Search PubMed⌕ Search

Biomedical subjects

B E Storer

Publications and source records attributed to B E Storer.

51 records · Page 3Linked to original sources
PubMed1992

A class of phase II designs with three possible outcomes.

In the Phase II design of Fleming (1982, Biometrics 38, 143-151), the possible outcomes are to reject H1:p less than or equal to p1 or to reject H2: p greater than or equal to p2, where p1 less than p2. The design is constrained by specifying that Pr(reject H1[p1) less than or equal to alpha and Pr(reject H2[p2) less than or equal to beta. This can lead to some ambiguity as to the appropriate practical decision at the end of the trial, as the confidence region for p may include a substantial part of the interval between p1 and p2. We propose a class of designs wherein an allowable outcome is not to reject either H1 or H2. An additional constraint is placed on the design by specifying Pr(reject Hj[pm) less than or equal to gamma (j = 1, 2), where p1 less than pm less than p2. This type of design can provide a more realistic basis for decision making following the trial, although traditional values of alpha and/or beta need to be viewed from a somewhat different perspective in order to maintain a reasonable sample size. Some optimal single-stage and sequential multistage designs are presented.

Biometry↗
PubMed1991

Nonrandom chromosome losses in stepwise neoplastic transformation in vitro of human uroepithelial cells.

An in vitro/in vivo transformation system was used to study chromosome region losses in stepwise neoplastic transformation and progression of human uroepithelial cells. Complete cytogenetic analyses were done on 17 independent carcinomas derived using this system and showed that losses of chromosome regions on 3p (P = 0.0003), 6q (P = 0.01), and 18q (P = 0.0003) were nonrandom. The smallest common losses [i.e., 3(p13----pter), 6(q21----q23), and 18(q21.1----qter)] were in putative cancer suppressor gene regions. In addition, cumulative losses from a group of 10 chromosome arms (i.e., 1p, 1q, 3p, 5q, 6q, 9q, 11p, 13q, 17p, and 18q) frequently deleted in clinical carcinomas were very significant (P = 0.0005) compared to losses from all other arms. Loss of 3p and 18q both correlated with transformation to high grade carcinomas (P = 0.001 and P = 0.004, respectively). These data provide new evidence supporting hypotheses that chromosome regions 3(p13----pter) and 6(q21----q23) contain genes that suppress cancer development. These results also provide new data confirming the hypothesis that genetic loss(es) in the 18(q21.1----qter) region are associated with the development of high grade malignancies.

Carcinoma, Transitional Cell↗
PubMed1991

Biological and clinical effects of intravenous tumor necrosis factor-alpha administered three times weekly.

Tumor necrosis factor (TNF) is a cytokine with pleiotropic biological and antitumor effects in vitro and in mouse models. The immunological effects of the molecule as a single agent, however, have not been well studied clinically. We conducted a Phase I trial of TNF in 53 patients with advanced malignancies in order to determine the biological and clinical effects of TNF when administered as a 30-min i.v. infusion three times/week. Dose levels of TNF ranged from 5 to 275 micrograms/m2; doses of TNF were escalated between patient groups. The most common clinical toxicities of TNF consisted of rigors, anorexia, headache, and fatigue. Dose-limiting toxicity consisted of hypotension, fatigue, and nausea. Four patients treated at the maximally tolerated dose of 225 micrograms/m2 received dexamethasone to determine whether the toxicities of TNF could be ameliorated. No significant differences in hypotension or subjective symptomatology were observed in those patients receiving dexamethasone and those who did not or between injections in which dexamethasone was administered and when it was not. One patient with colorectal carcinoma treated with 50 micrograms/m2 had a partial response lasting about 9 months. Biological responses were evaluated in 8 patients treated at the maximally tolerated dose before therapy and 24 h afterward. TNF significantly (P less than 0.05 for all) enhanced serum beta 2-microglobulin, serum neopterin, and serum interleukin-2 receptor (Tac antigen) levels. Indoleamine 2,3-dioxygenase activity was also increased 24 h following the administration of TNF, although this increase was only of borderline statistical significance (P = 0.07). TNF did not enhance granulocyte bactericidal activity. The expression of cell surface proteins on monocytes, including HLA-DR, HLA-DQ, beta 2-microglobulin, and the Fc receptor, and serum interleukin-1 activity also were not significantly increased by the administration of TNF. Thus, in humans TNF caused biological response modulation with evidence of HLA Class I (beta 2-microglobulin) increase and T-cell (Tac antigen) and monocyte (neopterin) activation.

2',5'-Oligoadenylate Synthetase↗
PubMed1991

Breast self-examination in relation to the occurrence of advanced breast cancer.

Two hundred nine female enrollees of the Group Health Cooperative of Puget Sound who developed advanced-stage breast cancer during the period 1982-1988 were interviewed about their practice of breast self-examination (BSE), use of other breast cancer screening modalities, and medical and reproductive histories. Each subject's description of how she performed the examination was scored according to her mention of up to 10 recommended BSE techniques. A random sample of 433 women without advanced-stage breast cancer from the same population was interviewed for comparison. Relative to women not practicing BSE, the risk of advanced-stage breast cancer among BSE users was 1.15 (95% confidence interval, 0.73-1.81). Frequency of BSE did not differ between women with advanced-stage breast cancer and control subjects, whether in all subjects or in subgroups defined by age, use of mammography, or frequency of clinical breast examinations. While self-described proficiency in BSE was generally low in both case and control subjects, the small percentage of women reporting more thorough self-examinations, regardless of frequency, had about a 35% decrease in the occurrence of advanced-stage breast cancer compared to women who did not perform BSE. These results suggest that, while carefully performed BSE may avoid the development of some advanced-stage breast cancers, BSE as practiced by most Seattle-area women is of little or no benefit.

Adult↗
PubMed1990

A sequential phase II/III trial for binary outcomes.

This paper describes a simple two-stage design for randomized clinical trials with a binary outcome. An early stopping criterion applies to results in the experimental arm only and seeks to evaluate that arm with respect to some external standard of efficacy. Stopping rules are similar to those commonly used in phase II designs. This design has no adverse impact on the overall type I error rate, though one must increase sample size to accommodate a modest loss in power.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1990

Biological and clinical effects of interferon-beta ser at two doses.

To assess biological response, therapeutic activity, and side effects, a randomized, double-blind trial of two doses of interferon-beta ser (IFN-beta ser), differing by 20-fold 4.5 and 90 x 10(6) units), was undertaken in 64 patients with metastatic renal carcinoma. Patients were treated intravenously with injections daily for 10 days with an 11-day rest before treatment was reinitiated. The trial confirmed the relatively good toleration of IFN-beta ser; in the first cycle only 4/63 patients had anorexia of moderate or greater severity. Median weight change over the duration on study was -1.5 kg; in the first cycle only 7% of patients had performance status decline greater than 1 level. Statistically significant changes (p less than 0.05) occurred in granulocytes, lymphocytes, calcium, cholesterol, alkaline phosphatase, and aspartate transferase (AST); however, except for AST, overall clinical differences in the two doses were not great. Of 60 patients evaluated, 1 developed neutralizing antibody. When assessed 24 h after IFN-beta ser at 4.5 x 10(6) units, significant (p less than 0.05) augmentation had occurred in beta 2-microglobulin, HLA-DR, and HLA-DQ expression on monocytes, 2',5'-oligoadenylate (2-5A) synthetase in peripheral mononuclear cells, and natural killer (NK) and K cells functional activity. Although the 90 x 10(6) unit dose also resulted in stimulation of these responses, little additional augmentation of biological response occurred at the higher dose. Except for a decline in monocyte HLA-DR expression, biological responses remained increased at both doses over the 10-day period of treatment. However, no objective regressions of metastatic disease occurred. In view of objective responses in metastatic renal carcinoma in other trials with IFN-beta ser, consideration should be given to alternative schedules.

2',5'-Oligoadenylate Synthetase↗
PubMed1989

Altered tryptophan and neopterin metabolism in cancer patients treated with recombinant interleukin 2.

Immune stimulation or interferon administration induces indoleamine 2,3-dioxygenase and GTP cyclohydrolase activity in humans, resulting, respectively, in tryptophan degradation to kynurenine and in neopterin production. To determine if similar effects result from interleukin 2 (IL-2) administration, plasma tryptophan and urinary kynurenine and neopterin were measured in patients undergoing a phase 1 toxicity trial of recombinant IL-2 given by daily bolus or continuous i.v. administration for 7 days at doses of 1 x 10(5) to 1 x 10(7) units/m2/day. Significant dose-dependent decreases in plasma tryptophan levels and corresponding increases in urinary kynurenine and neopterin were observed. These metabolic effects of IL-2 are probably mediated by induction of gamma-interferon production, although elevated levels of gamma-interferon were not found in the sera of these patients. In view of the indispensable role of tryptophan in synthesis of protein, niacin, and serotonin, we suggest that some of the toxic side effects may be the result of this loss of tryptophan. Since these metabolic changes were detected at relatively low doses of IL-2, these assays provide a highly sensitive means for monitoring in vivo metabolic responses to IL-2 therapy.

Biopterins↗
PubMed1989

Human biologic response modification by interferon in the absence of measurable serum concentrations: a comparative trial of subcutaneous and intravenous interferon-beta serine.

The effect on a range of biologic responses of interferon-beta serine (IFN-beta ser), administered by either the sc or the iv route, was examined in 16 patients. Despite the absence of IFN in the serum of 13 of 16 patients after sc administration, biologic changes associated with IFN administration occurred. Significant increases in peripheral mononuclear cell surface proteins were evident. Monocyte human leukocyte antigen-DR (HLA-DR) showed a 23% increase in mean fluorescent intensity (P = .04) and a 9% increase in percentage of positive cells (P = .02); lymphocyte OKT10 had an 11% increase in percentage of positive cells (P less than .0001) and a 26% increase in mean fluorescent intensity (P = .002). Natural killer cell activity against the Change target increased by 125% (P = .004). Intracellular activity of 2',5'-oligoadenylate synthetase increased 297% at 24 hours and 226% at 48 hours (P less than .0001). Significant increases in serum concentrations of beta 2 microglobulin (24% at 24 hr and 27% at 48 hr, P less than .0001) and neopterin (85%, P = .0001 and 165%, P = .00001) were observed. These alterations after sc administration were similar quantitatively to those resulting from the same dose of IFN-beta ser given iv. Thus, serum IFN concentrations did not have to be measurable for IFN-beta ser to exert biologic activity. The different effects of two dose levels, 45 X 10(6) IU and 180 X 10(6) IU, also were compared independent of route. The higher dose resulted in greater increases over baseline of 2',5'-oligoadenylate synthetase activity (344% vs. 145% at 24 hr; 231% vs. 83% at 48 hr) and serum neopterin concentrations (185% vs. 99% at 24 hr; 271% vs. 153% at 48 hr). For all the other parameters, there was no significant difference between the two doses.

2',5'-Oligoadenylate Synthetase↗
PubMed1989

Design and analysis of phase I clinical trials.

The Phase I clinical trial is a study intended to estimate the so-called maximum tolerable dose (MTD) of a new drug. Although there exists more or less a standard type of design for such trials, its development has been largely ad hoc. As usually implemented, the trial design has no intrinsic property that provides a generally satisfactory basis for estimation of the MTD. In this paper, the standard design and several simple alternatives are compared with regard to the conservativeness of the design and with regard to point and interval estimation of an MTD (33rd percentile) with small sample sizes. Using a Markov chain representation, we found several designs to be nearly as conservative as the standard design in terms of the proportion of patients entered at higher dose levels. In Monte Carlo simulations, two two-stage designs are found to provide reduced bias in maximum likelihood estimation of the MTD in less than ideal dose-response settings. Of the three methods considered for determining confidence intervals--the delta method, a method based on Fieller's theorem, and a likelihood ratio method--none was able to provide both usefully narrow intervals and coverage probabilities close to nominal.

Dose-Response Relationship, Drug↗
PubMed1985

General relative risk functions for case-control studies.

While multiplicative (log-linear and logistic) models have a firmly established place in epidemiologic methodology, additive and other more general model structures are needed also. The authors propose a parametric family of relative risk functions ranging from subadditive to supramultiplicative that is generated by varying the exponent in a power transform for the log relative risk. The choice of model is facilitated by graphic analysis of goodness-of-fit statistics computed for various values of the exponent. Intermediate quantities available as by-products of the fit are useful for checking the influence of particular observations on the estimated regression coefficients. Three examples illustrate the applications of these methods to random, stratified, and matched samples of cases and controls. Computer software is available for each of these situations. Even though different relative risk models may have markedly different implications for the multifactorial nature of the disease process, it may be difficult to distinguish between them unless the data are quite extensive.

Alcohol Drinking↗
PubMed1982

Further studies on skin melanomas apparently dependent on female sex hormones.

In the British Isles the incidence of mortality rates from malignant melanoma of the skin have been shown to be higher in females than in males in the later years of reproductive life. In populations with higher rates for malignant melanoma of skin (Scandinavia, Australasia etc), and also in Japan, where the rates are low, the ratio of female to male deaths is lower than in the British Isles. However, a similar pattern of age-specific sex ratios (risks for females compared with males peaking at some age in the latter half of reproductive life, and relatively low in middle age) is found in these populations. This 'gynaecologic' factor is not an artifact of interactions between age and year of birth effects, and appears to act multiplicatively with other aetiologic factors. These findings have implications for studies of the aetiology and pathogenesis of malignant melanoma, as well as for the descriptive mathematical modelling of the rates for purposes of environmental legislation.

Adolescent↗
PubMedDate not supplied

Excess of malignant melanomas in women in the British Isles.

The incidence and mortality of malignant melanoma in women of reproductive and menopausal age in the British Isles are higher than the corresponding rates for men. This is not found at older ages in these populations, or in other countries. Rates for malignant melanoma are generally low in the British Isles, although the high rates in Australia and New Zealand, largely populated from the British Isles, indicate that the populations are susceptible to the disease. It is suggested that the low rates for environmentally produced tumours enable a hormone-dependent variant of melanoma to reveal itself in British populations.

Adolescent↗
PubMedDate not supplied

Long-term survival among men with conservatively treated localized prostate cancer.

OBJECTIVE: To determine age-specific, all-cause mortality, disease-specific mortality, and life expectancy for men aged 65 to 75 years who are treated only with immediate or delayed hormonal therapy for newly diagnosed, clinically localized prostate cancer. DESIGN: A population-based, retrospective cohort study. SETTING: Patient records were abstracted from 37 acute care hospitals and two Veterans Affairs medical centers in Connecticut. Original pathology slides were sent to a referee pathologist who was blinded to case outcomes. SUBJECTS: All men identified by the Connecticut Tumor Registry with clinically localized prostate cancer diagnosed in 1971 to 1976 who were aged 65 to 75 years at the time of diagnosis and were untreated or treated with immediate or delayed hormonal therapy. MAIN OUTCOME MEASURES: Parametric proportional hazards models incorporating tumor histologic findings, comorbidity, and age at the time of diagnosis to compare cohort survival with that of men in the general population. RESULTS: After a mean follow-up of 15.5 years, the age-adjusted survival for men with Gleason score 2 to 4 tumors was not significantly different from that of the general population. Maximum estimated lost life expectancy for men with Gleason score 5 to 7 tumors was 4 to 5 years and for men with Gleason score 8 to 10 tumors was 6 to 8 years. Tumor histologic findings and patient comorbidities were powerful independent predictors of survival. CONCLUSIONS: Compared with the general population, men aged 65 to 75 years with conservatively treated low-grade prostate cancer incur no loss of life expectancy. Men with higher-grade tumors (Gleason scores 5 to 10) experience a progressively increasing loss of life expectancy. Case series reports of survival/mortality experienced by men with clinically localized prostate cancer that fail to control for age, tumor histologic features, and comorbidities risk significant bias.

Aged↗
PubMedDate not supplied

Pregnancy termination in relation to risk of breast cancer.

OBJECTIVE: To evaluate the association between pregnancy terminations and risk of breast cancer. DESIGN AND SETTING: Population-based case-control study in Wisconsin, Massachusetts, Maine, and New Hampshire. STUDY PARTICIPANTS: Cases were women younger than 75 years with a new diagnosis of breast cancer (n = 6888), identified from statewide tumor registries. Controls younger than 65 years (n = 9529) were randomly selected from lists of licensed drivers, or for older subjects, from lists of Medicare beneficiaries. EXPOSURES AND OUTCOMES: Breast cancer risk in relation to spontaneous or induced abortions. RESULTS: After adjustment for parity, age at first birth, and other risk factors, pregnancy termination (induced or spontaneous) was associated with a relative risk (RR) of breast cancer of 1.12 (95% confidence interval [CI], 1.04 to 1.21), compared with the risk among women who had never had a termination. Induced terminations were associated with a RR of 1.23 (95% CI, 1.00 to 1.51), which was somewhat greater than the risk associated with spontaneous terminations (RR, 1.11; 95% CI, 1.02 to 1.20). The association with induced abortions was stronger for those performed before legalization of abortion in 1973 (RR, 1.35; 95% CI, 1.01 to 1.80) than after this time (RR, 1.12; 95% CI, 0.84 to 1.49), suggesting a bias in reporting this sensitive procedure. CONCLUSIONS: A weak positive association was observed between abortion--whether induced or spontaneous--and risk of breast cancer. The increase in risk of breast cancer was somewhat greater among women with a history of induced terminations. However, this association may be due to reporting bias and was not significantly different than the slight risk for spontaneous terminations.

Abortion, Induced↗