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Anna E Barón

Publications and source records attributed to Anna E Barón.

At least 19 recordsLinked to original sources
PubMed2006

Non-linear random effects model for multivariate responses with missing data.

The use of random-effects models for the analysis of longitudinal data with missing responses has been discussed by several authors. In this paper, we extend the non-linear random-effects model for a single response to the case of multiple responses, allowing for arbitrary patterns of observed and missing data. Parameters for this model are estimated via the EM algorithm and by the first-order approximation available in SAS Proc NLMIXED. The set of equations for this estimation procedure is derived and these are appropriately modified to deal with missing data. The methodology is illustrated with an example using data coming from a study involving 161 pregnant women presenting to a private obstetrics clinic in Santiago, Chile.

Algorithms↗
PubMed2006

Epidermal growth factor receptor messenger RNA expression, gene dosage, and gefitinib sensitivity in non-small cell lung cancer.

PURPOSE: Epidermal growth factor receptor (EGFR) mRNA expression and EGFR gene dosage by quantitative PCR in tumor samples obtained from patients with gefitinib-treated non-small cell lung cancer were analyzed in order to determine the association with treatment outcome, clinical, and biological features [EGFR copy number by fluorescent in situ hybridization (FISH), EGFR tyrosine kinase mutations, and EGFR protein expression]. EXPERIMENTAL DESIGN: EGFR mRNA expression was measured by real-time quantitative reverse transcription-PCR in 64 patients, and EGFR gene dosage was analyzed by real-time quantitative PCR in 82 patients from paraffin-embedded specimens. RESULTS: EGFR mRNA expression was higher in responders to gefitinib as compared with nonresponders (P = 0.012). Patients with high EGFR mRNA expression (>5.01) had 43% response probability, whereas patients with low EGFR mRNA expression had 8% response probability (P = 0.006). Patients with high EGFR mRNA expression had longer median progression-free (5.3 versus 2.8 months, P = 0.028) but not overall survival (13.8 versus 10.9 months, P = 0.87). EGFR mRNA expression was higher in FISH-positive patients (P = 0.001) and in patients with positive EGFR immunostaining (P < 0.001) but not in patients with EGFR mutations (P = 0.19). EGFR gene dosage did not predict response (P = 0.54), progression-free (P = 0.73), or overall survival (P = 0.89). EGFR gene dosage was not associated with FISH positivity (P = 0.15), relative mRNA expression (P = 0.27), EGFR mutation status (P = 0.39), and EGFR protein expression (P = 0.35). CONCLUSION: EGFR mRNA expression is a predictive biomarker for response to gefitinib and to progression-free survival after gefitinib treatment. EGFR gene dosage is neither predictive for response nor progression-free nor overall survival.

Adult↗
PubMed2006

Human lung project: evaluating variance of gene expression in the human lung.

Nondiseased tissue is an important reference for microarray studies of pulmonary disease. We obtained 23 single lungs from multiorgan donors at time of procurement. Donors varied in age, sex, smoking history, and ethnicity. Lungs were dissected into upper and lower lobe peripheral sections for RNA extraction. Microarray analysis was performed using Affymetrix Hu-133 Plus 2.0 arrays. We observed that the relative variability of gene expression increased rapidly from technical (lowest), to regional, to population (highest). In addition, age and sex have measurable effects on gene expression. Gene expression variability is heterogeneously distributed among biologic categories. We conclude that gene expression variability is greater between individuals than within individuals and that population variability is the most important factor in the study design of microarray experiments of the human lung. Classes of genes with high population variability are biologically important and provide a novel perspective into lung physiology and pathobiology. Our study represents the first comprehensive analysis of nondiseased lung tissue. The generation of this robust dataset has important implications for the design and implementation of future comparative expression analysis with pulmonary disease states.

Adult↗
PubMed2006

Association between higher cumulative doses of recombinant erythropoietin and risk for retinopathy of prematurity.

BACKGROUND: Retinopathy of prematurity is a complication of premature birth that varies in its severity. The incidence and severity of retinopathy of prematurity at our perinatal center in a regional referral hospital changed substantially during 1995 to 1998 and presented us with an opportunity to examine whether there was a protective effect on risk of retinopathy associated with exposure to recombinant erythropoietin. METHODS: We undertook a retrospective cohort study. From January 1995 through December 1998, charts of infants weighing<1500 g, who were 30 weeks' gestation or less, and who were admitted and survived to the first eye examination at 6 weeks were reviewed. Primary and secondary risk factors were recorded from the first 6 weeks of life. Of the eligible infants, 327 of 390 (84%) had complete records and retinal examinations. The probability for progression of retinopathy was estimated by logistic regression multivariate analysis using the continuation-ratio model. RESULTS: The overall incidence of retinopathy of prematurity was 36%. Recombinant erythropoietin exposure, as total 6-week dose, was independently associated with an increased risk for progression of retinopathy, OR=1.27 per 500 units/kg (95%CI=1.04, 1.55, P=0.02). Postnatal day of recombinant erythropoietin initiation also was associated with retinopathy risk but did not reach conventional statistical significance, OR=1.07 (CI=1.00, 1.14, P=0.07). CONCLUSIONS: These findings identify an association between cumulative recombinant erythropoietin exposure, used to reduce blood transfusions in premature infants, and an increased risk for retinopathy of prematurity. The nonhematopoietic properties of erythropoietin may account for the above findings, however further evaluation with confirmation is required.

Disease Progression↗
PubMed2006

The relationship between patterns of alcohol use and mental and physical health disorders in two American Indian populations.

AIMS: First, define alcohol use categories among two reservation-based American Indian (AI) populations based on the relationship between alcohol consumption and dependence. Secondly, examine associations between the alcohol use categories and other indicators of health status. DESIGN, PARTICIPANTS AND MEASUREMENTS: Epidemiological data on 1287 AIs aged 18-57 years who consumed alcohol during the past year. CHAID tree analysis, a hierarchical partitioning method, was used to analyze alcohol quantity (highest number of drinks consumed during 1 day) and frequency (number of days drank during the past month) data to define quantity-frequency categories distinguished by differing rates of alcohol dependence. Multivariate analyses assessed relationships between the alcohol use categories thus identified and a number of health outcomes. FINDINGS: People who reported drinking 12 or more drinks during 1 day and more than 4 days a month had the highest prevalence of alcohol dependence. Among the males who drank > 18 drinks the prevalence was 42.12% and among females who drank 12 or more drinks, 44.58%. The prevalence among males who drank > 18 drinks yet drank less frequently was also high (24.06%). Although findings differed by gender, drinkers in the highest risk category for alcohol dependence were most likely to report drug use disorders, mood/anxiety disorders, alcohol-related physical disorders and lower quality of life. CONCLUSIONS: The quantity thresholds defined to identify AIs at highest risk for alcohol dependence in this study differed by gender and were higher than typically reported for non-AIs. They are consistent with previous findings regarding the pattern of high-quantity, low-frequency alcohol consumption among AIs residing on reservations.

Adolescent↗
PubMed2005

The effects of cetuximab alone and in combination with radiation and/or chemotherapy in lung cancer.

PURPOSE: The epidermal growth factor receptor (EGFR) overexpressed in approximately 80% of non-small cell lung cancers (NSCLC) is a target for novel therapeutics. Concurrent chemoradiation is the current standard of care for treatment of patients with locally advanced NSCLC. However, < 20% of patients remain disease-free at 5 years despite this aggressive treatment. Cetuximab is a humanized monoclonal antibody that recognizes the human EGFR, and in previous studies, inhibited the growth of EGFR-expressing human cancer cell lines. In this report, we investigated the cellular and molecular effects of cetuximab alone and in combination with radiation and/or chemotherapy in human NSCLC cell lines with varying levels of EGFR overexpression in vitro and in vivo. EXPERIMENTAL DESIGN: We evaluated the EGFR status of a panel of human NSCLC cancer cell lines by immunohistochemistry and flow cytometry. We then evaluated cetuximab effects on growth, cell cycle distribution, and downstream intracellular signaling molecules in this panel of NSCLC cancer cell lines. NSCLC cell lines were treated with cetuximab alone or in combination with radiation, chemotherapy, or chemoradiation to determine the cooperative effects of cetuximab both in vitro and in vivo in athymic nude mice bearing NSCLC xenografts. RESULTS: Cetuximab alone inhibited the in vitro growth of some but not all EGFR-expressing NSCLC cell lines in a dose-dependent manner. Flow cytometric analysis of cell cycle distribution after 24 hours of cetuximab treatment revealed a shift into the G(0)/G(1) phase of the cell cycle in cetuximab-sensitive EGFR-expressing cell lines and at concentrations that were growth-inhibitory. There were no cell cycle changes in the EGFR-negative cell lines. After 4 hours of exposure, cetuximab reduced epidermal growth factor (EGF)-induced phosphorylation of EGFR (pEGFR) and HER-2 (pHER2) in cetuximab-sensitive cell lines but not in cetuximab-resistant cell lines. Cetuximab reduced EGF-induced phosphorylation of extracellular signal-regulated kinase-1/2 (pERK) in all EGFR-expressing cell lines. In the absence of EGF, cetuximab alone increased the level of pEGFR and pHER2 above that seen in untreated control cells in both sensitive and resistant cell lines that were EGFR- and HER2-positive, but not in EGFR- or HER2-negative lines. Despite the cetuximab-induced increase in phosphorylation of EGFR and HER2, peak EGF-induced levels of pEGFR and pHER2 were reduced by cetuximab in the cetuximab-sensitive lines but not in the resistant lines. Cooperative (combination index values < 1.0) growth inhibitory effects were observed in vitro combination assays with cetuximab and radiation only in cetuximab-sensitive NSCLC cell lines. A lack of cooperation was seen in cetuximab-insensitive NSCLC cell lines. Similar findings were observed with in vitro combination studies of cetuximab plus cisplatin or paclitaxel. In nude mice bearing EGFR-expressing, cetuximab-sensitive, NSCLC cell line xenografts, cetuximab plus radiation induced a marked improvement in tumor growth inhibition over either agent alone. The growth inhibitory effects of cetuximab-radiation were similar to the growth inhibitory effects of concurrent chemoradiation. Triple combination therapy of cetuximab and chemoradiation yielded a nonsignificant advantage in tumor growth control over doublet combinations (cetuximab and radiation or chemoradiation) in vivo. CONCLUSIONS: Similar results in tumor growth inhibition observed in mice treated with cetuximab-radiation and cisplatin-radiation provide a rationale for the clinical investigation of cetuximab with concurrent radiation in selected patients with locally advanced NSCLC. Local tumor control and treatment toxicity should be evaluated between cetuximab-radiation and chemoradiation regimens. Proper patient selection will be critical to the success of such trials and further studies are needed to identify optimal patient selection criteria.

Animals↗
PubMed2005

Phase I and pharmacokinetic study of docetaxel combined with melphalan and carboplatin, with autologous hematopoietic progenitor cell support, in patients with advanced refractory malignancies.

The purpose of this study was to define the maximal tolerated dose (MTD), extramedullary toxicities, and pharmacokinetics of docetaxel combined with high-dose melphalan and carboplatin with autologous hematopoietic progenitor cell support. Fifty-nine patients with advanced refractory malignancy (32 breast cancer, 10 non-Hodgkin lymphoma, 6 germ cell tumors, 4 Hodgkin disease, 4 ovarian cancer, 2 sarcoma, and 1 unknown primary adenocarcinoma) with a median of 3 prior chemotherapy regimens and a median of 3 organs involved were enrolled. Treatment included docetaxel (150-550 mg/m2 infused over 2 hours on day -6), melphalan (150-165 mg/m2 infused over 15 minutes from day -5 to -3), and carboplatin (1000-1300 mg/m2 as a 72-hour continuous infusion from day -5). Five patients died from direct regimen-related organ toxicity (2 capillary leak syndrome, 2 enterocolitis, and 1 hepatic toxicity), and 1 additional patient died from pulmonary aspergillosis. The docetaxel MTD was defined as 400 mg/m 2 , combined with melphalan (150 mg/m2 ) and carboplatin (1000 mg/m2 ). The MTD cohort was expanded to enroll a total of 26 patients, 1 of whom died from toxic enterocolitis. The remaining 25 patients presented the following extramedullary toxicity profile, which was manageable and largely reversible: stomatitis, myoarthralgias, peripheral neuropathy, gastrointestinal and cutaneous toxicities, and syndrome of inappropriate antidiuretic hormone secretion. Docetaxel exhibited linear pharmacokinetics in the dose range tested (150-550 mg/m2 ). Pharmacodynamic correlations were noted between the docetaxel area under the curve and peripheral neuropathy or stomatitis. The response rate among 38 patients with measurable disease was 95%, with 47% complete responses. At a median follow-up of 26 months (range, 7-72 months), the 3-year event-free survival and overall survival were 26% and 36%, respectively. In conclusion, a 4-fold dose escalation of docetaxel, combined with melphalan and carboplatin, is feasible with autologous hematopoietic progenitor cell support. The notable activity of this regimen in treatment-refractory patients warrants its further evaluation.

Adolescent↗
PubMed2005

Evaluating ELISPOT summary measures with criteria for obtaining reliable estimates.

The ELISPOT assay is a commonly used technique for quantifying the occurrence of T lymphocyte cells secreting a cytokine after stimulation with an antigen or peptide. The assay endpoint, the number of spot-forming cells (SFC) at a specific concentration of effector cells, is typically estimated using either a simple arithmetic mean or the predicted value from a linear regression model. We compare statistical modeling approaches for summarizing these assays using data from the Pediatric AIDS Clinical Trial Group (PACTG) study 299. A simulation study was conducted to compare methods under controlled conditions. Assuming the optimal effector cell concentration is known, we demonstrate that the simple mean is appropriate if assays are conducted at the same concentration for all samples. Normalizing simple means to a summary concentration using results from a range of concentrations is not valid. A random effects or mixed model is superior to the simple mean when a large within-assay (subject) variance relative to between-subject variance exists. When assays are conducted over a range of effector cell concentrations for each individual, the theoretical linearity assumption of the regression model is often violated and can result in biased estimates. In this case, nonlinear models provide more accurate estimation. Collecting data over a range of concentrations allows reassessment of the optimal cell concentration after the data are generated.

Computer Simulation↗
PubMed2005

Retrospective clinicopathologic correlation of gross tumor size of hepatocellular carcinoma: implications for stereotactic body radiotherapy.

PURPOSE: To determine the degree of correlation between radiographic size and true gross pathologic size for subjects with primary hepatocellular carcinoma (HCC). METHODS AND MATERIALS: This analysis included 18 patients with 27 tumors who underwent either partial hepatectomy or orthotopic liver transplantation for HCC at the University of Colorado Hospital between 1997 and 2002. Preoperative imaging was performed using computed tomography (CT) or magnetic resonance imaging (MRI). After surgical resection the size of each tumor on gross pathologic examination was recorded. The maximal measurement in one dimension on axial imaging and pathologic examination was extracted for statistical analysis. The clinical and pathologic sizes were compared using a percent size difference (%Deltasize) as an end point for each patient. A regression analysis was applied to study the association between pathologic and clinical size. RESULTS: The median radiographic size was 2.90 cm (range 1.2-4.9). The median pathologic size was 2.50 cm (range 1-4.8). The radiographic size was larger than or equal to the pathologic size in 22/27 tumors (81%) and smaller in 5/27 (19%) tumors. The median %Deltasize was 17.5% (range -20-144%). Overall, the radiographic and pathologic sizes were positively correlated (r = 0.8). This correlation was not affected by choice of imaging modality (CT versus MRI, P = 0.71) or time of preoperative imaging (0-4 weeks versus 4-8 weeks before surgery, P = 0.61). CONCLUSIONS: Our study shows that in most instances (81%), imaging by CT or MRI overestimates true gross pathologic size of HCC. Nineteen percent of tumors appeared smaller on preoperative imaging than on the final pathologic specimen. Radiation therapy utilizing a 0.5 or 1.0 cm margin around the radiographic tumor would have encompassed the gross pathologic tumor in 93% and 100% of cases, respectively.

Carcinoma, Hepatocellular↗
PubMed2004

Phase II feasibility and pharmacokinetic study of concurrent administration of trastuzumab and high-dose chemotherapy in advanced HER2+ breast cancer.

PURPOSE: To evaluate the safety of concurrent treatment with trastuzumab and high-dose chemotherapy (HDC), using cyclophosphamide, cisplatin, and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), with autologous hematopoietic progenitor cells support, in patients with HER2+ advanced breast cancer. EXPERIMENTAL DESIGN: Patients with HER2-overexpressing high-risk primary breast cancer (HRPBC; defined as > or =4 involved nodes or inflammatory disease), or metastatic breast cancer (MBC) were eligible. Treatment consisted of a loading dose of trastuzumab at 4 mg/kg (day -5), HDC (days -5 to -2), autologous hematopoietic progenitor cells infusion on day 0, and weekly maintenance trastuzumab (2 mg/kg) from day +1 (minimum of 9 doses). Cardiac monitoring included serial left ventricular ejection fraction measurements before treatment and on days +20 and +65. RESULTS: Thirty-three patients were prospectively enrolled (13 HRPBC, 20 MBC). Toxicity seemed similar to that expected with this HDC regimen alone. Neutrophils and platelets engrafted promptly. There were no cases of grade 4 or 5 toxicity. One patient experienced symptomatic grade 3 acute cardiac failure on day -4, responsive to treatment. Trastuzumab did not alter the pharmacokinetics of HDC. Eleven of twelve MBC patients with measurable disease (nine of them refractory to previous chemotherapy) experienced an objective response (9 complete and 2 partial responses). At median follow-up of 34 (13-58) months, all HRPBC patients remain alive and free of disease; the MBC group has event-free survival and overall survival rates of 45 and 70%, respectively. CONCLUSIONS: Incorporation of trastuzumab into HDC (cyclophosphamide, cisplatin, and BCNU) is feasible, with no apparent increased toxicity or pharmacokinetic interactions.

Adult↗
PubMed2004

Epidermal growth factor receptor and cyclin D1 are independently amplified and overexpressed in esophageal squamous cell carcinoma.

PURPOSE: To assess the status of EGFR, HER-2, and CCND1 at the gene and protein levels in esophageal squamous cell carcinoma. METHODS: Dual-color FISH assays were performed using DNA probes for EGFR/CEP 7, HER-2/CEP 17, and CCND1/CEP 11. The respective proteins, furthermore, was assessed in IHC assays and correlated with patient and tumor characteristics. RESULTS: From 55 ESCCs, 8 (15%) tumors showed gene amplification and 20 (36%) had gene overrepresentation (balanced gene and chromosome 7 polysomy) for EGFR. High-level protein expression was frequent (49%), positively correlated with gene copy numbers (kappa=0.4), and associated with well-differentiated histology (p=0.02). For HER-2, gene amplification was detected in a single tumor (2%) and protein overexpression was rare (9%). CCND1 gene was amplified in 23 (42%) tumors; likewise, CCND1 protein overexpression was common (58%) and prevailed in gene overrepresentation or amplification. Only 1 patient showed gene amplification for both EGFR and CCND1. Survival was not associated with EGFR or CCND1 gene/protein status, whereas negative patients for HER-2 protein had a better survival than positive patients (p=0.04). CONCLUSIONS: Frequent overexpression and gene amplification of EGFR and CCND1 make these molecules and their pathways potential therapeutic targets for ESCC. In addition, EGFR and CCND1 appeared to be independently altered suggesting alternative mechanisms for pathway activation. Therapeutic agents targeting these molecules are urged to be tested in clinical trials and comprehensive biological analyses should be included to properly interpret the outcome.

Aged↗
PubMed2004

Seroepidemiology of infection with human papillomavirus 16, in men and women attending sexually transmitted disease clinics in the United States.

BACKGROUND: The study sought to characterize the seroprevalence, seropersistence, and seroincidence of human papillomavirus (HPV)-16 antibody, as well as the behavioral risk factors for HPV-16 seropositivity. METHODS: Serologic data at baseline and at 6- and 12-month follow-up visits were used to examine the seroprevalence, seropersistence, and seroincidence of HPV-16 antibody in 1595 patients attending United States clinics treating sexually transmitted disease. Testing for antibody to HPV-16 was performed by capture enzyme-linked immunosorbent assay (ELISA) using viruslike particles. RESULTS: The seroprevalence of HPV-16 antibody was 24.5% overall and was higher in women than in men (30.2% vs. 18.7%, respectively). In those who were HPV-16 seropositive at baseline, antibody response persisted to 12 months in 72.5% of women and in 45.6% of men. The seroincidence of HPV-16 antibody was 20.2/100 person-years (py) overall, 25.4/100 py in women, and 15.7/100 py in men. In multivariate analysis, the seroprevalence of HPV-16 antibody was significantly associated with female sex, age >20 years, and the number of episodes of sex with occasional partners during the preceding 3 months, whereas the seroincidence of HPV-16 antibody was significantly associated with female sex, age >20 years, baseline negative ELISA result greater than the median value, and the number of episodes of unprotected sex with occasional partners during the preceding 3 months. CONCLUSION: Sex- and age-related differences in both the seropositivity and seroincidence of HPV-16 antibody persisted after adjustment for behavioral and sociodemographic risk factors, and behavioral risk factors during the preceding 3 months were stronger predictors of the seroprevalence and seroincidence of HPV-16 antibody than was lifetime sexual behavior.

Adolescent↗
PubMed2004

Lung cancer and internal lung doses among plutonium workers at the Rocky Flats Plant: a case-control study.

The authors conducted a nested case-control study of the association between lung cancer mortality and cumulative internal lung doses among a cohort of workers employed at the Rocky Flats Plant in Colorado from 1951 to 1989. Cases (n = 180) were individually matched with controls (n = 720) on age, sex, and birth year. Annual doses to the lung from plutonium, americium, and uranium isotopes were calculated for each worker with an internal dosimetry model. Lung cancer risk was elevated among workers with cumulative internal lung doses of more than 400 mSv in several different analytical models. The dose-response relation was not consistent at high doses. Restricting analysis to those employed for 15-25 years produced a statistically significant linear trend with dose (chi-square = 67.2, p < 0.001), suggesting a strong healthy worker survivor effect. The association between age at first internal lung dose and lung cancer mortality was statistically significant (odds ratio = 1.05, 95% confidence interval: 1.01, 1.10). No associations were found between lung cancer mortality and cumulative external penetrating radiation dose or cumulative exposures to asbestos, beryllium, hexavalent chromium, or nickel.

Adult↗
PubMed2004

Challenges in operationalizing the DSM-IV clinical significance criterion.

BACKGROUND: An explicit clinical significance (CS) criterion was added to many DSM-IV diagnoses in an attempt to more closely approximate the clinical diagnostic process and reduce the proportion of false positives in epidemiological studies. The American Indian Service Utilization, Psychiatric Epidemiology, Risk and Protective Factors Project (AI-SUPERPFP) offered a unique opportunity to examine the success of this effort. OBJECTIVE: To determine the impact of distress, impairment, and help-seeking reported in a lay structured interview on concordance with a clinical reappraisal. Further, to test the efficacy of 5 operationalizations of CS on the concordance and prevalence of DSM-IV lifetime disorders. DESIGN: Completed between 1997 and 2000, a cross-sectional probability sample survey with clinical reappraisal of approximately 10% of participants. SETTING: General community. PARTICIPANTS: A population-based sample of 3084 members of 2 American Indian tribal groups, who were between the ages of 15 and 54 years and resided on or near their home reservations, were randomly sampled from the tribal rolls and participated in structured psychiatric interviews. Clinical reappraisals were conducted with approximately 10% of the lay-interview participants. The response rate for the lay interview was 75%, and for the clinical reappraisal it was 72%. MAIN OUTCOMES MEASURES: The AI-SUPERPFP Composite International Diagnostic Interview (CIDI), a culturally adapted version of the CIDI, University of Michigan version. Adapted to assess DSM-IV diagnoses, questions assessing the CS criterion were inserted in all diagnostic modules. The Structured Clinical Interview for DSM-III-R (SCID) was used in the clinical reappraisal. RESULTS: Most participants who qualified as having AI-SUPERPFP CIDI lifetime disorders reported at least moderate levels of distress or impairment. Evidence of increased concordance between the CIDI and the SCID was lacking when more restrictive operationalizations of CS were used; indeed, the CIDI was very likely to underdiagnose disorders compared with the SCID (false negatives). Concomitantly, the CS operationalizations affected prevalence rates dramatically. CONCLUSION: The CS criterion, at least as operationalized to date, demonstrates little effectiveness in increasing the validity of diagnoses using lay-administered structured interviews.

Algorithms↗
PubMed2004

Prognostic significance of occult tumor cells in the apheresis products of patients with advanced breast cancer receiving high-dose chemotherapy and autologous hematopoietic progenitor cell support.

We prospectively evaluated the prognostic significance of occult tumor cells (OTCs) contaminating the peripheral blood progenitor cell apheresis products of patients with advanced breast cancer receiving high-dose chemotherapy. Immunocytochemistry of peripheral blood progenitor cells was performed in 242 patients with high-risk primary breast cancer (HRPBC) and in 111 patients with metastatic breast cancer (MBC). OTCs were detected in 6.6% of HRPBC patients and in 16.2% of MBC patients (P = .005). In HRPBC, OTCs correlated with worse prognostic scores and larger tumor sizes, but not with axillary nodal status, hormone receptors, or HER2. In the MBC group, OTCs correlated with bone marrow involvement and with disease status at transplantation. The number of apheresis procedures was not associated with the risk of contamination. In HRPBC patients, at a median follow-up of 7 years (range, 1.5-11 years), the presence of OTCs correlated with worse event-free survival (P = .007) and overall survival (P = .002). In the MBC group, OTCs correlated with worse event-free survival (P = .04), but not overall survival (P = .2). In multivariate analyses, the presence of OTCs had an independent adverse effect on outcome in HRPBC, but not MBC. Our observations imply a direct role of OTCs in posttransplantation relapse in HRPBC.

Adult↗
PubMed2004

American Indian substance use: the hazards for substance use initiation and progression for adolescents aged 14 to 20 years.

OBJECTIVE: To describe the risks and risk factors for substance use initiation and progression among a large sample of American Indian (AI) adolescents. METHOD: Data came from surveys completed by 2,356 AI adolescents aged 14 to 20 years who participated in two or more consecutive waves of a longitudinal study between 1993 and 1996 (response rate 74%). Discrete-time survival analysis was used to describe the risks and risk factors for substance use initiation and progression. RESULTS: The risk for initiating use of any substance accelerated in early adolescence and peaked at age 18. The risk for progression from use of alcohol, marijuana, and/or inhalants to the use of other illicit drugs (e.g., cocaine) increased over the first 4.5 years after initiating substance use, then diminished in subsequent years. The risk of substance use initiation and progression varied across the four participating communities and by season of the year. Compared to adolescents who initiated substance use with alcohol only, adolescents who initiated substance use with marijuana or inhalants were more likely to progress to use other illicit drugs. CONCLUSIONS: Prevention programs for AI communities should be designed to address these community, age, and seasonal variations in the risks for substance use initiation and progression.

Adolescent↗
PubMed2003

Epidermal growth factor receptor in non-small-cell lung carcinomas: correlation between gene copy number and protein expression and impact on prognosis.

PURPOSE: The epidermal growth factor receptor (EGFR) is frequently overexpressed in non-small-cell lung carcinoma (NSCLC), and EGFR inhibitors are promising new therapeutic agents. The molecular mechanisms responsible for EGFR overexpression are poorly understood. MATERIALS AND METHODS: Gene copy number and protein status of EGFR were investigated in microarrayed tumors from 183 NSCLC patients, including squamous cell carcinoma (SCC; 89 patients) and non-SCC (94 patients) histologies. Protein expression was assessed by immunohistochemistry on a scale from 0 to 400 (percentage of positive cells x staining intensity). Gene and chromosome 7 copy numbers were identified by fluorescent in situ hybridization (FISH). RESULTS: EGFR protein overexpression was observed in 62% of the NSCLC (25% scored 201 to 300; 37% scored 301 to 400), more frequently in SCC than non-SCC (82% v 44%; P <.001), and in 80% of the bronchioloalveolar carcinomas. The prevalent FISH patterns were balanced disomy (40%) and trisomy (38%) for EGFR gene and chromosome 7 (40%), whereas balanced polysomy was seen in 13% and gene amplification was seen in 9% of the patients. Gene copy number correlated with protein expression (r = 0.4; P <.001). EGFR overexpression or high gene copy numbers had no significant influence on prognosis. CONCLUSION: EGFR overexpression is frequent in NSCLC, is most prominent in SCC, and correlates with increased gene copy number per cell. High gene copy numbers per cell showed a trend toward poor prognosis. It will be important to evaluate EGFR gene and EGFR protein status and signal protein expression to properly interpret future clinical trials using EGFR inhibitors.

Adenocarcinoma, Bronchiolo-Alveolar↗