bluuebunny/crossref_metadata_2025 huggingface dataset:
Establishing the Scope and Methodological Approach to Out‐of‐hospital Outcomes and Effectiveness Research
Authors: Keim Samuel M. , Spaite Daniel W. , Maio Ronald F. , Garrison Herbert G. , Desmond Jeffrey S. , Gregor Mary Ann , O'Malley Patricia J. , Stiell Ian G. , Cayten C. Gene , Chew John L. , MacKenzie Ellen J. , Miller David R.
Published: October 2004

Outcomes research offers out‐of‐hospital medicine a valuable methodology for studying the effectiveness of services provided in the out‐of hospital setting. A clear understanding of the history and constructs of outcomes research is necessary for its integration into emergency medical services research. This report describes the conceptual framework of outcomes research and key methodological considerations for the successful implementation of out‐of‐hospital outcomes research. Illustrations of the specific applications of outcomes research and implications to existing methodologies are given, as well as suggestions for improved interdisciplinary research.
Cerebral Cortical Aquaporin‐4 Expression in Brain Edema following Cardiac Arrest in Rats
Authors: Xiao Feng , Arnold Thomas C. , Zhang Shu , Brown Carlos , Alexander J. Steven , Carden Donna L. , Conrad Steven A.
Published: October 2004

Objectives: Brain edema occurs following clinical as well as experimental cardiac arrest (CA) and predicts a poor neurologic outcome. The objective of this study was to determine the expression of cerebral cortex aquaporin (AQP)‐4, a member of a family of membrane water‐channel proteins, in brain edema formation following normothermic or hypothermic CA. Methods: Twenty‐four rats were subjected to time‐matched normothermic (N‐Sham, 37.5°C ± 0.5°C, n= 6) or hypothermic (H‐Sham, 34°C ± 0.5°C, n= 6) sham experiments and normothermic (N‐CA, n= 6) or hypothermic (H‐CA, n= 6) CA induced by asphyxiation for 8 minutes. Hypothermia was induced before CA. The animals were resuscitated with cardiopulmonary resuscitation, ventilation, and epinephrine administration. Brain edema was determined by brain wet‐to‐dry weight ratio at one hour of resuscitation. AQP4 immunoactivity in the cerebral cortex was determined using immunohistochemical staining and was semiquantified as an intensity of staining with an automated cell imaging system. Results: Mild hypothermia in the sham experiments did not alter cerebral cortex AQP4 immunoactivity (mean ± SD) (55.0 ± 3.7 in H‐Sham vs. 53.3 ± 1.7 in N‐Sham, p > 0.05). N‐CA resulted in a significant increase in AQP4 immunoactivity (61.8 ± 4.5) compared with N‐Sham (p = 0.01) and H‐Sham (p = 0.03). H‐CA attenuated AQP4 compared with N‐CA (53.4 ± 1.3, p = 0.01). Brain wet‐to‐dry weight ratios were 4.41 ± 0.07 in N‐Sham, 4.40 ± 0.08 in H‐Sham (p > 0.05 vs. N‐Sham), 4.55 ± 0.04 in N‐CA (p = 0.004 vs. N‐Sham; p = 0.005 vs. H‐Sham), and 4.43 ± 0.09 in H‐CA (p = 0.02 vs. N‐CA; p > 0.05 vs. N‐Sham and H‐Sham). Conclusions Cerebral cortical AQP4 expression is up‐regulated after normothermic CA, which is attenuated by hypothermia induced before CA.
Rapid Emergency Medicine Score Can Predict Long‐term Mortality in Nonsurgical Emergency Department Patients
Authors: Olsson Thomas , Terent Andreas , Lind Lars
Published: October 2004

Objectives: To examine the Rapid Emergency Medicine Score (REMS) as a predictor of long‐term (4.7 years) mortality in the nonsurgical emergency department (ED). Methods: This was a prospective cohort study. A total of 12,006 nonsurgical patients consecutively presenting to an adult ED at a 1,200‐bed university hospital during a period of one year were enrolled. REMS (including blood pressure, respiratory rate, pulse rate, Glasgow Coma Scale score, peripheral oxygen saturation, and patient age) was calculated for all patients admitted to the ED. The statistical associations between REMS and long‐term mortality were examined. Results: REMS could predict mortality over 4.7 years (hazard ratio, 1.26; p < 0.0001). Similar results were obtained in the major patient groups (chest pain, stroke, coma, dyspnea, and diabetes). Conclusions: REMS was a powerful predictor of long‐term mortality in patients attending the ED for a wide range of common nonsurgical disorders.
Confronting the Ethical Challenges to Informed Consent in Emergency Medicine Research
Authors:   SAEM Ethics Committee, Schmidt Terri A. , Salo David , Hughes Jason A. , Abbott Jean T. , Geiderman Joel M. , Johnson Catherine X. , McClure Katie B. , McKay Mary Pat , Razzak Junaid A. , Schears Raquel M. , Solomon Robert C.
Published: October 2004

The Society for Academic Emergency Medicine believes that protection of human subjects is vital in emergency medicine research and that, whenever feasible, informed consent is at the heart of that protection. At the same time, the emergency setting presents unique barriers to informed consent both because of the time frame in which the research is performed and because patients in the emergency department are a vulnerable population. This report reviews the concept of informed consent, empirical data on patients' cognitive abilities during an emergency, the federal rules allowing exemption from consent under certain circumstances, issues surrounding consent forms, and the new Health Insurance Portability and Accountability Act regulations as they relate to research. The authors conclude that, in many circumstances, informed consent is possible if the researcher is diligent and takes time to adequately explain the study to the potential subject. In cases in which it is possible to obtain consent, precautions must be taken to ensure that subjects have decision‐making capacity and are offered time to have their questions answered and their needs met. Sometimes resuscitation and other emergency medicine research must be conducted without the ability to obtain consent. In these cases, special protections of subjects under the exception from consent guidelines must be followed. Protection of research subjects is the responsibility of every researcher in emergency medicine.
An Evaluation of a Blind Rotational Technique for Selective Mainstem Intubation
Authors: Bair Aaron E. , Doherty Melissa J. , Harper Richart , Albertson Timothy E.
Published: October 2004

Objectives: Although rare, massive hemoptysis and major bronchial disruptions are associated with high mortality. Selective ventilation of the uninvolved lung can increase the likelihood of survival. Specialized devices used for single lung ventilation are often not readily available and can be difficult to place in the emergency department. The authors evaluated a blind rotational technique for selective mainstem intubation using either a standard endotracheal tube (ET) or a directional‐tip endotracheal tube (DTET). Methods: This was a prospective, randomized trial on 25 human cadavers. The desired side of mainstem intubation was determined by randomization. Each cadaver was used for four ET, four DTET, and four control intubations. In the ET group, the trachea was intubated. The tube was then rotated 90° in the direction of the desired placement and advanced until resistance was met. In the DTET group, the technique was identical, except the trigger was activated to flex the tip during advancement. In the control group, an ET was advanced in neutral alignment until resistance was met. A bronchoscopist blinded to the desired placement determined tube position. Comparison testing was performed using Pearson's chi‐square test. Results: When attempting to intubate the left mainstem, use of the ET with the rotational technique was successful 72.3% of the time (95% confidence interval [95% CI] = 57% to 84%). Intubation of the left mainstem using the DTET was successful 68.5% of the time (95% CI = 54% to 81%; p = 0.67). Attempts to selectively intubate the right mainstem using the rotational technique were highly successful in both groups: 94% for the ET (95% CI = 84% to 99%) versus 97.8% for the DTET (95% CI = 89% to 100%). Among controls, the right mainstem was intubated 93% of the time (95% CI = 86% to 97%). Conclusions: In a cadaveric model, the left mainstem bronchus can be selectively intubated with moderate reliability using this rotational technique. Use of a DTET confers no significant advantage. The ability to generalize these findings to living subjects is unknown.
Characteristics and Admission Patterns of Patients Presenting with Syncope to U.S. Emergency Departments, 1992–2000
Authors: Sun Benjamin C. , Emond Jennifer A. , Camargo Carlos A.
Published: October 2004

Objectives: To describe the characteristics and admission patterns of patients with syncope presenting to U.S. emergency departments (EDs). Methods: The ED portion of the National Hospital Ambulatory Medical Care Survey, 1992–2000, was analyzed. Nationally representative weighted estimates for incidence and admission rates were estimated and stratified by demographic variables. Presence of cardiovascular diagnoses on ED discharge was noted. Results: Of the 865 million ED visits during the nine‐year study period, an estimated 6.7 million (0.77%; 95% confidence interval [95% CI] = 0.69% to 0.85%) were related to syncope. Higher incidences of ED visits for syncope were found in elder, female, and non‐Hispanic patients compared with their reference groups. The overall admission rate was 32% (95% CI = 28% to 36%). Older, male, and white patients were admitted more frequently than their counterparts. Of patients older than 80 years of age, 58% (95% CI = 49% to 67%) were admitted. Associated cardiovascular International Classification of Diseases, Ninth Revision (ICD‐9), codes for ischemic, structural, and arrhythmic heart disease were noted in 10% (95% CI = 8% to 13%) of patients, and 66% (95% CI = 56% to 76%) of these patients were admitted. Conclusions: Syncope is a frequent reason for ED visits and admissions. Elders and patients with associated cardiovascular diagnoses are frequently discharged, and admission practices appear to deviate from consensus panel guidelines.
The Association between White Blood Cell Count and Acute Myocardial Infarction In‐hospital Mortality: Findings from the National Registry of Myocardial Infarction
Authors: Grzybowski Mary , Welch Robert D. , Parsons Lori , Ndumele Chiadi E. , Chen Edmond , Zalenski Robert , Barron Hal V.
Published: October 2004

Objectives: Although cross‐sectional and prospective studies have shown that the white blood cell (WBC) count is associated with long‐term mortality for patients with ischemic heart disease, the role of the WBC count as an independent predictor of short‐term mortality in patients with acute myocardial infarction (AMI) has not been examined as extensively. The objective of this study was to determine whether the WBC count is associated with in‐hospital mortality for patients with ischemic heart disease after controlling for potential confounders. Methods: From July 31, 2000, to July 31, 2001, the National Registry of Myocardial Infarction 4 enrolled 186,727 AMI patients. A total of 115,273 patients were included in the analysis. Results: WBC counts were subdivided into intervals of 1,000/mL, and in‐hospital mortality rates were determined for each interval. The distribution revealed a J‐shaped curve. Patients with WBC counts >5,000/mL were subdivided into quartiles, whereas patients with WBC counts <5,000/mL were assigned to a separate category labeled “subquartile” and were analyzed separately. A linear increase in in‐hospital mortality by WBC count quartile was found. The unadjusted odds ratio (OR) for the fourth versus the first quartile showed strong associations with in‐hospital mortality among the entire population and by gender: 4.09 (95% confidence interval [95% CI] = 3.83 to 4.73) for all patients, 4.31 (95% CI = 3.93 to 4.73) for men, and 3.65 (95% CI = 3.32 to 4.01) for women. Following adjustment for covariates, the magnitude of the ORs attenuated, but the ORs remained highly significant (OR, 2.71 [95% CI = 2.53 to 2.90] for all patients; OR, 2.87 [95% CI = 2.59 to 3.19] for men; OR, 2.61 [95% CI = 2.36 to 2.99] for women). Reperfused patients had consistently lower in‐hospital mortality rates for all patients and by gender (p < 0.0001). Conclusions: The WBC count is an independent predictor of in‐hospital AMI mortality and may be useful in assessing the prognosis of AMI in conjunction with other early risk‐stratification factors. Whether elevated WBC count is a marker of the inflammatory process or is a direct risk factor for AMI remains unclear. Given the simplicity and availability of the WBC count, the authors conclude that the WBC count should be used in conjunction with other ancillary tests to assess the prognosis of a patient with AMI.
Ethanol and Illicit Drugs Do Not Affect the Diagnostic Utility of Base Deficit and Lactate in Differentiating Minor from Major Injury in Trauma Patients
Authors: Zehtabchi Shahriar , Baron Bonny J. , Sinert Richard , Yadav Kabir , Lucchesi Michael
Published: October 2004

Objectives: Base deficit (BD) and lactate are valuable screening tools for injured patients. They reflect the degree of oxygen debt and have been shown to predict outcome. Intake of ethanol and illicit drugs may further derange acid–base status. The authors evaluated the effect of blood alcohol level (BAL) and illicit drugs on admission BD and lactate levels in trauma patients.Methods: Prospective, observational study of trauma patients in a Level 1 trauma center. Patients with penetrating or blunt trauma were included in the study. Patients were further stratified into major or minor categories. Major was defined by an Injury Severity Score >15, blood transfusions, or a decrease in hematocrit of more than ten points. Injury categories were further divided into several subgroups based on presence or absence of ethanol (BAL ≥0.08 g/dL) or positive urine toxicology screen (Utox).Results: A total of 520 patients (84% male) with a mean (±SD) age of 33 (±15) years were studied. Compared with the minor injury categories, BD and lactate levels were significantly higher in the major injury categories in all different intoxication subgroups. Testing the diagnostic performance of BD and lactate in detecting major injury, the authors observed significant (p < 0.05) differences between the areas under the receiver operating characteristic curves for these two diagnostic tests compared with baseline in both intoxicated (BAL ≥0.08 g/dL and/or positive Utox) and nonintoxicated (BAL <0.08 g/dL and negative Utox) patients.Conclusions: The presence of ethanol and/or illicit drugs did not affect the ability of BD or lactate to identify patients with major injuries.
A Multicasualty Event: Out‐of‐hospital and In‐hospital Organizational Aspects
Authors: Avitzour Malka , Libergal Meir , Assaf Jacob , Adler Jakov , Beyth Shaul , Mosheiff Rami , Rubin Amir , Feigenberg Zvi , Slatnikovitz Ruth , Gofin Rosa , Shapira Shmuel Chaim
Published: October 2004

In a wedding celebration of 700 participants, the third floor of the hall in which the celebration was taking place suddenly collapsed. While the walls remained intact, all three floors of the building collapsed, causing Israel's largest disaster. Objectives: To study the management of a multicasualty event (MCE), in the out‐of‐hospital and in‐hospital phases, including rescue, emergency medical services (EMS) deployment and evacuation of casualties, emergency department (ED) deployment, recalling staff, medical care, imaging procedures, hospitalization, secondary referral, and interhospital transfer of patients. Methods: Data on all the victims who arrived at the four EDs in Jerusalem were collected through medical files, telephone interviews, and hospital computerized information. Results: The disaster resulted in 23 fatalities and 315 injured people; 43% were hospitalized. During the first hour, 42% were evacuated and after seven hours the scene was empty. Ninety‐seven basic life support ambulances, 18 mobile intensive care units, 600 emergency medical technicians, 40 paramedics, and 15 physicians took part in the out‐of‐hospital stage. At the hospitals, about 1,300 staff members arrived immediately, either on demand or voluntarily, a number that seems too large for this disaster. Computed tomography (CT) demand was over its capability. Conclusions: During this MCE, the authors observed “rotating” bottleneck phenomena within out‐of‐hospital and in‐hospital systems. For maximal efficiency, hospitals need to fully coordinate the influx and transfer of patients with out‐of‐hospital rescue services as well as with other hospitals. Each hospital has to immediately deploy its operational center, which will manage and monitor the hospital's resources and facilitate coordination with the relevant institutions.
Care in the Emergency Department: How Crowded Is Overcrowded?
Authors: Hwang Ula , Concato John
Published: October 2004

Objectives: To examine how emergency department (ED) overcrowding has been defined in the medical literature. Methods: Using the National Library of Medicine's PubMed and MEDLINE databases (1966 to 2002), a comprehensive review of the English‐language medical literature was conducted to identify explicit criteria for defining ED overcrowding. Inclusion criteria were original articles, editorials, and reviews; news articles and letters to the editor were excluded. Using a standardized extraction form, publications were described as primary if the title or an objective statement in the introductory or methods paragraph referred to crowding or overcrowding; all other citations were categorized as secondary. Each report was then evaluated to determine whether crowding or overcrowding was defined explicitly or implicitly. Explicit definitions included phrases such as “Crowding was defined as …” or “Overcrowding occurred when …”; other definitions were characterized as implicit. Results: A total of 231 candidate articles were identified; 91 met inclusion criteria, and 53 (58%) were primary articles about ED crowding or overcrowding. Among these primary articles, 23 (43%) had explicit definitions of crowding or overcrowding. The definitions varied widely in content and focus, including ED, hospital, or external (nonhospital) factors. Conclusions: Although ED overcrowding has been a topic of frequent investigation, current definitions of the problem are often implicit or focus on factors outside of the ED itself. A more consistent approach to defining ED overcrowding would help to clarify the distinctions between causes, characteristics, and outcomes of overcrowding.
Advanced Opportunities for Student Education in Emergency Medicine
Authors: Pacella Charissa B.
Published: October 2004

Many medical students are excited about emergency medicine (EM) following a standard clerkship and seek out additional learning opportunities. An advanced EM elective may accomplish several educational goals, including development of clinical skills in evaluating the undifferentiated patient, broader exploration of the field of EM, and more focused study of one particular aspect of EM. Previously cited examples include pediatric EM, medical toxicology, occupational medicine, sports medicine, and EM research. Numerous other EM specialty courses for senior medical students are emerging, as reflected in the “Undergraduate Rotations” listings on the Society for Academic Emergency Medicine. A few examples drawn from the list include emergency ultrasound, international EM, wilderness medicine, disaster medicine, geriatric EM, and hyperbaric medicine. Educators aspiring to develop, or in the process of developing, an advanced EM elective may benefit from a brief overview of necessary course considerations, including didactic format, the clinical role of the medical student in the emergency department, and involvement with patient procedures. Suggestions are made regarding additional educational opportunities, including follow‐up of patients seen in the emergency department and development of an emergency department radiology case file. This article also addresses several related concerns, including suggested prerequisites, administration and cost considerations, appropriate didactic topics, and methods for evaluating students. Several EM subspecialty areas, namely pediatric EM, medical toxicology, and out‐of‐hospital care, are specifically discussed. Formal advanced cardiac life support training is also often included in an advanced EM elective and is briefly discussed. The overall intent of this article is to provide medical student educators with resources and ideas to assist them in developing a unique advanced EM elective.
Putting the Rap on Akt
Authors: Thompson James E. , Thompson Craig B.
Published: October 2004

The protein kinase Akt is activated in a wide variety of cancers, and this activation results in enhanced resistance to apoptosis through multiple mechanisms. This article reviews the control of Akt activation by the opposing actions of the oncogene phosphoinositide 3-kinase (PI3-K) and the tumor suppressor phosphatase and tensin homolog deleted on chromosome 10. The activation of Akt by transforming mutations, such as the amplification of HER-2/neu in breast cancer and the formation of the BCR/ABL fusion gene in chronic myelogenous leukemia, seems to be essential for the transforming activity of these oncogenes. We discuss several of the proposed mechanisms for the antiapoptotic effect of activated Akt, including the inhibition of the proapoptotic protein Bad, downregulation of death receptors, and enhancement of the glycolytic rate. Increased glycolysis is seen in many malignancies and forms the basis for the increasing use of positron emission tomography imaging for diagnosis and staging. Finally, we discuss rapamycin and its analogs, which are now in trials as antineoplastic therapy; these agents show particular promise in tumors in which Akt has been activated.
GABAergic System Gene Expression Predicts Clinical Outcome in Patients With Neuroblastoma
Authors: Roberts Stephen S. , Mori Motomi , Pattee Patrick , Lapidus Jodi , Mathews Ravi , O'Malley Jean P. , Hsieh Yi Ching , Turner Mark A. , Wang Zhaohong , Tian Qi , Rodland Matthew J. , Reynolds C. Patrick , Seeger Robert C. , Nagalla Srinivasa R.
Published: October 2004

Purpose

Neuroblastoma (NB) is a common childhood malignancy characterized by heterogeneous clinical behavior. The purpose of this study was to identify potential NB biomarkers that may improve outcome prediction.

Patients and Methods

The suppression subtractive hybridization (SSH) technique was used to identify the genes differentially expressed between NB and control tissue. RNA isolated from 235 primary NB tumor samples obtained from the Children's Cancer Group was evaluated for expression of the candidate markers using quantitative reverse transcriptase polymerase chain reaction (Taqman assays). The association between the mRNA expression levels in the identified candidate genes and clinical outcome was evaluated.

Results

SSH analysis identified differential expression of members of the GABAergic gene family in NB. Lower levels of gamma-aminobutyric acid (GABA) receptor–associated protein (GABARAP) gene expression predict decreased survival among all patients. GABAA δ receptor subunit gene expression was predictive of a poor outcome among Evans stage IV-S patients. An index of five coexpressed GABAA receptor subunits was identified (GABAA profile [GAP score]). Patients with a higher GAP score (> −1) had a survival advantage. Multivariate analysis showed that GABARAP and GABAA α2 receptor subunit gene expression levels and GAP score remained predictors of clinical outcome after accounting for current prognostic indicators.

Conclusion

Dysregulation of the GABAergic system may constitute a fundamental event in the development of NB, and assessment of GABAergic system gene expression could provide improved patient stratification and potential new therapies.
Suicide Risk in Cancer Patients From 1960 to 1999
Authors: Hem Erlend , Loge Jon H. , Haldorsen Tor , Ekeberg Øivind
Published: October 2004

Purpose

Suicide risk is reportedly higher for cancer patients than for the general population, but estimates vary and analyses of trends are few. The aim of the present study was to determine whether cancer patients had a higher suicide risk between 1960 and 1999.

Patients and Methods

A cohort comprising patients from the Cancer Registry of Norway 1960 to 1997 was linked to suicide diagnosis in the Register of Deaths at Statistics Norway and observed during 1960 to 1999. The cohort consisted of all cancer patients registered in the Cancer Registry of Norway 1960 to 1997 (N = 490,245 patients with 520,823 cancer diagnoses). Suicide was defined according to death certificates based on the International Classification of Diseases (versions 7, 8, 9, and 10).

Results

During the period, 589 cancer patients (407 males and 182 females) committed suicide. The relative risk was elevated for males and females, with standardized mortality ratios (SMRs) of 1.55 (95% CI, 1.41 to 1.71) and 1.35 (95% CI, 1.17 to 1.56), respectively. Risk was highest in the first months after diagnosis. For both sexes, there was a significant decrease in the relative suicide risk over decades. The risk was markedly increased among male patients with cancer of respiratory organs (SMR, 4.08; 95% CI, 2.96 to 5.47). Otherwise, the SMRs varied from 0.76 to 3.67 across cancer types.

Conclusion

Cancer may be a risk factor for suicide, particularly shortly after diagnosis. However, the relative risk gradually decreased during the period 1960 to 1999.
Midline Carcinoma of Children and Young Adults With NUT Rearrangement
Authors: French Christopher A. , Kutok Jeffery L. , Faquin William C. , Toretsky Jeffrey A. , Antonescu Cristina R. , Griffin Constance A. , Nose Vania , Vargas Sara O. , Moschovi Mary , Tzortzatou-Stathopoulou Fotini , Miyoshi Isao , Perez-Atayde Antonio R. , Aster Jon C. , Fletcher Jonathan A.
Published: October 2004

Purpose

A balanced chromosomal translocation, t(15;19), resulting in the BRD4-NUT oncogene, has been identified in a lethal carcinoma of young people, a disease described primarily in case reports. We sought to amass a more definitive series of tumors with NUT and/or BRD4 gene rearrangements and to determine distinct clinicopathologic features.

Patients and Methods

Carcinomas (N = 98) in young individuals (median age, 32.5 years) were screened for NUT and BRD4 rearrangements using dual-color fluorescence in situ hybridization. Four published carcinomas with BRD4 and NUT rearrangements were also evaluated. Immunophenotypic analyses were performed.

Results

Eleven tumors had NUT gene rearrangements, including eight with BRD4-NUT fusions and three with novel rearrangements, which were designated as NUT variant. All NUT-rearranged carcinomas (NRCs) arose from midline epithelial structures, including the first example arising below the diaphragm. Patients were young (median age, 17.6 years). Squamous differentiation (seen in 82% of NRCs) was particularly striking in NUT-variant cases. In this first description of NUT-variant carcinomas, the average survival (96 weeks, n = 3) was longer than for BRD4-NUT carcinomas (28 weeks, n = 8). Strong CD34 expression was found in six of 11 NRCs but in zero of 45 NUT wild-type carcinomas.

Conclusion

NRCs arise from midline structures in young people, and NRCs with BRD4-NUT are highly lethal, despite intensive therapies. NUT-variant carcinomas might have a less fulminant clinical course than those with BRD4-NUT fusions. CD34 expression is characteristic in NRCs and, therefore, holds promise as a diagnostic test for this distinctive clinicopathologic entity.
Frequency and Heritability of WT1 Mutations in Nonsyndromic Wilms' Tumor Patients: A UK Children’s Cancer Study Group Study
Authors: Little Suzanne E. , Hanks Sandra P. , King-Underwood Linda , Jones Chris , Rapley Elizabeth A. , Rahman Nazneen , Pritchard-Jones Kathy
Published: October 2004

Purpose

Constitutional WT1 mutations in patients with Wilms' tumor (WT) have specifically been associated with genitourinary abnormalities, such as cryptorchidism and hypospadias. We sought to ascertain the frequency and heritability of constitutional WT1 mutations in nonsyndromic WT patients.

Patients and Methods

Constitutional DNA from 282 patients treated at seven United Kingdom Children's Cancer Study Group centers was screened for WT1 mutations using heteroduplex analysis. Bidirectional sequencing was used to confirm the mutation and to analyze the corresponding parental DNA samples.

Results

Five different constitutional WT1 mutations were identified in six children. Mutations in four patients were confirmed to be de novo, and all five mutations are predicted to produce truncated protein. The WT1 mutation group had a young median age at diagnosis of 13.8 months, compared with 34.9 months in the group in whom no WT1 mutations were found; four were female and two were male; and all tumors were of favorable histology. The three tumors with known histologic subtype were stromal-predominant. Contrary to expectation, four of six mutations occurred in children with unilateral tumors without any associated genitourinary abnormality.

Conclusion

Constitutional WT1 mutations occur with a low frequency (2.1%; 95% CI, 0.8% to 4.6%) in nonsyndromic WT patients. Most mutations occurred in children with unilateral WT without associated genitourinary abnormalities, creating difficulties in identifying individuals with germline mutations on phenotype alone. Two factors that may indicate that an individual is carrying a germline WT1 mutation are an early age of onset and stromal-predominant histology of the WT.
Is Eligibility for a Chemotherapy Protocol a Good Prognostic Factor for Invasive Bladder Cancer After Radical Cystectomy?
Authors: Madersbacher Stephan , Thalmann George N. , Fritsch Johannes C. , Studer Urs E.
Published: October 2004

Purpose

To assess whether eligibility to an adjuvant chemotherapy protocol in itself represents a good prognostic factor after radical cystectomy for bladder cancer.

Patients and Methods

Between April 1984 and May 1989, our institution entered 35 patients with invasive bladder cancer into the Swiss Group for Clinical and Epidemiological Cancer Research (SAKK) study 09/84. They were randomly assigned to either observation or three postoperative courses of cisplatin monotherapy after cystectomy. This study had a negative result. The outcome of these 35 patients (protocol group) was compared with an age- and tumor-stage–matched cohort (matched group; n = 35) who also underwent cystectomy during the same period, but were not entered into the SAKK study, as well as the remaining 57 patients treated during the study period for the same indication (remaining group).

Results

Median overall survival decreased from 76.3 months in the protocol group to 52.1 months in the matched group and to 20.3 months in the remaining group. The respective times of median recurrence-free survival were 67.2, 16.0, and 9.4 months. Tumor progression occurred in 46% of the protocol group compared with 69% in the matched group and 65% in the remaining group (P < .05). Cancer-related death was noted in 40% of the protocol group, 57% in the matched group, and 56% in the remaining group.

Conclusion

These data suggest that being willing and fit enough for a chemotherapy protocol is a good prognostic factor for invasive bladder cancer. This eligibility bias emphasizes the need for prospective, randomized trials, and indicates that single-group studies using historical or matched controls have to be interpreted with caution.
Quality of Life After Transhiatal Compared With Extended Transthoracic Resection for Adenocarcinoma of the Esophagus
Authors: de Boer A.G.E.M. , van Lanschot J.J.B. , van Sandick J.W. , Hulscher J.B.F. , Stalmeier P.F.M. , de Haes J.C.J.M. , Tilanus H.W. , Obertop H. , Sprangers M.A.G.
Published: October 2004

Purpose

To assess 3 years of quality of life in patients with esophageal cancer in a randomized trial comparing limited transhiatal resection with extended transthoracic resection.

Patients and Methods

Quality-of-life questionnaires were sent at baseline and at 5 weeks; 3, 6, 9, and 12 months; and 1.5, 2, 2.5, and 3 years after surgery. Physical and psychological symptoms, activity level, and global quality of life were assessed with the disease-specific Rotterdam Symptom Checklist. Generic quality of life was measured with the Medical Outcomes Study Short Form-20.

Results

A total of 199 patients participated. Physical symptoms and activity level declined after the operation and gradually returned toward baseline within the first year (P < .01). Psychological well-being consistently improved after baseline (P < .01), whereas global quality of life showed a small initial decline followed by continuous gradual improvement (P < .01). Quality of life stabilized in the second and third year. Three months after the operation, patients in the transhiatal esophagectomy group (n = 96) reported fewer physical symptoms (P = .01) and better activity levels (P < .01) than patients in the transthoracic group (n = 103), but no differences were found at any other measurement point. For psychological symptoms and global quality of life, no differences were found at any follow-up measurement. A similar pattern was found for generic quality of life.

Conclusion

No lasting differences in quality of life of patients who underwent either transhiatal or transthoracic resection were found. Compared with baseline, quality of life declined after the operation but was restored within a year in both groups.
Health-Related Quality of Life and Psychosocial Status in Breast Cancer Prognosis: Analysis of Multiple Variables
Authors: Goodwin Pamela J. , Ennis Marguerite , Bordeleau Louise J. , Pritchard Kathleen I. , Trudeau Maureen E. , Koo Jarley , Hood Nicky
Published: October 2004

Purpose

Evidence that psychosocial status and health-related quality of life (HRQOL) are associated with breast cancer (BC) outcomes is weak and inconsistent. We examined prognostic effects of these factors in a prospective cohort study.

Patients and Methods

Three hundred ninety-seven women with surgically resected T1 to T3, N0/N1, M0 BC completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (Core 30 items), Profile of Mood States, Psychosocial Adjustment to Illness Scale, Impact of Events Scale, Mental Adjustment to Cancer Scale, and the Courtauld Emotional Control Scale 2 months after diagnosis and 1 year later. Data on tumor-related factors, treatment, and outcomes were obtained prospectively from medical records, and Cox survival analyses were performed.

Results

Mean age was 52.0 ± 9.9 years. Two hundred twenty-five women had T1, 136 women had T2, 16 women had T3, and 20 women had TX tumors; 127 were N1. One hundred thirteen women received adjuvant chemotherapy, 130 received hormone therapy, 45 received both, and 109 received neither. We investigated 140 prognostic associations; four were found to be statistically significant at a P value of ≤ .05 (three fewer than expected by chance). Two were in the hypothesized direction of effect, and two were in the opposite direction. All arose from measurements 1 year after diagnosis, which were most susceptible to confounding by treatment. There was no evidence of consistency of associations across outcomes or questionnaires. These results are in keeping with chance as the explanation for our statistically significant findings.

Conclusion

HRQOL and psychosocial status at diagnosis and 1 year later are not associated with medical outcome in women with early-stage BC.
Clinical Decisions Associated With Positron Emission Tomography in a Prospective Cohort of Patients With Suspected or Known Cancer at One United States Center
Authors: Hillner Bruce E. , Tunuguntla Renuka , Fratkin Melvin
Published: October 2004

Purpose

In 2001, Medicare approved reimbursement of F-18 fluorodeoxyglucose positron emission tomography (PET) for a variety of cancers. PET has been observed to be more accurate than other imaging in cancer patients, but the impact of PET on management in routine practice is uncertain.

Patients and Methods

We studied a prospective cohort having noninvestigational PET at one university center. Before and after PET, a questionnaire was administered to solicit information regarding each physician's preceding actions, intended management, and probability estimates.

Results

Seventy-one physicians provided data on 248 patients, of whom 40% had new or suspected cancer and 60% were undergoing restaging or had suspected recurrence. Lung, lymphoma, and head/neck cancers accounted for two thirds of cases. Sixteen physicians made 64% of requests. Physicians changed their intended management in 61% of patients (95% CI, 54% to 66%). For individual physicians ordering at least 10 scans, the average kappa was 0.16 (range, −0.04 to 0.36), reflecting only slight level of agreement between their before and after PET plan. PET was associated with a change in 90 (79%) of 114 patients if the pre-PET intended plan involved more testing or biopsy. In 32% of cases, physicians changed to a treatment from a nontreatment strategy. The therapeutic goal and mode changed in 22 (7%) and 21 cases (8%), respectively.

Conclusion

This study confirms that physicians often change their decision making based on PET. This impact is likely due to combined effects of PET's improved accuracy and reduced physician uncertainty. Physicians may also be overconfident in interpreting PET and use it as the final arbiter after an extensive evaluation in lieu of tissue biopsy.
Spatial mapping of integrin interactions and dynamics during cell migration by Image Correlation Microscopy
Authors: Wiseman Paul W. , Brown Claire M. , Webb Donna J. , Hebert Benedict , Johnson Natalie L. , Squier Jeff A. , Ellisman Mark H. , Horwitz A. F.
Published: October 2004

Image correlation microscopy methodology was extended and used to determine retrospectively the density, dynamics and interactions of α5-integrin in migrating cells. α5-integrin is present in submicroscopic clusters containing 3-4 integrins before it is discernibly organized. The integrin in nascent adhesions, as identified by the presence of paxillin, is ∼1.4 times more concentrated, ∼4.5 times more clustered and much less mobile than in surrounding regions. Thus, while integrins are clustered throughout the cell, they differ in nascent adhesions and appear to initiate adhesion formation, despite their lack of visible organization. In more mature adhesions where the integrin is visibly organized there are ∼900 integrins μm–2 (about fivefold higher than surrounding regions). Interestingly, α5-integrin and α-actinin, but not paxillin, reside in a complex throughout the cell, where they diffuse and flow together, even in regions where they are not organized. During adhesion disassembly some integrins diffuse away slowly, α-actinin undergoes a directed movement at speeds similar to actin retrograde flow (0.29 μm min–1), while all of the paxillin diffuses away rapidly.
Suppression ofNek2Ain mouse early embryos confirms its requirement for chromosome segregation
Authors: Sonn Seongkeun , Khang Inkoo , Kim Kyungjin , Rhee Kunsoo
Published: October 2004

Nek2, a mammalian structural homologue of Aspergillus protein kinase NIMA, is predominantly known as a centrosomal kinase that controls centriole-centriole linkage during the cell cycle. However, its dynamic subcellular localization during mitosis suggested that Nek2 might be involved in diverse cell cycle events in addition to the centrosomal cycle. In order to determine the importance of Nek2 during mammalian development, we investigated the expression and function of Nek2 in mouse early embryos. Our results show that both Nek2A and Nek2B were expressed throughout early embryogenesis. Unlike cultured human cells, however, embryonic Nek2A appeared not to be destroyed upon entry into mitosis, suggesting that the Nek2A protein level is controlled in a unique manner during mouse early embryogenesis. Suppression of Nek2 expression by RNAi resulted in developmental defects at the second mitosis. Many of the blastomeres in Nek2-suppressed embryos showed abnormality in nuclear morphology, including dumbbell-like nuclei, nuclear bridges and micronuclei. These results indicate the importance of Nek2 for proper chromosome segregation in embryonic mitoses.
Linking JNK signaling to NF-κB: a key to survival
Authors: Papa Salvatore , Zazzeroni Francesca , Pham Can G. , Bubici Concetta , Franzoso Guido
Published: October 2004

In addition to marshalling immune and inflammatory responses, transcription factors of the NF-κB family control cell survival. This control is crucial to a wide range of biological processes, including B and T lymphopoiesis, adaptive immunity, oncogenesis and cancer chemoresistance. During an inflammatory response, NF-κB activation antagonizes apoptosis induced by tumor necrosis factor (TNF)-α, a protective activity that involves suppression of the Jun N-terminal kinase (JNK) cascade. This suppression can involve upregulation of the Gadd45-family member Gadd45β/Myd118, which associates with the JNK kinase MKK7/JNKK2 and blocks its catalytic activity. Upregulation of XIAP, A20 and blockers of reactive oxygen species (ROS) appear to be important additional means by which NF-κB blunts JNK signaling. These recent findings might open up entirely new avenues for therapeutic intervention in chronic inflammatory diseases and certain cancers; indeed, the Gadd45β-MKK7 interaction might be a key target for such intervention.
How Do Value Creation and Competition Determine Whether a Firm Appropriates Value?
Authors: MacDonald Glenn , Ryall Michael D.
Published: October 2004

How does competition among economic actors determine the value that each is able to appropriate? We provide a formal, general framework within which this question can be posed and answered, and then provide several results. Chief among them is a condition that is both required for, and guarantees, value appropriation. We apply our methodology to (i) assess the familiar notion that uniqueness, inimitability, and competition imply value appropriation, and (ii) determine the value appropriation possibilities for an innovator whose unique discovery is of use to several others who can compete for the right to use it.
Demand Allocation in Multiple-Product, Multiple-Facility, Make-to-Stock Systems
Authors: Benjaafar Saif , ElHafsi Mohsen , Véricourt Francis de
Published: October 2004

We consider the problem of allocating demand arising from multiple products to multiple production facilities with finite capacity and load-dependent lead times. Production facilities can choose to manufacture items either to stock or to order. Products vary in their demand rates, holding and backordering costs, and service-level requirements. We develop models and solution procedures to determine the optimal allocation of demand to facilities and the optimal inventory level for products at each facility. We consider two types of demand allocation, one in which we allow the demand for a product to be split among multiple facilities and the other in which demand from each product must be entirely satisfied by a single facility. We also consider two forms of inventory warehousing, one in which inventory locations are factory based and one in which they are centralized. For each case, we offer a solution procedure to obtain optimal demand allocations and optimal inventory base-stock levels. For systems with multiple customer classes, we also determine optimal inventory rationing levels for each class for each product. We use the models to characterize analytically several properties of the optimal solution. In particular, we highlight eight principles that relate the effects of cost, congestion, inventory pooling, multiple sourcing, customer segmentation, inventory rationing, and process and demand variability.
Two Faces: Effects of Business Groups on Innovation in Emerging Economies
Authors: Mahmood Ishtiaq P. , Mitchell Will
Published: October 2004

This paper shows that business groups in emerging economies exert dual effects on innovation. While groups facilitate innovation by providing institutional infrastructure, groups also discourage innovation by creating entry barriers for nongroup firms and thereby inhibit the proliferation of new ideas. This pattern reflects an evolutionary process in which the interplay of the availability of innovation infrastructure and variety of ideas influences the level of innovation in an industry. We show that group market share has an inverted-U impact on innovation in industrial sectors of both Korea and Taiwan during the 1981–1995 period. Institutional differences between Korea and Taiwan in terms of market structure and industrial policies lead to different innovation thresholds, the point at which the marginal costs of increasing group share begin to dominate the marginal benefits in the two countries.
From T-Mazes to Labyrinths: Learning from Model-Based Feedback
Authors: Denrell Jerker. , Fang Christina. , Levinthal Daniel A.
Published: October 2004

Many organizational actions need not have any immediate or direct payoff consequence but set the stage for subsequent actions that bring the organization toward some actual payoff. Learning in such settings poses the challenge of credit assignment (Minsky 1961), that is, how to assign credit for the overall outcome of a sequence of actions to each of the antecedent actions. To explore the process of learning in such contexts, we create a formal model in which the actors develop a mental model of the value of stage-setting actions as a complex problem-solving task is repeated. Partial knowledge, either of particular states in the problem space or inefficient and circuitous routines through the space, is shown to be quite valuable. Because of the interdependence of intelligent action when a sequence of actions must be identified, however, organizational knowledge is relatively fragile. As a consequence, while turnover may stimulate search and have largely benign implications in less interdependent task settings, it is very destructive of the organization's near-term performance when the learning problem requires a complementarity among the actors' knowledge.
Selectionism and Learning in Projects with Complexity and Unforeseeable Uncertainty
Authors: Sommer Svenja C. , Loch Christoph H.
Published: October 2004

Companies innovating in dynamic environments face the combined challenge of unforeseeable uncertainty (the inability to recognize the relevant influence variables and their functional relationships; thus, events and actions cannot be planned ahead of time) and high complexity (large number of variables and interactions; this leads to difficulty in assessing optimal actions beforehand).

There are two fundamental strategies to manage innovation with unforeseeable uncertainty and complexity: trial and error learning and selectionism. Trial and error learning involves a flexible (unplanned) adjustment of the considered actions and targets to new information about the relevant environment as it emerges. Selectionism involves pursuing several approaches independently of one another and picking the best one ex post.

Neither strategy nor project management literatures have compared the relative advantages of the two approaches in the presence of unforeseeable uncertainty and complexity. We build a model of a complex project with unforeseeable uncertainty, simulating problem solving as a local search on a rugged landscape. We compare the project payoff performance under trial and error learning and selectionism, based on a priori identifiable project characteristics: whether unforeseeable uncertainty is present, how high the complexity is, and how much trial and error learning and parallel trials cost. We find that if unforeseeable uncertainty is present and the team cannot run trials in a realistic user environment (indicating the project's true market performance), trial and error learning is preferred over selectionism. Moreover, the presence of unforeseeable uncertainty can reverse an established result from computational optimization: Without unforeseeable uncertainty, the optimal number of parallel trials increases in complexity. But with unforeseeable uncertainty, the optimal number of trials might decrease because the unforeseeable factors make the trials less and less informative as complexity grows.