Neural HO-1/sterol interactions in vivo: implications for Alzheimer's disease.

BACKGROUND: Up-regulation of heme oxygenase-1 (HO-1) and altered cholesterol (CH) metabolism are characteristic of Alzheimer-diseased (AD) neural tissues. We previously provided evidence of significant HO-1/sterol interactions in vitro (cultured rat astroglia) and in post-mortem human AD brain (Religious Orders Study). METHODS: The current experiments were designed to further delineate these interactions in vivo by comparing the behavior of HO-1/sterol interactions in two mouse models; (1) a novel HO-1 transgenic mouse (GFAP.HMOX1) engineered to selectively express human HO-1 in the astrocytic compartment and (2) the previously described triple transgenic AD mouse (3xTg-AD). In samples of frontal cortex, total CH, CH precursors and relevant oxysterols were quantified by gas chromatography-mass spectrometry (GC-MS) and HO-1 protein expression was assessed by ELISA. The relationships of HO-1 expression to total CH, CH precursors and total oxysterols were determined for both mouse models using linear regression analysis. RESULTS: HO-1 expression is increased in GFAP.HMOX1 mice relative to wild type and in 11-12-month-old 3xTg-AD mice (with AD-like phenotype) relative to control mice and 5-6-month-old 3xTg-AD mice (no AD-like phenotype). Total oxysterols significantly decreased as HO-1 expression increased in GFAP.HMOX1 mice expressing high levels of HO-1, whereas total oxysterols increased as HO-1 expression increased in aged 3xTg-AD mice. Total CH and total CH precursors increased as HO-1 protein expression increased in 11-12-month-old 3xTg-AD mice relative to 5-6-month old 3xTg-AD mice. CONCLUSIONS: Our findings indicate a differential impact of HO-1 on patterns of brain sterol and redox homeostasis that is contingent on the presence or absence of AD-like neuropathology. These data provide fresh insight concerning the regulation of sterol homeostasis within the aging and degenerating CNS which may inform the development of novel therapeutic and preventive strategies for the management of AD and related conditions.

Surgery combined with controlled-release doxorubicin silk films as a treatment strategy in an orthotopic neuroblastoma mouse model.

BACKGROUND: Neuroblastoma tumour resection goal is maximal tumour removal. We hypothesise that combining surgery with sustained, local doxorubicin application can control tumour growth. METHODS: We injected human neuroblastoma cells into immunocompromised mouse adrenal gland. When KELLY cell-induced tumour volume was >300 mm(3), 80-90% of tumour was resected and treated as follows: instantaneous-release silk film with 100 µg doxorubicin (100IR), controlled-release film with 200 µg (200CR) over residual tumour bed; and 100 and 200 µg intravenous doxorubicin (100IV and 200IV). Tumour volume was measured and histology analysed. RESULTS: Orthotopic tumours formed with KELLY, SK-N-AS, IMR-32, SH-SY5Y cells. Tumours reached 1800±180 mm(3) after 28 days, 2200±290 mm(3) after 35 days, 1280±260 mm(3) after 63 days, and 1700±360 mm(3) after 84 days, respectively. At 3 days post KELLY tumour resection, tumour volumes were similar across all groups (P=0.6210). Tumour growth rate was similar in untreated vs control film, 100IV vs 100IR, and 100IV vs 200IV. There was significant difference in 100IR vs 200CR (P=0.0004) and 200IV vs 200CR (P=0.0003). Tumour growth with all doxorubicin groups was slower than that of control (P: <0.0001-0.0069). At the interface of the 200CR film and tumour, there was cellular necrosis, surrounded by apoptotic cells before reaching viable tumour cells. CONCLUSIONS: Combining surgical resection and sustained local doxorubicin treatment is effective in tumour control. Administering doxorubicin in a local, controlled manner is superior to giving an equivalent intravenous dose in tumour control.

Predictors of post-thrombotic syndrome in a population with a first deep vein thrombosis and no primary venous insufficiency.

BACKGROUND: Post-thrombotic syndrome (PTS) is the most frequent complication of deep vein thrombosis (DVT). Its diagnosis is based on clinical characteristics. However, symptoms and signs of PTS are non-specific, and could result from concomitant primary venous insufficiency (PVI) rather than DVT. This could bias evaluation of PTS. METHODS: Using data from the REVERSE multicenter study, we assessed risk factors for PTS in patients with a first unprovoked unilateral proximal DVT 5-7 months earlier who were free of clinically significant PVI (defined as absence of moderate or severe venous ectasia in the contralateral leg). RESULTS: Among the 328 patients considered, the prevalence of PTS was 27.1%. Obesity (odds ratio [OR] 2.6 [95% confidence interval (CI) 1.5-4.7]), mild contralateral venous ectasia (OR 2.2 [95% CI 1.1-4.3]), poor International Normalized Ratio (INR) control (OR per additional 1% of time with INR < 2 during anticoagulant treatment of 1.018 [95% CI 1.003-1.034]) and the presence of residual venous obstruction on ultrasound (OR 2.1 [95% CI 1.1-3.7]) significantly increased the risk for PTS in multivariable analyses. When we restricted our analysis to patients without any signs, even mild, of contralateral venous insufficiency (n = 244), the prevalence of PTS decreased slightly to 24.6%. Only obesity remained an independent predictor of PTS (OR 2.6 [95% CI 1.3-5.0]). Poor INR control and residual venous obstruction also increased the risk, but the results were no longer statistically significant (OR 1.017 [95% CI 0.999-1.035] and OR 1.7 [95% CI 0.9-3.3], respectively). CONCLUSIONS: After a first unprovoked proximal DVT, obese patients and patients with even mild PVI constitute a group at increased risk of developing PTS for whom particular attention should be paid with respect to PTS prevention. Careful monitoring of anticoagulant treatment may prevent PTS.

Comparison of the Villalta post-thrombotic syndrome score in the ipsilateral vs. contralateral leg after a first unprovoked deep vein thrombosis.

BACKGROUND: Post-thrombotic syndrome (PTS) is the most frequent complication of a deep vein thrombosis (DVT). International guidelines recommend assessing PTS with the Villalta scale, a clinical measure that incorporates venous symptoms and signs in the leg ipsilateral to a DVT. However, these signs and symptoms are not specific for PTS and their prevalence and relevance in the contralateral leg have not previously been studied. METHODS: Using data from the REVERSE prospective multicentre cohort study, we compared the Villalta total score and prevalence of venous signs and symptoms in the ipsilateral vs. contralateral leg in patients with a first, unilateral DVT 5 to 7 months previously. RESULTS: Among the 367 patients analyzed, the mean Villalta score was higher in the ipsilateral than in the contralateral leg (mean ± standard deviation [SD] 3.7 [3.4] vs. 1.9 [2.5], respectively; P<0.0001). Villalta scores in the ipsilateral and contralateral legs were strongly correlated (r=0.68; P<0.0001). Ipsilateral PTS (defined by a Villalta total score >4) was present in 31.6% (n=116) of patients. Among these, 39.7% (n=46) of patients had a Villalta score >4 in the contralateral leg, and the distribution of Villalta symptoms and signs components was similar between the legs. CONCLUSIONS: Villalta scores in the ipsilateral and contralateral legs are strongly correlated. Almost half of cases considered to be PTS might reflect pre-existing symptomatic chronic venous disease. Alternatively, patients with pre-existing chronic venous disease might be more prone to developing PTS after a DVT. Performing a bilateral assessment of Villalta scores at the acute phase of DVT could be of clinical interest from a diagnostic, prognostic and therapeutic point of view.

The risk of venous thrombosis, including cerebral vein thrombosis, among women with thrombophilia and oral contraceptive use: a meta-analysis.

Several small studies have reported an elevated risk of venous thrombosis (VT) with thrombophilia and oral contraceptive (OCP) use. We aimed to summarize the risk of VT among women with thrombophilia and OCP use and to assess the interaction between the 2 factors. We selected 15 studies that assessed the prevalence of OCP use and thrombophilia among reproductive-aged women. Odds ratios (ORs) were calculated for each study and pooled using the random effects model. We found an increased risk of VT among women with OCP use (pooled OR 3.0, 95% confidence interval [CI] 1.9-4.5) and with thrombophilia (pooled OR 4.5, CI 3.4-5.9), respectively. Heterogeneity was significant (I (2) >80%). Women with both thrombophilia and OCP use had a 14-fold risk of VT compared to healthy OCP nonusers (pooled OR 14.25, CI 6.2-32.8). Oral contraceptive use and thrombophilia similarly increase VT risk. Our study confirms an interaction between OCP use and thrombophilia.

Deviations between intra-operative navigation data and post-operative weight-bearing X-rays.

Several studies have shown that computer-navigated TKA reduces the rate of outliers. Thirty-one consecutive patients were operated on by the same surgeon using a computer assisted navigation system. Data collected by the system included the final mechanical axis of the extremity (HKA angle) and the coronal angle of the tibial and femoral implants. These same values were measured using CAD software on full weight-bearing long X-rays taken 6 weeks post-surgery. Deviations were observed when X-ray measurements were compared to intra-operative data collected from the navigation system. A statistically significant difference was found in the tibial cut (1.29 degrees +/- 1.35 degrees; p < 0.0001) and in the HKA (1.59 degrees +/- 2.36 degrees; p = 0.0007). Outliers of more than 3 degrees were observed in the coronal plane of the tibial implant in 9.6% of patients, in the coronal plane of the femoral implant in 6.4% of patients, and in the HKA angle of 29% of patients. Our results indicate that the use of navigation alone is insufficient to prevent outliers beyond an acceptable range of 3 degrees .

Reducing silica and dust exposures in construction during use of powered concrete-cutting hand tools: efficacy of local exhaust ventilation on hammer drills.

Concrete cutting in construction is a major source of exposure to respirable crystalline silica. To reduce exposures, local exhaust ventilation (LEV) may be integrated into the hand tools used in concrete cutting. Volunteers from the New England Laborers Training Center participated in a field study focused on the use of LEV on concrete-cutting hammer drills. A randomized block design field experiment employing four workers measured the efficacy of four hood-vacuum source combinations compared with no LEV in reducing dust and silica exposures. Using four-stage personal cascade impactors (Marple 294) to measure dust exposure, a total of 18 personal samples were collected. Reductions of over 80% in all three biologically relevant size fractions of dust (inhalable, thoracic, and respirable) were obtained by using any combination of hood and vacuum source. This study found that respirable dust concentrations were reduced from 3.77 mg/m(3) to a range of 0.242 to 0.370 mg/m(3); thoracic dust concentrations from 12.5 mg/m(3) to a range of 0.774 to 1.23 mg/m(3); and inhalable dust concentration from 47.2 mg/m(3) to a range of 2.13 to 6.09 mg/m(3). Silica concentrations were reduced from 0.308 mg/m(3) to a range of 0.006 to 0.028 mg/m(3) in the respirable size fraction, from 0.821 mg/m(3) to a range of 0.043 to 0.090 mg/m(3) in the thoracic size fraction, and from 2.71 mg/m(3) to a range of 0.124 to 0.403 mg/m(3) in the inhalable size fraction. Reductions in dust concentrations while using the four LEV systems were not statistically significantly different from each other.

Determinants of health-related quality of life during the 2 years following deep vein thrombosis.

BACKGROUND/OBJECTIVES: We prospectively measured change in quality of life (QOL) during the 2 years after a diagnosis of deep vein thrombosis (DVT) and evaluated determinants of QOL, including development of the post-thrombotic syndrome (PTS). PATIENTS/METHODS: Consecutive patients with acute DVT were recruited from 2001 to 2004 at eight hospitals in Canada. At study visits at baseline, and 1, 4, 8, 12 and 24 months, clinical data were collected, standardized PTS assessments were performed, and QOL questionnaires were self-completed. Generic QOL was measured using the Short-Form Health Survey-36 (SF-36) questionnaire. Venous disease-specific QOL was measured using the Venous Insufficiency Epidemiological and Economic Study (VEINES)-QOL/Sym questionnaire. The change in QOL scores over a 2-year follow-up was assessed. The influence of PTS and other characteristics on QOL at 2 years was evaluated using multivariable regression analyses. RESULTS: Among the 387 patients recruited, the average age was 56 years, two-thirds were outpatients, and 60% had proximal DVT. The cumulative incidence of PTS was 47%. On average, QOL scores improved during follow-up. However, patients who developed PTS had lower scores at all visits and significantly less improvement in QOL over time (P-values for PTS*time interaction were 0.001, 0.012, 0.014 and 0.006 for PCS, MCS, VEINES-QOL and VEINES-Sym). Multivariable regression analyses showed that PTS (P < 0.0001), age (P = 0.0009), proximal DVT (P = 0.01) and inpatient status (P = 0.04) independently predicted 2-year SF-36 PCS scores. PTS alone independently predicted 2-year VEINES-QOL (P < 0.0001) and VEINES-Sym (P < 0.0001) scores. CONCLUSIONS: Development of PTS is the principal determinant of health-related QOL 2 years after DVT. Our study provides prognostic information on patient-reported outcomes after DVT and emphasizes the need for effective prevention and treatment of the PTS.

Small fetal abdominal circumference in the second trimester and subsequent low maternal plasma glucose after a glucose challenge test is associated with the delivery of a small-for-gestational age neonate.

OBJECTIVES: To evaluate the predictive value of a combination of the 1 h 50-g glucose challenge test (GCT) and second-trimester ultrasound measurement of fetal abdominal circumference (AC) in identifying patients who will go on to deliver small-for-gestational age (SGA) neonates. The individual predictive power of these tests has been indicated by previous studies, but this study examines the combined use of these indicators in predicting SGA. METHODS: This retrospective cohort study included 576 consecutive patients with singleton gestations examined over a 3-year period. Patients' electronic medical records were abstracted to obtain the result of the GCT, the fetal AC measured by ultrasound examination between 18 and 22 weeks' gestation, and the birth weight. SGA and small AC were defined as birth weight or AC < 10(th) percentile for gestational age, according to published nomograms. A low GCT was defined as < 100 mg/dL. P < 0.05 was considered significant. RESULTS: The prevalence of SGA in the study population was 8.7% (50/576). The frequency of SGA neonates was significantly higher in patients with a low GCT (27/207) in the second trimester than in those with a normal GCT (23/369) (13% vs. 6.2%, P = 0.005). Similarly, the frequency of SGA neonates was higher among patients with fetal AC < 10(th) percentile than among those with a normal fetal AC on second-trimester ultrasound examination (17% vs. 8%, P = 0.08), although this difference did not reach statistical significance. Of interest, among patients with both a small fetal AC and a low GCT the incidence of SGA neonates was 32% (6/19), but there were no SGA neonates among those with a small AC and normal GCT (0/17) (P = 0.014). Among patients with a small fetal AC the sensitivity of using low GCT to predict subsequent delivery of a SGA neonate was 100%, with a specificity of 57%, positive predictive value 32% and negative predictive value 100%. CONCLUSIONS: Small AC on routine second-trimester anomaly sonogram should trigger a closer evaluation of maternal GCT. If the GCT is also low, more intensive surveillance for the possible development of a SGA infant is warranted.

Evidence of intrapartum hypoxia-ischemia is not present in the majority of cases of neonatal seizures.

OBJECTIVE: To determine the extent to which neonatal seizures are associated with intrapartum hypoxia-ischemia. METHODS: In this case-control study, all neonates diagnosed with seizures at a single institution from 1988 to 1999 were compared to a control group without seizures matched in a 2:1 fashion for gestational age at delivery, birth weight and mode of delivery. Data were abstracted from the maternal and neonatal charts. Parametric variables were compared using an independent samples t test, and non-parametric variables were compared using a Fisher exact test, with p < 0.05 being considered significant. RESULTS: There were 13 cases of neonatal seizures identified, of which one was chromosomally abnormal and excluded from further analysis. For the cases, the mean gestational age at delivery was 34.8 +/- 6.9 weeks, with four preterm and eight term deliveries. The mean birth weight for the cases was 2684 +/- 1369 g (range 590-4350 g). For both cases and controls, 83% were delivered vaginally and 17% by Cesarean section. For term neonates with seizures, the mean length of stay was 11.6 +/- 5.0 days, as compared to 2.5 +/- 0.9 days in the control group (p < 0.001). A 1-min Apgar score of < 7 was found in six of 12 (50%) cases and seven of 24 (29%) controls, and a 5-min Apgar score of < 7 was found in four of 12 (33%) cases and four of 24 (17%) controls (non-significant). In the controls, the mean base excess was -2.8 +/- 2.6 mEq/l, and the mean umbilical arterial pH was 7.28 +/- 0.09. In the case group, two infants born at 24 weeks did not have an umbilical arterial blood gas obtained; in the remaining cases, the mean base excess was -7.6 +/- 6.9 mEq/l (p = 0.02), and the mean cord pH was 7.17 +/- 0.23 (p = 0.065), with only three of ten (30%) having a pH < 7.00 (p = 0.02). CONCLUSION: Clinically significant acidosis was found in only 30% of neonates who developed seizures, and only one of 12 cases (8%) could possibly have met the criteria of the American College of Obstetricians and Gynecologists for neurological morbidity linked to intrapartum asphyxia. The majority of cases of neonatal seizures were not associated with evidence of intrapartum hypoxia-ischemia.

Interdependence of activation at rhaSR by cyclic AMP receptor protein, the RNA polymerase alpha subunit C-terminal domain, and rhaR.

The Escherichia coli rhaSR operon encodes two AraC family transcription activators, RhaS and RhaR, and is activated by RhaR in the presence of L-rhamnose. beta-Galactosidase assays of various rhaS-lacZ promoter fusions combined with mobility shift assays indicated that a cyclic AMP receptor protein (CRP) site located at -111.5 is also required for full activation of rhaSR expression. To address the mechanisms of activation by CRP and the RNA polymerase alpha-subunit C-terminal domain (alpha-CTD) at rhaSR, we tested the effects of alanine substitutions in CRP activating regions 1 and 2, overexpression of a truncated version of alpha (alpha-Delta235), and alanine substitutions throughout alpha-CTD. We found that DNA-contacting residues in alpha-CTD are required for full activation, and for simplicity, we discuss alpha-CTD as a third activator of rhaSR. CRP and RhaR could each partially activate transcription in the absence of the other two activators, and alpha-CTD was not capable of activation alone. In the case of CRP, this suggests that this activation involves neither an alpha-CTD interaction nor cooperative binding with RhaR, while in the case of RhaR, this suggests the likelihood of direct interactions with core RNA polymerase. We also found that CRP, RhaR, and alpha-CTD each have synergistic effects on activation by the others, suggesting direct or indirect interactions among all three. We have some evidence that the alpha-CTD-CRP and alpha-CTD-RhaR interactions might be direct. The magnitude of the synergistic effects was usually greater with just two activators than with all three, suggesting possible redundancies in the mechanisms of activation by CRP, alpha-CTD, and RhaR.

Roles of cyclic AMP receptor protein and the carboxyl-terminal domain of the alpha subunit in transcription activation of the Escherichia coli rhaBAD operon.

The Escherichia coli rhaBAD operon encodes the enzymes for catabolism of the sugar L-rhamnose. Full rhaBAD activation requires the AraC family activator RhaS (bound to a site that overlaps the -35 region of the promoter) and the cyclic AMP receptor protein (CRP; bound immediately upstream of RhaS at -92.5). We tested alanine substitutions in activating regions (AR) 1 and 2 of CRP for their effect on rhaBAD activation. Some, but not all, of the substitutions in both AR1 and AR2 resulted in approximately twofold defects in expression from rhaBAD promoter fusions. We also expressed a derivative of the alpha subunit of RNA polymerase deleted for the entire C-terminal domain (alpha-Delta235) and assayed expression from rhaBAD promoter fusions. The greatest defect (54-fold) occurred at a truncated promoter where RhaS was the only activator, while the defect at the full-length promoter (RhaS plus CRP) was smaller (13-fold). Analysis of a plasmid library expressing alanine substitutions at every residue in the carboxyl-terminal domain of the alpha subunit (alpha-CTD) identified 15 residues (mostly in the DNA-binding determinant) that were important at both the full-length and truncated promoters. Only one substitution was defective at the full-length but not the truncated promoter, and this residue was located in the DNA-binding determinant. Six substitutions were defective only at the promoter activated by RhaS alone, and these may define a protein-contacting determinant on alpha-CTD. Overall, our results suggest that CRP interaction with alpha-CTD may not be required for rhaBAD activation; however, alpha-CTD does contribute to full activation, probably through interactions with DNA and possibly RhaS.

Journal writing as a complementary therapy for reactive depression: a rehabilitation teaching program.

Brief, recurrent, reactive, or situational depression is a common and costly comorbidity that affects chronically ill patients and their family members. This article describes a program that teaches those individuals how to monitor and cope with symptoms of depression by writing daily in a journal. Twenty patients and family members attended teaching sessions at which videotaped scenes of other patients managing symptoms of depression were shown. After viewing the six scenes, participants wrote about their reactions to each scene and listed the emotions they had experienced that were similar to those shown in the tape. They were then asked to record daily for 4 months their emotions and reactions to situations and to also daily self-rate their levels of energy. They were also provided with a list of recommended activities in which to engage when they were depressed. Two psychiatric nurses evaluated the writings and concluded that the program was influential in helping patients and families overcome many emotionally draining reactions to adverse circumstances.

Design of validation studies for estimating the odds ratio of exposure-disease relationships when exposure is misclassified.

We compared several validation study designs for estimating the odds ratio of disease with misclassified exposure. We assumed that the outcome and misclassified binary covariate are available and that the error-free binary covariate is measured in a subsample, the validation sample. We considered designs in which the total size of the validation sample is fixed and the probability of selection into the validation sample may depend on outcome and misclassified covariate values. Design comparisons were conducted for rare and common disease scenarios, where the optimal design is the one that minimizes the variance of the maximum likelihood estimator of the true log odds ratio relating the outcome to the exposure of interest. Misclassification rates were assumed to be independent of the outcome. We used a sensitivity analysis to assess the effect of misspecifying the misclassification rates. Under the scenarios considered, our results suggested that a balanced design, which allocates equal numbers of validation subjects into each of the four outcome/mismeasured covariate categories, is preferable for its simplicity and good performance. A user-friendly Fortran program is available from the second author, which calculates the optimal sampling fractions for all designs considered and the efficiencies of these designs relative to the optimal hybrid design for any scenario of interest.

A strategy to reduce healthy worker effect in a cross-sectional study of asthma and metalworking fluids.

This report describes the reanalysis of a cross-sectional study of asthma in a large cohort of autoworkers with exposure to metalworking fluids (MWF). There is strong evidence from case reports, clinical studies, and medical surveillance data that exposure to MWF can cause asthma, yet no association was found in the original analysis. The central hypothesis of the reanalysis was that the absence of an association between asthma and MWF exposure was the result of bias caused by the self-selection of asthmatics out of exposed jobs. We addressed the potential job transfer bias by redefining exposure and disease status at the time of asthma onset, rather than at the time of the health survey. This permitted us to treat the cross-sectional study as if it were a historical cohort study, despite the fact that the population was a biased sample of the full cohort. This approach resulted in a significantly elevated incidence rate ratio of 3.2 (95% CI: 1.2-8.3) for synthetic MWF estimated in a Cox proportional hazards model. Although the cross-sectional design makes it impossible to document or control for differential selection out of the workforce, the approach described here provides a strategy for reducing the healthy-worker effect due to job transfer bias in cross-sectional studies.

Ten-year follow-up study of premenopausal women with metastatic breast cancer: an Eastern Cooperative Oncology Group study.

PURPOSE: To investigate the long-term survival of premenopausal women with previously untreated first recurrence or metastases of breast cancer entered on Eastern Cooperative Oncology Group (ECOG) study 2177 (EST 2177), which completed accrual in June 1983. MATERIALS AND METHODS: One hundred forty-seven premenopausal women with metastatic breast cancer were entered onto the study. Eighty-nine patients with estrogen receptor (ER)-positive and ER-unknown disease were randomized to receive cyclophosphamide (CTX), doxorubicin (ADR), and fluorouracil (FU) (CAF) or surgical oophorectomy plus CAF (O+CAF). Fifty-eight patients with known ER-negative disease were treated with CAF. Survival time was measured from the time of study entry. Randomization was stratified by performance status (PS), dominant metastatic site, and ER status. RESULTS: One hundred thirty patients were eligible. The median survival time of randomized patients was 35 months (90% confidence interval, 28.9 to 54.3), with 28% alive at 5 years. The overall median survival duration, including ER-negative patients, was 30 months. There was no significant difference in survival time between the randomized treatments (median, 42 months for O+CAF and 30 months for CAF). In models of survival time, age > or = 45 years and last menstruation within 1 month were associated with significantly longer survival (P < .004 for each). There were also three significant interactions with treatment (even after correction for multiple comparisons): age (P = .00009; O+CAF associated with longer survival in patients < 45 years, CAF associated with longer survival in patients > 45 years), PS (P = .002; O+CAF associated with consistently better survival in PS O patients), and disease-free interval (DFI). CONCLUSION: Long-term follow-up data of premenopausal women with metastatic breast cancer show a longer than expected median survival time at 2.5 years overall and close to 5 years for patients treated with O+CAF who were ER-positive or had a good PS.