Biomedical subjects

L A Dawson

Publications and source records attributed to L A Dawson.

At least 19 recordsLinked to original sources

PubMed2005

Lecozotan (SRA-333): a selective serotonin 1A receptor antagonist that enhances the stimulated release of glutamate and acetylcholine in the hippocampus and possesses cognitive-enhancing properties.

Recent data has suggested that the 5-hydroxytryptamine (5-HT)(1A) receptor is involved in cognitive processing. A novel 5-HT(1A) receptor antagonist, 4-cyano-N-{2R-[4-(2,3-dihydrobenzo[1,4]-dioxin-5-yl)-piperazin-1-yl]-propyl}-N-pyridin-2-yl-benzamide HCl (lecozotan), which has been characterized in multiple in vitro and in vivo pharmacological assays as a drug to treat cognitive dysfunction, is reported. In vitro binding and intrinsic activity determinations demonstrated that lecozotan is a potent and selective 5-HT(1A) receptor antagonist. Using in vivo microdialysis, lecozotan (0.3 mg/kg s.c.) antagonized the decrease in hippocampal extracellular 5-HT induced by a challenge dose (0.3 mg/kg s.c.) of 8-hydroxy-2-dipropylaminotetralin (8-OH-DPAT) and had no effects alone at doses 10-fold higher. Lecozotan significantly potentiated the potassium chloride-stimulated release of glutamate and acetylcholine in the dentate gyrus of the hippocampus. Chronic administration of lecozotan did not induce 5-HT(1A) receptor tolerance or desensitization in a behavioral model indicative of 5-HT(1A) receptor function. In drug discrimination studies, lecozotan (0.01-1 mg/kg i.m.) did not substitute for 8-OH-DPAT and produced a dose-related blockade of the 5-HT(1A) agonist discriminative stimulus cue. In aged rhesus monkeys, lecozotan produced a significant improvement in task performance efficiency at an optimal dose (1 mg/kg p.o.). Learning deficits induced by the glutamatergic antagonist MK-801 [(-)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate] (assessed by perceptually complex and visual spatial discrimination) and by specific cholinergic lesions of the hippocampus (assessed by visual spatial discrimination) were reversed by lecozotan (2 mg/kg i.m.) in marmosets. The heterosynaptic nature of the effects of lecozotan imbues this compound with a novel mechanism of action directed at the biochemical pathologies underlying cognitive loss in Alzheimer's disease.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed2005

Accuracy of finite element model-based multi-organ deformable image registration.

As more pretreatment imaging becomes integrated into the treatment planning process and full three-dimensional image-guidance becomes part of the treatment delivery the need for a deformable image registration technique becomes more apparent. A novel finite element model-based multiorgan deformable image registration method, MORFEUS, has been developed. The basis of this method is twofold: first, individual organ deformation can be accurately modeled by deforming the surface of the organ at one instance into the surface of the organ at another instance and assigning the material properties that allow the internal structures to be accurately deformed into the secondary position and second, multi-organ deformable alignment can be achieved by explicitly defining the deformation of a subset of organs and assigning surface interfaces between organs. The feasibility and accuracy of the method was tested on MR thoracic and abdominal images of healthy volunteers at inhale and exhale. For the thoracic cases, the lungs and external surface were explicitly deformed and the breasts were implicitly deformed based on its relation to the lung and external surface. For the abdominal cases, the liver, spleen, and external surface were explicitly deformed and the stomach and kidneys were implicitly deformed. The average accuracy (average absolute error) of the lung and liver deformation, determined by tracking visible bifurcations, was 0.19 (s.d.: 0.09), 0.28 (s.d.: 0.12) and 0.17 (s.d.: 0.07) cm, in the LR, AP, and IS directions, respectively. The average accuracy of implicitly deformed organs was 0.11 (s.d.: 0.11), 0.13 (s.d.: 0.12), and 0.08 (s.d.: 0.09) cm, in the LR, AP, and IS directions, respectively. The average vector magnitude of the accuracy was 0.44 (s.d.: 0.20) cm for the lung and liver deformation and 0.24 (s.d.: 0.18) cm for the implicitly deformed organs. The two main processes, explicit deformation of the selected organs and finite element analysis calculations, require less than 120 and 495 s, respectively. This platform can facilitate the integration of deformable image registration into online image guidance procedures, dose calculations, and tissue response monitoring as well as performing multi-modality image registration for purposes of treatment planning.

Algorithms↗

PubMed2004

Rapid high-throughput assay for the measurement of amino acids from microdialysates and brain tissue using monolithic C18-bonded reversed-phase columns.

A rapid precolumn high-performance liquid chromatography method based on fluorescence detection has been developed for the measurement of multiple amino acids from both ex vivo and in vivo biological samples using monolithic C18 columns. A mixture of 18 primary amino acids were derivatised with napthalene-2,3-dicarboxaldehyde (NDA) in the presence of cyanide. The resulting isoindole derivatives were resolved within 10 min using a linear binary gradient elution profile with Rs values in the range 1.2-9.0. The limit of detection (LOD) was found to be between 6.0 and 60 fmol for 5 microl injection with a signal to noise ratio of 3:1. The NDA derivatives were found to be stable for 9 h at 4 degrees C. This assay has been employed for the rapid analysis of amino acids from brain tissue and microdialysis samples. Examples of application of the method are given.

Amino Acids↗

PubMed2004

Stromal-epithelial interactions influence prostate cancer cell invasion by altering the balance of metallopeptidase expression.

Perturbations of stromal-epithelial interactions in the developing tumour can contribute to cancer invasion and metastasis. The structurally related metallopeptidases endothelin-converting enzyme (ECE) and neutral endopeptidase (NEP) contribute sequentially to the synthesis and inactivation of ET-1, a mitogenic peptide that has been shown to affect tumour behaviour. This study has investigated the interaction between metastatic tumour epithelial cells, which lack NEP, and stromal cells, which we have shown to express ECE-1 (stromal-epithelial interactions), using Matrigel invasion chambers. The epithelial cell lines utilised in this study include androgen-sensitive LNCaP, androgen-independent PC-3, Du145 and recently established PNT-1a, PNT2-C2 and P4E6 prostate cell lines. Specific inhibition of endogenous ECE-1 activity in stromal cells reduced PC-3 and Du145 invasion by 70 and 50%, respectively. Addition of recombinant NEP to inactivate endogenous mitogenic peptides resulted in 50 and 20% reductions in invasion in PC-3 and Du145 cells, respectively. Neutral endopeptidase effects were reversed in the presence of thiorphan, a specific NEP inhibitor. Supplementation of defined media with bradykinin and ET-1 significantly increased PC-3 invasion by 40 and 50%, respectively. Du145 cell invasion increased by approximately 100% on adding ET-1. These studies implicate the metallopeptidases NEP and ECE-1 as mediators of prostate cancer invasion via a stromal/epithelial interaction.

Aspartic Acid Endopeptidases↗

PubMed2003

Effects of 5-HT(6) receptor blockade on the neurochemical outcome of antidepressant treatment in the frontal cortex of the rat.

Using in vivo microdialysis in the freely moving rat we have examined the effects of 5-HT(6) receptor antagonism on the neurochemical outcome of antidepressant treatment. Acute administration of both desipramine (10 mg/kg s.c.) and venlafaxine (10 mg/kg s.c.) produced a 2 fold increase in extracellular noradrenaline (NA) but no change in frontal cortex dopamine (DaA), 5-HT or glutamate. Fluoxetine (20 mg/kg s.c.) produced no change in extracellular levels of any of the neurotransmitters examined. SB-271046 produced a 3 fold increase in extracellular glutamate. Combination treatment of SB-271046 with each antidepressant produced no change in the antidepressant-induced changes in NA, DA or 5-HT. In contrast, both fluoxetine and venlafaxine attenuated the SB-271046-induced increase in extracellular glutamate, suggesting that 5-HT and possibly NA may be having an inhibitory action on the excitatory pathways enhanced by 5-HT(6) receptor blockade. Furthermore, these data indicate that the neurochemical effects induced by NA and/or 5-HT reuptake inhibitors are not enhanced by 5-HT(6) receptor blockade indicating that 5-HT(6) receptor antagonists are unlikely to augment the therapeutic efficacy of these types of antidepressants.

Adrenergic Uptake Inhibitors↗

PubMed2003

LPA1 receptor-deficient mice have phenotypic changes observed in psychiatric disease.

Several psychiatric diseases, including schizophrenia, are thought to have a developmental aetiology, but to date no clear link has been made between psychiatric disease and a specific developmental process. LPA(1) is a G(i)-coupled seven transmembrane receptor with high affinity for lysophosphatidic acid. Although LPA(1) is expressed in several peripheral tissues, in the nervous system it shows relatively restricted temporal expression to neuroepithelia during CNS development and to myelinating glia in the adult. We report the detailed neurological and behavioural analysis of mice homozygous for a targeted deletion at the lpa(1) locus. Our observations reveal a marked deficit in prepulse inhibition, widespread changes in the levels and turnover of the neurotransmitter 5-HT, a brain region-specific alteration in levels of amino acids, and a craniofacial dysmorphism in these mice. We suggest that the loss of LPA(1) receptor generates defects resembling those found in psychiatric disease.

Animals↗

PubMed2003

Inclusion of organ deformation in dose calculations.

A previously described system for modeling organ deformation using finite element analysis has been extended to permit dose calculation. Using this tool, the calculated dose to the liver during radiotherapy can be compared using a traditional static model (STATIC), a model including rigid body motion (RB), and finally a model that incorporates rigid body motion and deformation (RBD). A model of the liver, consisting of approximately 6000 tetrahedral finite elements distributed throughout the contoured volume, is created from the CT data obtained at exhale. A deformation map is then created to relate the liver in the exhale CT data to the liver in the inhale CT data. Six intermediate phase positions of each element are then calculated from their trajectories. The coordinates of the centroid of each element at each phase are used to determine the dose received. These intermediate dose values are then time weighted according to a population-modeled breathing pattern to determine the total dose to each element during treatment. This method has been tested on four patient datasets. The change in prescribed dose for each patient's actual tumor as well as a simulated tumor of the same size, located in the superior, intermediate, and inferior regions of the liver, was determined using a normal tissue complication model, maintaining a predicted probability of complications of 15%. The average change in prescribed dose from RBD to STATIC for simulated tumors in the superior, intermediate, and inferior regions are 4.0 (range 2.1 to 5.3), -3.6 (range -5.0 to -2.2), and -14.5 (range -27.0 to -10.0) Gy, respectively. The average change in prescribed dose for the patient's actual tumor was -0.4 Gy (range -4.1 to 1.7 Gy). The average change in prescribed dose from RBD to RB for simulated tumors in the superior, intermediate, and inferior regions are -0.04 (range -2.4 to 2.2), 0.2 (range -1.5 to 1.9), and 3.9 (range 0.8 to 7.3) Gy, respectively. The average change in the prescribed dose for the patient's actual tumor was 0.7 Gy (range 0.2 to 1.1 Gy). This patient sampling indicates the potential importance of including deformation in dose calculations.

Computer Simulation↗

PubMed2003

Automated generation of a four-dimensional model of the liver using warping and mutual information.

The use of mutual information (MI) based alignment to map changes in liver shape and position from exhale to inhale was investigated. Inhale and exhale CT scans were obtained with intravenous contrast for six patients. MI based alignment using thin-plate spine (TPS) warping was performed between each inhale and exhale image set. An expert radiation oncologist identified corresponding vessel bifurcations on the exhale and inhale CT image and the transformation for identified points was determined. This transformation was then used to determine the accuracy of the MI based alignment. The reproducibility of the vessel bifurcation identification was measured through repeat blinded vessel bifurcation identification. Reproducibility [standard deviation (SD)] in the L/R, A/P, and I/S directions was 0.11, 0.09, and 0.14 cm, respectively. The average absolute difference between the transformation obtained using MI based alignment and the vessel bifurcation in the L/R, A/P, and I/S directions was 0.13 cm (SD=0.10 cm), 0.15 cm (SD=0.12 cm), and 0.15 cm (SD-0.14 cm), respectively. These values are comparable to the reproducibility of bifurcation identification, indicating that MI based alignment using TPS warping is accurate to within measurement error and is a reliable tool to aid in describing deformation that the liver undergoes from the exhale to inhale state.

Algorithms↗

PubMed2002

Attenuation of ischemic efflux of endogenous amino acids by the novel 5-HT(1A)/5-HT(2) receptor ligand adatanserin.

Using sodium azide (NaN3)-induced anoxia plus aglycaemia as a model of chemically-induced ischemia in the hippocampal slice, we have evaluated the effects of the novel 5-HT(1A) partial agonist/5-HT(2) receptor antagonist adatanserin and the 5-HT(1A) receptor agonist BAYx3702 on the efflux of endogenous glutamate, aspartate and GABA. BAYx3702 (10-1000 nM) produced a significant (P<0.05) dose-related attenuation of ischemic efflux of both glutamate and GABA with maximum decrease being observed at 100 nM (73 and 69%, respectively). This attenuation was completely reversed by the addition of the 5-HT(1A) antagonist, WAY-100635 (100 nM). Similarly, adatanserin (10-1000 nM) produced a significant (P<0.05) dose-related attenuation in glutamate and GABA efflux with a maximum of 72 and 81% at 100 nM, respectively. This effect was completely reversed by the 5-HT(2A/C) receptor agonist, DOI but unaffected by WAY-100635. The 5-HT(2A) receptor antagonist MDL-100907 produced a comparable attenuation of glutamate when compared to adatanserin, while the 5-HT(2C) receptor antagonist, SB-206553, had no effect on ischemic efflux. None of these compounds significantly altered aspartate efflux from this preparation. In conclusion, the 5-HT(1A) receptor partial agonist 5-HT(2) receptor antagonist, adatanserin is able to attenuate ischemic amino acid efflux in a comparable manner to the full 5-HT(1A) agonist BAYx3702. However, in contrast to BAYx3702, adatanserin appears to produce it effects via blockade of the 5-HT(2A) receptor. This suggests that adatanserin may be an effective neuroprotectant, as has been previously demonstrated for full 5-HT(1A) receptor agonists such as BAYx3702.

Amino Acids↗

PubMed2002

Technical note: creating a four-dimensional model of the liver using finite element analysis.

Finite element analysis and two liver CT scans were used to construct a four-dimensional (4D) model of the liver during breathing. A linear elastic, small deformation mechanical model was applied to one patient to obtain intermediate organ position and shape between exhale and inhale. Known transformations between anatomically defined subsections of the exhale and inhale liver surfaces were applied as constraints to the exhale CT liver model. Intermediate states were then calculated and time weighted to determine a 4D model of the liver as it deforms during the breathing cycle. This model can be used to calculate a more accurate dose distribution during radiotherapy.

Algorithms↗

PubMed2002

Effect of chronic fluoxetine and WAY-100635 treatment on serotonergic neurotransmission in the frontal cortex.

Clinical augmentation strategies have shown that some improvement in antidepressant efficacy can be achieved by combining the beta-adrenergic/serotonin (5-HT)1A/1B receptor antagonist (+/-)pindolol with a selective serotonin reuptake inhibitor (SSRI). This has lead to the hypothesis that a combination of a 5-HT1A receptor antagonist with an SSRI will lead to a faster onset of antidepressant action. Although there is a significant accumulation of acute preclinical data supporting this rationale, until recently, there have been no investigations examining the chronic effects of combining an SSRI with a 5-HT1A receptor antagonist. Here, we determined the chronic effects of fluoxetine (10 mg/kg o.d.), administered in combination with the selective 5-HT1A receptor antagonist WAY-100635 (1 mg/kg b.i.d.), on serotonergic neurotransmission in the frontal cortex using in-vivo microdialysis. Following chronic administration of fluoxetine +/- WAY-100635, functional changes in serotonergic neurotransmission, as well as 5-HT1A autoreceptors, were assessed by administering fluoxetine or (+/-) 8-hydroxy-2-(di-n-propylamino)tetralin [(+/-) 8-OH-DPAT] 24 h after the last chronic dose. Chronic administration of WAY-100635 alone produced no detectable change in the functional status of the 5-HT1A receptor. However, fluoxetine alone produced a time-dependent adaptation in serotonergic transmission such that fluoxetine (acutely administered on day 15) was able to produce a two-fold increase in extracellular 5-HT levels but the decrease in response to 8-OH-DPAT was completely attenuated. These data indicate that the fluoxetine-induced adaptation was mediated by desensitization of the 5-HT1A receptor. WAY-100635 given chronically in combination with fluoxetine blocked the SSRI-induced desensitization of the 5-HT1A receptor. Furthermore, chronic treatment with this combination produced no tolerance in terms of its ability to acutely increase forebrain 5-HT levels. These data suggest that augmentation of an SSRI by combined pharmacotherapy with a 5-HT1A antagonist would be effective upon prolonged exposure.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed2002

The potential utility of 5-HT1A receptor antagonists in the treatment of cognitive dysfunction associated with Alzheimer s disease.

The 5-HT1A receptor has been extensively studied over the last two decades. There is a plethora of information describing its anatomical, physiological and biochemical roles in the brain. In addition, the development of selective pharmacological tools coupled with our understanding of psychiatric pathology has lead to multiple hypotheses for the therapeutic utility of 5-HT1A agents and in particular 5-HT1A receptor antagonists. Over the last decade it has been suggested that 5-HT1A receptor antagonists may have therapeutic utility in such diseases as depression, anxiety, drug and nicotine withdrawal as well as schizophrenia. However, a very compelling rationale has been developed for the therapeutic potential of 5-HT1A receptor antagonists in Alzheimer s disease and potentially other diseases with associated cognitive dysfunction. Receptor blockade by a 5-HT1A receptor antagonist appears to enhance activation and signaling through heterosynaptic neuronal circuits known to be involved in cognitive processes and, as such, represents a novel therapeutic approach to the treatment of cognitive deficits associated with Alzheimer s disease and potentially other disorders with underlying cognitive dysfunction.

Alzheimer Disease↗

PubMed2001

The reproducibility of organ position using active breathing control (ABC) during liver radiotherapy.

PURPOSE: To evaluate the intrafraction and interfraction reproducibility of liver immobilization using active breathing control (ABC). METHODS AND MATERIALS: Patients with unresectable intrahepatic tumors who could comfortably hold their breath for at least 20 s were treated with focal liver radiation using ABC for liver immobilization. Fluoroscopy was used to measure any potential motion during ABC breath holds. Preceding each radiotherapy fraction, with the patient setup in the nominal treatment position using ABC, orthogonal radiographs were taken using room-mounted diagnostic X-ray tubes and a digital imager. The radiographs were compared to reference images using a 2D alignment tool. The treatment table was moved to produce acceptable setup, and repeat orthogonal verification images were obtained. The positions of the diaphragm and the liver (assessed by localization of implanted radiopaque intra-arterial microcoils) relative to the skeleton were subsequently analyzed. The intrafraction reproducibility (from repeat radiographs obtained within the time period of one fraction before treatment) and interfraction reproducibility (from comparisons of the first radiograph for each treatment with a reference radiograph) of the diaphragm and the hepatic microcoil positions relative to the skeleton with repeat breath holds using ABC were then measured. Caudal-cranial (CC), anterior-posterior (AP), and medial-lateral (ML) reproducibility of the hepatic microcoils relative to the skeleton were also determined from three-dimensional alignment of repeat CT scans obtained in the treatment position. RESULTS: A total of 262 fractions of radiation were delivered using ABC breath holds in 8 patients. No motion of the diaphragm or hepatic microcoils was observed on fluoroscopy during ABC breath holds. From analyses of 158 sets of positioning radiographs, the average intrafraction CC reproducibility (sigma) of the diaphragm and hepatic microcoil position relative to the skeleton using ABC repeat breath holds was 2.5 mm (range 1.8-3.7 mm) and 2.3 mm (range 1.2-3.7 mm) respectively. However, based on 262 sets of positioning radiographs, the average interfraction CC reproducibility (sigma) of the diaphragm and hepatic microcoils was 4.4 mm (range 3.0-6.1 mm) and 4.3 mm (range 3.1-5.7 mm), indicating a change of diaphragm and microcoil position relative to the skeleton over the course of treatment with repeat breath holds at the same phase of the respiratory cycle. The average population absolute intrafraction CC offset in diaphragm and microcoil position relative to skeleton was 2.4 mm and 2.1 mm respectively; the average absolute interfraction CC offset was 5.2 mm. Analyses of repeat CT scans demonstrated that the average intrafraction excursion of the hepatic microcoils relative to the skeleton in the CC, AP, and ML directions was 1.9 mm, 0.6 mm, and 0.6 mm respectively and the average interfraction CC, AP, and ML excursion of the hepatic microcoils was 6.6 mm, 3.2 mm, and 3.3 mm respectively. CONCLUSION: Radiotherapy using ABC for patients with intrahepatic cancer is feasible, with good intrafraction reproducibility of liver position using ABC. However, the interfraction reproducibility of organ position with ABC suggests the need for daily on-line imaging and repositioning if treatment margins smaller than those required for free breathing are a goal.

Humans↗

PubMed2001

Determination of ventilatory liver movement via radiographic evaluation of diaphragm position.

PURPOSE: To determine the accuracy of estimation of liver movement inferred by observing diaphragm excursion on radiographic images. METHODS AND MATERIALS: Eight patients with focal liver cancer had platinum embolization microcoils implanted in their livers during catheterization of the hepatic artery for delivery of regional chemotherapy. These patients underwent fluoroscopy, during which normal breathing movement was recorded on videotape. Movies of breathing movement were digitized, and the relative projected positions of the diaphragm and coils were recorded. For 6 patients, daily radiographs were also acquired during treatment. Retrospective measurements of coil position were taken after the diaphragm was aligned with the superior portion of the liver on digitally reconstructed radiographs. RESULTS: Coil movement of 4.9 to 30.4 mm was observed during normal breathing. Diaphragm position tracked inferior-superior coil displacement accurately (population sigma 1.04 mm) throughout the breathing cycle. The range of coil movement was predicted by the range of diaphragm movement with an accuracy of 2.09 mm (sigma). The maximum error observed measuring coil movement using diaphragm position was 3.8 mm for a coil 9.8 cm inferior to the diaphragm. However, the distance of the coil from the top of the diaphragm did not correlate significantly with the error in predicting liver excursion. Analysis of daily radiographs showed that the error in predicting coil position using the diaphragm as an alignment landmark was 1.8 mm (sigma) in the inferior-superior direction and 2.2 mm in the left-right direction, similar in magnitude to the inherent uncertainty in alignment. CONCLUSIONS: This study demonstrated that the range of ventilatory movement of different locations within the liver is predicted by diaphragm position to an accuracy that matches or exceeds existing systems for ventilatory tracking. This suggests that the diaphragm is an acceptable anatomic landmark for radiographic estimation of liver movement in anterior-posterior projections for most patients.

Diaphragm↗

PubMed2001

Xerostomia and its predictors following parotid-sparing irradiation of head-and-neck cancer.

PURPOSE: To assess long-term xerostomia in patients receiving parotid-sparing radiation therapy (RT) for head-and-neck cancer, and to find the patient and therapy-related factors that affect its severity. PATIENTS AND METHODS: From March 1994 through January 2000, 84 patients received comprehensive bilateral neck RT using conformal and multisegmental intensity-modulated RT (IMRT) aiming to spare the major salivary glands. Before RT and periodically through 2 years after the completion of RT, salivary flow rates from each of the major salivary glands were selectively measured. At the same time intervals, each patient completed an 8-item self-reported xerostomia-specific questionnaire (XQ). To gain a relative measure of the effect of RT on the minor salivary glands, whose output could not be measured, the surfaces of the oral cavity (extending to include the surface of the base of tongue) were outlined in the planning CT scans. The mean doses to the new organ ("oral cavity") were recorded. Forty-eight patients receiving unilateral neck RT were similarly studied and served as a benchmark for comparison. Factors predicting the XQ scores were analyzed using a random-effects model. RESULTS: The XQ was found to be reliable and valid in measuring patient-reported xerostomia. The spared salivary glands which had received moderate doses in the bilateral RT group recovered to their baseline salivary flow rates during the second year after RT, and the spared glands in the unilateral RT group, which had received very low doses, demonstrated increased salivary production beyond their pre-RT levels. The increase in the salivary flow rates during the second year after RT paralleled an improvement in xerostomia in both patient groups. The improvement in xerostomia was faster in the unilateral compared with the bilateral RT group, but the difference narrowed at 2 years. The major salivary gland flow rates had only a weak correlation with the xerostomia scores. Factors found to be independently associated with the xerostomia scores were the pre-RT baseline scores, the time since RT, and the mean doses to the major salivary glands (notably to the submandibular glands) and to the oral cavity. CONCLUSION: An improvement over time in xerostomia, occurring in tandem with rising salivary production from the spared major salivary glands, suggests a long-term clinical benefit from their sparing. The oral cavity mean dose, representing RT effect on the minor salivary glands, was found to be a significant, independent predictor of xerostomia. Thus, in addition to the major salivary glands, sparing the uninvolved oral cavity should be considered as a planning objective to further reduce xerostomia.

Adult↗

PubMed2001

Conformal re-irradiation of recurrent and new primary head-and-neck cancer.

PURPOSE: To review the outcome of head-and-neck cancer patients re-irradiated using conformal radiation. PATIENTS AND METHODS: From 1983 to 1999, 60 patients with recurrent or new primary head-and-neck cancer received re-irradiation at the University of Michigan. Twenty patients were excluded due to the planned cumulative radiation dose being less than 100 Gy (18) and absence of prior radiation details (2), leaving 40 patients. Thirty-five patients were re-irradiated for unresectable disease, while 4 patients received adjuvant re-irradiation for high-risk disease. Thirty-eight patients had recurrences from previously treated cancer (19 regional, 14 local, 5 regional and local), and 2 patients had new primary tumors. The median time from the first course of radiation to re-irradiation was 21 months. Thirty-one patients (78%) were re-irradiated with curative intent, whereas 9 were treated with palliative intent. Re-irradiation was delivered using conformal techniques in the majority of patients and with concurrent chemotherapy in 14 patients. The median re-irradiation dose was 60 Gy. The median cumulative dose received was 121 Gy. Five patients (13%) did not complete their prescribed course of re-irradiation. RESULTS: The median survival following completion of re-irradiation was 12.5 months. The 1- and 2-year actuarial survival rates were 51.1% and 32.6%, respectively. On multivariate analysis, palliative intent of treatment, tumor bulk, and tumor site other than nasopharynx or larynx were associated with worse survival. The patients treated for unresectable disease did no worse than those treated adjuvantly. The median times to relapse-free survival, local-regional recurrence (LRR)-free survival, and ultimate LRR-free survival (allowing for surgical salvage) were 3.9 months, 7.8 months, and 8.7 months, respectively. Seven patients (18%) are presently alive with no evidence of disease, with a median follow-up of 49.9 months (range 3.3-78.9). Severe radiation-induced complications were seen in 7 patients (18%). Two other patients developed orocutaneous fistulas in the presence of tumor recurrence. Moderate fibrosis and trismus were common. CONCLUSION: Despite the use of conformal techniques, the prognosis of patients treated with re-irradiation is poor, and complications are not infrequent. A subset of patients is salvageable, and high-dose re-irradiation should be considered in selected patients.

Adolescent↗

PubMed2001

Radiation concurrent with gemcitabine for locally advanced head and neck cancer: a phase I trial and intracellular drug incorporation study.

PURPOSE: To examine the feasibility and dose-limiting toxicity (DLT) of once-weekly gemcitabine at doses predicted in preclinical studies to produce radiosensitization, concurrent with a standard course of radiation for locally advanced head and neck cancer. Tumor incorporation of gemcitabine triphosphate (dFdCTP) was measured to assess whether adequate concentrations were achieved at each dose level. PATIENTS AND METHODS: Twenty-nine patients with unresectable head and neck cancer received a course of radiation (70 Gy over 7 weeks, 5 days weekly) concurrent with weekly infusions of low-dose gemcitabine. Tumor biopsies were performed after the first gemcitabine infusion (before radiation started), and the intracellular concentrations of dFdCTP were measured. RESULTS: Severe acute and late mucosal and pharyngeal-related DLT required de-escalation of gemcitabine dose in successive patient cohorts receiving dose levels of 300 mg/m(2)/wk, 150 mg/m(2)/wk, and 50 mg/m(2)/wk. No DLT was observed at 10 mg/m(2)/wk. The rate of endoscopy- and biopsy-assessed complete tumor response was 66% to 87% in the various cohorts. Tumor dFdCTP levels were similar in patients receiving 50 to 300 mg/m(2) (on average, 1.55 pmol/mg, SD 1.15) but were barely or not detectable at 10 mg/m(2). CONCLUSION: A high rate of acute and late mucosa-related DLT and a high rate of complete tumor response were observed in this regimen at the dose levels of 50 to 300 mg/m(2), which also resulted in similar, subcytotoxic intracellular dFdCTP concentrations. These results demonstrate significant tumor and normal tissue radiosensitization by low-dose gemcitabine. Different regimens of combined radiation and gemcitabine should be evaluated, based on newer preclinical data promising an improved therapeutic ratio.

Adult↗

PubMed2001

The 5-HT(6) receptor antagonist SB-271046 selectively enhances excitatory neurotransmission in the rat frontal cortex and hippocampus.

Preclinical evidence has suggested a possible role for the 5-HT(6) receptor in the treatment of cognitive dysfunction. However, currently there is little neurochemical evidence suggesting the mechanism(s) which may be involved. Using the selective 5-HT(6) antagonist SB-271046 and in vivo microdialysis, we have evaluated the effects of this compound on the modulation of basal neurotransmitter release within multiple brain regions of the freely moving rat. SB-271046 produced no change in basal levels of dopamine (DA), norepinephrine (NE) or 5-HT in the striatum, frontal cortex, dorsal hippocampus or nucleus accumbens. Similarly, this compound had no effect on excitatory neurotransmission in the striatum or nucleus accumbens. Conversely, SB-271046 produced 3- and 2-fold increases in extracellular glutamate levels in both frontal cortex and dorsal hippocampus, respectively. These effects were completely attenuated by infusion of tetrodotoxin but unaffected by the muscarinic antagonist, atropine. Here we demonstrate for the first time the selective enhancement of excitatory neurotransmission by SB-271046 in those brain regions implicated in cognitive and memory function, and provide mechanistic evidence in support of a possible therapeutic role for 5-HT(6) receptor antagonists in the treatment of cognitive and memory dysfunction.

Animals↗