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R A Hawkins

Publications and source records attributed to R A Hawkins.

At least 19 recordsLinked to original sources
PubMed2002

Outcome after extended follow-up in a prospective study of operable breast cancer: key factors and a prognostic index.

In 1990, 215 patients with operable breast cancer were entered into a prospective study of the prognostic significance of five biochemical markers and 15 other factors (pathological/chronological/patient). After a median follow-up of 6.6 years, there were 77 recurrences and 77 deaths (59 breast cancer-related). By univariate analysis, patient outcome related significantly to 13 factors. By multivariate analysis, the most important of nine independent factors were: number of nodes involved, steroid receptors (for oestrogen or progestogen), age, clinical or pathological tumour size and grade. Receptors and grade exerted their influence only in the first 3 years. Progestogen receptors (immunohistochemical) and oestrogen receptors (biochemical) were of similar prognostic significance. The two receptors were correlated (r=+0.50, P=0.001) and displaced each other from the analytical model but some evidence for the additivity of their prognostic values was seen when their levels were discordant.

Biomarkers, Tumor↗
PubMed2001

In vivo hippocampal glucose metabolism in mesial temporal lobe epilepsy.

BACKGROUND: The appearance of decreased 2-[(18)F]fluoro-2-deoxy-D-glucose (FDG) uptake in the mesial temporal region in temporal lobe epilepsy may simply reflect loss of gray matter due to hippocampal atrophy. Increased partial volume effects due to atrophic hippocampi may further increase appearance of hypometabolism. METHODS: The authors used a combination of MRI-PET coregistration, with MRI-based gray matter segmentation, and partial volume correction to improve the examination of hippocampal specific glucose uptake in FDG PET. The goal was to determine 1) if relative mesial temporal hypometabolism is an artifact of gray matter (hippocampal) atrophy, 2) whether hippocampal metabolism correlates with atrophy evaluated on MRI, and 3) if MRI-based partial volume correction influences measurement of hippocampal metabolic-volume relationships, including epilepsy lateralization. RESULTS: Findings showed that ipsilateral hippocampi of mesial temporal lobe epilepsy (MTLE) are relatively hypometabolic per unit of gray matter volume, and that hippocampal metabolism directly correlates with hippocampal volume. Specifically, partial volume corrected hippocampal metabolism correlated strongly (r = 0.613, p < 0.001) with hippocampal volume. Without partial volume correction, a weaker, but still significant, correlation was present (r = 0.482, p < 0.001). Degree of asymmetry was consistently greater and provided higher sensitivity of lateralization with partial volume vs non-partial volume corrected metabolic measurements. CONCLUSIONS: Although, decreased metabolism may occur in the absence of neuronal cell loss, hippocampal atrophy and presumed degree of neuronal cell loss appears to be a primary factor involved in the cause of decreased metabolism in epileptogenic hippocampi. Partial volume correction is recommended for optimal interpretation of hippocampal structure and function relationships.

Adolescent↗
PubMed2001

Glucose transporter asymmetries in the bovine blood-brain barrier.

The transport of glucose across the mammalian blood-brain barrier is mediated by the GLUT1 glucose transporter, which is concentrated in the endothelial cells of the cerebral microvessels. Several studies supported an asymmetric distribution of GLUT1 protein between the luminal and abluminal membranes (1:4) with a significant proportion of intracellular transporters. In this study we investigated the activity and concentration of GLUT1 in isolated luminal and abluminal membrane fractions of bovine brain endothelial cells. Glucose transport activity and glucose transporter concentration, as determined by cytochalasin B binding, were 2-fold greater in the luminal than in the abluminal membranes. In contrast, Western blot analysis using a rabbit polyclonal antibody raised against the C-terminal 20 amino acids of GLUT1 indicated a 1:5 luminal:abluminal distribution. Western blot analysis with antibodies raised against either the intracellular loop of GLUT1 or the purified erythrocyte protein exhibited luminal:abluminal ratios of 1:1. A similar ratio was observed when the luminal and abluminal fractions were exposed to the 2-N-4[(3)H](1-azi-2,2,2,-trifluoroethyl)benzoxyl-1,3-bis-(d-mannos-4-yloxyl)-2-propylamine ([(3)H]ATB-BMPA) photoaffinity label. These observations suggest that either an additional glucose transporter isoform is present in the luminal membrane of the bovine blood-brain barrier or the C-terminal epitope of GLUT1 is "masked" in the luminal membrane but not in the abluminal membranes.

Affinity Labels↗
PubMed2001

Neuroblastoma imaging using a combined CT scanner-scintillation camera and 131I-MIBG.

UNLABELLED: High-dose administration of 131I-metaiodobenzylguanidine (131I-MIBG) continues to be a promising treatment for neuroblastoma. However, currently used methods of estimating 131I-MIBG uptake in vivo may be too inaccurate to properly monitor patient radiation exposure doses. To improve localization and uptake measurements over currently practiced techniques, we evaluated different methodologies that take advantage of the correlated patient data available from a combined CT-scintillation camera imaging system. METHODS: Serial CT and radionuclide scans of three patients were obtained on a combined imaging system. SPECT images were reconstructed using both filtered backprojection and maximum-likelihood expectation maximization (MLEM). Volumes of interest (VOIs) were defined on anatomic images and automatically correlated to spatial volumes in reconstructed SPECT images. Several radionuclide quantification methods were then compared. First, the mean reconstructed values within coregistered SPECT VOIs were estimated from MLEM reconstructed images. Next, we assumed that reconstructed activity in SPECT voxels were linear combinations of activities present in individual objects, weighted by geometric factors derived from CT images. After calculating the weight factors by modeling the SPECT imaging process with anatomically defined VOIs, least-squares fitting was used to estimate the activities within lesion volumes. We also estimated the lesion activities directly from planar radionuclide images of the patients using similar linearity assumptions. Finally, for comparison, lesion activities were estimated using a standard conjugate view method. RESULTS: Activities were quantified from three patients having a total of six lesions with volumes ranging from 0.67 to 117 mL. Methods that used CT data to quantify lesion activities gave similar results for planar and tomographic radionuclide data. Estimating activity directly from mean VOI values in MLEM-reconstructed images alone consistently provided estimates lower than CT-aided methods because of the limited spatial resolution of SPECT. Values obtained with conjugate views produced differences up to fivefold in comparison with CT-aided methods. CONCLUSION: These results show that anatomic information available from coregistered CT images may improve in vivo localization and measurement of 131I-MIBG uptake in tumors.

3-Iodobenzylguanidine↗
PubMed2001

Correlation of tumor and whole-body dosimetry with tumor response and toxicity in refractory neuroblastoma treated with (131)I-MIBG.

UNLABELLED: The purpose of our study was to determine the effect of tumor-targeted radiation in neuroblastoma by correlating administered (131)I-metaiodobenzylguanidine (MIBG) activity to tumor and whole-body dosimetry, tumor volume change, overall response, and hematologic toxicity. METHODS: Eligible patients had MIBG-positive lesions and tumor-free, cryopreserved hematopoietic stem cells. Activity was administered according to body weight and protocol as part of a phase I and phase II study. The whole-body radiation dose was derived from daily 1-m exposure measurements, the tumor self-absorbed radiation dose (TSARD) was determined from scintillation-camera conjugate views, and the tumor volume was measured using CT or MRI. RESULTS: Forty-two patients with refractory neuroblastoma (16 with prior hematopoietic stem cell transplant) received a median activity of 555 MBq/kg (15 mCi/kg) (range, 93-770 MBq/kg) and a median total activity of 11,470 MBq (310 mCi) (range, 3,330-30,969 MBq). The median whole-body radiation dose was 228 cGy (range, 57-650 cGy) and the median TSARD was 3,300 cGy (range, 312-30,500 cGy). Responses among evaluable patients included 16 partial response, 3 mixed response, 14 stable disease, and 9 progressive disease. Higher TSARD values predicted better overall disease response (P < 0.01). The median decrease in tumor volume was 19%; 18 tumors decreased, 4 remained stable, and 5 increased in size. Correlation was seen between administered activity per kilogram and whole-body dose as well as hematologic toxicity (assessed by blood platelet and neutrophil count nadir) (P < 0.05). The median whole-body dose was higher in the 11 patients who required hematopoietic stem cell infusion for prolonged neutropenia versus the 31 patients who did not (323 vs. 217 cGy; P = 0.03). CONCLUSION: Despite inaccuracies inherent in dosimetry methods, (131)I-MIBG activity per kilogram correlated with whole-body radiation dose and hematologic toxicity. The TSARD by conjugate planar imaging predicted tumor volume decrease and also correlated with overall tumor response.

3-Iodobenzylguanidine↗
PubMed2000

Glucose transporters and glucose utilization in rat brain after acute ethanol administration.

In the normal adult brain, glucose provides 90% of the energy requirements as well as substrate for nucleic acid and lipid synthesis. In the present study, effects of ethanol on glucose transporters (GLUT) and glucose utilization were examined in rat brain. Male Sprague-Dawley rats weighing 250-300 gms were given either ethanol 3 gm/kg BW or saline i.p. 4 hrs prior to the animal sacrifice and removal of the cerebral cortical tissue. The cortical plasma membranes analyzed by cytochalasin B binding assay showed a decrease in GLUT number but not in GLUT affinity in the ethanol treated rats as compared to the control rats. The estimated Ro values were 70 +/- 8.9 Vs 91 +/- 8.9 pmoles/mg protein (p < 0.05 N=4) and the estimated Kd values were 0.37 +/- 0.03 and 0.28 +/- 0.05 microM (p: NS) in ethanol and control experiments respectively. Immunoblots of purified cerebral plasma membranes and low density microsomal fraction showed 17% and 71% decrease for GLUTI and 54% and 21% (p<0.05 or less; n=6) for GLUT3 respectively in ethanol treated rats than in control animals. Immunofluoresence studies also showed reduction of GLUT1 immunoreactively in choroid plexus and cortical microvessels of ethanol treated rats as compared to control rats. The effect of ethanol on regional cerebral metabolic rates for glucose (CMR(Glc)) was studied using [6-(14)C] glucose and showed statistically insignificant decrease in brain glucose utilization. These data suggest that ethanol in-vivo decrease GLUT number and protein content in rat cerebral cortex.

Animals↗
PubMed2000

The prostate: diagnostic evaluation of metastatic disease.

One of the single most important considerations in clinical management of the patient with prostate cancer is whether or not metastatic disease is present. The identification of metastatic disease in a patient with newly diagnosed prostate cancer represents an absolute contraindication to definitive local therapies such as radial prostatectomy or radiation therapy. Similarly, the identification of metastatic disease in a patient with disease recurrence after definitive local therapy represents an absolute contraindication to salvage radiotherapy or cryosurgery. Patients with metastatic disease do not benefit from definitive therapy, and the cost and morbidity associated with such treatment should therefore be avoided in these patients. Because of the significance of metastatic disease to clinical management, it is important for the diagnostic radiologist to be aware of important considerations in the metastatic work-up of patients with newly diagnosed prostate cancer and patients with suspected cancer recurrence after definitive local therapy.

Bone Neoplasms↗
PubMed2000

How best to express oestrogen receptor activity.

Oestrogen receptor (ER) activity, detected and expressed in a variety of ways, is important in breast cancer. Experience in Edinburgh (1973-1996) showed that [1] no single mode of expression was entirely satisfactory, [2] the probability of a good 'outcome' (prognosis or response to endocrine therapy) increased with increasing activity (either fmol ER sites/mg protein or per cent cells staining for ER). Thus the use of a single 'cut-off' should be avoided and activity quantified, or stratified into categories.

Breast Neoplasms↗
PubMed2000

Expression of mucosal homing receptor alpha4beta7 is associated with enhanced migration to the Chlamydia-infected murine genital mucosa in vivo.

The CD4 T helper cell type 1 (Th1) response is essential for the resolution of chlamydial genital infection in mice. However, not all Th1 clones are equally protective in eradicating the infection. Since oral immunization regimens produce protective immunity, we evaluated the role of the mucosa-associated homing receptor, alpha4beta7, in trafficking to the genital mucosa. Using a panel of CD4, Th1 cell lines and clones, we compared the lymphocyte homing patterns of a Chlamydia-specific, protective clone (P-MoPn), a nonprotective clone (N-MoPn), and a keyhole limpet hemocyanin (KLH)-specific cell line (KLH-1). T cells were labeled with the fluorescent dye PKH-26, adoptively transferred into Chlamydia-infected mice, and monitored at different time points throughout the course of a genital infection. We found that clones P-MoPn and N-MoPn migrated to similar extents to the genital tract and in significantly greater numbers than the KLH-specific T-cell line. Both clones and the KLH-1 line expressed similar levels of the adhesion molecules alpha4, beta1, CD44, and CD11a. However, clones P-MoPn and N-MoPn expressed higher levels of the mucosal homing receptor, alpha4beta7. Also, clones P-MoPn and N-MoPn but not the KLH-1 line migrated to the mesenteric lymph node, suggesting a mucosal recirculation pattern. Moreover, blocking alpha4beta7 adhesion interaction in vivo significantly reduced the recruitment of P-MoPn but not KLH-1 to the genital tract. These findings show that the mucosal homing receptor alpha4beta7 is utilized by a subset of CD4 cells during migration to the Chlamydia-infected genital tract.

Animals↗
PubMed1999

Na(+)-dependent glutamate transporters (EAAT1, EAAT2, and EAAT3) of the blood-brain barrier. A mechanism for glutamate removal.

Na(+)-dependent transporters for glutamate exist on astrocytes (EAAT1 and EAAT2) and neurons (EAAT3). These transporters presumably assist in keeping the glutamate concentration low in the extracellular fluid of brain. Recently, Na(+)-dependent glutamate transport was described on the abluminal membrane of the blood-brain barrier. To determine whether the above-mentioned transporters participate in glutamate transport of the blood-brain barrier, total RNA was extracted from bovine cerebral capillaries. cDNA for EAAT1, EAAT2, and EAAT3 was observed, indicating that mRNA was present. Western blot analysis demonstrated all three transporters were expressed on abluminal membranes, but none was detectable on luminal membranes of the blood-brain barrier. Measurement of transport kinetics demonstrated voltage dependence, K(+)-dependence, and an apparent K(m) of 14 microM (aggregate of the three transporters) at a transmembrane potential of -61 mV. Inhibition of glutamate transport was observed using inhibitors specific for EAAT2 (kainic acid and dihydrokainic acid) and EAAT3 (cysteine). The relative activity of the three transporters was found to be approximately 1:3:6 for EAAT1, EAAT2, and EAAT3, respectively. These transporters may assist in maintaining low glutamate concentrations in the extracellular fluid.

ATP-Binding Cassette Transporters↗
PubMed1999

Unusual appearance of thromboembolism on perfusion lung imaging.

A 46-year-old woman with advanced ovarian carcinoma had progressive dyspnea and was evaluated with ventilation and perfusion lung imaging. A characteristic pattern of multiple branching perfusion defects of a segmental nature on the perfusion scan suggested tumor microembolism and lymphangitic carcinomatosis. However, in this case, this pattern was associated with pulmonary thromboembolism and was documented by the post mortem examination. Pulmonary thromboembolism should be included among the differential diagnoses in a patient with clinical symptoms and a perfusion scan that reveals multiple branching perfusion defects.

Adenocarcinoma↗
PubMed1999

Metastatic head and neck cancer: role and usefulness of FDG PET in locating occult primary tumors.

PURPOSE: To assess the usefulness of 2-[fluorine-18]fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) of the head and neck in locating occult primary lesions in patients with metastatic cervical adenopathy. MATERIALS AND METHODS: Seventeen patients with metastatic cervical adenopathy of unknown primary origin were referred for FDG PET of the head and neck. All patients had undergone correlative anatomic imaging within 1 month of FDG PET. Surgical, clinical, and histopathologic findings were used to assess the performance of FDG PET. RESULTS: Increased apical lung uptake at FDG PET led to a biopsy-proved diagnosis of primary lung cancer in two patients. Of the remaining 15 patients, 10 had a focus of increased activity; directed biopsy of these sites led to confirmation of a primary carcinoma in seven patients. Correlative anatomic imaging failed to demonstrate the primary sites of disease in two of these seven patients. None of the five patients with negative FDG PET studies have manifested evidence of a primary site of disease during follow-up of 8-42 months (mean, 29 months). CONCLUSION: FDG PET allows effective localization of the unknown primary site of origin in metastatic head and neck cancer and can contribute substantially to patient care.

Adenocarcinoma↗
PubMed1999

Quantification of myocardial blood flow using 13N-ammonia and PET: comparison of tracer models.

UNLABELLED: Several tracer kinetic methods have been proposed for quantification of regional myocardial blood flow (MBF) with 13N-ammonia and PET. Merits and limitations specific to each approach, however, generally are not clear, because they have not been evaluated in the same experimental environment. Therefore, we compared six different commonly used methods (11 modifications) to characterize the accuracy of each approach. The methods included the two-parameter model (method 1), the modified two-parameter model (method 2), the four-parameter model (method 3), the graphical analysis (method 4), the first-pass extraction method (method 5) and the dose uptake index (DUI; method 6). METHODS: Eleven studies in four dogs, 16 studies in eight healthy human volunteers and 14 studies in seven patients were performed using 13N-ammonia and PET. MBF in dogs was varied with dipyridamole and coronary occlusions and was measured independently and simultaneously with microspheres. Volunteers and patients were studied at baseline and after dipyridamole. MBF and DUI were estimated using a time-activity curve (Qi[t]) derived from dynamic images and regions of interest (ROls) and using the six methods. DUI was defined as Qi(t = 2 min) x weight/dose. RESULTS: MBF estimated by methods 1-5 correlated well with microsphere MBF in dogs. MBF estimates by method 1 correlated well with those by methods 2, 4 and 5 and to a lesser degree with those by method 3 in both dog and human studies. DUI correlated poorly with MBF by microspheres and by methods 1-5 in both dog and human studies. MBF estimates by method 3 showed larger dispersion (SD/mean flow) and higher sensitivity to metabolites correction in arterial blood than those by methods 1, 2, 4 and 5. CONCLUSION: MBF can be measured accurately using 13N-ammonia PET and tracer kinetic methods. DUI is a poor indicator of MBF values. The results indicate that preference should be given to the two-parameter model, incorporating geometrical ROI representation (method 2) among the compartment models, and to the graphical analysis (method 4) among the noncompartmental approaches.

Adult↗
PubMed1998

Internalization of Chlamydia by dendritic cells and stimulation of Chlamydia-specific T cells.

Chlamydia species are the causative agents of trachoma, various forms of pneumonia, and the most common sexually transmitted diseases. Although the infection cycle has been extensively characterized in epithelial cells, where the Chlamydia entry-vacuoles avoid fusion with host-cell lysosomes, the cellular immune response has received less attention. Moreover, despite the abundant presence of dendritic cells (DC) in the sites of infection, the interaction between Chlamydia and DC has never been studied. We observe that DC kill Chlamydia trachomatis and Chlamydia psittaci. The chlamydiae are internalized by the DC in a nonspecific manner through macropinocytosis, and the macropinosomes fuse subsequently with DC lysosomes expressing MHC class II molecules. The interaction induces maturation of the DC, since presentation of an exogenous Ag is severely inhibited after a 1-day incubation, although chlamydial Ags are still presented and recognized by Chlamydia-specific CD4+ T cells. Thus, DC most likely play a role in initiating the T cell response in vivo and could potentially be used in adoptive transfer therapies to vaccinate against Chlamydia.

Animals↗
PubMed1998

Apoptotic death of pancreatic cancer cells induced by polyunsaturated fatty acids varies with double bond number and involves an oxidative mechanism.

Polyunsaturated fatty acids (PUFAs), reported to be cytotoxic at micromolar concentrations for cancer cells in vitro and in vivo, are currently being tested in clinical trials as anti-cancer agents. This study has shown that seven PUFAs all inhibited the growth in vitro of three pancreatic cancer cell lines and the HL-60 leukaemic cell line. Five PUFAs induced cell death within 20-30 h, but two less potent PUFAs induced death between 50 and 75 h. Apoptosis was demonstrated to be the mode of cell death by light, UV fluorescence, and electron microscopy, together with studies of DNA fragmentation. In a time-course study of PUFA-treated Mia-Pa-Ca-2 cells, apoptosis accounted for an average of 80 per cent of the loss of viability, with 'secondary necrosis', a feature of late apoptosis, apparently accounting for the remainder. Correlations were found between the number of fatty acid double bonds and the proportion of cells undergoing apoptosis induced in both Mia-Pa-Ca-2 cells (R = 0.88, P = 0.0001) and HL-60 cells (R = 0.85, P = 0.0001) and inversely with the micromolar concentrations of PUFAs required for 50 per cent inhibition of growth (IC50) of Mia-Pa-Ca-2 cells (R = -0.73, P = 0.05). Cell death was preceded by progressively increasing lipid peroxidation. The extent of PUFA-induced lipid peroxidation, measured as malondialdehyde (MDA), also correlated with the proportion of apoptosis induced in Mia-Pa-Ca-2 cells (R = 0.69, P = 0.025) or HL-60 cells (R = 0.64, P = 0.043), as well as with the number of fatty acid double bonds (R = 0.82, P = 0.0015). PUFA-induced apoptosis was oxidative, being blocked by both vitamin E acetate and sodium selenite, the latter in a critically time-dependent manner. The cytotoxic effects of exposure to a PUFA and to gamma-irradiation simultaneously with, or prior to, the addition of PUFA.

Animals↗
PubMed1998

Estrogen regulation of transforming growth factor-alpha in ovarian cancer.

Transforming growth factor alpha (TGFalpha) may be induced by estrogen in estrogen responsive systems and can contribute to the growth-modulatory effects of this hormone. To test whether TGFalpha contributes to estrogen-regulated growth in ovarian cancers, we have compared the effects of 17beta-estradiol (E2) and TGFalpha in a range of ovarian carcinoma cell lines. Addition of E2 to the estrogen receptor (ER)-positive cell lines (PE01, PE04 and PE01CDDP) produced a 2-4 fold increase in TGFalpha protein concentrations in media conditioned by the cells. Both E2 and TGFalpha stimulated the growth of the PE01 and PE04 lines and inhibited the growth of the PE01CDDP line. Furthermore, the E2-mediated growth effects could be reversed by an epidermal growth factor (EGF) receptor-targeted antibody. E2 also down-regulated EGF receptor expression in ER-positive cell lines. In a series of primary ovarian tumors, higher concentrations of ER were associated with an increased percentage of tumors expressing TGFalpha mRNA and a decreased percentage expressing EGF receptor protein. All these data are consistent with E2 increasing production of TGFalpha in ER-positive ovarian cancer and this in turn acting through the EGF receptor to modulate growth in an autocrine manner.

Antibodies, Monoclonal↗
PubMed1998

PS2 mRNA expression adds prognostic information to node status for 6-year survival in breast cancer.

Expression of pS2, an oestrogen-regulated gene, has been associated with a good short-term prognosis and response to endocrine therapy. The aim of this study was to determine whether expression of mRNA for the pS2 gene in breast cancer could contribute useful information on disease behaviour and survival at medium-term follow-up. Northern blotting was used to detect pS2 messenger ribonucleic acid (mRNA) in the primary tumour tissue from each of 90 patients with breast cancer. Axillary node status was established by sampling or clearance, oestrogen receptor concentration by enzyme immunosorbant assay and follow-up was continued for at least 6 years or until death. At 83 months mean follow-up, 29 of 90 (32%) patients had recurrent disease and, of these, 18 (20%) had died from breast cancer. pS2 mRNA expression, present in 26 of 90 (29%) cancers, was associated with freedom from disease recurrence (P = 0.026) and was significantly associated with survival at a minimum of 6 years follow-up (P < 0.001). Pathological node status and tumour size were also significantly associated with disease recurrence (P < 0.001 and P = 0.002 respectively) and inversely with survival (P < 0.001 and P < 0.001 respectively). After multiple Cox regression analysis, pS2 expression was still a significant predictor of recurrence (but not survival) after adjusting for node status and tumour size; oestrogen receptor was an independent predictor of survival. The combination of node status and pS2 expression discriminated patients with particularly good prognosis (node negative, pS2 positive: no mortality at 6 years) or poor prognosis (node positive, pS2 negative; 41% mortality at 6 years). Evaluation of pS2 expression in breast cancer at diagnosis may provide additional useful prognostic information to conventional staging.

Breast Neoplasms↗