Azathioprine treatment in multiple sclerosis; pretreatment assessment of metaboliser status.
Explore the source record for details and available documents.
Azathioprine↗
Biomedical subjects
F J Thomas
Publications and source records attributed to F J Thomas.
Dysphagia and nutritional status in multiple sclerosis.
In this observational study of patients with multiple sclerosis (MS) admitted to a regional neurology centre we assessed the frequency of dysphagia (objectively defined), dysphagia related symptoms, bulbar signs and nutritional status. We studied 79 consecutive admissions with MS (24 at diagnostic admission and 55 more advanced cases admitted for treatment and/or rehabilitation): normative swallowing data were from 181 healthy controls. Swallowing symptoms and signs were semi-quantitatively measured and compared to healthy controls. Dysphagia was defined by a quantitative water test. Disability was determined by Kurtzke's Expanded Disability Status Scale and Barthel's index. Nutritional status was assessed by body mass index, estimated percentage body fat from skin fold thickness measurements at four sites, a global evaluation of nutrition, the presence of pressure sores and the pressure sore risk using the Waterlow score. Patients with MS were more likely to complain of abnormal swallowing, of coughing when eating, and of food 'going down the wrong way' than healthy controls (P < 0.005). These significantly associated symptoms had high specificity but relatively low sensitivity. 43% of patients had abnormal swallowing, almost half of whom did not complain of it: abnormal swallowing was associated with several factors including abnormal brainstem/cerebellar function, disability, vital capacity, and depression score. Those with abnormal swallowing had higher Waterlow scores (P < 0.001), but, overall, abnormal swallowing was not associated with a difference in nutritional indices or incidence of pressure sores. In summary, abnormal swallowing is common in MS although often not complained of. It is associated with disordered brainstem/cerebellar function, overall disability, depressed mood and low vital capacity. It was not associated with major nutritional failure or pressure sores in this study.
Adolescent↗
Corticosteroid metabolism in human granulosa-lutein cells.
OBJECTIVE: The aims of this study were to determine the type and level of 11 beta-hydroxysteroid dehydrogenase (11 beta HSD) in human granulosa-leutein cells (GLE) shortly before ovulation and to correlate activity with the outcome of treatment in patients undergoing in vitro fertilization and embryo transfer (IVF/ET). DESIGN: GLC from 32 patients undergoing IVF/ET were tested for type and level of 11 beta HSD activity in relation to treatment outcome. PATIENTS: Periovulatory follicles were aspirated by ultrasound guided transvaginal puncture following a standard controlled ovarian stimulation protocol, approximately 36 h after administering an ovulation-inducing dose of human chorionic gonadotrophin (HCG). GLC were separated from follicular fluid by density-gradient centrifugation and taken for measurement of 11 beta HSD activity in vitro; oocytes were used for IVF/ET. MEASUREMENTS: Interconversion of cortisol (F) and cortisone (E), and dexamethasone (D) and 11-dehydrodexamethasone (DHD) was measured in standardized assays comprising incubation of GLC with 3H-labelled substrate, with separation of substrate and product by thin-layer radiochromatography. RESULTS: Conversion of F to E varied from 10.5 to 30.9% while that of E to F was between 2.4 and 44.6%. In the GLC of 25 patients in whom both activities were measured, dehydrogenase (F to E) activity predominated in 13 and reductase (E to F) in 12. By contrast, D (substrate for 11 beta HSD2 but not 11 beta HSD1) showed less than 1% metabolism in this system while DHD (substrate for 11 beta HSD1 and 11 beta HSD2) was converted significantly (65.6-90.5%) to D in the four patients tested. There was no significant difference in the interconversion of F and E between patients who became pregnant and those who did not. CONCLUSIONS: The dehydrogenase and oxoreductase reactions catalysed by 11 beta HSD both occur in granulosa-lutein cells at the time of follicular rupture, probably due to 11 beta HSD1. A lack of measurable conversion of dexamethasone to 11-dehydrodexamethasone suggests that dehydrogenation due to 11 beta HSD2 is low or absent. Neither type nor level of 11 beta HSD activity measured under the present assay conditions correlates with IVF outcome.
11-beta-Hydroxysteroid Dehydrogenases↗
Differential expression of messenger ribonucleic acids encoding 11beta-hydroxysteroid dehydrogenase types 1 and 2 in human granulosa cells.
In glucocorticoid target organs 11beta-hydroxysteroid dehydrogenase (11betaHSD) regulates the levels of active glucocorticoids available to glucocorticoid receptors. To date two isoforms of 11betaHSD, NADP-dependent type 1 11betaHSD (11betaHSD1) with predominant reductase activity and NAD-dependent type 2 11betaHSD (11betaHSD2) with dehydrogenase activity have been identified. Human ovarian granulosa cells have been shown to possess both dehydrogenase and reductase 11betaHSD activities and express 11betaHSD1 mRNA. However, whether 11betaHSD2 mRNA is also present or if the expression of either mRNA is developmentally regulated in the human ovary is unknown. We therefore used northern analysis to examine 11betaHSD1 and 11betaHSD2 mRNA levels in non-luteinized and luteinizing granulosa cells, corpora lutea (CL) and ovarian stroma obtained from human ovaries. Here we show that non-luteinized granulosa cells express relatively high levels of 11betaHSD2 mRNA but not 11betaHSD1. Conversely, luteinizing granulosa cells abundantly express 11betaHSD1 mRNA but not 11betaHSD2. CL also expresses 11betaHSD2 to lesser extent. Neither 11betaHSD mRNA is detectable in ovarian stroma. These results indicate that mRNAs encoding both 1lbetaHSD isozymes are present in human granulosa cells and they are developmentally--but differentially--regulated during preovulatory follicular development. The existence of developmentally regulated 11betaHSD in human granulosa cells is important new evidence that glucocorticoids, acting directly on the ovary, serve physiologically significant roles in the regulation of folliculogenesis.
11-beta-Hydroxysteroid Dehydrogenases↗
Tissue and endocrine responses to gestrinone and danazol in the treatment of endometriosis.
An open comparative study of gestrinone and danazol in the treatment of endometriosis demonstrated a similar decrease in the extent of active endometriotic deposits, assessed visually following therapy. Biochemical endocrinological changes during therapy with gestrinone showed that basal concentrations of gonadotrophin remained unchanged, oestradiol concentrations varied and the free fraction of testosterone increased. A similar range of side effects was reported in both treatment groups, consisting predominantly of 'androgenic' effects in 10 of 15 women treated with gestrinone and 5 of 12 treated with danazol. The results suggest that gestrinone is an effective alternative agent for the treatment of endometriosis.
Amenorrhea↗
Fast neutron radiotherapy for locally advanced prostate cancer. Final report of Radiation Therapy Oncology Group randomized clinical trial.
Between June 1977 and April 1983 the Radiation Therapy Oncology Group (RTOG) sponsored a Phase III randomized trial investigating the use of fast neutron radiotherapy for patients with locally advanced (Stages C and D1) adenocarcinoma of the prostate gland. Patients were randomized to receive either conventional photon radiation or fast neutron radiation used in a mixed-beam (neutron/photon) treatment schedule. A total of 91 analyzable patients were entered into the study, and the two patient groups were balanced with respect to the major prognostic variables. Actuarial curves are presented for local/regional control and "overall" survival. Ten-year results for clinically assessed local control are 70% for the mixed-beam group versus 58% for the photon group (p = 0.03) and for survival are 46% for the mixed-beam group versus 29% for the photon group (p = 0.04). This study suggests that a regional method of treatment can influence both local tumor control and survival in patients with locally advanced adenocarcinoma of the prostate gland.
Adenocarcinoma↗
Nuclear-encoded chloroplast ribosomal protein L12 of Nicotiana tabacum: characterization of mature protein and isolation and sequence analysis of cDNA clones encoding its cytoplasmic precursor.
Poly(A)+ mRNA isolated from Nicotiana tabacum (cv. Petite Havana) leaves was used to prepare a cDNA library in the expression vector lambda gt11. Recombinant phage containing cDNAs coding for chloroplast ribosomal protein L12 were identified and sequenced. Mature tobacco L12 protein has 44% amino acid identity with ribosomal protein L7/L12 of Escherichia coli. The longest L12 cDNA (733 nucleotides) codes for a 13,823 molecular weight polypeptide with a transit peptide of 53 amino acids and a mature protein of 133 amino acids. The transit peptide and mature protein share 43% and 79% amino acid identity, respectively, with corresponding regions of spinach chloroplast ribosomal protein L12. The predicted amino terminus of the mature protein was confirmed by partial sequence analysis of HPLC-purified tobacco chloroplast ribosomal protein L12. A single L12 mRNA of about 0.8 kb was detected by hybridization of L12 cDNA to poly(A)+ and total leaf RNA. Hybridization patterns of restriction fragments of tobacco genomic DNA probed with the L12 cDNA suggested the existence of more than one gene for ribosomal protein L12. Characterization of a second cDNA with an identical L12 coding sequence but a different 3'-noncoding sequence provided evidence that at least two L12 genes are expressed in tobacco.
Amino Acid Sequence↗
High energy (42-66 MeV reactions) fast neutron dose optimization studies in the head and neck, thorax, upper abdomen, pelvis and extremities.
Five hundred and fifty patients were entered into a set of dose-searching studies designed to determine normal tissue tolerance to high energy (42-66 MeV reactions) fast neutrons delivered in 12 equal fractions over 4 weeks. Participating institutions included: The Fermilab (66 MeV p+----Be), The University of Washington (50 MeVp+----Be), U.C.L.A. (45 MeVH-----Be), M.D. Anderson Hospital (42 MeVH-----Be), and The Cleveland Clinic (42 MeVp+----Be). Patients were stratified by treatment facility and then randomized to receive 16, 18 or 20 Gy for tumors located in the upper abdomen or pelvis, and 18, 20 or 22 Gy for tumors located in the head and neck, thorax or extremities. Following completion of the randomized protocols, additional patients were studied at the 20.4 Gy level in the head and neck, thorax and pelvis. Normal tissue effect scoring was accomplished using the RTOG-EORTC acute and late normal tissue effect scales. Acute Grade 3 + toxicity rates in the head and neck were 19% for 20/20.4 Gy and 20% for 22 Gy. Time adjusted late toxicity rates in the head and neck at 12 months were 15% for 20/20.4 Gy and 0% for 22 Gy. The 18 Gy treatment arm of the head and neck protocol was dropped early in the study after only two patients were accrued. For cases treated in the thorax, acute Grade 3 + toxicity rates were 6% for 18 Gy, 15% for 20/20.4 Gy and 7% for 22 Gy. Late toxicity rates at 12 months were 0% for 18 Gy, 11% for 20/20.4 Gy and 18% for 22 Gy. Acute Grade 3+ toxicity rates in the upper abdomen were 0% for 16 Gy, 8% for 18 Gy and 12% for 20 Gy. There were no Grade 3 + late toxicities in the upper abdomen. In the pelvis, acute Grade 3 + toxicity rates were 0% for 16 Gy, 3% for 18 Gy and 3% for 20/20.4 Gy. Late Grade 3 + toxicities at 24 months were 20% for 16 Gy, 5% for 18 Gy and 24% for 20/20.4 Gy. In extremities, acute Grade 3 + toxicity rates were 7% for 20 Gy and 21% for 22 Gy while at 12 months, late Grade 3 + toxicity rates were 14 and 35%, respectively. The 18 Gy treatment arm of the extremities protocol was dropped early in the study after only two patients were accrued. Factors associated with normal tissue effects in addition to treatment dose are discussed.
Abdominal Neoplasms↗
Therapeutic response of breast carcinoma monitored by 31P MRS in situ.
In situ phosphorous MRS was employed to study the metabolites of normal and cancerous breasts, and the alterations of tumor response to therapy. In a group of 7 normal volunteers and 12 patients, the total mobile phosphate content of breast carcinomas was found to be at least two to three times higher than that of the normal breast measured off menstruation. The metabolite profiles of normal and tumorous breasts are coarsely similar. In both cases the intracellular pH (pHi) was either neutral or slightly alkaline (pH greater than 7.0). Prior to treatments, the metabolite levels of phosphoryl monoester-to-ATP ratio of breast neoplasms were higher than those of the controls and decreased after the patients received a few treatments while the pHi fluctuated at a value greater than 7.0. The phosphoryl diester-to-ATP ratio also demonstrated to a lesser extent a decreasing trend in response to therapy.
Breast↗
Mixed neutron/photon irradiation of unresectable squamous cell carcinomas of the head and neck: the final report of a randomized cooperative trial.
Three hundred and twenty-seven patients with inoperable squamous cell carcinomas of the head and neck were entered on a randomized study comparing a mixture of neutron and photon ("mixed beam") radiation therapy with photon/electron radiation therapy. Neutron treatment was delivered with fixed-beam, physics-laboratory-based equipment. Patients with histologically proven tumors of T-stage T2, T3, or T4 and any N-stage were eligible for randomization. Primary tumor sites were limited to cancers originating in the oral cavity, oropharynx, supraglottic larynx, or hypopharynx. Patients entered on this study now have a minimum at-risk follow-up period of 6 years. Study results reveal no significant differences in overall loco-regional tumor control rates or survival. Subgroup analysis reveals significant differences based on whether or not patients presented with positive lymph nodes. Loco-regional tumor control rates for patients presenting with positive lymph nodes were 30% for mixed-beam-treated patients versus 18% for photon-treated patients (p = 0.05). Loco-regional tumor control rates for patients presenting without positive lymph nodes were 64% for photon-treated patients and 33% for mixed-beam-treated patients (p = 0.004). Control of tumor located in the nodal sites favored mixed beam over photons by a margin of 45% (49/109) to 26% (23/87) with a significance of p = 0.004. Possible explanations for these contradictory findings are discussed.
Adult↗
Application of thermal dilution measurements for thermal treatment planning.
The use of thermal dilution measurements is demonstrated in quantifying effective thermal conductivity distributions through tumours. For focused acoustic sources these data are applied in the solution of the heat diffusion equation to estimate steady-state temperature distributions. The advantages and disadvantages of this approach are presented. The effective conductivity measurements are found to be useful in predicting the circumstances under which this simple model can be applied and in aiding the selection of the most appropriate heating modality.
Animals↗
Evaluation of neutron irradiation of pancreatic cancer. Results of a randomized Radiation Therapy Oncology Group clinical trial.
Between 1980-84, the Radiation Therapy Oncology Group conducted a trial in patients with untreated, unresectable localized carcinomas of the pancreas. Patients were randomly chosen to receive either 6,400 cGy with photons, the equivalent dose with a combination of photons and neutrons (mixed-beam irradiation), or neutrons alone. A total of 49 cases were evaluable, of which 23 were treated with photons, 11 with mixed-beam therapy, and 15 with neutrons alone. The median survival time was 5.6 months with neutrons, 7.8 months with mixed-beam radiation, and 8.3 months with photons. The median local control time was 6.7 months with neutrons, 6.5 months with mixed-beam radiation, and 2.6 months with photons. These differences are not statistically significant. Evidence of moderate-to-life-threatening gastrointestinal or hepatic injury was present in three patients treated with neutrons and one patient treated with photons. The causes of this apparent difference are discussed. This study demonstrates there is no evidence to suggest that neutron irradiation, either alone or in combination with photon irradiation, produces better local control or survival rates than photon irradiation.
Adenocarcinoma↗
Human neoplasm pH and response to radiation therapy: P-31 MR spectroscopy studies in situ.
Thirty-five human neoplasms from various sites and of various histologic types and stages were examined with phosphorus-31 magnetic resonance spectroscopy in situ. The tumors included 13 squamous cell carcinomas of the head and neck (lymph nodes), eight Hodgkin lymphomas, six non-Hodgkin lymphomas, four carcinomas of the breast, one melanoma, one sarcoma, one neuroblastoma, and one mucoepidermoid sarcoma of the salivary glands. Thirty-four of the neoplasms had normal to slightly alkaline pH before irradiation. During fractionated radiation therapy, the pH stayed in a range of from near neutral to alkaline and rose to 7.6-8.0 at several time points of radiation therapy for some tumors. These results suggest that most tumor cells in human neoplasms are well oxygenated and that only a negligible fraction are chronic hypoxic cells. The fluctuating alkaline pH during radiation therapy occurred regardless of the responsiveness of the treated tumors.
Carcinoma, Squamous Cell↗
The effect of vasoactive intestinal peptide, secretin, and glucagon on human duodenal bicarbonate secretion.
Duodenal luminal acidification increases duodenal mucosal bicarbonate production and also releases both secretin and vasoactive intestinal peptide (VIP). The effect of these two structurally similar peptides on human duodenal bicarbonate production has not been examined in humans. Our purpose was therefore to assess the effect of VIP and secretin and also glucagon, a homologous hormone, on human duodenal bicarbonate secretion. A 4-cm portion of either proximal or distal duodenum was isolated and perfused with iso-osmolar NaCl. Pure porcine VIP (200 and 400 pmol/kg-h intravenously) significantly increased proximal duodenal bicarbonate secretion. Although secretin (0.01 to 0.18 CU/kg-h intravenously) markedly increased pancreatic bicarbonate secretion, it failed to alter duodenal mucosal bicarbonate output in either the proximal or the distal duodenum. Glucagon (1 to 8 micrograms/kg-h intravenously) did not affect proximal duodenal mucosal bicarbonate output. It is concluded that VIP, but neither secretin nor glucagon, significantly stimulates human duodenal mucosal bicarbonate secretion.
Adult↗
Less well known parameters of in vitro radiosensitivity.
In addition to well known parameters used for measuring in vitro cellular radiosensitivity (mean lethal dose, extrapolation number, quasithreshold dose), there are other, less well known measures that may be more important. The authors recently surveyed the literature and found that mean activation dose (D) has been neglected in the analyses. Among 70 articles published in the radiation oncology and biology literature that used cell survival curves or parameters to measure radiosensitivity, only two used the values of D in their analysis. By recalculating D from published survival curves, different conclusions may be drawn. The authors see a definite need for more prospective application of D and surviving fraction at 2 Gy.
Cell Survival↗
Neutron therapy in cervical cancer: results of a phase III RTOG Study.
Between October 1976 and May 1984, 156 patients with locally advanced cervical cancer were entered into a Phase III trial with the participation of five institutions. Patients were randomly assigned to receive photons only (50 Gy in 25 fractions over 5 weeks plus intracavitary applications or external-beam boost) or mixed-beam radiotherapy (2 fractions a week of neutrons, 3 fractions a week of photons to a total RBE-adjusted dose of 50 Gy over 5 weeks plus intracavitary applications or external mixed-beam boost). Only patients with squamous carcinoma of FIGO Stages IIB, III, or IVA with negative para-aortic nodes on lymphangiogram were eligible. Ten patients were excluded from the analysis because of ineligibility or cancellation. Of the 146 patients analyzed, 80 were treated with mixed-beam radiotherapy and 66 with photons. Patients were grouped by stage and institution. The percentage of patients undergoing intracavitary applications was 50% on mixed beam and 75% on photons (p less than 0.01). Tumor clearance was 52% and 72% for mixed beam and photons, respectively (p less than 0.03). Local control at 2 years was 45% for mixed beam and 52% for photons. Median survivals were 1.9 years on mixed beam and 2.3 years on photons. Severe complications occurred in 19% and 11% in mixed beam and photons respectively (p less than 0.13). The inferior outcome with neutron therapy in this study may have resulted from the use of horizontal neutron beams of varying energy and penetration. A new randomized trial using high-energy hospital-based cyclotrons with gantry-mounted beam-delivery systems has recently been activated to evaluate more rigorously the role of fast-neutron therapy for advanced cervical cancer.
Adult↗
Randomized neutron dose searching study for malignant gliomas of the brain: results of an RTOG study. Radiation Therapy Oncology Group.
From September 1980 through January 1985, the Radiation Therapy Oncology Group (RTOG) conducted a randomized, dose-searching study testing the efficacy of a concomitant neutron boost along with whole brain photon irradiation in the treatment of malignant gliomas of the brain. Patients had to have biopsy-proven, supratentorial, anaplastic astrocytoma or glioblastoma multiforme (Nelson schema) to be eligible for the study. The whole brain photon irradiation was given at 1.5 Gy per treatment, 5 days-a-week to a total dose of 45 Gy. Two days-a-week the patients were to receive neutron boost irradiation to the tumor volume as determined on CT scans. The neutron irradiation was to be given prior to and within 3 hours of the photon irradiation on that day. The rationale for this particular treatment regime is discussed. A total of 190 evaluable patients were randomized among 6 different neutron dose levels: 3.6, 4.2, 4.8, 5.2, 5.6 and 6.0 Gyn gamma. There was no difference in overall survival among the 6 different dose levels, but for patients having less aggressive tumor histology (anaplastic astrocytoma), there was a suggestion that patients on the higher dose levels had poorer overall survival than patients on the lower dose levels and also did worse than historical photon controls. Important prognostic factors were identified using a Cox stepwise regression analysis. Tumor histology, Karnofsky performance status, and patient age were found to be related to survival while extent of surgery and neutron dose had no significant impact. Autopsies were performed on 35 patients and the results correlated with the actual neutron dose as determined by central-axis isodose calculations. At all dose levels there were some patients with both radiation damage to normal brain tissue and evidence of viable tumor. No evidence was found for a therapeutic window using this particular treatment regimen.
Astrocytoma↗
Posterior spinal cord block: a dosimetric study.
To determine the optimal width of a midline posterior spinal block (MPSB) (to avoid delivering too great a dose to the cord and too small a dose to adjacent tissue), the authors determined with magnetic resonance (MR) imaging normal ranges of cord depth and width and correlated them with film dosimetric data. In 59 randomly selected patients there was a wide range for both depth and width. The average depths of the anterior and posterior surfaces of the cord were 6.7 cm +/- 1.4 and 5.4 cm +/- 1.3, respectively. The average cord width was 1.6 cm +/- 0.4. Optimal cord block width as a function of cord width was determined for a 6-MV photon beam. The optimal cord block width at the surface (half-value layer [HVL] thickness = 6) varied from 1.5 to 3.0 cm for cord widths of 0.8-2.4 cm, which correspond to two standard deviations from the average. There was no significant dependence on depth of the cord. For optimal treatment outcome, the MPSB width may have to be determined for each patient individually.
Film Dosimetry↗