Promising results of a cooperative group phase II trial of preoperative chemoradiation for locally advanced rectal cancer (TROG 9801)

PURPOSE: This article reports the overall survival, failure-free survival, local failure, and late radiation toxicity of a phase II trial of preoperative radiotherapy with continuous infusion 5-fluorouracil for rectal cancer after a minimum 3.5 years of follow-up. METHODS: Eligible patients were those with newly diagnosed localized adenocarcinoma of the rectum, within 12 cm of the anal verge, staged T3-T4 and deemed suitable for curative resection. Radiotherapy (50.4 Gy in 28 fractions in five weeks and three days) was given with continuous infusion 5-fluorouracil throughout the course of radiotherapy. RESULTS: A total of 82 patients were accrued in 13 months. The median follow-up time was 4.1 (range, 2.3-4.5) years. There were 55 males (67 percent) and the median age was 59 (range, 27-87) years. Patients were staged pretreatment as T3 (89 percent) and resectable T4 (11 percent). Endorectal ultrasound was performed in 70 percent and magnetic resonance imaging in another 5 percent. The four-year overall and failure-free survival rates were 82 percent (95 percent Cl: 72-89) and 69 percent (95 percent Cl: 58-78), respectively. The cumulative incidence of local failure at four years was 3.9 percent (95 percent CI: 1.3-11). Risk of failures, local and distant, has not reached a plateau phase. CONCLUSION: This regimen can be delivered safely and without leading to a significant increase in late toxicity. It provides excellent local control and favorable overall survival. There is a need for longer follow-up than has commonly been used for the proper evaluation of failures after an effective regimen of preoperative chemoradiation.

Evaluation of 1-site and 5-site models of methane on its adsorption on graphite and in graphitic slit pores

In this paper, we evaluate the performance of the 1- and 5-site models of methane on the description of adsorption on graphite surfaces and in graphitic slit pores. These models have been known to perform well in the description of the fluid-phase behavior and vapor-liquid equilibria. Their performance in adsorption is evaluated in this work for nonporous graphitized thermal carbon black, and simulation results are compared with the experimental data of Avgul and Kiselev (Chemistry and Physics of Carbon; Dekker: New York, 1970; Vol. 6, p 1). On this nonporous surface, it is found that these models perform as well on isotherms at various temperatures as they do on the experimental isosteric heat for adsorption on a graphite surface. They are then tested for their performance in predicting the adsorption isotherms in graphitic slit pores, in which we would like to explore the effect of confinement on the molecule packing. Pore widths of 10 and 20 angstrom are chosen in this investigation, and we also study the effects of temperature by choosing 90.7, 113, and 273 K. The first two are for subcritical conditions, with 90.7 K being the triple point of methane and 113 K being its boiling point. The last temperature is chosen to represent the supercritical condition so that we can investigate the performance of these models at extremely high pressures. We have found that for the case of slit pores investigated in this paper, although the two models yield comparable pore densities (provided the accessible pore width is used in the calculation of pore density), the number of particles predicted by the I-site model is always greater than that predicted by the 5-site model, regardless of whether temperature is subcritical or supercritical. This is due to the packing effect in the confined space such that a methane molecule modeled as a spherical particle in the I-site model would pack better than the fused five-sphere model in the case of the 5-site model. Because the 5-site model better describes the liquid- and solid-phase behavior, we would argue that the packing density in small pores is better described with a more detailed 5-site model, and care should be exercised when using the 1-site model to study adsorption in small pores.

Evaluation of the Western Australian Department of Health telehealth project

In 1999, the Department of Health in Western Australia began a telehealth project, which finished in 2004. The 75 videoconferencing sites funded by the project were part of a total state-wide videoconference network of 104 sites. During the period from January 2002 to December 2003, a total of 3266 consultations, case reviews and patient education sessions took place. Clinical use grew to 30% of all telehealth activity. Educational use was approximately 40% (1416 sessions) and management use was about 30% (1031 sessions). The average overhead cost per telehealth session across all regions and usage types was $A192. Meaningful comparisons of the results of the present study with other public health providers were difficult, because many of the available Websites on telehealth were out of date. Despite the successful use of telehealth to deliver clinical services in Western Australia, sustaining the effort in the post-project phase will present significant challenges.

W/O microemulsions for ocular delivery: Evaluation of ocular irritation and precorneal retention

Water-in-oil microemulsions (w/o ME) capable of undergoing a phase-transition to lamellar liquid crystals (LC) or bicontinuous ME upon aqueous dilution were formulated using Crodarnol EO, Crill 1 and Crillet 4, an alkanol or alkanediol as cosurfactant and water. The hypothesis that phase-transition of ME to LC may be induced by tears and serve to prolong precomeal retention was tested. The ocular irritation potential of components and formulations was assessed using a modified hen's egg chorioallantoic membrane test (HET-CAM) and the preocular retention of selected formulations was investigated in rabbit eye using gamma scintigraphy. Results showed that Crill 1, Crillet 4 and Crodamol EO were non-irritant. However, all other cosurfactants investigated were irritant and their irritation was dependent on their carbon chain length. A w/o ME formulated without cosurfactant showed a protective effect when a strong irritant (0.1 M NaOH) was used as the aqueous phase. Precorneal clearance studies revealed that the retention of colloidal and coarse dispersed systems was significantly greater than an aqueous solution with no significant difference between ME systems (containing 5% and 10% water) as well as o/w emulsion containing 85% water. Conversely, a LC system formulated without cosurfactant displayed a significantly greater retention compared to other formulations. (c) 2005 Elsevier B.V. All rights reserved.

Development and evaluation of the Clinician Suicide Risk Assessment Checklist

This paper describes the development and evaluation of a new instrument – the Clinician Suicide Risk Assessment Checklist (CSRAC). The instrument assesses the clinician’s competency in three areas: clinical interviewing, assessment of specific suicide risk factors, and formulating a management plan. A draft checklist was constructed by integrating information from 1) literature review 2) expert clinician focus group and 3) consultation with experts. It was utilised in a simulated clinical scenario with clinician trainees and a trained actor in order to test for inter-rater agreement. Agreement was calculated and the checklist was re-drafted with the aim of maximising agreement. A second phase of simulated clinical scenarios was then conducted and inter-rater agreement was calculated for the revised checklist. In the first phase of the study, 18 of 35 items had inadequate inter-rater agreement (60%>), while in the second phase, using the revised version, only 3 of 39 items failed to achieve adequate inter-rater agreement. Further evidence of reliability and validity are required. Continued development of the CSRAC will be necessary before it can be utilised to assess the effectiveness of risk assessment training programs.

A phase I biological and pharmacologic study of the heparanase inhibitor PI-88 in patients with advanced solid tumors

Purpose: PI-88 is a mixture of highly sulfated oligosaccharides that inhibits heparanase, an extracellular matrix endoglycosidase, and the binding of angiogenic growth factors to heparan sulfate. This agent showed potent inhibition of placental blood vessel angiogenesis as well as growth inhibition in multiple xenograft models, thus forming the basis for this study. Experimental Design: This study evaluated the toxicity and pharmacokinetics of PI-88 (80-315 mg) when administered s.c. daily for 4 consecutive days bimonthly (part 1) or weekly (part 2). Results: Forty-two patients [median age, 53 years (range, 19-78 years); median performance status, 1] with a range of advanced solid tumors received a total of 232 courses. The maximum tolerated dose was 250 mg/d. Dose-limiting toxicity consisted of thrombocytopenia and pulmonary embolism. Other toxicity was generally mild and included prolongation of the activated partial thromboplastin time and injection site echymosis. The pharmacokinetics were linear with dose. Intrapatient variability was low and interpatient variability was moderate. Both AUC and C-max correlated with the percent increase in activated partial thromboplastin time, showing that this pharmacodynamic end point can be used as a surrogate for drug exposure, No association between PI-88 administration and vascular endothelial growth factor or basic fibroblast growth factor levels was observed. One patient with melanoma had a partial response, which was maintained for >50 months, and 9 patients had stable disease for >= 6 months. Conclusion: The recommended dose of PI-88 administered for 4 consecutive days bimonthly or weekly is 250 mg/d. PI-88 was generally well tolerated. Evidence of efficacy in melanoma supports further evaluation of PI-88 in phase II trials.

Synthesis and immunological evaluation of M protein targeted tetra-valent and tri-valent group A streptococcal vaccine candidates based on the lipid-core peptide system

Group A streptococcus (GAS) is responsible for causing many clinical complications including the relatively benign streptococcal pharyngitis and impetigo. However. if left untreated. these conditions may lead to more severe diseases such as rheumatic fever (RF) and rheumatic heart disease (RHD). These diseases exhibit high morbidity and mortality, Particularly in developing countries and in indigenous populations of affluent countries. Only ever occur following GAS infection, a vaccine offers Promise for their Prevention. As stich, we have investigated the Use of the lipid-core peptide (LCP) system for the development of multi-valent Prophylactic GAS vaccines. The current study has investigated the capacity of this system to adjuvant LIP to four different GAS peptide epitopes. Presented are the synthesis and immunological assessment of tetra-valent and tri-valent GAS LCP systems. We demonstrated their capacity to elicit systemic IgG antibody responses in B10.BR mice to all GAS peptide epitopes. The data also showed that the LCP systems Were self-adjuvanting. These findings are particularly encouraging for the development of multi-valent LCP-based GAS vaccines.

Synthesis and evaluation of scintillant-containing poly(oxyethylene glycol) polymer (POP-Sc) supports

Co-polymerisation of α-styryl-poly(ethylene glycol)300, α,ω-bis(styryl)-penta(ethylene glycol) and 2,5-diphenyl-4-(4′-vinylbenzyl)oxazole in varying molar ratios resulted in the production of chemically functionalised scintillant-containing poly(oxyethylene glycol) polymer (POP-Sc) supports. These materials are compatible with both aqueous and organic solvents, and possess the ability to scintillate efficiently in the presence of ionising radiation, even after prolonged and repeated exposure to organic solvents. The utility of POP-Sc supports in both solid-phase peptide chemistry and a functional scintillation proximity assay has been exemplified.

Synthesis and evaluation of novel ligands for quantum dot stabilisation and polymerisation studies

This thesis describes the design and synthesis of a variety of functionalised phosphine oxides and sulfides, based on the structure of trioctylphosphine oxide, synthesised for the purpose of surface modification of quantum dots. The ability of the ligands to modify the surface chemistry via displacement of the original hexadecylamine capping layer of quantum dots was evaluated. Finally the surface modified quantum dots were investigated for enhancement in their inherent properties and improved compatibility with the various applications for which they were initially designed. Upon the commencement of research involving quantum dots it became apparent that more information on their behaviour and interaction with the environment was required. The limits of the inherent stability of hexadecylamine capped quantum dots were investigated by exposure to a number of different environments. The effect upon the stability of the quantum dots was monitored by changes in the photoluminescence ability of their cores. Subtle differences between different batches of quantum dots were observed and the necessity to account for these in future applications noted. Lastly the displacement of the original hexadecylamine coating with the "designer" functionalised ligands was evaluated to produce a set of conditions that would result in the best possible surface modification. A general procedure was elucidated however it was discovered that each displacement still required slight adjustment by consideration of the other factors such as the difference in ligand structure and the individuality of the various batches of quantum dots. This thesis also describes a procedure for the addition of a protective layer to the surface of quantum dots by cross-linking the functionalised ligands bound to the surface via an acyclic diene metathesis polymerisation. A detailed description of the problems encountered in the analysis of these materials combined with the use of novel techniques such as diffusion ordered spectroscopy is provided as a means to overcome the limitations encountered. Finally a demonstration of the superior stability, upon exposure to a range of aggressive environments of these protected materials compared with those before cross-linking provided physical proof of the cross-linking process and the advantages of the cross-linking modification. Finally this thesis includes the presentation of initial work into the production of luminescent nanocrystal encoded resin beads for the specific use in solid phase combinatorial chemistry. Demonstration of the successful covalent incorporation of quantum dots into the polymeric matrices of non-functionalised and functionalised resin beads is described. Finally by preliminary work to address and overcome the possible limitations that may be encountered in the production and general employment of these materials in combinatorial techniques is given.

Synthesis and biological evaluation of potential anti-cancer agents

The new technology of combinational chemistry has been introduced to pharmaceutical companies, improving and making more efficient the process of drug discovery. Automated combinatorial chemistry in the solution-phase has been used to prepare a large number of compounds of anti-cancer screening. A library of caffeic acid derivatives has been prepared by the Knoevenagel condensation of aldehyde and active methylene reagents. These products have been screened against two murine adenocarcinoma cell lines (MAC) which are generally refractive to standard cytotoxic agents. The target of anti-proliferative action was the 12- and 15-lipoxygenase enzymes upon which these tumour cell lines have been shown to be dependent for proliferation and metastasis. Compounds were compared to a standard lipoxygenase inhibitor and if found to be active anti-proliferative agents were tested for their general cytotoxicity and lipoxygenase inhibition. A solid-phase bound catalyst, piperazinomethyl polystyrene, was devised and prepared for the improved generation of Knoevenagel condensation products. This piperazinomethyl polystyrene was compared to the traditional liquid catalyst, piperidine, and was found to reduce the amount of by-products formed during reaction and had the advantage of easy removal from the reaction. 13C NMR has been used to determine the E/Z stereochemistry of Knoevenagel condensation products. Soluble polymers have been prepared containing different building blocks pendant to the polymer backbone. Aldehyde building blocks incorporated into the polymer structure have been subjected to the Knoevenagel condensation. Cleavage of the resultant pendant molecules has proved that soluble linear polymers have the potential to generate combinatorial mixtures of known composition for biological testing. Novel catechol derivatives have been prepared by traditional solution-phase chemistry with the intention of transferring their synthesis to a solid-phase support. Catechol derivatives prepared were found to be active inhibitors of lipoxygenase. Soluble linear supports for the preparation of these active compounds were designed and tested. The aim was to develop a support suitable for the automated synthesis of libraries of catechol derivatives for biological screening.

Synthesis and evaluation of polystyrene based soluble polymeric supports for organic synthesis

Several copolymers of linear polystyrene were prepared for evaluation as soluble polymeric supports for organic synthesis. These polymers were utilized for the synthesis of ?2-isoxazoline compounds. The target compounds were synthesized via 1,3-dipolar cycloaddition reactions between polymer bound alkenes and nitrile oxides generated in situ from their corresponding aldoximes. The cleaved ?2-isoxazoline compounds were tested for biological activity against Mycobacterium fortuitum. To compare the success of these linear polystyrene copolymers, some of the ?2-isoxazoline compounds synthesized on soluble polymeric supports were also prepared via traditional crosslinked polymer supports. The polymer-bound ?2-isoxazolines were also tested for antimicrobial activity. In addition attempts were made to prepare polymers containing the ?2-isoxazolines but anchored by non-hydrolysable bonds. Although the copolymers of polystyrene gave good loading capacity in mmol/g, and being soluble in chlorinated solvents it was possible to monitor the reactions by 1H NMR spectroscopy, the cleavage of the polymer bound products proved to be quite troublesome. Product purification was not as straightforward as it was anticipated. Isolation of the cleaved target compounds proved to be time consuming and laborious when compared to the traditional organic synthesis and solid phase organic synthesis (SPOS). Polymer-bound ?2-isoxazolines close to the polymer backbone exhibited some biological activity against Staphylococcus aureus. Polymers with substitution at the para-position of the aryl substituent at position 3 of isoxazoline ring showed antimicrobial activity.

The single-phase induction motor:a critical appraisal of the rotating-field and cross-field theories with particular reference to skin effect

The purpose of this thesis is twofold: to examine the validity of the rotating-field and cross-field theories of the single-phase induction motor when applied to a cage rotor machine; and to examine the extent to which skin effect is likely to modify the characteristics of a cage rotor machine. A mathematical analysis is presented for a single-phase induction motor in which the rotor parameters are modified by skin effect. Although this is based on the usual type of ideal machine, a new form of model rotor allows approximations for skin effect phenomena to be included as an integral part of the analysis. Performance equations appropriate to the rotating-field and cross-field theories are deduced, and the corresponding explanations for the steady-state mode of operation are critically examined. The evaluation of the winding currents and developed torque is simplified by the introduction of new dimensionless factors which are functions of the resistance/reactance ratios of the rotor and the speed. Tables of the factors are included for selected numerical values of the parameter ratios, and these are used to deduce typical operating characteristics for both cage and wound rotor machines. It is shown that a qualitative explanation of the mode of operation of a cage rotor machine is obtained from either theory; but the operating characteristics must be deduced from the performance equations of the rotating-field theory, because of the restrictions on the values of the rotor parameters imposed by skin effect.

Waveform type evaluation in congenital nystagmus

Congenital nystagmus is an ocular-motor disorder characterised by involuntary, conjugated and bilateral to and fro ocular oscillations. In this study a method to recognise automatically jerk waveform inside a congenital nystagmus recording and to compute foveation time and foveation position variability is presented. The recordings were performed with subjects looking at visual targets, presented in nine eye gaze positions; data were segmented into blocks corresponding to each gaze position. The nystagmus cycles were identified searching for local minima and maxima (SpEp sequence) in intervals centred on each slope change of the eye position signal (position criterion). The SpEp sequence was then refined using an adaptive threshold applied to the eye velocity signal; the outcome is a robust detection of each slow phase start point, fundamental to accurately compute some nystagmus parameters. A total of 1206 slow phases was used to compute the specificity in waveform recognition applying only the position criterion or adding the adaptive threshold; results showed an increase in negative predictive value of 25.1% using both features. The duration of each foveation window was measured on raw data or using an interpolating function of the congenital nystagmus slow phases; foveation time estimation less sensitive to noise was obtained in the second case. © 2010.

Large scale organisational intervention to improve patient safety in four UK hospitals:mixed method evaluation

Objectives: To conduct an independent evaluation of the first phase of the Health Foundation's Safer Patients Initiative (SPI), and to identify the net additional effect of SPI and any differences in changes in participating and non-participating NHS hospitals. Design: Mixed method evaluation involving five substudies, before and after design. Setting: NHS hospitals in United Kingdom. Participants: Four hospitals (one in each country in the UK) participating in the first phase of the SPI (SPI1); 18 control hospitals. Intervention: The SPI1 was a compound (multicomponent) organisational intervention delivered over 18 months that focused on improving the reliability of specific frontline care processes in designated clinical specialties and promoting organisational and cultural change. Results: Senior staff members were knowledgeable and enthusiastic about SPI1. There was a small (0.08 points on a 5 point scale) but significant (P<0.01) effect in favour of the SPI1 hospitals in one of 11 dimensions of the staff questionnaire (organisational climate). Qualitative evidence showed only modest penetration of SPI1 at medical ward level. Although SPI1 was designed to engage staff from the bottom up, it did not usually feel like this to those working on the wards, and questions about legitimacy of some aspects of SPI1 were raised. Of the five components to identify patients at risk of deterioration - monitoring of vital signs (14 items); routine tests (three items); evidence based standards specific to certain diseases (three items); prescribing errors (multiple items from the British National Formulary); and medical history taking (11 items) - there was little net difference between control and SPI1 hospitals, except in relation to quality of monitoring of acute medical patients, which improved on average over time across all hospitals. Recording of respiratory rate increased to a greater degree in SPI1 than in control hospitals; in the second six hours after admission recording increased from 40% (93) to 69% (165) in control hospitals and from 37% (141) to 78% (296) in SPI1 hospitals (odds ratio for "difference in difference" 2.1, 99% confidence interval 1.0 to 4.3; P=0.008). Use of a formal scoring system for patients with pneumonia also increased over time (from 2% (102) to 23% (111) in control hospitals and from 2% (170) to 9% (189) in SPI1 hospitals), which favoured controls and was not significant (0.3, 0.02 to 3.4; P=0.173). There were no improvements in the proportion of prescription errors and no effects that could be attributed to SPI1 in non-targeted generic areas (such as enhanced safety culture). On some measures, the lack of effect could be because compliance was already high at baseline (such as use of steroids in over 85% of cases where indicated), but even when there was more room for improvement (such as in quality of medical history taking), there was no significant additional net effect of SPI1. There were no changes over time or between control and SPI1 hospitals in errors or rates of adverse events in patients in medical wards. Mortality increased from 11% (27) to 16% (39) among controls and decreased from17%(63) to13%(49) among SPI1 hospitals, but the risk adjusted difference was not significant (0.5, 0.2 to 1.4; P=0.085). Poor care was a contributing factor in four of the 178 deaths identified by review of case notes. The survey of patients showed no significant differences apart from an increase in perception of cleanliness in favour of SPI1 hospitals. Conclusions The introduction of SPI1 was associated with improvements in one of the types of clinical process studied (monitoring of vital signs) and one measure of staff perceptions of organisational climate. There was no additional effect of SPI1 on other targeted issues nor on other measures of generic organisational strengthening.

A new three phase method (SDP method) for the multi-objective vehicle routing problem with simultaneous delvery and pickup (VRPSDP)

Transportation service operators are witnessing a growing demand for bi-directional movement of goods. Given this, the following thesis considers an extension to the vehicle routing problem (VRP) known as the delivery and pickup transportation problem (DPP), where delivery and pickup demands may occupy the same route. The problem is formulated here as the vehicle routing problem with simultaneous delivery and pickup (VRPSDP), which requires the concurrent service of the demands at the customer location. This formulation provides the greatest opportunity for cost savings for both the service provider and recipient. The aims of this research are to propose a new theoretical design to solve the multi-objective VRPSDP, provide software support for the suggested design and validate the method through a set of experiments. A new real-life based multi-objective VRPSDP is studied here, which requires the minimisation of the often conflicting objectives: operated vehicle fleet size, total routing distance and the maximum variation between route distances (workload variation). The former two objectives are commonly encountered in the domain and the latter is introduced here because it is essential for real-life routing problems. The VRPSDP is defined as a hard combinatorial optimisation problem, therefore an approximation method, Simultaneous Delivery and Pickup method (SDPmethod) is proposed to solve it. The SDPmethod consists of three phases. The first phase constructs a set of diverse partial solutions, where one is expected to form part of the near-optimal solution. The second phase determines assignment possibilities for each sub-problem. The third phase solves the sub-problems using a parallel genetic algorithm. The suggested genetic algorithm is improved by the introduction of a set of tools: genetic operator switching mechanism via diversity thresholds, accuracy analysis tool and a new fitness evaluation mechanism. This three phase method is proposed to address the shortcoming that exists in the domain, where an initial solution is built only then to be completely dismantled and redesigned in the optimisation phase. In addition, a new routing heuristic, RouteAlg, is proposed to solve the VRPSDP sub-problem, the travelling salesman problem with simultaneous delivery and pickup (TSPSDP). The experimental studies are conducted using the well known benchmark Salhi and Nagy (1999) test problems, where the SDPmethod and RouteAlg solutions are compared with the prominent works in the VRPSDP domain. The SDPmethod has demonstrated to be an effective method for solving the multi-objective VRPSDP and the RouteAlg for the TSPSDP.