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Terry Jones

Publications and source records attributed to Terry Jones.

At least 19 recordsLinked to original sources
PubMed2006

Carbogen and nicotinamide increase blood flow and 5-fluorouracil delivery but not 5-fluorouracil retention in colorectal cancer metastases in patients.

PURPOSE: To examine whether carbogen and nicotinamide increases 5-fluorouracil (5-FU) delivery to colorectal cancer metastases. EXPERIMENTAL DESIGN: Six patients were scanned using positron emission tomography. Two scans were done to coincide with the start of separate chemotherapy cycles. At the second positron emission tomography session, 60 mg/kg nicotinamide was given orally 2 to 3 hours before 10-minute carbogen inhalation. In the middle of carbogen treatment, [15O]H2O (to measure regional tissue perfusion) and then [18F]5-FU (to measure 5-FU tissue pharmacokinetics) were administered. RESULTS: Regions of interest were drawn in 12 liver metastases, 6 spleens, 6 livers, and 12 kidneys. Nicotinamide and carbogen administration increased mean blood pO2 from 93 mm Hg (95% confidence interval, 79-198) to 278 mm Hg (95% confidence interval, 241-316; P = 0.031). Regional perfusion (mL(blood)/min/mL(tissue)) increased in metastases (mean change = 52%, range -32% to +261%, P = 0.024), but decreased in kidney (mean change = -42%, range -82% to -11%, P = 0.0005) and liver (mean change = -34%, range -43% to -26%, P = 0.031). 5-FU uptake at 3.75 minutes (m(2)/mL) increased in tumor (mean change = 40%, range -39% to +196%, P = 0.06) and decreased in kidney (mean change = -25%, range -71% to 12%, P = 0.043). 5-FU delivery measured as K1 increased in tumor (mean change = 74%, range -23% to +293%, P = 0.0039). No differences were seen in [18F]5-FU tumor exposure (net area under curve) and retention. CONCLUSION: Nicotinamide and carbogen administration can increase 5-FU delivery to colorectal cancer liver metastases. Despite an increase in perfusion and 5-FU delivery, the effects were not directly related and did not increase 5-FU retention or tissue exposure.

Administration, Inhalation↗
PubMed2006

Overexpression of ICAT highlights a role for catenin-mediated canonical Wnt signalling in early T cell development.

Transcription factors of the T cell factor/lymphoid enhancing factor (Tcf/Lef) family are key regulators in the development of T cell precursors to the CD4+8+ stage. These factors are known targets of the canonical Wnt signalling pathway, and regulate transcription of Wnt target genes following interaction with the armadillo repeat-containing protein beta-catenin. However, as recent studies show normal thymocyte maturation in the absence of either beta-catenin or its homologue gamma-catenin, the role of Wnt signalling in Tcf/Lef activation during T cell development is controversial. To directly investigate the importance of catenin-mediated Wnt signalling in early thymocytes, we have compared the expression of beta- and gamma-catenin and analysed distinct stages of T cell precursor maturation following overexpression of inhibitor of beta-catenin and Tcf (ICAT), which inhibits Wnt signalling by preventing binding of armadillo repeat-containing proteins to Tcf/Lef. By direct retroviral gene targeting of CD4-8- and CD4+8+ precursors, we show that ICAT overexpression inhibits the CD4-8--to-CD4+8+ transition, but not the CD4+8+-to-CD4+8- or -CD4-8+ transition. Collectively, our data support a model in which canonical Wnt signalling influences T cell development in the thymus by playing an essential role in the maturation of CD4-8- but not CD4+8+ thymocytes.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Establishment and functioning of intrathymic microenvironments.

The thymus supports the production of self-tolerant T cells from immature precursors. Studying the mechanisms regulating the establishment and maintenance of stromal microenvironments within the thymus therefore is essential to our understanding of T-cell production and ultimately immune system functioning. Despite our ability to phenotypically define stromal cell compartments of the thymus, the mechanisms regulating their development and the ways by which they influence T-cell precursors are still unclear. Here, we review recent findings and highlight unresolved issues relating to the development and functioning of thymic stromal cells.

Animals↗
PubMed2005

2-[11C]thymidine positron emission tomography reproducibility in humans.

PURPOSE: To evaluate the reproducibility of 2-[11C]thymidine positron emission tomography (PET) scanning in patients with advanced intra-abdominal malignancies. PATIENTS AND METHODS: The reproducibility of 2-[11C]thymidine PET was studied by comparing interpatient and intrapatient variability (coefficient of variability, COV) of both blood and tissue data. Arterial plasma metabolite levels were measured using on-line sampling and high-pressure liquid chromatography. 2-[11C]Thymidine retention in tissue was measured as the standardized uptake value at the end of the scan (SUV(end)), the area under the time-activity curve (AUC(0-1 hour)), and the fractional retention of thymidine (FRT). A group of seven patients were scanned 1 week apart with no intervening anticancer therapy. RESULTS: There was interpatient variability in the levels of 2-[11C]thymidine and its main metabolite, 11CO2, in plasma. Variability in 2-[11C]thymidine PET data was greater between (COV: SUV(end) = 38%, AUC(0-1 hour) = 32%, FRT = 47%) than within (COV: SUV(end) = 8%, AUC(0-1 hour) = 2%, FRT = 9%) patients. There was a borderline significant difference between the paired tumor data for SUV(end) (P = 0.041), but not for AUC(0-1 hour) (P = 0.81) or FRT (P = 0.90). There was a good correlation between paired data for SUV(end) (r = 0.98), AUC(0-1 hour) (r = 0.99), and FRT (r = 0.95). CONCLUSIONS: This is the first report showing that 2-[11C]thymidine PET scanning is reproducible in humans. Repeat scanning of tumor proliferation using 2-[11C]thymidine PET is feasible to perform in human intra-abdominal malignancies and should aid the future rapid assessment of antiproliferative tumor agents.

Abdominal Neoplasms↗
PubMed2005

Hydroquinone 4%, tretinoin 0.05%, fluocinolone acetonide 0.01%: a safe and efficacious 12-month treatment for melasma.

This article describes a long-term, multicenter, open-label, 12-month study of once-daily fluocinolone acetonide 0.01%, hydroquinone 4%, tretinoin 0.05% (Tri-Luma Cream, hereinafter called TC [triple combination]) application in the treatment of melasma. A total of 228 patients with facial melasma were enrolled and treated; 173 patients (76%) completed the study. Most patients had 1 to 2 courses of treatment lasting approximately 6 months in total. TC cream showed a favorable safety profile. only 3 patients (1%) withdrew from the study due to treatment-related adverse events (AEs). A total of 129 patients (57%) experienced at least one treatment-related AE. Most AEs were expected application-site reactions that were mild and transient in nature and did not require remedial therapy. There were no cases of skin atrophy or skin thinning and only 6 cases of telangiectasia (5 mild and 1 moderate), most of which had improved by the end of the study. Results of the efficacy assessments were positive, with both the patient and the physician assessing melasma to be either completely or nearly cleared by the end of the study in more than 90% of cases. In this study, a once-daily application of TC cream over an extended period of 12 months showed no notable safety concerns and offered an effective treatment for melasma.

Antioxidants↗
PubMed2004

Measuring tumor pharmacodynamic response using PET proliferation probes: the case for 2-[(11)C]-thymidine.

[(18)F]-fluorodeoxyglucose ((18)F-FDG) positron emission tomography (PET) is becoming accepted as a diagnostic tool for cancer, but the potential uses of PET in oncology extend beyond the imaging of glucose metabolism. The development of a PET proliferation probe would be a useful pharmacodynamic tool. [(11)C]-thymidine PET has been assessed in man as a specific measure of tumor proliferation. Uptake of [(11)C]-thymidine is related to DNA synthesis and, in human tumors, correlates with proliferation. When compared with (18)F-FDG, it has been shown to be a more sensitive discriminator of early clinical tumor response. 2-[(11)C]-thymidine PET scanning of patients enrolled in early phase clinical trials is feasible and should support future drug development. Although recent research is moving away from the validation of thymidine towards thymidine analogues radiolabeled with (18)F, the better specificity of thymidine for DNA should be the rationale for its continued development and application as a PET probe. This review describes the historical development, application and current research status of [(11)C]-thymidine PET, and aims to highlight the need for its continuing development as a marker of tumor proliferation.

Carbon Radioisotopes↗
PubMed2004

Cerebral decreases in opioid receptor binding in patients with central neuropathic pain measured by [11C]diprenorphine binding and PET.

Central neuropathic pain (CNP) is pain resulting from damage to the central nervous system. Up till now, it has not been possible to identify a common lesion or pharmacological deficit in these patients. This preliminary study in a group of patients with CNP with predominantly post-stroke pain, demonstrates that there is significantly less opioid receptor binding in a number of cortical and sub-cortical structures that are mostly, but not exclusively, within the medial pain system in patients compared to age-matched pain-free controls. The reductions in opioid receptor binding within the medial system were observed mainly in the dorsolateral (Brodman area 10) and anterior cingulate (Brodman area 24 with some extension into area 23) and insula cortices and the thalamus. There were also reductions in the lateral pain system within the inferior parietal cortex (Brodman area 40). These changes in binding could not be accounted for by the cerebral lesions shown by CT or MRI, which were outside the areas of reduced binding and the human pain system. To our knowledge this is the first systematic demonstration of a reduction in opioid receptor-binding capacity in neurones within the human nociceptive system in patients with CNP. This may be a key common factor resulting in undamped nociceptor activity within some of the structures that are predominantly within the medial nociceptive system. If confirmed, these findings may explain why certain patients with CNP require high doses of synthetic opiates to achieve optimum analgesia. The findings also raise the possibility of new pharmacological approaches to treatment.

Aged↗
PubMed2004

Effect of a single course of isotretinoin therapy on bone mineral density in adolescent patients with severe, recalcitrant, nodular acne.

BACKGROUND: Adverse changes in bone have been reported for patients undergoing high-dose, long-term (several years) isotretinoin therapy for disorders of cornification. The effect of short-term (4-5 months) therapy at the lower dose recommended for acne on bone development in younger, growing adolescent (12-17 years) patients has not been well studied. OBJECTIVE: The purpose of the study was to evaluate the effect of a standard, single course of isotretinoin (Accutane) therapy on bone mineral density (BMD) of the lumbar spine and hip in adolescents ages 12 to 17 years with severe, recalcitrant, nodular acne. METHODS: In this open-label, multicenter study, 217 adolescents (81 girls) with severe, recalcitrant, nodular acne were enrolled and treated with isotretinoin twice daily with food at the recommended total dose of approximately 1 mg/kg for 16 to 20 weeks. BMD in the lumbar spine and hip was measured at baseline and at the end of therapy by dual energy radiograph absorptiometry. RESULTS: There was no clinically significant mean change in BMD measured at the lumbar spine (+1.4%, range: -4.9% to +12.3%) or total hip (-0.26%, range: -11.3% to +15.0%). Hyperostosis was not observed in any patient. Typical efficacy expected in the treatment of acne was observed. CONCLUSIONS: A 16- to 20-week course of isotretinoin treatment at the recommended dose for severe acne has no clinically significant effect on lumbar spine and total hip BMD in the adolescent (12-17 years) population.

Acne Vulgaris↗
PubMed2003

Assessment of inter- and intrapatient variability in C15O2 positron emission tomography measurements of blood flow in patients with intra-abdominal cancers.

PURPOSE: The aim of the study was to evaluate the inter- and intrapatient variability of positron emission tomography (PET) measurements of perfusion in advanced solid cancers. EXPERIMENTAL DESIGN: Thirty-seven patients with predominantly intra-abdominal tumors underwent PET imaging using inhaled C15O2. Repeat data were obtained by scanning five patients twice, 1 week apart, with no intervening therapy. Regional flow and the volume of distribution (V(d)) were measured from dynamic images by use of a one-compartment model. Inter- and intrapatient variability were measured as the coefficient of variability (CV). Data were also obtained for regions of interest in normal liver, spleen, and kidney. RESULTS: The mean (+/-SD) regional flow in the tumors was 0.46 +/- 0.19 ml(blood)/min/ml(tissue), and the mean V(d) was 0.74 +/- 0.15 ml(blood)/ml(tissue). Variability in tumor flow was greater between (n = 37; CV = 41%) than within (n = 5; CV = 11%) patients. Variability in tumor V(d) was greater between (CV = 21%) than within (CV = 6%) patients. There was a good correlation between the repeat tumor data for both regional flow (rho = 0.82; P = 0.023) and V(d) (rho = 0.89; P = 0.007). Normal tissue variability was also greater between than within patients. In all cases, no statistically significant differences were seen between repeat measurements in the same patient. CONCLUSIONS: Dynamic C15O2 PET measurements of regional flow are reproducible in patients with predominantly intra-abdominal malignancies and may be useful for the pharmacodynamic evaluation of novel antivascular and antiangiogenic cancer therapeutic agents.

Abdominal Neoplasms↗
PubMed2003

Assessment of pharmacodynamic vascular response in a phase I trial of combretastatin A4 phosphate.

PURPOSE: Clinical evaluation of novel agents that target tumor blood vessels requires pharmacodynamic end points that measure vascular damage. Positron emission tomography (PET) was used to measure the effects of the vascular targeting agent combretastatin A4 phosphate (CA4P) on tumor and normal tissue perfusion and blood volume. PATIENTS AND METHODS: Patients with advanced solid tumors were enrolled onto part of a phase I, accelerated-titration, dose-escalation study. The effects of 5 to 114 mg/m2 CA4P on tumor, spleen, and kidney were investigated. Tissue perfusion was measured using oxygen-15 (15O)-labeled water and blood volume was measured using 15O-labeled carbon monoxide (C15O). Scans were performed immediately before, and 30 minutes and 24 hours after the first infusion of each dose level of CA4P. All statistical tests were two sided. RESULTS: PET data were obtained for 13 patients with intrapatient dose escalation. Significant dose-dependent reductions were seen in tumor perfusion 30 minutes after CA4P administration (mean change, -49% at >or= 52 mg/m2; P =.0010). Significant reductions were also seen in tumor blood volume (mean change, -15% at >or= 52 mg/m2; P =.0070). Although by 24 hours there was tumor vascular recovery, for doses >or= 52 mg/m2 the reduction in perfusion remained significant (P =.013). Thirty minutes after CA4P administration borderline significant changes were seen in spleen perfusion (mean change, -35%; P =.018), spleen blood volume (mean change, -18%; P =.022), kidney perfusion (mean change, -6%; P =.026), and kidney blood volume (mean change, -6%; P =.014). No significant changes were seen at 24 hours in spleen or kidney. CONCLUSION: CA4P produces rapid changes in the vasculature of human tumors that can be assessed using PET measurements of tumor perfusion.

Adult↗
PubMed2003

Metabolic activation of temozolomide measured in vivo using positron emission tomography.

The purpose of this research was to quantitate and confirm the mechanism of in vivo metabolic activation of temozolomide. The secondary aims were to evaluate the tumor, normal tissue, and plasma pharmacokinetics of temozolomide in vivo, and to determine whether such pharmacokinetics resulted in tumor targeting. [(11)C]temozolomide kinetics were studied in men using positron emission tomography (PET). It has been postulated that temozolomide undergoes decarboxylation and ring opening in the 3-4 position to produce the highly reactive methyldiazonium ion that alkylates DNA. To investigate this, a dual radiolabeling strategy, with [(11)C]temozolomide separately radiolabelled in the 3-N-methyl and 4-carbonyl positions, was used. We hypothesized that (11)C in the C-4 position of [4-(11)C-carbonyl]temozolomide would be converted to [(11)C]CO(2) if the postulated mechanism of metabolic conversion was true resulting in lower [(11)C]temozolomide tumor exposure. Paired studies were performed with both forms of [(11)C]temozolomide in 6 patients with gliomas. Another PET scan with (11)C-radiolabelled bicarbonate was performed and used to account for the metabolites of temozolomide using a data-led analytical approach. Plasma was analyzed for [(11)C]temozolomide and [(11)C]metabolites throughout the scan duration. Exhaled air was also sampled throughout the scan for [(11)C]CO(2). The percentage ring opening of temozolomide over 90 min was also calculated to evaluate whether there was a differential in metabolic breakdown among plasma, normal tissue, and tumor. There was rapid systemic clearance of both radiolabelled forms of [(11)C]temozolomide over 90 min (0.2 liter/min/m(2)), with [(11)C]CO(2) being the primary elimination product. Plasma [(11)C]CO(2) was present in all of the studies with [4-(11)C-carbonyl]temozolomide and in half the studies with [3-N-(11)C-methyl]temozolomide. The mean contributions to total plasma activity by [(11)C]CO(2) at 10 and 90 min were 12% and 28% with [4-(11)C-carbonyl]temozolomide, and 1% and 4% with [3-N-(11)C-methyl]temozolomide, respectively. There was a 5-fold increase in exhaled [(11)C]CO(2) sampled with [4-(11)C-carbonyl]temozolomide compared with [3-N-(11)C-methyl]temozolomide (P < 0.05). A decrease in tissue exposure [area under the curve between 0 and 90 min (AUC(0-90 min))] to [(11)C]temozolomide was also observed with [4-(11)C-carbonyl] temozolomide compared with [3-N-(11)C-methyl]temozolomide. Of potential therapeutic advantage was the higher [(11)C]radiotracer and [(11)C]temozolomide exposure (AUC(0-90 min)) in tumors compared with normal tissue. [(11)C]temozolomide ring opening over 90 min was less in plasma (20.9%; P < 0.05) compared with tumor (26.8%), gray matter (29.7%), and white matter (30.1%), with no differences (P > 0.05) between tumor and normal tissues. The significantly higher amounts of [(11)C]CO(2) sampled in plasma and exhaled air, in addition to the lower normal tissue and tumor [(11)C]temozolomide AUC(0-90 min) observed with [4-(11)C-carbonyl]temozolomide, confirmed the postulated mechanism of metabolic activation of temozolomide. A higher tumor [(11)C]temozolomide AUC(0-90 min) in tumors compared with normal tissue and the tissue-directed metabolic activation of temozolomide may confer potential therapeutic advantage in the activity of this agent. This is the first report of a clinical PET study used to quantify and confirm the in vivo mechanism of metabolic activation of a drug.

Adult↗
PubMed2003

The design and implementation of a motion correction scheme for neurological PET.

A method is described to monitor the motion of the head during neurological positron emission tomography (PET) acquisitions and to correct the data post acquisition for the recorded motion prior to image reconstruction. The technique uses an optical tracking system, Polaris, to accurately monitor the position of the head during the PET acquisition. The PET data are acquired in list mode where the events are written directly to disk during acquisition. The motion tracking information is aligned to the PET data using a sequence of pseudo-random numbers, which are inserted into the time tags in the list mode event stream through the gating input interface on the tomograph. The position of the head is monitored during the transmission acquisition, and it is assumed that there is minimal head motion during this measurement. Each event, prompt and delayed, in the list mode event stream is corrected for motion and transformed into the transmission space. For a given line of response, normalization, including corrections for detector efficiency, geometry and crystal interference and dead time are applied prior to motion correction and rebinning in the sinogram. A series of phantom experiments were performed to confirm the accuracy of the method: (a) a point source located in three discrete axial positions in the tomograph field of view, 0 mm, 10 mm and 20 mm from a reference point, (b) a multi-line source phantom rotated in both discrete and gradual rotations through +/- 5 degrees and +/- 15 degrees, including a vertical and horizontal movement in the plane. For both phantom experiments images were reconstructed for both the fixed and motion corrected data. Measurements for resolution, full width at half maximum (FWHM) and full width at tenth maximum (FWTM), were calculated from these images and a comparison made between the fixedand motion corrected datasets. From the point source measurements, the FWHM at each axial position was 7.1 mm in the horizontal direction, and increasing from 4.7 mm at the 0 mm position, to 4.8 mm, 20 mm offset, in the vertical direction. The results from the multi-line source phantom with +/- 5 degrees rotations showed a maximum degradation in FWHM, when compared with the stationary phantom, of 0.6 mm, in the horizontal direction, and 0.3 mm in the vertical direction. The corresponding values for the larger rotation, +/- 15 degrees, were 0.7 mm and 1.1 mm, respectively. The performance of the method was confirmed with a Hoffman brain phantom moved continuously, and a clinical acquisition using [11C]raclopride (normal volunteer). A visual comparison of both the motion and non-motion corrected images of the Hoffman brain phantom clearly demonstrated the efficacy of the method. A sample time-activity curve extracted from the clinical study showed irregularities prior to motion correction, which were removed after correction. A method has been developed to accurately monitor the motion of the head during a neurological PET acquisition, and correct for this motion prior to image reconstruction. The method has been demonstrated to be accurate and does not add significantly to either the acquisition or the subsequent data processing.

Algorithms↗
PubMed2003

Techniques for imaging neuroscience.

In the last 20 years, a number of non-invasive spatial mapping techniques have been demonstrated to provide powerful insights into the operation of the brain during task performance. These are, in order of their emergence as robust technologies: positron emission tomography, source localization with EEG and MEG, and functional magnetic resonance imaging. The imaging neuroscience study areas represented in this volume use the first or last of these - PET and fMRI. The physical principles underlying both of these techniques are outlined, and the important assumptions and limitations are made explicit. The range of applications for each is briefly indicated.

Brain↗
PubMed2003

Efficacy and safety of a new triple-combination agent for the treatment of facial melasma.

Treatment of melasma, a hyperpigmentation disorder, remains a challenge. The primary objective of two 8-week, multicenter, randomized, investigator-blind studies was to compare the efficacy and safety of a hydrophilic cream formulation containing tretinoin 0.05%, hydroquinone 4.0%, and fluocinolone acetonide 0.01% (RA+HQ+FA) with the dual-combination agents tretinoin plus hydroquinone (RA+HQ), tretinoin plus fluocinolone acetonide (RA+FA), and hydroquinone plus fluocinolone acetonide (HQ+FA). All agents had the same drug concentration and vehicle. A total of 641 adult patients, predominantly female, with moderate to severe melasma and Fitzpatrick skin types I through IV, were randomized to the various treatment groups. Due to the similarity of the study designs, the results of the 2 studies were combined and are reported here. The primary efficacy analysis involved the proportion of intent-to-treat patients in each treatment group whose condition had completely cleared by week 8. The results of the combined clinical trials demonstrated that significantly more of the patients treated with RA+HQ+FA (26.1%) experienced complete clearing compared with the other treatment groups (4.6%) at the end of week 8 (P<.0001). In addition, at week 8, a 75% reduction in melasma/pigmentation was observed in more than 70% of patients treated with RA+HQ+FA compared with 30% in patients treated with the dual-combination agents. The most common adverse reactions seen with all treatment groups were erythema, skin peeling, burning, and/or stinging sensation. The majority of treatment-related adverse events were of mild severity.

Administration, Topical↗
PubMed2002

Assessment of proliferation in vivo using 2-[(11)C]thymidine positron emission tomography in advanced intra-abdominal malignancies.

The purpose of this study was to determine the relationship between 2-[(11)C]thymidine positron emission tomography (PET) in vivo-derived parameters and the ex vivo Ki-67 index of proliferation in human tumors. The study comprised 17 treatment-naïve patients with advanced intra-abdominal malignancies. Tumor thymidine kinetics were measured using 2-[(11)C]thymidine PET. Tissue data were analyzed to give the standardized uptake value, the area under the time activity curve, and the fractional retention of thymidine (FRT) obtained by kinetic modeling. For the latter, the contribution of labeled metabolites was accounted for by measuring thymidine metabolites in arterial plasma. To examine the influence of tumor blood flow on the thymidine PET data, a perfusion scan using inhaled [(15)O]CO(2) was carried out in a subset of 11 patients. Biopsies were stained with a MIB1 antibody to obtain a Ki-67 index, and correlations with the PET-derived parameters were investigated. There was no relationship between tumor blood flow and the thymidine PET data, showing that the retention of 2-[(11)C]thymidine in tumors was independent of tumor perfusion. There was no correlation between the Ki-67 index and either standard uptake value or area under the curve. There was a correlation between the Ki-67 index and FRT (r = 0.58; P = 0.01). The correlation between the Ki-67 index and FRT in this dataset was not influenced by the interval between biopsy and imaging (0.1-126 weeks), the origin of the biopsy for Ki-67 staining (primary tumor or metastasis), or whether the biopsy was from an imaged or a nonimaged tumor. This is the first report in human tumors showing that 2-[(11)C]thymidine PET-derived parameters correlate with the level of tumor proliferation measured using Ki-67 immunohistochemistry. The study shows that the in vivo measurement of 2-[(11)C]thymidine in tumors using PET can provide a surrogate marker of proliferation and supports the potential use of the technique in the early assessment of response to antiproliferative cancer treatment.

Abdominal Neoplasms↗