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Biomedical subjects

L A Dawson

Publications and source records attributed to L A Dawson.

17 recordsLinked to original sources

A comparison of ventilatory prostate movement in four treatment positions.

PURPOSE: To ensure target coverage during radiotherapy, all sources of geometric uncertainty in target position must be considered. Movement of the prostate due to breathing has not traditionally been considered in prostate radiotherapy. The purpose of this study is to report the influence of patient orientation and immobilization on prostate movement due to breathing. METHODS AND MATERIALS: Four patients had radiopaque markers implanted in the prostate. Fluoroscopy was performed in four different positions: prone in alpha cradle, prone with an aquaplast mold, supine on a flat table, and supine with a false table under the buttocks. Fluoroscopic movies were videotaped and digitized. Frames were analyzed using 2D-alignment software to determine the extent of movement of the prostate markers and the skeleton for each position during normal and deep breathing. RESULTS: During normal breathing, maximal movement of the prostate markers was seen in the prone position (cranial-caudal [CC] range: 0.9-5.1 mm; anterior-posterior [AP] range: up to 3.5 mm). In the supine position, prostate movement during normal breathing was less than 1 mm in all directions. Deep breathing resulted in CC movements of 3.8-10.5 mm in the prone position (with and without an aquaplast mold). This range was reduced to 2.0-7.3 mm in the supine position and 0.5-2.1 mm with the use of the false table top. Deep breathing resulted in AP skeletal movements of 2.7-13.1 mm in the prone position, whereas AP skeletal movements in the supine position were negligible. CONCLUSION: Ventilatory movement of the prostate is substantial in the prone position and is reduced in the supine position. The potential for breathing to influence prostate movement, and thus the dose delivered to the prostate and normal tissues, should be considered when positioning and planning patients for conformal irradiation.

Adenocarcinoma↗

The role of 5-HT(1A) and 5-HT(1B/1D) receptors on the modulation of acute fluoxetine-induced changes in extracellular 5-HT: the mechanism of action of (+/-)pindolol.

Some clinical evidence has suggested that (+/-)pindolol can be effective at producing a shortened time to onset of antidepressant activity when co-administered with a serotonin specific reuptake inhibitor (SSRI). This effect has been attributed to the antagonist effects of pindolol at the 5-HT(1A) receptor. In the present study, we compared the pharmacology of (+/-)pindolol, WAY-100635 (a 5-HT(1A) antagonist), GR127935 (a 5-HT(1B/1D) antagonist), and isamoltane (a 5-HT(1B) antagonist), when given acutely in combination with fluoxetine, using in vivo microdialysis in the frontal cortex of the freely moving rat. We have determined that the acute fluoxetine-induced increases in extracellular 5-HT can be augmented by (+/-)pindolol, WAY100635, GR127935 and isamoltane with maximum increases of 216+/-32%, 235+/-49%, 240+/-18% and 171+/-47% of preinjection control levels, respectively. Combination of both 5-HT(1A) and 5-HT(1B/1D) autoreceptor antagonists with fluoxetine produced additive increases in extracellular 5-HT (i.e. WAY100635+GR127935+fluoxetine and WAY100635+isamoltane+fluoxetine produced a four- and five-fold potentiation, respectively), suggesting that this strategy may be useful in further augmenting the action of a SSRI in the treatment of depression. In addition, by comparing the combined administration of (+/-)pindolol with either WAY100635, GR127935 or isamoltane, we have determined that (+/-)pindolol produces much of its acute potentiation of fluoxetine-induced increases in extracellular 5-HT via its action at the 5-HT(1B/D) receptor in addition to any activity it has at the presynaptic 5-HT(1A) receptor.

Animals↗

Patterns of local-regional recurrence following parotid-sparing conformal and segmental intensity-modulated radiotherapy for head and neck cancer.

PURPOSE: To analyze the patterns of local-regional recurrence in patients with head and neck cancer treated with parotid-sparing conformal and segmental intensity-modulated radiotherapy (IMRT). METHODS AND MATERIALS: Fifty-eight patients with head and neck cancer were treated with bilateral neck radiation (RT) using conformal or segmental IMRT techniques, while sparing a substantial portion of one parotid gland. The targets for CT-based RT planning included the gross tumor volume (GTV) (primary tumor and lymph node metastases) and the clinical target volume (CTV) (postoperative tumor bed, expansions of the GTVs and lymph node groups at risk of subclinical disease). Lymph node targets at risk of subclinical disease included the bilateral jugulodigastric and lower jugular lymph nodes, bilateral retropharyngeal lymph nodes at risk, and high jugular nodes at the base of skull in the side of the neck at highest risk (containing clinical neck metastases and/or ipsilateral to the primary tumor). The CTVs were expanded by 5 mm to yield planning target volumes (PTVs). Planning goals included coverage of all PTVs (with a minimum of 95% of the prescribed dose) and sparing of a substantial portion of the parotid gland in the side of the neck at less risk. The median RT doses to the gross tumor, the operative bed, and the subclinical disease PTVs were 70.4 Gy, 61.2 Gy, and 50.4 Gy respectively. All recurrences were defined on CT scans obtained at the time of recurrence, transferred to the pretreatment CT dataset used for RT planning, and analyzed using dose-volume histograms. The recurrences were classified as 1) "in-field," in which 95% or more of the recurrence volume (V(recur)) was within the 95% isodose; 2) "marginal," in which 20% to 95% of V(recur) was within the 95% isodose; or 3) "outside," in which less than 20% of V(recur) was within the 95% isodose. RESULTS: With a median follow-up of 27 months (range 6 to 60 months), 10 regional recurrences, 5 local recurrences (including one noninvasive recurrence) and 1 stomal recurrence were seen in 12 patients, for a 2-year actuarial local-regional control rate of 79% (95% confidence interval 68-90%). Ten patients (80%) relapsed in-field (in areas of previous gross tumor in nine patients), and two patients developed marginal recurrences in the side of the neck at highest risk (one in the high retropharyngeal nodes/base of skull and one in the submandibular nodes). Four regional recurrences extended superior to the jugulodigastric node, in the high jugular and retropharyngeal nodes near the base of skull of the side of the neck at highest risk. Three of these were in-field, in areas that had received the dose intended for subclinical disease. No recurrences were seen in the nodes superior to the jugulodigastric nodes in the side of the neck at less risk, where RT was partially spared. CONCLUSIONS: The majority of local-regional recurrences after conformal and segmental IMRT were "in-field," in areas judged to be at high risk at the time of RT planning, including the GTV, the operative bed, and the first echelon nodes. These findings motivate studies of dose escalation to the highest risk regions.

Adult↗

In vivo effects of the 5-HT(6) antagonist SB-271046 on striatal and frontal cortex extracellular concentrations of noradrenaline, dopamine, 5-HT, glutamate and aspartate.

Although the 5-HT(6) receptor subtype was identified some 5 years ago, very little is known about its function within the brain. Here we demonstrate, for the first time, the neurochemical effects of a selective 5-HT(6) receptor ligand. Using in vivo microdialysis in the freely moving rat, we evaluated the effects of the selective 5-HT(6) receptor antagonist SB-271046 by simultaneous measurement of 5-hydroxytryptamine (5-HT), dopamine (DA), noradrenaline (NA), glutamate and aspartate from the striatum and frontal cortex. SB-271046 did not alter basal levels of 5-HT, DA and NA in either brain region. Similarly, there was no change basal levels of either of the excitatory amino acids within the striatum. In contrast, administration of SB-271046 (10 mg kg(-1) s.c.) produced a significant (P<0.05), tetrodotoxin-dependent, increase in extracellular levels of both glutamate and aspartate within the frontal cortex, reaching maximum values of 375.4+/-82.3 and 215. 3+/-62.1% of preinjection values, respectively.

Animals↗

Effects of chronic fluoxetine treatment in the presence and absence of (+/-)pindolol: a microdialysis study.

Using in vivo microdialysis in the frontal cortex of the freely moving rat we evaluated the effects of chronic treatment with the serotonin specific reuptake inhibitor (SSRI) fluoxetine in the presence and absence of the 5-HT(1A)/beta-adrenergic antagonist (+/-)pindolol. Chronic vehicle treated animals produced no significant response to a challenge with fluoxetine (10 mg kg(-1)) on day 8 and 15. Alternatively, a significant (P<0.05) decrease in extracellular 5-HT was observed in control animals upon challenge with the 5-HT(1A) agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT; 0.03 and 0.1 mg kg(-1)). Conversely, animals treated with fluoxetine (10 mg kg(-1) o.d.) for 7 and 14 days produced a significant (P<0.05) 2 fold increase in extracellular 5-HT when challenged with fluoxetine (10 mg kg(-1)) on day 8 and 15. Moreover, no significant decrease in extracellular 5-HT was observed upon challenge with either dose of 8-OH-DPAT. Animals chronically treated with (+/-)pindolol (10 or 20 mg kg(-1) b.i.d.) produced a significant dose-related increase in extracellular 5-HT upon challenge with fluoxetine on day 15 only. Furthermore, both doses produced a significantly blunted response to the low dose challenge of 8-OH-DPAT (0.03 mg kg(-1)). In addition, 20 mg kg(-1) (+/-)pindolol treated animals also had no response to the higher 0.1 mg kg(-1) dose of 8-OH-DPAT. Animals treated for 14 days with a combination of (+/-)pindolol (10 or 20 mg kg(-1)) and fluoxetine were not significantly different from vehicle treated animals when challenged with fluoxetine or 8-OH-DPAT. Taken together it would therefore appear that although (+/-)pindolol alone has sufficient intrinsic activity to produce a desensitization of the 5-HT(1A) receptor, when given in combination with fluoxetine it is able to prevent the desensitization induced by not only fluoxetine but also itself. This may suggest that the clinical augmentation of antidepressant action by pindolol, when co-administered with a SSRI, is via antagonism of the 5-HT(1A) receptor.

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

Escalated focal liver radiation and concurrent hepatic artery fluorodeoxyuridine for unresectable intrahepatic malignancies.

PURPOSE: To evaluate the response, time to progression, survival, and impact of radiation (RT) dose on survival in patients with intrahepatic malignancies treated on a phase I trial of escalated focal liver RT. PATIENTS AND METHODS: From April 1996 to January 1998, 43 patients with unresectable intrahepatic hepatobiliary cancer (HB; 27 patients) and colorectal liver metastases (LM; 16 patients) were treated with high-dose conformal RT. The median tumor size was 10 x 10 x 8 cm. The median RT dose was 58.5 Gy (range, 28.5 to 90 Gy), 1.5 Gy twice daily, with concurrent continuous-infusion hepatic arterial fluorodeoxyuridine (0.2 mg/kg/d) during the first 4 weeks of RT. RESULTS: The response rate in 25 assessable patients was 68% (16 partial and one complete response). With a median potential follow-up period of 26.5 months, the median times to progression for all tumors, LM, and HB were 6, 8, and 3 months, respectively. The median survival times of all patients, patients with LM, and patients with HB were 16, 18, and 11 months, respectively. On multivariate analyses, escalated RT dose was independently associated with improved progression-free and overall survival. The median survival of patients treated with 70 Gy or more has not yet been reached (16.4+ months), compared with 11.6 months in patients treated with lower RT doses (P =.0003). CONCLUSION: The excellent response rate, prolonged intrahepatic control, and improved survival in patients treated with RT doses of 70 Gy or more motivate continuation of dose-escalation studies for patients with intrahepatic malignancies.

Adult↗

Design and models for estimating antagonist potency (pA2, Kd and IC50) following the detection of antagonism observed in the presence of intrinsic activity.

The antagonist activity of the metabotropic glutamate receptor ligand (2S,1'S,2'S)-2-methyl-2(carboxycyclopropyl)glycine (MCCG) was examined using the [35S]GTPgammaS binding and forskolin (FSK)-stimulated adenosine 3':5'-cyclic monophosphate (cAMP) assays with recombinant Chinese hamster ovary (CHO) cells expressing the G protein-coupled human subtype 2 metabotropic glutamate (hmGlu2) receptor. Whereas MCCG proved to be a partial agonist in the GTPgammaS binding assay, it not only antagonized the agonist effect of (IS,3R)-ACPD in the cAMP assay but further produced an anomalous increase of the cAMP level relative to baseline. The anomalous MCCG response was also observed following treatment of the cells with MCCG in the absence of added agonist. Determination of the glutamate concentration in the incubate at the start and end of the cAMP reaction revealed the existence of micromolar concentrations of cellularly released glutamate throughout the course of the assay, reaching levels which exceeded its reported affinity for the mGlu2 receptor. Considering MCCG's partial agonist effect in the GTPgammaS binding assay and its pseudo-inverse agonist effect in the cAMP assay, available methods of estimating its antagonist potency were inappropriate since the classical Schild method and the alternative model suggested by Waud both assume the antagonist to lack a concentration-response relationship. We derived an alternate design and models that permit estimation of the pA2 (pAx), Kd and IC50 for antagonists which produce a concentration related effect when applied by themselves. With their use, the data acquired in both assays support the designation of MCCG as a competitive antagonist of the hmGlu2 receptor and provide similar pA2 estimates between assays. In addition, the newly derived models and design permit the determination of antagonist potency for partial and inverse agonists so characterized in studies employing the Schild design.

Amino Acids, Dicarboxylic↗

Effects of venlafaxine on extracellular concentrations of 5-HT and noradrenaline in the rat frontal cortex: augmentation via 5-HT1A receptor antagonism.

Venlafaxine is a novel serotonin/noradrenaline reuptake inhibitor (SNRI) which has been shown clinically to be an effective antidepressant (AD) with a faster onset of action than serotonin specific reuptake inhibitors (SSRI). Preclinically, venlafaxine has been shown to potently inhibit dorsal raphe neuronal (DRN) firing through a 5-HT1A mediated mechanism, in a similar manner to SSRIs. Here we demonstrate the acute neurochemical effects of venlafaxine on extracellular concentrations of 5-HT and noradrenaline (NA) from the rat frontal cortex using in vivo microdialysis. Administration of venlafaxine (3-50 mg/kg s.c.) resulted in a significant dose-dependent increase in extracellular NA, but produced no significant increase in 5-HT concentrations. Combination treatment with the selective 5-HT1A antagonist WAY100635 produced a dose-dependent augmentation of venlafaxine-induced (3-30 mg/kg s.c) extracellular 5-HT concentrations, but had no further effect on NA above that produced by venlafaxine alone. WAY100635, at doses as low as 0.03 mg/kg s.c., maintained this potentiation effect. The beta-adrenergic/5-HT1A receptor antagonist (+/-)pindolol and the selective 5-HT1B/D antagonist GR127935 produced no significant augmentation of venlafaxine-induced changes in either 5-HT or NA. Using the alpha1 and alpha2-adrenoceptor antagonists, prazosin and idazoxane, we also demonstrate the role of the alpha-adrenoceptors in the augmentation of venlafaxine-induced changes. The possible mechanisms underlying venlafaxines improved clinical AD action and the potential for further enhancement of this SNRIs clinical effects are discussed.

Adrenergic alpha-Antagonists↗

Conformal and intensity modulated irradiation of head and neck cancer: the potential for improved target irradiation, salivary gland function, and quality of life.

PURPOSE: To develop techniques which facilitate sparing of the major salivary glands while adequately treating the targets in patients requiring comprehensive bilateral neck irradiation (RT). PATIENTS AND METHODS: Conformal and static, multisegmental intensity modulated (IMRT) techniques have been developed. The salivary flow rates before and periodically after RT have been measured selectively from each major salivary gland and the residual flows correlated with glands' dose volume histograms. Subjective xerostomia questionnaires have been developed and validated. The pattern of local-regional recurrences has been examined using CT scans at the time of recurrence, transferring the recurrence volumes to the planning CT scans and regenerating the dose distributions at the recurrence sites. RESULTS: Target coverage and dose homogeneity in IMRT treatment plans were found to be significantly better than standard RT plans. Significant parotid gland sparing was achieved. The relationships among dose, irradiated volume and saliva flow rates from the parotid glands were characterized by dose and volume thresholds. A mean dose of 26 Gy was found to be the threshold for stimulated saliva. Subjective xerostomia was significantly reduced in patients irradiated with parotid sparing techniques, compared to patients with similar tumors treated with standard RT. The large majority of recurrences occurred inside high-risk targets. CONCLUSIONS: Tangible gains in salivary gland sparing and target coverage are being achieved and an improvement in some measures of quality of life is suggested by our findings. A mean parotid gland dose of < or = 26 Gy should be a planning objective if significant parotid function preservation is desired. The pattern of recurrence suggests that careful escalation of the dose to targets judged to be at highest risk may improve tumor control.

Dose-Response Relationship, Radiation↗

Target position variability throughout prostate radiotherapy.

PURPOSE: To quantify the variability in prostate and seminal vesicle position during a course of external beam radiotherapy, and to measure the proportion of target variability due to setup error. METHODS AND MATERIALS: Forty-four weekly planning computerized tomography (CT) studies were obtained on six patients undergoing radiotherapy for prostate cancer. All patients were scanned in the radiotherapy treatment position, supine with an empty bladder, with no immobilization device. All organs were outlined on 3-mm-thick axial CT images. Anterior and lateral beam's eye view digitally reconstructed radiographs and multiplanar reformatted images were generated. The position of the prostate and seminal vesicles relative to the isocenter location as set that day was recorded for each CT study. Target position relative to a bony landmark was measured to determine the relative contribution of setup error to the target position variability. RESULTS: The seminal vesicle and prostate position variability was most significant in the anterior-posterior (AP) direction, followed by cranial-caudal (CC) and mediolateral (ML) directions. Setup error contributed significantly to the total target position variability. Rectal filling was associated with a trend to anterior movement of the prostate, whereas bladder filling was not associated with any trends. Although most deviations from the target position determined at the initial planning CT scan were within 10 mm, deviations as large as 15 mm and 19 mm were seen in the prostate and seminal vesicles respectively. Target position variations were evenly distributed around the initial target position for some patient studies, but unpredictable patterns were also seen. From a simulation based on the observed variability in target position, the AP, CC, and ML planning target volume (PTV) borders around the clinical target volume (CTV) required for target coverage with 95% certainty are 12.4 mm, 10.3 mm, and 5.6 mm respectively for the prostate and 13.8 mm, 8.6 mm, and 3.9 mm respectively for the seminal vesicles. CONCLUSION: Target position variability is significant during prostate radiotherapy, requiring large PTV borders around the CTV. This target position variability may be potentially reduced by improving the setup accuracy.

Humans↗

Effects of 5-HT1A receptor antagonists on fluoxetine-induced changes in extracellular serotonin concentrations in rat frontal cortex.

Clinical studies in which serotonin specific reuptake inhibitors have been co-administered with pindolol have demonstrated a shortened time to onset of antidepressant activity. This effect has been attributed to the antagonist effects of pindolol at the presynaptic 5-HT1A receptor which augments the action of the serotonin specific reuptake inhibitors. In the present study, we demonstrate that acute fluoxetine-induced increases in extracellular serotonin concentrations, as measured by microdialysis in the frontal cortex, can be potentiated by 5-HT1A receptor blockade using N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(pyridinyl)cyclohexa necarboxamide (WAY100635), the silent and selective 5-HT1A receptor antagonist. WAY100635 at doses as low as 0.03 mg/kg s.c. maintained this potentiation effect across a range of fluoxetine doses. In addition, using antagonists with different intrinsic agonist activities for the 5-HT1A receptor, we have determined that only compounds with very low intrinsic agonist activity can produce a potentiation of the acute fluoxetine-induced increases in extracellular serotonin.

Animals↗

Evolving perspectives in contralateral breast cancer.

Despite extensive publications reviewing contralateral breast cancer (CBC), the role of screening and preventative measures for contralateral tumours is controversial and optimal clinical management remains undefined. This paper addresses the incidence, the predisposing factors, the prevention and the treatment of bilateral breast cancer based on a review of the literature. Risk factors for CBC include young age at primary breast cancer diagnosis, hereditary breast cancer (due to a germline mutation), familial breast cancer (one or more affected relatives), radiation exposure at a young age, lobular carcinoma in situ (LCIS), lobular invasive carcinoma and multicentricity. Retrospective studies suggest that contralateral mammographic surveillance results in the early detection of breast cancer, but no clear survival benefit has been demonstrated. Trials of adjuvant tamoxifen in breast cancer patients have shown a reduction in the incidence of CBC in both pre- and postmenopausal women. In addition, breast cancer patients treated with ovarian ablation and prednisone have significantly reduced CBC versus controls. In patients with primary breast cancer there is no evidence that contralateral breast biopsies or contralateral prophylactic mastectomy reduce mortality. Randomised, prospective trials to determine optimal surveillance, prevention and treatment strategies for the contralateral breast in breast cancer patients have not been conducted. Based on the published literature, contralateral breast surveillance in breast cancer patients reasonably includes breast self-examination, regular physical examinations and annual mammography. In women who have no evidence of distant metastasis at the time of CBC diagnosis, we recommend that the CBC be treated in the same manner as a first breast cancer, taking into account prior local and systemic therapy.

BRCA2 Protein↗

Capillary electrophoresis and microdialysis: current technology and applications.

Microdialysis sampling has become an important method for the continuous monitoring from an in vivo environment. This technique has been used to monitor many endogenous molecules, such as neurotransmitters, as well as exogenous species such as drug substances. Microdialysis samples have traditionally been analyzed by liquid chromatographic (LC) methods to gain resolution and quantification of the molecules of interest. However, LC separations have a relatively large injection volume requirement which, as a consequence, increases microdialysis sampling times. Capillary electrophoresis (CE), with its very small sample volume requirements and high resolving power, has therefore gained popularity as an alternative to LC. Reviewed here are many of the technologies currently available for CE and examples of how this technique has been effectively applied to the analysis of microdialysis samples.

Amino Acids↗

Improved method for the measurement of glutamate and aspartate using capillary electrophoresis with laser induced fluorescence detection and its application to brain microdialysis.

We have previously published data on the analysis of glutamate in microdialysis samples using a commercially available CE apparatus. Here we demonstrate further improvements in the analysis of both glutamate and aspartate from very small volume microdialysates. The limit of detection of our system has been increased to 10(-9) M for both glutamate and aspartate. This permits microdialysis sampling time to be reduced to 2 min, thus improving the temporal resolution of microdialysis sampling. Concurrently, migration time has also been reduced such that resolution of both amino acids can be achieved inside 2 min. This new analytical method has been applied to the measurement of the EAA from microdialysis samples from the dentate gyrus of the hippocampus. Extracellular concentrations of both glutamate and aspartate increased to a maximum of 5- and 4.5-fold of preinfusion values, respectively, during infusion of 100 mM K+ through the microdialysis probe. This is consistent with the depolarization-evoked release of both amino acids from this brain region.

Animals↗

Differential effects of potassium channel blockers on extracellular concentrations of dopamine and 5-HT in the striatum of conscious rats.

1. The selective Ca(2+)-activated K+ channel blocker apamin increased extracellular 5-hydroxytryptamine (5-HT) concentrations in the striatum when administered through the microdialysis probe at doses of 0.1 mM and 1 mM. Extracellular dopamine concentrations increased only at the highest dose administered (1 mM). 2. Mast cell degranulating peptide (MCDP), which blocks the dendrotoxin sensitive delayed rectifier (DR) current, increased extracellular concentrations of dopamine at dose of 10 microM-100 microM but had no effect on 5-HT. 3. The non selective K+ channel blocker tetraethylammonium (TEA) induced a dose-dependent (1 mM-10 mM) increase in extracellular dopamine concentrations and an increase in 5-HT which showed little or no dose-dependency. 4. 4-Aminopyridine (4-AP), a blocker with some similar characteristics to MCDP, increased extracellular dopamine concentrations at doses of 10 microM-1 mM, but had no effect on 5-HT. 5. These findings suggest that dopamine release may be modulated by DR-like current and/or A-current K+ channels. However, in view of the similar effects of MCDP and 4-AP at the concentrations used it is more likely that the dendrotoxin-sensitive DR-like current is involved. In contrast, 5-HT release appears to be modulated by Ca(2+)-activated K+ channels.

4-Aminopyridine↗

Postoperative borderline elevated CEA predicts for earlier relapse in patients with rectal cancer receiving adjuvant postoperative therapy.

PURPOSE: The purpose of this study was to determine the impact of a borderline elevated postoperative carcinoembryonic antigen (CEA) on the duration of disease-free survival in patients with rectal cancer treated with postoperative adjuvant radiotherapy and chemotherapy. PATIENTS AND METHODS: A retrospective review was undertaken of 145 patients undergoing curative surgery for rectal adenocarcinoma (American Joint Committee on Cancer stages II and III) and treated with postoperative radiotherapy and chemotherapy from January 1994 to February 1997. Patients with known metastatic disease, with gross residual disease after surgery, or without an available postoperative CEA level before adjuvant therapy were not included. All patients were monitored for a minimum of 1 year or until death. The rates of relapse, disease-free survival and overall survival were estimated according to the Kaplan-Meier method. Univariate analyses for the endpoint time to relapse was carried out for the following potential prognostic factors: age, gender, American Joint Committee on Cancer stage, number of lymph nodes, perineural invasion, capillary-like space invasion, margin status, and postoperative CEA level (< or = 4.0 microg/L vs > 4.0 microg/L). A mulitvariate regression analyses was conducted with the Cox proportional hazards model. RESULTS: With a median follow-up of 45 months, the disease-free and overall survival rates at 2 years were 78% and 90% respectively. Eight patients were identified who expressed an elevated postoperative CEA (4.1-10.2 microg/L). Two patients had T3N0 tumors; one tumor was T4N0, four tumors were T3N1, and one was T4N1. The median time to first relapse in these eight patients was 26 months, compared with 69 months for the 137 patients with a postoperative CEA in the normal range (0-4.0 microg/L), (log-rank Chi-squared test = 4.92). As determined by a proportional hazards model, an elevated CEA remained an independent predictor (along with number of positive nodes) for early relapse. DISCUSSION: Postoperative CEA in patients undergoing curative surgery for rectal cancer provides additional prognostic information in those patients embarking on adjuvant postoperative therapy. An elevated CEA predicts for early relapse and may help define a high-risk subset of patients in whom more aggressive adjuvant therapies should be considered.

Aged↗