bluuebunny/crossref_metadata_2025 huggingface dataset:
Quality of life in multiple sclerosis: influence of interferon-β1a (Avonex®) treatment
Authors: Vermersch P , de Seze J , Delisse B , Lemaire S , Stojkovic T
Published: September 2002

Background: Numerous data argue for initiating treatment with interferon-β(IFN-β) at an early stage in multiple sclerosis (MS). The consequences of its use may negatively influence the MS patient’s quality of life (QoL). Objective: To evaluate the QoL of MS patients before and after a one-year period of treatment with IFN-β1a (Avonex®). Patients and Methods: QoL was assessed using the SF-36 in 121 relapsing-remitting MS patients. We compared QoL before and after treatment and with data from a normal population. We also studied the possible influence of disease progression on the SF-36 scores. Results: One hundred six patients completed the study (87%). Compared to a normal population, patients were, at baseline, worse off for all QoL scales, varying from a minimum decrease of 0.73 SD in mental health, to a maximum decrease of 1.55 SD in general health. After treatment, we found no significant changes in any of the QoL scores, except for physical function, where we noted a slight but significant decrease (p=0.03). Furthermore, there was no significant change either in the physical component summary (PCS) or mental component summary (MCS). The ‘reported health transition’ item was significantly improved compared to baseline (p=0.001). At inclusion, significant correlations were found between EDSS scores and scores of physical function (p<0.001), role - physical (p<0.01), general health and social function (both p<0.01), and with the PCS (p<0.01). Patients with clinical relapses and/or disability progression had a more significant decrease in physical function (p<0.05) and also in social function (p<0.05). Conclusion: The QoL, assessed by the SF-36 scale, is correlated with disability in MS. IFN-β1a treatment (Avonex®) has no negative effect on MS patient’s QoL.
The reliability and validity of the Nottingham Extended Activities of Daily Living Scale in patients with multiple sclerosis
Authors: Nicholl C R , Lincoln N B , Playford E D
Published: September 2002

Objective: To investigate whether the Nottingham Extended Activities of Daily Living Scale (EADL) is reliable and valid for the assessment of disability in patients with multiple sclerosis (MS). Design: Questionnaire measures were administered on two occasions four months apart. Subjects: A total of 240 patients recruited through a randomized controlled trial of cognitive assessment and treatment in MS. Measures: The Nottingham EADL, Guys Neurological Disability Scale (GNDS) and SF-36 quality of life scale. Results: The EADL items did not form a Guttman Scale (CR 0.8, CS 0.3). The EADL and its four subscales all had high internal consistency (α 0.72-0.94). Test-retest reliability was satisfactory (rs 0.81-0.90) with a mean difference in scores on the two occasions of 0.29. Factor analysis generally supported the subscale structure. There were significant but weak correlations with quality of life measures. Conclusions: The EADL shows promise for the assessment of disability in MS, but the range of items needs to be extended. Further evaluation of the scale seems warranted.
Three screening batteries to detect cognitive impairment in multiple sclerosis
Authors: Aupperle R L , Beatty W W , deNAP Shelton F , Gontkovsky S T
Published: September 2002

To compare the sensitivities for detecting cognitive impairment in patients with multiple sclerosis (MS) and administration times of three brief batteries of neuropsychological tests, 64 patients with MS completed the Neuropsychological Screening Battery for Multiple Sclerosis (NPSBMS), the Screening Examination for Cognitive Impairment (SEFCI), and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Failure on a particular test was defined as a score below the 5th percentile for healthy controls, and the number of patients who failed at least one or two tests (out of four) was determined for each battery. Both the SEFCI and the NPSBMS identified significantly more patients with impairment than the RBANS, which was no more sensitive than the Mini-Mental State Exam (MMSE). Results were similar at both the one- and two-failed-tests criteria, but there were no significant differences between the SEFCI and the NPSBMS at either failure criterion. Mean administration time was 22.6 min for the SEFCI compared to 31.7 min for the NPSBMS (p <0.001). Eleven (17%) of the patients refused to attempt the Paced Auditory Serial Addition Test (PASAT), one component of the NPSBMS. For screening patients on a single occasion, the SEFCI is preferred because its administration time is shorter than the NPSBMS.
Brain atrophy in multiple sclerosis: impact of lesions and of damage of whole brain tissue
Authors: Kalkers N F , Vrenken H , Uitdehaag B MJ , Polman C H , Barkhof F
Published: September 2002

Introduction: In multiple sclerosis (MS), brain atrophy measurement on magnetic resonance imaging (MRI) reflects overall tissue loss, especially demyelination and axonal loss. We studied which factor contributes most to the development of brain atrophy: extent and severity of lesions or damage of whole brain tissue (WBT). Methods: Eighty-six patients with MS [32 primary progressive (PP), 32 secondary progressive (SP)] and 22 relapsing-remitting (RR) were studied. MRI included T1- and T2-weighted imaging to obtain hypointense T1 lesion volume (T1LV) and two brain volume measurements: 1) the parenchymal fraction (PF; whole brain parenchymal volume/intracranial volume) as a marker of overall brain volume, and 2) the ventricular fraction (VF; ventricular volume/intracranial volume) as a marker of central atrophy. From magnetization transfer ratio (MTR) histograms, the relative peak height (rHp) was derived as an index of damage of WBT (a lower peak height reflects damage of WBT). Results: Multiple linear regression analysis revealed that damage of WBT explains most of the variance of PF (standardized coefficient b=0.59, p <0.001 for WBT and b= −0.19, p <0.05 for T1LV). These findings are independent of disease phase; even in RR patients, damage of WBT plays a dominant role in explaining the variance in overall brain volume. By contrast, the variance in VF is explained by both T1LV and damage of WBT (standardized coefficient b =0.43, p<0.001 for T1LV and b = −0.38, p <0.001 for WBT). Conclusion: This study shows that overall brain volume (PF) is best explained by damage of WBT, supporting the significance of nonfocal pathology in MS in producing tissue loss. Central atrophy (VF) is determined by both lesion volume and damage of WBT. Our results underline the importance of nonfocal pathology even in the early (RR) phase of the disease.
CADASIL imitating multiple sclerosis: the importance of MRI markers
Authors: O'Riordan S , Nor A M , Hutchinson M
Published: September 2002

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) can mimic multiple sclerosis (MS), leading to diagnostic confusion. We report a family with CADASIL in which the index case and the daughter of the index case were initially erroneously diagnosed with MS. Relatively specific magnetic resonance imaging (MRI) markers of CADASIL include involvement of the anterior temporal lobes and external capsules and, as illustrated in this report, these MRI findings may aid in the differentiation of the two conditions.
Multiple sclerosis functional composite: impact of reference population and interpretation of changes
Authors: Uitdehaag B MJ , Adèr H J , Roosma T JA , de Groot V , Kalkers N F , Polman C H
Published: September 2002

The Multiple sclerosis functional composite (MSFC) has been recommended as a clinical outcome measure to be used in future MS trials. A specific characteristic of the MSFC is that it is defined as a measure of impairment relative to a reference population. Using different reference populations affects actual MSFC scores. If the selection of a reference population also has an effect on sensitivity to change of the MSFC, comparison of data from clinical trials will be almost impossible when different reference populations are used. We studied the effect of the selection of a reference population on the outcome of a trial by simulating 343 intervention trials and comparing results obtained by using three different reference populations: two previously published MS patient populations and a healthy population. Scores of the healthy population were collected in the first part of the study. The effects of sex, age and education level on test scores of healthy subjects were studied as well. In the healthy controls, sex, age and education level had a different impact on individual test scores of MSFC components and overall MSFC score. Our study shows that, with the use of the MSFC, the selection of different reference populations does not affect the trial statistics and significance, but it does affect comparability of results between different trials, and complicates the clinical interpretation of any observed change.
A study of therapy-related acute leukaemia after mitoxantrone therapy for multiple sclerosis
Authors: Ghalie R G , Mauch E , Edan G , Hartung H P , Gonsette R E , Eisenmann S , Le Page E , Butine M D , Goodkin D E
Published: September 2002

To evaluate the incidence of therapy-related acute leukaemia (t-AL) after single-agent mitoxantrone (MITO) treatment, we reviewed medical records of patients in three studies of single-agent MITO therapy for multiple sclerosis (MS) and existing literature on MITO therapy in MS, leukaemia, and solid tumors. Of 1378 MITO recipients in the three MS studies (mean cumulative dose of 60 mg/m2 and mean follow-up of 36 months), one patient had t-AL, an observed incidence proportion of 0.07% [95% confidence interval (CI)=0.00-0.40%]. There were no cases of t-AL in published reports of nine additional studies of single-agent MITO therapy for MS. There was one published case report of acute promyelocytic leukaemia detected five years after initiating MITO therapy for MS. The observed incidence proportion of t-AL is very low in patients who received MITO as single-agent therapy for MS. Although these observations provide preliminary reassurance, extended follow-up of these patients and those who receive higher cumulative doses of MITO is required to define the long-term risk of t-AL after MITO therapy for MS.
Cytokines in multiple sclerosis: methodological aspects and pathogenic implications
Authors: Özenci V , Kouwenhoven M , Link H
Published: September 2002

Multiple sclerosis (MS) is one of the leading causes of disability among young adults of Caucasian origin. One hundred and fifty years after the first description of the disease, the cause of MS remains unknown. Ironically, the few hypotheses concerning MS pathogenesis that are valid today were first proposed over a hundred years ago. However, equipped with the advanced technology of molecular biology and imaging systems, we are at present progressively uncovering clues to understanding the pathogenesis of the disease. It is clearly evident that aberrant immune responses occur in MS, and it is likely that the spectrum of cytokines produced decisively influences disease outcome. The detrimental consequences of IFN-γ and the beneficial effects of IFN-βtreatment in MS support this hypothesis. However, there are still major gaps in our knowledge of the involvement of cytokines in MS. Numerous studies have addressed the question of cytokine levels in MS, often with conflicting results; elevated, normal and decreased levels of almost all cytokines have been reported. This scenario most probably reflects methodological dilemmas as well as the complex biology of cytokines. Here we focus on possible reasons for the discrepancies of results reported on cytokines in MS and summarize findings obtained in particular by the application of enzyme-linked immunospot (ELISPOT) assays to cytokine studies in MS.
Cerebral volume changes in multiple sclerosis patients treated with high-dose intravenous methylprednisolone
Authors: Hoogervorst E LJ , Polman C H , Barkhof F
Published: September 2002

Objective: Multiple sclerosis (MS) patients develop varying degrees of cerebral atrophy, which may already begin at disease onset. The purpose of this study is to examine the effect of steroid treatment on cerebral volume in MS patients. Methods: Thirty-five MS patients participating in a clinical trial of oral interferon beta, which included monthly MRI, were included in this study. They suffered from an acute relapse and were treated with intravenous methylprednisolone (IV-MP); 13 of the patients were treated with oral prednisolone tapering after IV-MP. The last MRI scan before and the first (and second for oral tapering patients) scan after IV-MP treatment were used for measuring parenchymal fraction (PF) and ventricular fraction (VF). Changes in PF and VF were analysed using Student’s t test. Results: For the total population no significant changes in PF or VF were found. However, the subgroup of patients receiving oral tapering after IV-MP showed changes, compatible with atrophy in both PF and VF, that were significant immediately after IV-MP treatment and still persisted (though not statistically significant anymore) after a mean interval of 30 days. The magnitude of these changes was about the same as the annual change in cerebral volume as reported in natural history studies. Conclusion: Our data indicate that short courses of intravenous steroids (restricted to three or five days) have no major impact, whereas prolonged treatment with oral tapering does significantly affect brain volume. These findings are important for longitudinal studies and clinical trials in which brain volume is used as an outcome measure.
Chlamydia pneumoniae infection associated with enhanced MRI spinal lesions in multiple sclerosis
Authors: Hao Q , Miyashita N , Matsui M , Wang H-Y , Matsushima T , Saida T
Published: September 2002

Cerebrospinal fluid (CSF) from 66 patients with multiple sclerosis (MS) and 25 patients with other neurological diseases (OND) were examined for the infection of Chlamydia pneumoniae by culture, polymerase chain reaction (PCR) assay, and determination of antibodies to C. pneumoniae. PCR was positive not only in 9 of 28 (32%) patients with MS but also in 2 patients with inflammatory disorders in 15 (13%) OND controls (p=0.18). Viable C. pneumoniae was isolated from one patient with MS and one with paraneoplastic encephalomyelitis. C. pneumoniae could be detected only in cell-containing CSF. In MS, enhanced spinal magnetic resonance imaging (MRI) lesions were detected in all of four PCR-positive patients but none of five PCR-negative patients, and the difference was significant (p=0.0079). However, no correlation was found between enhanced brain MRI lesions and CSF C. pneumoniae DNA. Elevated titers of anti-C. pneumoniae IgG were detected in CSF in 13 of 66 (20%) patients with MS and 1 of 25 (4%) OND controls (p=0.064). CNS C. pneumoniae infection is not uncommon in MS as well as in other inflammatory disorders of the nervous system. The association of active spinal lesions with Chlamydia in CSF collected by lumber puncture suggests the detection of a recent infection. On the other hand, the lack of association of active MS brain lesions with CSF Chlamydia and the presence of PCR-positive patients who are clinically stable and have no enhancing MRI lesions imply the existence of a chronic infectious process.
Expression of chemokine receptors in the different clinical forms of multiple sclerosis
Authors: Martínez-Cáceres E M , Espejo C , Brieva L , Pericot I , Tintoré M , Sáez-Torres I , Montalban X
Published: September 2002

Chemokines and their receptors are important in the trafficking of peripheral leukocytes into the central nervous system, a major event in the pathogenesis of multiple sclerosis (MS). Evidence based on clinical, pathological and magnetic resonance imaging grounds supports some divergence between forms of MS with relapses [relapsing-remitting (RR) and secondary progressive (SP)] and the primary progressive (PP) form. To elucidate whether different pathogenic mechanisms are involved in PPMS, we compared membrane expression of a group of CC and CXC chemokine receptors (CCR1, CCR5, CXCR3, CXCR4) in peripheral blood of 68 MS patients (25 PPMS, 23 SPMS and 20 RRMS) and 26 healthy controls. We found a significant increase in surface expression of CCR5 in CD4+, CD8+, CD19+ and CD14+ cells as well as an increased percentage of CXCR3 and CXCR4 in CD14+ cells in MS patients compared to controls. Increased levels of CXCL10 (IP-10) and CCL5 (RANTES) in cerebrospinal fluid were also observed in a subgroup of MS patients. These results support that chemokines and their receptors are involved in the pathogenesis of MS. However, a pattern of chemokine-chemokine receptor expression characteristic of each clinical form of the disease failed to be observed.
The Multiple Sclerosis Functional Composite: a new clinical outcome measure for multiple sclerosis trials
Authors: Rudick R A , Cutter G , Reingold S
Published: September 2002

With the advent and widespread use of partially effective disease modifying drug therapies for multiple sclerosis (MS), future clinical trials will undoubtedly test experimental interventions against standard therapy, or will test combinations of drugs against standard therapy. In either case, incremental progress in slowing disability progression in future MS clinical trials will require much larger sample sizes, more sensitive outcome measures, or a combination of the two. Because improved clinical outcome methods would likely accelerate progress in MS therapeutics, the National Multiple Sclerosis Society (NMSS) convened an international task force in 1994 to recommend improved clinical outcome measures. As the result of a two-year process of discussion and data analysis, the task force recommended the Multiple Sclerosis Functional Composite (MSFC) as a new clinical outcome measure for future MS trials. MSFC consists of timed tests of walking, arm function, and cognitive function, expressed as a single score along a continuous scale. The task force recommended that MSFC be included in future MS trials, and recommended a series of validation studies. Subsequent studies have provided evidence that MSFC correlates moderately with Expanded Disability Status Scale (EDSS), and that correlation is driven by strong correlations with the ambulatory function component; arm function and cognitive function correlate at lower levels with EDSS. The MSFC correlates better than EDSS with magnetic resonance imaging (MRI) variables, including brain atrophy, and shows significant correlation with patient-reported disease-related quality of life (QOL). MSFC and short-term change in MSFC correlate with future clinical and MRI status, and the strength of the correlations compares favorably with well-known cardiovascular risk factors. The studies in aggregate indicate that MSFC and MSFC change are clinically meaningful, and that MSFC has substantial advantages over alternative clinical outcome measures for MS clinical trials.
Phase I Trial Evaluating the Concurrent Combination of Radiotherapy and Capecitabine in Rectal Cancer
Authors: Dunst Jürgen , Reese Thomas , Sutter Thomas , Zühlke Helmut , Hinke Axel , Kölling-Schlebusch Katrin , Frings Stefan
Published: September 2002

PURPOSE: To establish the feasibility of concurrent radiotherapy and capecitabine and define the maximum-tolerated dose (MTD) in patients with rectal cancer.

PATIENTS AND METHODS: Thirty-six patients with rectal cancer received treatment in the adjuvant, neoadjuvant, or palliative setting with a total irradiation dose of 50.4 Gy with 1.8 Gy/d in approximately 6 weeks. Capecitabine was administered at escalating doses from 250 to 1,250 mg/m2 bid (including weekends) for the duration of radiotherapy. The MTD was defined when two or more patients in a cohort of three or six patients experienced dose-limiting toxicities.

RESULTS: Dose-limiting grade 3 hand-foot syndrome was observed in two of six patients treated at a capecitabine dose of 1,000 mg/m2 bid. Other toxicities were generally rare and/or mild, with only one case of non–dose-limiting grade 3 diarrhea and a single patient with grade 3 skin toxicity. Myelosuppression consisted mainly of leukocytopenia, with a maximum severity of grade 2. Thus, a dosage of 825 mg/m2 bid is the recommended dose level for further evaluation. One pathologic complete remission of a T3N1 tumor and nine partial remissions were observed in 10 patients treated in the neoadjuvant setting.

CONCLUSION: The recommended dose for phase II evaluation is capecitabine 825 mg/m2 bid, administered without break during a conventional radiotherapy period of about 6 weeks. This combined-modality approach proved to be a feasible and well-tolerated treatment option with promising preliminary efficacy results in rectal cancer.
Quality of Life of Women With Recurrent Breast Cancer and Their Family Members
Authors: Northouse Laurel L. , Mood Darlene , Kershaw Trace , Schafenacker Ann , Mellon Suzanne , Walker Julie , Galvin Elizabeth , Decker Veronica
Published: September 2002

PURPOSE: Little information is available about the effects of recurrent breast cancer on the quality of life of women and their family members. The present study assessed patients’ and family members’ quality of life within 1 month after recurrence, and effects of multiple factors on quality-of-life scores.

PATIENTS AND METHODS: Patient/family member dyads (N = 189) participated in this study. A stress-appraisal model guided selection of person factors, social/family factors, illness-related factors, appraisal factors, and quality of life, measured with psychometrically sound instruments. Quality of life was measured with both generic (Medical Outcomes Study SF-36) and cancer-specific (Functional Assessment of Cancer Therapy) scales.

RESULTS: Patients reported significant impairments in physical, functional, and emotional well-being. Family members reported significant impairments in their own emotional well-being. Structural equation modeling revealed that self-efficacy, social support, and family hardiness had positive effects on quality of life, whereas symptom distress, concerns, hopelessness, and negative appraisal of illness or caregiving had detrimental effects. Study variables accounted for a sizable amount of variance in patients’ and family members’ physical and mental dimensions of quality of life (72% to 81%). Contrary to findings observed in studies of newly diagnosed breast cancer patients and spouses, little relationship was found between recurrent patients’ and family members’ quality of life.

CONCLUSION: Women with recurrent breast cancer are in need of programs to assist them with the severe effects of the disease on their quality of life. Programs need to include family members to help counteract the negative effects of the recurrent disease on their mental health, and to enable them to continue as effective caregivers.
Standard Versus Intensified Chemotherapy With Granulocyte Colony-Stimulating Factor Support in Small-Cell Lung Cancer: A Prospective European Organization for Research and Treatment of Cancer–Lung Cancer Group Phase III Trial—08923
Authors: Ardizzoni Andrea , Tjan-Heijnen Vivianne C.G. , Postmus Pieter E. , Buchholz Erica , Biesma Bonne , Karnicka-Mlodkowska Hanna , Dziadziuszko Rafal , Burghouts Jos , van Meerbeeck Jan P. , Gans Steven , Legrand Catherine , Debruyne Channa , Giaccone Giuseppe , Manegold for the Christian ,   European Organization for Research and Treatment of Cancer–Lung Cancer Group
Published: September 2002

PURPOSE: To assess the impact on survival of increasing dose-intensity (DI) of cyclophosphamide, doxorubicin, and etoposide (CDE) in small-cell lung cancer (SCLC).

PATIENTS AND METHODS: Previously untreated SCLC patients were randomized to standard CDE (cyclophosphamide 1,000 mg/m2 and doxorubicin 45 mg/m2 on day 1, and etoposide 100 mg/m2 on days 1 to 3 every 3 weeks, for five cycles) or intensified CDE (cyclophosphamide 1,250 mg/m2 and doxorubicin 55 mg/m2 on day 1, and etoposide 125 mg/m2 on days 1 to 3 with granulocyte colony-stimulating factor [G-CSF] 5 μg/kg/d on days 4 to 13 every 2 weeks, for four cycles). Projected cumulative dose was almost identical on the two arms, whereas projected DI was nearly 90% higher on the intensified arm. Two hundred forty-four patients were enrolled. The first 163 patients were also randomized (2 × 2 factorial design) to prophylactic antibiotics or placebo to assess their impact on preventing febrile leukopenia (FL). This report focuses on chemotherapy DI results.

RESULTS: With a median follow-up of 54 months, 216 deaths have occurred. Actually delivered DI on the intensified arm was 70% higher than on the standard arm. Intensified CDE was associated with more grade 4 leukopenia (79% v 50%), grade 4 thrombocytopenia (44% v 11%), anorexia, nausea, and mucositis. FL and number of toxic deaths were similar on the two arms. The objective response rate was 79% for the standard arm and 84% for the intensified arm (P = .315). Median survival was 54 weeks and 52 weeks, and the 2-year survival rates were 15% and 18%, respectively (P = .885).

CONCLUSION: A 70% increase of CDE actual DI does not translate into an improved outcome in SCLC patients.
Randomized Clinical Trial of an Implantable Drug Delivery System Compared With Comprehensive Medical Management for Refractory Cancer Pain: Impact on Pain, Drug-Related Toxicity, and Survival
Authors: Smith Thomas J. , Staats Peter S. , Deer Timothy , Stearns Lisa J. , Rauck Richard L. , Boortz-Marx Richard L. , Buchser Eric , Català Elena , Bryce David A. , Coyne Patrick J. , Pool George E.
Published: September 2002

PURPOSE: Implantable intrathecal drug delivery systems (IDDSs) have been used to manage refractory cancer pain, but there are no randomized clinical trial (RCT) data comparing them with comprehensive medical management (CMM).

PATIENTS AND METHODS: We enrolled 202 patients on an RCT of CMM versus IDDS plus CMM. Entry criteria included unrelieved pain (visual analog scale [VAS] pain scores ≥ 5 on a 0 to 10 scale). Clinical success was defined as ≥ 20% reduction in VAS scores, or equal scores with ≥ 20% reduction in toxicity. The main outcome measure was pain control combined with change of toxicity, as measured by the National Cancer Institute Common Toxicity Criteria, 4 weeks after randomization.

RESULTS: Sixty of 71 IDDS patients (84.5%) achieved clinical success compared with 51 of 72 CMM patients (70.8%, P = .05). IDDS patients more often achieved ≥ 20% reduction in both pain VAS and toxicity (57.7% [41 of 71] v 37.5% [27 of 72], P = .02). The mean CMM VAS score fell from 7.81 to 4.76 (39% reduction); for the IDDS group, the scores fell from 7.57 to 3.67 (52% reduction, P = .055). The mean CMM toxicity scores fell from 6.36 to 5.27 (17% reduction); for the IDDS group, the toxicity scores fell from 7.22 to 3.59 (50% reduction, P = .004). The IDDS group had significant reductions in fatigue and depressed level of consciousness (P < .05). IDDS patients had improved survival, with 53.9% alive at 6 months compared with 37.2% of the CMM group (P = .06).

CONCLUSION: IDDSs improved clinical success in pain control, reduced pain, significantly relieved common drug toxicities, and improved survival in patients with refractory cancer pain.
Effectiveness of Adjuvant Fluorouracil in Clinical Practice: A Population-Based Cohort Study of Elderly Patients With Stage III Colon Cancer
Authors: Iwashyna Theodore J. , Lamont Elizabeth B.
Published: September 2002

PURPOSE: Although randomized controlled trials (RCTs) consistently show that adjuvant fluorouracil (5-FU) extends the survival of patients with stage III colon cancer, it is not yet known whether this benefit exists in populations underrepresented on clinical trials, particularly the elderly with medical comorbidity treated in the community. In this study, we ask the following: (1) What is the hazard of death associated with adjuvant 5-FU in the general population of elderly stage III colon cancer patients? (2) Does the hazard vary with patient age?

PATIENTS AND METHODS: In this prospective, nonrandomized, population-based cohort study of 3,357 elderly Medicare beneficiaries who had undergone resection of stage III colon cancer according to the Surveillance, Epidemiology, and End-Results registries, we use propensity score matching to compare the all-cause mortality of patients who received 5-FU to matched untreated patients.

RESULTS: 5-FU reduces the hazard of death by 27% (hazard ratio, 0.73; 95% confidence interval [CI], 0.65 to 0.82) across the 6 years of our data in a Cox model. At 5 years, 52.7% (95% CI, 49.6% to 55.6%) of the treated and 40.7% (95% CI, 38.1% to 43.4%) of the matched untreated are still alive. We find that these effects do not diminish with advancing patient age.

CONCLUSION: The survival benefit of adjuvant 5-FU that has been demonstrated in participants of RCTs is also evident in a population sample of elderly Medicare beneficiaries with stage III colon cancer treated in the community. Furthermore, this survival benefit does not appear to diminish with patient age. These findings support the continued use of adjuvant 5-FU in the general population of elderly patients with stage III colon cancer and suggest that oncologists in the community are practicing at a high level of effectiveness.
Recursive Partitioning Identifies Patients at High and Low Risk for Ipsilateral Tumor Recurrence After Breast-Conserving Surgery and Radiation
Authors: Freedman G. M. , Hanlon A. L. , Fowble B. L. , Anderson P. R. , Nicoloau N.
Published: September 2002

PURPOSE: Recursive partitioning analysis (RPA), a method of building decision trees of significant prognostic factors for outcome, was used to determine subgroups at significantly different risk for ipsilateral breast tumor recurrence (IBTR) in early-stage breast cancer.

PATIENTS AND METHODS: Nine hundred twelve women underwent breast-conserving surgery, axillary dissection, and radiation. Systemic therapy was chemotherapy with or without tamoxifen in 32%, tamoxifen in 27%, or none in 41%. RPA was used to create a decision tree according to predictive variables that classify patients by IBTR risk, and the Kaplan-Meier method was used to calculate 10-year risks. Median follow-up was 5.9 years.

RESULTS: Age was the first split in the partition tree. Patients more than 55 years old had a 4% 10-year IBTR, the only further division being use of tamoxifen or not (2% v 5%, P = .03). For patients ≤ 55 years old, extensive intraductal component (EIC) was the next significant split. For EIC-negative tumors, age ≤ 35 years and negative margins were associated with a 10-year IBTR of 3%; with close (≤ 2 mm) or positive margins, 34%. Patients 36 to 55 years old with estrogen receptor–positive tumors receiving tamoxifen had a risk of IBTR of 5%, but had a 20% risk without tamoxifen.

CONCLUSION: This RPA showed that age ≤ 55 versus more than 55 years was the most significant factor for IBTR. Patients ≤ 35 years old had a low risk of IBTR when tumors were EIC-negative with negative margins. EIC was an independent factor for IBTR for ages ≤ 55 years. Use of tamoxifen was the most significant factor for patients older than 55 years, but it resulted in a greater absolute decrease in risk of IBTR for patients 36 to 55 years old.
Prophylaxis of Radiation-Associated Mucositis in Conventionally Treated Patients With Head and Neck Cancer: A Double-Blind, Phase III, Randomized, Controlled Trial Evaluating the Clinical Efficacy of an Antimicrobial Lozenge Using a Validated Mucositis Scoring System
Authors: El-Sayed S. , Nabid A. , Shelley W. , Hay J. , Balogh J. , Gelinas M. , MacKenzie R. , Read N. , Berthelet E. , Lau H. , Epstein J. , Delvecchio P. , Ganguly P. K. , Wong F. , Burns P. , Tu D. , Pater J.
Published: September 2002

PURPOSE: Mucositis occurs in almost all patients treated with radiotherapy for head and neck cancer. The aim of this multicenter, double-blind, prospective, randomized trial was to evaluate the clinical efficacy of an economically viable antimicrobial lozenge (bacitracin, clotrimazole, and gentamicin [BcoG]) in the alleviation of radiation-induced mucositis in patients with head and neck cancer.

PATIENTS AND METHODS: One hundred thirty-seven eligible patients were randomized to treatment with either antimicrobial lozenge (69 patients) or placebo lozenge (68 patients). The primary end point of the study was the time to development of severe mucositis from the start of radiotherapy. Secondary end points included severity and duration of mucositis, pain measurement, radiation therapy interruption, and quality of life. Mucositis was scored using a validated mucositis scoring system.

RESULTS: Toxicity profiles were similar between the two arms of the study. The median time to development of severe mucositis from the start of radiotherapy was 3.61 weeks on BCoG and 3.96 weeks on placebo (P = .61). There were no statistically significant differences between the arms in the extent of severe mucositis as measured by physician, in oral toxicities as recorded by patients, or in radiotherapy delays.

CONCLUSION: This study was conducted on the basis of a pilot study that demonstrated the BCoG lozenge to be tolerable and microbiologically efficacious. A validated mucositis scoring system was used. However, in this group of patients treated with conventional radiotherapy, the lozenge did not impact significantly on the severity of mucositis. Whether such a lozenge would be beneficial in treatment situations where rate of severe mucositis is higher (ie, in patients treated with unconventional fractionation or with concomitant chemotherapy) is unknown.
Tyrosinase mRNA in Blood of Patients With Melanoma Treated With Adjuvant Interferon
Authors: Mellado Begoña , del Carmen Vela Maria , Colomer Dolors , Gutierrez Lorena , Castel Teresa , Quintó Llorenç , Fontanillas Montserrat , Reguart Noemi , Domingo-Domènech José M. , Montagut Clara , Estapé Jordi , Gascón Pedro ,   Melanoma Group
Published: September 2002

PURPOSE: To evaluate the clinical significance of the detection of circulating melanoma cells in patients treated with adjuvant interferon and to determine their potential value as a marker of interferon response.

PATIENTS AND METHODS: We prospectively analyzed 616 peripheral-blood samples from 120 melanoma patients with stage IIA (n = 33), IIB (n = 22), III (n = 50), or IV (surgically resected) (n = 15) disease receiving adjuvant interferon alfa-2b therapy. Tyrosinase mRNA was assayed by reverse transcriptase polymerase chain reaction (RT-PCR) as a marker of circulating melanoma cells before the start of interferon and every 2 to 3 months thereafter.

RESULTS: With a median follow-up time of 32.3 months (range, 7.1 to 77.5 months), 47 patients (39.8%) relapsed and 31 (26%) died. During adjuvant interferon treatment, 76 patients (64%) had undetected circulating melanoma cells and 44 patients (36%) had a positive RT-PCR result in at least one sample. Actuarial 5-year disease-free survival was 62% in patients with persistently negative RT-PCR during interferon treatment and 38% for patients with positive RT-PCR during interferon (P = .02). Actuarial 5-year overall survival was 75% and 50%, respectively (P = .03).

CONCLUSION: Patients with melanoma and tyrosinase mRNA detected in the blood during adjuvant interferon therapy had a worse prognosis compared with patients with undetected tyrosinase mRNA during treatment. Further investigation into the detection of circulating melanoma cells as a surrogate marker of response to adjuvant interferon therapy is warranted.
Nomogram for Overall Survival of Patients With Progressive Metastatic Prostate Cancer After Castration
Authors: Smaletz Oren , Scher Howard I. , Small Eric J. , Verbel David A. , McMillan Alex , Regan Kevin , Kelly W. Kevin , Kattan Michael W.
Published: September 2002

PURPOSE: To develop a pretreatment prognostic model for survival of patients with progressive metastatic prostate cancer after castration using parameters that are measured during routine clinical management.

PATIENTS AND METHODS: Pretreatment clinical and biochemical determinants from 409 patients enrolled onto 19 consecutive therapeutic protocols from June 1989 through January 2000 were evaluated. The factors selected were age, Karnofsky performance status (KPS), hemoglobin (HGB), prostate-specific antigen (PSA), lactate dehydrogenase (LDH), alkaline phosphatase (ALK), and albumin. These factors were combined in an accelerated failure time regression model to produce a nomogram to predict median, 1-year, and 2-year survival. The nomogram was validated internally and externally using data from a multicenter randomized trial of suramin plus hydrocortisone versus hydrocortisone alone.

RESULTS: The median survival of the entire group was 15.8 months (range, 0.9 to 77.8 months); 87% have died. In multivariable analysis, KPS, HGB, ALK, albumin, and LDH were significantly associated with survival (P < .05), whereas age and PSA were not. All seven factors were included in the nomogram. When applied to the external validation data set, the nomogram achieved a concordance index of 0.67. Calibration plots suggested that the nomogram was well calibrated for all predictions.

CONCLUSION: A nomogram derived from pretreatment parameters that are measured on a routine basis was constructed. It can be used to predict the median, 1-year, and 2-year survival of patients with progressive castrate metastatic disease with reasonable accuracy. The information is useful to assess prognosis, guide treatment selection, and design clinical trials.
Role of Nonmyeloablative Allogeneic Stem-Cell Transplantation After Failure of Autologous Transplantation in Patients With Lymphoproliferative Malignancies
Authors: Branson Katharine , Chopra Rajesh , Kottaridis Panagiotis D. , McQuaker Grant , Parker Anne , Schey Stephen , Chakraverty Ronjon K. , Craddock Charles , Milligan Donald W. , Pettengell Ruth , Marsh Judith C.W. , Linch David C. , Goldstone Anthony H. , Williams Catherine D. , Mackinnon Stephen
Published: September 2002

PURPOSE: Conventional allogeneic stem-cell transplantation (SCT) after a prior failed autograft is associated with a transplant-related mortality rate of 50% to 80%. The aim of the current study was to evaluate the safety and efficacy of sibling, HLA-matched, nonmyeloablative allogeneic SCT with donor lymphocyte infusion (DLI) in patients with lymphoid malignancy after failure of autologous SCT.

PATIENTS AND METHODS: A total of 38 patients with refractory, progressive, or relapsed disease after autologous SCT were entered onto this study. The conditioning regimen consisted of the humanized monoclonal antibody CAMPATH-1H, fludarabine, and melphalan. Fifteen of 35 assessable patients received DLI after SCT.

RESULTS: Sustained neutrophil engraftment was achieved in 37 recipients, and platelet engraftment was achieved in 35 patients. The estimated transplant-related mortality was 7.9% at day 100 and 20% at 14 months, the median duration of follow-up. Eight patients experienced grade I/II acute graft-versus-host disease (GVHD) after transplantation, but no grade III/IV GVHD was observed in this setting. However, grade III/IV GVHD occurred in seven patients who received DLI. The actuarial overall survival at 14 months was 53%, with a progression-free survival of 50%. DLI produced a further response in three of 15 recipients.

CONCLUSION: Nonmyeloablative allogeneic SCT after CAMPATH-1H–containing conditioning is a relatively safe option compared with conventional allogeneic transplantation for patients who have failed previous autologous SCT. The low incidence of early GVHD enabled the subsequent administration of DLI to improve further clinical responses in this poor-risk group of lymphoma and myeloma patients.
Biweekly Chemotherapy With Oxaliplatin, Irinotecan, Infusional Fluorouracil, and Leucovorin: A Pilot Study in Patients With Metastatic Colorectal Cancer
Authors: Falcone Alfredo , Masi Gianluca , Allegrini Giacomo , Danesi Romano , Pfanner Elisabetta , Brunetti Isa Maura , Di Paolo Antonello , Cupini Samanta , Del Tacca Mario , Conte Pierfranco
Published: September 2002

PURPOSE: To determine the feasibility, recommended doses, plasma pharmacokinetics, and antitumor activity of a biweekly chemotherapy regimen with oxaliplatin (L-OHP), irinotecan (CPT-11), infusional fluorouracil (5-FU), and leucovorin (LV) in metastatic colorectal cancer patients.

PATIENTS AND METHODS: Patients received CPT-11 followed by L-OHP and LV 200 mg/m2 and followed by 5-FU 3,800 mg/m2 as a 48-hour infusion, repeated every 2 weeks. In the first part of the study, an escalation of CPT-11 dose and/or a decrease of the L-OHP dose were planned. Once the recommended doses of CPT-11 and L-OHP were determined, all subsequent patients were treated at the recommended doses.

RESULTS: Forty-two patients entered the study. CPT-11 175 mg/m2 and L-OHP 100 mg/m2 in combination with LV 200 mg/m2 and 5-FU 3,800 mg/m2 could be administered with acceptable toxicities; 39 patients were treated at these dose levels. The pharmacokinetics parameters of the agents used and their metabolites did not seem to be influenced by the concomitant use of the other drugs. The most relevant toxicities were diarrhea and neutropenia, with 14% of patients experiencing one episode of febrile neutropenia. In five patients (11.9%) a complete and in 25 (59.5%) a partial response was demonstrated, for an objective response rate of 71.4% (95% confidence interval, 47% to 83%). In 11 patients (26%), a surgical resection of residual disease could be performed. Median progression-free and overall survival times were 10.4 and 26.5 months, respectively.

CONCLUSION: This biweekly regimen is feasible and has acceptable and manageable toxicities and no apparent relevant pharmacokinetics interactions. This combination is associated with a promising antitumor activity, time to progression, and survival. A phase III randomized trial in Italy planned by the Gruppo Oncologico Nord Ovest has just started.
Characterization of a Novel and Functional Human Prolactin Receptor Isoform (ΔS1PRLr) Containing Only One Extracellular Fibronectin-Like Domain
Authors: Kline J. Bradford , Rycyzyn Michael A. , Clevenger Charles V.
Published: September 2002

Prolactin (PRL)-dependent signaling occurs as the result of ligand-induced homodimerization of the PRL receptor (PRLr). To date, short, intermediate, and long human PRLr isoforms have been characterized. To investigate the expression of other possible human PRLr isoforms, RT-PCR was performed on mRNA isolated from the breast carcinoma cell line T47D. A 1.5-kb PCR fragment was isolated, subcloned, and sequenced. The PCR product exhibited a nucleotide sequence 100% homologous to the human long isoform except bp 71–373 were deleted, which code for the S1 motif of the extracellular domain. Therefore, this isoform was designated the ΔS1 PRLr. Northern analysis revealed variable ΔS1 PRLr mRNA expression in a variety of tissues. Transfection of Chinese hamster ovary cells with ΔS1 cDNA showed the isoform is expressed at the protein level on the cell surface with a molecular mass of approximately 70 kDa. Kinetic studies indicated the ΔS1 isoform bound ligand at a lower affinity than wild-type receptor. The ΔS1 PRLr was also shown to activate the proximal signaling molecule Jak2 upon addition of ligand to transfected cells, and, unlike the long PRLr, high concentrations of ligand did not function as a self-antagonist to signaling during intervals of PRL serum elevation, i.e. stress and pregnancy. Given its apparent widespread expression, this PRLr isoform may contribute to PRL action. Furthermore, the functionality of this receptor raises interesting questions regarding the minimal extracellular domain necessary for ligand-induced receptor signaling.
Identification of Indian Hedgehog as a Progesterone-Responsive Gene in the Murine Uterus
Authors: Takamoto Norio , Zhao Bihong , Tsai Sophia Y. , DeMayo Francesco J.
Published: September 2002

Progesterone (P4) plays a central role in normal uterine function, from embryo implantation in endometrium to establishment and maintenance of uterine quiescence during pregnancy in the myometrium. Considering its diverse physiological effects on female reproductive function, rather little is known about downstream events of P4 action. Recent progress in differential screening technologies facilitated identification of such inducible genes. We used uteri of wild-type and progesterone receptor null mutant mice as a starting material and screened for differentially expressed genes by medium-density cDNA expression array. Here, we report that the expression of the morphogen, Indian hedgehog (Ihh), is rapidly stimulated by P4 in the mouse uterus. The level of Ihh mRNA is induced within 3 h, after a single administration of P4 to ovariectomized mice. The induced Ihh mRNA and protein were localized to the luminal and glandular epithelial compartment of the endometrium. During pseudopregnancy, the Ihh mRNA level was transiently increased in the preimplantation period and d 3 and d 4 post coitum and then decreased rapidly at d 5 post coitum. Furthermore, the expression profile of patched-1, hedgehog interacting protein-1, and chicken ovalbumin upstream promoter-transcription factor II, genes known to be in the hedgehog signaling pathway in other tissues, followed the expression pattern of Ihh during the periimplantation period. Our results suggested that Ihh is regulated by P4, and the Ihh signaling axis may play a role in the preparation of the uterus for implantation during the periimplantation period.
Dopamine-D2S Receptor Inhibition of Calcium Influx, Adenylyl Cyclase, and Mitogen-Activated Protein Kinase in Pituitary Cells: Distinct Gα and Gβγ Requirements
Authors: Banihashemi Behzad , Albert Paul R.
Published: September 2002

The G protein specificity of multiple signaling pathways of the dopamine-D2S (short form) receptor was investigated in GH4ZR7 lactotroph cells. Activation of the dopamine-D2S receptor inhibited forskolin-induced cAMP production, reduced BayK8644- activated calcium influx, and blocked TRH-mediated p42/p44 MAPK phosphorylation. These actions were blocked by pretreatment with pertussis toxin (PTX), indicating mediation by Gi/o proteins. D2S stimulation also decreased TRH-induced MAPK/ERK kinase phosphorylation. TRH induced c-Raf but not B-Raf activation, and the D2S receptor inhibited both TRH-induced c-Raf and basal B-Raf kinase activity. After PTX treatment, D2S receptor signaling was rescued in cells stably transfected with individual PTX-insensitive Gα mutants. Inhibition of adenylyl cyclase was partly rescued by Gαi2 or Gαi3, but Gαo alone completely reconstituted D2S-mediated inhibition of BayK8644-induced L-type calcium channel activation. Gαo and Gαi3 were the main components involved in D2S-mediated p42/44 MAPK inhibition. In cells transfected with the carboxyl-terminal domain of G protein receptor kinase to inhibit Gβγ signaling, only D2S-mediated inhibition of calcium influx was blocked, but not inhibition of adenylyl cyclase or MAPK. These results indicate that the dopamine-D2S receptor couples to distinct Gi/o proteins, depending on the pathway addressed, and suggest a novel Gαi3/Gαo-dependent inhibition of MAPK mediated by c-Raf and B-Raf-dependent inhibition of MAPK/ERK kinase.