Laryngeal cancer treatment and survival differences across regional cancer centres in Ontario, Canada.

AIMS: We conducted a population-based study of practice patterns and outcome across the regional cancer centres providing care to patients with laryngeal cancer in the Province of Ontario, Canada. MATERIALS AND METHODS: : This was a retrospective cohort study of 1547 patients with cancers of the glottic or supraglottic larynx diagnosed between 1982 and 1995. Data were collected via chart review, including: patient and disease characteristics, treatment, waiting times and treatment volumes. Vital status was obtained from the Ontario Cancer Registry. Variations across the nine regional cancer centres are described and their effect on outcome explored. All analyses were stratified by stage I and II separately from stage III and IV. RESULTS: Treatments differed across centres (P<0.0001); for instance, in the stage I and II group, use of a daily dose of >2.54Gy varied from 0 to 87.6% and in the stage III and IV group, total laryngectomy rates varied from a low of 6% to a high of 53%. The percentage of patients waiting more than 6 weeks from diagnosis to first treatment varied from 17 to 49% (P<0.0001). Multivariate analysis revealed cause-specific survival differences that were not explained by control for case mix, treatment or waiting times. Differences ranged from an 82% risk reduction in one centre compared with the reference (stage I and II group, P=0.008) to a 153% increase in risk (stage III and IV group, P=0.02). Centre case volumes were not associated with cause-specific survival. CONCLUSIONS: This study quantifies the degree of variation that can occur in the treatment and outcome of people with cancer. We cannot properly assess whether care delivery is of high quality until we have a better understanding of the factors that drive such variations.

Explaining socioeconomic status effects in laryngeal cancer.

INTRODUCTION: People with lower socioeconomic status (SES) experience shorter survival times after a cancer diagnosis for many disease sites. We determined whether area-level SES was associated with the outcomes: cause-specific survival and local-regional failure in laryngeal cancer in Ontario, Canada. When we found an association we sought explanations that might be related to access to care including age, sex, rural residence, tumor stage, lymph node status, use of diagnostic imaging, treatment type, percentage of prescribed radiotherapy delivered, number of radiotherapy interruption days, treatment waiting time, and treating cancer center. MATERIALS AND METHODS: The study population consisted of 661 glottic and 495 supraglottic stage-stratified randomly-sampled patients identified using the Ontario Cancer Registry. Area-level SES quintiles were assigned using adjusted median household income from the Canadian Census. Other data were collected from patient charts. Explanations for SES effects were determined by measuring whether the effect moved toward the null value by at least 10% when an access indicator was added to a the model. RESULTS: Socioeconomic status was not related to either outcome for those with supraglottic cancer, but an association was present in glottic cancer. With the highest socioeconomic status quintile as the referent group, the relative risks for patients in the lowest socioeconomic quintile were 2.75 (95% CI 1.48, 5.12) for cause-specific survival and 1.90 (95% CI 1.24, 2.93) for local-regional failure. Disease stage as measured by T-category explained between 3% and 23% of these socioeconomic effects. None of the other access indicators met our 10% change criterion. CONCLUSION: We question why people in lower socioeconomic quintiles were not diagnosed earlier in the disease progression. Having ruled out several variables that may be related to access to care, additional biologic and social variables should be examined to further understand socioeconomic status effects.

Radiotherapy patterns of practice: T1N0 glottic cancer in Ontario, Canada.

AIMS: To describe the variation in the delivery of radiation therapy to patients with T1N0 glottic cancer who were diagnosed in Ontario, Canada, between 1982 and 1995. MATERIALS AND METHODS: The patient population consisted of a random sample of 461 patients treated with curative intent from the nine cancer centres that administer radiation therapy in the province. Abstracted variables included prescribed dose (Gy) and fractionation (f), beam energy and arrangement, set-up, field size, beam modifiers, positioning and treatment interruptions. RESULTS: Thirteen prescribed dose-fractionation schemes (> or = four cases each) were identified, including 50.0-53.0 Gy/20 f (54.5%), 55.0-61.0 Gy/25 f (30.3%), and 60.0-66.0 Gy/30-33 f (7.7%). All regimens used one fraction per day, 5 days per week. An isocentric set-up was used (94.3%), with megavoltage (MV) beam energies of Cobalt-60 (87.9%), 6 MV (6.1%) and 4 MV (6.1%). A lateral parallel-opposed pair of beams was the predominant technique (76.4%) versus an anterior oblique pair (17.2%) or angle-down pair (caudally directed fields to achieve shoulder clearance, 5.7%). Wedging (96.3%) and bolus (11.8%) were used as beam-modifying devices. Predominant field-width dimensions were 5.0-6.0 cm (43.4%) and 6.5-7.0 cm (43.1%), and field length dimensions were 5.0-6.0 cm (49.5%) and 6.5-7.0 cm (35.0%). Head, neck or chin immobilisation was used in 86.9% of the cases, with 94.6% of these being custom-made. We found that radiotherapy practice was stable over time, except for a trend of increasing field size and increasing use of immobilisation. In contrast, we found practice variations among the province's cancer centres. On the basis of our findings, we defined a predominant technical practice consisting of Cobalt-60 (reflecting machine availability during the period of the study), an isocentric set-up, a lateral parallel-opposed pair technique with wedging, and supine-head neutral positioning with custom immobilisation. Forty-two per cent of the cases had one or more components of treatment that differed from this definition. CONCLUSIONS: Description of practice variation can provoke discussion about unrecognised differences in practice policies, perhaps identifying the need for better evidence, treatment guidelines, or both.

The role of computed tomography in the T classification of laryngeal carcinoma.

BACKGROUND: The objectives of this study were 1) to describe patterns of use of computed tomography (CT) in laryngeal carcinoma, and 2) to characterize the contribution of CT to the T classification of laryngeal carcinoma. METHODS: The study population comprised 1195 patients with laryngeal carcinoma diagnosed from 1982 through 1995 chosen randomly from the Ontario provincial cancer registry. A chart review was conducted to obtain data on each case. Patient-related, tumor-related, and health-system-related factors were analyzed to identify factors associated with the use of CT. Descriptions of clinical exams and CT reports were reviewed to see how CT information modified T classification. Actuarial local control and cause specific survival curves were plotted by clinical T classification without and with CT to evaluate stage migration. The percentage of the variance in outcome explained by T classification in a Cox analysis was used to evaluate whether the prognostic accuracy of T classification was improved with the use of information from CT. RESULTS: Patients with glottic (20.1%) and supraglottic (41.7%) carcinoma underwent CT. The use of CT increased over time in glottic and supraglottic carcinoma combined from 17.2% in 1982-5 to 33.9% in 1991-5. Computed tomography was used less often in older patients with a 16% (95% confidence interval, 5-27%) decrease in the odds of having CT with each 10-year age increment. Computed tomography use varied considerably across the cancer center regions in Ontario. Computed tomography altered the T classification in 20.2% of those patients who had CT, with most being "upstages." Stage migration due to CT was demonstrated. Using information from CT in the assignment of T classification for 27.8% of this study population did not make a significant contribution to the ability of T classification to predict outcome over the entire group. CONCLUSIONS: There is large variation in the use of CT among different age groups and regions. The ability to compare outcomes by stage across geographic areas is compromised when the use of CT varies.

Glottic cancer in Ontario, Canada and the SEER areas of the United States. Do different management philosophies produce different outcome profiles?

We compared the management and outcome of glottic cancer in Ontario, Canada to that in the Surveillance, Epidemiology and End Results (SEER) Program areas in the United States to determine whether the greater use of primary radiotherapy with surgery reserved for salvage in Ontario was associated with similar survival and better larynx retention rates than the U.S. approach where primary surgery is used more often. Electronic, clinical and hospital data were linked to cancer registry data and supplemented by chart review where necessary. Initial treatment and survival in patients diagnosed in the SEER areas from 1988 through 1994 were compared to patients from Ontario diagnosed from 1982 through 1995. Actuarial laryngectomy rates were compared for patients over 65 at diagnosis in the two regions. Analyses were conducted over all cases and stratified by disease stage. In localized disease (T1 or T2), conservative treatment was the most common initial treatment in both regions, although total laryngectomy was used more often in SEER than Ontario (6.2% vs. 0.2%, respectively, P <.001). In advanced disease (T3 or T4), total laryngectomy was more commonly used as initial treatment in SEER (62.9% vs. 21.0% in Ontario, P < or =.001). Over all cases, the relative survival rate was 80% in Ontario at 5 years compared to 78% in SEER (P =.33). In localized disease, the relative survival rates were 4 to 5% higher in Ontario from the second year on, while in advanced disease 2 to 3% higher rates in SEER did not approach statistical significance. Actuarial laryngectomy rates at 3 years differed between the two regions, with a 4% higher rate in SEER (P =.01). In localized disease, 12.6% of Ontario patients had a laryngectomy by 3 years postdiagnosis compared to 17.9% in SEER (P =.05). In advanced disease, the rates were 63.3% and 79.2%, respectively (P =.07). There are large differences in the management of glottic cancer between the SEER areas of the U.S. and Ontario and no evidence that a policy emphasizing radiotherapy with surgery reserved for salvage is associated with worse survival. Ultimate laryngectomy rates are lower in Ontario for localized disease and may be lower for advanced disease. Conservation treatment should be used for localized disease while the treatment decision in advanced disease may be especially sensitive to patient values for voice retention versus initial cure.

PD 158771, a potential antipsychotic agent with D(2)/D(3) partial agonist and 5-HT(1A) agonist actions. I. Neurochemical effects.

The neurochemical effects of a novel dopamine (DA) D(2)-like and serotonin (5-HT) 5-HT(1A) agonist, PD 158771, are described. PD 158771 exhibited affinities for human D(2L), D(3) and D(4.2) receptors expressed in Chinese hamster ovary (CHO)-K1 cells with K(i) (nM) values of 5.2, 13.7 and 34.8 respectively. PD 158771 showed high affinity for cloned human 5-HT(1A) (K(i) = 2.6 nM) and rat hippocampal 5-HT(1A) receptors (K(i) = 3.5 nM). Weaker affinities were observed at alpha 1-adrenergic (K(i) = 43 nM), histamine H(1) (IC(50) = 30 nM), 5-HT(2A) (K(i) = 24.5 nM) and sigma (sigma) -1 binding sites (K(i) = 24.5 nM). In measures of in vitro functional activity, PD 158771 stimulated [(3)H]thymidine uptake in CHO p-5 cells transfected with hD(3) receptors with a maximal effect of 23% relative to quinpirole. In hD(2)L, the corresponding value was 60% with an EC(50) of 29 nM, again indicating partial DA agonist action of PD 158771. In vivo, PD 158771 produced a dose-related decrease in DA synthesis in the striatum and mesolimbic regions of rat brain treated with gamma-butyrolactone (GBL), indicating a DA autoreceptor agonist action. In animals not treated with GBL, PD 158771 produced a dose-related decrease in DA synthesis and extracellular DA. A decrease in 5-HT synthesis in several brain areas was observed consistent with an agonist response. Further support for DA autoreceptor agonist action is that PD 158771 produced a partial inhibition of the firing of substantia nigra zona compacta DA neurons, an effect reversed by haloperidol. In conclusion, PD 158771 exhibited affinities for DA and 5-HT receptors, appears to possess DA and 5-HT agonist actions; and it could provide improved antipsychotic profile with minimal side effects.

Comparing treatment outcomes of radiotherapy and surgery in locally advanced carcinoma of the larynx: a comparison limited to patients eligible for surgery.

PURPOSE: The use of radical radiotherapy and surgery for salvage (RRSS) in locally advanced squamous cell carcinoma (SCC) of the larynx is controversial. In the absence of randomized studies, it is unclear if RRSS can match the rates of locoregional control and survival reported for primary surgery in this setting. The aim of this study was to compare treatment outcomes of radiotherapy and surgery in comparable patients with CS III-IV SCC of the larynx. METHODS AND MATERIALS: Eighty-two patients with untreated T2N+M0 or T3T4NM0 SCC of the larynx were treated with a policy RRSS at the Toronto-Sunnybrook Regional Cancer Centre between June 1980 and December 1990. The medical records at presentation were reviewed independently by a panel of three surgical oncologists blinded as to treatment outcome to determine patient suitability for laryngectomy and neck dissection using eligibility criteria adopted by recent clinical trials. Treatment outcomes for surgery-eligible patients were compared to results of comparably staged patients in the surgical literature since 1980. RESULTS: Sixty-three patients (77%) were eligible for study. With a median follow-up of 3 years, radiotherapy controlled the primary in 8/20 evaluable glottic primaries and 21/41 evaluable supraglottic primaries. Forty-five percent of patients surviving 5 years retained a functional larynx. Sixteen of 29 relapsing patients were salvaged with surgery. Disease above the clavicles was controlled in 65% of T3T4N0N+ glottic primaries (compared to a published range of 53% to 79%) and 82% of T3N0 glottic primaries (compared to a published range of 69% to 84%). The 5-year overall survival of patients with T3T4 glottic cancer was 54% compared to a published range of 50% to 63%. The cause-specific survival (CSS) of patients with T3N0 glottic primaries (86% at 1 year and 73% at 2 years) was identical to the only published report of CSS in the surgical literature. CONCLUSION: A policy of RRSS offers a good chance of laryngeal conservation without compromising ultimate locoregional control or survival when compared to primary laryngectomy and neck dissection in patients with locally advanced carcinoma of the larynx meeting the surgical eligibility of clinical trials.

Adolescent medicine: a model for the millennium.

This article summarizes the past decade of technological development and the past century of adolescent development in order to predict the future of adolescent medicine. The technology of communication will revolutionize behavior change approaches in the 21st century. Health will be seen as an interactive loop of connections between patients, physicians, families, institutions, peers, and support networks that may be voluntarily navigated and searched. The low-tech of counseling will be replaced with the high-tech of the interactive sensor that will be developed from our knowledge of human development. The inter-relationships between social and personal ecology-a basic premise of adolescent health care-will take on new importance in the first decade of the 21st century. The old will guide the application; the new will define the science. The major morbidities of adolescence of the 20th century will now be correctable and preventable. Models of care for all age groups will draw heavily on the experience of ephebiatrics. With application of the new science, biobehavioral issues will surface as the new technology and the practitioners of adolescent health care have the potential to lead the way.

Primary Hodgkin's disease of the CNS in an immunocompetent patient: a case study and review of the literature.

Primary Hodgkin's disease limited to the CNS is exceedingly rare. Little is known regarding etiologic risk factors, optimal management, and prognosis. A case of Hodgkin's disease confined to the CNS, with cerebrospinal fluid negative for cytology, is described in an immunocompetent patient previously treated for hyperthyroidism with 131I. The patient underwent craniotomy, with resection of two lesions in close proximity within the parenchyma of the temporoparietal lobe. Histopathology revealed classic nodular sclerosing Hodgkin's disease, without evidence of Epstein-Barr viral infection. Treatment included radiation to the whole brain with a boost to the tumor bed. The patient made a full neurologic recovery and remains free of disease recurrence 21 months after treatment. A literature review has identified only 9 additional cases. Seven of 8 evaluable patients remain alive and free of recurrence with a median follow-up of 13 months. The risk factors for this presentation remain undefined. Although follow-up is short, radiotherapy alone appears to provide excellent disease-free survival. Chemotherapy may be reserved for patients with positive cerebrospinal fluid, extracranial disease, or subsequent relapse.

Risk-adapted therapy for clinical stage I-II Hodgkin's disease: 7-years results of radiotherapy alone for low-risk disease, and ABVD and radiotherapy for high-risk disease.

Treatment outcomes were documented for 204 adult patients with clinical Stage I-II Hodgkin's disease who were treated with risk-adapted ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) and radiotherapy (RT) at the Toronto-Sunnybrook Regional Cancer Centre between 1984 and 1994. Forty-nine patients with clinical Stage I disease (excluding bulky mediastinal presentations) and 50 patients with a combination of clinical Stage IIA disease, age 50 years or less, and favourable pathology (lymphocyte predominant or nodular sclerosing histology) were identified as low risk and treated with RT alone to 35 Gy. One hundred and five high-risk patients were treated with chemotherapy (86 with ABVD) followed by RT to 25 Gy. The 7-year cause-specific, overall and disease-free survivals were 95%, 90% and 75% respectively for the low-risk cohort, and 91%, 90% and 88% respectively for the high-risk cohort. In-field relapses accounted for 50% of the failures in both groups. Sixteen of 24 (67%) patients with RT failure and 6/14 (43%) with combined modality therapy (CMT) failure were salvaged. Twenty-eight per cent of the patients treated with RT and 21% of those treated with CMT developed hypothyroidism by 7 years. Fatal complications were recorded in 6% of the low-risk patients managed with RT and 8% of high-risk patients managed with CMT. Septic death and second malignancy accounted for the majority of treatment-related fatalities. Risk-adapted therapy emphasizing RT alone for selected patients with favourable prognostic factors and CMT based on ABVD provides excellent long-term disease control. Further treatment refinements, including the wider application of CMT with lower doses of chemotherapy and RT, will be required to reduce the rate of fatal complications to more acceptable levels.

Functional characterization of mutations in melanocortin-4 receptor associated with human obesity.

Melanocortin-4 receptor (MC4R) is a G protein-coupled receptor implicated in the regulation of body weight. Genetic studies in humans have identified two frameshift mutations of MC4R associated with a dominantly inherited form of obesity. We have generated and expressed the corresponding MC4R mutants in 293T cells and found that cells transfected with the truncation mutants failed to exhibit agonist binding or responsiveness despite retention of structural motifs potentially sufficient for binding and signaling. Immunofluorescence studies showed that the mutant proteins were expressed and localized in the intracellular compartment but absent from the plasma membrane, suggesting that these mutations disrupted the proper cellular transport of MC4R. Further studies identified a sequence in the cytoplasmic tail of MC4R necessary for the cell surface targeting. We further investigated a possible dominant-negative activity of the mutants on wild-type receptor function. Co-transfection studies showed that the mutants affected neither signaling nor cell surface expression of wild-type MC4R. We also characterized three human sequence variants of MC4R, but these exhibited identical affinities for peptide ligands and identical agonist responsiveness. Thus, unlike the obesity-associated MC4R truncation mutants, the polymorphisms of MC4R are unlikely to be contributors to human obesity.

Does the dose fractionation schedule influence local control of adjuvant radiotherapy for early stage breast cancer?

PURPOSE: To explore the correlation between dose fractionation and local control for the adjuvant radiotherapy of early stage breast cancer. METHODS AND MATERIALS: A matched-pair analysis of early stage invasive breast cancer treated adjuvantly with two different dose fractionation schedules, 4000 cGy in 16 fractions (Cohort A) vs. 5000 cGy in 25 fractions (Cohort B) was undertaken to compare local control rates. A systematic review of the published experience in similar patient populations was conducted and the reported dose fractionation schedule was converted to a biologic effect dose (BED) based upon the linear quadratic equation. The BED was then used as a basis for comparing reported local control rates with different dose fractionation schemes. RESULTS: The 118 patient pairs were matched from Cohort A and Cohort B using known significant prognostic factors including age, histology, surgical margins, receptor status, lymphvascular space invasion, extensive intraductal disease, lymph node status, and systemic therapy. The local recurrence rate at 5 years for those treated with 4000 cGy (BED = 65 cGy4) and 5000 cGy (BED = 75 cGy4) was 12.7% and 6.8%, respectively, and this difference was not statistically significant (p = 0.09). Overall survival was 84% at 5 years for both groups. Comparison of the different dose fractionation schemes reported in the literature revealed a highly statistically significant difference between those treated with less than a BED of 75 Cy4 and those treated with a BED of 75 Gy4 or greater. CONCLUSION: Although not statistically significant, there was a trend in the matched pair analysis which suggests that 4000 cGy in 16 fractions (BED = 65 cGy4) provides inferior local control compared to 5000 cGy in 25 fractions (BED = 75 cGy4). Moreover, the literature review demonstrates that a dose control relationship may exist for local control in the adjuvant setting. A dose fractionation schedule equivalent to 5000 cGy in 25 fractions to the whole breast may represent the optimal dose fractionation schedule for local control.

A point mutation in Galphao and Galphai1 blocks interaction with regulator of G protein signaling proteins.

Regulator of G protein-signaling (RGS) proteins accelerate GTP hydrolysis by Galpha subunits and are thought to be responsible for rapid deactivation of enzymes and ion channels controlled by G proteins. We wanted to identify and characterize Gi-family alpha subunits that were insensitive to RGS action. Based on a glycine to serine mutation in the yeast Galpha subunit Gpa1(sst) that prevents deactivation by Sst2 (DiBello, P. R., Garrison, T. R., Apanovitch, D. M., Hoffman, G., Shuey, D. J., Mason, K., Cockett, M. I., and Dohlman, H. G. (1998) J. Biol. Chem. 273, 5780-5784), site-directed mutagenesis of alphao and alphai1 was done. G184S alphao and G183S alphai1 show kinetics of GDP release and GTP hydrolysis similar to wild type. In contrast, GTP hydrolysis by the G --> S mutant proteins is not stimulated by RGS4 or by a truncated RGS7. Quantitative flow cytometry binding studies show IC50 values of 30 and 96 nM, respectively, for aluminum fluoride-activated wild type alphao and alphai1 to compete with fluorescein isothiocyanate-alphao binding to glutathione S-transferase-RGS4. The G --> S mutant proteins showed a greater than 30-100-fold lower affinity for RGS4. Thus, we have defined the mechanism of a point mutation in alphao and alphai1 that prevents RGS binding and GTPase activating activity. These mutant subunits should be useful in biochemical or expression studies to evaluate the role of endogenous RGS proteins in Gi function.

Regulation of RGS mRNAs by cAMP in PC12 cells.

The RGS (regulators of G protein signaling) proteins represent a novel family of proteins which attenuate G protein mediated signaling. Using antisense riboprobes selective for rat RGS4, RGS7, and RGS2, we examined the regulation of these RGS mRNAs in PC12 cells in response to agents which elevate intracellular cAMP. Treatment of the PC12 cells with forskolin, dibutryl cAMP, or 8-CPT-cAMP for three hours decreased RGS4 message by nearly 50%. Actinomycin D, a potent inhibitor of transcription, did not affect the forskolin-induced decrease in RGS4 message, suggesting that forskolin does not alter RGS4 message half-life. RGS7 message is also present in these cells, but was not affected by forskolin. In contrast, RGS2 message is not evident in unstimulated cells but is strongly induced by one hour of treatment with forskolin. Taken together, these data suggest that mRNA levels of different RGS2 family members respond in an idiosynchratic fashion to cAMP challenge.

(Aryloxy)alkylamines as selective human dopamine D4 receptor antagonists: potential antipsychotic agents.

The discovery of a series of novel (aryloxy)alkylamines with selective affinity for the dopamine D4 receptor is described. Target compounds were tested for binding to cloned human dopamine D2, D3, and D4 receptor subtypes expressed in Chinese hamster ovary (CHO) K-1 cells. A number of compounds demonstrated subnanomolar Ki values for binding to the D4 receptor, with several 100-fold selectivities toward the D2 and D3 receptors. Several compounds with combined D3/D4 receptor binding selectivity were also identified. A limited structure-activity relationship study of this chemical series is discussed. In a mitogenesis functional assay, the effect of the test compounds on cellular uptake of [3H]thymidine in D4-transfected CHO 10,001 cells was measured and compared to the response of the full dopamine agonist quinpirole. The activity of the compounds varied from full antagonist to weak partial agonist activity (intrinsic activity of 0-19% in comparison to quinpirole).

Breast cancer patients' attitudes about rationing postlumpectomy radiation therapy: applicability of trade-off methods to policy-making.

PURPOSE: Along with evidence, clinical policies must take patients' values into account. Particularly where evidence is limited and where assumptions of utility-maximizing behavior may not be valid, new methods such as trade-off techniques (TOTs), which allow elicitation of patients' treatment alternatives, might be useful in policy formulation. We used TOTs to assess breast cancer patients' attitudes toward two clinical policies designed to ration adjuvant postlumpectomy breast radiation therapy. METHODS: Cross-sectional interviews were performed in a tertiary cancer center. A total of 102 patients were presented with information about the side effects and benefits associated with two hypothetical decisions: (1) willingness to receive treatment elsewhere to shorten the wait for radiation therapy, and (2) foregoing radiation therapy in the face of small marginal benefits. For each scenario, a TOT was used to identify the maximal acceptable wait time (MAWT) for therapy and the benefit threshold at which the patient would forego therapy. Associations of clinical and demographic factors with these decisions were determined by regression analysis. RESULTS: Patients would be willing to wait, on average, 7 weeks before wanting to leave their city for radiation therapy, less than the 13-week delay our patients actually faced. Older patients were less willing to wait (P = .013); 46% of patients would not give up radiation therapy, even in the face of no stated benefit. Willingness to give up radiation therapy was predicted by willingness to accept delay (odds ratio [OR], 1.84; 95% confidence interval [CI], 1.05 to 3.37) and being employed (OR, 2.61; 95% CI, 1.08 to 6.54). Patients with larger tumors were less willing to give up radiation therapy (OR, 0.57; 95% CI, 0.31 to 0.97). CONCLUSION: Even in difficult decisions such as rationing postlumpectomy breast cancer radiation therapy, TOTs can inform policy formulation by indicating the distributions of patients' preferences.

Chromeno[3,4-c]pyridin-5-ones: selective human dopamine D4 receptor antagonists as potential antipsychotic agents.

The discovery of a series of chromeno[3,4-c]pyridin-5-ones with selective affinity for the dopamine D4 receptor is described. Target compounds were tested for binding to cloned human dopamine D2, D3, and D4 receptor subtypes expressed in Chinese hamster ovary (CHO) K-1 cells. Several compounds demonstrated single digit nanomolar Ki values for binding to the D4 receptor with several hundred-fold selectivities toward the D2 and D3 receptors. A limited SAR study of this series is discussed. In a mitogenesis assay measuring [3H]thymidine uptake, the target compounds showed antagonist to weak partial agonist activity at the D4 receptor, with intrinsic activities ranging from 0 to 35%. Compound 6, 3-benzyl-8-methyl-1,2,3,4-tetrahydrochromeno[3,4-c]pyridin-5-one, increased DOPA (L-3,4-dihydroxyphenylalanine) synthesis 84% in the hippocampus and 10% in the striatum of rat brain when dosed orally at 10 mg/kg.