bluuebunny/crossref_metadata_2025 huggingface dataset:
Associations between premorbid intellectual performance, early-life exposures and early-onset schizophrenia
Authors: Gunnell David , Harrison Glynn , Rasmussen Finn , Fouskakis Dimitris , Tynelius Per
Published: October 2002

Background

Impaired intellectual performance is associated with an increased risk of schizophrenia.

Aims

To investigate whether this association is due to the influence of prenatal and early childhood exposures on both intellectual development and the risk of schizophrenia.

Method

Cohort of 197 613 Swedish male conscripts with linked birth, census and hospital admission data together with five measures of verbal and non-verbal intellectual performance recorded at conscription.Results109 643 subjects had complete data; over a mean 5-year follow-up, 60 developed schizophrenia and 92 developed other non-affective psychoses. Poor scores for each of the five tests were associated with 3-to 14-fold increased risk of psychosis, particularly schizophrenia. Controlling for birth-related exposures, including birth weight, and parental education did not attenuate these associations.

Results

109 643 subjects had complete data; over amean 5-year follow-up,60 developed schizophrenia and 92 developed other non-affective psychoses. Poor scores for each of the five testswere associatedwith 3-to 14-foldincreasedrisk of psychosis, particularly schizophrenia. Controlling for birth-related exposures, including birthweight, and parental education didnot attenuate these associations.

Conclusions

Poor intellectual performance at 18 years of age is associated with early-onset psychotic disorder. Associations do not appear to be confounded by prenatal adversity or childhood circumstances, as indexed by parental education.
Deconstructing current comorbidity: data from the Australian National Survey of Mental Health and Well-Being
Authors: Andrews Gavin , Slade Tim , Issakidis Cathy
Published: October 2002

Background

Comorbidity in epidemiological surveys of mental disorders is common and of uncertain importance.

Aims

To explore the correlates of current comorbidity.

Method

Data from the Australian National Survey of Mental Health and Well-Being were used to evaluate the relationships between comorbidity, disability and service utilisation associated with particular mental disorders.

Results

The number of current comorbid disorders predicted disability, distress, neuroticism score and service utilisation. Comorbidity is more frequent than expected, which might be due to the effect of one disorder on the symptom level of another, or to the action of common causes on both. The combination of affective and anxiety disorders was more predictive of disability and service utilisation than any other two or three group combinations. When people nominated their principal disorder as the set of symptoms that troubled them the most, the affective and anxiety disorders together were associated with four-fifths of the disability and service utilisation.

Conclusions

To make clinical interventions more practical, current comorbidity is best reduced to a principal disorder and subsidiary disorders.
Fluoxetine v. placebo in prevention of relapse in post-traumatic stress disorder
Authors: Martenyi Ferenc , Brown Eileen B. , Zhang Harry , Koke Stephanie C. , Prakash Apurva
Published: October 2002

Background

Little is known about the effect of pharmacotherapy in the prevention of post-traumatic stress disorder (PTSD) relapse.

Aims

To assess the efficacy and tolerability of fluoxetine in preventing PTSD relapse.

Method

This was a double-blind, randomised, placebo-controlled study. Following 12 weeks of acute treatment, patients who responded were re-randomised and continued in a 24-week relapse prevention phase with fluoxetine (n=69) or placebo (n=62). The primary efficacy assessment was the prevention of PTSD relapse, based on the time to relapse.

Results

Patients in the fluoxetine/fluoxetine group were less likely to relapse than patients in the fluoxetine/placebo group (P=0.027). There were no clinically significant differences in treatment-emergent adverse events between treatment groups.

Conclusions

Fluoxetine is effective and well tolerated in the prevention of PTSD relapse for up to 6 months.
Defining the Outcome Measures for Out‐of‐hospital Trials in Acute Pulmonary Edema
Authors: Welsford Michelle , Morrison Laurie J.
Published: October 2002

Objective: Comparing studies of the effectiveness of out‐of‐hospital interventions in acute pulmonary edema (APE) is difficult due to the diversity of outcome measures used in the literature. The objective of this study was to define a set of clinically relevant outcome measures for future out‐of‐hospital trials in APE. Methods: A Medline search and hand‐search of bibliographies was undertaken to develop a list of APE outcome measures. A survey was mailed to a sample of 227 Canadian emergency physicians using the Dillman methodology, requesting that respondents select clinically relevant outcome measures from this list and rank them by importance. A selection frequency of ≥70% and a median ranking score were used to determine relevant outcome measures. Results: The Medline and bibliography search identified 21 APE outcome measures. The survey response rate was 71%. Outcome measures selected most frequently were heart rate, respiratory rate, respiratory distress scale, subjective dyspnea scale, out‐of‐hospital intubation, emergency department (ED) intubation, survival to discharge, and out‐of‐hospital mortality. The median ranking score identified a similar set of measures: heart rate, respiratory rate, respiratory distress scale, subjective dyspnea scale, out‐of‐hospital intubation rate, and ED intubation rate. There was no significant difference in outcome selection between physicians who worked in communities with and without advanced out‐of‐hospital care. Conclusions: Clinically relevant out‐of‐hospital APE outcome measures were identified and endorsed by a representative survey of Canadian emergency physicians. Clinicians appear to favor short‐term and non‐mortality outcomes for out‐of‐hospital interventions. The use of this set of APE outcome measures may improve the design and comparability of future out‐of‐hospital trials.
Mental Status Screening of Emergency Department Patients: Normative Study of the Quick Confusion Scale
Authors: Irons M. Janie , Farace Elana , Brady William J. , Huff J. Stephen
Published: October 2002

Objective: In order to increase the utility of the Quick Confusion Scale (QCS), a six‐item, 15‐point instrument used in screening for impaired mental status in an emergency department (ED) setting, clinical norms were established for an ED patient population. Methods: The QCS was administered to ED patients of a university‐based hospital during a nine‐week period. All subjects scoring less than 15 on the QCS were also administered the Mini‐Mental State Examination (MMSE); 731 patients provided QCS scores for use in this study and 295 provided MMSE scores in addition to their QCS scores. Results: The internal consistency of the QCS was found to be within acceptable limits given that the briefness of the scale forced restriction in the variability coefficient. QCS scores were converted to a standardized metric (percentile ranks), population parameters were consulted, and two cutoff scores were established: one that suggests the likelihood of a cognitive impairment, signaling a need for further evaluation (QCS score of 11); and one that indicates an almost certain cognitive impairment (QCS score of 7). Percentile rank comparisons between subjects' scores on the MMSE and on the QCS provided additional validity for the cutoff scores. Conclusions: The QCS, in its focus on providing a quickly obtained, easily calculated, and readily interpreted score, presents a viable alternative to currently existing practices for assessing mental status in ED patients.
The Effect of Hypertension on Uncontrolled Hemorrhage in a Rodent Model
Authors: Sinert Richard , Spencer Matthew T. , Wilson Renee , Silverberg Mark , Patel Minal , Doty Christopher I. , Sapan Anat , Baron Bonny J.
Published: October 2002

Patients with essential hypertension (EH) have higher mortality rates from hemorrhage. How the complex physiologic changes seen in EH affect the response to uncontrolled hemorrhage has yet to be adequately described. Objective: To test the null hypothesis that there would be no difference in the hemorrhage volumes and hemodynamic responses to uncontrolled hemorrhage between hypertensive rats (SHRs) and normotensive rats (WKYs). Methods: Twenty‐four adult rats (12 WKYs and 12 SHRs) were anesthetized with althesin via the intra‐peritoneal route. The femoral artery was cannulated by cutdown for mean arterial pressure (MAP) measurement and blood gas sampling. Twelve rats (6 WKYs and 6 SHRs) underwent uncontrolled hemorrhage by 50% tail amputation. Twelve rats (6 WKYs and 6 SHRs) served as non‐hemorrhage controls. The MAP, base excess (BE), and cumulative blood loss were measured pre‐hemorrhage and then every 15 minutes post‐hemorrhage for 90 minutes. Data were reported as mean ± standard error of the mean. Comparisons between control and uncontrolled hemorrhage groups were analyzed by analysis of variance (ANOVA) with repeated‐measures post‐hoc testing by Bonferroni. Statistical significance was defined by an alpha = 0.05. Results: Mortality rates were significantly higher (p < 0.05) for the SHRs (100%) as compared with the WKYs (33%). Changes in time‐averaged MAP post‐hemorrhage were significantly greater (p < 0.001) in the SHR group (88 ± 10 mm Hg) as compared with the WKY group (48 ± 4 mm Hg). Hemorrhage volume was significantly lower (p = 0.02) in the SHR group (3.7 ± 0.5 mL) as compared with the WKY group (6.1 ± 0.7 mL). Conclusions: Hypertensive rats had a higher mortality rate than normotensives from a comparable vascular injury with lower hemorrhage volumes.
Cervical Infections in Emergency Department Patients with Vaginal Bleeding
Authors: Hoffman Lance , Ma O. John , Gaddis Gary , Schwab Robert A.
Published: October 2002

To the best of the authors' knowledge, no previous study has compared the prevalences of Chlamydia trachomatis (CT) or Neisseria gonorrhoeae (NG) cervical infection among pregnant and non‐pregnant patients presenting to the emergency department (ED) with vaginal bleeding. Objectives: To determine the prevalence of these infections in a simultaneously assembled cohort, and to determine whether pregnancy is associated with altered rates of CT or NG cervical infection among patients with vaginal bleeding. Methods: This was a prospective, seven‐month, cross‐sectional study of a convenience sample of patients (aged ≥ 15 years) who presented to an urban, teaching ED with the chief complaint of vaginal bleeding. A urine pregnancy test was administered to each patient. Cervical swab specimens were analyzed for CT or NG via polymerase chain reaction technology (DNA probe). The hospital laboratory's baseline 18% rate of positive tests was used for sample size planning. Chisquare analysis and Fisher's exact test, where appropriate, were used to compare pregnant and non‐pregnant patient groups. Results: Cervical infection rates did not differ between pregnant and non‐pregnant patients. Testing for CT showed that 13 of 114 (11%) of the pregnant patients were positive, while 11 of 147 (8%) non‐pregnant patients tested positive (χ2= 0.759, p = 0.384). Testing for NG revealed that seven of 114 (6%) pregnant patients tested positive, while 16 of 147 (11%) non‐pregnant patients tested positive (χ2= 1.256, p = 0.262). Combined testing showed that 18 of 114 (16%) of the pregnant patients and 25 of 147 (17%) of the non‐pregnant patients harbored a cervical infection with one or both pathogens (χ2= 0.009, p = 0.925). Conclusions: The prevalence of CT or NG cervical infection in pregnant patients presenting to the ED with vaginal bleeding is 16%. Pregnant and non‐pregnant patients with vaginal bleeding are at similar risks for having CT or NG cervical infection. Cervical swab specimens should be obtained in all patients with vaginal bleeding.
Ultrasound Guidance versus the Landmark Technique for the Placement of Central Venous Catheters in the Emergency Department
Authors: Miller Adam H. , Roth Brett A. , Mills Trevor J. , Woody Jay R. , Longmoor Charles E. , Foster Barbara
Published: October 2002

Objective: To compare ultrasound (US)‐guided vs. landmark‐guided techniques for central venous access (CVA) in the emergency department. Methods: This was a prospective study of consecutive patients enrolled at a university teaching hospital with an annual census of approximately 100,000. On even days patients had CVA with ultrasonic assistance; patients presenting on odd days had CVA via traditional landmark techniques. Ultrasound users were emergency medicine faculty or residents who completed a one‐hour training session. A data collection tool with 17 variables was completed for each central line placed. Variables were compared using the independent t‐test, Fisher's exact test, and the non‐parametric Mann‐Whitney U test. Results: Between August 1, 2000, and February 1, 2001, data for 122 subjects (n = 51 for US, and n = 71 for landmark) were collected. Variables with statistically significant differences are as follows. Mean (±SD) time from skin puncture to blood flash was 115 (±184) seconds for the US group vs. 512 (±698) seconds for the landmark group (p < 0.0001). The mean number of CVA attempts in the US group was 1.6 (±1.0) vs. 3.5 (±2.7) in the landmark group (p < 0.0001). Acute complications were comparable between groups. Comparisons for time, number of CVA attempts, and complications were done specifically for a subset of patients considered to be “difficult stick” due to predefined criteria regarding body habitus or vascular disease. Patients considered to be “difficult sticks” required a significantly longer amount of time (p < 0.001) for CVA via the landmark technique than patients considered to be “difficult sticks” who had CVA with ultrasonic guidance. Time to line placement for the landmark group was 462.7 (±627) seconds vs. 93.3 (±176) seconds in the US group. Comparing the same subset also revealed an increase in number of required CVA attempts for the landmark technique group. The number of acute complications in the “difficult stick” patients did not show statistical significance (p = 1.00). The landmark group had 60%“difficult sticks,” while the ultrasound group had 80%, although the difference was not statistically significant (p = 0.08). Conclusions: Emergency physicians with limited training and experience are able to use ultrasound as an adjunct for central venous access. Ultrasound technology may decrease the number of CVA attempts required to cannulate a central vein and will decrease the amount of time required to cannulate the vein starting from the time when the needle is on the skin, after the ultrasound machine has been set up and turned on. These results are especially true for those patients considered to be “difficult sticks.”
Guidelines for the Management of Severe Head Injury: Are Emergency Physicians Following Them?
Authors: Huizenga James E. , Zink Brian J. , Maio Ronald F. , Hill Elizabeth M.
Published: October 2002

The Brain Trauma Foundation published “Guidelines for the Management of Severe Head Injury” in 1995. These evidence‐based clinical guidelines (CGs) recommended against prophylactic hyperventilation and glucocorticoid use and advocated for aggressive blood pressure (BP) resuscitation, and the careful use of mannitol. Objective: To survey Michigan emergency physicians (MEPs) to test their adherence to these guidelines. Methods: An anonymous mail survey was sent to all 566 MEPs who are members of the American College of Emergency Physicians. Three clinical scenarios involving severe head injury were presented, all with Glasgow Coma Scale (GCS) scores of 8 or less. The physicians were asked to choose from 15 diagnostic and treatment options, which included: intubation and hyperventilation, BP resuscitation, intravenous (IV) mannitol administration, and IV glucocorticoid administration. Results: Three hundred nineteen (56%) surveys were returned. Forty‐six percent [95% confidence interval (95% CI) = 40% to 51%] of the MEPs elected to use prophylactic hyperventilation; very few administered IV glucocorticoids. Seventy‐eight percent (95% CI = 75% to 81%) corrected hypotension with systolic BP < 90 mm Hg; 83% (95% CI = 80% to 86%) also administered mannitol appropriately. Conclusions: A majority of MEPs are managing severe head injury patients in accordance with the “Guidelines for the Management of Severe Head Injury,” with the exception of avoiding prophylactic hyperventilation. More education and/or exposure to the evidence regarding prophylactic hyperventilation of severely head injured patients may improve adherence to the guidelines.
Managing the Unique Size‐related Issues of Pediatric Resuscitation: Reducing Cognitive Load with Resuscitation Aids
Authors: Luten Robert , Wears Robert L. , Broselow James , Croskerry Patrick , Joseph Madeline Matar , Frush Karen
Published: October 2002

A resuscitation is a complicated event that requires for its optimal outcome the effective completion of a distinct series of actions, some simple, some complex, most occurring simultaneously or in close proximity. In children, these actions are determined not only by the clinical situation, but also by a series of age and size factors particular to each child. Different tasks require different levels of cognitive load, or mental effort. Cognitive load describes the mental burden experienced by the decision maker and will be higher when the task is less familiar or more demanding. In the setting of resuscitation, it refers to the cumulative demands of patient assessment, the ongoing decisions for each of the various steps, and decisions around procedural intervention (e.g., intubation). In children, the level of task complexity and, hence, cognitive load is increased by the unique component of variability of pediatric age and size, introducing logistical factors, many of which involve computations. The purpose of this paper is to examine the effects of age/size‐related variables on the pediatric resuscitative process and to explore how these effects can be mitigated using resuscitation aids. The concept of cognitive load and its relation to performance in resuscitation is introduced and is used to demonstrate the effect of the various aids in the pediatric resuscitative process.
Transport Refusal by Hypoglycemic Patients after On‐scene Intravenous Dextrose
Authors: Carter Alix J. E. , Keane Paul S. , Dreyer Jonathan F.
Published: October 2002

Objectives: Administration of intravenous (IV) dextrose to hypoglycemic patients is delegated to advanced care paramedics in Ontario. Following a quality assurance review, which revealed that 47% of patients refused transport after receiving IV dextrose, the authors studied whether such patients seek additional medical care in the three days following the initial refusal. Methods: Sequential ambulance call reports for on‐scene treatments of hypoglycemia were examined, and a standardized telephone survey of the patients was conducted. Patient satisfaction was assessed using a five‐point Likert scale. Data were collected from April 1999 to March 2000. Results: One hundred patients were studied, with ages ranging from 20 to 92 years (mean 53.2 years). The average Glasgow Coma Scale (GCS) score on presentation was 8.7 ± 3.5. The average blood glucose level before administration of IV dextrose was 1.91 ± 0.63 mmol/L. Sixty‐eight percent of the patients refused transport. Significant differences between the transported group and the refusal group were age (transported 64.7 years, refused 47.8 years, p = 0.002) and initial blood glucose (transported 1.8, refused 2.1, p = 0.001). No difference was found in terms of repeat access to health care for related complaints. Patient satisfaction was high in both groups, with no difference in the overall satisfaction with paramedics' care (4.76 ± 0.58 vs 4.75 ± 0.45). Conclusions: The practice of treating patients for symptomatic hypoglycemia and leaving them at the scene appears to be safe. Further study is required to confirm this.
A Training Program in Portable Fluoroscopy for the Detection of Glass in Soft Tissues
Authors: Levine Matthew R. , Yarnold Paul R. , Michelson Edward A.
Published: October 2002

Objectives: The role of emergency department (ED) bedside fluoroscopy is incompletely defined. One potential application is the evaluation of glass foreign bodies (GFBs). We studied the effect of a training intervention on the ability of emergency physicians to detect GFBs in an established chicken leg model. We also studied performance one week after training. Methods: Assessment of this teaching intervention involved nine emergency medicine residents with minimal prior hands‐on fluoroscopy experience. Zero, one, or two clear glass shards no larger than 1.0 mm in any dimension were inserted into fresh chicken legs. Each subject scanned 12 to 15 legs without being given any feedback to determine baseline accuracy. Next, 27 to 30 more legs were immediately scanned with feedback given after each response. Subjects scanned 15 more legs one week later without feedback as follow‐up. Data were analyzed using mixed‐model analysis of variance. Results: At baseline, overall sensitivity and specificity were 0.40 and 0.61, respectively. At follow‐up, sensitivity and specificity were 0.93 and 0.91, respectively. Subjects were significantly more accurate during training and follow‐up than at baseline. This level of proficiency reached during training was maintained and continued to improve one week later. Conclusions: Emergency medicine residents previously inexperienced in fluoroscopy may, through a brief training intervention, acquire the skill to accurately detect small pieces of glass in a chicken leg model, and maintain proficiency one week later. Further studies of emergency department fluoroscopy in GFB management in humans are warranted.
Roundtable on Bioterrorism Detection
Authors: Lober William B. , Karras Bryant Thomas , Wagner Michael M. , Overhage J. Marc , Davidson Arthur J. , Fraser Hamish , Trigg Lisa J. , Mandl Kenneth D. , Espino Jessi , Tsui Fu-Chiang
Published: October 2002

During the 2001 AMIA Annual Symposium, the Anesthesia, Critical Care, and Emergency Medicine Working Group hosted the Roundtable on Bioterrorism Detection. Sixty-four people attended the roundtable discussion, during which several researchers discussed public health surveillance systems designed to enhance early detection of bioterrorism events. These systems make secondary use of existing clinical, laboratory, paramedical, and pharmacy data or facilitate electronic case reporting by clinicians. This paper combines case reports of six existing systems with discussion of some common techniques and approaches. The purpose of the roundtable discussion was to foster communication among researchers and promote progress by 1) sharing information about systems, including origins, current capabilities, stages of deployment, and architectures; 2) sharing lessons learned during the development and implementation of systems; and 3) exploring cooperation projects, including the sharing of software and data. A mailing list server for these ongoing efforts may be found at http://bt.cirg.washington.edu.
Radical Radiation for Localized Prostate Cancer: Local Persistence of Disease Results in a Late Wave of Metastases
Authors: Coen John J. , Zietman Anthony L. , Thakral Harjot , Shipley William U.
Published: October 2002

PURPOSE: To assess whether failure to maintain local control (LC) of prostate cancer after radiation therapy results in a higher incidence of distant metastasis (DM).

PATIENTS AND METHODS: From 1972 to 1999, 1,469 patients with clinically localized prostate cancer were treated with radical radiation therapy. Disease outcome was retrospectively reviewed for all patients with more than 2 years of follow-up.

RESULTS: The actuarial 10-year LC rate was 79%. Gleason score ≥ 7, prostate-specific antigen (PSA) more than 15, and T3 to T4 tumors predicted a higher incidence of local failure (LF) (palpable recurrence or positive rebiopsy). The 10-year distant metastasis-free survival (DMFS) was 74%. Gleason score ≥ 7, PSA more than 15, and T3 to T4 tumors predicted a higher incidence of distant failure. LF was the strongest predictor for DM in a multivariate model. The 10-year DMFS for LC and LF patients was 77% and 61%, respectively. Median time to distant failure was prolonged in patients with LF compared with patients with locally controlled disease (54 v 34 months). Hazard rate analysis of the time to DM revealed that patients who maintain LC have a lower rate of DM, which remains constant over time. Patients who ultimately develop LF have a higher initial rate of DM, which increases with time.

CONCLUSION: Patients with locally persistent prostate cancer are at greater risk of DM. The higher initial hazard of DM is consistent either with an increased likelihood of subclinical micrometastases before treatment or with posttreatment tumor embolization. The prolonged time to appearance of DM in locally failing patients and the increasing hazard of DM over time is most consistent with a late wave of metastases from a locally persistent tumor.
Concurrent Cisplatin, Etoposide, and Chest Radiotherapy in Pathologic Stage IIIB Non–Small-Cell Lung Cancer: A Southwest Oncology Group Phase II Study, SWOG 9019
Authors: Albain Kathy S. , Crowley John J. , Turrisi Andrew T. , Gandara David R. , Farrar William B. , Clark Joseph I. , Beasley Kristie R. , Livingston Robert B.
Published: October 2002

PURPOSE: There are no published survival data after chemoradiotherapy (chemoRT) in pathologically documented stage IIIB non–small-cell lung cancer. Studies of radiotherapy (RT) alone or chemotherapy followed by RT yield 5-year survivals less than 10%. The Southwest Oncology Group (SWOG) employed the same concurrent chemoRT induction regimen used in its predecessor trimodality trial to determine the efficacy, safety, and long-term outcome of replacing postinduction surgery with additional chemoRT.

PATIENTS AND METHODS: Eligible patients for SWOG-9019 had pathologic documentation of T4N0/1, T4N2, or N3 stage IIIB non–small-cell lung cancer. They had pulmonary function adequate to withstand combined-modality therapy, identical to the requirements of the previous trial with postchemoRT surgery. Induction therapy was two cycles of cisplatin plus etoposide (PE) concurrent with once-daily thoracic RT (45 Gy). In the absence of progressive disease, RT was completed to 61 Gy, with two additional cycles of cisplatin plus etoposide.

RESULTS: Fifty eligible patients were accrued with tumor-node (TN) substage confirmed on central review: 18, T4N0/1; 12, T4N2; and 20, N3. Grade 4 neutropenia was the most common toxicity (32%). Grade 3/4 esophagitis occurred in 12% and 8%. Median follow-up was 52 months, and overall median survival was 15 months (10 to 22, 95% confidence interval). Three- and 5-year survivals were 17% and 15% (5-year T4N0/1, 17%; T4N2, 13%; and N3, 15%).

CONCLUSION: Feasibility and long-term survival support the application of these results as a standard against which mature outcomes of chemoRT trials with new chemotherapy agents can be compared. These results also justify use of the SWOG-9019 approach as a control arm in ongoing phase III trials.
American Society of Clinical Oncology Technology Assessment of Pharmacologic Interventions for Breast Cancer Risk Reduction Including Tamoxifen, Raloxifene, and Aromatase Inhibition
Authors: Chlebowski Rowan T. , Col Nananda , Winer Eric P. , Collyar Deborah E. , Cummings Steven R. , Vogel Victor G. , Burstein Harold J. , Eisen Andrea , Lipkus Isaac , Pfister David G.
Published: October 2002

OBJECTIVE: To update an evidence-based technology assessment of chemoprevention strategies for breast cancer risk reduction.

POTENTIAL INTERVENTIONS: Tamoxifen, raloxifene, aromatase inhibition, and fenretinide.

OUTCOMES: Outcomes of interest include breast cancer incidence, breast cancer–specific survival, overall survival, and net health benefit.

EVIDENCE: A comprehensive, formal literature review was conducted for relevant topics. Testimony was collected from invited experts and interested parties. The American Society of Clinical Oncology (ASCO) prescribed technology assessment procedure was followed.

VALUES: More weight was given to published randomized trials.

BENEFITS/HARMS: A woman’s decision regarding breast cancer risk reduction strategies is complex and will depend on the importance and weight attributed to information regarding both cancer- and noncancer-related risks and benefits.

CONCLUSIONS: For women with a defined 5-year projected breast cancer risk of ≥ 1.66%, tamoxifen (at 20 mg/d for 5 years) may be offered to reduce their risk. Risk/benefit models suggest that greatest clinical benefit with least side effects is derived from use of tamoxifen in younger (premenopausal) women (who are less likely to have thromboembolic sequelae and uterine cancer), women without a uterus, and women at higher breast cancer risk. Data do not as yet suggest that tamoxifen provides an overall health benefit or increases survival. In all circumstances, tamoxifen use should be discussed as part of an informed decision-making process with careful consideration of individually calculated risks and benefits. Use of tamoxifen combined with hormone replacement therapy or use of raloxifene, any aromatase inhibitor or inactivator, or fenretinide to lower the risk of developing breast cancer is not recommended outside of a clinical trial setting. This technology assessment represents an ongoing process and recommendations will be updated in a timely matter.

VALIDATION: The conclusions were endorsed by the ASCO Health Services Research Committee and the ASCO Board of Directors.

SPONSOR: American Society of Clinical Oncology.
Neuroprotective Effect of Reduced Glutathione on Oxaliplatin-Based Chemotherapy in Advanced Colorectal Cancer: A Randomized, Double-Blind, Placebo-Controlled Trial
Authors: Cascinu Stefano , Catalano Vincenzo , Cordella Luigi , Labianca Roberto , Giordani Paolo , Baldelli Anna Maria , Beretta Giordano D. , Ubiali Emilio , Catalano Giuseppina
Published: October 2002

PURPOSE: We performed a randomized, double-blind, placebo-controlled trial to assess the efficacy of glutathione (GSH) in the prevention of oxaliplatin-induced neurotoxicity.

PATIENTS AND METHODS: Fifty-two patients treated with a bimonthly oxaliplatin-based regimen were randomized to receive GSH (1,500 mg/m2 over a 15-minute infusion period before oxaliplatin) or normal saline solution. Clinical neurologic evaluation and electrophysiologic investigations were performed at baseline and after four (oxaliplatin dose, 400 mg/m2), eight (oxaliplatin dose, 800 mg/m2), and 12 (oxaliplatin dose, 1,200 mg/m2) cycles of treatment.

RESULTS: At the fourth cycle, seven patients showed clinically evident neuropathy in the GSH arm, whereas 11 patients in the placebo arm did. After the eighth cycle, nine of 21 assessable patients in the GSH arm suffered from neurotoxicity compared with 15 of 19 in the placebo arm. With regard to grade 2 to 4 National Cancer Institute common toxicity criteria, 11 patients experienced neuropathy in the placebo arm compared with only two patients in the GSH arm (P = .003). After 12 cycles, grade 2 to 4 neurotoxicity was observed in three patients in the GSH arm and in eight patients in the placebo arm (P = .004). The neurophysiologic investigations (sural sensory nerve conduction) showed a statistically significant reduction of the values in the placebo arm but not in the GSH arm. The response rate was 26.9% in the GSH arm and 23.1% in the placebo arm, showing no reduction in activity of oxaliplatin.

CONCLUSION: This study provides evidence that GSH is a promising drug for the prevention of oxaliplatin-induced neuropathy, and that it does not reduce the clinical activity of oxaliplatin.
Effect of Breast Magnetic Resonance Imaging on the Clinical Management of Women With Early-Stage Breast Carcinoma
Authors: Tillman Gayle F. , Orel Susan G. , Schnall Mitchell D. , Schultz Delray J. , Tan Jacqueline E. , Solin Lawrence J.
Published: October 2002

PURPOSE: To determine the impact of breast magnetic resonance imaging (MRI) on the clinical management of patients with early-stage breast cancer.

PATIENTS AND METHODS: A review was performed of the records of 207 women with early-stage breast cancer (including five women with bilateral disease) who underwent breast MRI during work-up for breast conservation treatment. All patients presented with clinical stage 0, I, or II disease. For each patient, a determination was made whether the breast MRI affected the clinical management, and if so, whether the patient was well served by the change in management.

RESULTS: The MRI findings affected the clinical management in 43 cases (20% of 212 breast cancers). Based on the pathology findings and the overall clinical course for each case, the breast MRI was judged to have had a strongly favorable effect on management in 18 cases (8%), a somewhat favorable effect in six cases (3%), an uncertain effect in five cases (2%), a somewhat unfavorable effect in 11 cases (5%), and a strongly unfavorable effect in three cases (1%). The effect of MRI was not significantly different for invasive carcinoma compared with ductal carcinoma-in-situ (all P ≥ .27). However, the effect of MRI was significantly greater when the MRI was performed before an excisional biopsy (P = .0011) or for larger tumors (P = .0089).

CONCLUSIONS: Breast MRI alters the clinical management for a sizable fraction of women with early-stage breast cancer and appears to offer clinically useful information for determining optimal local treatment.
Double-Blind, Randomized Trial Comparing the Efficacy and Tolerability of Fulvestrant Versus Anastrozole in Postmenopausal Women With Advanced Breast Cancer Progressing on Prior Endocrine Therapy: Results of a North American Trial
Authors: Osborne C.K. , Pippen J. , Jones S.E. , Parker L.M. , Ellis M. , Come S. , Gertler S.Z. , May J.T. , Burton G. , Dimery I. , Webster A. , Morris C. , Elledge R. , Buzdar A.
Published: October 2002

PURPOSE: To compare the efficacy and tolerability of fulvestrant (formerly ICI 182,780) with anastrozole in the treatment of advanced breast cancer in patients whose disease progresses on prior endocrine treatment.

PATIENTS AND METHODS: In this double-blind, double-dummy, parallel-group study, postmenopausal patients were randomized to receive either an intramuscular injection of fulvestrant 250 mg once monthly or a daily oral dose of anastrozole 1 mg. The primary end point was time to progression (TTP). Secondary end points included objective response (OR) rate, duration of response (DOR), and tolerability.

RESULTS: Patients (n = 400) were followed for a median period of 16.8 months. Fulvestrant was as effective as anastrozole in terms of TTP (hazard ratio, 0.92; 95.14% confidence interval [CI], 0.74 to 1.14; P = .43); median TTP was 5.4 months with fulvestrant and 3.4 months with anastrozole. OR rates were 17.5% with both treatments. Clinical benefit rates (complete response + partial response + stable disease ≥ 24 weeks) were 42.2% for fulvestrant and 36.1% for anastrozole (95% CI, −4.00% to 16.41%; P = .26). In responding patients, median DOR (from randomization to progression) was 19.0 months for fulvestrant and 10.8 months for anastrozole. Using all patients, DOR was significantly greater for fulvestrant compared with anastrozole; the ratio of average response durations was 1.35 (95% CI, 1.10 to 1.67; P < 0.01). Both treatments were well tolerated.

CONCLUSION: Fulvestrant was at least as effective as anastrozole, with efficacy end points slightly favoring fulvestrant. Fulvestrant represents an additional treatment option for postmenopausal women with advanced breast cancer whose disease progresses on tamoxifen therapy.
Phase I Clinical and Pharmacokinetic Study of Pemetrexed and Carboplatin in Patients With Malignant Pleural Mesothelioma
Authors: Hughes Andy , Calvert Paula , Azzabi Ashraf , Plummer Ruth , Johnson Rob , Rusthoven Jim , Griffin Melanie , Fishwick Kevin , Boddy Alan V , Verrill Mark , Calvert Hilary
Published: October 2002

PURPOSE: To determine the maximum tolerated dose (MTD) of pemetrexed and carboplatin given in combination, to derive a recommended dose for phase II studies, and to explore its efficacy. We assessed toxicities and explored the activity of the drug combination exclusively in patients with malignant pleural mesothelioma (MPM). The pharmacokinetics of both agents was investigated.

PATIENTS AND METHODS: Twenty-seven patients (23 male, four female) with MPM were treated on five escalating dose levels. Doses ranged from pemetrexed 400 mg/m2 (as a 10-minute intravenous infusion), followed by carboplatin area under the plasma concentration-time curve (AUC) 4 mg/mL·min (as a 30-minute intravenous infusion) to pemetrexed 500 mg/m2, carboplatin AUC 6 mg/mL·min. All patients had a World Health Organization performance status of 1. A total of 163 courses of treatment were administered (median, six; range, one to 10).

RESULTS: The main toxicity was hematologic, particularly neutropenia, although this was characteristically short-lived and caused few clinical problems. The MTD was pemetrexed 500 mg/m2, carboplatin AUC 6, because three of the five patients treated at this dose level experienced a dose-limiting toxicity. Eight partial responses (in 25 assessable patients) were observed for a response rate of 32%. Seventy percent of patients noticed an improvement in symptoms, usually (84%) after only two courses. Median time to progression was 305 days, and median survival time was 451 days.

CONCLUSION: The MTD was pemetrexed 500 mg/m2 and carboplatin AUC 6 mg/mL·min. The recommended phase II dose of the combination is pemetrexed 500 mg/m2 and carboplatin AUC 5 mg/mL·min. The combination is both active and well tolerated in MPM and deserves further exploration.
Tobacco Use Outcomes Among Patients With Lung Cancer Treated for Nicotine Dependence
Authors: Cox Lisa Sanderson , Patten Christi A. , Ebbert Jon O. , Drews Amanda A. , Croghan Gary A. , Clark Matthew M. , Wolter Troy D. , Decker Paul A. , Hurt Richard D.
Published: October 2002

PURPOSE: There is a current lack of consensus about the effectiveness of nicotine dependence treatment for cancer patients. This retrospective study examined the 6-month tobacco abstinence rate among lung cancer patients treated clinically for nicotine dependence.

PATIENTS AND METHODS: A date-of-treatment matched case control design was used to compare lung cancer patients (201 lung cancer patients, 41% female) and nonlung cancer patients (201 controls, 45% female) treated in the Mayo Clinic Nicotine Dependence Center between 1988 and 2000. The intervention involves a brief consultation with a nicotine dependence counselor. A treatment plan individualized to the patient’s needs is then developed. The primary end point was the self-reported, 7-day point prevalence abstinence from tobacco at 6-month follow-up.

RESULTS: At baseline, compared with the controls, the lung cancer patients were significantly older (P < .001), reported higher motivation to stop smoking (P = .003), and were at a higher stage of change (P = .002). The 6-month tobacco abstinence rate was 22% for the lung cancer patients compared with 14% of the control patients (P = .024). After adjusting for age, sex, baseline cigarettes smoked per day, and stage of change, no significant difference was detected between lung cancer patients and controls on the tobacco abstinence rate.

CONCLUSION: The results suggest that nicotine dependence treatment is effective for patients with a diagnosis of lung cancer. The majority of lung cancer patients were motivated to stop smoking.
Effect of Timing of Pulmonary Metastases Identification on Prognosis of Patients With Osteosarcoma: The Japanese Musculoskeletal Oncology Group Study
Authors: Tsuchiya Hiroyuki , Kanazawa Yoshimitsu , Abdel-Wanis Mohamed E. , Asada Naohiro , Abe Satoshi , Isu Kazuo , Sugita Takashi , Tomita Katsuro
Published: October 2002

PURPOSE: The prognostic value of the time of identification of lung metastasis was investigated in 280 patients with metastatic lung osteosarcoma as a multi-institutional study of the Japanese Musculoskeletal Oncology Group.

PATIENTS AND METHODS: The 280 patients with lung metastasis were divided into four groups: group 1, patients with lung metastasis identified at initial presentation; group 2, those with lung metastasis identified during preoperative chemotherapy; group 3, those with lung metastasis identified during postoperative chemotherapy, and group 4, those with lung metastasis identified after completion of treatment. Survivals of the four groups were compared. Additionally, the effects of number of metastatic nodules, metastasectomy, and the effect of chemotherapy on the primary tumor on survival of the four groups were analyzed.

RESULTS: There were 46 patients in group 1, 30 in group 2, 94 in group 3, and 110 in group 4. The overall 2-year survival rates from the time of identification of lung metastasis were 33%, 31%, 24%, and 40% for groups 1, 2, 3, and 4, respectively, whereas the 5-year survival rates were 18%, 0%, 6%, and 31%, respectively. Patients in group 4 thus demonstrated significantly better prognosis than any of the other patients (P < .0001).

CONCLUSION: Time of identification of lung metastasis is an important prognostic factor. In terms of clinical behavior, groups 2 and 3 are completely different than group 4. These data ensure the need to stratify stage III osteosarcomas into subgroups according to the time of diagnosis of lung metastases. To improve the survival of osteosarcoma patients, new treatment modalities should be introduced into the treatment armamentarium for lung metastasis from osteosarcoma, especially in groups 1, 2, and 3.
Phase III Study of Gemcitabine in Combination With Fluorouracil Versus Gemcitabine Alone in Patients With Advanced Pancreatic Carcinoma: Eastern Cooperative Oncology Group Trial E2297
Authors: Berlin Jordan D. , Catalano Paul , Thomas James P. , Kugler John W. , Haller Daniel G. , Benson Al Bowen
Published: October 2002

PURPOSE: Gemcitabine is generally considered to constitute first-line therapy for pancreatic cancer. To determine whether the addition of fluorouracil (5-FU) improves on the results from single-agent gemcitabine, the Eastern Cooperative Oncology Group (ECOG) compared gemcitabine plus bolus 5-FU with gemcitabine alone for patients with advanced pancreatic carcinoma.

PATIENTS AND METHODS: This trial involved patients with biopsy-proven, advanced carcinoma of the pancreas not amenable to surgical resection. Patients were randomized to receive either gemcitabine alone (1,000 mg/m2/wk) weekly for 3 weeks of every 4 or to receive gemcitabine (1,000 mg/m2/wk) followed by 5-FU (600 mg/m2/wk) weekly on the same schedule. The primary end point of the trial was survival, with secondary end points of time to progression and response rate.

RESULTS: Of 327 patients enrolled over 18 months, 322 were eligible. Overall, the median survival was 5.4 months for gemcitabine alone and 6.7 months for gemcitabine plus 5-FU (P = .09). Progression-free survival for gemcitabine alone was 2.2 months, compared with 3.4 months for gemcitabine plus 5-FU (P = .022). Objective responses were uncommon and were observed in only 5.6% of patients treated with gemcitabine and 6.9% of patients treated with gemcitabine plus 5-FU. Most toxicities were hematologic or gastrointestinal; no significant differences were noted between the two treatment arms.

CONCLUSION: 5-FU, administered in conjunction with gemcitabine, did not improve the median survival of patients with advanced pancreatic carcinoma compared with single-agent gemcitabine. Further studies with other combinations of gemcitabine and 5-FU are not compelling, and clinical trial resources should address other combinations and novel agents.
Synthesis of New 2-(Aminomethyl)-4-phenylpyrrolo[1,2-a]-quinoxalines and their Preliminary In-vivo Central Dopamine Antagonist Activity Evaluation in Mice
Authors: Guillon J , Boulouard M , Lisowski V , Stiebing S , Lelong V , Dallemagne P , Rault S
Published: October 2002

In the search for antipsychotic agents that are not associated with extrapyramidal side effects, efforts have been focused on finding selective D4-receptor antagonists and investigating their pharmacology. Our laboratory has developed a synthesis program for new pyrroloquinoxalines with therapeutic potential. We have described the synthesis of some new pyrroloquinoxalines with substituted arylpiperazino or aryltetrahydropyrido chain at position 3 of the quinoxaline ring (2-(4-phenylpiperazin-1-ylmethyl)-4-phenylpyr-rolo[1,2-a]quinoxalinium oxalate (3a), 2-[4-(2-methoxyphenyl)piperazin-1-ylmethyl]-4-phenylpyrrolo[1,2-a]quinoxalinium oxalate (3b), 2-[4-(3-trinuoromethylphenyl)piperazin-1-ylmethyl]-4-phenylpyrrolo[l,2-a]quinoxalinium oxalate (3c), 2-[4-(4-chlorophenyl)piperazin-1-ylmethyl]-4-phenylpyrrolo[1,2-a]quinoxalinium oxalate (3d), 2-(4-pyridin-2-ylpiper-azin-1-ylmethyl)-4-phenylpyrrolo[1,2-a]quinoxalinium oxalate (3e), and 2-(4-phenyl-1,2,3,6-tetrahydropyridin-1-ylmethyl)-4-phenylpyrrolo[1,2-a]quinoxalinium oxalate (3f)).

A preliminary pharmacological study of these products was conducted using climbing behaviour induced by apomorphine (2.5 mg kg−1, s.c.) in mice. The derivatives were administered intraperitoneally 30 min before apomorphine. Haloperidol, chlorpromazine and clozapine were used as references.

Among this series, 3b, 3c and 3f revealed a central dopamine antagonist activity. The most active derivative was 3b, which exhibited a profile relatively close to clozapine.
Inhibitory Effects of Amlexanox on Carbachol-induced Contractions of Rabbit Ciliary Muscle and Guinea-pig Taenia Caecum
Authors: Watanabe Noriko , Tominaga Yukari , Mizutani Kazuya , Ogawa Takahiro , Tsunobuchi-Ushijima Hiromi , Gomi Yasuo
Published: October 2002

Instillation of amlexanox, an anti-allergic drug, over a long period improves myopia in some allergy patients and in monkeys. The relaxing effect of amlexanox on persistent contraction of ciliary muscle may be involved in the improvement of myopia. In this study, the mechanism of the noncompetitive inhibition of carbachol-induced contractions by amlexanox (1–100 μM) was investigated in isolated smooth muscle preparations of the rabbit ciliary body and guinea-pig taenia caecum.

In ciliary muscles, amlexanox (100 n̈m) inhibited both the phasic and tonic components of carbachol-induced contractions even in the presence of cyclopiazonic acid (10 n̈m) where the function of the sarcoplasmic reticulum was impaired, while diltiazem (3.2, 32μM) did not. In taenia caecum, diltiazem (3.2 μM) slightly inhibited the phasic component and abolished the tonic component of carbachol-induced contractions. Amlexanox also abolished the tonic component, but it did not decrease the 45Ca2+ uptake into taenia caecum smooth muscle cells induced by carbachol. Amlexanox did not increase the cyclic adenosine monophosphate (cyclicAMP) content of ciliary muscles in the presence of 3-isobutyl-1-methylxanthine (10 μm), while forskolin (1 μm) did. Gel-shift assay showed that the inhibition of carbachol-induced contractions by amlexanox was accompanied by a decrease in phosphorylation of the 20-kDa myosin light chain in taenia caecum tissue preparations. Amlexanox had no effect on calmodulin activity, whereas it inhibited phosphorylation of the myosin light chain by purified myosin light-chain kinase from chicken gizzard.

These results suggested that amlexanox may not affect either Ca2+ mobilization or calmodulin activity, although it inhibits myosin light-chain kinase, which may inhibit carbachol-induced contraction.