Neoadjuvant Endocrine Therapy Versus Neoadjuvant Chemotherapy in Node-Positive Invasive Lobular Carcinoma.

BACKGROUND: Neoadjuvant chemotherapy (NACT) is often recommended for patients with node-positive invasive lobular carcinoma (ILC) despite unclear benefit in this largely hormone receptor-positive (HR+) group. We sought to compare overall survival (OS) between patients with node-positive ILC who received neoadjuvant endocrine therapy (NET) and those who received NACT. METHODS: Women with cT1-4c, cN1-3 HR+ ILC in the National Cancer Data Base (2004-2014) who underwent surgery following neoadjuvant therapy were identified. Kaplan-Meier curves and Cox proportional hazards modeling were used to estimate unadjusted and adjusted overall survival (OS), respectively. RESULTS: Of the 5942 patients in the cohort, 855 received NET and 5087 received NACT. NET recipients were older (70 vs. 54 years) and had more comorbidities (Charlson-Deyo score ≥ 1: 21.1% vs. 11.5%), lower cT classification (cT3-4: 44.2% vs. 51.0%), lower rates of mastectomy (72.5% vs. 82.2%), lower rates of pathologic complete response (0% vs. 2.5%), and lower rates of postlumpectomy (73.2% vs. 91.0%) and postmastectomy (60.0% vs. 80.8%) radiation versus NACT recipients (all p < 0.001). NACT recipients had higher unadjusted 10-year OS versus NET recipients (57.9% vs. 36.0%), but after adjustment, there was no significant difference in OS between the two groups (p = 0.10). CONCLUSIONS: Patients with node-positive ILC who received NET presented with smaller tumors, older age, and greater burden of comorbidities versus NACT recipients but had similar adjusted OS. While there is evidence from clinical trials supporting efficacy of NET in HR+ breast cancer, our findings suggest the need for further, histology-specific investigation regarding the optimal inclusion and sequence of endocrine therapy and chemotherapy in ILC.

Evaluating the addition of bevacizumab to endocrine therapy as first-line treatment for hormone receptor-positive metastatic breast cancer: a pooled analysis from the LEA (GEICAM/2006-11_GBG51) and CALGB 40503 (Alliance) trials.

BACKGROUND: Randomised trials comparing the efficacy of standard endocrine therapy (ET) versus experimental ET + bevacizumab (Bev) in 1st line hormone receptor-positive patients with metastatic breast cancer have thus far shown conflicting results. PATIENTS AND METHODS: We pooled data from two similar phase III randomised trials of ET ± Bev (LEA and Cancer and Leukemia Group B 40503) to increase precision in estimating treatment effect. Primary end-point was progression-free survival (PFS). Secondary end-points were overall survival (OS), objective response rate (ORR), clinical benefit rate (CBR) and safety. Exploratory analyses were performed within subgroups defined by patients with recurrent disease, de novo disease, prior endocrine sensitivity or resistance and reported grades III-IV hypertension and proteinuria. RESULTS: The pooled sample consisted of 749 patients randomised to ET or ET + Bev. Median PFS was 14.3 months for ET versus 19 months for ET + Bev (unadjusted hazard ratio [HR] 0.77; 95% confidence interval [CI] 0.66-0.91; p < 0.01). ORR and CBR with ET and ET + Bev were 40 versus 61% (p < 0.01) and 64 versus 77% (p < 0.01), respectively. There was no difference in OS (HR 0.96; 95% CI 0.77-1.18; p = 0.68). PFS was superior for ET + Bev for endocrine-sensitive patients (HR 0.68; 95% CI 0.53-0.89; p = 0.004). Grade III-IV hypertension (2.2 versus 20.1%), proteinuria (0 versus 9.3%), cardiovascular (0.5 versus 4.2%) and liver events (0 versus 2.9%) were significantly higher for ET + Bev (all p < 0.01). Hypertension and proteinuria were not predictors of efficacy (interaction test p = 0.33). CONCLUSION: The addition of Bev to ET increased PFS overall and in endocrine-sensitive patients but not OS at the expense of significant additional toxicity. TRIALS REGISTRATION: ClinicalTrial.Gov NCT00545077 and NCT00601900.

Steroid induction of therapy-resistant cytokeratin-5-positive cells in estrogen receptor-positive breast cancer through a BCL6-dependent mechanism.

Therapy resistance remains a major problem in estrogen receptor-α (ERα)-positive breast cancer. A subgroup of ERα-positive breast cancer is characterized by mosaic presence of a minor population of ERα-negative cancer cells expressing the basal cytokeratin-5 (CK5). These CK5-positive cells are therapy resistant and have increased tumor-initiating potential. Although a series of reports document induction of the CK5-positive cells by progestins, it is unknown if other 3-ketosteroids share this ability. We now report that glucocorticoids and mineralocorticoids effectively expand the CK5-positive cell population. CK5-positive cells induced by 3-ketosteroids lacked ERα and progesterone receptors, expressed stem cell marker, CD44, and displayed increased clonogenicity in soft agar and broad drug-resistance in vitro and in vivo. Upregulation of CK5-positive cells by 3-ketosteroids required induction of the transcriptional repressor BCL6 based on suppression of BCL6 by two independent BCL6 small hairpin RNAs or by prolactin. Prolactin also suppressed 3-ketosteroid induction of CK5+ cells in T47D xenografts in vivo. Survival analysis with recursive partitioning in node-negative ERα-positive breast cancer using quantitative CK5 and BCL6 mRNA or protein expression data identified patients at high or low risk for tumor recurrence in two independent patient cohorts. The data provide a mechanism by which common pathophysiological or pharmacologic elevations in glucocorticoids or other 3-ketosteroids may adversely affect patients with mixed ERα+/CK5+ breast cancer. The observations further suggest a cooperative diagnostic utility of CK5 and BCL6 expression levels and justify exploring efficacy of inhibitors of BCL6 and 3-ketosteroid receptors for a subset of ERα-positive breast cancers.

Prolactin suppresses a progestin-induced CK5-positive cell population in luminal breast cancer through inhibition of progestin-driven BCL6 expression.

Prolactin controls the development and function of milk-producing breast epithelia but also supports growth and differentiation of breast cancer, especially luminal subtypes. A principal signaling mediator of prolactin, Stat5, promotes cellular differentiation of breast cancer cells in vitro, and loss of active Stat5 in tumors is associated with antiestrogen therapy failure in patients. In luminal breast cancer, progesterone induces a cytokeratin-5 (CK5)-positive basal cell-like population. This population possesses characteristics of tumor stem cells including quiescence, therapy resistance and tumor-initiating capacity. Here we report that prolactin counteracts induction of the CK5-positive population by the synthetic progestin (Pg) R5020 in luminal breast cancer cells both in vitro and in vivo. CK5-positive cells were chemoresistant as determined by fourfold reduced rate of apoptosis following docetaxel exposure. Pg-induction of CK5 was preceded by marked upregulation of BCL6, an oncogene and transcriptional repressor critical for the maintenance of leukemia-initiating cells. Knockdown of BCL6 prevented induction of CK5-positive cell population by Pg. Prolactin suppressed Pg-induced BCL6 through Jak2-Stat5 but not Erk- or Akt-dependent pathways. In premenopausal but not postmenopausal patients with hormone receptor-positive breast cancer, tumor protein levels of CK5 correlated positively with BCL6, and high BCL6 or CK5 protein levels were associated with unfavorable clinical outcome. Suppression of Pg-induction of CK5-positive cells represents a novel prodifferentiation effect of prolactin in breast cancer. The present progress may have direct implications for breast cancer progression and therapy as loss of prolactin receptor-Stat5 signaling occurs frequently and BCL6 inhibitors currently being evaluated for lymphomas may have value for breast cancer.

c-Myb and its target Bmi1 are required for p190BCR/ABL leukemogenesis in mouse and human cells.

Expression of c-Myb is required for normal hematopoiesis and for proliferation of myeloid leukemia blasts and a subset of T-cell leukemia, but its role in B-cell leukemogenesis is unknown. We tested the role of c-Myb in p190(BCR/ABL)-dependent B-cell leukemia in mice transplanted with p190(BCR/ABL)-transduced marrow cells with a c-Myb allele (Myb(f/d)) and in double transgenic p190(BCR/ABL)/Myb(w/d) mice. In both models, loss of a c-Myb allele caused a less aggressive B-cell leukemia. In p190(BCR/ABL)-expressing human B-cell leukemia lines, knockdown of c-Myb expression suppressed proliferation and colony formation. Compared with c-Myb(w/f) cells, expression of Bmi1, a regulator of stem cell proliferation and maintenance, was decreased in pre-B cells from Myb(w/d) p190(BCR/ABL) transgenic mice. Ectopic expression of a mutant c-Myb or Bmi1 enhanced the proliferation and colony formation of Myb(w/d) p190(BCR/ABL) B-cells; by contrast, Bmi1 downregulation inhibited colony formation of p190(BCR/ABL)-expressing murine B cells and human B-cell leukemia lines. Moreover, c-Myb interacted with a segment of the human Bmi1 promoter and enhanced its activity. In blasts from 19 Ph(1) adult acute lymphoblastic leukemia patients, levels of c-Myb and Bmi1 showed a positive correlation. Together, these findings support the existence of a c-Myb-Bmi1 transcription-regulatory pathway required for p190(BCR/ABL) leukemogenesis.

Prognostic significance of high-grade dysplasia in colorectal adenomas.

AIM: Colonoscopy to detect and remove polyps has contributed to a reduction in colorectal carcinoma. Three-year follow up is recommended for patients considered to be at high risk (at least three adenomas, adenoma ≥ 1 cm, villous or high-grade features). Our study focused on patients diagnosed with high-grade dysplasia with regard to initial management and follow up. METHOD: A search of patients who had had endoscopic removal of a high-grade adenoma was carried out. Patients with the following were excluded: follow up of < 1 year, polyposis syndromes, prior colon cancer and a diagnosis of adenocarcinoma within 6 months following initial diagnosis. RESULTS: Eighty-three patients treated between 1999 and 2007 for high-grade dysplasia (HGD) in a colorectal adenoma were identified. Over a median follow-up period of 4 years, 53 (64%) developed further adenomatous polyps. Among these, 7% had an adenoma with HGD or an adenocarcinoma. In all these patients, the initial high-grade adenoma was > 1 cm in diameter. Initial follow-up colonoscopy was performed on average 7 months following the initial diagnosis. Ten per cent of patients underwent prophylactic segmental resection, and 6% received argon laser therapy. CONCLUSION: The study demonstrates that patients who have a colorectal adenoma > 1 cm with HGD may be at high risk of developing further adenomas with HGD or carcinoma. Close follow up is warranted.

Polymorphisms in adenosine receptor genes are associated with infarct size in patients with ischemic cardiomyopathy.

The goal of this experiment was to identify the presence of genetic variants in the adenosine receptor genes and assess their relationship to infarct size in a population of patients with ischemic cardiomyopathy. Adenosine receptors play an important role in protecting the heart during ischemia and in mediating the effects of ischemic preconditioning. We sequenced DNA samples from 273 individuals with ischemic cardiomyopathy and from 203 normal controls to identify the presence of genetic variants in the adenosine receptor genes. Subsequently, we analyzed the relationship between the identified genetic variants and infarct size, left ventricular size, and left ventricular function. Three variants in the 3'-untranslated region of the A(1)-adenosine gene (nt 1689 C/A, nt 2206 Tdel, nt 2683del36) and an informative polymorphism in the coding region of the A3-adenosine gene (nt 1509 A/C I248L) were associated with changes in infarct size. These results suggest that genetic variants in the adenosine receptor genes may predict the heart's response to ischemia or injury and might also influence an individual's response to adenosine therapy.

Use of cancer susceptibility testing among primary care physicians.

Primary care physicians (PCPs) are assuming greater roles in cancer risk assessment and susceptibility testing of patients. The objective of this study was to assess the beliefs and practices of PCPs relative to genetic susceptibility testing for cancer. A cross-sectional survey was mailed to 726 PCPs in community-based practices in southeastern Pennsylvania and southern New Jersey. Data were collected on physician background, cognitive and psychosocial factors, practice environment, and patient factors. The main outcome measure was physician self-reported recommendation or referral of patients for cancer genetic susceptibility testing in a 12-month period prior to the survey. Of those surveyed, 475 (65%) PCPs responded. Complete survey data were available for 433 PCPs. Multivariable analyses show that factors positively associated with PCP recommendation/referral included: patient inquiry about their need for genetic testing for cancer (p < 0.001); PCP belief that patient age is the best predictor of cancer risk (p = 0.01); PCP self-reported frequency of collecting patient diet information (p = 0.01) and medical history information (p = 0.01); and PCP participation in an integrated health system (p = 0.01). PCP use of cancer genetic susceptibility testing may be influenced by patient inquiry, provider beliefs about factors that affect cancer risk, provider collection of risk-assessment data, and provider practice environment.

In vitro sealing of punctured fetal membranes: potential treatment for midtrimester premature rupture of membranes.

OBJECTIVE: Midtrimester premature rupture of membranes causes significant perinatal morbidity and death. No effective treatment exists. We investigated (1) whether a needle puncture in the fetal membranes could be sealed in vitro and (2) the optimal composition of the sealant to be used. STUDY DESIGN: Membranes from second trimester pregnancies (16-24 weeks of gestation) were stretched over a modified syringe with a 2.5-cm open diameter. The syringe was filled with 20 mL of second trimester amniotic fluid, and the membrane was punctured with a 20-gauge needle. Sealants were injected into the amniotic fluid. The primary outcome variable was time for leakage of amniotic fluid. Median times for leakage for the formulations were compared by Wilcoxon exact rank sum test. RESULTS: Platelets alone failed to seal the puncture site. All other formulations stopped leakage temporarily. Tisseel (Baxter Corp, Glendale, Calif) and cryoprecipitate/thrombin preparations led to more prolonged sealing of punctured amniotic membranes than platelets (P <.01) and were not significantly different from each other. CONCLUSION: Of the sealants tested in vitro, amniotic membranes are best sealed by a fibrin/thrombin-based sealant.

Complete diagnostic evaluation in colorectal cancer screening: research design and baseline findings.

BACKGROUND: While indicated by guidelines, complete diagnostic evaluation, or CDE (i.e., colonoscopy or combined flexible sigmoidoscopy plus barium enema X ray), is often not recommended and performed for persons with an abnormal screening fecal occult blood test (FOBT) result. We initiated a randomized trial to assess the impact of a physician-oriented intervention on CDE rates in primary care practices. METHODS: In 1998, we identified 1,184 primary care physicians (PCPs) in 584 practices whose patients received FOBTs that are mailed annually by a managed care organization screening program. A total of 470 PCPs in 318 practices completed a baseline survey. Practices were randomly assigned either to a Control Group (N = 198) or to an Intervention Group (N = 120). Control Group practices received the screening program. Intervention Group practices received the screening program and the intervention (i.e., CDE reminder-feedback plus educational outreach). Practice CDE recommendation and performance rates are the primary outcomes to be measured in the study. RESULTS: Baseline CDE recommendation and performance rates were low and were comparable in Control and Intervention Group practices (54 to 57% and 39 to 40%, respectively). PCPs in the practices tended to view FOBT screening and CDE favorably, but had concerns about screening efficacy, time involved in CDE, and patient discomfort and adherence. Control Group physicians were more likely than Intervention Group physicians to believe that a mail-out FOBT screening program helps in the practice of medicine. CONCLUSIONS: We were able to enroll a high proportion of targeted primary care practices, measure practice characteristics and CDE rates at baseline, and develop and implement the intervention. Study outcome analyses will take into account baseline differences in practice characteristics.

Measuring complete diagnostic evaluation in colorectal cancer screening.

Complete diagnostic evaluation, or CDE (i.e., a colonoscopy or combined barium enema X-ray and flexible sigmoidoscopy) is recommended for individuals who have an abnormal screening fecal occult blood test result. Accurate measures of CDE use are needed in colorectal cancer (CRC) screening programs. This study compares the sensitivity and specificity of different methods for measuring CDE recommendation and performance. We identified 17 primary-care practices with 120 patients who had a positive fecal occult blood test result in a CRC screening program operated by a managed-care organization. Approaches used to measure CDE recommendation and performance included external chart audit (ECA) only; internal chart audit (ICA) only; administrative data review (ADR) of electronic claims data; ICA plus ADR; and ECA plus ADR (the "gold standard"). Sensitivity and specificity of each method were assessed relative to CDE recommendation and performance as measured by ECA plus ADR. For CDE recommendation, sensitivity measures were ECA only, 0.926; ICA only, 0.790; ADR only, 0.617; and ICA plus ADR, 0.901. The specificity of each method for CDE recommendation was no less than 0.95. In terms of CDE performance, sensitivity measures were ECA only, 0.877; ICA only, 0.790; ADR only, 0.877; and ICA plus ADR, 0.965. The specificity of each method for CDE performance was 1.0. The ICA-plus-ADR method was a highly sensitive and specific measure of CDE use. This method should be considered in situations that involve primary-care physician follow-up of patients with abnormal CRC screening test results.

Population adjustment of the definition of the vaginal birth after cesarean rate.

OBJECTIVE: The vaginal birth after cesarean delivery rate is calculated with a denominator equal to the number of all women who give birth after a previous cesarean delivery, including those who are not candidates for a trial of labor. We evaluated the impact of adjustment for noncandidates for a trial of labor on vaginal birth after cesarean delivery rates. STUDY DESIGN: All women with a previous cesarean delivery who were delivered during 1998 were classified as either candidates or noncandidates for a trial of labor. An adjusted vaginal birth after cesarean delivery rate was calculated by eliminating noncandidates for a trial of labor from the denominator. The percentage of noncandidates for a trial of labor, the vaginal birth after cesarean delivery rate, and the adjusted vaginal birth after cesarean delivery rate were compared among 3 clinical services. RESULTS: The maternal-fetal medicine service had a significantly higher percentage of noncandidates for a trial of labor than did either the low-risk resident clinic or the low-risk private service. The maternal-fetal medicine service had a significantly lower vaginal birth after cesarean delivery rate than did the private service, but this difference was no longer present after application of an adjusted vaginal birth after cesarean delivery definition. CONCLUSION: For accurate comparison of vaginal birth after cesarean delivery rates among providers it is essential to account for patient risk status in the vaginal birth after cesarean delivery definition through the elimination of noncandidates for a trial of labor.

An individual bioequivalence criterion: regulatory considerations.

Over the years, concerns have been raised regarding the appropriateness of using the average bioequivalence approach for evaluation of comparability between formulations. In lieu of average bioequivalence, scientists from academia, industry and regulatory agencies have spent considerable effort and time in exploring the concepts of population and individual bioequivalence, and developing the statistical methods to assess the bioavailability metrics using these approaches. Recently, the Food and Drug Administration (FDA) has published a preliminary draft guidance entitled 'In vivo bioequivalence studies based on population and individual bioequivalence approaches'. The concept of prescribability and switchability underscores the difference between the population and individual bioequivalence approaches. The most important consideration for individual bioequivalence, the focus of this paper, rests on the assurance that products deemed bioequivalent can be used interchangeably in the target population (switchability). In addition to the comparison of averages, the individual bioequivalence approach compares within-subject variabilities and assesses subject-by-formulation interaction. The proposed criterion represents substantial departure from the current practice and thus has resulted in extensive public discussion. In contrast to the current average bioequivalence procedure, the proposed individual bioequivalence approach offers flexible equivalence criteria based on the individual therapeutic window and variability of the reference drug product. The proposed criterion rewards manufacture of less variable drug products, allows scaling criteria for highly variable/narrow therapeutic range drugs, and promotes the use of subjects from the general population in bioequivalence studies. The FDA is currently considering various approaches for resolution of issues raised from the public debate on the subject-by-formulation interaction term, statistical methods and resource implications.

A small sample confidence interval approach to assess individual bioequivalence.

The concept of interchangeable pharmaceutical products has been examined in great detail in the literature. Anderson and Hauck proposed a statistical random coefficient model to study 'switchability', and coined the phrase 'individual bioequivalence' which they defined with a probability-based inequality. Since that paper there has been considerable work and discussion. The Food and Drug Administration has recommended the introduction of individual bioequivalence (IBE) and population bioequivalence (PBE) methods in a draft guidance document. The proposal in the draft guidance includes criteria for IBE and PBE and recommends the use of non-parametric bootstrap 95 per cent upper confidence intervals for the conclusion of either IBE or PBE. However, this method requires intensive computations. We have developed an alternative confidence interval procedure to assess IBE by the FDA recommended criteria. This method utilizes Howe's approximation I to a Cornish-Fisher expansion. Our proposed method is applicable to balanced or unbalanced data in a broad class of extended cross-over designs, and can be easily programmed using readily available software.

Overexpression of p21WAF1/CIP1 and MDM2 characterizes serous borderline ovarian tumors.

Ovarian epithelial tumors are classically divided into benign, malignant, and borderline or of low malignant potential. It is controversial whether this last group of tumors should be considered benign or malignant. Expression of cell cycle markers has recently been linked to tumor behavior and response to treatment. It has been shown that one of the pathways through which the p53 gene controls the cell cycle is by transactivating p21WAF1/CIP1, a cyclin-dependent kinase (cdk) inhibitor. By inhibiting cdks, p21WAF1/CIP1 blocks the G-1 to S-phase transition in the cell cycle. p53 can be regulated by MDM2 (murine double minute-2) through direct inactivation or promotion of its cytoplasmic degradation. In an attempt to investigate the cell cycle checkpoint mechanisms of these tumors, we studied the expression of p53, Ki-67, MDM2, and p21WAF1/CIP1 by immunohistochemistry. We analyzed the expression of these proteins in 19 cystadenomas (8 serous and 11 mucinous), 40 borderline tumors (31 serous and 9 mucinous), and 18 serous carcinomas of the ovary. p21WAF1/CIP1 was expressed in 7 of 19 (37%) benign cystadenomas, 32 of 40 (80%) borderline tumors (93.5% of serous and 33% of mucinous), and in 9 of 18 (50%) serous carcinomas. Ki-67 was only weakly expressed in 8 of 19 (42%) benign cystadenomas, all borderline tumors showed Ki-67 staining in less than 50% of the cells, and 55% of serous carcinomas stained in more than 50% of tumor cells. p53 was absent in all but 1 of the cystadenomas, was expressed in 9 of 40 (22.5%) borderline tumors (25.8% of serous and 11% of mucinous), and in 10 of 18 (55%) carcinomas. All 11 implants of serous borderline tumors expressed p21WAF1/CIP1. Most serous borderline tumors expressed higher levels of MDM2 compared with the benign cystadenomas and carcinomas. Four of the serous borderline implants (40%) expressed MDM2. Coexpression of p21WAF1/CIP1 and MDM2 characterizes serous borderline tumors of the ovary and their implants, which suggests that these cell cycle control proteins are important in these tumors and may be related to tumor progression. Low expression of p53 protein in serous borderline tumors might be in part mediated by MDM2. This suggests that the p53 pathway is intact in most of these tumors, in contrast with carcinomas, in which high expression of p53 has been related to mutations of this gene.

Bilateral breast carcinoma: risk factors and outcomes for patients with synchronous and metachronous disease.

BACKGROUND: The aim of this study was to compare the outcomes of bilateral breast carcinoma (BBC) patients with those of patients who had unilateral disease. METHODS: From 1960 to 1995, 1465 Stage 0-III patients with primary breast carcinoma were treated with either mastectomy or breast conservation therapy at the Kimmel Cancer Center of Jefferson Medical College and Thomas Jefferson University Hospital. There were 1315 (89.9%) unilateral, 103 (7.1%) metachronous, and 47 (3.0%) synchronous breast carcinoma patients. Patients with synchronous breast carcinoma were defined as having a contralateral cancer diagnosed within 1 year of initial diagnosis. The percentage of patients with Stage 0-I disease at initial diagnosis was 49.4%, whereas 68% had Stage 0-I disease at subsequent diagnosis. For patients with metachronous breast carcinomas, the median interval between the first and second diagnosis was 44 months (range, 13-287 months). The median follow-up time was 58 months (range, 12-229 months) for patients with synchronous cancers and 87 months (range, 0.25-414 months) for those with metachronous cancers. Rates of overall survival and survival with no evidence of disease (NED survival), local control, and distant metastasis from the time of the second diagnosis were calculated for patients with synchronous and metachronous disease. These figures were then compared with each other and also with those for unilateral breast carcinoma patients. RESULTS: Patients with synchronous and metachronous breast carcinoma had worse 5- and 8-year NED survival rates compared with unilateral breast carcinoma patients, as well as an increased risk of distant metastasis. In multivariate analysis, differences in local control and overall survival were not statistically significant for patients who had bilateral disease compared with those who had unilateral disease. There was no difference when patients with metachronous and unilateral breast carcinoma were compared with respect to local control and overall survival. CONCLUSIONS: Patients with bilateral breast carcinoma who present with synchronous disease are at greater risk for distant metastasis than women with unilateral or metachronous breast tumors. There was a trend toward decreased overall survival and local control for patients with synchronous bilateral breast carcinoma compared with patients who had either metachronous or unilateral disease.

Subject-by-formulation interaction in bioequivalence: conceptual and statistical issues. FDA Population/Individual Bioequivalence Working Group. Food and Drug Administration.

PURPOSE: The FDA has proposed replacing the current average bioequivalence criterion with population and individual bioequivalence criteria that consider variances in addition to the difference of averages. One of these variances in the individual bioequivalence criterion measures subject-by-formulation interaction, the extent to which the test-reference difference varies from person to person. This paper discusses conceptual and statistical issues raised in various publications and presentations with respect to the presence and estimation of such an interaction. METHODS: We focus on the importance of subject-by-formulation interaction, an understanding of what is a large interaction, and the assessment of the magnitude of this interaction in bioequivalence studies. Simulation studies, examples from the literature, and data from FDA files are used to demonstrate the magnitude of the interaction and its distribution under various conditions. RESULTS: The concept of a large interaction is tied to the concept of a large mean difference. We suggest that an interaction greater than 0.15 is a conservative criterion for a large interaction. Magnitudes of estimated interaction are affected by variability, sample size, and the selection of data sets that pass average bioequivalence. CONCLUSIONS: Examples of substantial interactions are beginning to appear. More data is needed before reaching definitive conclusions regarding the frequency and importance of observed interactions.

African-American men and intention to adhere to recommended follow-up for an abnormal prostate cancer early detection examination result.

OBJECTIVES: To assess the intention of African-American men to have the recommended follow-up in the event of an abnormal prostate cancer early detection examination and to identify the variables that help to explain adherence intention. METHODS: In the spring of 1995, we selected a random sample of 548 African-American men who were patients at the University of Chicago Health Service. The sample included men who were 40 to 70 years of age, did not have a personal history of prostate cancer, and had a working telephone number. A total of 413 men who completed the telephone survey received an invitation to consider undergoing a prostate cancer early detection examination. The survey provided data on personal background characteristics, knowledge, attitudes, and beliefs related to prostate cancer and early detection. Respondents were asked whether they would choose to have the recommended follow-up in the event of an abnormal early detection examination result. Univariate and multivariate analyses of intention to have follow-up were performed. RESULTS: An intention to have the recommended follow-up was reported by 77% of the survey respondents. The results of multivariate analyses revealed that the intention to have the follow-up was positively associated with education beyond high school (odds ratio [OR] 1.9); perceived self-efficacy related to prostate cancer screening (OR 2.1); the belief that prostate cancer can be cured (OR 3.3); the belief that prostate cancer screening should be done in the absence of prostate problems (OR 2.3); and physician support for prostate cancer screening (OR 2.1). CONCLUSIONS: African-American men who have a high school education or less may be at risk of nonadherence to recommended follow-up. Adherence also may be low among men who do not have favorable views of early detection or do not perceive strong physician support for early detection. Research is needed to determine whether intention and other factors predict actual adherence to follow-up in this population group.

Generalized treatment effects for clinical trials.

Practice in the analysis of clinical trials with continuously measured endpoints is to focus on the difference or percentage change in mean or median response. However, treatments may have effects on the distribution of responses other than on the average response. We sought an approach to such generalized treatment effects that: (i) targets a parameter that is easily understood by our clinical colleagues; and (ii) employs confidence intervals as the basis for inference. We consider one such approach based on work in reliability theory, namely setting Pr[Y>X] as the target parameter, and compare this approach to an earlier one due to O'Brien. The two approaches have similar properties when they both seek to reject the null hypothesis of no effect due to different variances but differ when the larger variance corresponds to the larger mean. In that case, our approach views that the larger variance attenuates the effect of the larger mean. Out suggested approach applies easily to positive control (clinical) equivalence trials.

DNA-dependent protein kinase stimulates an independently active, nonhomologous, end-joining apparatus.

Double-strand breaks (DSBs) can be efficiently removed from the DNA of higher eukaryotes by nonhomologous end-joining (NHEJ). Genetic studies implicate the DNA-dependent protein kinase (DNA-PK) in NHEJ, but the exact function of this protein complex in the rejoining reaction remains to be elucidated. We compared rejoining of DNA DSBs in a human glioma cell line, M059-J, lacking the catalytic subunit of DNA-PK (DNA-PKcs), and their isogenic but DNA-PK-proficient counterpart, M059-K. In both cell lines, rejoining of DNA DSBs was biphasic, with a fast and a slow component operating with a half-life of approximately 22 min and 12 h, respectively. Deficiency in DNA-PK activity did not alter the half-times of either of these components of rejoining but increased from 17 to 72% the proportion of DNA DSB rejoining with slow kinetics. DNA DSB rejoining was nearly complete in both cell lines, and there was only a small increase in the number of unrejoined breaks in M059-J as compared with M059-K cells after 30 h of incubation. Wortmannin radiosensitized to killing M059-K cells and strongly inhibited DNA DSB rejoining. Wortmannin did not affect the radiosensitivity to killing and produced only a modest inhibition in DNA DSB rejoining in M059-J cells, suggesting that, for these end points, DNA-PK is the principal target of the drug. These observations demonstrate that DNA-PK deficiency profoundly decreases the proportion of DNA DSB rejoining with fast kinetics but has only a small effect on the fraction remaining unrejoined. We propose that in higher eukaryotes, an evolutionarily conserved, independently active, but inherently slow NHEJ pathway is stimulated 30-fold by DNA-PKcs to rapidly remove DNA DSBs from the genome. The stimulation is expected to be of local nature and the presence of DNA-PKcs in the vicinity of the DNA DSB determines whether rejoining will follow fast or slow kinetics. Structural and regulatory functions of DNA-PKcs may mediate this impressive acceleration of DNA DSB rejoining, and regions of chromatin within a certain range from this large protein may benefit from these activities. We propose the term DNA-PK surveillance domains to describe these regions.