vitreous seeding. Since then, intravitreal chemotherapy is being progressively implemented worldwide with great success, but still awaits formal validation by the ongoing prospective phase II clinical trial. As far as preliminary results are concerned, IViC appears to achieve complete vitreous response in 100% of the 35 newly recruited patients irrespective of the previous treatment regimen, including external beam radiotherapy and/or intra-arterial melphalan. In other words, vitreous seeding, still considered as the major cause of primary and secondary enucleation, can now be controlled by IViC. However, sterilization of vitreous seeding does not necessarily translate into eye survival, unless the retinal source of the seeds receives concomitant therapy. In conclusion, IViC, an unsophisticated and cost-effective treatment, is about to revolutionize the eye survival prognosis of vitreous disease in advanced retinoblastoma.

Embankment Quality: Phase III, TR-401, 2002

This report describes test results from a full-scale embankment pilot study conducted in Iowa. The intent of the pilot project was to field test and refine the proposed soil classification system and construction specifications developed in Phase II of this research and to evaluate the feasibility of implementing a contractor quality control (QC) and Iowa DOT quality assurance (QA) program for earthwork grading in the future. One of the primary questions for Phase III is “Was embankment quality improved?” The project involved a “quality conscious” contractor, well-qualified and experienced Iowa Department of Transportation field personnel, a good QC consultant technician, and some of our best soils in the state. If the answer to the above question is “yes” for this project, it would unquestionably be “yes” for other projects as well. The answer is yes, the quality was improved, even for this project, as evidenced by dynamic cone penetrometer test data and the amount of disking required to reduce the moisture content to within acceptable control limits (approximately 29% of soils by volume required disking). Perhaps as important is that we know what quality we have. Increased QC/QA field testing, however, increases construction costs, as expected. The quality management-earthwork program resulted in an additional $0.03 per cubic meter, or 1.6%, of the total construction costs. Disking added about $0.04 per cubic meter, or 1.7%, to the total project costs. In our opinion this is a nominal cost increase to improve quality. It is envisioned that future contractor innovations have the potential for negating this increase. The Phase III results show that the new soil classification system and the proposed field test methods worked well during the Iowa Department of Transportation soils design phase and during the construction phase. Recommendations are provided for future implementation of the results of this study by city, county, and state agencies.

Planning, Developing, and Implementing the Iowa Pavement Marking Management System (IPMMS): Phases I and II, 2006

With an annual pavement marking program of approximately $2 million and another $750 thousand invested in maintenance of durable markings each year, the Iowa DOT is seeking every opportunity to provide all-year markings staying in acceptable condition under all weather conditions. The goal of this study is to analyze existing pavement marking practices and to develop a prototype Pavement Marking Management System (PMMS). This report documents the first two phases of a three-phase research project. Phase I includes an overview of the Iowa DOT’s existing practices and a literature review regarding pavement marking practices in other states. Based on this information, a work plan was developed for Phases II and III of this study. Phase II organized the key components necessary to develop a prototype PMMS for the Iowa DOT. The two primary components are (1) performance/life cycle curves for pavement marking products, and (2) an application matrix tailored to the pavement marking products and roadway and environmental conditions faced by the Iowa DOT. Both components will continue to be refined and tailored to Iowa materials and conditions as more performance data becomes available.

Material and Construction Optimization for Prevention of Premature Pavement Distress in PCC Pavements, Phase III Final Report, 2008

Mixture materials, mix design, and pavement construction are not isolated steps in the concrete paving process. Each affects the other in ways that determine overall pavement quality and long-term performance. However, equipment and procedures commonly used to test concrete materials and concrete pavements have not changed in decades, leaving gaps in our ability to understand and control the factors that determine concrete durability. The concrete paving community needs tests that will adequately characterize the materials, predict interactions, and monitor the properties of the concrete. The overall objectives of this study are (1) to evaluate conventional and new methods for testing concrete and concrete materials to prevent material and construction problems that could lead to premature concrete pavement distress and (2) to examine and refine a suite of tests that can accurately evaluate concrete pavement properties. The project included three phases. In Phase I, the research team contacted each of 16 participating states to gather information about concrete and concrete material tests. A preliminary suite of tests to ensure long-term pavement performance was developed. The tests were selected to provide useful and easy-to-interpret results that can be performed reasonably and routinely in terms of time, expertise, training, and cost. The tests examine concrete pavement properties in five focal areas critical to the long life and durability of concrete pavements: (1) workability, (2) strength development, (3) air system, (4) permeability, and (5) shrinkage. The tests were relevant at three stages in the concrete paving process: mix design, preconstruction verification, and construction quality control. In Phase II, the research team conducted field testing in each participating state to evaluate the preliminary suite of tests and demonstrate the testing technologies and procedures using local materials. A Mobile Concrete Research Lab was designed and equipped to facilitate the demonstrations. This report documents the results of the 16 state projects. Phase III refined and finalized lab and field tests based on state project test data. The results of the overall project are detailed herein. The final suite of tests is detailed in the accompanying testing guide.