Reproductive factors and subtypes of breast cancer defined by hormone receptor and histology.

Reproductive factors are associated with reduced risk of breast cancer, but less is known about whether there is differential protection against subtypes of breast cancer. Assuming reproductive factors act through hormonal mechanisms they should protect predominantly against cancers expressing oestrogen (ER) and progesterone (PR) receptors. We examined the effect of reproductive factors on subgroups of tumours defined by hormone receptor status as well as histology using data from the NIHCD Women's Contraceptive and Reproductive Experiences (CARE) Study, a multicenter case-control study of breast cancer. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) as measures of relative risk using multivariate unconditional logistic regression methods. Multiparity and early age at first birth were associated with reduced relative risk of ER + PR + tumours (P for trend=0.0001 and 0.01, respectively), but not of ER - PR - tumours (P for trend=0.27 and 0.85), whereas duration of breastfeeding was associated with lower relative risk of both receptor-positive (P for trend=0.0002) and receptor-negative tumours (P=0.0004). Our results were consistent across subgroups of women based on age and ethnicity. We found few significant differences by histologic subtype, although the strongest protective effect of multiparity was seen for mixed ductolobular tumours. Our results indicate that parity and age at first birth are associated with reduced risk of receptor-positive tumours only, while lactation is associated with reduced risk of both receptor-positive and -negative tumours. This suggests that parity and lactation act through different mechanisms. This study also suggests that reproductive factors have similar protective effects on breast tumours of lobular and ductal origin.

Development and validation of a telephone questionnaire to characterize lymphedema in women treated for breast cancer.

BACKGROUND AND PURPOSE: Accurate and economical characterization of lymphedema is needed for population-based studies of incidence and risk. The purpose of this study was to develop and validate a telephone questionnaire for characterizing lymphedema. SUBJECTS: Forty-three women who were treated previously for breast cancer and who were recruited from physical therapy practices and a cancer support organization were studied. METHODS: Questionnaire assessment of the presence and degree of lymphedema was compared with physical therapists' diagnoses, based primarily on circumferential measurements. Twenty-five of the 43 subjects were measured independently by 2 physical therapists to assess interobserver agreement. RESULTS: Interobserver agreement on clinical assessments of the presence and degree of lymphedema was high (20/25, weighted kappa=.80); all of the disagreements were between judgments of whether there was no lymphedema or mild lymphedema. For the diagnosis of at least moderate lymphedema (differential in the circumferences of the upper extremities greater than 2 cm), sensitivity of the questionnaire varied from 0.86 to 0.92 and specificity was 0.90. However, sensitivity (varying from 0.93 to 0.96) was higher than specificity (varying from 0.69 to 0.75) for the diagnosis of any lymphedema. DISCUSSION AND CONCLUSION: A few straightforward questions exhibited excellent agreement with physical therapists' assessments for identifying at least moderate lymphedema.

Identification of transforming growth factor-beta1-binding protein overexpression in carmustine-resistant glioma cells by MRNA differential display.

BACKGROUND: The authors previously demonstrated the presence of cells in primary human malignant gliomas that intrinsically are resistant to carmustine (BCNU). Numerous studies have identified mechanisms of therapy resistance in these cells; however, the authors' work and that of others suggest that additional mechanisms of resistance exist. METHODS: The authors identified a glioma cell line that lacks detectable methylguanine methyltransferase expression and does not alter its expression of glutathione-S-transferase-pi in response to BCNU chemotherapy. This cell line was used in mRNA differential display experiments to identify genes involved in what to the authors' knowledge were previously undescribed mechanisms of resistance. RESULTS: The overexpression of the gene encoding the transforming growth factor latency binding protein was demonstrated in glioma cells selected for resistance to BCNU, compared with their parental unselected cells. CONCLUSIONS: Transforming growth factor-beta1 has pleiotropic functions in transformed and normal cells. Although activation of TGF-beta1 does not appear to be a causative factor in BCNU resistance in the current study, it may be involved in the growth of these resistant cells.

Altered gene expression in human astrocytoma cells selected for migration: I. Thromboxane synthase.

Human glioma cells from a long-term cell line were selected for their ability to migrate on a glioma-derived extracellular matrix. When tested over 28 serial passages, the migration-selected strain showed a genetically stable, enhanced migration rate compared with the parental cells. Proliferation studies demonstrated that the growth rate of migration-selected cells was slightly arrested. Both the selected strain and the parental culture showed anchorage-independent growth in soft agarose and were tumorigenic in athymic mice. Using molecular genetic strategies' display to isolate genes expressed differentially between the 2 populations, a 300-bp sequence homologous to thromboxane synthase was upregulated in the migration-selected cells relative to the parental cells. Expression levels of thromboxane synthase were highly elevated in the migration-selected cells when assessed by RNAse-protection assay and by flow cytometry. Two specific thromboxane synthase inhibitors, Dazmegrel and Furegrelate, reduced the migration rate of the migration-selected cells to a rate equal to or less than the rate exhibited by the parental cells, respectively. The inhibitors effect on the parental cells was inconsequential. These results suggest that aberrations in the regulation of thromboxane synthase expression or activity may influence the motility of human glioma cells.

Expression of a receptor protein tyrosine phosphatase in human glial tumors.

We have analyzed expression of a receptor protein tyrosine phosphatase (RPTPzeta/beta) in tissue samples from 23 human gliomas. Using the reverse transcription-polymerase chain reaction (RT-PCR) technique, we assayed for the presence or absence of mRNA transcripts encoding the intact receptor and 2 alternatively spliced forms of RPTPzeta/beta. Transcripts encoding the intact and truncated receptors were expressed in all of the lower grade gliomas (WHO grade 1-3) analyzed, but not in 55% of the grade 4 glioblastomas multiforme (GBM). However, this subset of GBMs did express an alternatively spliced secreted form comprised of only the RPTPzeta/beta extracellular domain. Our data suggests there may be a correlation between the loss of transcripts encoding the receptor forms of RPTPzeta/beta and progression from low to high grade gliomas. This work provides additional evidence for the importance of phosphatase isoform expression in human tumors.

Expression of the genes encoding myelin basic protein and proteolipid protein in human malignant gliomas.

Pathological differentiation of oligodendroglioma and mixed oligoastrocytoma from astrocytoma is difficult, relying on morphological characteristics due to the lack of reliable immunohistochemical stains. Oligodendrocytes, the presumed cell of origin of oligodendrogliomas, highly express the genes encoding myelin basic protein (MBP) and proteolipid protein (PLP). We analyzed the expression of these genes to determine whether they might be useful molecular markers of oligodendrocytic tumors. MBP and PLP were highly expressed in all oligodendrogliomas and minimally expressed in glioblastomas multiforme. MBP was highly expressed in mixed oligoastrocytomas, whereas PLP expression was minimal. The association between tumor classification and expression of the MBP and PLP genes was statistically significant. Expression of these genes may serve as a useful molecular marker for some subtypes of human gliomas.

Contrasting migratory response of astrocytoma cells to tenascin mediated by different integrins.

Tenascin, an extracellular matrix protein, is expressed in human gliomas in vitro and in vivo. The distribution of tenascin at the invasive edge of these tumors, even surrounding solitary invading cells, suggests a role for this protein as a regulator of glioma cell migration. We tested whether purified tenascin, passively deposited on surfaces, influenced the adhesion or migration of a human gliomaderived cell line, SF-767. Adhesion of glioma cells to tenascin increased in a dose-dependent fashion up to a coating concentration of 10 micrograms/ml. Higher coating concentrations resulted in progressively fewer cells attaching. Cell adhesion could be blocked to basal levels using anti-beta 1 integrin antibodies. In contrast, when anti-alpha v antibodies were added to the medium of cells on tenascin, cell adhesion was enhanced slightly. Using a microliter scale migration assay, we found that cell motility on tenascin was dose dependently stimulated at coating concentrations of 1 and 3 micrograms/ml, but migration was inhibited below levels of non-specific motility when tested at coating concentrations of 30 and 100 micrograms/ml. Migration on permissive concentrations of tenascin could be reversibly inhibited with anti-beta 1, while treatment with anti-alpha v antibodies increased migration rates. We conclude that SF-767 glioma cells express two separate integrin receptors that mediate contrasting adhesive and migratory responses to tenascin.

Breast cancer and mammography: an American Cancer Society profile of Philadelphia and Montgomery Counties.

The American Cancer Society, Philadelphia Division, has completed a comprehensive profile of breast cancer and mammography in Philadelphia and Montgomery Counties. The profile consists of three segments: (1) data on incidence of breast cancer and trends in stage at diagnosis; (2) estimates of breast cancer screening practices based on surveys of the population; and (3) results from a survey of mammography providers assessing the region's capacity for and access to mammography. The profile demonstrated that the Philadelphia Division is already close to achieving the national American Cancer Society's goals for breast cancer detection for the year 2000 for the percent of women screened and percent of cancers diagnosed in early stages. New and more ambitious goals for the Division must be set. Although capacity for mammography is high, outreach programs by mammography providers represent only 1% to 2% of all mammograms performed. The profile has been the cornerstone of new programmatic initiatives for the Division.

Biological and molecular analysis of a low-grade recurrence of a glioblastoma multiforme.

We and others have reported that human malignant gliomas demonstrate intratumor heterogeneity in which many regions may be benign; however, the presence of regions of increased malignancy in these same tumors is generally indicative of poor patient prognosis. These data suggested that tumor progression may be a local phenomenon, resulting in regions that progress to a more malignant type prior to the progression of the entire tumor. Implicit in this premise is the idea that molecular markers of tumor progression may be detectable prior to histological evidence of progression. This report details analyses performed on a primary and recurrent tumor obtained from the same patient in which the primary tumor was of a higher histological grade than the recurrent tumor. Results of molecular, cytogenetic, flow cytometric, and histological analyses of the primary tumor were indicative of a grade 4 glioblastoma multiforme. Standard cytogenetic and flow cytometric analyses demonstrated that the cells were near-diploid with a stem line population of 46,XX normal G-banded karyotypes. In contrast, tissue resected from the recurrent tumor 5 months later was histologically less malignant; however, the molecular, cytogenetic, and flow cytometric analyses of this sample demonstrated the presence of specific genetic abnormalities typically found in more malignant tumors. These data demonstrate that specific molecular and/or genetic changes leading to tumor progression may become detectable in a glioma prior to the appearance of histological features of a higher grade tumor.

Cancer incidence in a group of workers potentially exposed to ethylene oxide.

BACKGROUND: Cytogenetic changes associated with ethylene oxide (ETO) exposure at a worksite prompted a study of cancer incidence in that cohort. METHOD: Cancer incidence through 31 December 1987 was ascertained in a cohort of 1132 individuals employed at the worksite at any time from 1 July 1974 through 30 September 1980, the period of potential exposure to ETO at the plant. The number of observed cancers was compared with that expected based on age- and sex-specific incidence rates reported by the National Cancer Institute's Surveillance Epidemiology and End Results Program. Standardized morbidity ratios (SMR) were calculated separately for regular and temporary employees. RESULTS: Of the 28 cancers observed in the cohort, 12 were breast cancers. The SMR for breast cancer among regular female employees ranged from 2.55 (95% CI: 1.31-4.98, P = 0.02) to 1.70 (95% CI: 0.89-3.23, P = 0.09) depending on calendar year of follow-up, assumptions about completeness of follow-up, and the reference rates used. The excess of breast cancer over expected in regular female employees diminished over time. No statistically significant excess of breast cancer was noted for temporary female employees at any point during follow-up. No increase in cancer incidence was found over that expected for any cancer sites associated with ETO in previous studies--leukaemia, brain, pancreas and stomach. CONCLUSIONS: Factors such as appropriateness of latency periods, length of follow-up and lack of a common histopathological type need to be considered in evaluating the excesses in observed breast cancer incidence, which diminished over time.

Percutaneous injuries on the "front line": a survey of housestaff and nurses.

Our objective was to assess the frequency of work-related percutaneous injuries in two high-risk groups and to compare patterns of injury and reporting in these groups. Data were collected through an anonymous, self-administered survey distributed to all full-time nurses and housestaff. The survey results were compared to Employee Health Service records. Surveys were returned by 258 of 330 housestaff and 455 of 593 nurses for a response rate of 77% (housestaff = 78%; nurses = 76%). The respondents were highly representative of the nursing divisions and residency programs surveyed. The percentage of nurses who had ever sustained percutaneous injuries was 64.7%; for housestaff it was 74.1% (prevalence difference = -9.4%, 95% confidence interval [CI] = -16.4%, -2.4%). The percentage of nurses who had sustained recent injuries was 34.6%; for housestaff it was 43.0% (prevalence difference = -8.4%, 95% CI = -15.9%, -0.9%). Injuries with syringe needles were the most common, followed by injuries with suture needles, scalpels, and then a variety of other sharp objects and instruments. The nurses were more likely to seek care as directed by hospital policy at the Employee Health Service (reporting difference = 29.7%, 95% CI = 19.5%, 39.9%) or the Emergency Room (reporting difference = 11.9%, 95% CI = 8.1%, 20.0%). Knowledge of policy increased the probability of reporting by nurses. The housestaff were more likely to evaluate injuries themselves (reporting difference = -16.7%, 95% CI = -26.8%, -6.6%).(ABSTRACT TRUNCATED AT 250 WORDS)

Molecular cloning and chromosomal localization of a human skeletal muscle PP-1 gamma 1 cDNA.

Type-1-protein phosphatase (PP-1) activity is reduced in skeletal muscle from human subjects with insulin resistance (Kida et al. 1990). This reduced phosphatase activity probably leads to the abnormal insulin action for glucose storage observed in insulin-resistant subjects. In the present study, a human homolog of rat liver PP-1 gamma 1 cDNA was isolated from human skeletal muscle. The nucleotide sequence contains a 957-nucleotide open reading frame encoding an amino acid sequence identical to that encoded by rat liver PP-1 gamma 1 cDNA. Northern blot analysis shows PP-1 gamma 1-specific mRNA is expressed in human heart, brain, placenta, lung, liver, skeletal muscle, kidney, and pancreas. PP-1 gamma 1 was localized to human Chromosome 12.

Selection of neighborhood controls for a study of factors related to the diagnosis of cervical cancer.

The level of effort required to generate neighborhood controls for a statewide matched case-control study of cervical cancer was investigated, with the aim of identifying hard-to-reach demographic subgroups. Cross reference telephone directories were used to identify households on the same street as the case. Letters were then sent to the households, followed by 'phone calls. A total of 2920 households were contacted to obtain 147 controls. Overall, 63.6% of age-eligible contacts participated in the study. In 49.3% of all households the major reason for not obtaining a control was "no age-eligible women". Level of effort required to obtain a matched control was greater for black women than for white women--on average 24 letters and 40 'phone calls for black women vs 12 letters and 20 calls for white women. Fewer eligible younger women refused to be interviewed than older. No marked differences were noted when the data were stratified by urban-rural area of residence.

Benefits of collecting local data on breast cancer and mammography practices in northwestern Pennsylvania.

The use of local data on cancer incidence and mortality and on risk-related behaviors to help communities set priorities and guide program planning is an important facet of the National Cancer Institute's Program, "Data-Based Intervention Research for Public Health Agencies." As a participant in this program, the Pennsylvania Department of Health has developed a "breast cancer profile" for a seven-county, predominantly rural region of northwestern Pennsylvania. Community hospitals in the area are collaborating with the health department to develop interventions to enhance screening mammography. The availability of the profiles allowed hospitals to compare local breast cancer risk and screening activities with those of the State and nation, to target interventions, and to establish a baseline to measure changes over time. The data generated great interest among health professionals in northwestern Pennsylvania because, contrary to their expectations, the region was quite similar to the State and nation. While the proportion of women ages 40 and older who had ever had a mammogram was relatively high (66 percent), the proportion with more than one mammogram was considerably lower (43 percent), suggesting that hospitals focus on promoting regular mammography. Although it is feasible to develop data-based interventions for local areas, the effort is not trivial. State and national agencies must cooperate to ensure comparability of data collection and reports so that comparisons of local, State, and national data can be produced routinely.

Characterization of Nicotinic Acetylcholine Receptors Expressed by Cells of the SH-SY5Y Human Neuroblastoma Clonal Line.

Radioligand binding studies show that cells of the SH-SY5Y human neuroblastoma clonal line express a single class of neuronal/nicotinic alpha-bungarotoxin binding sites (nBgtS). These sites are defined by their ability to bind radioiodinated alpha-bungarotoxin (Bgt) with high affinity (K(D) = 4 nM) and nicotinic ligands with lower (muM) affinities. Radioligand binding studies also show that SH-SY5Y cells express high affinity specific binding sites for (3) H-labeled acetylcholine that could reflect interactions with two classes of sites (K(D') - 1 n/M, K(D'') = 100 nM). These sites are distinguished from nBgtS by their insensitivity to blockade by Bgt and by their ability to bind other nicotinic agonists with high (nM) affinity. (86) Rb(+) efflux studies indicate that SH-SY5Y cells express functional nicotinic acetylcholine receptor (nAChR) ion channels that, like radioagonist binding sites, are insensitive to blockade by Bgt. However, there are far more functional nAChR than high affinity radioagonist binding sites. Functional nAChR have a pharmacological profile expected of ganglia-type receptors composed of nAChR alpha3 and beta4 subunits. Northern blot analysis indicates that genes corresponding to human alpha3, alpha5, beta2, and beta4 subunits are expressed by SH-SY5Y cells. We conclude that SH-SY5Y cells express at least two members of the nAChR family (nBgtS and ganglia-type nAChR) and that high affinity radioagonist binding sites are a subset of functional ganglia-type nAChR.

Oxygenation and ventilation during cardiopulmonary resuscitation utilizing continuous oxygen delivery via a modified pharyngeal-tracheal lumened airway.

Use of continuous transtracheal oxygen delivery systems combined with rhythmic chest compressions can provide excellent oxygenation and ventilation during cardiopulmonary resuscitation. However, occasional displacement of the transtracheal catheter results in life-threatening pneumomediastinal complications. We investigated using the pharyngeal lumen of a pharyngeal-tracheal lumened airway (PtL) as an alternative delivery system for continuous oxygen flow in 21 large mongrel dogs. Excellent ventilation was possible in anesthetized, apneic, and paralyzed dogs in normal sinus rhythm from the "bellows" effect of chest compressions. The hypercapnia and respiratory acidemia resulting from 5 min of complete apnea in ten dogs during normal sinus rhythm was readily corrected (p less than 0.01). In an additional 11 dogs, external chest compressions were performed and oxygen was delivered continuously via the PtL during 20 min of ventricular fibrillation. During this period of cardiac arrest, pH declined (7.38 +/- 0.01 vs 7.19 +/- 0.02; p less than 0.01), but PaCO2 (35 +/- 1 vs 38 +/- 3 mm Hg) and PaO2 (67 +/- 2 vs 68 +/- 3 mm Hg) were not significantly different from prearrest values. Successful resuscitation was achieved in 8 of 11 (73 percent) animals, which is similar to the results in historical controls with endotracheal intubation. No pneumomediastinal complications were seen with use of the PtL. We conclude that using the pharyngeal lumen of the PtL for continuous delivery of oxygen combined with external chest compressions can provide a safe and effective mode of oxygenation and ventilation during cardiac arrest.

A 5'-flanking region of the bovine tyrosine hydroxylase gene is involved in cell-specific expression, activation of gene transcription by phorbol ester, and transactivation by c-Fos and c-Jun.

Tyrosine hydroxylase (TH) is expressed specifically in catecholaminergic cells and is transcriptionally activated via a protein kinase C (PKC)-dependent pathway. To identify regulatory regions of the TH gene, transfected neural crest-derived catecholaminergic cells [human neuroblastoma SH-SY5Y and bovine adrenal medullary (BAM) cells] or glia-derived SF-763 cells were used to analyze expression of a chloramphenicol acetyltransferase (CAT) reporter gene under the control of 5'-flanking sequences of the bovine TH gene. Plasmid pTH(-245/+21)CAT was constructed by fusing the -245 to +21 region of the TH gene to CAT sequences in the promoterless pCAT basic plasmid. Cells transfected with pTH(-245/+21)CAT expressed CAT activity at levels 8- to 100-fold higher than those of cells transfected with pCAT basic. In SH-SY5Y or BAM cells, pTH(-245/+21)CAT supported the expression of CAT at levels similar to or higher than that supported by the tissue nonspecific viral SV40 promoter/enhancer. In glia-like cells, CAT expression from pTH(-245/+2 1)CAT was about 13-fold lower than that under the control of the SV40 promoter. Incubation of neuroblastoma cells with the active phorbol ester, phorbol 12-myristate 13-acetate (PMA), increased expression of CAT from pTH(-245/+2 1)CAT over 6-fold and was accompanied by induction of c-fos and c-jun mRNAs and proteins. The regulation of TH promoter function by c-Fos/c-Jun was corroborated by transactivation of the TH promoter in SH-SY5Y cells engineered to overexpress exogenous c-Fos and c-Jun. TH gene sequences essential for c-Fos/c-Jun transactivation were located in the -245 to -52 region, upstream from a CRE-like element. Gel mobility assays demonstrated binding of c-Fos-antigen(s) to the region of the TH promoter that supports activation by PMA and c-Fos/c-Jun. Temporal patterns of nicotinic agonist-stimulated induction of c-fos and TH mRNA are also consistent with a role for c-Fos in TH gene transcription. Our results demonstrate that the 5'-flanking region of the bovine TH gene operates as an authentic promoter capable (i) of directing cell-specific expression of a bacterial CAT gene and (ii) of conferring responsivity to PKC-stimulation. The results also suggest that the nuclear proteins c-Fos and c-Jun contribute to PKC pathway-mediated activation of the TH gene via direct interaction with the TH gene promoter. The activation of TH gene expression by PKC/c-Fos/c-Jun may serve as an additional or alternative mechanism to activation by the cAMP-CRE pathway.

Demographic, psychosocial, and medical correlates of Pap testing: a literature review.

The approaches used to ensure regular Pap testing must be tailored to sociodemographic, psychosocial, medical, and motivational factors that may change over a woman's life. Careful descriptions of the determinants of Pap testing at different stages are needed; the success of Pap-emphasizing programs designed without this information may be severely limited. We review the literature on demographic and psychosocial correlates of Pap testing and on the relationship of Pap smear frequency to contact with the medical care system and to preventive health behaviors. We include a discussion of factors related to preventive health behavior in general, so that the Pap test can be viewed against a range of behaviors. Pap program efforts must focus more precisely; our review of the available literature provides recommendations for improving Pap screening programs.

The relationship of Papanicolaou testing and contacts with the medical care system to stage at diagnosis of cervical cancer.

The relationship of Papanicolaou (Pap) testing and physician visits to stage at diagnosis of cervical cancer was assessed by interviews with 149 women with invasive cervical cancer and 214 women with in situ cervical cancer. A significantly smaller percent of study subjects with invasive disease than in situ disease had at least one Pap test in the 3 years prior to diagnosis (age- and race-adjusted odds ratio: 3.38). The two groups did not differ in visits to a physician for other reasons during this period. Pap testing decreased with increasing age for both groups, but not physician visits. While 65% percent of the subjects with invasive disease aged between 65 and 79 years had never had a Pap test until diagnosis, 88% had seen a physician in the preceding 3 years. Women with regional or distant invasive disease were least likely to have had Pap tests, and, within this group, those aged between 35 and 64 years were also least likely to have seen a physician. Strategies for early detection must reflect missed opportunities and the need to bring those not receiving care into the system.