John Dwyer

Applications of Fourier transform infrared microspectroscopy in studies of benign prostate and prostate cancer. A pilot study.

Fourier transform infrared (FTIR) microspectroscopy has been applied to a study of prostate cancer cell lines derived from different metastatic sites and to tissue from benign prostate and Gleason‐graded malignant prostate tissue. Paraffin‐embedded tissue samples were analysed by FTIR, after mounting onto a BaF2 plate and subsequent removal of wax using Citroclear followed by acetone. Cell lines were analysed as aliquots of cell suspension held between two BaF2 plates. It was found that the ratio of peak areas at 1030 and 1080 cm−1, corresponding to the glycogen and phosphate vibrations respectively, suggests a potential method for the differentiation of benign from malignant cells. The use of this ratio in association with FTIR spectral imaging provides a basis for estimating areas of malignant tissue within defined regions of a specimen. Initial chemometric treatment of FTIR spectra, using the linear discriminant algorithm, demonstrates a promising method for the classification of benign and malignant tissue and the separation of Gleason‐graded CaP spectra. Using the principle component analysis, this study has achieved for the first time the separation of FTIR spectra of prostate cancer cell lines derived from different metastatic sites. Copyright

Thermolysis of low density polyethylene catalysed by zeolites

Plastic wastes, which cause a serious environmental problem in urban areas, can serve as sources of energy. Thermal degradation of low density polyethylene (LDPE) has shown that, under appropriate conditions, polyethylene can yield chemicals in the gasoline range of hydrocarbons as well as those found in jet fuels. In the reactions catalysed by H-mordenite and H-Theta-1, hydrocarbons in the range C11 to C19 are the significant components of the non-volatile fraction, whereas over H-ZSM-5, no hydrocarbon higher that C14 is detected and alkalines are the significant products. H-ZSM-5 catalysed degradation results in a significant amount of aromatics compared with H-mordenite and H-Theta-1 where the yield of aromatics is small.

Celecoxib plus hormone therapy versus hormone therapy alone for hormone-sensitive prostate cancer: first results from the STAMPEDE multiarm, multistage, randomised controlled trial

Summary Background Long-term hormone therapy alone is standard care for metastatic or high-risk, non-metastatic prostate cancer. STAMPEDE—an international, open-label, randomised controlled trial—uses a novel multiarm, multistage design to assess whether the early additional use of one or two drugs (docetaxel, zoledronic acid, celecoxib, zoledronic acid and docetaxel, or zoledronic acid and celecoxib) improves survival in men starting first-line, long-term hormone therapy. Here, we report the preplanned, second intermediate analysis comparing hormone therapy plus celecoxib (arm D) with hormone therapy alone (control arm A). Methods Eligible patients were men with newly diagnosed or rapidly relapsing prostate cancer who were starting long-term hormone therapy for the first time. Hormone therapy was given as standard care in all trial arms, with local radiotherapy encouraged for newly diagnosed patients without distant metastasis. Randomisation was done using minimisation with a random element across seven stratification factors. Patients randomly allocated to arm D received celecoxib 400 mg twice daily, given orally, until 1 year or disease progression (including prostate-specific antigen [PSA] failure). The intermediate outcome was failure-free survival (FFS) in three activity stages; the primary outcome was overall survival in a subsequent efficacy stage. Research arms were compared pairwise against the control arm on an intention-to-treat basis. Accrual of further patients was discontinued in any research arm showing safety concerns or insufficient evidence of activity (lack of benefit) compared with the control arm. The minimum targeted activity at the second intermediate activity stage was a hazard ratio (HR) of 0·92. This trial is registered with ClinicalTrials.gov, number NCT00268476, and with Current Controlled Trials, number ISRCTN78818544. Findings 2043 patients were enrolled in the trial from Oct 17, 2005, to Jan 31, 2011, of whom 584 were randomly allocated to receive hormone therapy alone (control group; arm A) and 291 to receive hormone therapy plus celecoxib (arm D). At the preplanned analysis of the second intermediate activity stage, with 305 FFS events (209 in arm A, 96 in arm D), there was no evidence of an advantage for hormone therapy plus celecoxib over hormone therapy alone: HR 0·98 (95% CI 0·90–1·06). 2-year FFS was 51% (95% CI 46–56) in arm A and 51% (95% CI 43–58) in arm D. There was no evidence of differences in the incidence of adverse events between groups (events of grade 3 or higher were noted at any time in 123 [23%, 95% CI 20–27] patients in arm A and 64 [25%, 19–30] in arm D). The most common grade 3–5 events adverse effects in both groups were endocrine disorders (55 [11%] of patients in arm A vs 19 [7%] in arm D) and musculoskeletal disorders (30 [6%] of patients in arm A vs 15 [6%] in arm D). The independent data monitoring committee recommended stopping accrual to both celecoxib-containing arms on grounds of lack of benefit and discontinuing celecoxib for patients currently on treatment, which was endorsed by the trial steering committee. Interpretation Celecoxib 400 mg twice daily for up to 1 year is insufficiently active in patients starting hormone therapy for high-risk prostate cancer, and we do not recommend its use in this setting. Accrual continues seamlessly to the other research arms and follow-up of all arms will continue to assess effects on overall survival. Funding Cancer Research UK, Pfizer, Novartis, Sanofi-Aventis, Medical Research Council (London, UK).

The conversion of butanes in HZSM-5

The distribution of products from the conversion of iso- and normal butane on HZSM-5 has been determined from 300 to 550°C over a wide range of conversions. The results clearly indicate that the nature of the products changes significantly in altering both the temperature and conversion conditions. High temperatures and low conversions favor low molecular weight products expected from a protolytic or radical attack on the butane. Reverse conditions favor C3 and higher hydrocarbons. These products are indicative of a classical carbenium ion mechanism. As conditions were changed the transition in mechanism was indicated by the amount of methane produced. For the first time H2 was detected as a primary product in the conversion of normal butane indicating that a tertiary C-H bond is not required for its production.

Catalytic degradation of high density polyethylene: An evaluation of mesoporous and microporous catalysts using thermal analysis☆

Abstract Catalytic degradation of waste polymers offers the potential for the selective recovery of useful chemical fractions by influencing the product distributions. Thermogravimetric analysis has been used to investigate the activity of various aluminosilicate catalysts in the degradation of high density polyethylene (HDPE). Amorphous silica-alumina significantly reduced the apparent activation energy as compared with uncatalysed thermal processes. Zeolites Y and ZSM-5 further reduced the activation energy resulting in more rapid degradation. Aluminium containing MCM-41 was found to be active in the degradation of HDPE at a rate similar to that of HZSM-5, confirming the potential of this family of materials in the cracking of heavier hydrocarbons.

Deactivation of US-Y zeolite by coke formation during the catalytic pyrolysis of high density polyethylene

Abstract Catalytic pyrolysis of waste polymers over zeolitic catalysts has the potential to recover valuable hydrocarbons. Thermogravimetric analysis has been used as a tool to characterise the activity, regenerability and deactivation behaviour of zeolite US-Y in the degradation of high density polyethylene (HDPE). Deactivation of the catalyst occurs due to the deposition of coke. Analysis of the TGA results allowed a relationship between catalyst activity and coke content to be derived. The catalyst activity was found to fall exponentially with coke content.

Flexible trial design in practice - stopping arms for lack-of-benefit and adding research arms mid-trial in STAMPEDE: a multi-arm multi-stage randomized controlled trial

BackgroundSystemic Therapy for Advanced or Metastatic Prostate cancer: Evaluation of Drug Efficacy (STAMPEDE) is a randomized controlled trial that follows a novel multi-arm, multi-stage (MAMS) design. We describe methodological and practical issues arising with (1) stopping recruitment to research arms following a pre-planned intermediate analysis and (2) adding a new research arm during the trial.MethodsSTAMPEDE recruits men who have locally advanced or metastatic prostate cancer who are starting standard long-term hormone therapy. Originally there were five research and one control arms, each undergoing a pilot stage (focus: safety, feasibility), three intermediate ‘activity’ stages (focus: failure-free survival), and a final ‘efficacy’ stage (focus: overall survival). Lack-of-sufficient-activity guidelines support the pairwise interim comparisons of each research arm against the control arm; these pre-defined activity cut-off becomes increasingly stringent over the stages. Accrual of further patients continues to the control arm and to those research arms showing activity and an acceptable safety profile. The design facilitates adding new research arms should sufficiently interesting agents emerge. These new arms are compared only to contemporaneously recruited control arm patients using the same intermediate guidelines in a time-delayed manner. The addition of new research arms is subject to adequate recruitment rates to support the overall trial aims.Results(1) Stopping Existing Therapy: After the second intermediate activity analysis, recruitment was discontinued to two research arms for lack-of-sufficient activity. Detailed preparations meant that changes were implemented swiftly at 100 international centers and recruitment continued seamlessly into Activity Stage III with 3 remaining research arms and the control arm. Further regulatory and ethical approvals were not required because this was already included in the initial trial design.(2) Adding New Therapy: An application to add a new research arm was approved by the funder, (who also organized peer review), industrial partner and regulatory and ethical bodies. This was all done in advance of any decision to stop current therapies.ConclusionsThe STAMPEDE experience shows that recruitment to a MAMS trial and mid-flow changes its design are achievable with good planning. This benefits patients and the scientific community as research treatments are evaluated in a more efficient and cost-effective manner.Trial registrationISRCTN78818544, NCT00268476First patient into trial: 17 October 2005First patient into abiraterone comparison: 15 November 2011

A Critical Evaluation of the Concepts of Bröunsted Acidity Related to Zeolites.

Abstract The concepts of Bronsted and Lewis acidity in zeolites are examined in relation to selected experimental and theoretical studies.

Systemic therapy for advancing or metastatic prostate cancer (STAMPEDE): a multi-arm, multistage randomized controlled trial.

There is a need to improve the outcomes for men with high‐risk localised, nodal or metastatic prostate cancer, or with aggressively relapsing disease after initial therapy for local disease. This group of men is currently managed with long‐term hormone therapy. Thus we aim to evaluate the toxicity and efficacy of three different systemic therapies (docetaxel, zoledronic acid and celecoxib) used alone or combined at the initiation of hormone manipulation for high‐risk prostate cancer. A novel statistical design (multi‐arm, multistage method) simultaneously tests multiple distinct strategies in parallel against a single control arm. The trial has several ‘stages’, from initial confirmation of safety to a phase III assessment of survival, with a series of intervening activity stages. This method provides a means of assessing several agents more quickly and efficiently, and allows inactive treatments to be dropped from further study at an early stage. STAMPEDE has been designed to address in parallel the activity and efficacy of these agents for this patient group. It is a flagship randomized clinical trial for academic research into prostate cancer in the UK. More than 500 patients have been recruited on schedule, confirming the acceptability of this complex trial design to patients and clinicians. The trial targets a population of ≈3000 patients.

In situ FTIR study of the formation of MCM-41

The formation of both siliceous and aluminium-containing MCM-41 has been followed insitu using attenuated total reflectance Fourier-transform infrared (ATR FTIR) spectroscopy together with a range of complementary techniques. Key stages in the reaction are reflected by changes in the intensity of IR bands at 1030 and 1105 cm−1, which are assigned to the internal Si–O vibrations of Si(OSi)3 and Si(OSi)4 groupings (Q3 and Q4, respectively). Assignments were confirmed using solid state NMR. Under the conditions of these experiments, the reaction rate is limited by the relatively slow dissolution of the silica source. The resulting silicate oligomers then react more rapidly with surfactant cations in a co-operative assembly process to give the embryonic MCM-41 structure. Slower condensation reactions subsequently increase the product Q4/Q3 ratio as further crosslinking develops. From an analysis of both the CH3 head group and CH2 in-chain IR vibrations, the surfactant appears to be complexed or micellised at all times during the synthesis.