Wolfe's parenchymal pattern and percentage of the breast with mammographic densities: redundant or complementary classifications?

Mammographic breast densities are one of the strongest breast cancer risk factors. The two most frequently used classifications of breast densities are Wolfe's parenchymal pattern and the percentage of the breast with densities. In this analysis, associations of these two classifications with breast cancer risk were compared, and the dose response curve of risk with densities was examined. Three case-control studies were combined totaling 1060 cases with newly diagnosed breast cancer and 2352 controls. A single observer had assessed parenchymal pattern and percent density without any information on subjects. Relative risks (RRs) were estimated with logistic regression and spline functions adjusting for age and body weight. The two classifications were strongly correlated (r = 0.81, P = 0.0001). Breast cancer risk increased progressively with percent density reaching a 5-6-fold increase for women with 85% or more of the breast with densities compared with women with no density. In contrast, women with P2 or DY patterns had only a 2-3-fold increase in risk compared with women with N1 pattern. More importantly, among women with P2 or DY, RR varied substantially with percent density, whereas, among women with a given percent density, RR varied little with parenchymal pattern. Comparisons of multivariate models reveal that in the presence of parenchymal pattern, inclusion of percent density in the model improved the prediction of breast cancer risk (chi(2) = 35.5, P = 0.0082) but not the opposite (chi(2) = 1.1, P = 0.7662). These findings show that the percentage of the breast with densities provide more information on breast cancer risk than Wolfe's parenchymal patterns and that, once percent breast density is taken into account, no more information on breast cancer risk is given by assessing parenchymal pattern.     

Mouse mammary tumor virus-like gene sequences in breast tumors of Australian and Vietnamese women.

PURPOSE: There is considerable evidence that the presence of mouse mammary tumor virus (MMTV)-like gene sequences in human breast cancer is highly associated with human breast carcinoma. Previous studies have found MMTV-like gene sequences in 38% of breast cancer tissue from United States women. The prevalence of these sequences in Australian and Vietnamese women has never been reported. EXPERIMENTAL DESIGN: Using PCR and primers that amplify MMTV-like gene sequences, we tested cancerous and benign breast tissue from Caucasian-Australian, Vietnamese-Australian, and Vietnamese women. RESULTS: MMTV-like gene sequences were amplified in 19 of 45 (42.2%) archival breast cancer biopsy tissues from Caucasian-Australian women, but only 1 of 120 (0.8%) and 0 of 41 breast cancer biopsy tissues from Vietnamese and Vietnamese-Australian women, respectively. The same sequences were found in only 2 of 111 (1.8%) and 0 of 60 normal (benign) breast tissue samples from Australian and Vietnamese women, respectively. CONCLUSIONS: MMTV-like gene sequences are found in only some human populations and are rarely found in normal human breast tissue from all populations, suggesting they are not present in the normal human genome and have been acquired.     

Antiretroviral therapy in adults: updated recommendations of the International AIDS Society-USA Panel

OBJECTIVE: To update recommendations for antiretroviral therapy for adult human immunodeficiency virus type 1 (HIV-1) infection, based on new information and drugs that are available. PARTICIPANTS: A 17-member international physician panel with antiretroviral research and HIV patient care experience initially convened by the International AIDS Society-USA in December 1995. EVIDENCE: Available clinical and basic science data including phase 3 controlled trials; data on clinical, virologic, and immunologic end points; research conference reports; HIV pathogenesis data; and panel expert opinion. Recommendations were limited to therapies available (US Food and Drug Administration approved) in 1999. CONSENSUS PROCESS: The panel assesses new research reports and interim results and regularly meets to consider how the new data affect therapy recommendations. Recommendations are updated via full-panel consensus. Guidelines are presented as recommendations if the supporting evidence warrants routine use in the particular situation and as considerations if data are preliminary or incomplete but suggestive. CONCLUSIONS: The availability of new antiretroviral drugs has expanded treatment choices. The importance of adherence, emerging long-term complications of therapy, recognition and management of antiretroviral failure, and new monitoring tools are addressed. Optimal care requires individualized management and ongoing attention to relevant scientific and clinical information in the field.     

Antiretroviral drug resistance testing in adult HIV-1 infection: recommendations of an International AIDS Society-USA Panel

Martin S. Hirsch, MD; Françoise Brun-Vézinet, MD; Richard T. D'Aquila, MD; Scott M. Hammer, MD; Victoria A. Johnson, MD; Daniel R. Kuritzkes, MD; Clive Loveday, MD, PhD; John W. Mellors, MD; Bonaventura Clotet, MD, PhD; Brian Conway, MD; Lisa M. Demeter, MD; Stefano Vella, MD; Donna M. Jacobsen; Douglas D. Richman, MD

JAMA. 2000;283:2417-2426.

Objective  Assays for drug resistance testing in human immunodeficiency virus type 1 (HIV-1) infection are now available and clinical studies suggest that viral drug resistance is correlated with poor virologic response to new therapy. The International AIDS Society–USA sought to update prior recommendations to provide guidance for clinicians regarding indications for HIV-1 resistance testing.

Participants  An International AIDS Society–USA 13-member physician panel with expertise in basic science, clinical research, and patient care involving HIV resistance to antiretroviral drugs was reconvened to provide recommendations for the clinical use of drug resistance testing.

Evidence and Consensus Process  The full panel met regularly between January and October 1999. Resistance and resistance testing data appearing in the last decade through April 2000 and presentations at national and international research conferences were reviewed. Recommendations and considerations were developed by 100% group consensus, acknowledging that definitive data to support final recommendations are not yet available.

Conclusions  Emerging data indicate that despite limitations, resistance testing should be incorporated into patient management in some settings. Resistance testing is recommended to help guide the choice of new regimens after treatment failure and for guiding therapy for pregnant women. It should be considered in treatment-naive patients with established infection, but cannot be firmly recommended in this setting. Testing also should be considered prior to initiating therapy in patients with acute HIV infection, although therapy should not be delayed pending the results. Expert interpretation is recommended given the complexity of results and assay limitations.

     

Nodal disease in purely glottic carcinoma: Is elective neck treatment worthwhile?

Objective: Although there is a generalized understanding of the relatively low overall incidence of nodal disease from purely glottic carcinoma, the exact role for elective neck treatment in the management of this disease remains controversial. The purpose of this study was to identify the incidence of occult nodal disease (including paratracheal) in patients who have glottic carcinoma without significant extra-glottic extension and to identify which patients are at risk for this. A retrospective chart review of 92 such patients who had either undergone neck dissection or been observed for a minimum of 2 years was performed. Results: For the 92 patients, neck treatment consisted of observation in 68 patients, paratracheal node dissection in four, unilateral neck dissection in four, unilateral neck dissection and excision of paratracheal nodes in 14, and bilateral neck dissection with paratracheal node excision in two. Of the 24 nodal dissections performed, four were positive for occult metastatic disease. No patient in the observation group developed nodal disease. Conclusion: The incidence of occult nodal disease in NO glottic carcinoma is low, 0% in early stage disease (T1–T2) and 19% in late stage disease (T3–T4). Nodes at highest risk included only the paratracheal, level II, and level III. Elective neck treatment should only be undertaken for advanced (T3–T4) disease and even then is of questionable benefit. If undertaken, it should have a low potential morbidity, such as selective neck dissection or radiation. Computed tomography was not useful in staging the neck for this subset of patients.     

Chromosomal Mosaicism in Cleavage-Stage Human Embryos and the Accuracy of Single-Cell Genetic Analysis

Purpose: Our purpose was to assess the effect of chromosomal mosaicism in cleavage-stage human embryos on the accuracy of single-cell analysis for preimplantation genetic diagnosis. Methods: Multicolor fluorescence in situ hybridization with X, Y, and 7 or X, Y, 7, and 18 chromosome-specific probes was used to detect aneuploidy in cleavage-stage human embryos. Results: Most nuclei were diploid for the chromosomes tested but there was extensive mosaicism including monosomic, double-monosomic, nullisomic, chaotic, and haploid nuclei. Conclusions: Identification of sex by analysis of a single cleavage-stage nucleus is accurate but 7% of females are not identified. One or both parental chromosomes 7 were absent in at least 6.5% of the nuclei. With autosomal recessive conditions such as cystic fibrosis, carriers would be misdiagnosed as normal or affected. With autosomal dominant conditions, failure to analyze the affected parents allele (1.6–2.5%) would cause a serious misdiagnosis and analysis of at least two nuclei is necessary to reduce errors.     

Evaluation of time-dependent inactivation of CYP3A in cryopreserved human hepatocytes.

Irreversible CYP3A inhibition by drugs constitutes one of the major causes of inhibition-based drug interactions. We evaluated time-dependent inactivation of CYP3A in cryopreserved human hepatocytes for six structurally diverse compounds known to exhibit this property. Inactivation kinetic parameters were also determined using human liver microsomes. Except for diclofenac, which did not cause CYP3A inactivation either in microsomes or in hepatocytes at concentrations up to 100 microM, time-dependent inactivation was observed in hepatocytes for amprenavir, diltiazem, erythromycin, raloxifene, and troleandomycin. The observed inactivation potency in hepatocytes (observed IC50) was compared with the potency predicted using microsomal parameters (predicted IC50). Despite satisfactory prediction for troleandomycin (1.35 and 2.14 microM for the predicted and observed IC50, respectively), over-prediction of inactivation was observed for raloxifene, amprenavir, and erythromycin (observed IC50 values 6.2-, 55-, and 7.8-fold higher, respectively, than the predicted IC50). By contrast, the observed IC50 for diltiazem in hepatocytes was approximately 4-fold lower than the IC50 predicted from microsomal data (under-prediction). After correcting for factors including nonspecific binding and inactivator consumption, prediction was significantly improved for raloxifene (the observed IC50 then became 2-fold higher than the predicted IC50) and for amprenavir to a lesser extent. A specific P-glycoprotein inhibitor, 4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-N-[2-(3.4-dimethoxyphenyl)ethyl]-6,7-dimethoxyquinazolin-2-amine (CP-100356), modulated the observed CYP3A inactivation potency by erythromycin and troleandomycin. In summary, these studies reveal three important factors that must be considered when microsomal inactivation parameters are used to predict inhibition-based drug interactions in intact cell systems.     

An exploration of relative health stock in advanced cancer patients.

OBJECTIVE: The authors sought to empirically test whether relative health stock, a measure of patients' sense of loss in their health due to illness, influences the treatment decisions of patients facing life-threatening conditions. Specifically, they estimated the effect of relative health stock on advanced cancer patients' decisions to participate in phase I clinical trials. METHOD: A multicenter study was conducted to survey 328 advanced cancer patients who were offered the opportunity to participate in phase I trials. The authors asked patients to estimate the probabilities of therapeutic benefits and toxicity, their relative health stock, risk preference, and the importance of quality of life. RESULTS: Controlling for health-related quality of life, an increase in relative health stock by 10 percentage points reduced the odds of choosing to participate in a phase I trial by 16% (odds ratio = 0.84, 95% confidence interval = 0.72, 0.97). CONCLUSION: Relative health stock affects advanced cancer patients' treatment decisions.     

Understanding Employee Awareness of Health Care Quality Information: How Can Employers Benefit?

Objective. To analyze the factors associated with employee awareness of employer-disseminated quality information on providers.
Data Sources. Primary data were collected in 2002 on a stratified, random sample of 1,365 employees in 16 firms that are members of the Buyers Health Care Action Group (BHCAG) located in the Minneapolis–St. Paul region. An employer survey was also conducted to assess how employers communicated the quality information to employees.
Study Design. In 2001, BHCAG sponsored two programs for reporting provider quality. We specify employee awareness of the quality information to depend on factors that influence the benefits and costs of search. Factors influencing the benefits include age, sex, provider satisfaction, health status, job tenure, and Twin Cities tenure. Factors influencing search costs include employee income, education, and employer communication strategies. We estimate the model using bivariate probit analysis.
Data Collection. Employee data were collected by phone survey.
Principal Findings. Overall, the level of quality information awareness is low. However, employer communication strategies such as distributing booklets to all employees or making them available on request have a large effect on the probability of quality information awareness. Employee education and utilization of providers' services are also positively related to awareness.
Conclusions. This study is one of the first to investigate employee awareness of provider quality information. Given the direct implications for medical outcomes, one might anticipate higher rates of awareness regarding provider quality, relative to plan quality. However, we do not find empirical evidence to support this assertion.     

Pre-emptive therapy for severe nausea and vomiting of pregnancy and hyperemesis gravidarum.

Nausea and vomiting of pregnancy (NVP) affects 80% of pregnancies. Its severe form, hyperemesis gravidarum (HG), results in dehydration, electrolyte imbalance, the need for hospitalisation and can, rarely, be fatal. This was a prospective, open-labelled, controlled, interventional study to evaluate the effectiveness of pre-emptive treatment of NVP symptoms in women who experienced severe NVP or HG in their previous pregnancy. Twenty-five women who reported severe symptoms of NVP with or without HG in their previous pregnancy were recruited and counselled to commence the use of antiemetics as soon as they became aware of the present pregnancy, and no later than the beginning of symptoms. They were followed-up prospectively through the index pregnancy for symptoms of NVP, and were counselled continuously as to how to modify antiemetic doses based on symptoms. A comparison group consisted of randomly selected women also counselled by us for NVP, who had also had severe NVP in the previous pregnancy, but who did not call before a planned pregnancy and thus could not be offered pre-emptive therapy. The recruited women commenced pre-emptive drug therapy for NVP before conception or up to 7 weeks' gestation, before the appearance of NVP symptoms in all cases. In comparison to the previous pregnancy, only eight of these 18 women experienced a HG again in the index pregnancy (P = 0.01). The majority of study the women had an improvement in severity of NVP symptoms compared to the previous pregnancy. In the comparison group (n = 35), symptoms in the index pregnancy remained severe in 28 cases (80%), decreased to moderate in six (16.6%) and decreased to mild in five cases (13.9%). There were five cases of HG in the previous pregnancy and three in the index pregnancy. The pre-emptive group was improved significantly compared to the control group (P = 0.01). Pre-emptive symptom management appears to be effective in preventing severe NVP in general, and HG in particular. Women who have experienced severe NVP in a previous pregnancy may benefit from taking antiemetics before, or immediately at the start of symptoms in a subsequent pregnancy.