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.

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.

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.

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.

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.

Physician intention to recommend complete diagnostic evaluation in colorectal cancer screening.

Primary care physicians (PCPs) often do not recommend complete diagnostic evaluation (CDE; i.e., diagnostic colonoscopy or the combination of flexible sigmoidoscopy and barium enema X-ray procedures) for patients with an abnormal screening fecal occult blood test (FOBT+) result.

Inbreeding effects on fertility in humans: evidence for reproductive compensation.

The effects of inbreeding on prereproductive mortality have been demonstrated in many natural populations, including humans. However, little is known about the effects in inbred individuals who survive to adulthood. We have investigated the effects of inbreeding on fertility among inbred adult Hutterites and demonstrate significantly reduced fecundity among the most inbred Hutterite women, as evidenced by longer interbirth intervals (P=.

Hyperplastic ductal and lobular lesions and carcinomas in situ of the breast: reproducibility of current diagnostic criteria among community- and academic-based pathologists.

Due to the increased efforts of early detection and biopsy of breast lesions, the number of cases with hyperplastic and in situ lesions seen in most pathology laboratories has increased significantly. Pathologists are faced with a greater number of biopsies and a wider spectrum of lobular and ductal lesions including papillary lesions. A set of 31 randomly selected glass slides of ductal, lobular and papillary lesions (benign, borderline, and carcinomas in situ) was circulated among five community- and five academic-based pathologists (median 9 years of experience).

Stage T3 prostate cancer: a nonrandomized comparison between definitive irradiation and induction hormonal manipulation plus prostatectomy.

Objectives: At our institution, a Phase II trial using androgen suppression followed by surgery was completed for men with Stage T3 disease and negative laparoscopic nodal dissection. We recently reported the unfavorable biochemical outcome of that experience. Because that analysis did not include a control group of irradiated patients, the current project was undertaken to compare that Phase II experience with clinical Stage T3 patients treated at our institution with definitive irradiation during an overlapping period of time.

Human leukocyte antigen matching and fetal loss: results of a 10 year prospective study.

The role that maternal and fetal human leukocyte antigen (HLA) genes play in pregnancy is unknown, but it has been suggested that fetuses whose HLA alleles do not differ from maternal alleles (i.e. histocompatible fetuses) are more likely to be aborted than fetuses with HLA alleles that differ from maternal alleles (i.

Prostate imaging may not be necessary in nonpalpable carcinoma of the prostate.

Objectives: Stage T1c carcinoma of the prostate is defined as a nonpalpable carcinoma (NPC-P) that is not visible by imaging and is identified by needle biopsy performed because of elevated prostate-specific antigen (PSA) concentrations. The purpose of this study was to define the incidence of normal findings on transrectal ultrasound (TRUS) and/or endorectal coil magnetic resonance imaging (EMRI) among patients with NPC-P, as well as to investigate the value of differentiating patients with Stage T1c disease from all other patients with NPC-P.

Methods: The records of 2211 patients diagnosed with prostate carcinoma between 1988 and 1995 were reviewed to identify 291 men with NPC-P.

Long-term outcome following sympathectomy for complex regional pain syndrome type 1 (RSD).

We performed a retrospective study of 29 patients with CRPS1 (RSD) who were initially examined between 1983 and 1993, and had either transthoracic (lower third of stellate ganglia to T3) or lumbar (L2-L4) sympathectomy. The patients were followed from 24 to 108 months after surgery. Patients with unsuccessful surgical outcomes had significantly longer duration of symptoms before surgery (median, 36 months) than those with successful outcomes (median, 16 months) by Wilcoxon rank sum test (chi2=8.

External beam irradiation for choroid metastases: identification of factors predisposing to long-term sequelae.

Purpose: To improve overall quality of life, palliative treatments should attempt to minimize associated complications while effectively controlling specific symptoms. We reviewed our experience treating posterior uveal metastases with external beam radiotherapy (EBRT) to determine the complication rate and to identify the relationship between patient, tumor, or treatment-related factors and the development of ocular complications.

Methods And Materials: 483 consecutive patients (pts) (578 eyes) were diagnosed with intraocular metastatic disease from solid tumors between 1972-1995.

Functional vision is improved in the majority of patients treated with external-beam radiotherapy for choroid metastases: a multivariate analysis of 188 patients.

Purpose: Metastatic deposits are the most common intraocular malignancies. We evaluated the efficacy of external-beam radiotherapy (EBRT) in the palliation of posterior uveal metastases in terms of clinically relevant outcomes: functional vision, tumor control, and globe preservation.

Patients And Methods: Four hundred eighty-three consecutive patients (578 eyes) were diagnosed with intraocular metastatic disease from solid tumors between 1972 and 1995.

Performance status and age as independent predictors of survival among AIDS patients with primary CNS lymphoma: a multivariate analysis of a multi-institutional experience.

Purpose: There is limited information about the outcome of AIDS patients with primary central nervous system lymphoma treated with definitive irradiation. The purpose of this study was to determine factors associated with increased survival in such patients.

Methods: An analysis was performed of 163 patients with AIDS who were evaluated at nine urban hospitals.

Mean difference vs. variability reduction: tradeoffs in aggregate measures for individual bioequivalence. FDA Individual Bioequivalence Working Group.

Aggregate criteria for individual bioequivalence allow a tradeoff between difference in average bioavailability and reduction in within-subject variability. That is, a large difference in the average bioavailability between a test and a reference formulation can be offset by a sufficient reduction in variability of the test formulation. This offset could allow the test formulation to pass many individual bioequivalence criteria.

Induction androgen deprivation plus prostatectomy for stage T3 disease: failure to achieve prostate-specific antigen-based freedom from disease status in a phase II trial.

Objectives: There is interest in treating prostate cancer with induction androgen deprivation prior to radical prostatectomy. Data on long-term prostate-specific antigen (PSA)-based survival analyses among patients treated with neoadjuvant hormonal therapy (NHT) and prostatectomy are limited. In 1991 we instituted a pilot study for T3 disease based on endorectal coil magnetic resonance imaging (eMRI), mandatory negative laparoscopic nodal dissection prior to hormonal manipulation, and prostatectomy followed by pathologic and PSA-based outcome determinations.

Cytokine patterns during progression to AIDS in children with perinatal HIV infection.

Patterns of cytokine expression were analyzed in polyclonal and antigenic responses in children with perinatal HIV infection. Responses of PBL to PMA and A23187 calcium ionophore studied in patients in different stages of HIV infection revealed reduced levels of IL-2 in HIV-infected children beginning before 6 mo of age, and age-dependent increases in expression of IL-4, IL-10, and IFN-gamma. The levels of IL-4, IL-10, and IFN-gamma expression did not differ significantly between HIV-infected and age-matched uninfected children of HIV-seropositive mothers, except for a small reduction in HIV-infected children in late stages of infection.

Muscle sodium channel inactivation defect in paramyotonia congenita with the thr1313met mutation.

Mutations of the skeletal muscle sodium (Na) channel have been reported in families with paramyotonia congenita (PC), an autosomal dominant disorder with cold and/or exercise induced stiffness and myotonia. Functional consequences of specific Na channel mutations responsible for PC have not been described. Patch clamp recording of single Na channels were made in cultured myotubes at 22 and 34 degrees C from a PC patient with the thr1313met mutation.