bluuebunny/crossref_metadata_2025 huggingface dataset:
Radiology Services in Emergency Medicine Residency Programs: A National Survey
Authors: Lowe Robert A. , Abbuhl Stephanie B. , Baumritter Agnieshka , Brensinger Colleen , Propert Kathleen , Horii Steven , Kundel Harold
Published: October 2002

Objectives: To determine who reads plain film radiographs, how quickly radiologists' interpretations are available, how many initial readings require correction, and how satisfied emergency physicians (EPs) are with radiology in emergency departments (EDs) with emergency medicine (EM) residency programs. Methods: A questionnaire was sent to the chairs of all U.S. EM residencies, asking about EM radiology services. Results: Of 120 sites surveyed, 97 (81%) responded. Respondents reported that, on weekday days, EM attendings or residents performed the radiograph interpretation used for clinical decision making at 66% of sites; on nights and weekends, EPs performed the clinically relevant readings at 79% of sites. Twenty‐one percent of sites reported that no radiologist reviewed images before patients left the ED on nights and weekends. Only 39% of sites reported that all images were read within four hours on weekday days, and only 19% of sites reported readings within this time frame on nights and weekends. Median misinterpretation rates were reported as 1% on weekday days and 1.5% at other times. Overall, EPs were satisfied with their interactions with radiology at 63% of EDs. Conclusions: This study summarizes the perceptions of EPs regarding radiology services; the findings must be interpreted with caution, given the lack of external validation. Nevertheless, EPs report that many EM residency programs depend on EPs' interpretations of radiographs. Emergency physicians report that attending radiologists rarely read images on nights and weekends and that images are misread more frequently at these times. Although EPs were satisfied with many aspects of radiology, EPs expressed the most dissatisfaction with turnaround times and misreads.
Parents and Practitioners Are Poor Judges of Young Children's Pain Severity
Authors: Singer Adam J. , Gulla Janet , Thode Henry C.
Published: October 2002

Objective: Visual analog pain scales are reliable measures in older children and adults; however, pain studies that include young children often rely on parental or practitioner assessments for measuring pain severity. The authors correlated patient, parental, and practitioner pain assessments for young children with acute pain. Methods: This was a prospective, descriptive study of a convenience sample of 63 emergency department patients aged 4‐7 years, with acute pain resulting from acute illness or painful invasive procedures. A trained research assistant administered a structured pain survey containing demographic and historical features to all parents/guardians. Children assessed their pain severity using a validated ordinal scale that uses five different faces with varying degrees of frowning (severe pain) or smiling (no pain). Each face was converted to a numeric value from 0 (no pain) to 4 (severe pain). Parents and practitioners independently assessed their child's pain using a validated 100‐mm visual analog scale (VAS) marked “most pain” at the high end. Pairwise correlations between child, parent, and practitioner pain assessments were performed using Spearman's or Pearson's test as appropriate. The association between categorical data was assessed using χ2 tests. Results: Sixty‐three children ranging in age from 4 to 7 were included. Mean age (±SD) was 5.7 (±1.1); 42% were female. Fifty‐seven successfully completed the face scale. The distribution of the children's scores was 0‐17%, 1‐9%, 2‐30%, 3‐14%, and 4‐30%. Mean parental and practitioner scores (±SD) on the VAS were 61 (±26) mm and 37 (±26) mm, respectively (maximal = 100 mm). Correlation between child and parent scores was 0.47 (p < 0.001). Correlation between child and practitioner scores was 0.08 (p = 0.54). Correlation between parent and practitioner scores was 0.04 (p = 0.001). Conclusions: There is poor agreement between pain ratings by children, parents, and practitioners. It is unclear which assessment best approximates the true degree of pain the child is experiencing.
Referral of Medically Uninsured Emergency Department Patients to Primary Care
Authors: McCarthy Melissa Lee , Hirshon Jon Mark , Ruggles Rebecca L. , Docimo Anne Boland , Welinsky Melvin , Bessman Edward S.
Published: October 2002

Objective: To examine the impact primary care referral has on subsequent emergency department (ED) utilization. Methods: Uninsured ED patients who reported not having a primary care (PC) provider were referred to PC services at a community health center (CHC). The number of CHC visits completed was documented and the utilization rates of hospital‐based services (i.e., ED visits, outpatient clinic visits, and admissions) were compared for patients who completed a CHC visit and those who did not before and after referral. Results: Of the 655 referred patients, 22% completed at least one CHC visit. Patients who completed a visit were more likely to be older, to be female, and to have a chronic medical problem (p = 0.001). The number of visits to the CHC was significantly related to the payment method. Only 19% of those who were self‐pay completed three or more CHC visits, compared with 63% of those who qualified for a sliding fee or insurance (p < 0.001). There was no significant difference in pre‐ or post‐ED utilization between those who completed a CHC visit and those who did not. The only significant difference in utilization between the two study groups was for subsequent outpatient visits. Patients who completed a CHC visit were more likely to receive outpatient specialty care (23%) compared with patients who did not (12%) (p = 0.001). Conclusions: For uninsured patients with no regular health care provider, improving access to primary care services is not enough to reduce their visits to the ED.
Intramuscular Droperidol versus Intramuscular Dimenhydrinate for the Treatment of Acute Peripheral Vertigo in the Emergency Department: A Randomized Clinical Trial
Authors: Irving Carol , Richman Peter , Kaiafas Costas , Eskin Barnet , Allegra John
Published: October 2002

Objective: The emergency department (ED) treatment of acute peripheral vertigo (APV) has not been well studied. The purpose of this study was to determine the efficacy of intramuscular (IM) droperidol vs IM dimenhydrinate, in the treatment of ED patients with APV.

Methods: The study was a randomized, double‐blinded clinical trial, performed at a suburban, teaching ED. A convenience sample of adult patients with symptoms and signs consistent with rigid diagnostic criteria for APV were randomized to one of two treatment groups. Patients more than 65 years of age were excluded to reduce the likelihood of diagnostic misclassification. Demographic and historical features were recorded on a standardized data form. Patients recorded their initial level (t0) of discomfort on a 10‐centimeter (cm) visual analog scale (VAS). Treatment group 1 received 2.5 mg droperidol IM, while treatment group 2 received 50 mg dimenhydrinate IM. After 30 minutes (t30), patients again recorded the severity of their symptoms on the VAS. Chi‐square, t‐tests, and Mann‐Whitney were used for statistical comparison as appropriate. All tests were two‐tailed, with alpha set at 0.05. Primary outcome parameters were the mean change in VAS score from t0 to t30, and the percentage of patients in each treatment group who felt well enough to go home after t30 without further ED intervention. Results: There were 20 patients in the droperidol group and 20 in the dimenhydrinate group. The two groups were similar with respect to mean age (40 ± 13 years droperidol vs. 42 ± 13 years dimenhydrinate; p = 0.6), female sex (60% vs. 50%; p = 0.7), and mean median duration of symptoms [3 (interquartile range 2‐12) vs 9 (interquartile range 2‐30) hours; p = 0.2]. Mean initial t0 VAS scores were 7.2 ± 2.3 and 7.8 ± 1.9 (p = 0.47). Both treatment groups had mean reductions in VAS scores at t30 of 3.3 [95% confidence interval (95% CI) = 2.3 to 4.3]. At t30, 42% of patients in the droperidol group and 45% of patients in the dimenhydrinate group felt well enough to go home without further ED intervention. Conclusions: The authors found no difference between the therapeutic efficacies of IM droperidol and dimenhydrinate for the treatment of acute peripheral vertigo.
Factors Influencing Admission among Children with a Traumatic Brain Injury
Authors: McCarthy Melissa Lee , Serpi Tracey , Kufera Joseph A. , Demeter Lori A. , Paidas Charles
Published: October 2002

Objectives: To describe the epidemiology of traumatic brain injury (TBI) among children in Maryland and to examine factors that influence hospital admission. Methods: Statewide mortality, hospital discharge, and ambulatory care data were used to identify all TBI‐related emergency department (ED) visits, hospitalizations, and deaths that occurred in 1998 to children aged 0‐19 years according to the Centers for Disease Control and Prevention's standard case definition and protocol. Inpatient admission was modeled as a function of patient, injury, and hospital characteristics. Results: The overall incidence of pediatric TBI (i.e., ED visits, hospitalizations, and deaths) in 1998 was 670/100,000. After controlling for injury severity and other factors, uninsured children were 40% less likely to be hospitalized (95% CI = 0.43 to 0.82) and children with Medicaid were 90% more likely to be hospitalized (95% CI = 1.42 to 2.54) than were those with private insurance. The presence of a major associated injury significantly influenced the likelihood of hospitalization, especially among children with a minor (OR = 8.8) to moderate (OR = 11.6) TBI. Children who presented to a trauma center hospital were significantly more likely to be hospitalized than children treated at a non‐trauma center hospital, although this varied depending on income (OR = 1.8 for high versus low) and hospital volume (OR = 2.6 for a small hospital and OR = 29.0 for a large hospital). Conclusions: After adjusting for TBI severity and the presence of associated injuries, significant differences in hospitalization rates may exist among different patient subgroups and hospitals for children who sustain TBIs.
Diagnostic Errors
Authors: Kuhn Gloria J.
Published: October 2002

One of the most complex and challenging tasks facing physicians is the need to make a diagnosis. Recent research has focused attention on medical errors alleged to have resulted in increased patient morbidity and mortality. A number of authorities have suggested methods to track and prevent errors. Most have dealt with systems' changes and fail‐safe methods to prevent medication errors and commission of errors during treatment. Few have addressed methods to find and prevent diagnostic errors. Unless diagnostic error is either avoided or corrected early, fail‐safe methods to prevent medication and treatment errors will ultimately fail to improve patient outcome. American medical literature, particularly postmortem studies, have documented diagnostic error since at least 1912. European literature shows the problem is worldwide. The limits of human memory and errors in both observation and processing of information during problem solving contribute to the commission of errors. The purpose of this article is to examine the thinking patterns and cognitive errors that can result in diagnostic error, and suggest instructional strategies that can be used to alert residents and attending physicians to these potential problems so they can be avoided.
Attitudes of Law Enforcement Officers Regarding Automated External Defibrillators
Authors: Groh William J. , Lowe Miriam R. , Overgaard Amanda D. , Neal Jeanie M. , Fishburn W. Craig , Zipes Douglas P.
Published: October 2002

Objective: To assess the knowledge and attitudes of law enforcement officers regarding treating out‐of‐hospital cardiac arrest (OHCA) and using automated external defibrillators (AEDs). Methods: This was a survey conducted among officers serving Marion County, Indiana. Results: Of 1,130 surveys distributed, 929 (82.2%) were returned. Among these officers, 603 (66.4%) were certified in cardiopulmonary resuscitation (CPR) and 103 (11.3%) had received AED training. Most officers had limited knowledge regarding OHCA. A 100‐point knowledge score (mean ± SD: 31.9 ± 14.3) was higher in officers who had performed CPR while on duty [35.0, 95% confidence interval (95% CI) = 32.9 to 37.2, p = 0.005] and who were AED‐trained (40.8, 95% CI = 38.0 to 43.6, p < 0.001). Of the respondents, 367 (40.1%) believed that AED usage by local law enforcement was needed, and 323 (35.6%) stated that they would feel comfortable using an AED if trained. A 100‐point attitude score (mean ± SD: 32.1 ± 21.0) was higher in officers who had CPR certification (38.2, 95% CI = 35.6 to 40.8), who had performed CPR while on duty (40.6, 95% CI = 37.7 to 43.5), who were AED‐trained (39.5, 95% CI = 35.6 to 43.4), and who had improved OHCA knowledge (+3.8 per 10 points knowledge score, 95% CI = 3.0 to 4.7), p < 0.001, all significant factors. Conclusions: Limited knowledge and negative attitudes of law enforcement officers regarding their involvement in treating OHCA and using AEDs are commonly present. These factors could result in barriers that negatively impact law enforcement AED programs.
Thrombolysis Candidates for the Treatment of Stroke at an Emergency Department in Japan
Authors: Yamaguchi Keiji , Hori Shingo , Nogawa Shigeru , Tanahashi Norio , Fukuuchi Yasuo , Aikawa Naoki
Published: October 2002

Objectives: To study the proportion and characteristics of potential candidates for the intravenous administration of tissue plasminogen activator (IV‐tPA) among patients with cerebral infarction in a Japanese emergency department (ED). Methods: A retrospective observational study was performed using patients who had been transported by ambulance between August 1988 and April 2000 to an urban ED of a university hospital located in the Tokyo metropolitan area. Potential candidates for IV‐tPA were identified using the criteria of the National Institute of Neurological Disorders and Stroke (NINDS) study. Results: Of all 30,064 patients transported by ambulance, 526 were diagnosed as having cerebral infarction. Among them, 190 patients arrived at the ED within two hours of symptom onset (early ED arrivers). In comparison of their demographics with late ED arrivers (n = 319), atrial fibrillation, male gender, and consciousness disturbance were related with early ED arrivers, while aging and diabetes were related with late ED arrivers. As to the stroke subtype, patients with an embolic infarction accounted for 76.8% among early ED arrivers. Application of exclusion criteria identified 114 patients, who were suitable for the thrombolysis treatment, indicating that the proportion of potential IV‐tPA candidates was 21.7% among all cerebral infarction patients and 0.38% among all ED patients. Conclusions: The number of potential IV‐tPA candidates among patients transported to the ED by ambulance in Japan was substantial, where the proportion of embolic infarction cases was extremely high.
PAX3-FKHR and PAX7-FKHR Gene Fusions Are Prognostic Indicators in Alveolar Rhabdomyosarcoma: A Report From the Children’s Oncology Group
Authors: Sorensen Poul H.B. , Lynch James C. , Qualman Stephen J. , Tirabosco Roberto , Lim Jerian F. , Maurer Harold M. , Bridge Julia A. , Crist William M. , Triche Timothy J. , Barr Frederic G.
Published: October 2002

PURPOSE: Alveolar rhabdomyosarcoma (ARMS) is an aggressive soft tissue malignancy of children and adolescents. Most ARMS patients express PAX3-FKHR or PAX7-FKHR gene fusions resulting from t(2;13) or t(1;13) translocations, respectively. We wished to confirm the diagnostic specificity of gene fusion detection in a large cohort of RMS patients and to evaluate whether these alterations influence clinical outcome in ARMS.

PATIENTS AND METHODS: We determined PAX3-FKHR or PAX7-FKHR fusion status in 171 childhood rhabdomyosarcoma (RMS) patients entered onto the Intergroup Rhabdomyosarcoma Study IV, including 78 ARMS patients, using established reverse transcriptase polymerase chain reaction assays. All patients received central pathologic review and were treated using uniform protocols, allowing for meaningful outcome analysis. We examined the relationship between gene fusion status and clinical outcome in the ARMS cohort.

RESULTS: PAX3-FKHR and PAX7-FKHR fusion transcripts were detected in 55% and 22% of ARMS patients, respectively; 23% were fusion-negative. All other RMS patients lacked transcripts, confirming the specificity of these alterations for ARMS. Fusion status was not associated with outcome differences in patients with locoregional ARMS. However, in patients presenting with metastatic disease, there was a striking difference in outcome between PAX7-FKHR and PAX3-FKHR patient groups (estimated 4-year overall survival rate of 75% for PAX7-FKHR v 8% for PAX3-FKHR; P = .0015). Multivariate analysis demonstrated a significantly increased risk of failure (P = .025) and death (P = .019) in patients with metastatic disease if their tumors expressed PAX3-FKHR. Among metastatic ARMS, bone marrow involvement was significantly higher in PAX3-FKHR–positive patients.

CONCLUSION: Not only are PAX-FKHR fusion transcripts specific for ARMS, but expression of PAX3-FKHR and PAX7-FKHR identifies a very high-risk subgroup and a favorable outcome subgroup, respectively, among patients presenting with metastatic ARMS.
Hepatocellular Carcinoma in Children: Results of the First Prospective Study of the International Society of Pediatric Oncology Group
Authors: Czauderna P. , Mackinlay G. , Perilongo G. , Brown J. , Shafford E. , Aronson D. , Pritchard J. , Chapchap P. , Keeling J. , Plaschkes J. , Otte J.B.
Published: October 2002

PURPOSE: To improve survival and reduce operative morbidity and mortality in children with primary epithelial liver tumors by using preoperative chemotherapy, as well as to collect information on the epidemiology, natural history, and prognostic factors.

PATIENTS AND METHODS: Forty children with hepatocellular carcinoma (HCC) were registered onto the Group for Epithelial Liver Tumors International Society of Pediatric Oncology’s first study from January 1990 to February 1994. The outcome could be analyzed in 39 of those patients. Disease was often advanced at the time of diagnosis; metastases were identified in 31% of the children and extrahepatic tumor extension, vascular invasion, or both in 39%. Multifocal tumors were common (56%). Thirty-three percent of tumors were associated with hepatic cirrhosis. All but two patients received preoperative chemotherapy (cisplatin and doxorubicin).

RESULTS: Partial response was observed in 18 (49%) of 37 patients; there was no response or progression in the remainder. Complete tumor resection was achieved in 14 patients (36%). Twenty patients (51%) never became operable. Overall survival at 5 years was 28%, and event-free survival was 17%. Most deaths resulted from tumor progression (26 of 28). Presence of metastases and pretreatment extent of disease system grouping at diagnosis had an adverse influence on overall survival in multivariate analysis.

CONCLUSION: Survival for pediatric HCC patients is significantly inferior to that for children with hepatoblastoma. Complete tumor excision remains the only realistic chance of cure, although it is often prevented by advanced disease. The presence of metastases is the most potent predictor of poor prognosis. A prospective worldwide cooperation in the field of pediatric HCC should be encouraged to look for novel therapeutic concepts.
High Response Rate to Cisplatin/Etoposide Regimen in Childhood Low-Grade Glioma
Authors: Massimino Maura , Spreafico Filippo , Cefalo Graziella , Riccardi Riccardo , Tesoro-Tess John David , Gandola Lorenza , Riva Daria , Ruggiero Antonio , Valentini Laura , Mazza Elena , Genitori Lorenzo , Di Rocco Concezio , Navarria Piera , Casanova Michela , Ferrari Andrea , Luksch Roberto , Terenziani Monica , Balestrini Maria Rosa , Colosimo Cesare , Fossati-Bellani Franca
Published: October 2002

PURPOSE: The aim of this study was to avoid radiotherapy and to induce an objective response in children with low-grade glioma (LGG) using a simple chemotherapy regimen based on cisplatin and etoposide.

PATIENTS AND METHODS: Thirty-four children (median age, 45 months) with unresectable LGG were treated with 10 monthly cycles of cisplatin (30 mg/m2/d on days 1 to 3) and etoposide (150 mg/m2/d on days 1 to 3). Tumor originated in the visual pathway in 29 patients, in the temporal lobe in two, in the frontal lobe in two, and in the spine in one. Eight children were affected by neurofibromatosis type 1. Objective tumor response and toxicity were evaluated by magnetic resonance imaging and neurologic and functional tests at 3-month intervals.

RESULTS: An objective response was obtained in 24 (70%) of 34 patients, whereas the others had stable disease. None of the children were electively irradiated. In 31 previously untreated children, overall survival was 100% and progression-free survival was 78% at 3 years, with a median follow-up of 44 months. Acute toxicity was unremarkable; 28% patients evaluated for acoustic neurotoxicity revealed a loss of perception of high frequencies.

CONCLUSION: Cisplatin and etoposide combined treatment is one of the most active regimens for LGG in children and allows avoidance of radiotherapy in the vast majority of patients.
Doxorubicin and Paclitaxel Versus Doxorubicin and Cyclophosphamide as First-Line Chemotherapy in Metastatic Breast Cancer: The European Organization for Research and Treatment of Cancer 10961 Multicenter Phase III Trial
Authors: Biganzoli L. , Cufer T. , Bruning P. , Coleman R. , Duchateau L. , Calvert A.H. , Gamucci T. , Twelves C. , Fargeot P. , Epelbaum R. , Lohrisch C. , Piccart M.J.
Published: October 2002

PURPOSE: To compare the efficacy and tolerability of the combination of doxorubicin and paclitaxel (AT) with a standard doxorubicin and cyclophosphamide (AC) regimen as first-line chemotherapy for metastatic breast cancer.

PATIENTS AND METHODS: Eligible patients were anthracycline-naive and had bidimensionally measurable metastatic breast cancer. Two hundred seventy-five patients were randomly assigned to be treated with AT (doxorubicin 60 mg/m2 as an intravenous bolus plus paclitaxel 175 mg/m2 as a 3-hour infusion) or AC (doxorubicin 60 mg/m2 plus cyclophosphamide 600 mg/m2) every 3 weeks for a maximum of six cycles. A paclitaxel (200 mg/m2) and cyclophosphamide (750 mg/m2) dose escalation was planned at cycle 2 if no grade ≥ 3 neutropenia occurred in cycle 1. The primary efficacy end point was progression-free survival (PFS). Secondary end points were response rate (RR), safety, overall survival (OS), and quality of life.

RESULTS: A median number of six cycles were delivered in the two treatment arms. The relative dose-intensity and delivered cumulative dose of doxorubicin were lower in the AT arm. Dose escalation was only possible in 17% and 20% of the AT and AC patients, respectively. Median PFS was 6 months in the two treatments arms. RR was 58% versus 54%, and median OS was 20.6 versus 20.5 months in the AT and AC arms, respectively. The AT regimen was characterized by a higher incidence of febrile neutropenia, 32% versus 9% in the AC arm.

CONCLUSION: No differences in the efficacy study end points were observed between the two treatment arms. Treatment-related toxicity compromised doxorubicin-delivered dose-intensity in the paclitaxel-based regimen
Prognostic Impact of Micrometastatic Tumor Cells in the Lymph Nodes and Bone Marrow of Patients With Completely Resected Stage I Non–Small-Cell Lung Cancer
Authors: Osaki Toshihiro , Oyama Tsunehiro , Gu Chun-Dong , Yamashita Toshihiro , So Tomoko , Takenoyama Mitsuhiro , Sugio Kenji , Yasumoto Kosei
Published: October 2002

PURPOSE: This study was designed to substantiate the prognostic impact of occult micrometastatic tumor cells in the lymph nodes (LNs) and bone marrow (BM) in stage I non–small-cell lung cancer (NSCLC) patients using cytokeratin (CK) as a micrometastatic marker and the relationship between the micrometastases in the LNs and BM.

PATIENTS AND METHODS: A total of 2,432 hilar and mediastinal LNs were removed during surgery from 115 patients with completely resected stage I NSCLC. The LNs were analyzed for micrometastasis using immunohistochemistry with the biclonal anti-CK antibody AE1/AE3. BM aspirates from 115 patients were immunocytochemically stained with the monoclonal anti-CK antibody CK2.

RESULTS: CK-positive (CK+) cells were detected in 42 (1.7%) of 2,432 LNs, in 32 (27.8%) of 115 patients, and in 32 (27.8%) of 115 BM aspirates. There was no relationship between the frequencies of CK+ cells in the LNs and in the BM. The patients with CK+ cells in the LNs had a poor prognosis by both univariate (P = .008) and multivariate analyses (P = .01), whereas the presence of CK+ cells in the BM did not allow prediction of survival (P = .32). The prognostic impact of LNs micrometastasis was independent even after adjusting for the status of BM micrometastasis.

CONCLUSION: The detection of lymph nodal micrometastatic tumor cells provides an accurate assessment of tumor staging and has powerful prognostic implications for completely resected stage I NSCLC patients.
ChlVPP/EVA Hybrid Versus the Weekly VAPEC-B Regimen for Previously Untreated Hodgkin’s Disease
Authors: Radford J. A. , Rohatiner A. Z.S. , Ryder W. D.J. , Deakin D. P. , Barbui T. , Lucie N. P. , Rossi A. , Dunlop D. J. , Cowan R. A. , Wilkinson P. M. , Gupta R. K. , James R. D. , Shamash J. , Chang J. , Crowther D. , Lister T. A.
Published: October 2002

PURPOSE: To test the hypothesis that a chemotherapy regimen of relatively low toxicity and 11 weeks’ duration (doxorubicin, cyclophosphamide, etoposide, vincristine, bleomycin, and prednisolone [VAPEC-B]) is at least as effective in terms of disease control as 6 months’ treatment with chlorambucil, vinblastine, procarbazine, and prednisone/etoposide, vincristine, and doxorubicin (ChlVPP/EVA hybrid), which is associated with a high risk of permanent sterility.

PATIENTS AND METHODS: Two hundred eighty-two patients with previously untreated Hodgkin’s disease, clinical stages I/II (plus mediastinal bulk and/or B symptoms) and clinical stages III/IV were randomized at three United Kingdom and one Italian center to receive either six monthly cycles of ChlVPP/EVA hybrid or 11 weekly cycles of VAPEC-B. After chemotherapy and a restaging evaluation, radiotherapy was administered to sites of previous bulk or residual radiographic abnormality before patients were observed off treatment.

RESULTS: Further accrual to the trial was halted at the planned third interim analysis in September 1996. After a median follow-up of 4.9 years, freedom from progression (FFP), event-free survival (EFS), and overall survival (OS) are all significantly better in the population treated with ChlVPP/EVA than VAPEC-B, where the comparative 5-year results are 82% and 62% (FFP), 78% and 58% (EFS), and 89% and 79% (OS), respectively. The superiority of ChlVPP/EVA was seen in both low-risk and intermediate/high-risk patients, although subset analysis suggested that ChlVPP/EVA and VAPEC-B produce equivalent results in the best-prognosis patients (Hasenclever score ≤ 2, nonbulky disease).

CONCLUSION: Apart from possibly in the best-prognosis group, where results are equivalent, ChlVPP/EVA hybrid produces significantly better FFP, EFS, and OS than VAPEC-B in patients with previously untreated Hodgkin’s disease.
Comparing the Costs of Radiation Therapy and Radical Prostatectomy for the Initial Treatment of Early-Stage Prostate Cancer
Authors: Burkhardt Jeffrey H. , Litwin Mark S. , Rose Christopher M. , Correa Roy J. , Sunshine Jonathan H. , Hogan Christopher , Hayman James A.
Published: October 2002

PURPOSE: Radical prostatectomy and external-beam radiation are the most common treatments for localized prostate cancer. Given the absence of clinical consensus in favor of one treatment or the other, relative costs may be a significant factor. This study compares the direct medical costs during the month before and 9 months after diagnosis for patients treated primarily with external-beam radiation or radical prostatectomy for early-stage prostate cancer.

METHODS: Patients age 65 or older and coded by the Surveillance, Epidemiology, and End Results (SEER) registry as having been diagnosed with adenocarcinoma of the prostate treated primarily with external-beam radiation or radical prostatectomy during 1992 and 1993 were identified. The initial treatment costs, as measured by Medicare-approved payment amounts, for each strategy were analyzed using linked SEER-Medicare claims data after adjusting for differences in comorbidity and age. An intent-to-treat analysis was also performed to adjust for differences in staging between the two groups.

RESULTS: For patients in the treatment-received analysis, the average costs were significantly different; $14,048 (95% confidence interval [CI], $13,765 to $14,330) for radiation therapy and $17,226 (95% CI, $16,891 to $17,560) for radical prostatectomy (P < .001). The average costs for patients in the intent-to-treat analysis were also significantly less for radiation therapy patients ($14,048; 95% CI, $13,765 to $14,330) than for those who underwent radical prostatectomy ($17,516; 95% CI, $17,195 to $17,837; P < .001).

CONCLUSION: For patients with early-stage prostate cancer, average costs during the initial treatment interval were at least 23% greater for radical prostatectomy than for external-beam radiation. Major limitations of the research include not studying costs after the initial treatment interval and questionable current applicability, given changes in management of early prostate cancer.
Monoclonal anti-epidermal growth factor receptor (ior EGF/r3) antibody pharmacokinetic studies on nude mice I: a radio-receptor analysis applied to drug serum quantification
Authors: Fernández-Sánchez E , Ducongé J , Castillo R , Garcia I , Beausoleil I , Macías A
Published: October 2002

Due to its antagonistic properties upon ligand-epidermal growth factor receptor (EGFr) interaction, the monoclonal antibody anti-EGFr ior EGF/r3 is considered a potential therapeutic agent against several epithelium-derived tumours. This paper affords further analysis of the relevant corporal interaction of this monoclonal antibody in terms of its pharmacodynamic properties, using nude mice, following a single bolus intravenous dose administration. The radio-receptor assay allows quantification of the serum ior EGF/r3 level. The dose selection procedure, according to the Kolmogorov-Smirnov test, suggested using doses of 12.5–16 mg kg−1 for pharmacokinetic assessments. The experimental data were best fitted to a biexponential function (r2 = 0.985), through the classical two-compartment open modelling approach. The model selection was corroborated by the AKAIKE information criteria, and also the SCHWARTZ and ESTRIPtest were used. The estimated pharmacokinetic parameters (e.g. = 34.65 h, Vc = 2.84 mL, Vss = 4.21 mL and CL = 0.09 mL h−1) bear out the strategies for the evaluation of the therapeutic application of this drug. Finally, the radio-receptor analysis has provided a rationale for the proposed serum monoclonal antibody ior EGF/r3 quantification to characterize its concentration-time course.
Intratumoral cancer chemotherapy and immunotherapy: opportunities for nonsystemic preoperative drug delivery
Authors: Goldberg Eugene P , Hadba Ahmad R , Almond Brett A , Marotta James S
Published: October 2002

The recent literature documents the growing interest in local intratumoral chemotherapy as well as systemic preoperative chemotherapy with evidence for improved outcomes using these therapeutic modalities. Nevertheless, with few exceptions, the conventional wisdom and standard of care for clinical and surgical oncology remains surgery followed by radiation and/or systemic chemotherapy, as deemed appropriate based on clinical findings. This, in spite of the fact that the toxicity of conventional systemic chemotherapy and immunotherapy affords limited effectiveness and frequently compromises the quality of life for patients. Indeed, with systemic chemotherapy, the oncologist (and the patient) often walks a fine line between attempting tumour remission with prolonged survival and damaging the patient's vital functions to the point of death. In this context, it has probably been obvious for more than 100 years, due in part to the pioneering work of Ehrlich (1878), that targeted or localized drug delivery should be a major goal of chemotherapy. However, there is still only limited clinical use of nonsystemic intratumoral chemotherapy for even those high mortality cancers which are characterized by well defined primary lesions i.e. breast, colorectal, lung, prostate, and skin. There has been a proliferation of intratumoral chemotherapy and immunotherapy research during the past two to three years. It is therefore the objective of this review to focus much more attention upon intratumoral therapeutic concepts which could limit adverse systemic events and which might combine clinically feasible methods for localized preoperative chemotherapy and/or immunotherapy with surgery. Since our review of intratumoral chemo-immunotherapy almost 20 years ago (McLaughlin & Goldberg 1983), there have been few comprehensive reviews of this field; only one of broad scope (Brincker 1993), three devoted specifically to gliomas (Tomita 1991; Walter et al. 1995; Haroun & Brem 2000), one on hepatomas (Venook 2000), one concerning veterinary applications (Theon 1998), and one older review of dermatological applications (Goette 1981). However, none have shed light on practical opportunities for combining intratumoral therapy with subsequent surgical resection. Given the state-of-the-art in clinical and surgical oncology, and the advances that have been made in intratumoral drug delivery, minimally invasive tumour access i.e. fine needle biopsy, new drugs and drug delivery systems, and preoperative chemotherapy, it is timely to present a review of studies which may suggest future opportunities for safer, more effective, and clinically practical non-systemic therapy.
In-vitro distribution of terbinafine in rat and human blood
Authors: Yeganeh Mahboubeh Hosseini , McLachlan Andrew J
Published: October 2002

The association of drugs with plasma lipoproteins has the potential to influence drug action and disposition. In this study, the uptake and distribution of the lipophilic antifungal drug, terbinafine, was investigated in rat and human blood and plasma. Fresh plasma was incubated with terbinafine (200–1000 ng mL−1), then subjected to vertical spin density gradient ultra-centrifugation to separate protein fractions. Theconcentrations of terbinafine in each fraction was determined using a validated reversed-phase HPLC method. The association of terbinafine with very-low-density lipoproteins (15.5 ± 7.1 % of total concentration) in human plasma was significantly lower than that associated with fractions containing soluble proteins (28.0 ± 6.2 %), high-(26.8 ± 7.7 %) and low-density lipoproteins (31.6 ± 4.6%). In rats terbinafine was found to be distributed evenly through plasma protein fractions. The association of terbinafine in lipoproteins was independent of concentration (over the range 200–1000 ng mL−1) and species. The distribution of terbinafine was examined in human and rat blood and the blood-to-plasma ratio of terbinafine was 0.70 ± 0.09 and 1.01 ± 0.20, respectively, indicating higher association of terbinafine with plasma components than erythrocytes in humans. This study suggests that in humans and rats, terbinafine associates with a number of plasma proteins independently of terbinafine concentration. Alteration in plasma lipoprotein concentrations are therefore likely to influence terbinafine binding in blood and distribution in the body.
Comparative inhibitory effects of niflumic acid and novel synthetic derivatives on the rat isolated stomach fundus
Authors: Criddle David N , Meireles Ana Vanesca P , Macêdo Liana B , Leal-Cardoso José H , Scarparo Henrique C , Jaffar Mohammed
Published: October 2002

Novel derivatives of 2-[3-(trifluoromethyl)-analino]nicotinic acid (niflumic acid) were synthesized. The compounds were compared for their inhibitory effects on 5-hydroxytryptamine (5-HT)- and KCl-induced contraction of the rat fundus. The aim was to assess structure-activity relationships regarding the selectivity and potency of these compounds. Niflumic acid (1–100 μM) concentration-dependently inhibited 5-HT-induced tonic contractions with an IC50 value (concentration reducing the control contractile response by 50%, calculated from semilog graphs) of 0.24 × 10−4 M (n = 9). In contrast, it was significantly less potent at inhibiting KCl-induced responses (IC50 = 1.49 × 10−4 M, n = 9). The methyl ester (NFAme) and amido (NFAm) analogues showed no selectivity between 5-HT- and KCl-induced contractions with IC50 values of 1.64 × 10−4 M (n = 8) and 1.87 × 10−4 M (n = 9) for 5-HT responses, and 2.61 × 10−4 M (n = 8) and 2.55 × 10−4 M (n = 7) for KCl-induced responses, respectively. Our results suggest that alteration of the carboxylic acid moiety of niflumic acid reduces the selectivity and potency of its inhibitory action on 5-HT-induced contractile responses of the rat fundus, possibly via a reduced interaction with calcium-activated chloride channels.
In-vitro cytotoxic/cytostatic activity of anionic liposomes containing vinblastine against leukaemic human cell lines
Authors: Maswadeh H , Demetzos C , Dimas K , Loukas Y L , Georgopoulos A , Mavromoustakos T , Papaioannou G Th
Published: October 2002

Liposomes prepared from lipids dipalmitoylphosphatidylcholine (DPPC) and dipalmitoylphosphatidylglycerol (DPPG) with cholesterol were used to investigate the percentage of vinblastine encapsulation and the influence of lipid composition on the retention properties of vinblastine in buffer as well as in cell culture medium. Differential scanning calorimetry (DSC) was applied, to study the effect of cholesterol on the phase transition temperature and on the ΔH of the two liposome formulations. The cytotoxic and cytostatic activity of the liposome-encapsulated vinblastine was also examined against six leukaemic human cell lines. The results showed that encapsulation of vinblastine into liposomes was greater than 98% with a drug-phospholipid molar ratio of 0.13-0.18. The major improvement in vinblastine retention in buffer as well as in culture medium was achieved by employing DPPG. The DSC data showed that vinblastine exerted a more perturbing effect in DPPC-cholesterol bilayers than in DPPG-cholesterol bilayers and this may explain their lower retention time. The 50% growth-inhibiting (GI50) and cytostatic (TGI) activity of liposomal vinblastine did not seem to be affected by the type of the liposome while the 50 % cytotoxic activity (LC50) was affected in four out of the six cell lines tested. The parameters GI50, TGI and LC50 were estimated according to the instructions given by the NCI.
Tissue distribution of and species differences in deacetylation of N-acetyl-L-cysteine and immunohistochemical localization of acylase I in the primate kidney
Authors: Yamauchi Aiko , Ueda Nobuhiko , Hanafusa Sayuri , Yamashita Eri , Kihara Masaru , Naito Shinsaku
Published: October 2002

Species differences in the biotransformation of N-acetyl-L-cysteine (NAC) have been investigated to evaluate the usefulness of NAC as a constituent in parenteral nutrition solutions in place of cysteine. The activity of NAC-deacetylating enzyme (acylase) was measured in various tissues of different species (rat, rabbit, dog, monkey, and man). Acylase activity was highest in the kidney in all species studied. Enzyme activity in the liver was 10%-22% of that in the kidney in the rat, rabbit, monkey, and man, but almost no hepatic activity was seen in the dog. NAC-deacetylating activity was very low in other organs. The tissue distribution of acylase I was determined by Western blotting and an immunohistochemical method employing specific antibody against porcine acylase I (EC 3.5.1.14). The immunoblotting study showed a 46-kDa protein band corresponding to porcine acylase I in the kidney of all species. In liver cytosol, 46 kDa and/or 29 kDa bands were observed in the rat, rabbit, monkey, and man, but not in the dog. In the immunohistochemical study, positive staining with anti-acylase I antibody was observed clearly in the renal proximal tubules in the monkey and man. These results suggested that the kidney and liver were the main organs responsible for the biotransformation of NAC to cysteine in mammals other than the dog.
Transport of D-glucose across cultured stratified cell layer of human oral mucosal cells
Authors: Kimura Toshikiro , Yamano Hitoshi , Tanaka Akihiro , Matsumura Tomohiro , Ueda Minoru , Ogawara Ken-ichi , Higaki Kazutaka
Published: October 2002

To evaluate the role of several specialized mechanisms for D-glucose transport in human oral mucosa, a cultured stratified cell layer derived from human oral mucosa was employed. Although this culture system has been used for reconstructive surgery, we, for the first time, tried to apply this system to the evaluation of nutrients and drug transport. Cell number and transepithelial electrical resistance (TEER) reached steady state 7–8 days after inoculation on the Transwell and TEER values at steady state were 130–140 Ω cm2, which was higher or lower than that of small intestine or Caco-2 cells, respectively. The transport studies were carried out using the cultured epithelium on the Transwell. The transport of D-glucose across the cultured stratified layer of oral epithelial cells was much more extensive than L-glucose, and was inhibited by 2-deoxy-D-glucose, a substrate of facilitative glucose transporters, and α-methyl-D-glucoside, a specific substrate of a Na+/glucose cotransporter (SGLT1). The results indicate that the sugar transporters function not only to take up D-glucose by the epithelial cells but also to transport the sugar across the stratified epithelial layer.
In-vitro and in-vivo pharmacokinetic interactions of amprenavir, an HIV protease inhibitor, with other current HIV protease inhibitors in rats
Authors: Shibata Nobuhito , Gao Weihua , Okamoto Hiroyuki , Kishida Tomoyuki , Yoshikawa Yukako , Takada Kanji
Published: October 2002

The drug interactions between a new human immune deficiency virus (HIV) protease inhibitor, amprenavir, and four other protease inhibitors which are presently used have been characterized by in-vitro metabolic studies using rat liver microsomal fractions and in-vivo oral administration studies. The metabolic clearance rates (Vmax/Km) of amprenavir, saquinavir, indinavir and nelfinavir in rat liver microsomes were 50.67 ± 3.77, 170.88 ± 15.34, 73.01 ± 2.76 and 126.06 ± 6.23 μL min−1 (mg protein)−1, respectively, and the degree of metabolic clearance was in the order of saquinavir > nelfinavir > indinavir > amprenavir > ritonavir. The inhibition constants (Ki) of ritonavir for amprenavir, indinavir, nelfinavir and saquinavir were 2.29, 0.95, 1.01 and 1.64 μM, respectively, and that of indinavir for amprenavir was 0.67, indicating that amprenavir metabolism in rat liver microsomes was strongly inhibited by indinavir. The Ki values of amprenavir for indinavir, nelfinavir and saquinavir were 7.41, 2.13 and 16.11 μM, respectively, and those of nelfinavir and saquinavir for amprenavir were 9.15 and 34.57 μM, respectively. The area under the concentration vs time curve (AUC) of amprenavir after oral co-administration with saquinavir, indinavir, nelfinavir or ritonavir (20 mg kg−1 for each oral dose in rats) was increased by 1.6-, 2.0-, 1.2- and 9.1-fold, respectively. The AUC values of saquinavir, indinavir and nelfinavir by co-administration with amprenavir showed about 7.3-, 1.3-, and 7.9-fold increase, respectively. These observations suggested that the oral bioavailability of amprenavir was not so affected by co-administration with saquinavir, nelfinavir or indinavir, compared with ritonavir, whereas amprenavir markedly affected the oral bioavailability of saquinavir and nelfinavir. In addition, the in-vivo effects after coadministration of two kinds of HIV protease inhibitors cannot always be predicted from in-vitro data, suggesting the presence of other interaction processes besides metabolism in the liver. However, these results provide useful information for the treatment of AIDS patients when they receive a combination therapy with two kinds of HIV protease inhibitor.
Metabolism of sulphobromophthalein II. Species differences between rats, guinea-pigs and rabbits
Authors: Sano Kazumi , Totsuka Yukari , Ikegami Yoji , Uesugi Takashi
Published: October 2002

Interesting species differences in the metabolism of sulphobromophthalein sodium have been observed between rats, guinea-pigs and rabbits. The species difference was measured in terms of sulphobromophthalein monoglutathione conjugate (mGSH) positional isomer formation. After an intravenous injection of sulphobromophthalein to rats, 92% of sulphobromophthalein-mGSH excreted into bile was the α -isomer. In contrast, in guinea-pigs the three isomers α, β and δ were excreted in equivalent amounts. In rabbits, the majority of sulphobromophthalein-mGSH was excreted as the β-isomer. The formation ratio of glutathione (GSH) conjugates in-vitro using cytosolic glutathione S-transferases (GSTs) prepared from livers generally accounted for the biliary excretion ratio of α-, β - and δ-monomercaptide isomers in-vivo. GSTs from the livers of rat, guinea-pig, and rabbit were purified and characterized. Although their main GSTs produced different isomers, their 20 amino acid residues showed that they belonged to the same class mu of GSTs. The results suggested differences of the three-dimensional structure of GSTs that formed sulphobromophthalein-mGSH isomers between the three animal species.
Synthesis and physicochemical assessment of novel 2-substituted 3-hydroxypyridin-4-ones, novel iron chelators
Authors: Moridani Majid Y , Tilbrook Gary S , Khodr Hicham H , Hider Robert C
Published: October 2002

Novel 3-hydroxypyridin-4-one containing tridentate ligands were synthesised and their physicochemical properties characterised, including ionisation constants and stoichiometric titration with Fe(III). There is an urgent demand for orally active iron chelators with potential for the treatment of thalassaemia. In principle, tridentate ligands are likely to be more kinetically stable than bidentate molecules, but to date no satisfactory molecules have been identified. Fe(III) stability constants were assessed by competition with the hexadentate ligand EDTA. In all cases no evidence was found for a tridentate mode of iron chelation; instead the ligands behaved as bidentate hydroxypyridinones. As a consequence they provide no advantage over the more simple alkyl hydroxypyridinones.